Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update

Accepted Manuscript Title: Amorphous Solid Dispersions and Nanocrystal Technologies for Poorly Water-Soluble Drug Delivery – An Update Authors: Scott V. Jermain, Chris Brough, Robert O. Williams III PII: DOI: Reference:

S0378-5173(17)31031-1 https://doi.org/10.1016/j.ijpharm.2017.10.051 IJP 17107

To appear in:

International Journal of Pharmaceutics

Received date: Revised date: Accepted date:

28-7-2017 22-10-2017 27-10-2017

Please cite this article as: Jermain, Scott V., Brough, Chris, Williams, Robert O., Amorphous Solid Dispersions and Nanocrystal Technologies for Poorly Water-Soluble Drug Delivery – An Update.International Journal of Pharmaceutics https://doi.org/10.1016/j.ijpharm.2017.10.051 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Amorphous Solid Dispersions and Nanocrystal Technologies for

Scott V. Jermain, Chris Brough, Robert O. Williams III

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Poorly Water-Soluble Drug Delivery – An Update

Scott V. Jermain - Division of Molecular Pharmaceutics and Drug Delivery, College of

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Pharmacy, The University of Texas at Austin, 2409 University Ave., A1920, Austin, TX

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78712, USA.

Chris Brough - DisperSol Technologies, LLC, 111 Cooperative Way, Georgetown, TX

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78626, USA

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Robert O. Williams III - Division of Molecular Pharmaceutics and Drug Delivery,

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Austin, TX 78712, USA.

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College of Pharmacy, The University of Texas at Austin, 2409 University Ave., A1920,

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Graphical abstract

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Abstract: Poor water-solubility remains a typical property of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate, and bioavailability of these active ingredients belonging to biopharmaceutical classification system (BCS) II and IV classifications. Since the early 2000s, nanocrystal delivery and amorphous solid dispersions are more established techniques to overcome the limitations of poorlywater soluble drugs in FDA available products. This article provides an updated review of nanocrystal and amorphous solid dispersion techniques primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercially relevant scientific literature.

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Keywords: Amorphous solid dispersion; nanocrystal; solubility; oral delivery, FDA approved product

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1. INTRODUCTION Poorly-water soluble drug substances represent a significant percentage of

the molecular entities in the industry’s drug development pipeline and are a growing percentage of those commercially available [1-3]. While approximately 2

40% of the currently marketed products are poorly soluble based on the biopharmaceutical classification system (BCS), an estimated 90% of drugs in development can be classified as poorly soluble [4]. In the past, the industry

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consensus was to view these as highly risky development candidates [5]. However,

given their prevalence, industry consensus has shifted from an attitude of avoidance to one of acceptance as increasing research dedication is given to solving solubility challenges [6]. Whether the increase in number of poorly water-soluble entities is

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due to modern high-through put screening methodologies [7] or credited to

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development on increasingly biocomplex diseases requiring higher lipophilicity and

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larger molecular weight, the challenge of poor solubility is not disappearing in the

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foreseeable future [8, 9].

Addressing this issue, the pharmaceutical industry has developed multiple

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methods for increasing the apparent solubility of crystalline drugs. Traditionally,

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salt formation was preferred by medicinal and synthetic chemists for weak bases or

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weak acids [10]. Unfortunately, only 20-30% of new molecules form salts easily, so 70-80% of those entities must find another route to improved solubility [11].

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Cyclodextrins [12], self-emulsifying drug delivery systems (SEDDS)[13], solid lipid nanoparticles [14], liposomes [15], micelles [16], soft gelatin capsules [17], co-

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crystals [18], pH micro-environmental modifiers [19], and high energy polymorphs [20] are some of the routes available to pharmaceutical scientists. However, more recently there has been an increased prevalence of two solubility/dissolution rate 3

improvement technologies reported in the literature and employed in approved products, those based on nanocrystal technologies and amorphous solid dispersions.

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This review article provides a comparison of nanocrystal technologies and

amorphous solid dispersions based on literature reports and is an update to Brough and Williams’ review [21]. Processes and technologies for each methodology will be discussed along with a sampling of scientific literature in which they are compared

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in developmental research. Finally, FDA-approved nanocrystal and amorphous solid

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dispersion products are examined and contrasted against the number of patent

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applications filed each year for the respective technology with observations of

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2. SCIENTIFIC FOUNDATION

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current trends in product approvals in the United States.

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Solubility, an intrinsic property of the drug substance, plays a significant role in the absorption (and therefore bioavailability) of the compound (i.e., drug).

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Therefore, solubility is taken into consideration in the BCS. The BCS was established

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in order to classify intestinal absorption taking into account three fundamental parameters: solubility, intestinal permeability, and dissolution rate [22]. Poorly

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water-soluble compounds are grouped into BCS Class II (high permeability, low solubility) or BCS Class IV (low permeability, low solubility) depending upon their permeability categorization [23].

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There are multiple complex factors in drug absorption, but a straightforward conceptual approach to understanding solubility’s role can be expressed by the

𝑀𝐴𝐷 = 𝐾𝑎 ∙ 𝑆𝑝𝐻 ∙ 𝑉𝑆𝐼 ∙ 𝑡

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maximum absorbable dose (MAD) formula:

Equation 1

Where Ka is the intestinal absorption rate constant (related to permeability), SpH is the solubility at intestinal pH, VSI is the volume of fluid in the small intestine

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available for drug dissolution and t is the transit time through the small intestine

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[24, 25]. This model illustrates important points in the challenge of poorly soluble

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drug absorption. First, the solubility at the site of absorption is critical after the pH

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transition from the acidic gastric environment [26]. Delivery forms must either

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include dissolution in the gastric environment and maintenance of solubility

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through the pH transition into the intestines or acceptably rapid dissolution rates at intestinal pH to achieve solubility during the intestinal transit time. Second, Ka, the

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intestinal absorption rate, must also be considered with increased solubility. At low solubility, the SpH is likely the limiting factor in the maximum absorbable dose. If the

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drug solubility is increased substantially, the limiting factor can shift from solubility

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to the intestinal absorption rate [27]. Thus, it may be more important to maintain drug solubility for the entire intestinal transit time rather than maximize solubility for a portion of it.

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2.1 Nanocrystal Delivery Forms Both nanocrystal forms and amorphous solid dispersions increase the amount of drug dissolved at the site of absorption, and they accomplish this by

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different mechanisms. Nanocrystal delivery relies on reduced particle size for

increased solubility and dissolution rate [28]. The Nernst-Brunner equation (NoyesWhitney equation modified with Fick’s second law) illustrates the effect of smaller

𝑑𝐶

𝐷𝑆 𝑉ℎ

(𝐶𝑠 − 𝐶)

Equation 2

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𝑑𝑡

=

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particle size on dissolution as seen in Equation 2:

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Where dC/dt is the change of concentration over time (dissolution rate), D is

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the diffusion coefficient, S is the surface area, V is the volume of the dissolution

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medium, h is the thickness of the diffusion layer, CS is the saturation solubility and C

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is the instantaneous concentration at time t [29]. Particle size reduction leads to an increase in surface area, where reduction from the micron range to the nanosized

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range can significantly increase the extent and rate of solubility of drugs [30]. In

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addition to affecting surface area, with particle sizes less than about 50 µm the thickness of the diffusion layer appears to decreases as well [31]. Thus, nano sizing

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increases dissolution by simultaneously increasing surface area in the numerator and decreasing the diffusion layer thickness in the denominator of Equation 2.

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The relationship of solubility of a small particle in a bulk solution is given by the Ostwald-Freundlich equation (Equation 3), which is analogous to the Gibbs-

γ

𝑥𝑅

2σαγ υ2

𝑥∞

𝑘𝐵 𝑅𝑇

ln ( ) =

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Kelvin equation [32]

Equation 3

Where the solubility, xR, of a small solid particle (phase γ) in the ideal bulk

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solution (phase α) is related to radius, R. The other variables are as follows: x∞ is the

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relative concentration of solute in phase α, σαγ is the surface tension of the solid

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particle at its boundary with phase α, υ2γ is the volume per molecule in the solid

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particle, kB is the Boltzmann constant and T is the temperature. According to the equation, particles with a very small radius will have increased solubility. This

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indicates that nanoparticles not only affect surface area, S, and the diffusion layer

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thickness, h, in the Nernst-Brunner equation, but also the saturation solubility, CS. Entering values to simulate a drug in intestinal fluid (assuming a drug molecular

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weight of 500 and an σαγ value of 15-20 mN m-1 for the crystal-intestinal fluid

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surface tension) Equation 3 is used as the basis of understanding the fundamental property of increased solubility at reduced particle sizes [33].

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Further illustrations of increased solubility of small particles have been

reported [34, 35]. Junghanns et al. used an equation related to the OstwaldFreundlich equation, the Kelvin equation, which describes the relationship between

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the radius of a liquid droplet and the vapor pressure leading to evaporation. Equation 4 is the Kelvin equation. 2γ𝑉𝑚

𝑝o

Ȓ𝑅𝑇

Equation 4

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𝑝

ln ( ) =

Where p is the vapor pressure, po is the saturated vapor pressure, γ is the surface

tension, Vm is the molar volume, Ȓ is the universal gas constant, R is the radius of the droplet and T is the temperature. Under the assumption that a transfer of molecules

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from a liquid phase to a gas phase is in principal identical to the transfer of

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molecules from a solid phase to a liquid phase, the properties of BaSO4 were entered

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into the Equation 4. Using the curvature of the nanoparticle surfaces to estimate

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particles smaller than 1 µm.

