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Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals
Accepted Manuscript Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals
Roni Sverdlov Arzi, Alejandro Sosnik PII: DOI: Reference:
S0169-409X(18)30178-9 doi:10.1016/j.addr.2018.07.012 ADR 13347
To appear in:
Advanced Drug Delivery Reviews
Received date: Revised date: Accepted date:
30 April 2018 12 July 2018 17 July 2018
Please cite this article as: Roni Sverdlov Arzi, Alejandro Sosnik , Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals. Adr (2018), doi:10.1016/j.addr.2018.07.012
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ACCEPTED MANUSCRIPT ADVANCED DRUG DELIVERY REVIEWS Theme Issue “Drug Nanoparticles and Nano-Cocrystals: From Bottom-up Production and Characterization to Clinical Translation”, A Sosnik and S Mühlebach (Guest Editors)
Electrohydrodynamic atomization and spray-drying for the
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production of pure drug nanocrystals and co-crystals
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Roni Sverdlov Arzi and Alejandro Sosnik*
Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials
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Science and Engineering, Technion-Israel Institute of Technology, Haifa, Israel
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*Corresponding author: Prof. Alejandro Sosnik, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, De-Jur Building, Office 607, Technion City, 3200003 Haifa, Israel; Phone #: +972-77887-1971; Email: [email protected]
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ACCEPTED MANUSCRIPT List of abbreviations Active pharmaceutical ingredient
BCS
Biopharmaceutics classification system
BSA
Bovine serum albumin
DSC
Differential Scanning Calorimetry
EHDA
Electrohydrodynamic atomization
ICH
International Conference for Harmonization
IDV
Indinavir
PLGA
Poly(lactic-co-glycolic) acid
PXRD
Powder X-ray diffraction
SCF
Supercritical fluid
SEM
Scanning Electron Microscopy
XRD
X-ray diffraction
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API
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ACCEPTED MANUSCRIPT Abstract In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been
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made on those that increase the dissolution rate and the saturation solubility by
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the reduction of the particle size of pure drugs to the nanoscale and the
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associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and
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cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an
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anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to features such as size, size distribution,
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morphology and to control the amorphous/crystalline nature of the product. In
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this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability.
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Moreover, they do not necessarily need suspension stabilizers and dry products
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are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.
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ACCEPTED MANUSCRIPT Keywords: Pure drug nanoparticles; nanopharmaceuticals; drug nanocrystals; drug co-crystals; bottom-up nanonization; electrohydrodynamic atomization; spray-drying. Table of Contents
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1. Introduction 2. Solvents in pharmaceutical production
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3. Electrohydrodynamic atomization
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3.1. The method
3.2. Control of particle size, size distribution and morphology
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3.3. Production of pure drug particles by electrohydrodynamic
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atomization 4. Spray-drying The method
4.2.
Control of particle size, size distribution and morphology
4.3.
Production of pure drug particles by spray-drying
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5. Electrohydrodynamic atomization and spray-drying to produce drug co-
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crystals
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6. Conclusions and future challenges Acknowledgements References
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ACCEPTED MANUSCRIPT 1. Introduction The pharmaceutical industry is found in a persistent and urgent search for new scalable
and
cost-effective
technological
strategies
to
overcome
(bio)pharmaceutical drawbacks of drugs such as poor aqueous solubility, low physicochemical stability in the biological milieu, short half-life and reduced
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bioavailability [1–5]. For instance, >50% of the approved drugs and 70% of new
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chemical entities under development are classified into Class II and IV of the
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Biopharmaceutics Classification System (BCS) [6,7]. These limitations increase drug attrition rates [8,9] and lead to a decline in the ability to translate them into
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new pharmaceutical products [10–12].
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Numerous strategies have been applied to overcome these drawbacks. Nanonization of pure drug particles via top-down or bottom-up techniques to produce nanoparticles of amorphous or crystalline nature with sizes ranging
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from a few nanometers up to 1 μm enhances the dissolution rate and the saturation solubility by increasing the specific surface area-to-volume ratio [1,13–16] (Figure 1). The Noyes–Whitney Equation 1 describes the dissolution
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rate of spherical particles. The process is controlled by diffusion and no
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chemical reaction takes place [10,17–20] 𝑑𝐶𝑥 𝑑𝑡
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= 𝐴 h (𝐶𝑠 − 𝐶𝑥 ) (Eq. 1)
Where dCx/dt is the dissolution rate, A is particle surface area, D is the diffusion coefficient, h is the effective thickness of the boundary layer, Cs is particle saturation solubility and Cx is concentration in the surrounding liquid at time x. The Ostwald–Freundlich Equation 2 establishes the increase in solubility of a
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ACCEPTED MANUSCRIPT given compound based on the increase of the interfacial energy at high curvatures or in other words, for very small particles. 2𝛾𝑀
𝑆 = 𝑆∞ exp (𝑟𝜌𝑅𝑇) (Eq. 2) Where S is the saturation solubility of the nanosized active pharmaceutical
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ingredient, S∞ is saturation solubility of an infinitely large active pharmaceutical ingredient crystal, γ is the crystal-medium interfacial tension, M is the molecular
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constant and T is the absolute temperature.
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weight of the compound, r is the particle radius, ρ is the density, R is the gas
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Thus, an increase in the specific surface area-to-volume ratio of the nanonized crystals leads to a faster dissolution rate. In addition, when the particle size is
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smaller than 100 nm, the saturation solubility increases exponentially. Both phenomena result in an enhancement in the oral bioavailability of the drug [13].
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Moreover, the number of contact points with the surrounding tissues (e.g.,
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mucus) increases substantially, favoring the adhesiveness to biological structures and the prolongation of the residence time [13].
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Over the last decades, nanosizing techniques have gained increased interest
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in terms of both new intellectual property and clinical impact [1,5,10,13,21]. Pure drug nanoparticles can be used dispersed in aqueous media in the socalled nanosuspensions [21,22] or to produce solid formulations such as tablets [20]. The degree of crystallinity of the drug in the nanoparticle may vary widely and can be controlled by adjusting the conditions of the production method [1,10].
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Figure 1. Features (f) of pure drug nanocrystals. (1) Increased saturation solubility (Cs) due to increased dissolution pressure of strongly curved small nanocrystals, (2) increased dissolution rate (dc/dt) due to decreased diameter (d) and increased surface area (A) of the particles and (3) increased adhesiveness of nanomaterial due to increased contact area of nanoparticles versus microparticles (at identical total particle mass), note: surface calculations were performed as cubes. Reproduced from [13] with permission of Elsevier.
In some cases, the relatively slow dissolution rate of pure nanocrystals of highly hydrophobic drugs combined with their ability to undergo entrapment by the intestinal mucosa resulted in a dramatic increase of the drug half-life with respect to the unprocessed counterpart (Figure 2), a concept that we coined nanocarrier-less delivery systems [23,24].
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1 m
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*Statistically significant increase of the amount of drug dissolved when compared to the unprocessed drug (p<0.05).
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Figure 2. Indinavir free base (IDV) plasma concentration versus time profile of raw indinavir free base (IDV powder), and nanocrystals produced by nanoprecipitation (NP) and supercritical fluids (SCF) after oral administration of a single dose (10 mg/kg) to mongrel dogs (n = 4). The different pharmacokinetic parameters were calculated using a non-compartmental model and TOPFIT software (version 2.0, Dr. Karl Thomae Gmbh, Schering AG, Germany). Reproduced with modifications from [23] with permission of Elsevier. Pure drug nanoparticles have been also used by other minimally-invasive administration routes such as inhalation, transdermal, ophthalmic and buccal [10,25]. For example, pure drug nanocrystals of hydrophobic drugs (e.g., pranlukat hemihydrate) have been investigated for the treatment of chronic bronchial asthma by pulmonary delivery [26–28]. Drug nanocrystals have been also assessed to improve skin deposition and permeation of the non-steroidal
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ACCEPTED MANUSCRIPT anti-inflammatory drug diclofenac by the transdermal route [30]. More recently, pure drug nanocrystals of hydrophobic drugs (e.g., the antiretroviral rilpivirine) have been investigated to sustain the release upon intramuscular injection in the chronic therapy of the human immunodeficiency virus infection [31,32]. Unlike other drug nanocarriers that have been extensively researched (i.e.,
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liposomes, nanoemulsions and polymeric nanoparticles) and for which
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encapsulation efficiency and drug loading have to be defined in the final
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product, pure drug nanocrystals/co-crystals offer a theoretical drug content of up to 100%. Thus, the encapsulation efficiency is not a constraint [13,33,34].
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On the other hand, small drug particles are thermodynamically instable and they tend to grow in size by agglomeration [25,35,36]. This is why they are
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usually physically stabilized using surfactants or other polymeric stabilizers [1,25,33] what brings the typical total drug content to ~50-90% w/w [34].
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Another important advantage of drug nanocrystals is the maturity and scalability
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of their fabrication technologies, which can be demonstrated by multiple commercial products that are currently on the market. Table 1 summarizes oral
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pharmaceutical formulations based on pure drug nanocrystals currently on the
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market or under preclinical trials (Table 1) [45].
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Table 1. Overview of drug nanocrystals for oral administration currently on the market or under preclinical trials. Adapted from [45] with permission of Elsevier. Drug Sirolimus Aprepitant Fenofibrate Fenofibrate Megestrol acetate Griseofulvin Nabilone Danazol
Tradename/Company Rapamune®/Wyeth Emend®/Merck Tricor®/Abbott TriglideTM/First Horizon Pharmaceutical Megace® ES/Par Pharmaceutical Gris-PEG®/Novartis Cesamet®/Lilly -
Indication Immunosuppressant Antiemetic Hypercholesterolemia Hypercholesterolemia
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Status Marketed Marketed Marketed Marketed
Refs. [37] [37] [37] [37]
Oral suspension
Marketed
[37] [38] [38] [39]
Appetite stimulant Antifungal Antiemetic Estrogen antagonist
Bottom-up, co-precipitation Bottom-up, co-precipitation Top-down, media milling
Tablet Capsule Nanosuspension
Top-down, media milling Top-down, media milling
Nanosuspension Nanosuspension Pellets containing dried nanocrystals powder Nanosuspension
Marketed Marketed In vivo (dog) In vivo (rat) In vivo (dog) In vivo (dog) In vivo (pig)
Nanosuspension
In vivo (rat)
[43]
Nanosuspension
In vivo (rat)
[44]
N A
M
-
Anti-inflammatory Antiplatelet agent
Ketoprofen
-
Anti-inflammatory
Top-down, media milling
Cyclosporine
-
Immunosuppressant
Spironolactone
-
Itraconazole
-
Top-down, high-pressure homogenization Top-down, high-pressure homogenization Bottom-up, precipitation
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T P E
C C
Diuretic
Antifungal
I R
C S U
Naproxen Cilostazol
A
Dosage form Tablet Capsule Tablet Tablet
Applied technology Top-down, media milling Top-down, media milling Top-down, media milling Top-down, high-pressure homogenization Top-down, media milling
[40] [15] [41] [42]
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such as π-π stacking, van der Waals forces, H-bonds and ionic bonds [49,50].
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The main advantage of drug co-crystallization is the ability to alter the
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physicochemical characteristics of the pure drug to improve its solubility, stability, dissolution rate and oral bioavailability, while maintaining their
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therapeutic activity [37,51]. Conventional co-crystals are formed by a drug and a pharmacologically inert co-former. More recently, drug-drug and multidrug co-
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crystals were introduced [52,53]. Their advantage over conventional co-crystals is that the components display a synergistic pharmacological activity as well as
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enhanced physicochemical properties for at least one of the co-crystal
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components [52,54,55]. Moreover, the combination of multiple therapeutic agents in single unit doses facilitates patient management with complex
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diseases and increases patient compliance [52,56].
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The techniques applied to nanosize drugs can be classified into three main categories: bottom-up (e.g., nanoprecipitation), top-down (e.g., wet ball milling, high pressure homogenization) and combination techniques [57]. Each one presents pros and cons though in general, all of them have to fulfill similar requirements such as controlled and reproducible size, narrow size distribution, high purity, low content of solvent residues, good physicochemical stability and desired morphology and density [57]. In cases where the nanoparticles are used in the production of solid formulations (e.g., tablets), the mechanical and flow 11
ACCEPTED MANUSCRIPT properties of the nanoparticle will govern the tableting process and the final properties of the formulation [58,59]. Moreover, different production methods influence differently the solid state characteristics of the nanoparticles [60]. In general, once the production conditions have been optimized, bottom-up techniques enable a better control of the particle crystallinity/amorphousness
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and shape, and thus, in recent years, they have gained significant impulse [38].
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The current review revisits two bottom-up technologies based on the
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atomization of a liquid drug solution in a pharmaceutically compatible aqueous or organic solvent into small droplets that undergoes relatively fast drying,
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namely electrohydrodynamic atomization (EHDA) or electrospraying (these are equivalent terms used to describe the same technique) and spray-drying, for
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the production of amorphous or crystalline pure drug nanoparticles and nanoco-crystals and critically analyzes their potential to play a fundamental role in
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the production of innovative pharmaceutical formulations.
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2. Solvents in pharmaceutical production Both EHDA and spray-drying rely on the atomization of a drug solution
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employing different mechanisms and the drying of the formed liquid droplets to
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produce dry drug particles. In general, both technologies have been developed to enable the safe use of a broad spectrum of aqueous and organic solvents, including flammable (e.g., alcohols, ketones), halogenated (e.g., chloroform, 1,1,1,3,3,3 hexafluoro-2-propanol) and aromatic ones (e.g., toluene). However, this equipment has been developed for use in a plethora of industries and exclusively in pharmaceutical R & D. Thus, safety in equipment operation does not necessarily mean that all the solvents used are compatible with pharmaceutical production. 12
ACCEPTED MANUSCRIPT Organic solvents are commonly used in the production of pharmaceutical products, especially in the synthesis and purification of active pharmaceutical ingredients (APIs) and during their processing (e.g., nanonization) and formulation (e.g., film-coating of particles and solid forms) [61]. In general, small amounts of these solvents (called residual solvents) may remain in the final
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product depending on the production technique and the product. Due to the
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relevance of this issue, we briefly describe the classification of organic solvents
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for pharmaceutical use. Organic solvents are classified into four classes [61,62]. Class I comprises human carcinogens, compounds strongly suspected
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of being human carcinogens and environmental hazards such as benzene, carbon tetrachloride and halogenated ethane derivatives. These solvents are
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not allowed in the pharmaceutical industry and their use has to be very strongly justified. Thus, regardless of their feasibility in EHDA and spray-drying they are
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less relevant.
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Class II solvents are non-genotoxic animal carcinogens or solvents that can cause irreversible or reversible toxicity [61,62]. Some of the solvents in this
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category such as chloroform, 1,2-dichloromethane, methanol and toluene are
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commonly used in EHDA and spray-drying. The maximum allowed concentration of these solvents in the tested material is defined in parts per million (ppm) or the permitted daily dose in mg/day. The International Conference for Harmonization (ICH) has published harmonized guidelines (ICH Q3C guideline) for the approval or rejection of pharmaceutical products containing Class II residual solvents [62]. Class III solvents are recognized as safe and allowed in daily exposures of 50 mg/day or less. In some production setups, higher amounts could be also 13
ACCEPTED MANUSCRIPT acceptable. They include ethanol, propanol, acetone, dimethyl sulfoxide and ethyl acetate [61,62]. Finally, Class IV solvents are those for which toxicological data are not available and thus, they cannot be used [61,62].
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Most research for the production of pure drug particles by EHDA and spraydrying utilized aqueous solvents or organic solvents of Classes II and III. The
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3. Electrohydrodynamic atomization
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of solvent elimination during the drying process.
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choice depends on the solubility of the particle components and also the ease
3.1. The method
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EHDA or electrospraying is a versatile technology based on the use of electrically charged fluids, which derives from the electrospinning technology
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used to produce micro- and nanofibers, though to obtain particles [63,64]. It is
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reproducible due to the ability to control the process parameters and it can be easily operated in a continuous manner. Therefore, it has the potential to
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replace multiple unit operations in pharmaceutical manufacturing [65,66]. The main advantages of EHDA over other conventional methods
(e.g.,
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nanoprecipitation) are its ability to produce particles in an easy, one-step process, with narrow size distribution and without the use of surfactants or stabilizers [66–68]. In addition, products are collected as dry powders with a very low content of residual solvents. For example, Wang et al. investigated the residual amount of 1,2-dichloromethane in collected polymeric microparticles fabricated by EHDA using gas chromatography/mass spectrometry [69]. Results of several experiments showed that the content of residual solvent in
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The standard configuration of the instrument consists of four major
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components: a pumping system, a metal nozzle wired with a high voltage power
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supply and a grounded substrate as a collector (Figure 3) [70].
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Figure 3. Setup of a conventional instrument for the production of particles by electrohydrodynamic atomization. Reproduced from [70] with permission of Elsevier.
The setup for the process can be operated under ambient temperature and
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pressure or under inert environment to better control the drying process and prevent possible external contaminations [64]. There are several modes of spraying, which differ in the process of formation of the meniscus and the jet emerging from this meniscus [64,71–73]. The different modes depend on properties of the liquid such as conductivity, surface tension, viscosity and the applied voltage and flow rate [68,72]. Among the various electrospraying modes that can be operated, the Taylor cone-jet mode is most preferred for an efficient production of highly monodisperse particles [64]. In this technique, a high 15
ACCEPTED MANUSCRIPT voltage of several kilovolts is applied to a capillary nozzle, which causes the solution interface at the tip to change its shape due to the accumulation of an electrostatic charge. As the electrostatic Coulomb forces become stronger, the effect of surface tension on the shape of the interface decreases until the two forces are equal and the liquid meniscus at the capillary exit develops a conical
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shape (the so-called Taylor cone) [63,66,74,75]. If the cone is disturbed by
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additional charge, the liquid flowing out of the capillary is forced to disperse into
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droplets. The shape and forces in the liquid cone are described in Figure 4 [76].
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Figure 4. Forces in the liquid cone. Reproduced from [76] with permission of Elsevier.
Coalescence is prevented by the electrostatic repulsion between the generated
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droplets [63,66]. The size of the droplets can range from hundreds of micrometers down to several tens of nanometers and it can be controlled to some extent via the flow rate of the liquid, its viscosity, the surface tension, the applied voltage at the capillary nozzle and the distance to the collector [63,66,68,75,77,78]. If the primary generated droplets reach the Rayleigh limit, which is the theoretical predicted limit for the determination of a drop break, then the droplets experience a phenomenon called Rayleigh disintegration or
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ACCEPTED MANUSCRIPT Coulomb fission [64,66,79]. When Coulomb fission occurs, primary droplets fly to the collector and undergo solvent evaporation and shrinkage. The shrinkage of the droplets leads to an increase in their charge concentration and their subsequent breakage into smaller off-springs [63,64,66], which is usually detrimental due to the undesired loss of size monodispersity of the residual
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particles (Figure 5) [64].