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pressures, the Kelvin equation shows an increase in saturation solubility for

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Nanoparticles are much more unstable than microparticles because of the extra Gibbs free energy contribution related to reducing particle size and primarily

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due to surface energy [36]. Addressing this extra contribution is key to formulating

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pharmaceutical nanoparticles because they will tend to agglomerate to minimize their total energy [37]. Approaches to stabilizing drug nanoparticles can be

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categorized into two groups: thermodynamic stabilization which uses surfactants or block copolymers for particle stability or kinetic stabilization which uses energy input to compensate for Gibbs free energy [36]. For maximum effectiveness, the two approaches are often combined [38]. Careful selection of the amount of stabilizer is 8

as important as the selection of the type of stabilizer. For example, one obstacle to stabilization is Ostwald ripening, which is the phenomenon in which smaller particles in solution dissolve and deposit on larger particles in order to reach a more

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thermodynamically stable state by minimizing the surface to area ratio [39]. Too little stabilizer allows agglomeration of nanoparticles and too much stabilizer promotes Ostwald ripening [40]. 2.2 Amorphous Dispersions

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Understanding the benefit of solid amorphous dispersions must be explained

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solubility (S) of a given solid solute [8]:

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in terms of enthalpic energy. There are three basic quantities governing the

Equation 5

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𝑆 = 𝑓(𝐶𝑟𝑦𝑠𝑡𝑎𝑙 𝑃𝑎𝑐𝑘𝑖𝑛𝑔 𝐸𝑛𝑒𝑟𝑔𝑦 + 𝐶𝑎𝑣𝑖𝑡𝑎𝑡𝑖𝑜𝑛 𝐸𝑛𝑒𝑟𝑔𝑦 + 𝑆𝑜𝑙𝑣𝑎𝑡𝑖𝑜𝑛 𝐸𝑛𝑒𝑟𝑔𝑦)

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The crystal packing energy term accounts for the energy necessary to disrupt the crystal lattice and remove isolated molecules. The cavitation energy term

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accounts for the energy required to disrupt water in order to create a cavity in

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which to host the solute molecule. The solvation energy term accounts for the release of energy as favorable interactions are formed between the solvent and

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solute. A graphical representation is shown in Figure 1. In relative terms, the crystal packing energy is larger than both cavitation

and solvation energies and thus, the driving force behind solubility. The intent in formulating an amorphous solid dispersion is to minimize this energy component by 9

disrupting the drug crystal lattice in the delivery form. In conjunction with solubility enhancing polymeric carriers, the apparent solubility can be increased by up to 10,000-fold or more [41-44]. In terms of the Nernst-Brunner equation, drastic

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increases of the saturation solubility, CS, result in a much faster dissolution rate.

Amorphous solid dispersions essentially contain stored potential energy

similar to mechanical systems like a compressed spring. When placed in the desired media, the potential energy is released and the dispersion ‘springs’ the molecular

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entity into a supersaturated state [45, 46]. Since supersaturation is

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thermodynamically unstable, the formulation must also provide a ‘parachute’ to

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keep the solubility from rapidly returning to the crystalline drug equilibrium

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solubility, Ceq (Figure 2), to maintain elevated drug concentrations for the duration of intestinal transit to achieve the maximum absorbable dose. In general, solubility

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enhancing polymers are reported to function well as a parachute or stabilizer due to

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drug-polymer interactions in solution and by adsorption of the polymer on the

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growing crystal [47]. Other solubility enhancing formulations may require additional excipients to function as the parachute to retard the descent from high to

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low energy forms of the drug. Examples of polymers that have been investigated for their stabilizing effect include polyvinylpyrrolidrone (PVP) [48], polyethylene glycol

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(PEG) [49], methylcellulose (MC) [50], hydroxypropylmethylcellulose (HPMC) [51], and hydroxypropylmethylcellulose acetate succinate (HPMCAS) [52].

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A concern with solid dispersions is the possibility of the amorphous drug substance undergoing crystallization during storage. The effect of moisture on storage stability is an another concern because the presence of water may increase

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drug mobility and promote drug crystallization [53]. Additionally, some polymers used in solid dispersions are hygroscopic, which may result in phase separation,

crystal growth or conversion from a metastable crystalline form to a more stable

crystalline structure during storage [54]. This would result in continually decreasing

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the solubility and dissolution rate as well as lower the in vivo performance during

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the product’s shelf-life.

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The above challenges can be mitigated by proper polymer selection, drug

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loading optimization and appropriate product packaging selection. Amorphous solid dispersions can be rendered physically stable via kinetic stabilization (i.e., freezing

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the amorphous drug substance within the polymer matrix to restrict molecular

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mobility to prevent nucleation and crystal growth). It has been reported that for

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adequate kinetic stability, the Tg of the composite matrix should be 50 °C above the maximum storage temperature [55]. From this perspective, polymer selection is

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important to ensure a high composite Tg for the preservation of the amorphous drug. A polymer may also stabilize an amorphous drug substance via drug-polymer

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intermolecular interactions such as hydrogen bonding, Van der Waals forces, etc. Such interactions can be estimated a priori utilizing calculated solubility parameters or empirically via the use of analytical techniques such as Fourier transform 11

infrared spectroscopy (FTIR) [56-58]. These interactions provide thermodynamic stability to the amorphous drug substance and can result in product stability irrespective of Tg [59].

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The necessity of rational polymer selection and drug loading can be aided by implementing the Flory-Huggins theory during pre-formulation assessment. The

Flory-Huggins theory has been applied to determine miscibility in polymer-polymer, polymer-solvent, and drug-polymer systems by utilizing the drug-polymer

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interaction parameter, χ, to calculate the free-energy of mixing for the system. The χ

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value takes into consideration the non-ideal entropy of mixing of a large polymer

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molecule with small solvent molecules and the contribution due to the enthalpy of

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mixing [60]. The Flory-Huggins theory can be understood using the following

∆𝐺𝑀

= 𝑛𝑑𝑟𝑢𝑔 𝑙𝑛 Φ𝑑𝑟𝑢𝑔 + 𝑛𝑝𝑜𝑙𝑦𝑚𝑒𝑟 𝑙𝑛 Φ𝑝𝑜𝑙𝑦𝑚𝑒𝑟 + 𝑛𝑑𝑟𝑢𝑔 Φ𝑝𝑜𝑙𝑦𝑚𝑒𝑟 χ

Equation 6

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𝑅𝑇

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equation:

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Where n is the moles of the drug or polymer, Φ is the volume fraction of the drug or polymer, ∆GM is the free energy of mixing for the system, R is the ideal gas constant,

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and T is the temperature of interest [61]. χ is then used to predict the stable, metastable, and unstable regions for the solid dispersions of the system by

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generating a spinodal (boundary between unstable and metastable regions) and binodal (boundary between metastable and stable regions) curves for the system [62]. A stable system is defined as a system where the components of the solid 12

amorphous dispersion remain in a single-phase, while metastable and unstable systems will tend to phase separate and produce polymer-rich and drug-rich regions. Due to thermodynamic instability and the higher energy amorphous state,

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the drug-rich region favors a lower energy state and has a tendency to recrystallize [63, 64]. Figure 3 is used to depict an example of a phase diagram produced from

Flory-Huggins modeling. Figure 3 shows regions A and B that demonstrate a stable amorphous dispersion, regions C and D that suggest a metastable amorphous

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dispersion, and regions E and F that demonstrate instability of the system [65].

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The primary method for χ determination is by analyzing the melting point

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depression of the system, which can be evaluated using differential scanning

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calorimetry (DSC). DSC is utilized to measure the melting point onset [66], melting

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temperature [67, 68], or melt endpoint [65]. It is important to evaluate which of

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these values provides the most reproducible results for the system. Following analysis of melting point depressions, χ, can be calculated using the following

(

1

1

∆𝐻𝑓𝑢𝑠

− 𝑇 𝑝𝑢𝑟𝑒) ( 𝑀

−𝑅

1

2 ) − 𝑙𝑛Φ𝑑𝑟𝑢𝑔 − (1 − 𝑚) Φ𝑝𝑜𝑙𝑦𝑚𝑒𝑟 = χΦ𝑝𝑜𝑙𝑦𝑚𝑒𝑟

Equation 7

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𝑚𝑖𝑥 𝑇𝑀

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rearranged equation [61]:

Where TM values are the melting points of the mixture of pure drug, R is the ideal gas

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constant, ∆Hfus is the heat of fusion for the pure drug, m is a constant for the relative size of the polymer to the drug, and the Φ values are volume fraction of drug or polymer. If a plot of the left-hand side of the equation vs. the Φ2 value for the 13

polymer demonstrates a linear relationship, the slope of the best-fit line is equivalent to χ. The drug-polymer interaction parameter can be visualized using Figure 4, which is a schematic of free energy of mixing versus composition. This

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phase diagram can be derived to generate the binodal and spinodal decomposition curves used to predict the regions of stability in Flory-Huggins theory [69]. More negative χ values predict miscibility while more positive χ values predict immiscibility [61].

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Drug loading can impact both kinetic and thermodynamic stability of an

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amorphous solid dispersion. For a low Tg drug in a kinetically stabilized dispersion,

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the higher the drug loading means the lower the composite Tg, and hence the more

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unstable the composition. For a thermodynamically stabilized amorphous solid

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dispersion, increasing drug loading can saturate bonding sites, and thus result in a

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less stable amorphous dispersion. Practically speaking, most amorphous solid dispersions are formulated in a metastable region where the mode of stabilization is

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a combination of both kinetic and thermodynamic mechanisms [70]. As drug loading impacts both of these stabilizing mechanisms, it is critical to conduct accelerated

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stability studies on a range of drug loadings to arrive at a physically stable

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amorphous dispersion with an acceptable drug load. Finally, packaging is critical when the amorphous solid dispersion is susceptible to destabilization by moisture absorption [71]. Adsorbed moisture can lead to crystallization by plasticizing the polymer matrix and increasing the molecular mobility, displacing drug substances 14

from bonding sites on the polymer, or both. Utilizing the appropriate dosage form, the packaging configuration can eliminate moisture contact and stabilize the

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amorphous product for an acceptable shelf-life.

3. PROCESSES 3.1 Nanocrystal Technologies

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Wet ball milling (also called bead milling or pearl milling) is the most

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frequently used production method for drug nanocrystals in the pharmaceutical

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industry [72]. This can be attributed in part to the simplicity of the process allowing

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it to be performed in almost every lab. The simplest way of doing ball milling is

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feeding coarse drug substance into a jar filled with milling media with at least one

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stabilizing agent. Then, agitate the milling media by magnetic stirrer or by rotating or tumbling the jar. This will generally yield very fine particles with a narrow size

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distribution when allowed to operate long enough.

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Alternatively, wet ball milling operations based on higher energy media movement can accomplish particle size reduction in times more suitable for

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industrial pharmaceutical applications [73]. The NanoCrystal® process is a high energy wet ball milling process regarded as the standard procedure to produce nanosuspensions [74]. To operate, the milling chamber is filled with milling media, water, drug, and stabilizer. A shaft with projectiles spins within the milling chamber 15

which allows drug particles to collide with the chamber wall, milling media and other drug particles. The high shear forces provide the energy input to fracture drug crystals into nanometer-size particles. Normal processing times ranging from 30

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minutes to 2 hours yield nanosuspensions of good quality. The process has

demonstrated scalability; batch mode R&D equipment can process 10 mg of drug substance and larger continuous mode equipment is being used to produce

commercial products [75]. Because it is part of the process, one inherent benefit of

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wet ball milling is creating a very stable aqueous suspension. This suspension can be

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directly formed into liquid oral, injectable and nebulized inhalation delivery forms

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[76].

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High pressure homogenization can be considered the second most frequently used technique to produce nanocrystals [72]. Like wet ball milling, it is a particle

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size reduction technology, but uses jet-stream homogenization by pumping drug,

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dispersion medium, surfactants and/or stabilizers under high pressure through a

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micro fluidizing nozzle. The particle size reduction is caused by cavitation forces, shear forces and collision through multiple homogenization cycles. The number of

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passes depends upon many factors comprising the type of homogenizer and process conditions, which has led to various technologies: IDD-P™, Dissocubes® and

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Nanopure® [34]. Combination technologies have also been developed that integrate a pre-

treatment step with a subsequent high energy step, like high pressure 16

homogenization. The NANOEDGE™ technology is one example that combines a first classical precipitation step with a subsequent annealing step by applying high energy (high pressure homogenization)[34]. The term annealing was used meaning

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nanoparticles achieve a lower surface energy by application of energy followed by

thermal relaxation. Other combination technologies, bottom-up methodologies and other processes are available to produce nanocrystal drug delivery forms [77-79]. 3.2 Amorphous Dispersion Technologies

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Processes for the preparation of solid amorphous dispersions can be

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categorized into two general types: solvent methods and fusion or melting methods.

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For solvent-based methods, solid dispersions are obtained by evaporating a

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common solvent (or combination of solvents) from a drug and carrier solution. In

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general, fusion methods heat a drug and carrier composition above their melting or

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glass transition temperatures, mix at the elevated temperature, and then cool the composition in such a way to keep the active ingredient in its amorphous state.

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Operating temperatures for solvent techniques are generally lower than fusion

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techniques and are advantageous for thermolabile drug substances. However, finding a common solvent is not always straightforward. For example, in the case for

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solid dispersions for immediate drug release, hydrophobic drugs are typically combined with hydrophilic carriers, which can limit solvent selection. A secondary drying step is often required to reduce residual solvent below accepted levels for safety issues. In addition, small amounts of residual solvent could negatively affect 17

drug chemical stability and can plasticize the solid dispersion matrix to subsequently impact physical stability [47]. Practical applications of the solvent method are spray drying and freeze

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drying. In spray drying, the drug and carrier solution is atomized into hot gas that causes the solvent to evaporate resulting in spherical particles containing

amorphous drug [80]. The spray drying process can be summarized by dividing the process into four steps: (1) spray formation-atomization of the feed

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solution/suspension/emulsion; (2) droplet-gas contact; (3) droplet drying and

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particle formation; and (4) separation of solid particles from the wet drying gas

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[81]. Freeze-drying or lyophilization is a technique in which the drug and polymer

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solution is frozen and the solvent is sublimed under vacuum. Another solvent method is using a fluidized bed system to coat multiparticulates (i.e., beads or

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dispersion coating [82].

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pellets) with drug-carrier solutions resulting in pellets with a solid amorphous

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Hot-melt extrusion (HME), a well-known fusion technique, has been a topic of interest in recent pharmaceutical research literature [83]. HME is the process of

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pumping compositions through a heated barrel by one or more screws under pressure followed by discharging the extrudate through a die. Solvents are not

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necessary thereby eliminating the aforementioned solvent related issues. The intense mixing and agitation imposed by the rotating screw(s) causes uniform distribution of drug and the processes is continuous and efficient. Screw geometries 18

can be optimized to ensure adequate homogenization of the extrudate. The extrudate discharge is dense and can be post-processed without the bulk density issues of some solvent methods. Compositions with a complex viscosity greater than

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10,000 Pa.s [84] may require the aid of a plasticizing agent to allow the composition

to flow through the heated barrel and out the die without over torqueing the electric motor. The inclusion of plasticizer in a formulation increases molecular mobility

upon storage and can allow for crystallization if the composition’s glass transition

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temperature is not at least 50 °C above the storage temperature [55].

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Another fusion-based process reported for the creation of amorphous solid

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dispersions is KinetiSol® Dispersing (KSD). KSD is a high-energy fusion-based

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mixing process that has been shown to create amorphous dispersions of high temperature, thermolabile drug substances without degradation [85-88]. The

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process consists of a shaft with protruding blades that rotates at speeds of up to

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3,500 rpm within a sealed processing chamber containing a drug-polymer blend

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[89]. A combination of friction and shear leads to the processing of a molten mass without the need for external heat input [90]. The rapid and thorough mixing

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provided by KSD leads to single-phase homogenous amorphous solid dispersion systems [87, 90, 91]. The KSD unit includes a computer-control module that

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monitors the real-time temperature and ejects the composition at a predetermined ejection temperature, where processing times are on the order of 15-20 seconds and elevated temperatures are typically only sustained for less than 5 seconds [89]. 19

This process is reportedly advantageous in that it does not have the same viscosity limitations as HME and thus compositions can be processed without the inclusion of a plasticizer [92]. KSD also allows for processing of matrix polymers that were once

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considered impossible to extrude due to thermal or rheological limitations [93]. While KSD has produced compositions for human clinical testing and received

increased attention in the literature, there are currently no marketed products produced by this technology.

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Following the FDA’s approval of the first 3D printed drug product, Spritam®

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in July 2015, interest in 3D printing drug products continues to build. 3D printing

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has many advantages including the capability of dispensing low volumes with

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accuracy, spatial control, and layer-by-layer assembly to prepare complex compositions [89]. 3D printing opens up the possibility for the use in enhancing the

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solubility of poorly soluble compounds by employing fused deposition modeling

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(FDM). FDM is a method of 3D printing that utilizes thermoplastic polymer carriers

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as the feed material that are heated to a molten state and extruded through a nozzle tip. Upon deposition, the extrudate cools and solidifies building a structure in a

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layer-by-layer method [89, 94]. The filaments incorporated in FDM can be prepared by HME or by an extruder upstream from the printer nozzle, which allows for more

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modification of the composition and the potential for incorporation of an amorphous solid dispersion as the feed filament [95-97]. This methodology shows promise in the continually growing field of amorphous solid dispersions. 20

Lastly, spray congealing is a fusion process used to create amorphous solid dispersions. Spray congealing is a process where molten compositions are atomized into particles of spherical shape and then rapidly cooled to solidification [98]. The

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large fluctuation in temperature has potential for adverse effects on product

stability, where crystallization may occur in a metastable or unstable polymorph, which will eventually undergo conversion to the stable polymorph [99]. Spray congealing is a solvent-free process that imparts thermal stress on the drug

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particles.

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4. RESEARCH COMPARISONS

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Numerous papers have been published on amorphous solid dispersions and

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nanocrystal formulations. For the purposes of this comparison review, only original

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research papers that directly compare the two in a formulation development effort are discussed. Additionally, literature was limited to those studies that included

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participation and/or support from a pharmaceutical company as this was

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considered to be an indicator of the study’s commercial relevance. Fakes et al. reported on the enhancement of an HIV-attachment inhibitor,

A

BMS-488043 [100]. The molecule was classified as a BSC class II compound with low aqueous solubility of 0.04 mg/ml and a permeability of 178 nm/s in a caco2 cell-line model. To increase bioavailability of the molecule, a nanosuspension formulation was developed and compared to an amorphous solid dispersion made 21

by a solvent evaporation method. The nanosuspension formulation was produced by a Nanomill™ at a 10% (w/w) concentration using hydroxypropyl cellulose (HPCSL) at 2% (w/w) and sodium lauryl sulfate (SLS) at 0.1% (w/w). The resulting

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median particle size, Dv50, was 0.120 µm, and the suspension was physically stable when stored at room temperature for up to 4 weeks. The amorphous solid

dispersion was produced by flash evaporation from an acetonitrile solution in a

Buchi Rotovapor®. PVP K-30 was the selected polymer with drug loadings of 20 and

U

40%. The dispersions were determined to be amorphous by X-ray diffraction (XRD)

N

following storage at 50°C up to 3 weeks. Further, a high drug loaded amorphous

A

dispersion of 80/20 BMS-488043/PVP remained amorphous after storage at 50°C

M

for 17 weeks. The two amorphous formulations and a single nanosuspension formulation were compared to a wet-milled crystalline drug in a capsule in a

D

crossover beagle dog study. The two solid dispersions were dosed as 200 mg tablets

TE

with the nanosuspension administered via a standard gavage tube at the equivalent

EP

dose. The nanosuspension showed a 4.7-fold increase in Cmax and 4.6-fold increase in AUC over the capsule. The 20% amorphous solid dispersion showed an 18.2- and

CC

7.0-fold increase in Cmax and AUC, respectively. The 40% dispersion showed a 15.7fold increase in Cmax and 8.7-fold increase in AUC. The authors concluded that the

A

amorphous dispersions were the best option, when compared to the nanosuspension, for increased bioavailability of BMS-488043.