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Figure 5. Schematic illustration of Coloumb fission phenomenon during the process of electrospraying. Reproduced from [64] with permission of Elsevier.
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Thus, in order to produce uniformly sized droplets with narrow size distribution and good reproducibility, the Coulomb fission has to be minimized [80]. To discharge the precursor droplets and prevent their fission, a supplementary configuration of nozzle ring/needle called corona discharge was recently introduced [79–83]. This configuration consists of a discharging stainless-steel ring or needle that is charged at a voltage of opposite polarity with respect to
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nozzle (Figure 6) [80].
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Figure 6. Experimental set up for the corona discharge. Reproduced from [80] with permission of Elsevier.
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The electric field at the tip of these neutralizers causes electrical breakdown of
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the surrounding air and generates a corona with a plasma of negative electrons, which then migrate and flow in an opposite direction with respect to the
[64,80].
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electrosprayed droplets, leading to their partial neutralization through collisions
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3.2. Control of particle size, size distribution and morphology One of the advantages of bottom-up techniques is the ability to better control the
size,
the
size
distribution,
the
morphology
and
the
crystallinity/amorphousness of the produced particles [10]. At the same time, the process conditions have to be optimized. In the case of EHDA, most of the research on the production of particles of controlled size and morphology was conducted on polymeric particles. Nevertheless, the lessons learned through 18
ACCEPTED MANUSCRIPT the years in this field could be rationally adopted to optimize the properties of pure drug nanoparticles as well [71–73]. Among the various parameters affecting particle size in EHDA, flow rate is one of the most important [64,66,84]. Gañan-Calvo et al. estimated the size of a
3 [85] 𝑄3𝜀 𝜌
1/6
0 𝑑 = α ( 𝜋4 𝜎𝛾 )
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(3)
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droplet generated by EHDA using a theoretical model represented by Equation
Where α is a constant, Q is the solution flow rate, 𝜀0 is the dielectric constant in
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vacuum, 𝜌 is the solution density, 𝜎 is the solution surface tension and 𝛾 is the conductivity of the solution. It is clear from this equation that the size of the
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droplet is proportional to the square-root of the solution flow rate. Thus, the higher the flow rate, the larger the size of the droplet size and vice versa.
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Several studies explained that when the solvent is sprayed at higher flow rates
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its evaporation until reaching the collector is incomplete and thus, the contact between wet and partly solvated particles results in particle fusion and
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consequently in larger particle size, less consistent morphology and often broader size distribution [64,85,86]. Implications of this model can be observed
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in several works that focused mainly on polymeric particles [78,84,87] though that may also affect the properties of pure drug particles [86,87] and inorganic particles [88]. For example, Wang et al. produced carbamazepine nanocrystals using EHDA using methanol as solvent [89]. Smaller flow rates resulted in smaller, denser and more monodisperse particles. It is important to stress that as in many bottom-up production techniques, particles were mainly amorphous. Later annealing at 90oC which is above the glass transition temperature of the 19
ACCEPTED MANUSCRIPT amorphous phase for 5 min enabled the crystallization of the drug to produce the most stable polymorph form III. It is important to stress that methanol is classified as a Class II solvent and hence is approved for the production pharmaceutical products [61,62]. Other studies that employed this technique to produce polymeric particles
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showed a similar trend, highlighting the relevance of the data produced with
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different materials. For example, Yao et al. fabricated poly(lactic-co-glycolic
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acid) particles in acetonitrile (8% w/v) and in dichloromethane (7% w/v) using a modified electrospray system and investigated the effect of flow rate, among
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other processing parameters, on the size and morphology of the particles [90]. Nine different flow rates were used 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 mL/h
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and the size and morphology of the particles were visualized by scanning electron microscopy (SEM). Higher flow rates led to larger particle size and a
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wet product, due to insufficient time for solvent evaporation, whereas lower flow
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rates led to larger dry particles [90], in good agreement with the theoretical model [85]. A similar trend was observed by Zheng et al. that characterized the
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properties of NaCl crystals formed by EHDA at 150 °C from highly diluted water
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solutions under different flow rates ranging from 10 to 200 μL min –1 [89]. NaCl was used as a model compound. The mean size of the nanocrystals increased from 48 to 95 nm at higher flow rates and their size distribution became more polydisperse [89], as previously shown for other pure drugs and polymers. It is worth stressing that the formation of particles of an ionic inorganic material differs from that of organic ones, and thus, further studies need to be conducted to understand the effect of flow on the properties of produced particles.
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ACCEPTED MANUSCRIPT Another key parameter is the concentration of the electrosprayed solution owing to its viscosity [91]. In general, the higher the viscosity of the liquid feed, the larger the size of the particles produced and the broader their size distribution [92–94]. In this context, Jayasinghe and Edirisinghe measured the size of electrosprayed water/glycerol mixtures and glycerol containing citric acid
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to control the conductivity of the solutions with different viscosities under the
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same conditions of voltage, flow rate and electrical conductivity [91]. Results
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showed that the viscosity increase led to a change in the cone and jet (Figure 7) and a significant growth in size and size distribution of the relics (Figure 8)
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[91].
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Figure 7. Cone-jet obtained from the electrohydrodynamic atomization of water:glycerol:citric acid solutions with weight ratio of (a) 23.74:71.21:5.05 ( = 1.22 g mL-1; = 603 mPa.s) and (b) 0:93.27:6.73 ( = 1.31 g mL-1; = 1338 mPa.s). Reproduced from [91] with permission of Elsevier.
Intriguingly, even though citric acid (a small organic molecule) was not used as a model compound/drug, it served as such and thus, microscopy analysis of the relics shed light into the effect of viscosity, flow rate and solution concentration on the size and the morphology of the droplets and eventually of the produced particles, where lower water content and higher viscosity resulted in larger relics [91,95,96]. These results indicated that to reduce the size of the particles, lower viscosities could be used. 21
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Figure 8. Optical micrographs of droplet relics obtained from the electrohydrodynamic atomization of water:glycerol:citric acid solutions with weight ratio of (a) 98.35:0:1.65 ( = 1.00 g mL-1; = 1 mPa.s), (b) 72.67:24.22:3.11 ( = 1.05 g mL-1; = 94 mPa.s), (c) 48.09:48.09:3.83 ( = 1.09 g mL-1; = 298 mPa.s), (d) 23.74:71.21:5.05 ( = 1.22 g mL-1; = 603 mPa.s) and (e) 0:93.27:6.73 ( = 1.31 g mL-1; = 1338 mPa.s). The relics of the mixtures appear much darker compared with the silicone release paper background which is also dotted in some places. Reproduced from [91] with permission of Elsevier.
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The electrical conductivity of the solution can also be adjusted to control particle
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size as it could be easily increased by adding small amounts of dopants (e.g., organic salts) to the solvent [63,77,79,97]. Furthermore, since the conductivity of the solution affects the stability of the cone-jet, it basically determines the range of flow rates at which monodisperse particles can be obtained and, in turn, the size of the obtained particles [80,95]. For example, a diluted solution of high electrical conductivity will be stably electrosprayed at low flow rates, leading to the generation of finer particles than highly concentrated solutions
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ACCEPTED MANUSCRIPT with low electrical conductivity that will be stably electrosprayed at higher flow rates, leading to the generation of larger particles [80]. Particle size and morphology can also be modified by changing the operating voltage which is an important process parameter as it provides the driving force for the electrospraying [64]. In general, high applied voltages are associated
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with a decrease in particle size because the applied voltage affects the
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breakdown of the jet [88]. An increase in the applied voltage causes the jet
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current to increase, leading to more repulsion between adjacent droplets, less coalescence and the formation of particles with smaller sizes and narrower size
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distributions [66,88,95].
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The spectrum of materials that can be electrosprayed is very broad. Pareta et al. investigated the effect of applied voltage and flow rate on the operation
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mode during EHDA in the production of bovine serum albumin (BSA)
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nanoparticles using water solutions at two different concentrations (Figure 9) [98]. BSA is not an active molecule though it is used very frequently as a model protein. In addition, it could serve as drug nanocarrier. As it can be seen, the
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mapping structure changes when the concentration of the solution is modified
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(Figure 9). The maps present a delicate interplay between the applied voltage and flow rate of the solution, which results in a limited range in which a stable cone-jet mode can be achieved to produce fine particles with desired morphology.
23
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Figure 9. Mapping of the electrospraying process—the influence of flow rate and applied voltage on the operating modes of electrospraying a bovine serum albumin solution: (a) 5 mg/mL and (b) 20 mg/mL. Reproduced from [98] with permission of Springer Nature.
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An important aspect when working with sensitive molecules such as proteins that could be denatured upon the application of charge, heat or the use of
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organic solvents, is the assessment of its biological activity after processing. The inner diameter of the nozzle or the gauge of the needle can also affect the
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size and size distribution of the dry particles as it determines the diameter of
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the base of the Taylor cone, which in turn influences the size and the distribution of the generated droplets [64,99]. Arya et al. investigated the ability to control
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the size of chitosan particles by changing the needle diameter in the range of 20-26G (0.5-0.9 mm) and observed that the particles obtained at large needle
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gauges (e.g., small inner diameters) were finer in size and less polydisperse compared to particles obtained at small needle gauges (and larger inner diameters) [100]. EHDA using small needle gauges resulted in either larger particle size or sputtering of the polymer solution without forming any particles at all, due to the increased effective flow rate of the solution at larger inner needle diameter [100]. This work was carried out on the production of polymeric
24
ACCEPTED MANUSCRIPT particles. At the same time, it is another example of the great flexibility to adjust the process parameters and to tailor the properties of the product. Another parameter that is relatively easy to control is the distance between the tip of the nozzle and the collector [66,84,101]. In general, the shorter the distance, the stronger the electric field and the smaller the particles obtained
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[64]. However, when the distance is too small, particles usually undergo
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aggregation due to insufficient time for solvent evaporation and particle
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consolidation. On the other hand, when the distance is too long, higher applied voltages are required to compensate for the reduced electrical field strength,
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resulting in reduced particle deposition and yield [64,66]. Other parameters such as solution density, surface tension and dielectric constant can only be
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varied within narrow limits, and thus they are less relevant to tailor particle size, size distribution and morphology [80]. It is important to stress that although most
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of the systematic research on the effect of EHDA process parameters on the
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properties of particles was focused on polymeric particles, the general rules can also be applied in the case of pure drug particles, as discussed in the following
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section. The key operational parameters affecting the size of the droplets and
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thus, of the produced particles by EHDA are summarized in Table 2.
25
ACCEPTED MANUSCRIPT Table 2. Operational parameters affecting the size of particles produced by electrospraying or EHDA. Parameters that upon increase Parameters that upon increase lead to a decrease of the particle lead to an increase of the particle size size Nozzle diameter
Solvent conductivity
Molecular weight*
Solvent boiling point
Liquid feed concentration
Surface tension of the fluid feed
Liquid feed viscosity
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Distance from the nozzle to the Flow rate collector
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Voltage
pure
drug particles by electrohydrodynamic
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3.3. Production of
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*Valid for polymers and macromolecules. The effect of molecular weight of small molecules on particle size was not investigated.
atomization
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EHDA is convenient for the synthesis of pure drug particles in general and
represents
a
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nanocrystals, microcrystals and co-crystals in particular [48,65]. The technology new
versatile
platform
for
the
fabrication
of
both
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crystalline/amorphous particles with increased stability and improved physiochemical properties [48,70]. The high-energy vibration of the Taylor
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cone and the relatively fast evaporation of the solvent during the electrospraying process (most of the solvent has to be evaporated before the droplet touches the collector) are believed to be beneficial in the synthesis of pure drug crystals and co-crystals owing to the increased rate of crystal nucleation and growth [48]. At the same time, they can also contribute to the generation of APIs in an amorphous state as the molecules are instantly “frozen” and undergo rapid solidification which precludes nucleation and
26
ACCEPTED MANUSCRIPT crystallization [64,102]. In addition, solvent evaporation is very efficient, giving place to dry powders with low amounts of residual solvents and with higher physicochemical stability than nanosuspensions [64–66,78]. Regardless of these beneficial features, until today, this technology has been scarcely used in the production of pure drug particles. As exemplified above, Wang et al. used
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electrospraying followed by annealing at high temperatures to produce
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nanocrystals of the hydrophobic anticonvulsant drug carbamazepine [88].
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Solutions of various concentrations in methanol were electrosprayed to obtain carbamazepine particles with diameters ranging from 320 nm to several
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microns and the aqueous solubility increased by 26.4% with respect to the bulk saturation solubility (from 0.11 to 0.14 mg/mL). The average particle diameter
MA
increased with flow rate, in good agreement with the theoretical model developed by Gañan-Calvo [85] and the initial particle diameter increased with
D
the drug concentration in line with the trend observed in polymeric and inorganic
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particles. As the flow rate increased from 0.003 to 0.02 mL/h, the average particle diameter increased from 320 nm to 1.5 μm at a concentration of 0.5%
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w/v, from 383 nm to 1.8 μm at a concentration of 1.0% w/v, from 475 nm to 1.7 μm at a concentration of 3.0% w/v and from 617 nm to 1.8 μm at a concentration
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of 5.0% w/v (Figure 10). Annealing of the electrosprayed particles at 90oC (5 min) accelerated the crystallization process, increasing the drug crystallinity, as confirmed by X-ray diffraction (XRD) and SEM [88].
27
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Figure 10. Scanning electron microscopy images of carbamazepine nanoparticles by electrospray at different concentrations and different flow rates. (a) Carbamazepine concentration (Cw) = 0.5wt %, Q = 0.003 mL/min; (b) Cw = 0.5wt %, Q = 0.005 mL/min; (c) Cw = 0.5wt %, Q = 0.01 mL/min; (d) Cw = 1wt %, Q = 0.003 mL/min; (e) Cw = 3wt %, Q = 0.005 mL/ min; and (f) Cw = 5wt %, Q = 0.02 mL/min. Reproduced from [88] with permission of Elsevier.
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Li et al. produced pure drug microparticles (~6 μm) of aspirin by EHDA [87]. The flow rate was varied from 10-6 to 10-17 m3s-1 and optimized to 10-10 m3s-1 in an attempt to obtain the finest droplets, without deviating from stable cone jetmode [87]. Again, particle sizes were in good agreement with the Gañan-Calvo theoretical model [85]. Radacsi et al. and Ambrus et al. investigated the production of pure nanocrystals of the non-steroidal anti-inflammatory drug niflumic acid in the size range of 200-800 nm by electrospray crystallization [103,104]. The relationship between drug concentration and crystal size was 28
ACCEPTED MANUSCRIPT clearly observed: crystal size increased with at higher solution concentration (Figure 11) [103]. Moreover, the effect of the addition of excipients (D-mannitol and poloxamer 188) on the dissolution rate was assessed for both raw and nanonized drug. A significantly higher dissolution rate was observed after drug nanonization in the presence of the excipients, which prevented the process of
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drug agglomeration and led to improved drug absorption [103].
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Figure 11. The relationship between the crystal size and shape and used solution concentration when niflumic acid crystals are produced in electrospray crystallization. The crystal size increases with the increasing solution concentration, and the crystal shape becomes from somewhat spherical to needle-like. Reproduced with from [103] with permission of the American Chemical Society.
In addition, the electrospraying method was compared to conventional antisolvent crystallization (nanoprecipitation) and solvent evaporation techniques [104]. EHDA produced a dry powder with no agglomeration and substantially smaller particles (mean size = 500 ± 200 nm), whereas nanoprecipitation and solvent evaporation resulted in particles sizes in the range of 7-46 m [104].
29
ACCEPTED MANUSCRIPT These findings can be explained by the increased supersaturation achieved using EHDA which is less substantial in the other two methods (Figure 12)
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[104].
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Figure 12. Scanning electron microscopy images of niflumic acid. (A) conventional (unprocessed) drug, (B) particles produced by electrospray crystallization, (C) particles produced by anti-solvent crystallization and (D) particles produced by solvent evaporation. Reproduced with from [104] with permission of Elsevier.
Moreover, in EHDA, the crystallization process begins in the small and confined volume offered by the droplets, whereas in the other two techniques the crystallization volume is considerably larger, resulting in the formation of larger particles. Powder X-ray diffraction (PXRD) measurements of the immediately produced niflumic acid crystals showed that the products obtained by evaporative and anti-solvent crystallization were highly crystalline immediately 30
ACCEPTED MANUSCRIPT after production and remained crystalline after storage (two weeks later). On the other hand, the electrosprayed product was partly amorphous (81% crystalline) after production, due to the rapid evaporation of the solvent during electrospraying which prevented the complete crystallization of the drug. It is important to stress that crystallinity increased during storage (two weeks) from
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81% to 88%, according to results obtained by differential scanning calorimetry
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(DSC) [104]. These results probably stemmed from the fact that the glass
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transition temperature of the amorphous phase was below the storage temperature and thus, crystallinity gradually grew. One question that remains
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unanswered in this work is whether longer storage further increased the crystallinity or not. Changes in the degree of crystallinity of the drug and other
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transitions (e.g., polymorphs) during storage could have a strong impact on the dissolution rate and, eventually, on the oral bioavailability. Thus, from a
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translational point of view, they represent a serious product drawback. In this
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context, further studies should be conducted to ensure that the drug remains stable and the pharmacokinetics predictable during the shelf life.
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Other research groups investigated the formation of pure drug microcrystals,
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rather than of nanocrystals. It is worth mentioning that while the adjustment of the particle size is usually a time-consuming process, the production of nanoparticles is often more difficult than of microparticles. For example, Ijsebaert et al. prepared microparticles of the steroidal anti-inflammatory drug beclomethasone
dipropionate
and
the
antimicrobial
agent
methyl
parahydroxybenzoate used as preservative in pharmaceutical formulations for inhalation using ethanol as solvent [82]. The droplet size and consequently the microparticle diameter were controlled by optimizing the flow rate of the liquid 31
ACCEPTED MANUSCRIPT feed and the drug concentration in the electrosprayed solution. Particles showed sizes between 1.58 and 4.55 μm which fitted very well the aerodynamic diameter required to ensure efficient deposition in the lower airways (1-5 m) [28,105]; smaller particles are expelled, and their efficacy reduced. To prevent Coloumbic fission and a decrease of the particle size which would have been
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detrimental for this administration route, a corona discharge system was used.
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An increase in the flow rate and drug concentration led to an increase of the
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size distribution. The reason for this performance probably was stronger instabilities in the jet formed.
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Nyström et al. used EHDA to produce pure drug microparticles of three poorly water-soluble drugs: indomethacin, piroxicam and budesonide [106]. An
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innovative aspect of this work was the use of low pressure to favor the elimination of solvent residues [81,106]. Indomethacin was dissolved in ethanol
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(10 or 15 mg/mL), while piroxicam and budesonide were dissolved in chloroform (15 mg/mL) at room temperature [106]. As previously explained, ethanol and chloroform belong to Class III and II solvents, respectively.