22

Zheng et al. reported on the commercial development of LCQ789, a BCS Class II compound, investigated particle size reduction, amorphous dispersions, lipid based formulations and co-crystals[101]. LCQ789 is a crystalline, neutral compound

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with a molecular weight of 476.93 and a ClogP of 5.4 with extremely low solubility

(<1 µg/ml). Each formulation method was carefully screened: co-crystal screening was performed with four solvents and 27 co-crystal formers, solid dispersion

screening was conducted with seven polymers and a total of 64 variants, and lipid-

U

based formulations were screened with 25 GRAS listed excipients. Particle size

N

reduction on a research compound from the same scaffold at LCQ789 showed

A

minimal impact on its oral bioavailability, as confirmed by GastroPlus™ and in vivo

M

rat study. Consequently, the nanoparticle approach was not pursued for LCQ789. Optimized formulations were compared in rat and dog single dose

D

pharmacokinetic studies. Low bioavailability was observed with suspensions of

TE

crystalline LCQ789 and co-crystal compositions in rats, but the co-crystal form did

EP

show some improved bioavailability in dogs. In both species, significant improvement in bioavailability was achieved with the solid dispersion and lipid-

CC

based formulations. The in vivo pharmacokinetic studies indicated that the solid dispersion improved the oral bioavailability by 18-fold in rats and 50-fold in dogs,

A

while the lipid-based formulation increased the oral bioavailability by 25-fold in rats and 80-fold in dogs. The lipid-based formulation achieved the highest drug level, and the solid dispersion demonstrated less inter-subject variability. These two 23

formulations were continued on to dose escalation studies. Higher drug levels were achieved with the lipid-based formulation, but it also exhibited higher variability as compared to the solid dispersion. In addition, overall high organic solvent content

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was a concern for the long-term safety studies. As a result, the solid dispersion formulation was selected for use in safety studies.

Vogt et al. investigated formulations processed by micronization and co-

grinding versus nanosizing and subsequent spray-drying while using fenofibrate as

U

the model drug and compared their release profiles to the German and French

N

commercial products [102]. Micronization was conducted by jet milling while

A

nanosizing was performed by bead milling. Co-grinding was achieved by particle

M

size reduction with lactose, polyvinylpyrrolidone (PVP), sodium lauryl sulphate (SLS), and combinations of the three excipients. Spray dried particles were

D

produced by bead milling with lactose and SLS in water, then fed directly into a

TE

Buchi Mini Spray Dryer. All formulations were compared by dissolution in

EP

biorelevant media. The fenofibrate drug products commercially available on the German and French markets dissolved similarly to both the unprocessed and

CC

micronized fenofibrate formulations studied but demonstrated slower dissolution than the co-ground and spray-dried formulations. The co-ground formulations had

A

faster dissolution rates, but reached the same equilibrium concentration as the commercially available products. The spray-dried formulation produced substantial initial supersaturation, but returned to concentrations only slightly better than 24

equilibrium in 180 minutes because formulation did not contain a parachute component. This was termed as unstable by the authors, but they concluded that both co-grinding and spray-drying could potentially lead to better bioavailability of

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fenofibrate drug products.

Kwong et al. reported that toxicity is one of the leading causes of attrition in the clinic, and that good safety margins are imperative to reach proof of concept in clinical studies [103]. Research was conducted to identify a conventional

U

formulation that would provide the maximum exposure possible to define the dose

N

limiting toxicity for a molecule referred to as compound 3. Compound 3 existed as a

A

crystalline free base with poor solubility in water (0.0002 mg/ml in water, 0.0003

M

mg/ml in SGF and 0.004 mg/ml in FaSSIF), but was highly permeable. Thus, drug dissolution was the rate limiting step for absorption.

D

Various preparation methods and excipients were screened and the leading

TE

formulations were compared in a preclinical dose ranging study in rats. The three

EP

leading formulations were (1) crystalline form in 10% Tween 80, (2) amorphous form in 0.5% methylcellulose and 0.24% sodium lauryl sulfate and (3) a solid

CC

dispersion with 50% drug loading in HPMCAS-HF as seen in Figure 5. Unfortunately, the particle size for formulation 3 was not specifically mentioned in the reference.

A

At the lowest dose, 10 mg/kg, the drug levels achieved were similar for all three formulations. As the dose was increased to 100 mg/kg, the solubility of the crystalline phase limited the absorption of the compound and resulted in lower 25

bioavailability. It is interesting to note that the drug levels obtained from the amorphous form are comparable to those of the solid dispersion at this level. Finally, at 750 mg/kg the amorphous dispersion provided a significant increase in

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drug levels over that of the other two formulations (4-fold AUC as compared to the crystalline phase).

Thombre et al. compared amorphous, nanocrystalline and crystalline formulations of ziprasidone to FDA-approved Geodon® capsules in order to

U

minimize food effect [104]. The three formulations in the study were (A) an

N

amorphous inclusion complex of ziprasidone mesylate and a cyclodextrin, (B) a

A

nanosuspension of crystalline ziprasidone free base made by wet-milling, and (C)

M

jet-milled ziprasidone HCl coated crystals made by spray drying the drug with hypromellose acetate succinate. The pharmacokinetic studies in dogs showed that

D

the three formulations performed differently. Formulation B yielded the best fasted

TE

state absorption enhancement, indicating that improved dissolution rate with a low

EP

potential for precipitation might be the best combination to improve ziprasidone absorption in the fasted state. The in vivo data for formulation B was highly variable,

CC

but the mean summary parameters were comparable to the control capsule dosed in

A

the fed state. Formulation A also showed increase absorption of ziprasidone in the fasted

state compared to the FDA-approved capsule. Because of the solubilization technology used, ziprasidone likely went quickly into solution and was absorbed 26

(formulation A had the shortest observed Tmax). But, the extent of absorption was less than the control capsule dosed in the fed state, indicating possible precipitation in intestinal pH media. In vitro testing demonstrated that some amorphous complex

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formulations can achieve high enough supersaturation to cause precipitation of a lower solubility drug form such as the free base. Formulation C did not show

enhanced absorption in the fasted state compared to the FDA-approved capsule control.

U

In humans, both formulations A and B showed improved absorption in the

N

fasted state while formulation C did not [105]. Thus, the in vivo performance in dogs

A

was qualitatively similar to the in vivo performance of these formulations in

M

humans.

Sigfridsson et al. compared crystalline and amorphous nanosuspensions to a

D

solution of AZ68 [106]. AZ68 is a neurokinin NK receptor antagonist intended for

TE

schizophrenia treatment. The compound has high permeability and low solubility in

EP

the gastrointestinal track and thus fulfills the criteria for a BCS II compound. Crystalline nanosuspensions were prepared by bead milling; amorphous

CC

nanosuspensions were prepared by a solvent evaporation process and confirmed amorphous by XRPD (Powder X-ray Diffraction). Particle sizes for both suspensions

A

were approximately 200 nm and both formulations were dosed in rats by gavage at similar concentrations. The results indicate that AZ68 is absorbed at a lower rate for crystalline nanosuspensions compared to amorphous nanosuspensions and 27

solutions. However, the absorbed extent of the compound is similar in all three formulations. Sun et al. compared tablets of itraconazole that were formulated using a

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spray-dried nanosuspension to that of the marketed Sporanox® capsules [107].

Itraconazole is a BCS Class II broad-spectrum triazole antifungal agent which was selected because previous work demonstrated that in vivo absorption of

itraconazole can be enhanced significantly by particle size reduction [108]. The

U

itraconazole nanosuspension was prepared using high-pressure homogenization

N

and further processed by spray-drying. The spray-dried powder was then

A

formulated with excipients commonly used for direct tablet compression. The in

M

vitro dissolution profile and oral bioavailability of the spray-dried nanosuspension tablets were compared to that of bulk raw itraconazole and the marketed

D

Sporanox® capsules (which is processed by fluid bed bead layering) [109]. Scanning

TE

electron microscopy photomicrographs demonstrated neat itraconazole particles

EP

were converted to nanocrystals by homogenization with an average size of ~300 nm. XRD of the processed nanosuspension revealed characteristic crystalline peaks

CC

of itraconazole, which demonstrated itraconazole maintained crystallinity during

A

the spray-drying process. In vitro dissolution of the spray-dried nanosuspension tablets showed

improved dissolution properties compared to the neat drug substance and a comparable dissolution curve to the Sporanox® capsules. In vivo absorption studies 28

demonstrated no statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox® tablets at a dose of 100 mg in beagle dogs. The results indicate that the spray-dried nanosuspension of itraconazole might be

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comparable to that of the lead market product, Sporanox® capsules.

De Smet et al. evaluated the bioavailability of itraconazole using nanosized

cocrystals prepared by wet milling of itraconazole with dicarboxylic acids compared to the marketed Sporanox® capsules [109]. Nanosuspensions of itraconazole were

U

prepared by a wet milling technique using Tween® 80 as a stabilizer. The mean

N

particle size and polydispersity index was determined by photon correlation

A

spectroscopy; and the degree of crystallinity was determined by modulated DSC

M

(mDSC), x-ray diffraction (XRD), Raman, and Fourier transform infrared spectroscopy (FT-IR). The data confirmed that cocrystals between adipic acid and

D

itraconazole were formed and resulted in nanosized particles after manufacturing

TE

the nanococrystalline suspension. A bioavailability study was conducted in dogs in

EP

which in vivo results demonstrated the wet-milled nanosized cocrystals compared favorably to the FDA-approved Sporanox® capsules. The study suggests nanosized

CC

cocrystal technique using this approach might be an alternative to amorphous solid

A

dispersion systems to increase the solubility and dissolution of BCS class II drugs. To broadly summarize the findings from the aforementioned studies, drugs

formulated as an amorphous solid dispersion appear to perform favorably when compared to nanocrystal formulations. In the studies we reviewed, the amorphous 29

formulations generally demonstrated effective dissolution release profiles in vitro or higher blood concentrations in vivo when compared to other formulations [100-

implementation of nanocrystal formulations showed

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106]. For certain of the studies (e.g., see [102, 104, 105, 108, 109]), the

pharmacokinetic/pharmacodynamic parameters similar to amorphous solid

dispersion formulations, but overall, the methodology demonstrated weaknesses

(e.g., bioavailability [100, 101], drug levels [103], and absorption rate [106]) when

U

compared to amorphous solid dispersions. Based on our timeline, it appears that

N

these observations explain why amorphous solid dispersion technologies have

A

become more prevalent over the last 10 years when overcoming solubility

A

CC

EP

TE

D

M

limitations of poorly water soluble drugs is necessary.

30

5. NANOCRYSTAL MARKETED PRODUCTS Perhaps the best way to understand the utility of a technology is to review its application in marketed products. Table 1[72, 110] contains examples of FDA-

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approved products produced using nanocrystal technologies. We note that Gao et al. provides several drug products based on drug nanoparticle technology that are not included in Table 1 (Gris-PEG®, Cesamet®, Verelan PM®, Focalin XR®, Avinza®,

Ritalin LA®, Herbesser®, Zanaflex™, Naprelan®, and Theodur®) [110]. The products

U

listed in Table 1 only include FDA-approved BCS Class II and IV compounds that

N

employ nanocrystalline technologies. Our review of current industry literature

A

found no new nanocrystal product that has been approved by the FDA since 2009,

M

indicating a focus on alternative methods to formulate BCS Class II and IV compounds.

D

The first FDA-approved product using a pure nanoparticle technology was

TE

Rapamune®, a tablet formulation containing the immunosuppressant drug,

EP

sirolimus. It was originally marketed as an unpleasant tasting lipid based liquid solution that required cold storage and a dispensing protocol. Sirolimus is poorly

CC

water soluble (~2 µg/ml) and processed by NanoCrystal® technology into a fine nanoparticle dispersion with a mean particle size of <200 nm. The NanoCrystal

A

Colloidal Dispersion® intermediate is then post processed into tablets of 1 mg, 2 mg and 5 mg. The tablets have increased bioavailability (~27%), do not require special

31

storage conditions and have better patient compliance due to a more convenient dosage form [75, 111]. The second product, Emend®, is an antiemetic for the prevention of nausea

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and vomiting following chemotherapy and surgery. It is a spray coated capsule

formulation of aprepitant that has been formulated as a nanosuspension. Aprepitant (water solubility 3-7 µg/ml) is a free base crystalline compound that was processed into a fine particle dispersion using a wet milling technology, and then processed

U

into a solid dosage capsule formulation. The original dosage form showed a

N

significant food effect with drug levels exhibiting a 3-fold increase under fed

A

conditions for a 100 mg dose. The food effect was significantly higher at a 300 mg

M

dose [112]. The NanoCrystal® formulation was able to eliminate the food effect by increasing surface area 40 fold which resulted in a 4-fold increase in AUC values in

D

the fasted state of beagle dogs. The elimination of the food effect for antiemetic drug

TE

is significant as the commercial success may have been limited if required to

EP

consume with food [75].

TriCor® is the successor product for fenofibrate (for hypercholesterolemia)

CC

after patent expiration. Triglide is also a fenofibrate nanocrystal product, but produced by the IDD-P® technology. TriCor® has a dose of 48 mg or 145 mg in a

A

tablet form. The nanocrystal technology provided a life-cycle extension in the creation of a superior performing product. Fenofibrate showed 35% higher absorption in the fed state and significantly reduced the food effect [34]. 32

Megace ES® (ES stands for enhanced solubility) is for the delivery of megestrol acetate, a synthetic progestin used to treat anorexia, cachexia and AIDSrelated wasting. The FDA-approved formulation is an aqueous nanosuspension. The

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dose is 625 mg/5 ml and the nanosuspension reduces bioavailability differences

between fed and fasted conditions. It also has less administration volume than the previously given oral formulation (only ¼) while being less viscous [34].

The last approved nanocrystal product to be discussed is Janssen’s Invega

U

Sustenna®. This product, an atypical antipsychotic, is a once monthly intramuscular

N

extended release injectable dosage form of paliperidone palmitate. It is a liquid

A

dispersion product in prefilled syringes that has physical stability without the need

M

for special storage conditions for a two-year shelf life. This is a sterile product by way of conventional sterilization methods. Terminal heat is the preferred route, but

D

filtration, gamma irradiation and aseptic approaches are employed as alternatives

TE

[113]. The particulate nature of the formulation allowed for sustained release and in

EP

a patient population where compliance is a concern, the once a month dosage is a

CC

valuable option [75].

6. AMORPHOUS MARKETED PRODUCTS

A

Unlike nanocrystal technology, the FDA approval trend of amorphous solid

dispersion products suggests this technology continues to be a viable method to enhance poor water solubility by supersaturation. Since early 2010, 16 FDAapproved products have been formulated using this methodology. With the 33

introduction of new technologies to render drug in an amorphous state, amorphous solid dispersions will likely continue to be used as a means to overcome solubility limitations of drug substances. Table 2[114-120] contains examples of FDA-

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approved products produced using amorphous solid dispersion technologies. It is important to discuss a few of the drug products to better understand the utility of this methodology.

The first drug product to discuss is Kaletra®. The original solid oral

U

formulation of Kaletra® was a soft-gelatin capsule (SGC) containing 133.3 mg of

N

lopinavir (an HIV protease inhibitor) with 33.3 mg of ritonavir, with ritonavir acting

A

as a bioavailability enhancer for lopinavir [121]. The SGC dosage form required

M

refrigeration and the recommended adult dosage was 6 capsules daily with food to maximize the bioavailability of lopinavir. In order to more efficiently dose and

D

optimize delivery of Kaletra®, the product was reformulated as an amorphous solid

TE

dispersion utilizing HME technology. The result was a 200/50 mg

EP

lopinavir/ritonavir tablet formulation that reduced the number of dosage units and eliminated the requirement for refrigeration. Compared with the SGC formulation,

CC

the HME formed tablet resulted in more consistent lopinavir and ritonavir drug levels across meal conditions, which minimized the likelihood of extreme high or

A

low blood plasma concentrations. In addition, the removal of the refrigeration requirement allowed for worldwide distribution into underdeveloped areas that could not support a cold distribution chain. 34

The path toward the development of ritonavir into a solid oral dosage form based on amorphous solid dispersion technology was very similar to that of Kaletra®. Ritonavir was originally developed because it possesses anti-HIV activity,

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but it is no longer prescribed as a sole protease inhibitor in antiretroviral regimens

today. However, as a pharmacokinetic enhancer, ritonavir has become a mainstay in the management of both treatment-naïve and treatment-experienced patients. The basis for this enhancement is the inhibition of cytochrome P-450 (CYP) metabolic

U

pathways [122]. Inhibition of CYP 3A4 leads to a reduction in the metabolism of

N

most protease inhibitors and increases pharmacokinetic properties including area-

A

under-the-plasma concentration curve (AUC), maximum plasma concentration

M

(Cmax), and half-life (t½). These enhancements allow for a reduction of pill burden, dosing frequency and food restrictions while maintaining efficacy, all benefits for

D

the patient.

TE

With the emergence and dominance of polymorph Form II, Abbott

EP

Laboratories reevaluated their manufacturing process [123]. They reported a new method to control the conversion of Form I to Form II by choosing an appropriate

CC

ratio of solvent to antisolvent in a reactor process. Following the HME formulation development for Kaletra® in 2005, Abbott began developing a 100 mg HME-based

A

amorphous dispersion formulation for ritonavir. In the bioequivalence studies, the HME tablet demonstrated equivalence with SGC for AUC parameters. However, the ritonavir tablet Cmax was 26% higher than the SGC formulation [122]. This increase 35

in Cmax was not expected to alter the safety or pharmacokinetic enhancing profile of ritonavir. The tablet also exhibits less food effect than the SGC formulation. Itraconazole is another interesting example of a drug product that was

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commercialized using an amorphous solid dispersion technology. The compound is a potent broad-spectrum triazole antifungal drug, is insoluble in water (solubility

~4 ng/ml) and was among the first marketed solid amorphous dispersion products.

Itraconazole is so insoluble in intestinal fluids that drug therapy with the compound

U

could not be achieved without substantial solubility enhancement by formulation

N

intervention. The original solid oral formulation, Sporanox® Capsule, was produced

A

by a fluid bed bead layering process that used a co-solvent system of

M

dichloromethane and methanol to dissolve itraconazole and hydroxypropyl methylcellulose (HPMC) which was then sprayed on inert sugar spheres [124]. The

D

resultant product provided a significant enhancement of itraconazole bioavailability

TE

with approximately 55% of the administered dose absorbed [125]. Itraconazole has

EP

recently been reformulated into a tablet composition that contains an amorphous dispersion in HPMC 2910 by HME utilizing the MeltRx Technology®. The trade name

CC

is Onmel®; it is available in a 200 mg strength for once-daily administration and was approved by the FDA in April 2010 for the treatment of onychomycosis. The HME

A

formulation not only eliminated the use of organic solvents in manufacturing, but also reduced dosing frequency from twice-daily to once daily [126].