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Electrospraying was carried out using stable cone-jet mode in both atmospheric
AC
and reduced pressure and using a corona discharge. Atomization voltages ranged between 2.1-3.6 kV and the obtained particles sizes ranged from 1.75.5 μm (Figure 13) [106]. In addition, they introduced a simple method to estimate the size of the particles based on the size of the droplets. However, based on the published data, it is unclear whether this method could be used to produce particles in the submicron and nanometer-size range or not.
32
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ACCEPTED MANUSCRIPT
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Figure 13. Characterization of produced by electrohydrodynamic atomization. (A) Scanning electron microscopy images of the electrosprayed indomethacin (on the left), piroxicam (in the middle) and budesonide (on the right) particles. Below are magnifications of the corresponding particles and (B) Particle size distributions of the electrosprayed samples. The amount of analysed particles and the mean particle diameter is mentioned for each sample. Reproduced with from [106] with permission of Elsevier.
Moreover, drugs were converted into more soluble amorphous forms, most probably due to the fast solidification under both atmospheric and reduced pressure that minimized the crystallization process [106]. The supplied indomethacin (γ-form) and piroxicam (I-form) were originally crystalline (as confirmed by PXRD diffraction results). Budesonide was also originally crystalline. Samples of piroxicam and budesonide which were dissolved in
33
ACCEPTED MANUSCRIPT chloroform and electrosprayed under reduced pressure were significantly more amorphous than the ones fabricated in atmospheric pressure. On the contrary, the indomethacin sample, which was dissolved in ethanol, showed higher crystallinity under reduced pressure compared to atmospheric pressure. From these results, it seems that the reduction of the pressure influenced the
PT
amorphousness extent only if the solution was volatile enough, thus the
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observed differences in the degree of crystallinity under reduced and
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atmospheric pressure stemmed from the relative evaporation rate of the solvents used (as chloroform is more volatile than to ethanol) [106]. The drug
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amorphousness was suggested by the spherical morphology of the particles
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and confirmed by PXRD (Figure 14) and DSC.
Figure 14. The diffractograms of electrosprayed budesonide: (1) electrosprayed in 0.5 atm and (2) electrosprayed in 1.0 atm. (3) and (4) represent crystalline references (measured with corresponding sample holders), respectively. The loss of crystallinity after the processing (1 and 2) is clearly observed. Reproduced with from [106] with permission of Elsevier.
34
ACCEPTED MANUSCRIPT This is a noteworthy feature of the method that enables the adjustment of the conditions to amorphisize pure drugs during the particle size reduction and thus, to substantially increase the dissolution rate and the saturation solubility with respect to the crystalline counterparts. Standard EHDA can also be sophisticated by the incorporation of additional processing features such as the
PT
use of concentric needles [66]. In this context, Scholten et al. fabricated
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carbamazepine submicron and microparticles of different shapes and sizes (e.g., spheres, q-tips, elongated spheres and tear-shaped) [107]. Sizes ranged
SC
from 500 nm to 6.5 μm, depending on the concentration of the solution, which
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ranged from 1 to 12 mg/mL (Figure 15) [107].
Figure 15. Scanning electron microscopy (SEM) images of electrosprayed carbamazepine particles for solutions of various concentrations. Reproduced from [107] with permission of the American Chemical Society. They also studied how by changing the drug concentration in the 1,2dichloromethane solution, the interplay between jet formation, droplet breakup,
35
ACCEPTED MANUSCRIPT evaporation and solidification could be manipulated to control the size and shape of the obtained particles [107]. Thus, they produced spheres, q-tips, elongated spheres and tear-shaped particles. In general, the higher the drug concentration in solution, the less spherical and the larger the particles obtained.
PT
Overall, EHDA is considered a promising technology for the fabrication of pure
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drug particles. EHDA is a one-step and simple method to carry out. At the same
SC
time, the optimization of product properties such as size, size distribution, morphology and amorphous/crystalline nature are challenging. For this, a deep
NU
understanding of the effect of the features of the liquid feed (e.g., concentration, solvent, viscosity, conductivity, and boiling point) and the process parameters
MA
(e.g., temperature, pressure, nozzle diameter, and distance to the collector) is required. The knowledge at the interface of EHDA and the production of pure
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systematic research.
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drug particles still shows significant gaps that could only be closed by a more
Scalability is a critical aspect to ensure the translation of these production
CE
technologies to the pharmaceutical industry. Most of the academic research is
AC
conducted with equipment that displays relatively small flow rates [63]. To increase production capacity, the use of several nozzles or multiple spraying equipment at the same time has been proposed, making the process more expensive and difficult to maintain [63]. To face this challenge, several companies have developed equipment that is currently commercially available. For example, BioInicia S.L. (Valencia, Spain) developed the Fluidnatek® technology and together with nanoScience Instruments (Phoenix, AZ) offer a broad spectrum of instruments for the production of fibers and particles by 36
ACCEPTED MANUSCRIPT electrospinning and EHDA, respectively, at laboratory, pilot, pre-production and industrial scales. For example, the model Fluidnatek® LE 500 enables maximum flow rates of 400 mL/h, under a continuous regime [108]. These flow rates certainly enable the industrial production of pure drug nanoparticles in reasonable amounts, especially for very potent drugs. In addition, the model
PT
Fluidnatek® LE 1000 enables a much higher flow rate of up to ~4.8 L/h.
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Moreover, in other industries, several electrospraying instruments are used in
SC
parallel. This approach could be also extended to the pharmaceutical industry. At the same time, it is important to emphasize that the drug concentration in the
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solution is another key parameter that determines the mass of nanoparticles produced per time unit. Thus, optimization is required for each single API.
MA
4. Spray-drying 4.1. The method
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Spray-drying is a continuous, cost-effective and scalable process to produce dry powders from a fluid feed by atomization through an atomizer into a hot drying gas medium [109–111]. It is widely used in different industries including
CE
food, cosmetics, materials and pharmaceuticals [109,111]. The first patent
AC
concerning this technology can be tracked back to the early 1870s [110]. Thereafter, spray-drying underwent constant evolvement until the more advanced equipment and processes known today [110–112]. In both EHDA and spray-drying the final drying step, which is required in other common techniques (e.g., nanoprecipitation, emulsion/solvent evaporation), is not necessary, making the whole process cheaper and shorter [111]. Moreover, the use of surfactants and stabilizers, which are used to prevent particle agglomeration during particle production by other bottom-up techniques can be 37
ACCEPTED MANUSCRIPT prevented, usually resulting in higher yield. Furthermore, spray-drying fits well the drying of a variety of compounds including heat-sensitive products, due to fast drying and short exposure time to heat during the process, making it an appealing technology for pharmaceutical applications [63,111,113,114]. A typical spray-drying process consists of four fundamental steps that include
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atomization of the liquid feed, drying of the liquid feed through the drying gas,
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dry particle formation and subsequently particle separation and collection
SC
[111,115]. In this technique, the fluid is fed into the drying chamber by a peristaltic pump through an atomizer (rotary atomizer) or a nozzle (pressure
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nozzle or a two-fluid nozzle) [63,111,116,117]. Atomization then occurs by either centrifugal forces, pressure or kinetic energy, based on the type of
MA
atomizer or nozzle that is being used [111,117,118]. The feed breaks up into fine droplets due to the high air speed that is generated within the
D
atomizer/nozzle. The generated small droplets are then subjected to fast
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solvent evaporation, where they are dried and separated from the drying gas by a cyclone, a filter bag or an electric field precipitator that deposes them in a
CE
collector found at the bottom of the device [63,111,116]. Solvent evaporation can be performed via heat treatment using a heated carrier gas, a hot furnace
AC
or a reactor or via solvent-diffusion using a diffusion dryer and the heating configuration is selected based on the thermal and chemical properties of the feed [117,119–121]. The fluid feeds that can be converted into solid powder using spray-drying are solutions, suspensions, emulsions, pastes, slurries or melts though some limitations apply depending on the instrument used [111,118]; Since conventional spray-dryers display limitations such as relatively low yields on a laboratory scale (20-70%), high sample volumes and large
38
ACCEPTED MANUSCRIPT particle size, Büchi (Labotechnik AG, Switzerland) has introduced the Nano Spray Dryer B-90 for the controlled production of fine particles (300 nm-5 μm) with higher particle recovery rates [111,122,123]. This instrument utilizes vibration mesh spray technology, which allows the generation of tiny droplets and the production of powders in the submicron size range with narrower size
PT
distributions [111,124]. A scheme of the principle used in this instrument to
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produce particles is presented in Figure 16 [125].
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Principle of mesh vibration
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Figure 16. Scheme of the Nano Spray Dryer B-90 developed by Büchi and the functional principle of mesh vibration occurring at the piezoelectric driven spray head. Reproduced from [125] with permission of Elsevier.
The Nano Spray Dryer B-90 is designed to produce the particle during spraying and thus, the drying of preformed particles is limited by their size. In other words, if the preformed particles are sufficiently small to go through the mesh without significant impact (usually it is assumed that at least 10 times smaller than the mesh), the use of the spray-dryer can be extended to the drying of 39
ACCEPTED MANUSCRIPT nanoparticles produced by other top-down or bottom methods. The obtained solid products are considered more physically and chemically stable compared to the liquid formulations because they agglomerate less and degradation processes associated with the presence of solvents such as water are minimized [111]. More recently, the same company upgraded the system to the
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Nano Spray Dryer B-90 HP model that demonstrates better spray performance,
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especially of aqueous feeds. For example, Nano Spray Dryer B-90 results in
SC
aqueous flow rates of ˂10 mL/h, while the high performance version reaches 50-70 mL/h. In any event, it is important to stress that as opposed to EHDA
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where the drying process takes place usually at room temperature, in spraydrying, heating might have a detrimental effect on the stability of thermo-
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sensitive drugs (e.g., proteins). Thus, the stability of the product after spraydrying has to be validated.
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The size and morphology of the dried particles can be tailored by controlling the
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various parameters involved in the process, such as the type of atomization that is being used, the drying temperature, the flow rate and concentration of the
CE
feed, the air-to-feed ratio and the applied voltage and pressure [63]. In general,
AC
there are three different configuration modes that can be operated in the spraydryer and they are open cycle, closed cycle and semi-closed cycle [126]. The open cycle mode is applied to spray aqueous feeds. It uses air drawn from atmosphere as a drying gas that is not re-circulated during the process and is considered more stable and cost-effective compared to the closed cycle mode [111,127]. Close cycle mode is used to handle flammable solvents and/or toxic and oxygen sensitive products [126]. It uses an inert gas, such as nitrogen, that is recycled and reused in the drying chamber. Semi-closed cycle mode can be 40
ACCEPTED MANUSCRIPT either partial recycle mode (recycling of up to 60% of the exhaust air) or selfintertising mode. As to the flow pattern of the drying gas with respect to the direction of the liquid atomization can be either co-current (same direction), counter-current (opposite direction) or mixed-flow (Figure 17) [108]. In the cocurrent flow-pattern, the droplets of the feed come into contact with the coolest
PT
air, resulting in an optimal solvent evaporation for the spray-drying of heat-
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sensitive materials (e.g., peptides, proteins, enzymes). Whereas in the counter-
SC
current flow pattern the dry product is in contact with the hottest air, resulting in an increased powder flowability and median particle size for non-heat-sensitive
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materials [111]. There are also intermediate designs of mixed flow spray-dryers that combine co-current and counter-current flow patterns that could be useful
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when drying coarse droplets that require longer travel paths in the chamber to
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complete the removal of the solvent [111,118].
Figure 17. Airflow patterns in the spray-drying process. Reproduced from [108] with permission of Elsevier.
4.2. Control of particle size, size distribution and morphology There are several factors that can be tuned to better control particle size, size distribution and morphology in spray-drying. Among the process parameters, 41
ACCEPTED MANUSCRIPT liquid feed properties and system configuration are the most relevant [111,117]. Atomization, which is the first step in the process of spray-drying, has a crucial role in determining particle size [116,117]. In this step, the initial feed (called the precursor) is fed into the atomizer, converted into small droplets, which are then transformed into dry particles. Hence, the size of the droplets formed
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during atomization determines the size of the resultant dry particles [63,117].
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The size of the droplets can be affected by the physical and chemical properties
SC
of the feed, such as concentration, viscosity, surface tension, and amount of non-volatile material [63,128]. For example, a highly concentrated (and often
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more viscous) feed usually leads to an increase in particle size [111,124,125,128]. Moreover, the more non-volatile material the droplet
MA
contains, the larger the particle size will be and vice versa [63]. Droplet size and size distribution can also be affected by the settings of the
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atomizer (pressure and nozzle/mesh diameter) and the type of the applied
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atomization, which should therefore be carefully selected [117,125,129]. In general, the smaller the nozzle diameter the higher the kinetic forces generated
CE
at its base, and the smaller the size of the particles [111]. Baba et al. showed
AC
that the average particle size tends to decrease with decreasing mesh aperture size due to the generation of smaller droplets when using smaller mesh apertures [14]. Lee et al. investigated the production of BSA nanoparticles employing the Nano Spray Dryer B-90 and demonstrated that the particle size is predominantly influenced by the spray mesh size – the larger the mesh aperture size, the larger the size of the produced nanoparticles (Figure 18) [125]. As mentioned above, BSA is not an active molecule and it is used as a model protein. In some other applications, it has been used as drug carrier. In 42
ACCEPTED MANUSCRIPT any event, the sensitivity of proteins to pH, ionic strength and temperature varies very substantially among types and the biological properties could be
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altered.
Figure 18. Field emission scanning electron microscope images of bovine serum albumin nanoparticles produced using Nano Spray Dryer B-90 with a mesh aperture size of (a) 4.0 μm, (b) 5.5 μm and (c) 7.0 μm and showing the effect of spray mesh size on particle size. Reproduced from [125] with permission of Elsevier.
43
ACCEPTED MANUSCRIPT Thus, the extension of this technology to other polypeptides and proteins is not straightforward and their integrity and function has to be assayed after the spray-drying. The diameter of the generated droplet (𝐷𝑑 ), based on the previously discussed
expressed using Equation 4 [117,130]
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𝐷𝑑 = 𝐾𝑓 ∙ 𝑄 𝑛 [𝜌𝑎 ∙ 𝜎 𝑏 ∙ 𝜇 𝑐 ] (4)
PT
considerations of atomization settings and feed properties, can be empirically
SC
Where Kf, Q and n are the excitation equipment constant (centrifugal force,
NU
frequency, pressure, and carrier gas velocity which depend on the selected atomizer type), the precursor volumetric flow rate, and the power constant of
MA
volumetric flow rate, respectively. The symbols a, b and c are the power constants of the physical properties of the precursor: its density, surface
D
tension, and viscosity, respectively. Table 3 presents the power constants for
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the empirical atomization model, which implies that in general, the droplet size generated by the atomizer is mostly proportional to the flow rate of the liquid
CE
and the physical properties of the feed [117]. Other process parameters, such as the drying temperature, drying rate, flow rate and air-to-feed ratio also affect
AC
droplet size and morphology and need to be carefully considered [63,111,118,125,128,144–147].
After the atomization stage, the generated
droplets are dried by solvent evaporation and transformed into dry particles. It has been observed that the faster the evaporation rate of the solvent during this stage, the shorter the shrinkage time of the droplets and the more porous the morphology of the obtained particles [111,117,144].
44
ACCEPTED MANUSCRIPT Table 3. Power constants of some empirical atomizer models. Reproduced from [117] with permission of Elsevier. Power parameters
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a b c −0.37 0.33 – [131] −0.40 0.45 0.80 [132] – 2.40 −0.59 [133] – 1.00 0.50 [134] 0.30 0.30 0.30 [135] −0.30 0.30 0.10 [136] 0.41 −0.88 −1.01 [137] 0.93 1.22 0.22 [138] 0.19 0.95 1.34 [139] 0.34 1.00 0.50 [140] 0.80 0.95 0.82 [142] −0.67 0.33 [142] −0.27 0.11 0.17 [143]
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n −1.93 0.80 0.10 Spinning 0.50 discs 0.50 0.40 0.66 1.55 1.01 0.60 1.24 Ultrasonic – nebulizer 0.21 Air-shear nozzles
Refs.
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Atomizer types
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Porosity may have a dramatic impact of surface area and thus, it could certainly affect the drug particle dissolution rate [148]. However, a systematic study of
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the effect of the production conditions on the porosity of pure drug particles is
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missing. This property has been studied more systematically in polymeric particles that can form pores depending on the evaporation rate of the solvent.
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Finally, the dry particles are separated from the drying gas, usually by a cyclone that deposes them in a glass collector. Studies showed that the geometry of the
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cyclone is important when collecting particles of fine size. In general, the smaller the radii of the cyclone, the higher the generated resistance to the airflow and the more effective the process of particle recovery resulting in the collection of finer particles and an increased yield [63,149,150]. Table 4 lists the key parameters controlling the size of particles produced by spray-drying.
45
ACCEPTED MANUSCRIPT Table 4. Parameters affecting the size of particles produced by spray-drying. Parameters that upon increase Parameters that upon increase lead to a decrease of the particle lead to an increase of the particle size size Nozzle diameter
Atomization air flow
Liquid feed concentration
Atomization pressure
Liquid feed viscosity
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Feed flow rate*
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Solvent boiling point
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Gas inlet temperature Mesh size**
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*Increased flow rate is expected to decrease mass transfer rate during spray-drying and decrease the size of the droplets and the particles though in some cases, droplet collision and coalescence can result in the opposite phenomenon.
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**Relevant in spray-dryers based on mesh vibration such as the Nano Spray Dryer B-90 and its HP version.
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4.3. Production of pure drug particles by spray-drying
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Spray-drying has a great inherent potential to produce pure drug particles since it is a relatively fast, easy and reproducible method. It does not require a final
CE
drying step and it can offer general yield that is close to 100% at industrial scale [111,151]. While conventional spray-dryers are unable to produce drug particles
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smaller than 2 µm [152,153], the Nano Spray Dryer B-90 successfully manages to produce nanoparticles of pure drugs with or without combining them with polymers. In a study conducted by Baba et al., the preparation of pure nanocrystals of the steroidal drugs fluorometholone and dexamethasone in powder form was successfully carried out using the Nano Spray Dryer B-90 [14]. For this, both drugs were dissolved in ethanol. This solvent is classified as Class III and displays a relatively low boiling point, enabling the production of
46
ACCEPTED MANUSCRIPT the nanoparticles under drug-friendly temperature conditions. Nanocrystals
NU
SC
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showed sizes in the submicron-size range (Figure 19) [14].
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Figure 19. Scanning electron microscopy images of fluorometholone nanocrystals (upper) and dexamethasone nanocrystals (lower). The nanocrystals were prepared in the Nano Spray Dryer B-90 using mesh aperture sizes of (a) 4.0 µm, (b) 5.5 µm, and (c) 7.0 µm. Reproduced from [14].
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The crystalline structure of all the nanoparticles, regardless of the mesh size, was confirmed by powder XRD pattern analysis that showed no differences [14]. At the same time, a comparison with the respective unprocessed
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counterpart would have been of value to understand the effect of spray-drying
AC
nanonization on the crystalline structure. This comparison was not assessed. The idea behind the study was to improve the treatment of ophthalmic disorders by reducing the size of the particles to enhance their ocular penetration. The relationship between mesh aperture size and drug particle size was investigated (mesh aperture sizes of 4.0, 5.5, and 7.0 μm were used) [14]. Fluorometholone nanocrystals were formed by dissolving 1 mg/mL of drug in ethanol and spray-drying it to obtain nanocrystals with an average particle size and size distribution of 620 ± 268, 795 ± 285, and 856 ± 344 nm for mesh 47
ACCEPTED MANUSCRIPT aperture sizes of 4.0, 5.5, and 7.0 µm, respectively. Dexamethasone nanocrystals were formed by dissolving 10 mg/mL of drug in ethanol and spraydrying it to obtain nanocrystals with an average particle size of 833 ± 402, 1118 ± 573, and 1344 ± 857 nm for mesh aperture sizes of 4.0, 5.5, and 7.0 µm, respectively [14]. These results pointed out the influence of the drug properties
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on the process and the production rate. In another study conducted by the same
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researchers, nanocrystals of two calpain inhibitors, calpain inhibitor I and SNJ1945, as potential candidates for curing apoptosis-mediated intractable
SC
diseases such as Alzheimer’s and Parkinson’s disease, were produced using
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the same instrument [152]. Calpain inhibitor I nanocrystals were formed by dissolving 0.5 mg/mL of drug in ethanol and spray-drying it to obtain average
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particle sizes and size distributions of 378 ± 132, 527 ± 284, and 813 ± 484 nm against mesh aperture sizes of 4.0, 5.5, and 7.0 μm, respectively. Spray-drying
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of 0.5 mg/mL SNJ-1945 in ethanol resulted in nanocrystals with average size
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and size distribution of 418 ± 138, 605 ± 369, and 845 ± 567 nm with mesh aperture sizes of 4.0, 5.5, and 7.0 μm, respectively. The spherical morphology
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of both compounds was visualized by SEM (Figure 20) [152].
48
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ACCEPTED MANUSCRIPT
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Figure 20. SEM images of calpain inhibitor I (left) and SNJ-1945 (right) nanocrystals. The nanocrystals were prepared in the Nano Spray Dryer B-90 using mesh aperture sizes of 4.0 (a), 5.5 (b) and 7.0 μm (c). Reproduced from [152] with permission of Springer.
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In both studies, particle size increased significantly with increasing concentration of the drug solutions and the size distribution became narrower
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with decreasing mesh aperture size [14,152]. The effect of the inlet temperature and gas flow rate were also investigated in the latter study, however they did not significantly affect particle size [152]. Another work conducted by Martena et al. demonstrated the reproducible production of pure nicergoline nanoparticles, an ergot derivative used to treat senile dementia and disorders of vascular origin, using Nano Spray Dryer B-90 [154]. In this case, spherical and amorphous nanoparticles with a mean particle diameter of 790 nm were
49
ACCEPTED MANUSCRIPT produced and used to prepare a nanosuspension with high physicochemical stability and increased dissolution rate in vitro [154]. Drug nanocrystals were obtained by spraying a solution of 25 mg/mL of nicergoline in a mixture of ethanol:ultrapure water in a ratio of 1:3 using a mesh aperture size of 7.0 μm, an inlet temperature of 50°C and a feeding rate of 90 L/min [154]. Spray-drying
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not only produced nanoparticles but also amorphisized the drug (Figure 21)
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SC
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[154].
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Figure 21. Powder X-ray diffraction pattern of (a) native crystalline nicergoline and (b) nicergoline nanoparticles. Reproduced from [154] with permission of Springer Nature.
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In addition, the solubility profile in different media was measured (Figure 22) [154]. Amorphous nanoparticles showed a time-dependent behavior with a fast solubility increase and reached a maximum within a few minutes that was considered the maximum solubility at that specific time point. Then, the solubility decreased until reaching a lower value that remained constant for at least 120 min. Unprocessed drug did not show this profile and reached a lower value of maximum solubility that remained constant afterwards.
50
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ACCEPTED MANUSCRIPT
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Figure 22. Experimental solubility profiles of nicergoline pristine (unprocessed) particles (square symbol) and nanoparticles (round symbol) (batch A) in distilled water, HCl 0.1 N and phosphate buffer pH 8.0 at 10, 20, 30, and 37 °C. Reproduced from [154] with permission of Springer Nature.
Mizoe et al. produced pure drug nanocrystals of the hydrophobic drug pranlukat
AC
hemihydrate used to treat chronic bronchial asthma and encapsulated it within mannitol microparticles by spray-drying for improved pulmonary delivery [27]. Particle mean diameter was 2 μm, which is within the respirable range (1-5 μm). The mannitol microparticles dissolve rapidly on the surface of the pulmonary epithelium, leaving a suspension of pure drug nanocrystals of the insoluble drug (with diameter ranging from 100 to 430 nm) that can slowly dissolve and release the drug for local or systemic action [27]. Li et al. used the Nano Spray Dryer B-90 in their study to explore the production of nanoparticles of NaCl and 51
ACCEPTED MANUSCRIPT furosemide [124]. The former was used as a model of inorganic ionic hydrophilic compound, while the latter is a small poorly water-soluble molecule used as a diuretic drug to treat congestive heart failure and edema. NaCl nanocrystals were formulated from aqueous solutions and the obtained particles sizes ranged from 517 ± 182 nm (yield of 81.1%) to 993 ± 256 nm (yield of 85.4%)
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for salt concentrations of 0.1% w/w and 1% w/w, respectively. Furosemide was
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spray-dried at a concentration of 1.25% w/w in acetone and the obtained
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particle size was 1245 ± 482 nm with a yield of 69.3% [124]. These production yields are not optimal yet and could be improved probably by producing larger
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amounts. On the other hand, the electrostatic collector of this instruments has to be cleaned to enable the further deposition of the product. In a work by Chan
line
antibiotics
for
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et al., the production of an excipient-free micron-sized dry powder of three firstthe
treatment
of
tuberculosis
D
(pyrazinamide:rifampicin:isoniazid in a ratio of 5:2:1 w/w/w) was demonstrated
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using Mini Spray Dryer B-290 (Büchi) operated in a closed loop and connected in series with a B-296 dehumidifier and B-295 inert-loop (Büchi). The size of the
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particles was in the 0.2-5.0 μm range, which is in the suitable range for
AC
pulmonary delivery [155]. Another feasible approach would be the pre-formation of pure drug nanoparticles and their later spray-dying. For example, Swai et al. produced nanoparticles of the antiretroviral drug efavirenz by a modified doubleemulsion/spray-drying method [156]. A double-emulsion was fed into the Mini Spray Dryer B-290 and spray-dried at 96°C, with an atomizing pressure of 6 and 7 bars. The size of the nanoparticles obtained ranged from 200 to 250 nm
52
ACCEPTED MANUSCRIPT with a narrow size distribution. Moreover, the drug underwent amorphization during the spray-drying process as indicated by PXRD results [156]. In some cases, the combination of several technologies was also reported. For example, Monterrubio et al. combined simultaneous microcrystal spraying and polymer electrospinning [157]. The system consisted of matrices made of
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poly(lactic acid) electrospun polymer nanofibers loaded with sub-micron to
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micron crystals of the anti-cancer drug SN-38 (10-hydroxy-campthothecin) for
before spraying was 1.7 ± 0.34 μm [157].
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local release in pediatric solid tumors. The size of the SN-38 microcrystals
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Overall, spray-drying is a very flexible technology that upon optimization and
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validation of the process could eventually offer cost-effectiveness and reproducibility. However, at this stage, published data are limited and any
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conclusion on its potential to play a key role in the production of pure drug
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microparticles and nanoparticles in the pharmaceutical industry in the near future seems to be unfunded. As this technology keeps on evolving and our understanding of the impact that the critical parameters have on the properties
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and the performance of products continues to grow, the chances to realize its
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potential increase. Moreover, scalable production under an industrial setting is a bottleneck towards bench-to-bedside translation of pure drug nanoparticles of any kind produced by bottom-up techniques and it relies on the availability of commercial industrial equipment that can be operated under the strict good manufacturing practices of the pharmaceutical industry. In the case of spraydrying, this equipment is not available yet. 5. Electrohydrodynamic atomization and spray-drying to produce drug co-crystals 53
ACCEPTED MANUSCRIPT Production of drug co-crystals/drug-drug co-crystals has emerged as an approach to improve physicochemical properties of drugs such as saturation solubility, dissolution rate and chemical stability in biological media, while preserving pharmacological activity. Better dissolution profiles usually result in higher oral bioavailability. In addition, the mechanical properties of the solid can
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be modified to comply with a variety of formulation processes (e.g., tableting).
RI
Since traditional co-crystallization methods (e.g., slurry crystallization, ball
SC
milling, liquid assisted grinding and solvent evaporation) face significant challenges during scale-up, alternative methods are continuously searched for
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[158,159]. Both EHDA and spray-drying, thoroughly discussed in this review, are considered attractive methods for the fabrication of drug co-crystals. In most
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of the works in which drug co-crystallization was performed by these two methods, the size of the obtained co-crystals is in the micrometer rather than
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the nanometer range. However, these works represent a solid background for
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the design of nano-co-crystals. For example, Alhalaweh et al. produced and characterized co-crystals of theophylline, a bronchodilator used for treating
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asthma, with urea, saccharin and nicotinamide for pulmonary drug delivery and
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compared their performance with that of milled theophylline and theophyllinesaccharine that were used as controls. [160]. Pure theophylline and its cocrystals with saccharine and urea were sprayed from methanol solution, while the co-crystal with nicotinamide from water and the products were characterized by different methods [160]. The solvent selection was based on the solubility of both the active compound and the co-crystal former. It is important to stress that organic solutions are usually spray-dried in a closed configuration under nitrogen as the drying gas and the solvent is trapped using 54
ACCEPTED MANUSCRIPT a B-295 inert loop that prevents its release to the environment. An inert environment is also required to spray flammable solvents under heating. Conversely, aqueous solutions are spray-dried in an open configuration with air as the drying gas. Organic solvents such as methanol are more advantageous than water because they display lower boiling point and thus, the drying is
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achieved under milder conditions that prevent better thermal degradation of the
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active compound. At the same time, it is important to stress that spray-dryers
SC
are designed to shorten the exposure of the liquid feed to heat, thus being also feasible for thermo-sensitive materials. Moreover, elimination of methanol
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residues can be achieved faster than water; humidity can contribute to chemical instability. On the other hand, water is not toxic, while the concentration of
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residual methanol has to comply with regulatory guidelines [61,62]. Co-crystals were smaller than 5 μm, as determined by SEM [158]. Since theophyllin was
diameter
were
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aerodynamic
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envisioned for inhalation, the aerosol performance and the median measured.
Co-crystals
showed
lesser
agglomeration than pure spray-dried and milled crystals which is a relevant
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property towards inhalation administration. Pawar Jaywant et al. prepared cocrystals of efavirenz, a poorly water-soluble antiretroviral drug, and glutaric acid
AC
(2:1) by spray-drying [159]. In this case, both API and crystal co-former were dissolved in 1:1 v/v ethanol/methanol solution before spray-drying that was performed using a laboratory spray-dryer (JISL, Secunderabad, India) at the temperature range of 49-52°C and at a flow rate of 2 mL/min. The spray-dried product was recovered from the cyclone collector, stored in a desiccator and characterized for solid-state properties [159]. Co-crystals showed a 2.8 fold increase in dissolution rate as compared to the raw drug [159]. Walsh et al.
55
ACCEPTED MANUSCRIPT managed to form co-crystals of sulfadimidine, a poorly water soluble API, and 4-aminosalicylic acid, a hydrophilic molecule, by spray-drying in the presence of a third component (excipient) [161]. A solution of sulfadimidine and 4aminosalicylic acid (1% w/v) was prepared in ethanol and sonicated for complete dissolution of the components. An equal volume of 1%
4-aminosalicylic
acid
solution
and
mixed.
The
resultant
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and
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w/v excipient aqueous solution or suspension was added to the sulfadimidine
operating
in
the
open
SC
solutions/suspensions were spray-dried using a Mini Spray Dryer B-290 mode. Spray-drying
resulted
in
co-
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crystal microspheres with sizes in the 1–10 μm size range, depending on the excipient used [161]. For some of the systems, better tableting properties were
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achieved. This work emphasizes the feasibility to extend the use of these technologies to the production of a broad variety of formulations. In a research
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conducted by Patil et al. the synthesis of caffeine and maleic acid co-crystals
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was successfully carried out by EHDA [48]. For this, solvents with diverse physicochemical properties such as methanol, ethyl acetate, acetone and water
CE
were used. The prepared solutions of caffeine/maleic acid were electrosprayed using a E-Spin NANO electrospray (Pico, Chennai, India) under flow rate of 2
AC
mL/h, voltage of 20 kV and syringe of 10 mL [48].
In addition, different
caffeine:maleic acid molar ratios were used. 1:1 co-crystals were formed from methanol, ethyl acetate and acetone, while 2:1 co-crystals from water [48]. As previously explained water displays remarkable advantages over organic solvents. Among them, water is cheaper, safer for spraying-drying (it is not flammable as alcohols, organic esters and ketones), less contaminant of the environment, and it is non-toxic as opposed to many organic solvents for which
56
ACCEPTED MANUSCRIPT maximum residual limits have been defined [61,62]. On the other hand, the relatively high boiling point of water demands the use of higher drying temperature which in turn could result in thermal degradation of the active compound. Thus, these aspects need to be carefully evaluated when optimizing the process. In some cases, the use of solvent mixtures is beneficial as it
PT
enables the drying process at slightly lower temperature. In another study, the
carbamazepine/nicotinamide
and
itraconazole/fumaric
acid,
SC
of
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same research group utilized the same method to study the co-crystallization
itraconazole/succinic acid and itraconazole/maleic acid [158]. Carbamazepine
NU
and nicotinamide were dissolved in methanol and ethanol separately in 1:1 molar ratio by heating in a water bath to 50°C. Similarly, itraconazole and
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its co-formers were dissolved in a mixture of tetrahydrofuran and chloroform (1:1 v/v) in 2:1 molar ratio. The electrospraying was carried out using a 10 mL
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syringe, a flow rate of 2 mL/h, a voltage of 20 kV and a temperature of 40°C
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[158]. PXRD, DSC and Fourier-transform infrared spectroscopy analyses the formation of pure carbamazepine/nicotinamide co-crystals. Authors also
CE
suggested that the nucleation of the drug and the co-former took place in the Taylor cone. Conversely, in the case of itraconazole, only the co-crystals with
AC
fumaric acid and succinic acid were successfully formed. The dissolution rate in water was not assessed. An important constraint of these explorative works is the very low flow rate achieved with laboratory scale equipment. This could be overcome by employing commercially available equipment designed for pilot, pre-production and industrial production [108]. Overall, the research of EHDA and spray-drying as platforms for the production of drug co-crystals is very incipient. In our view, the few works presented here 57
ACCEPTED MANUSCRIPT constitute solid preliminary evidence that both technologies could serve as an alternative to more traditional methods and to eventually pave the way to the design of new and more complex nano-crystalline products with improved physicochemical properties.
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6. Conclusions and future challenges EHDA and spray-drying are two bottom-up techniques extensively explored for
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the fabrication of polymeric nanoparticles. Owing to the great versatility to
SC
adjust the process conditions for a broad variety of materials, they recently attracted the attention of pharmaceutical scientists to produce pure drug
NU
particles. In both techniques, the evaporation of the solvent is very efficient and,
MA
depending on the equipment design, also relatively fast. In fact, most of the solvent is eliminated within few seconds as opposed to other drying processes
D
such freeze-drying that require hours or days. To make the drying process more
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efficient, spray-drying uses temperature under a gas flow, while EHDA could be conducted at high temperature and low pressure and the operation conditions could be modified to find a good balance between solvent
CE
evaporation and formation of crystalline/amorphous particles. The question that
AC
remains is whether EHDA and spray-drying could be an alternative to wellestablished top-down technologies such as high-pressure homogenization. On one hand, bottom-up methods enable better control of the particle structure and morphology. In addition, with the proper adjustment of the conditions, crystalline drugs can be converted into amorphous counterparts that usually display with significantly faster dissolution rates. On the other, regardless of the great opportunities offered by these two technologies, data reported in the literature are not sufficient and robust enough to conclude about aspects such 58
ACCEPTED MANUSCRIPT reproducibility, cost-viability and scalability, that are crucial for industrial implementation. The design of industrial equipment that enables good control, follow up and validation of the process conditions is probably the first milestone in this direction. In the case EHDA, such equipment is already commercially available. Conversely, industrial spray-dryers are less appropriate for the mass
PT
production of nanoparticles. However, in our view, the most challenging stage
RI
is allocating time and funds to a more systematic research of the fundamental
SC
parameters that control the crystalline/amorphous structure of the particles, as well as their size, size distribution, morphology and porosity. In other words, the
NU
characterization of the particles should not be limited to assess their size, shape and crystallinity/amorphousness and to demonstrate changes (usually
MA
increase) in the dissolution rate and the saturation solubility, as most researchers do. They need to comprise a more comprehensive study of the
D
relationship between the nanoparticle structure and properties that govern its
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interaction with the biological system such as physicochemical stability under biologically-relevant conditions, permeability across barriers (e.g., models of
CE
intestinal epithelium), mucoadhesion and ultimately pharmacokinetics. Only then, the potential of these bottom-up technologies in general and EHDA and
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spray-drying in particular will be realized. Acknowledgments. This work was funded by the Phyllis and Joseph Gurwin Fund for Scientific Advancement. RSA dedicates this article to the memory of her father, Dov Sverdlov, who recently passed away and whose invaluable help, belief and support has made the writing of this article possible.
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ACCEPTED MANUSCRIPT 6596/170/1/012027. [146] R. Vehring, Pharmaceutical particle engineering via spray drying, Pharm. Res. 25 (2008) 999–1022. doi:10.1007/s11095-007-9475-1. [147] F.J. Wang, C.H. Wang, Effects of fabrication conditions on the characteristics of etanidazole spray-dried microspheres, J. Microencapsul. 19 (2002) 495–510. doi:10.1080/02652040210140483.