36

Like itraconazole, vemurafenib is another compound for which the drug therapy was enabled by the application of amorphous solid dispersion technology. Zelboraf™ is a tablet dosage form containing an amorphous dispersion of

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vemurafenib in HPMCAS-LF produced by a solvent/anti-solvent precipitation called microprecipitated bulk powder (MBP) technology [127]. The process utilizes N, Ndimethylacetamide to dissolve the drug and the ionic polymer. The solution is precipitated into acidified aqueous media, the precipitates are then filtered,

U

repeatedly washed to remove residual acid and solvent content, dried, and then

N

milled to form the amorphous powder intermediate, MBP. The MBP product

A

provides substantial enhancement of the solubility/dissolution properties and oral

M

bioavailability of vemurafenib with excellent physical stability. The stability of the amorphous dispersion is attributed to the high composite Tg, intermolecular

TE

provided by the polymer.

D

interactions between the drug and polymer as well as the moisture protective effect

EP

In initial Phase I clinical studies with a conventional formulation of vemurafenib, patients did not respond, i.e. no tumor regression, to doses as high as

CC

1,600 mg [128]. The issue was identified as low oral bioavailability stemming from poor solubility, which caused a halt to the clinical study until it could be

A

reformulated into a more bioavailable form. Due to melting point and organic solubility limitations, traditional amorphous solid dispersion processes could not be applied, therefore necessitating the application of the MBP technology. When 37

clinical trials resumed with the new MBP-based formulation, substantial tumor regression was achieved in a majority of patients as a result of the enhanced formulation [129]. The application of the MBP technology to vemurafenib is a

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compelling case study for the application of amorphous solid dispersion technology because formulation intervention was directly responsible for enabling the drug therapy and prolonging the lives of terminal patients suffering from metastatic melanoma.

U

An example of a FDA-approved spray-dried product is ivacaftor. It was

N

developed by Vertex Pharmaceuticals and is marketed under the trade name

A

Kalydeco®. Ivacaftor facilitates increased chloride transport by regulating the

M

chloride channel of the G551D-CFTR protein and is indicated for the treatment of cystic fibrosis. It exhibits solubility-limited oral absorption with an oral

D

bioavailability of 3-6% in rats when administered in the crystalline form [130]. To

TE

overcome the solubility limitations of ivacaftor, it was formulated in an amorphous

EP

spray-dried dispersion (ASDD). The ASDD was formulated using HPMCAS as a carrier to improve solubility and stability of the formulation. The formulation of

CC

ivacaftor demonstrated a solubility value of 67.4 µg/mL which was far superior to the crystalline polymorph form B solubility value (1 µg/mL) [131]. The ASDD

A

formulation was found to provide drug levels of more than 100% relative bioavailability compared to crystalline ivacaftor. This formulation demonstrated the

38

feasibility of using an ASDD to increase bioavailability of active drug and enable therapeutic activity at lower doses. Similar to itraconazole, posaconazole is a broad-spectrum triazole antifungal

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agent used as both prophylaxis and treatment against fungal infections. Prior to

2013, posaconazole was available as an oral suspension as Noxafil® Oral Suspension. The suspension formulation of posaconazole had variable bioavailability following

administration which lead to inconsistent pharmacokinetics [132]. Multiple factors

U

were known to have a negative effect on the bioavailability including agents that

N

raise gastric pH, nausea and vomiting, and agents that promote gastrointestinal

A

motility [133, 134]. Additionally, there was an observed food-effect that significantly

M

affected the bioavailability of posaconazole in the oral suspension, in which patients who were administered a high-fat meal demonstrated a 300% increase in drug

D

levels of posaconazole [135]. This same effect was observed in a lesser extent

TE

(168%) when patients were administered Noxafil® Oral Suspension with a nonfat

EP

meal.

To overcome the variable bioavailability and inconsistent pharmacokinetics

CC

a new oral posaconazole tablet (Noxafil® Delayed-Release Tablet) was developed. The formulation contains the active ingredient, posaconazole, and a pH-sensitive

A

polymer, HPMCAS, which is processed by HME. The polymer is used to function as a delayed-release mechanism, preventing release of posaconazole in the highly acidic environment of the stomach and allowing for release of posaconazole in the 39

intestines [136]. These properties significantly enhanced the oral bioavailability of the drug, which was confirmed from the results of the Phase Ib and III clinical trials. The delayed-release tablet achieved higher drug levels of posaconazole than the

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suspension formulation and less variability between patients. Also, there was no observed effect on the delayed-release tablet formulation based on the patient’s

fed/fasting state or the concomitant usage of medications that raise gastric pH or

speed gastric motility [137, 138]. The reformulation efforts of Noxafil® have yet to

U

demonstrate increased clinical efficacy, but the bioavailability and variability issues

N

have been mitigated by employing HME as a means to induce amorphicity [132].

A

Following the approval of Noxafil® Delayed-Release Tablets, another Merck

M

product, Belsomra®, was approved for patients suffering from insomnia. Belsomra® is a highly selective antagonist for the orexin receptors OX1R and OX2R which are

D

centrally responsible for wakefulness. The active ingredient, suvorexant, a BCS class

TE

II drug, was able to overcome solubility limitations by conversion to the amorphous

EP

form using HME with the pH independent polymer, Kollidon® VA64 [139]. pH dependent polymers were ineffective in this formulation because they

CC

demonstrated delayed Tmax due to the food effect [140]. Another observation during formulation studies was the impact that tablet compression has on disintegration

A

time, affecting dissolution and potentially absorption of suvorexant [141]. Ultimately, supersaturation and increased bioavailability was achieved for suvorexant using HME, and in 2014 Belsomra® was approved by the FDA. 40

7. Summary of Marketed Products and Patent Review

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Nanocrystal and amorphous solid dispersion products have been discussed to provide a contemporary perspective of their use in pharmaceutical development. To provide a broader perspective and view any trends in drug development, Figure 6 illustrates a timeline, in which FDA-approved amorphous solid dispersion and

nanocrystal products are displayed. From Figure 6, one can visualize the industry’s

U

trend towards developing amorphous solid dispersions over the last 10 years. From

N

this perspective, it appears that from the 1970s through the 1990s, the few poorly

A

water-soluble drug candidates formulated for commercialization solely employed

M

amorphous solid dispersion technologies. In the early 2000s, products employing

D

nanocrystalline technologies began to be used for the development of BCS class II

TE

and IV drugs based on the number of FDA-approved drug products available. The trend reverses near the end of the 2000s, where from 2007 to 2017 only one

EP

nanocrystal product was approved by the FDA while 19 amorphous solid dispersion

CC

products were approved during that same timespan. Additionally, the last two FDAapproved nanocrystal products were suspensions; the last one being an

A

intramuscular injection product. The ever-increasing number of FDA-approved amorphous solid dispersion products and lack of FDA-approved nanocrystalline products indicates a shifting of focus from more solubility enhancement of poorly

41

water-soluble drugs to the concept of supersaturation of drug to increase bioavailability of poorly water soluble drugs. To further the argument that amorphous solid dispersions appear more

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prevalent in the industry, we reviewed the patent literature (i.e., patent applications filed) for both amorphous solid dispersion and nanocrystal technologies. This

approach considers that a new product introduction is a result of a well-structured

patent protection system [142], and the fact that in the pharmaceutical industry the

U

patent virtually equals the product [143]. An increased number of patent

N

applications filed on a specific technology is useful in studying FDA-approved drug

A

products utilizing that technology. Figure 7 is used to illustrate the trend of new

M

patent application filings from 1990-2016 on both amorphous solid dispersions and nanocrystals. The number of patent applications filed in each year were retrieved

D

using a Google Scholar search and pre-specified search terms to include patents

TE

pertaining specifically to each technology. It is from this search and assessment that

EP

correlation between an uptick in amorphous solid dispersion patents in the early 2010s and an increase in FDA-approved amorphous solid dispersion products may

A

CC

be made.

8. CONCLUSION Nanocrystal delivery forms and amorphous solid dispersions are well

established techniques for addressing poor water solubility in pharmaceutical 42

compounds, however, the methodologies are quite different. While several marketed products are made by both nanocrystal and amorphous solid dispersion technologies, it appears the number of amorphous solid dispersion products

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continues to grow. The trend towards increased numbers of FDA-approved

amorphous solid dispersion products seems likely to continue with the introduction of new technologies to induce amorphicity, and patent literature is likely to reflect

this trend in the years to come. A timeline of FDA-approved drug products and filed

U

patents suggests solving solubility challenges for oral delivery is often successful

A

CC

EP

TE

D

M

A

N

when implementing amorphous solid dispersion technologies.

43

SC RI PT

A

CC

EP

TE

D

M

A

N

U

REFERENCES 1. Ku, M.S. and W. Dulin, A biopharmaceutical classification-based Right-FirstTime formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept. Pharmaceutical Development and Technology, 2012. 17(3): p. 285-302. 2. Takagi, T., et al., A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Molecular pharmaceutics, 2006. 3(6): p. 631-643. 3. Dahan, A., J.M. Miller, and G.L. Amidon, Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. The AAPS journal, 2009. 11(4): p. 740-746. 4. Loftsson, T. and M.E. Brewster, Pharmaceutical applications of cyclodextrins: basic science and product development. Journal of Pharmacy and Pharmacology, 2010. 62(11): p. 1607-1621. 5. Kipp, J.E., The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs. International Journal of Pharmaceutics, 2004. 284(1–2): p. 109-122. 6. Singh, A., Z.A. Worku, and G. Van den Mooter, Oral formulation strategies to improve solubility of poorly water-soluble drugs. Expert Opinion on Drug Delivery, 2011. 8(10): p. 1361-1378. 7. Keserü, G.M. and G.M. Makara, The influence of lead discovery strategies on the properties of drug candidates. Nature Reviews Drug Discovery, 2009. 8(3): p. 203-212. 8. Lipinski, C.A., et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 2012. 64, Supplement(0): p. 4-17. 9. Lipinski, C.A., Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods, 2000. 44(1): p. 235-249. 10. Serajuddin, A.T.M., Salt formation to improve drug solubility. Advanced Drug Delivery Reviews, 2007. 59(7): p. 603-616. 11. Serajuddin, A.T.M. and M. Pudipeddi, Salt-selection strategies. Handbook of pharmaceutical salts: properties, selection, and use. Weinheim: Wiley-VCH, 2008: p. 135-160. 44

19. 20. 21. 22.