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[155] J.G.Y. Chan, H.K. Chan, C.A. Prestidge, J.A. Denman, P.M. Young, D. Traini, A novel dry powder inhalable formulation incorporating three firstline anti-tubercular antibiotics, Eur. J. Pharm. Biopharm. 83 (2013) 285– 292. doi:10.1016/j.ejpb.2012.08.007. [156] L. Tshweu, L. Katata, L. Kalombo, D.A. Chiappetta, C. Hocht, A. Sosnik, H. Swai, Enhanced oral bioavailability of the antiretroviral efavirenz encapsulated in poly(epsilon-caprolactone) nanoparticles by a spraydrying method, Nanomedicine. 9 (2014) 1821–1833. doi:10.2217/nnm.13.167 [157] C. Monterrubio, G. Pascual-Pasto, F. Cano, M. Vila-Ubach, A. Manzanares, P. Schaiquevich, J.A. Tornero, A. Sosnik, J. Mora, A.M. Carcaboso, SN-38-loaded nanofiber matrices for local control of pediatric solid tumors after subtotal resection surgery, Biomaterials. 79 (2016) 69– 71
ACCEPTED MANUSCRIPT 78. doi:10.1016/j.biomaterials.2015.11.055. [158] S. Patil, V. Ujalambkar, A. Mahadik, Electrospray technology as a probe for cocrystal synthesis: Influence of solvent and coformer structure, J. Drug Deliv. Sci. Technol. 39 (2017) 217–222. doi:10.1016/j.jddst.2017.04.001. [159] N. Pawar Jaywant, D. Amin Purnima, Development of efavirenz cocrystals from stoichiometric solutions by spray drying technology, Mater. Today Proc. 3 (2016) 1742–1751. doi:10.1016/j.matpr.2016.04.069.
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Graphical abstract
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Roni Sverdlov Arzi, Alejandro Sosnik PII: DOI: Reference:
S0169-409X(18)30178-9 doi:10.1016/j.addr.2018.07.012 ADR 13347
To appear in:
Advanced Drug Delivery Reviews
Received date: Revised date: Accepted date:
30 April 2018 12 July 2018 17 July 2018
Please cite this article as: Roni Sverdlov Arzi, Alejandro Sosnik , Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals. Adr (2018), doi:10.1016/j.addr.2018.07.012
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ACCEPTED MANUSCRIPT ADVANCED DRUG DELIVERY REVIEWS Theme Issue “Drug Nanoparticles and Nano-Cocrystals: From Bottom-up Production and Characterization to Clinical Translation”, A Sosnik and S Mühlebach (Guest Editors)
Electrohydrodynamic atomization and spray-drying for the
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production of pure drug nanocrystals and co-crystals
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Roni Sverdlov Arzi and Alejandro Sosnik*
Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials
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Science and Engineering, Technion-Israel Institute of Technology, Haifa, Israel
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*Corresponding author: Prof. Alejandro Sosnik, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, De-Jur Building, Office 607, Technion City, 3200003 Haifa, Israel; Phone #: +972-77887-1971; Email: [email protected]
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ACCEPTED MANUSCRIPT List of abbreviations Active pharmaceutical ingredient
BCS
Biopharmaceutics classification system
BSA
Bovine serum albumin
DSC
Differential Scanning Calorimetry
EHDA
Electrohydrodynamic atomization
ICH
International Conference for Harmonization
IDV
Indinavir
PLGA
Poly(lactic-co-glycolic) acid
PXRD
Powder X-ray diffraction
SCF
Supercritical fluid
SEM
Scanning Electron Microscopy
XRD
X-ray diffraction
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API
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ACCEPTED MANUSCRIPT Abstract In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been
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made on those that increase the dissolution rate and the saturation solubility by
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the reduction of the particle size of pure drugs to the nanoscale and the
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associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and
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cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an
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anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to features such as size, size distribution,
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morphology and to control the amorphous/crystalline nature of the product. In
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this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability.
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Moreover, they do not necessarily need suspension stabilizers and dry products
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are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.
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ACCEPTED MANUSCRIPT Keywords: Pure drug nanoparticles; nanopharmaceuticals; drug nanocrystals; drug co-crystals; bottom-up nanonization; electrohydrodynamic atomization; spray-drying. Table of Contents
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1. Introduction 2. Solvents in pharmaceutical production
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3. Electrohydrodynamic atomization
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3.1. The method
3.2. Control of particle size, size distribution and morphology
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3.3. Production of pure drug particles by electrohydrodynamic
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atomization 4. Spray-drying The method
4.2.
Control of particle size, size distribution and morphology
4.3.
Production of pure drug particles by spray-drying
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5. Electrohydrodynamic atomization and spray-drying to produce drug co-
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crystals
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6. Conclusions and future challenges Acknowledgements References
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ACCEPTED MANUSCRIPT 1. Introduction The pharmaceutical industry is found in a persistent and urgent search for new scalable
and
cost-effective
technological
strategies
to
overcome
(bio)pharmaceutical drawbacks of drugs such as poor aqueous solubility, low physicochemical stability in the biological milieu, short half-life and reduced
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bioavailability [1–5]. For instance, >50% of the approved drugs and 70% of new
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chemical entities under development are classified into Class II and IV of the
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Biopharmaceutics Classification System (BCS) [6,7]. These limitations increase drug attrition rates [8,9] and lead to a decline in the ability to translate them into
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new pharmaceutical products [10–12].
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Numerous strategies have been applied to overcome these drawbacks. Nanonization of pure drug particles via top-down or bottom-up techniques to produce nanoparticles of amorphous or crystalline nature with sizes ranging
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from a few nanometers up to 1 μm enhances the dissolution rate and the saturation solubility by increasing the specific surface area-to-volume ratio [1,13–16] (Figure 1). The Noyes–Whitney Equation 1 describes the dissolution
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rate of spherical particles. The process is controlled by diffusion and no
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chemical reaction takes place [10,17–20] 𝑑𝐶𝑥 𝑑𝑡
D
= 𝐴 h (𝐶𝑠 − 𝐶𝑥 ) (Eq. 1)
Where dCx/dt is the dissolution rate, A is particle surface area, D is the diffusion coefficient, h is the effective thickness of the boundary layer, Cs is particle saturation solubility and Cx is concentration in the surrounding liquid at time x. The Ostwald–Freundlich Equation 2 establishes the increase in solubility of a
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ACCEPTED MANUSCRIPT given compound based on the increase of the interfacial energy at high curvatures or in other words, for very small particles. 2𝛾𝑀
𝑆 = 𝑆∞ exp (𝑟𝜌𝑅𝑇) (Eq. 2) Where S is the saturation solubility of the nanosized active pharmaceutical
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ingredient, S∞ is saturation solubility of an infinitely large active pharmaceutical ingredient crystal, γ is the crystal-medium interfacial tension, M is the molecular
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constant and T is the absolute temperature.
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weight of the compound, r is the particle radius, ρ is the density, R is the gas
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Thus, an increase in the specific surface area-to-volume ratio of the nanonized crystals leads to a faster dissolution rate. In addition, when the particle size is
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smaller than 100 nm, the saturation solubility increases exponentially. Both phenomena result in an enhancement in the oral bioavailability of the drug [13].
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Moreover, the number of contact points with the surrounding tissues (e.g.,
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mucus) increases substantially, favoring the adhesiveness to biological structures and the prolongation of the residence time [13].
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Over the last decades, nanosizing techniques have gained increased interest
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in terms of both new intellectual property and clinical impact [1,5,10,13,21]. Pure drug nanoparticles can be used dispersed in aqueous media in the socalled nanosuspensions [21,22] or to produce solid formulations such as tablets [20]. The degree of crystallinity of the drug in the nanoparticle may vary widely and can be controlled by adjusting the conditions of the production method [1,10].
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Figure 1. Features (f) of pure drug nanocrystals. (1) Increased saturation solubility (Cs) due to increased dissolution pressure of strongly curved small nanocrystals, (2) increased dissolution rate (dc/dt) due to decreased diameter (d) and increased surface area (A) of the particles and (3) increased adhesiveness of nanomaterial due to increased contact area of nanoparticles versus microparticles (at identical total particle mass), note: surface calculations were performed as cubes. Reproduced from [13] with permission of Elsevier.
In some cases, the relatively slow dissolution rate of pure nanocrystals of highly hydrophobic drugs combined with their ability to undergo entrapment by the intestinal mucosa resulted in a dramatic increase of the drug half-life with respect to the unprocessed counterpart (Figure 2), a concept that we coined nanocarrier-less delivery systems [23,24].
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1 m
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*Statistically significant increase of the amount of drug dissolved when compared to the unprocessed drug (p<0.05).
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Figure 2. Indinavir free base (IDV) plasma concentration versus time profile of raw indinavir free base (IDV powder), and nanocrystals produced by nanoprecipitation (NP) and supercritical fluids (SCF) after oral administration of a single dose (10 mg/kg) to mongrel dogs (n = 4). The different pharmacokinetic parameters were calculated using a non-compartmental model and TOPFIT software (version 2.0, Dr. Karl Thomae Gmbh, Schering AG, Germany). Reproduced with modifications from [23] with permission of Elsevier. Pure drug nanoparticles have been also used by other minimally-invasive administration routes such as inhalation, transdermal, ophthalmic and buccal [10,25]. For example, pure drug nanocrystals of hydrophobic drugs (e.g., pranlukat hemihydrate) have been investigated for the treatment of chronic bronchial asthma by pulmonary delivery [26–28]. Drug nanocrystals have been also assessed to improve skin deposition and permeation of the non-steroidal
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ACCEPTED MANUSCRIPT anti-inflammatory drug diclofenac by the transdermal route [30]. More recently, pure drug nanocrystals of hydrophobic drugs (e.g., the antiretroviral rilpivirine) have been investigated to sustain the release upon intramuscular injection in the chronic therapy of the human immunodeficiency virus infection [31,32]. Unlike other drug nanocarriers that have been extensively researched (i.e.,
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liposomes, nanoemulsions and polymeric nanoparticles) and for which
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encapsulation efficiency and drug loading have to be defined in the final
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product, pure drug nanocrystals/co-crystals offer a theoretical drug content of up to 100%. Thus, the encapsulation efficiency is not a constraint [13,33,34].
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On the other hand, small drug particles are thermodynamically instable and they tend to grow in size by agglomeration [25,35,36]. This is why they are
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usually physically stabilized using surfactants or other polymeric stabilizers [1,25,33] what brings the typical total drug content to ~50-90% w/w [34].
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Another important advantage of drug nanocrystals is the maturity and scalability
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of their fabrication technologies, which can be demonstrated by multiple commercial products that are currently on the market. Table 1 summarizes oral
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pharmaceutical formulations based on pure drug nanocrystals currently on the
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market or under preclinical trials (Table 1) [45].
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Table 1. Overview of drug nanocrystals for oral administration currently on the market or under preclinical trials. Adapted from [45] with permission of Elsevier. Drug Sirolimus Aprepitant Fenofibrate Fenofibrate Megestrol acetate Griseofulvin Nabilone Danazol
Tradename/Company Rapamune®/Wyeth Emend®/Merck Tricor®/Abbott TriglideTM/First Horizon Pharmaceutical Megace® ES/Par Pharmaceutical Gris-PEG®/Novartis Cesamet®/Lilly -
Indication Immunosuppressant Antiemetic Hypercholesterolemia Hypercholesterolemia
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Status Marketed Marketed Marketed Marketed
Refs. [37] [37] [37] [37]
Oral suspension
Marketed
[37] [38] [38] [39]
Appetite stimulant Antifungal Antiemetic Estrogen antagonist
Bottom-up, co-precipitation Bottom-up, co-precipitation Top-down, media milling
Tablet Capsule Nanosuspension
Top-down, media milling Top-down, media milling
Nanosuspension Nanosuspension Pellets containing dried nanocrystals powder Nanosuspension
Marketed Marketed In vivo (dog) In vivo (rat) In vivo (dog) In vivo (dog) In vivo (pig)
Nanosuspension
In vivo (rat)
[43]
Nanosuspension
In vivo (rat)
[44]
N A
M
-
Anti-inflammatory Antiplatelet agent
Ketoprofen
-
Anti-inflammatory
Top-down, media milling
Cyclosporine
-
Immunosuppressant
Spironolactone
-
Itraconazole
-
Top-down, high-pressure homogenization Top-down, high-pressure homogenization Bottom-up, precipitation
D E
T P E
C C
Diuretic
Antifungal
I R
C S U
Naproxen Cilostazol
A
Dosage form Tablet Capsule Tablet Tablet
Applied technology Top-down, media milling Top-down, media milling Top-down, media milling Top-down, high-pressure homogenization Top-down, media milling
[40] [15] [41] [42]
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ACCEPTED MANUSCRIPT Another approach currently investigated to overcome drug solubility issues is micro/nano-co-crystallization [46,47]. Pharmaceutical co-crystals are crystalline materials composed of at least two different molecules, typically a drug and a co-crystal former known as a co-former in the same crystal lattice [37,48,49]. There are several types of molecular interactions that can generate co-crystals
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such as π-π stacking, van der Waals forces, H-bonds and ionic bonds [49,50].
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The main advantage of drug co-crystallization is the ability to alter the
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physicochemical characteristics of the pure drug to improve its solubility, stability, dissolution rate and oral bioavailability, while maintaining their
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therapeutic activity [37,51]. Conventional co-crystals are formed by a drug and a pharmacologically inert co-former. More recently, drug-drug and multidrug co-
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crystals were introduced [52,53]. Their advantage over conventional co-crystals is that the components display a synergistic pharmacological activity as well as
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enhanced physicochemical properties for at least one of the co-crystal
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components [52,54,55]. Moreover, the combination of multiple therapeutic agents in single unit doses facilitates patient management with complex
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diseases and increases patient compliance [52,56].
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The techniques applied to nanosize drugs can be classified into three main categories: bottom-up (e.g., nanoprecipitation), top-down (e.g., wet ball milling, high pressure homogenization) and combination techniques [57]. Each one presents pros and cons though in general, all of them have to fulfill similar requirements such as controlled and reproducible size, narrow size distribution, high purity, low content of solvent residues, good physicochemical stability and desired morphology and density [57]. In cases where the nanoparticles are used in the production of solid formulations (e.g., tablets), the mechanical and flow 11
ACCEPTED MANUSCRIPT properties of the nanoparticle will govern the tableting process and the final properties of the formulation [58,59]. Moreover, different production methods influence differently the solid state characteristics of the nanoparticles [60]. In general, once the production conditions have been optimized, bottom-up techniques enable a better control of the particle crystallinity/amorphousness
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and shape, and thus, in recent years, they have gained significant impulse [38].
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The current review revisits two bottom-up technologies based on the
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atomization of a liquid drug solution in a pharmaceutically compatible aqueous or organic solvent into small droplets that undergoes relatively fast drying,
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namely electrohydrodynamic atomization (EHDA) or electrospraying (these are equivalent terms used to describe the same technique) and spray-drying, for
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the production of amorphous or crystalline pure drug nanoparticles and nanoco-crystals and critically analyzes their potential to play a fundamental role in
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the production of innovative pharmaceutical formulations.
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2. Solvents in pharmaceutical production Both EHDA and spray-drying rely on the atomization of a drug solution
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employing different mechanisms and the drying of the formed liquid droplets to
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produce dry drug particles. In general, both technologies have been developed to enable the safe use of a broad spectrum of aqueous and organic solvents, including flammable (e.g., alcohols, ketones), halogenated (e.g., chloroform, 1,1,1,3,3,3 hexafluoro-2-propanol) and aromatic ones (e.g., toluene). However, this equipment has been developed for use in a plethora of industries and exclusively in pharmaceutical R & D. Thus, safety in equipment operation does not necessarily mean that all the solvents used are compatible with pharmaceutical production. 12
ACCEPTED MANUSCRIPT Organic solvents are commonly used in the production of pharmaceutical products, especially in the synthesis and purification of active pharmaceutical ingredients (APIs) and during their processing (e.g., nanonization) and formulation (e.g., film-coating of particles and solid forms) [61]. In general, small amounts of these solvents (called residual solvents) may remain in the final
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product depending on the production technique and the product. Due to the
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relevance of this issue, we briefly describe the classification of organic solvents
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for pharmaceutical use. Organic solvents are classified into four classes [61,62]. Class I comprises human carcinogens, compounds strongly suspected
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of being human carcinogens and environmental hazards such as benzene, carbon tetrachloride and halogenated ethane derivatives. These solvents are
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not allowed in the pharmaceutical industry and their use has to be very strongly justified. Thus, regardless of their feasibility in EHDA and spray-drying they are
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less relevant.
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Class II solvents are non-genotoxic animal carcinogens or solvents that can cause irreversible or reversible toxicity [61,62]. Some of the solvents in this
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category such as chloroform, 1,2-dichloromethane, methanol and toluene are
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commonly used in EHDA and spray-drying. The maximum allowed concentration of these solvents in the tested material is defined in parts per million (ppm) or the permitted daily dose in mg/day. The International Conference for Harmonization (ICH) has published harmonized guidelines (ICH Q3C guideline) for the approval or rejection of pharmaceutical products containing Class II residual solvents [62]. Class III solvents are recognized as safe and allowed in daily exposures of 50 mg/day or less. In some production setups, higher amounts could be also 13
ACCEPTED MANUSCRIPT acceptable. They include ethanol, propanol, acetone, dimethyl sulfoxide and ethyl acetate [61,62]. Finally, Class IV solvents are those for which toxicological data are not available and thus, they cannot be used [61,62].
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Most research for the production of pure drug particles by EHDA and spraydrying utilized aqueous solvents or organic solvents of Classes II and III. The
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3. Electrohydrodynamic atomization
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of solvent elimination during the drying process.
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choice depends on the solubility of the particle components and also the ease
3.1. The method
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EHDA or electrospraying is a versatile technology based on the use of electrically charged fluids, which derives from the electrospinning technology
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used to produce micro- and nanofibers, though to obtain particles [63,64]. It is
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reproducible due to the ability to control the process parameters and it can be easily operated in a continuous manner. Therefore, it has the potential to
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replace multiple unit operations in pharmaceutical manufacturing [65,66]. The main advantages of EHDA over other conventional methods
(e.g.,
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nanoprecipitation) are its ability to produce particles in an easy, one-step process, with narrow size distribution and without the use of surfactants or stabilizers [66–68]. In addition, products are collected as dry powders with a very low content of residual solvents. For example, Wang et al. investigated the residual amount of 1,2-dichloromethane in collected polymeric microparticles fabricated by EHDA using gas chromatography/mass spectrometry [69]. Results of several experiments showed that the content of residual solvent in
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The standard configuration of the instrument consists of four major
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components: a pumping system, a metal nozzle wired with a high voltage power
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supply and a grounded substrate as a collector (Figure 3) [70].
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Figure 3. Setup of a conventional instrument for the production of particles by electrohydrodynamic atomization. Reproduced from [70] with permission of Elsevier.
The setup for the process can be operated under ambient temperature and
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pressure or under inert environment to better control the drying process and prevent possible external contaminations [64]. There are several modes of spraying, which differ in the process of formation of the meniscus and the jet emerging from this meniscus [64,71–73]. The different modes depend on properties of the liquid such as conductivity, surface tension, viscosity and the applied voltage and flow rate [68,72]. Among the various electrospraying modes that can be operated, the Taylor cone-jet mode is most preferred for an efficient production of highly monodisperse particles [64]. In this technique, a high 15
ACCEPTED MANUSCRIPT voltage of several kilovolts is applied to a capillary nozzle, which causes the solution interface at the tip to change its shape due to the accumulation of an electrostatic charge. As the electrostatic Coulomb forces become stronger, the effect of surface tension on the shape of the interface decreases until the two forces are equal and the liquid meniscus at the capillary exit develops a conical
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shape (the so-called Taylor cone) [63,66,74,75]. If the cone is disturbed by
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additional charge, the liquid flowing out of the capillary is forced to disperse into
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droplets. The shape and forces in the liquid cone are described in Figure 4 [76].
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Figure 4. Forces in the liquid cone. Reproduced from [76] with permission of Elsevier.
Coalescence is prevented by the electrostatic repulsion between the generated
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droplets [63,66]. The size of the droplets can range from hundreds of micrometers down to several tens of nanometers and it can be controlled to some extent via the flow rate of the liquid, its viscosity, the surface tension, the applied voltage at the capillary nozzle and the distance to the collector [63,66,68,75,77,78]. If the primary generated droplets reach the Rayleigh limit, which is the theoretical predicted limit for the determination of a drop break, then the droplets experience a phenomenon called Rayleigh disintegration or
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particles (Figure 5) [64].
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Figure 5. Schematic illustration of Coloumb fission phenomenon during the process of electrospraying. Reproduced from [64] with permission of Elsevier.
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Thus, in order to produce uniformly sized droplets with narrow size distribution and good reproducibility, the Coulomb fission has to be minimized [80]. To discharge the precursor droplets and prevent their fission, a supplementary configuration of nozzle ring/needle called corona discharge was recently introduced [79–83]. This configuration consists of a discharging stainless-steel ring or needle that is charged at a voltage of opposite polarity with respect to
17
ACCEPTED MANUSCRIPT the electrospray source and is placed opposite to or concentrically around the
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nozzle (Figure 6) [80].
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Figure 6. Experimental set up for the corona discharge. Reproduced from [80] with permission of Elsevier.
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The electric field at the tip of these neutralizers causes electrical breakdown of
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the surrounding air and generates a corona with a plasma of negative electrons, which then migrate and flow in an opposite direction with respect to the
[64,80].
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electrosprayed droplets, leading to their partial neutralization through collisions
AC
3.2. Control of particle size, size distribution and morphology One of the advantages of bottom-up techniques is the ability to better control the
size,
the
size
distribution,
the
morphology
and
the
crystallinity/amorphousness of the produced particles [10]. At the same time, the process conditions have to be optimized. In the case of EHDA, most of the research on the production of particles of controlled size and morphology was conducted on polymeric particles. Nevertheless, the lessons learned through 18
ACCEPTED MANUSCRIPT the years in this field could be rationally adopted to optimize the properties of pure drug nanoparticles as well [71–73]. Among the various parameters affecting particle size in EHDA, flow rate is one of the most important [64,66,84]. Gañan-Calvo et al. estimated the size of a
3 [85] 𝑄3𝜀 𝜌
1/6
0 𝑑 = α ( 𝜋4 𝜎𝛾 )
SC
RI
(3)
PT
droplet generated by EHDA using a theoretical model represented by Equation
Where α is a constant, Q is the solution flow rate, 𝜀0 is the dielectric constant in
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vacuum, 𝜌 is the solution density, 𝜎 is the solution surface tension and 𝛾 is the conductivity of the solution. It is clear from this equation that the size of the
MA
droplet is proportional to the square-root of the solution flow rate. Thus, the higher the flow rate, the larger the size of the droplet size and vice versa.
D
Several studies explained that when the solvent is sprayed at higher flow rates
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its evaporation until reaching the collector is incomplete and thus, the contact between wet and partly solvated particles results in particle fusion and
CE
consequently in larger particle size, less consistent morphology and often broader size distribution [64,85,86]. Implications of this model can be observed
AC
in several works that focused mainly on polymeric particles [78,84,87] though that may also affect the properties of pure drug particles [86,87] and inorganic particles [88]. For example, Wang et al. produced carbamazepine nanocrystals using EHDA using methanol as solvent [89]. Smaller flow rates resulted in smaller, denser and more monodisperse particles. It is important to stress that as in many bottom-up production techniques, particles were mainly amorphous. Later annealing at 90oC which is above the glass transition temperature of the 19
ACCEPTED MANUSCRIPT amorphous phase for 5 min enabled the crystallization of the drug to produce the most stable polymorph form III. It is important to stress that methanol is classified as a Class II solvent and hence is approved for the production pharmaceutical products [61,62]. Other studies that employed this technique to produce polymeric particles
PT
showed a similar trend, highlighting the relevance of the data produced with
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different materials. For example, Yao et al. fabricated poly(lactic-co-glycolic
SC
acid) particles in acetonitrile (8% w/v) and in dichloromethane (7% w/v) using a modified electrospray system and investigated the effect of flow rate, among
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other processing parameters, on the size and morphology of the particles [90]. Nine different flow rates were used 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 mL/h
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and the size and morphology of the particles were visualized by scanning electron microscopy (SEM). Higher flow rates led to larger particle size and a
D
wet product, due to insufficient time for solvent evaporation, whereas lower flow
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rates led to larger dry particles [90], in good agreement with the theoretical model [85]. A similar trend was observed by Zheng et al. that characterized the
CE
properties of NaCl crystals formed by EHDA at 150 °C from highly diluted water
AC
solutions under different flow rates ranging from 10 to 200 μL min –1 [89]. NaCl was used as a model compound. The mean size of the nanocrystals increased from 48 to 95 nm at higher flow rates and their size distribution became more polydisperse [89], as previously shown for other pure drugs and polymers. It is worth stressing that the formation of particles of an ionic inorganic material differs from that of organic ones, and thus, further studies need to be conducted to understand the effect of flow on the properties of produced particles.
20
ACCEPTED MANUSCRIPT Another key parameter is the concentration of the electrosprayed solution owing to its viscosity [91]. In general, the higher the viscosity of the liquid feed, the larger the size of the particles produced and the broader their size distribution [92–94]. In this context, Jayasinghe and Edirisinghe measured the size of electrosprayed water/glycerol mixtures and glycerol containing citric acid
PT
to control the conductivity of the solutions with different viscosities under the
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same conditions of voltage, flow rate and electrical conductivity [91]. Results
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showed that the viscosity increase led to a change in the cone and jet (Figure 7) and a significant growth in size and size distribution of the relics (Figure 8)
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[91].
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Figure 7. Cone-jet obtained from the electrohydrodynamic atomization of water:glycerol:citric acid solutions with weight ratio of (a) 23.74:71.21:5.05 ( = 1.22 g mL-1; = 603 mPa.s) and (b) 0:93.27:6.73 ( = 1.31 g mL-1; = 1338 mPa.s). Reproduced from [91] with permission of Elsevier.
Intriguingly, even though citric acid (a small organic molecule) was not used as a model compound/drug, it served as such and thus, microscopy analysis of the relics shed light into the effect of viscosity, flow rate and solution concentration on the size and the morphology of the droplets and eventually of the produced particles, where lower water content and higher viscosity resulted in larger relics [91,95,96]. These results indicated that to reduce the size of the particles, lower viscosities could be used. 21
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ACCEPTED MANUSCRIPT
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Figure 8. Optical micrographs of droplet relics obtained from the electrohydrodynamic atomization of water:glycerol:citric acid solutions with weight ratio of (a) 98.35:0:1.65 ( = 1.00 g mL-1; = 1 mPa.s), (b) 72.67:24.22:3.11 ( = 1.05 g mL-1; = 94 mPa.s), (c) 48.09:48.09:3.83 ( = 1.09 g mL-1; = 298 mPa.s), (d) 23.74:71.21:5.05 ( = 1.22 g mL-1; = 603 mPa.s) and (e) 0:93.27:6.73 ( = 1.31 g mL-1; = 1338 mPa.s). The relics of the mixtures appear much darker compared with the silicone release paper background which is also dotted in some places. Reproduced from [91] with permission of Elsevier.
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The electrical conductivity of the solution can also be adjusted to control particle
AC
size as it could be easily increased by adding small amounts of dopants (e.g., organic salts) to the solvent [63,77,79,97]. Furthermore, since the conductivity of the solution affects the stability of the cone-jet, it basically determines the range of flow rates at which monodisperse particles can be obtained and, in turn, the size of the obtained particles [80,95]. For example, a diluted solution of high electrical conductivity will be stably electrosprayed at low flow rates, leading to the generation of finer particles than highly concentrated solutions
22
ACCEPTED MANUSCRIPT with low electrical conductivity that will be stably electrosprayed at higher flow rates, leading to the generation of larger particles [80]. Particle size and morphology can also be modified by changing the operating voltage which is an important process parameter as it provides the driving force for the electrospraying [64]. In general, high applied voltages are associated
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with a decrease in particle size because the applied voltage affects the
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breakdown of the jet [88]. An increase in the applied voltage causes the jet
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current to increase, leading to more repulsion between adjacent droplets, less coalescence and the formation of particles with smaller sizes and narrower size
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distributions [66,88,95].
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The spectrum of materials that can be electrosprayed is very broad. Pareta et al. investigated the effect of applied voltage and flow rate on the operation
D
mode during EHDA in the production of bovine serum albumin (BSA)
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nanoparticles using water solutions at two different concentrations (Figure 9) [98]. BSA is not an active molecule though it is used very frequently as a model protein. In addition, it could serve as drug nanocarrier. As it can be seen, the
CE
mapping structure changes when the concentration of the solution is modified
AC
(Figure 9). The maps present a delicate interplay between the applied voltage and flow rate of the solution, which results in a limited range in which a stable cone-jet mode can be achieved to produce fine particles with desired morphology.
23
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ACCEPTED MANUSCRIPT
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Figure 9. Mapping of the electrospraying process—the influence of flow rate and applied voltage on the operating modes of electrospraying a bovine serum albumin solution: (a) 5 mg/mL and (b) 20 mg/mL. Reproduced from [98] with permission of Springer Nature.
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An important aspect when working with sensitive molecules such as proteins that could be denatured upon the application of charge, heat or the use of
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organic solvents, is the assessment of its biological activity after processing. The inner diameter of the nozzle or the gauge of the needle can also affect the
D
size and size distribution of the dry particles as it determines the diameter of
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the base of the Taylor cone, which in turn influences the size and the distribution of the generated droplets [64,99]. Arya et al. investigated the ability to control
CE
the size of chitosan particles by changing the needle diameter in the range of 20-26G (0.5-0.9 mm) and observed that the particles obtained at large needle
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gauges (e.g., small inner diameters) were finer in size and less polydisperse compared to particles obtained at small needle gauges (and larger inner diameters) [100]. EHDA using small needle gauges resulted in either larger particle size or sputtering of the polymer solution without forming any particles at all, due to the increased effective flow rate of the solution at larger inner needle diameter [100]. This work was carried out on the production of polymeric
24
ACCEPTED MANUSCRIPT particles. At the same time, it is another example of the great flexibility to adjust the process parameters and to tailor the properties of the product. Another parameter that is relatively easy to control is the distance between the tip of the nozzle and the collector [66,84,101]. In general, the shorter the distance, the stronger the electric field and the smaller the particles obtained
PT
[64]. However, when the distance is too small, particles usually undergo
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aggregation due to insufficient time for solvent evaporation and particle
SC
consolidation. On the other hand, when the distance is too long, higher applied voltages are required to compensate for the reduced electrical field strength,
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resulting in reduced particle deposition and yield [64,66]. Other parameters such as solution density, surface tension and dielectric constant can only be
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varied within narrow limits, and thus they are less relevant to tailor particle size, size distribution and morphology [80]. It is important to stress that although most
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of the systematic research on the effect of EHDA process parameters on the
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properties of particles was focused on polymeric particles, the general rules can also be applied in the case of pure drug particles, as discussed in the following
CE
section. The key operational parameters affecting the size of the droplets and
AC
thus, of the produced particles by EHDA are summarized in Table 2.
25
ACCEPTED MANUSCRIPT Table 2. Operational parameters affecting the size of particles produced by electrospraying or EHDA. Parameters that upon increase Parameters that upon increase lead to a decrease of the particle lead to an increase of the particle size size Nozzle diameter
Solvent conductivity
Molecular weight*
Solvent boiling point
Liquid feed concentration
Surface tension of the fluid feed
Liquid feed viscosity
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Distance from the nozzle to the Flow rate collector
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Voltage
pure
drug particles by electrohydrodynamic
MA
3.3. Production of
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*Valid for polymers and macromolecules. The effect of molecular weight of small molecules on particle size was not investigated.
atomization
D
EHDA is convenient for the synthesis of pure drug particles in general and
represents
a
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nanocrystals, microcrystals and co-crystals in particular [48,65]. The technology new
versatile
platform
for
the
fabrication
of
both
CE
crystalline/amorphous particles with increased stability and improved physiochemical properties [48,70]. The high-energy vibration of the Taylor
AC
cone and the relatively fast evaporation of the solvent during the electrospraying process (most of the solvent has to be evaporated before the droplet touches the collector) are believed to be beneficial in the synthesis of pure drug crystals and co-crystals owing to the increased rate of crystal nucleation and growth [48]. At the same time, they can also contribute to the generation of APIs in an amorphous state as the molecules are instantly “frozen” and undergo rapid solidification which precludes nucleation and
26
ACCEPTED MANUSCRIPT crystallization [64,102]. In addition, solvent evaporation is very efficient, giving place to dry powders with low amounts of residual solvents and with higher physicochemical stability than nanosuspensions [64–66,78]. Regardless of these beneficial features, until today, this technology has been scarcely used in the production of pure drug particles. As exemplified above, Wang et al. used
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electrospraying followed by annealing at high temperatures to produce
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nanocrystals of the hydrophobic anticonvulsant drug carbamazepine [88].
SC
Solutions of various concentrations in methanol were electrosprayed to obtain carbamazepine particles with diameters ranging from 320 nm to several
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microns and the aqueous solubility increased by 26.4% with respect to the bulk saturation solubility (from 0.11 to 0.14 mg/mL). The average particle diameter
MA
increased with flow rate, in good agreement with the theoretical model developed by Gañan-Calvo [85] and the initial particle diameter increased with
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the drug concentration in line with the trend observed in polymeric and inorganic
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particles. As the flow rate increased from 0.003 to 0.02 mL/h, the average particle diameter increased from 320 nm to 1.5 μm at a concentration of 0.5%
CE
w/v, from 383 nm to 1.8 μm at a concentration of 1.0% w/v, from 475 nm to 1.7 μm at a concentration of 3.0% w/v and from 617 nm to 1.8 μm at a concentration
AC
of 5.0% w/v (Figure 10). Annealing of the electrosprayed particles at 90oC (5 min) accelerated the crystallization process, increasing the drug crystallinity, as confirmed by X-ray diffraction (XRD) and SEM [88].
27
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ACCEPTED MANUSCRIPT
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Figure 10. Scanning electron microscopy images of carbamazepine nanoparticles by electrospray at different concentrations and different flow rates. (a) Carbamazepine concentration (Cw) = 0.5wt %, Q = 0.003 mL/min; (b) Cw = 0.5wt %, Q = 0.005 mL/min; (c) Cw = 0.5wt %, Q = 0.01 mL/min; (d) Cw = 1wt %, Q = 0.003 mL/min; (e) Cw = 3wt %, Q = 0.005 mL/ min; and (f) Cw = 5wt %, Q = 0.02 mL/min. Reproduced from [88] with permission of Elsevier.
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Li et al. produced pure drug microparticles (~6 μm) of aspirin by EHDA [87]. The flow rate was varied from 10-6 to 10-17 m3s-1 and optimized to 10-10 m3s-1 in an attempt to obtain the finest droplets, without deviating from stable cone jetmode [87]. Again, particle sizes were in good agreement with the Gañan-Calvo theoretical model [85]. Radacsi et al. and Ambrus et al. investigated the production of pure nanocrystals of the non-steroidal anti-inflammatory drug niflumic acid in the size range of 200-800 nm by electrospray crystallization [103,104]. The relationship between drug concentration and crystal size was 28
ACCEPTED MANUSCRIPT clearly observed: crystal size increased with at higher solution concentration (Figure 11) [103]. Moreover, the effect of the addition of excipients (D-mannitol and poloxamer 188) on the dissolution rate was assessed for both raw and nanonized drug. A significantly higher dissolution rate was observed after drug nanonization in the presence of the excipients, which prevented the process of
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SC
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drug agglomeration and led to improved drug absorption [103].
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Figure 11. The relationship between the crystal size and shape and used solution concentration when niflumic acid crystals are produced in electrospray crystallization. The crystal size increases with the increasing solution concentration, and the crystal shape becomes from somewhat spherical to needle-like. Reproduced with from [103] with permission of the American Chemical Society.
In addition, the electrospraying method was compared to conventional antisolvent crystallization (nanoprecipitation) and solvent evaporation techniques [104]. EHDA produced a dry powder with no agglomeration and substantially smaller particles (mean size = 500 ± 200 nm), whereas nanoprecipitation and solvent evaporation resulted in particles sizes in the range of 7-46 m [104].
29
ACCEPTED MANUSCRIPT These findings can be explained by the increased supersaturation achieved using EHDA which is less substantial in the other two methods (Figure 12)
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[104].
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Figure 12. Scanning electron microscopy images of niflumic acid. (A) conventional (unprocessed) drug, (B) particles produced by electrospray crystallization, (C) particles produced by anti-solvent crystallization and (D) particles produced by solvent evaporation. Reproduced with from [104] with permission of Elsevier.
Moreover, in EHDA, the crystallization process begins in the small and confined volume offered by the droplets, whereas in the other two techniques the crystallization volume is considerably larger, resulting in the formation of larger particles. Powder X-ray diffraction (PXRD) measurements of the immediately produced niflumic acid crystals showed that the products obtained by evaporative and anti-solvent crystallization were highly crystalline immediately 30
ACCEPTED MANUSCRIPT after production and remained crystalline after storage (two weeks later). On the other hand, the electrosprayed product was partly amorphous (81% crystalline) after production, due to the rapid evaporation of the solvent during electrospraying which prevented the complete crystallization of the drug. It is important to stress that crystallinity increased during storage (two weeks) from
PT
81% to 88%, according to results obtained by differential scanning calorimetry
RI
(DSC) [104]. These results probably stemmed from the fact that the glass
SC
transition temperature of the amorphous phase was below the storage temperature and thus, crystallinity gradually grew. One question that remains
NU
unanswered in this work is whether longer storage further increased the crystallinity or not. Changes in the degree of crystallinity of the drug and other
MA
transitions (e.g., polymorphs) during storage could have a strong impact on the dissolution rate and, eventually, on the oral bioavailability. Thus, from a
D
translational point of view, they represent a serious product drawback. In this
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context, further studies should be conducted to ensure that the drug remains stable and the pharmacokinetics predictable during the shelf life.