SC RI PT

CC

23.

U

18.

N

17.

A

16.

M

15.

D

14.

TE

13.

Stella, V.J. and Q. He, Cyclodextrins. Toxicologic Pathology, 2008. 36(1): p. 3042. Neslihan Gursoy, R. and S. Benita, Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomedicine & Pharmacotherapy, 2004. 58(3): p. 173-182. Muchow, M., P. Maincent, and R.H. Müller, Lipid nanoparticles with a solid matrix (SLN®, NLC®, LDC®) for oral drug delivery. Drug development and industrial pharmacy, 2008. 34(12): p. 1394-1405. Fenske, D.B., A. Chonn, and P.R. Cullis, Liposomal Nanomedicines: An Emerging Field. Toxicologic Pathology, 2008. 36(1): p. 21-29. Letchford, K. and H. Burt, A review of the formation and classification of amphiphilic block copolymer nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes. European Journal of Pharmaceutics and Biopharmaceutics, 2007. 65(3): p. 259-269. Gullapalli, R.P., Soft gelatin capsules (softgels). Journal of Pharmaceutical Sciences, 2010. 99(10): p. 4107-4148. Schultheiss, N. and A. Newman, Pharmaceutical cocrystals and their physicochemical properties. Crystal Growth and Design, 2009. 9(6): p. 29502967. Stephenson, G.A., A. Aburub, and T.A. Woods, Physical stability of salts of weak bases in the solid‐state. Journal of Pharmaceutical Sciences, 2011. 100(5): p. 1607-1617. Singhal, D. and W. Curatolo, Drug polymorphism and dosage form design: a practical perspective. Advanced Drug Delivery Reviews, 2004. 56(3): p. 335347. Brough, C. and R.O. Williams, Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. International Journal of Pharmaceutics, 2013. 453(1): p. 157-166. Yu, L.X., et al., Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharmaceutical Research, 2002. 19(7): p. 921-925. Wu, C.-Y. and L.Z. Benet, Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharmaceutical Research, 2005. 22(1): p. 11-23. Curatolo, W., J.A. Nightingale, and S.M. Herbig, Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu. Pharmaceutical Research, 2009. 26(6): p. 1419-1431. Huang, L.-F. and W.-Q. Tong, Impact of solid state properties on developability assessment of drug candidates. Advanced Drug Delivery Reviews, 2004. 56(3): p. 321-334.

EP

12.

A

24.

25.

45

33. 34. 35. 36.

SC RI PT

CC

37.

U

32.

N

31.

A

30.

M

29.

D

28.

TE

27.

Dressman, J.B., et al., Estimating drug solubility in the gastrointestinal tract. Advanced Drug Delivery Reviews, 2007. 59(7): p. 591-602. Zhao, Y.H., et al., Rate-limited steps of human oral absorption and QSAR studies. Pharmaceutical Research, 2002. 19(10): p. 1446-1457. Möschwitzer, J., et al., Nanocrystal formulations for improved delivery of poorly soluble drugs. Nanomedicine in Health and Disease, 2011: p. 79. Dokoumetzidis, A. and P. Macheras, A century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. International Journal of Pharmaceutics, 2006. 321(1): p. 1-11. Morales, J.O., A.B. Watts, and J.T. McConville, Mechanical Particle-Size Reduction Techniques in Formulating Poorly Water Soluble Drugs, R.O. Williams III, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International Publishing: Cham, Switzerland. p. 165-213. Galli, C., Experimental determination of the diffusion boundary layer width of micron and submicron particles. International Journal of Pharmaceutics, 2006. 313(1): p. 114-122. Shchekin, A. and A. Rusanov, Generalization of the Gibbs–Kelvin–Köhler and Ostwald–Freundlich equations for a liquid film on a soluble nanoparticle. The Journal of chemical physics, 2008. 129: p. 154116. Kesisoglou, F., S. Panmai, and Y. Wu, Nanosizing — Oral formulation development and biopharmaceutical evaluation. Advanced Drug Delivery Reviews, 2007. 59(7): p. 631-644. Shegokar, R. and R.H. Müller, Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives. International Journal of Pharmaceutics, 2010. 399(1–2): p. 129-139. Junghanns, J.U.A.H. and R.H. Müller, Nanocrystal technology, drug delivery and clinical applications. International journal of nanomedicine, 2008. 3(3): p. 295. Choi, J.-Y., et al., Role of polymeric stabilizers for drug nanocrystal dispersions. Current Applied Physics, 2005. 5(5): p. 472-474. Van Eerdenbrugh, B., G. Van den Mooter, and P. Augustijns, Top-down production of drug nanocrystals: Nanosuspension stabilization, miniaturization and transformation into solid products. International Journal of Pharmaceutics, 2008. 364(1): p. 64-75. Lee, J., J.Y. Choi, and C.H. Park, Characteristics of polymers enabling nanocomminution of water-insoluble drugs. International Journal of Pharmaceutics, 2008. 355(1–2): p. 328-336. Voorhees, P.W., The theory of Ostwald ripening. Journal of Statistical Physics, 1985. 38(1-2): p. 231-252. Merisko-Liversidge, E., G.G. Liversidge, and E.R. Cooper, Nanosizing: a formulation approach for poorly-water-soluble compounds. European Journal of Pharmaceutical Sciences, 2003. 18(2): p. 113-120.

EP

26.

A

38. 39. 40.

46

47. 48. 49.

50. 51.

SC RI PT

U

CC

52.

N

46.

A

45.

M

44.

D

43.

TE

42.

Hancock, B.C. and M. Parks, What is the true solubility advantage for amorphous pharmaceuticals? Pharmaceutical Research, 2000. 17(4): p. 397404. Miller, D.A., et al., Targeted intestinal delivery of supersaturated itraconazole for improved oral absorption. Pharmaceutical Research, 2008. 25(6): p. 14501459. Miller, D.A., et al., Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug development and industrial pharmacy, 2008. 34(8): p. 890-902. DiNunzio, J.C., et al., Amorphous compositions using concentration enhancing polymers for improved bioavailability of itraconazole. Molecular pharmaceutics, 2008. 5(6): p. 968-980. Guzmán, H.R., et al., Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. Journal of Pharmaceutical Sciences, 2007. 96(10): p. 2686-2702. Brouwers, J., M.E. Brewster, and P. Augustijns, Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability? Journal of Pharmaceutical Sciences, 2009. 98(8): p. 2549-2572. Janssens, S. and G. Van den Mooter, Review: physical chemistry of solid dispersions. Journal of Pharmacy and Pharmacology, 2010. 61(12): p. 15711586. Lindfors, L., et al., Nucleation and crystal growth in supersaturated solutions of a model drug. Journal of colloid and interface science, 2008. 325(2): p. 404413. Janssens, S., et al., Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. European Journal of Pharmaceutics and Biopharmaceutics, 2008. 69(1): p. 158-166. Raghavan, S.L., et al., Crystallization of hydrocortisone acetate: influence of polymers. International Journal of Pharmaceutics, 2001. 212(2): p. 213-221. Raghavan, S.L., et al., Formation and stabilisation of triclosan colloidal suspensions using supersaturated systems. International Journal of Pharmaceutics, 2003. 261(1–2): p. 153-158. Sun, D.D. and P.I. Lee, Evolution of Supersaturation of Amorphous Pharmaceuticals: The Effect of Rate of Supersaturation Generation. Molecular Pharmaceutics, 2013. 10(11): p. 4330-4346. Vasanthavada, M., et al., Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility. Pharmaceutical Research, 2004. 21(9): p. 1598-1606. Wang, X., A. Michoel, and G. Van den Mooter, Solid state characteristics of ternary solid dispersions composed of PVP VA64, Myrj 52 and itraconazole. International Journal of Pharmaceutics, 2005. 303(1–2): p. 54-61.

EP

41.

A

53. 54.

47

61. 62. 63. 64.

SC RI PT

U

CC

65.

N

60.

A

59.

M

58.

D

57.

TE

56.