CE
Other research groups investigated the formation of pure drug microcrystals,
AC
rather than of nanocrystals. It is worth mentioning that while the adjustment of the particle size is usually a time-consuming process, the production of nanoparticles is often more difficult than of microparticles. For example, Ijsebaert et al. prepared microparticles of the steroidal anti-inflammatory drug beclomethasone
dipropionate
and
the
antimicrobial
agent
methyl
parahydroxybenzoate used as preservative in pharmaceutical formulations for inhalation using ethanol as solvent [82]. The droplet size and consequently the microparticle diameter were controlled by optimizing the flow rate of the liquid 31
ACCEPTED MANUSCRIPT feed and the drug concentration in the electrosprayed solution. Particles showed sizes between 1.58 and 4.55 μm which fitted very well the aerodynamic diameter required to ensure efficient deposition in the lower airways (1-5 m) [28,105]; smaller particles are expelled, and their efficacy reduced. To prevent Coloumbic fission and a decrease of the particle size which would have been
PT
detrimental for this administration route, a corona discharge system was used.
RI
An increase in the flow rate and drug concentration led to an increase of the
SC
size distribution. The reason for this performance probably was stronger instabilities in the jet formed.
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Nyström et al. used EHDA to produce pure drug microparticles of three poorly water-soluble drugs: indomethacin, piroxicam and budesonide [106]. An
MA
innovative aspect of this work was the use of low pressure to favor the elimination of solvent residues [81,106]. Indomethacin was dissolved in ethanol
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(10 or 15 mg/mL), while piroxicam and budesonide were dissolved in chloroform (15 mg/mL) at room temperature [106]. As previously explained, ethanol and chloroform belong to Class III and II solvents, respectively.
CE
Electrospraying was carried out using stable cone-jet mode in both atmospheric
AC
and reduced pressure and using a corona discharge. Atomization voltages ranged between 2.1-3.6 kV and the obtained particles sizes ranged from 1.75.5 μm (Figure 13) [106]. In addition, they introduced a simple method to estimate the size of the particles based on the size of the droplets. However, based on the published data, it is unclear whether this method could be used to produce particles in the submicron and nanometer-size range or not.
32
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ACCEPTED MANUSCRIPT
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Figure 13. Characterization of produced by electrohydrodynamic atomization. (A) Scanning electron microscopy images of the electrosprayed indomethacin (on the left), piroxicam (in the middle) and budesonide (on the right) particles. Below are magnifications of the corresponding particles and (B) Particle size distributions of the electrosprayed samples. The amount of analysed particles and the mean particle diameter is mentioned for each sample. Reproduced with from [106] with permission of Elsevier.
Moreover, drugs were converted into more soluble amorphous forms, most probably due to the fast solidification under both atmospheric and reduced pressure that minimized the crystallization process [106]. The supplied indomethacin (γ-form) and piroxicam (I-form) were originally crystalline (as confirmed by PXRD diffraction results). Budesonide was also originally crystalline. Samples of piroxicam and budesonide which were dissolved in
33
ACCEPTED MANUSCRIPT chloroform and electrosprayed under reduced pressure were significantly more amorphous than the ones fabricated in atmospheric pressure. On the contrary, the indomethacin sample, which was dissolved in ethanol, showed higher crystallinity under reduced pressure compared to atmospheric pressure. From these results, it seems that the reduction of the pressure influenced the
PT
amorphousness extent only if the solution was volatile enough, thus the
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observed differences in the degree of crystallinity under reduced and
SC
atmospheric pressure stemmed from the relative evaporation rate of the solvents used (as chloroform is more volatile than to ethanol) [106]. The drug
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amorphousness was suggested by the spherical morphology of the particles
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and confirmed by PXRD (Figure 14) and DSC.
Figure 14. The diffractograms of electrosprayed budesonide: (1) electrosprayed in 0.5 atm and (2) electrosprayed in 1.0 atm. (3) and (4) represent crystalline references (measured with corresponding sample holders), respectively. The loss of crystallinity after the processing (1 and 2) is clearly observed. Reproduced with from [106] with permission of Elsevier.
34
ACCEPTED MANUSCRIPT This is a noteworthy feature of the method that enables the adjustment of the conditions to amorphisize pure drugs during the particle size reduction and thus, to substantially increase the dissolution rate and the saturation solubility with respect to the crystalline counterparts. Standard EHDA can also be sophisticated by the incorporation of additional processing features such as the
PT
use of concentric needles [66]. In this context, Scholten et al. fabricated
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carbamazepine submicron and microparticles of different shapes and sizes (e.g., spheres, q-tips, elongated spheres and tear-shaped) [107]. Sizes ranged
SC
from 500 nm to 6.5 μm, depending on the concentration of the solution, which
AC
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ranged from 1 to 12 mg/mL (Figure 15) [107].
Figure 15. Scanning electron microscopy (SEM) images of electrosprayed carbamazepine particles for solutions of various concentrations. Reproduced from [107] with permission of the American Chemical Society. They also studied how by changing the drug concentration in the 1,2dichloromethane solution, the interplay between jet formation, droplet breakup,
35
ACCEPTED MANUSCRIPT evaporation and solidification could be manipulated to control the size and shape of the obtained particles [107]. Thus, they produced spheres, q-tips, elongated spheres and tear-shaped particles. In general, the higher the drug concentration in solution, the less spherical and the larger the particles obtained.
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Overall, EHDA is considered a promising technology for the fabrication of pure
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drug particles. EHDA is a one-step and simple method to carry out. At the same
SC
time, the optimization of product properties such as size, size distribution, morphology and amorphous/crystalline nature are challenging. For this, a deep
NU
understanding of the effect of the features of the liquid feed (e.g., concentration, solvent, viscosity, conductivity, and boiling point) and the process parameters
MA
(e.g., temperature, pressure, nozzle diameter, and distance to the collector) is required. The knowledge at the interface of EHDA and the production of pure
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systematic research.
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drug particles still shows significant gaps that could only be closed by a more
Scalability is a critical aspect to ensure the translation of these production
CE
technologies to the pharmaceutical industry. Most of the academic research is
AC
conducted with equipment that displays relatively small flow rates [63]. To increase production capacity, the use of several nozzles or multiple spraying equipment at the same time has been proposed, making the process more expensive and difficult to maintain [63]. To face this challenge, several companies have developed equipment that is currently commercially available. For example, BioInicia S.L. (Valencia, Spain) developed the Fluidnatek® technology and together with nanoScience Instruments (Phoenix, AZ) offer a broad spectrum of instruments for the production of fibers and particles by 36
ACCEPTED MANUSCRIPT electrospinning and EHDA, respectively, at laboratory, pilot, pre-production and industrial scales. For example, the model Fluidnatek® LE 500 enables maximum flow rates of 400 mL/h, under a continuous regime [108]. These flow rates certainly enable the industrial production of pure drug nanoparticles in reasonable amounts, especially for very potent drugs. In addition, the model
PT
Fluidnatek® LE 1000 enables a much higher flow rate of up to ~4.8 L/h.
RI
Moreover, in other industries, several electrospraying instruments are used in
SC
parallel. This approach could be also extended to the pharmaceutical industry. At the same time, it is important to emphasize that the drug concentration in the
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solution is another key parameter that determines the mass of nanoparticles produced per time unit. Thus, optimization is required for each single API.
MA
4. Spray-drying 4.1. The method
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Spray-drying is a continuous, cost-effective and scalable process to produce dry powders from a fluid feed by atomization through an atomizer into a hot drying gas medium [109–111]. It is widely used in different industries including
CE
food, cosmetics, materials and pharmaceuticals [109,111]. The first patent
AC
concerning this technology can be tracked back to the early 1870s [110]. Thereafter, spray-drying underwent constant evolvement until the more advanced equipment and processes known today [110–112]. In both EHDA and spray-drying the final drying step, which is required in other common techniques (e.g., nanoprecipitation, emulsion/solvent evaporation), is not necessary, making the whole process cheaper and shorter [111]. Moreover, the use of surfactants and stabilizers, which are used to prevent particle agglomeration during particle production by other bottom-up techniques can be 37
ACCEPTED MANUSCRIPT prevented, usually resulting in higher yield. Furthermore, spray-drying fits well the drying of a variety of compounds including heat-sensitive products, due to fast drying and short exposure time to heat during the process, making it an appealing technology for pharmaceutical applications [63,111,113,114]. A typical spray-drying process consists of four fundamental steps that include
PT
atomization of the liquid feed, drying of the liquid feed through the drying gas,
RI
dry particle formation and subsequently particle separation and collection
SC
[111,115]. In this technique, the fluid is fed into the drying chamber by a peristaltic pump through an atomizer (rotary atomizer) or a nozzle (pressure
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nozzle or a two-fluid nozzle) [63,111,116,117]. Atomization then occurs by either centrifugal forces, pressure or kinetic energy, based on the type of
MA
atomizer or nozzle that is being used [111,117,118]. The feed breaks up into fine droplets due to the high air speed that is generated within the
D
atomizer/nozzle. The generated small droplets are then subjected to fast
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solvent evaporation, where they are dried and separated from the drying gas by a cyclone, a filter bag or an electric field precipitator that deposes them in a
CE
collector found at the bottom of the device [63,111,116]. Solvent evaporation can be performed via heat treatment using a heated carrier gas, a hot furnace
AC
or a reactor or via solvent-diffusion using a diffusion dryer and the heating configuration is selected based on the thermal and chemical properties of the feed [117,119–121]. The fluid feeds that can be converted into solid powder using spray-drying are solutions, suspensions, emulsions, pastes, slurries or melts though some limitations apply depending on the instrument used [111,118]; Since conventional spray-dryers display limitations such as relatively low yields on a laboratory scale (20-70%), high sample volumes and large
38
ACCEPTED MANUSCRIPT particle size, Büchi (Labotechnik AG, Switzerland) has introduced the Nano Spray Dryer B-90 for the controlled production of fine particles (300 nm-5 μm) with higher particle recovery rates [111,122,123]. This instrument utilizes vibration mesh spray technology, which allows the generation of tiny droplets and the production of powders in the submicron size range with narrower size
PT
distributions [111,124]. A scheme of the principle used in this instrument to
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produce particles is presented in Figure 16 [125].
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Principle of mesh vibration
AC
Figure 16. Scheme of the Nano Spray Dryer B-90 developed by Büchi and the functional principle of mesh vibration occurring at the piezoelectric driven spray head. Reproduced from [125] with permission of Elsevier.
The Nano Spray Dryer B-90 is designed to produce the particle during spraying and thus, the drying of preformed particles is limited by their size. In other words, if the preformed particles are sufficiently small to go through the mesh without significant impact (usually it is assumed that at least 10 times smaller than the mesh), the use of the spray-dryer can be extended to the drying of 39
ACCEPTED MANUSCRIPT nanoparticles produced by other top-down or bottom methods. The obtained solid products are considered more physically and chemically stable compared to the liquid formulations because they agglomerate less and degradation processes associated with the presence of solvents such as water are minimized [111]. More recently, the same company upgraded the system to the
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Nano Spray Dryer B-90 HP model that demonstrates better spray performance,
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especially of aqueous feeds. For example, Nano Spray Dryer B-90 results in
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aqueous flow rates of ˂10 mL/h, while the high performance version reaches 50-70 mL/h. In any event, it is important to stress that as opposed to EHDA
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where the drying process takes place usually at room temperature, in spraydrying, heating might have a detrimental effect on the stability of thermo-
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sensitive drugs (e.g., proteins). Thus, the stability of the product after spraydrying has to be validated.
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The size and morphology of the dried particles can be tailored by controlling the
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various parameters involved in the process, such as the type of atomization that is being used, the drying temperature, the flow rate and concentration of the
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feed, the air-to-feed ratio and the applied voltage and pressure [63]. In general,
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there are three different configuration modes that can be operated in the spraydryer and they are open cycle, closed cycle and semi-closed cycle [126]. The open cycle mode is applied to spray aqueous feeds. It uses air drawn from atmosphere as a drying gas that is not re-circulated during the process and is considered more stable and cost-effective compared to the closed cycle mode [111,127]. Close cycle mode is used to handle flammable solvents and/or toxic and oxygen sensitive products [126]. It uses an inert gas, such as nitrogen, that is recycled and reused in the drying chamber. Semi-closed cycle mode can be 40
ACCEPTED MANUSCRIPT either partial recycle mode (recycling of up to 60% of the exhaust air) or selfintertising mode. As to the flow pattern of the drying gas with respect to the direction of the liquid atomization can be either co-current (same direction), counter-current (opposite direction) or mixed-flow (Figure 17) [108]. In the cocurrent flow-pattern, the droplets of the feed come into contact with the coolest
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air, resulting in an optimal solvent evaporation for the spray-drying of heat-
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sensitive materials (e.g., peptides, proteins, enzymes). Whereas in the counter-
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current flow pattern the dry product is in contact with the hottest air, resulting in an increased powder flowability and median particle size for non-heat-sensitive
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materials [111]. There are also intermediate designs of mixed flow spray-dryers that combine co-current and counter-current flow patterns that could be useful
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when drying coarse droplets that require longer travel paths in the chamber to
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complete the removal of the solvent [111,118].
Figure 17. Airflow patterns in the spray-drying process. Reproduced from [108] with permission of Elsevier.
4.2. Control of particle size, size distribution and morphology There are several factors that can be tuned to better control particle size, size distribution and morphology in spray-drying. Among the process parameters, 41
ACCEPTED MANUSCRIPT liquid feed properties and system configuration are the most relevant [111,117]. Atomization, which is the first step in the process of spray-drying, has a crucial role in determining particle size [116,117]. In this step, the initial feed (called the precursor) is fed into the atomizer, converted into small droplets, which are then transformed into dry particles. Hence, the size of the droplets formed
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during atomization determines the size of the resultant dry particles [63,117].
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The size of the droplets can be affected by the physical and chemical properties
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of the feed, such as concentration, viscosity, surface tension, and amount of non-volatile material [63,128]. For example, a highly concentrated (and often
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more viscous) feed usually leads to an increase in particle size [111,124,125,128]. Moreover, the more non-volatile material the droplet
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contains, the larger the particle size will be and vice versa [63]. Droplet size and size distribution can also be affected by the settings of the
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atomizer (pressure and nozzle/mesh diameter) and the type of the applied
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atomization, which should therefore be carefully selected [117,125,129]. In general, the smaller the nozzle diameter the higher the kinetic forces generated
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at its base, and the smaller the size of the particles [111]. Baba et al. showed
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that the average particle size tends to decrease with decreasing mesh aperture size due to the generation of smaller droplets when using smaller mesh apertures [14]. Lee et al. investigated the production of BSA nanoparticles employing the Nano Spray Dryer B-90 and demonstrated that the particle size is predominantly influenced by the spray mesh size – the larger the mesh aperture size, the larger the size of the produced nanoparticles (Figure 18) [125]. As mentioned above, BSA is not an active molecule and it is used as a model protein. In some other applications, it has been used as drug carrier. In 42
ACCEPTED MANUSCRIPT any event, the sensitivity of proteins to pH, ionic strength and temperature varies very substantially among types and the biological properties could be
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altered.
Figure 18. Field emission scanning electron microscope images of bovine serum albumin nanoparticles produced using Nano Spray Dryer B-90 with a mesh aperture size of (a) 4.0 μm, (b) 5.5 μm and (c) 7.0 μm and showing the effect of spray mesh size on particle size. Reproduced from [125] with permission of Elsevier.
43
ACCEPTED MANUSCRIPT Thus, the extension of this technology to other polypeptides and proteins is not straightforward and their integrity and function has to be assayed after the spray-drying. The diameter of the generated droplet (𝐷𝑑 ), based on the previously discussed
expressed using Equation 4 [117,130]
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𝐷𝑑 = 𝐾𝑓 ∙ 𝑄 𝑛 [𝜌𝑎 ∙ 𝜎 𝑏 ∙ 𝜇 𝑐 ] (4)
PT
considerations of atomization settings and feed properties, can be empirically
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Where Kf, Q and n are the excitation equipment constant (centrifugal force,
NU
frequency, pressure, and carrier gas velocity which depend on the selected atomizer type), the precursor volumetric flow rate, and the power constant of
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volumetric flow rate, respectively. The symbols a, b and c are the power constants of the physical properties of the precursor: its density, surface
D
tension, and viscosity, respectively. Table 3 presents the power constants for
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the empirical atomization model, which implies that in general, the droplet size generated by the atomizer is mostly proportional to the flow rate of the liquid
CE
and the physical properties of the feed [117]. Other process parameters, such as the drying temperature, drying rate, flow rate and air-to-feed ratio also affect
AC
droplet size and morphology and need to be carefully considered [63,111,118,125,128,144–147].
After the atomization stage, the generated
droplets are dried by solvent evaporation and transformed into dry particles. It has been observed that the faster the evaporation rate of the solvent during this stage, the shorter the shrinkage time of the droplets and the more porous the morphology of the obtained particles [111,117,144].
44
ACCEPTED MANUSCRIPT Table 3. Power constants of some empirical atomizer models. Reproduced from [117] with permission of Elsevier. Power parameters
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a b c −0.37 0.33 – [131] −0.40 0.45 0.80 [132] – 2.40 −0.59 [133] – 1.00 0.50 [134] 0.30 0.30 0.30 [135] −0.30 0.30 0.10 [136] 0.41 −0.88 −1.01 [137] 0.93 1.22 0.22 [138] 0.19 0.95 1.34 [139] 0.34 1.00 0.50 [140] 0.80 0.95 0.82 [142] −0.67 0.33 [142] −0.27 0.11 0.17 [143]
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n −1.93 0.80 0.10 Spinning 0.50 discs 0.50 0.40 0.66 1.55 1.01 0.60 1.24 Ultrasonic – nebulizer 0.21 Air-shear nozzles
Refs.
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Atomizer types
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Porosity may have a dramatic impact of surface area and thus, it could certainly affect the drug particle dissolution rate [148]. However, a systematic study of
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the effect of the production conditions on the porosity of pure drug particles is
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missing. This property has been studied more systematically in polymeric particles that can form pores depending on the evaporation rate of the solvent.
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Finally, the dry particles are separated from the drying gas, usually by a cyclone that deposes them in a glass collector. Studies showed that the geometry of the
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cyclone is important when collecting particles of fine size. In general, the smaller the radii of the cyclone, the higher the generated resistance to the airflow and the more effective the process of particle recovery resulting in the collection of finer particles and an increased yield [63,149,150]. Table 4 lists the key parameters controlling the size of particles produced by spray-drying.
45
ACCEPTED MANUSCRIPT Table 4. Parameters affecting the size of particles produced by spray-drying. Parameters that upon increase Parameters that upon increase lead to a decrease of the particle lead to an increase of the particle size size Nozzle diameter
Atomization air flow
Liquid feed concentration
Atomization pressure
Liquid feed viscosity
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Feed flow rate*
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Solvent boiling point
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Gas inlet temperature Mesh size**
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*Increased flow rate is expected to decrease mass transfer rate during spray-drying and decrease the size of the droplets and the particles though in some cases, droplet collision and coalescence can result in the opposite phenomenon.
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**Relevant in spray-dryers based on mesh vibration such as the Nano Spray Dryer B-90 and its HP version.
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4.3. Production of pure drug particles by spray-drying
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Spray-drying has a great inherent potential to produce pure drug particles since it is a relatively fast, easy and reproducible method. It does not require a final
CE
drying step and it can offer general yield that is close to 100% at industrial scale [111,151]. While conventional spray-dryers are unable to produce drug particles
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smaller than 2 µm [152,153], the Nano Spray Dryer B-90 successfully manages to produce nanoparticles of pure drugs with or without combining them with polymers. In a study conducted by Baba et al., the preparation of pure nanocrystals of the steroidal drugs fluorometholone and dexamethasone in powder form was successfully carried out using the Nano Spray Dryer B-90 [14]. For this, both drugs were dissolved in ethanol. This solvent is classified as Class III and displays a relatively low boiling point, enabling the production of
46
ACCEPTED MANUSCRIPT the nanoparticles under drug-friendly temperature conditions. Nanocrystals
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SC
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showed sizes in the submicron-size range (Figure 19) [14].
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Figure 19. Scanning electron microscopy images of fluorometholone nanocrystals (upper) and dexamethasone nanocrystals (lower). The nanocrystals were prepared in the Nano Spray Dryer B-90 using mesh aperture sizes of (a) 4.0 µm, (b) 5.5 µm, and (c) 7.0 µm. Reproduced from [14].
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The crystalline structure of all the nanoparticles, regardless of the mesh size, was confirmed by powder XRD pattern analysis that showed no differences [14]. At the same time, a comparison with the respective unprocessed
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counterpart would have been of value to understand the effect of spray-drying
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nanonization on the crystalline structure. This comparison was not assessed. The idea behind the study was to improve the treatment of ophthalmic disorders by reducing the size of the particles to enhance their ocular penetration. The relationship between mesh aperture size and drug particle size was investigated (mesh aperture sizes of 4.0, 5.5, and 7.0 μm were used) [14]. Fluorometholone nanocrystals were formed by dissolving 1 mg/mL of drug in ethanol and spray-drying it to obtain nanocrystals with an average particle size and size distribution of 620 ± 268, 795 ± 285, and 856 ± 344 nm for mesh 47
ACCEPTED MANUSCRIPT aperture sizes of 4.0, 5.5, and 7.0 µm, respectively. Dexamethasone nanocrystals were formed by dissolving 10 mg/mL of drug in ethanol and spraydrying it to obtain nanocrystals with an average particle size of 833 ± 402, 1118 ± 573, and 1344 ± 857 nm for mesh aperture sizes of 4.0, 5.5, and 7.0 µm, respectively [14]. These results pointed out the influence of the drug properties
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on the process and the production rate. In another study conducted by the same
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researchers, nanocrystals of two calpain inhibitors, calpain inhibitor I and SNJ1945, as potential candidates for curing apoptosis-mediated intractable
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diseases such as Alzheimer’s and Parkinson’s disease, were produced using
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the same instrument [152]. Calpain inhibitor I nanocrystals were formed by dissolving 0.5 mg/mL of drug in ethanol and spray-drying it to obtain average
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particle sizes and size distributions of 378 ± 132, 527 ± 284, and 813 ± 484 nm against mesh aperture sizes of 4.0, 5.5, and 7.0 μm, respectively. Spray-drying
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of 0.5 mg/mL SNJ-1945 in ethanol resulted in nanocrystals with average size
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and size distribution of 418 ± 138, 605 ± 369, and 845 ± 567 nm with mesh aperture sizes of 4.0, 5.5, and 7.0 μm, respectively. The spherical morphology
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of both compounds was visualized by SEM (Figure 20) [152].
48
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ACCEPTED MANUSCRIPT
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Figure 20. SEM images of calpain inhibitor I (left) and SNJ-1945 (right) nanocrystals. The nanocrystals were prepared in the Nano Spray Dryer B-90 using mesh aperture sizes of 4.0 (a), 5.5 (b) and 7.0 μm (c). Reproduced from [152] with permission of Springer.
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In both studies, particle size increased significantly with increasing concentration of the drug solutions and the size distribution became narrower
AC
with decreasing mesh aperture size [14,152]. The effect of the inlet temperature and gas flow rate were also investigated in the latter study, however they did not significantly affect particle size [152]. Another work conducted by Martena et al. demonstrated the reproducible production of pure nicergoline nanoparticles, an ergot derivative used to treat senile dementia and disorders of vascular origin, using Nano Spray Dryer B-90 [154]. In this case, spherical and amorphous nanoparticles with a mean particle diameter of 790 nm were
49
ACCEPTED MANUSCRIPT produced and used to prepare a nanosuspension with high physicochemical stability and increased dissolution rate in vitro [154]. Drug nanocrystals were obtained by spraying a solution of 25 mg/mL of nicergoline in a mixture of ethanol:ultrapure water in a ratio of 1:3 using a mesh aperture size of 7.0 μm, an inlet temperature of 50°C and a feeding rate of 90 L/min [154]. Spray-drying
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not only produced nanoparticles but also amorphisized the drug (Figure 21)
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D
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SC
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[154].
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Figure 21. Powder X-ray diffraction pattern of (a) native crystalline nicergoline and (b) nicergoline nanoparticles. Reproduced from [154] with permission of Springer Nature.
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In addition, the solubility profile in different media was measured (Figure 22) [154]. Amorphous nanoparticles showed a time-dependent behavior with a fast solubility increase and reached a maximum within a few minutes that was considered the maximum solubility at that specific time point. Then, the solubility decreased until reaching a lower value that remained constant for at least 120 min. Unprocessed drug did not show this profile and reached a lower value of maximum solubility that remained constant afterwards.
50
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ACCEPTED MANUSCRIPT
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Figure 22. Experimental solubility profiles of nicergoline pristine (unprocessed) particles (square symbol) and nanoparticles (round symbol) (batch A) in distilled water, HCl 0.1 N and phosphate buffer pH 8.0 at 10, 20, 30, and 37 °C. Reproduced from [154] with permission of Springer Nature.
Mizoe et al. produced pure drug nanocrystals of the hydrophobic drug pranlukat
AC
hemihydrate used to treat chronic bronchial asthma and encapsulated it within mannitol microparticles by spray-drying for improved pulmonary delivery [27]. Particle mean diameter was 2 μm, which is within the respirable range (1-5 μm). The mannitol microparticles dissolve rapidly on the surface of the pulmonary epithelium, leaving a suspension of pure drug nanocrystals of the insoluble drug (with diameter ranging from 100 to 430 nm) that can slowly dissolve and release the drug for local or systemic action [27]. Li et al. used the Nano Spray Dryer B-90 in their study to explore the production of nanoparticles of NaCl and 51
ACCEPTED MANUSCRIPT furosemide [124]. The former was used as a model of inorganic ionic hydrophilic compound, while the latter is a small poorly water-soluble molecule used as a diuretic drug to treat congestive heart failure and edema. NaCl nanocrystals were formulated from aqueous solutions and the obtained particles sizes ranged from 517 ± 182 nm (yield of 81.1%) to 993 ± 256 nm (yield of 85.4%)
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for salt concentrations of 0.1% w/w and 1% w/w, respectively. Furosemide was
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spray-dried at a concentration of 1.25% w/w in acetone and the obtained
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particle size was 1245 ± 482 nm with a yield of 69.3% [124]. These production yields are not optimal yet and could be improved probably by producing larger
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amounts. On the other hand, the electrostatic collector of this instruments has to be cleaned to enable the further deposition of the product. In a work by Chan
line
antibiotics
for
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et al., the production of an excipient-free micron-sized dry powder of three firstthe
treatment
of
tuberculosis
D
(pyrazinamide:rifampicin:isoniazid in a ratio of 5:2:1 w/w/w) was demonstrated
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using Mini Spray Dryer B-290 (Büchi) operated in a closed loop and connected in series with a B-296 dehumidifier and B-295 inert-loop (Büchi). The size of the
CE
particles was in the 0.2-5.0 μm range, which is in the suitable range for
AC
pulmonary delivery [155]. Another feasible approach would be the pre-formation of pure drug nanoparticles and their later spray-dying. For example, Swai et al. produced nanoparticles of the antiretroviral drug efavirenz by a modified doubleemulsion/spray-drying method [156]. A double-emulsion was fed into the Mini Spray Dryer B-290 and spray-dried at 96°C, with an atomizing pressure of 6 and 7 bars. The size of the nanoparticles obtained ranged from 200 to 250 nm
52
ACCEPTED MANUSCRIPT with a narrow size distribution. Moreover, the drug underwent amorphization during the spray-drying process as indicated by PXRD results [156]. In some cases, the combination of several technologies was also reported. For example, Monterrubio et al. combined simultaneous microcrystal spraying and polymer electrospinning [157]. The system consisted of matrices made of
PT
poly(lactic acid) electrospun polymer nanofibers loaded with sub-micron to
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micron crystals of the anti-cancer drug SN-38 (10-hydroxy-campthothecin) for
before spraying was 1.7 ± 0.34 μm [157].
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local release in pediatric solid tumors. The size of the SN-38 microcrystals
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Overall, spray-drying is a very flexible technology that upon optimization and
MA
validation of the process could eventually offer cost-effectiveness and reproducibility. However, at this stage, published data are limited and any
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conclusion on its potential to play a key role in the production of pure drug
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microparticles and nanoparticles in the pharmaceutical industry in the near future seems to be unfunded. As this technology keeps on evolving and our understanding of the impact that the critical parameters have on the properties
CE
and the performance of products continues to grow, the chances to realize its
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potential increase. Moreover, scalable production under an industrial setting is a bottleneck towards bench-to-bedside translation of pure drug nanoparticles of any kind produced by bottom-up techniques and it relies on the availability of commercial industrial equipment that can be operated under the strict good manufacturing practices of the pharmaceutical industry. In the case of spraydrying, this equipment is not available yet. 5. Electrohydrodynamic atomization and spray-drying to produce drug co-crystals 53
ACCEPTED MANUSCRIPT Production of drug co-crystals/drug-drug co-crystals has emerged as an approach to improve physicochemical properties of drugs such as saturation solubility, dissolution rate and chemical stability in biological media, while preserving pharmacological activity. Better dissolution profiles usually result in higher oral bioavailability. In addition, the mechanical properties of the solid can
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be modified to comply with a variety of formulation processes (e.g., tableting).
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Since traditional co-crystallization methods (e.g., slurry crystallization, ball
SC
milling, liquid assisted grinding and solvent evaporation) face significant challenges during scale-up, alternative methods are continuously searched for
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[158,159]. Both EHDA and spray-drying, thoroughly discussed in this review, are considered attractive methods for the fabrication of drug co-crystals. In most
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of the works in which drug co-crystallization was performed by these two methods, the size of the obtained co-crystals is in the micrometer rather than
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the nanometer range. However, these works represent a solid background for
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the design of nano-co-crystals. For example, Alhalaweh et al. produced and characterized co-crystals of theophylline, a bronchodilator used for treating
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asthma, with urea, saccharin and nicotinamide for pulmonary drug delivery and
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compared their performance with that of milled theophylline and theophyllinesaccharine that were used as controls. [160]. Pure theophylline and its cocrystals with saccharine and urea were sprayed from methanol solution, while the co-crystal with nicotinamide from water and the products were characterized by different methods [160]. The solvent selection was based on the solubility of both the active compound and the co-crystal former. It is important to stress that organic solutions are usually spray-dried in a closed configuration under nitrogen as the drying gas and the solvent is trapped using 54
ACCEPTED MANUSCRIPT a B-295 inert loop that prevents its release to the environment. An inert environment is also required to spray flammable solvents under heating. Conversely, aqueous solutions are spray-dried in an open configuration with air as the drying gas. Organic solvents such as methanol are more advantageous than water because they display lower boiling point and thus, the drying is
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achieved under milder conditions that prevent better thermal degradation of the
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active compound. At the same time, it is important to stress that spray-dryers
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are designed to shorten the exposure of the liquid feed to heat, thus being also feasible for thermo-sensitive materials. Moreover, elimination of methanol
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residues can be achieved faster than water; humidity can contribute to chemical instability. On the other hand, water is not toxic, while the concentration of
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residual methanol has to comply with regulatory guidelines [61,62]. Co-crystals were smaller than 5 μm, as determined by SEM [158]. Since theophyllin was
diameter
were
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aerodynamic
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envisioned for inhalation, the aerosol performance and the median measured.
Co-crystals
showed
lesser
agglomeration than pure spray-dried and milled crystals which is a relevant
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property towards inhalation administration. Pawar Jaywant et al. prepared cocrystals of efavirenz, a poorly water-soluble antiretroviral drug, and glutaric acid
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(2:1) by spray-drying [159]. In this case, both API and crystal co-former were dissolved in 1:1 v/v ethanol/methanol solution before spray-drying that was performed using a laboratory spray-dryer (JISL, Secunderabad, India) at the temperature range of 49-52°C and at a flow rate of 2 mL/min. The spray-dried product was recovered from the cyclone collector, stored in a desiccator and characterized for solid-state properties [159]. Co-crystals showed a 2.8 fold increase in dissolution rate as compared to the raw drug [159]. Walsh et al.
55
ACCEPTED MANUSCRIPT managed to form co-crystals of sulfadimidine, a poorly water soluble API, and 4-aminosalicylic acid, a hydrophilic molecule, by spray-drying in the presence of a third component (excipient) [161]. A solution of sulfadimidine and 4aminosalicylic acid (1% w/v) was prepared in ethanol and sonicated for complete dissolution of the components. An equal volume of 1%
4-aminosalicylic
acid
solution
and
mixed.
The
resultant
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and
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w/v excipient aqueous solution or suspension was added to the sulfadimidine
operating
in
the
open
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solutions/suspensions were spray-dried using a Mini Spray Dryer B-290 mode. Spray-drying
resulted
in
co-
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crystal microspheres with sizes in the 1–10 μm size range, depending on the excipient used [161]. For some of the systems, better tableting properties were
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achieved. This work emphasizes the feasibility to extend the use of these technologies to the production of a broad variety of formulations. In a research
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conducted by Patil et al. the synthesis of caffeine and maleic acid co-crystals
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was successfully carried out by EHDA [48]. For this, solvents with diverse physicochemical properties such as methanol, ethyl acetate, acetone and water
CE
were used. The prepared solutions of caffeine/maleic acid were electrosprayed using a E-Spin NANO electrospray (Pico, Chennai, India) under flow rate of 2
AC
mL/h, voltage of 20 kV and syringe of 10 mL [48].
In addition, different
caffeine:maleic acid molar ratios were used. 1:1 co-crystals were formed from methanol, ethyl acetate and acetone, while 2:1 co-crystals from water [48]. As previously explained water displays remarkable advantages over organic solvents. Among them, water is cheaper, safer for spraying-drying (it is not flammable as alcohols, organic esters and ketones), less contaminant of the environment, and it is non-toxic as opposed to many organic solvents for which
56
ACCEPTED MANUSCRIPT maximum residual limits have been defined [61,62]. On the other hand, the relatively high boiling point of water demands the use of higher drying temperature which in turn could result in thermal degradation of the active compound. Thus, these aspects need to be carefully evaluated when optimizing the process. In some cases, the use of solvent mixtures is beneficial as it
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enables the drying process at slightly lower temperature. In another study, the
carbamazepine/nicotinamide
and
itraconazole/fumaric
acid,
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of
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same research group utilized the same method to study the co-crystallization
itraconazole/succinic acid and itraconazole/maleic acid [158]. Carbamazepine
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and nicotinamide were dissolved in methanol and ethanol separately in 1:1 molar ratio by heating in a water bath to 50°C. Similarly, itraconazole and
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its co-formers were dissolved in a mixture of tetrahydrofuran and chloroform (1:1 v/v) in 2:1 molar ratio. The electrospraying was carried out using a 10 mL
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syringe, a flow rate of 2 mL/h, a voltage of 20 kV and a temperature of 40°C
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[158]. PXRD, DSC and Fourier-transform infrared spectroscopy analyses the formation of pure carbamazepine/nicotinamide co-crystals. Authors also
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suggested that the nucleation of the drug and the co-former took place in the Taylor cone. Conversely, in the case of itraconazole, only the co-crystals with
AC
fumaric acid and succinic acid were successfully formed. The dissolution rate in water was not assessed. An important constraint of these explorative works is the very low flow rate achieved with laboratory scale equipment. This could be overcome by employing commercially available equipment designed for pilot, pre-production and industrial production [108]. Overall, the research of EHDA and spray-drying as platforms for the production of drug co-crystals is very incipient. In our view, the few works presented here 57
ACCEPTED MANUSCRIPT constitute solid preliminary evidence that both technologies could serve as an alternative to more traditional methods and to eventually pave the way to the design of new and more complex nano-crystalline products with improved physicochemical properties.
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6. Conclusions and future challenges EHDA and spray-drying are two bottom-up techniques extensively explored for
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the fabrication of polymeric nanoparticles. Owing to the great versatility to
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adjust the process conditions for a broad variety of materials, they recently attracted the attention of pharmaceutical scientists to produce pure drug
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particles. In both techniques, the evaporation of the solvent is very efficient and,
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depending on the equipment design, also relatively fast. In fact, most of the solvent is eliminated within few seconds as opposed to other drying processes
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such freeze-drying that require hours or days. To make the drying process more
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efficient, spray-drying uses temperature under a gas flow, while EHDA could be conducted at high temperature and low pressure and the operation conditions could be modified to find a good balance between solvent
CE
evaporation and formation of crystalline/amorphous particles. The question that
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remains is whether EHDA and spray-drying could be an alternative to wellestablished top-down technologies such as high-pressure homogenization. On one hand, bottom-up methods enable better control of the particle structure and morphology. In addition, with the proper adjustment of the conditions, crystalline drugs can be converted into amorphous counterparts that usually display with significantly faster dissolution rates. On the other, regardless of the great opportunities offered by these two technologies, data reported in the literature are not sufficient and robust enough to conclude about aspects such 58
ACCEPTED MANUSCRIPT reproducibility, cost-viability and scalability, that are crucial for industrial implementation. The design of industrial equipment that enables good control, follow up and validation of the process conditions is probably the first milestone in this direction. In the case EHDA, such equipment is already commercially available. Conversely, industrial spray-dryers are less appropriate for the mass
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production of nanoparticles. However, in our view, the most challenging stage
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is allocating time and funds to a more systematic research of the fundamental
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parameters that control the crystalline/amorphous structure of the particles, as well as their size, size distribution, morphology and porosity. In other words, the
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characterization of the particles should not be limited to assess their size, shape and crystallinity/amorphousness and to demonstrate changes (usually
MA
increase) in the dissolution rate and the saturation solubility, as most researchers do. They need to comprise a more comprehensive study of the
D
relationship between the nanoparticle structure and properties that govern its
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interaction with the biological system such as physicochemical stability under biologically-relevant conditions, permeability across barriers (e.g., models of
CE
intestinal epithelium), mucoadhesion and ultimately pharmacokinetics. Only then, the potential of these bottom-up technologies in general and EHDA and
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spray-drying in particular will be realized. Acknowledgments. This work was funded by the Phyllis and Joseph Gurwin Fund for Scientific Advancement. RSA dedicates this article to the memory of her father, Dov Sverdlov, who recently passed away and whose invaluable help, belief and support has made the writing of this article possible.
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