Hancock, B.C., S.L. Shamblin, and G. Zografi, Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharmaceutical Research, 1995. 12(6): p. 799-806. Konno, H. and L.S. Taylor, Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. Journal of Pharmaceutical Sciences, 2006. 95(12): p. 2692-2705. Huang, J., R.J. Wigent, and J.B. Schwartz, Drug–polymer interaction and its significance on the physical stability of nifedipine amorphous dispersion in microparticles of an ammonio methacrylate copolymer and ethylcellulose binary blend. Journal of Pharmaceutical Sciences, 2008. 97(1): p. 251-262. Karavas, E., et al., Investigation of the release mechanism of a sparingly watersoluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug–polymer interactions. European Journal of Pharmaceutics and Biopharmaceutics, 2007. 66(3): p. 334-347. Chokshi, R.J., et al., Stabilization of Low Glass Transition Temperature Indomethacin Formulations: Impact of Polymer-Type and Its Concentration. Journal of Pharmaceutical Sciences, 2008. 97(6): p. 2286-2298. Bansal, K., U.S. Baghel, and S. Thakral, Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory. AAPS PharmSciTech, 2016. 17(2): p. 318-327. Marsac, P.J., S.L. Shamblin, and L.S. Taylor, Theoretical and Practical Approaches for Prediction of Drug–Polymer Miscibility and Solubility. Pharmaceutical Research, 2006. 23(10): p. 2417. Huang, S., et al., A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME. AAPS PharmSciTech, 2016. 17(1): p. 106-119. Marsac, P.J., et al., Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone). Journal of Pharmaceutical Sciences, 2010. 99(1): p. 169-185. Purohit, H.S. and L.S. Taylor, Phase Separation Kinetics in Amorphous Solid Dispersions Upon Exposure to Water. Molecular Pharmaceutics, 2015. 12(5): p. 1623-1635. Tian, Y., et al., Construction of Drug–Polymer Thermodynamic Phase Diagrams Using Flory–Huggins Interaction Theory: Identifying the Relevance of Temperature and Drug Weight Fraction to Phase Separation within Solid Dispersions. Molecular Pharmaceutics, 2013. 10(1): p. 236-248. Zhao, Y., et al., Prediction of the Thermal Phase Diagram of Amorphous Solid Dispersions by Flory–Huggins Theory. Journal of Pharmaceutical Sciences, 2011. 100(8): p. 3196-3207. Lin, D. and Y. Huang, A thermal analysis method to predict the complete phase diagram of drug–polymer solid dispersions. International Journal of Pharmaceutics, 2010. 399(1): p. 109-115.

EP

55.

A

66. 67.

48

74. 75.

76. 77. 78.

SC RI PT

U

CC

79.

N

73.

A

72.

M

71.

D

70.

TE

69.

Marsac, P.J., T. Li, and L.S. Taylor, Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters. Pharmaceutical Research, 2008. 26(1): p. 139. Page, S., R. Maurer, and N. Wyttenbach, Optimizing the Formulation of Poorly Water-Soluble Drugs, in Formulating Poorly Water Soluble Drugs, R.O. Williams III, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International: Cham, Switzerland. p. 329-382. Qian, F., J. Huang, and M.A. Hussain, Drug–polymer solubility and miscibility: Stability consideration and practical challenges in amorphous solid dispersion development. Journal of Pharmaceutical Sciences, 2010. 99(7): p. 2941-2947. Waterman, K.C. and B.C. MacDonald, Package selection for moisture protection for solid, oral drug products. Journal of Pharmaceutical Sciences, 2010. 99(11): p. 4437-4452. Möschwitzer, J.P., Drug nanocrystals in the commercial pharmaceutical development process. International Journal of Pharmaceutics, 2012. Möschwitzer, J., Particle Size Reduction Technologies in the Pharmaceutical Development Process. American Pharmaceutical Review, 2010 (April), 2010: p. 54-59. Merisko-Liversidge, E.M. and G.G. Liversidge, Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds. Toxicologic Pathology, 2008. 36(1): p. 43-48. Merisko-Liversidge, E. and G.G. Liversidge, Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology. Advanced Drug Delivery Reviews, 2011. 63(6): p. 427-440. Cooper, E.R., Nanoparticles: A personal experience for formulating poorly water soluble drugs. Journal of Controlled Release, 2010. 141(3): p. 300-302. Arunkumar, N., M. Deecaraman, and C. Rani, Nanosuspension technology and its applications in drug delivery. Asian journal of pharmaceutics, 2009. 3(3): p. 168. Texter, J., Precipitation and condensation of organic particles. Journal of dispersion science and technology, 2001. 22(6): p. 499-527. de Waard, H., W.L.J. Hinrichs, and H.W. Frijlink, A novel bottom–up process to produce drug nanocrystals: Controlled crystallization during freeze-drying. Journal of Controlled Release, 2008. 128(2): p. 179-183. Vehring, R., Pharmaceutical particle engineering via spray drying. Pharmaceutical Research, 2008. 25(5): p. 999-1022. Masters, K. and I. SprayDryConsult, Spray drying in practice. 2002, Charlottenlund. Wu, C. and J.W. McGinity, Influence of ibuprofen as a solid-state plasticizer in Eudragit® RS 30 D on the physicochemical properties of coated beads. AAPS PharmSciTech, 2001. 2(4): p. 35-43.

EP

68.

A

80. 81. 82.

49

86.

87.

88.

92.

D

CC

93.

TE

91.

EP

90.

M

A

89.

SC RI PT

85.

U

84.

Crowley, M.M., et al., Pharmaceutical applications of hot-melt extrusion: part I. Drug development and industrial pharmacy, 2007. 33(9): p. 909-926. Gupta, S.S., et al., Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion, I: Polyvinylpyrrolidone and related polymers. Journal of Excipients and Food Chemicals, 2014(1): p. 32-45. Miller, D.A., et al., KinetiSol: A New Processing Paradigm for Amorphous Solid Dispersion Systems. Drug Development and Delivery, 2012. 12(9). DiNunzio, J.C., et al., Fusion production of solid dispersions containing a heatsensitive active ingredient by hot melt extrusion and Kinetisol® dispersing. European Journal of Pharmaceutics and Biopharmaceutics, 2010. 74(2): p. 340-351. Hughey, J.R., et al., Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing. AAPS PharmSciTech, 2010. 11(2): p. 760-774. Hughey, J.R., et al., Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: The utility of KinetiSol® Dispersing. International Journal of Pharmaceutics, 2011. 419(1): p. 222-230. Prasad, L.K., et al., Emerging Technologies to Increase the Bioavailability of Poorly Water-Soluble Drugs, in Formulating Poorly Water Soluble Drugs, R.O. Williams III, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International: Cham, Switzerland. p. 691-740. DiNunzio, J.C., et al., Fusion processing of itraconazole solid dispersions by kinetisol dispersing: A comparative study to hot melt extrusion. Journal of Pharmaceutical Sciences, 2010. 99(3): p. 1239-1253. DiNunzio, J.C., et al., Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing. Drug Development and Industrial Pharmacy, 2010. 36(9): p. 1064-1078. DiNunzio, J.C., et al., Applications of KinetiSol® Dispersing for the production of plasticizer free amorphous solid dispersions. European Journal of Pharmaceutical Sciences, 2010. 40(3): p. 179-187. LaFountaine, J.S., et al., Enabling thermal processing of ritonavir–polyvinyl alcohol amorphous solid dispersions by KinetiSol® Dispersing. European Journal of Pharmaceutics and Biopharmaceutics, 2016. 101: p. 72-81. Campbell, I., D. Bourell, and I. Gibson, Additive manufacturing: rapid prototyping comes of age. Rapid Prototyping Journal, 2012. 18(4): p. 255-258. Hoque, M.E., Y.L. Chuan, and I. Pashby, Extrusion based rapid prototyping technique: An advanced platform for tissue engineering scaffold fabrication. Biopolymers, 2012. 97(2): p. 83-93. Sandler, N., et al., Towards fabrication of 3D printed medical devices to prevent biofilm formation. International Journal of Pharmaceutics, 2014. 459(1): p. 62-64.

N

83.

94.

A

95. 96.

50

103. 104. 105. 106.

SC RI PT

U

CC

107.

N

102.

A

101.

M

100.

D

99.

TE

98.

Wang, F., et al., Precision extruding deposition and characterization of cellular poly‐ε‐caprolactone tissue scaffolds. Rapid Prototyping Journal, 2004. 10(1): p. 42-49. Fini, A., et al., Ultrasound-compacted and spray-congealed indomethacin/polyethyleneglycol systems. International Journal of Pharmaceutics, 2002. 247(1–2): p. 11-22. Wong, P.C.H., P.W.S. Heng, and L.W. Chan, Determination of Solid State Characteristics of Spray-Congealed Ibuprofen Solid Lipid Microparticles and Their Impact on Sustaining Drug Release. Molecular Pharmaceutics, 2015. 12(5): p. 1592-1604. Fakes, M.G., et al., Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches. International Journal of Pharmaceutics, 2009. 370(1): p. 167-174. Zheng, W., et al., Selection of oral bioavailability enhancing formulations during drug discovery. Vol. 38. 2011. 235-47. Vogt, M., K. Kunath, and J.B. Dressman, Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: Comparison with commercial preparations. European Journal of Pharmaceutics and Biopharmaceutics, 2008. 68(2): p. 283-288. Kwong, E., J. Higgins, and A.C. Templeton, Strategies for bringing drug delivery tools into discovery. International Journal of Pharmaceutics, 2011. 412(1): p. 1-7. Thombre, A.G., et al., In vitro and in vivo characterization of amorphous, nanocrystalline, and crystalline ziprasidone formulations. International Journal of Pharmaceutics, 2012. 428(1): p. 8-17. Thombre, A.G., S.M. Herbig, and J.A. Alderman, Improved Ziprasidone Formulations with Enhanced Bioavailability in the Fasted State and a Reduced Food Effect. Pharmaceutical Research, 2011. 28(12): p. 3159-3170. Sigfridsson, K., et al., A formulation comparison, using a solution and different nanosuspensions of a poorly soluble compound. Vol. 67. 2007. 540-7. Sun, W., et al., Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation. Drug Development and Industrial Pharmacy, 2015. 41(6): p. 927933. Sun, W., et al., Nanonization of itraconazole by high pressure homogenization: Stabilizer optimization and effect of particle size on oral absorption. Journal of Pharmaceutical Sciences, 2011. 100(8): p. 3365-3373. De Smet, L., et al., Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs. European Journal of Pharmaceutics and Biopharmaceutics, 2014. 87(1): p. 107-113.

EP

97.

A

108. 109.

51

117. 118. 119. 120. 121.

SC RI PT

CC

122.

U

116.

N

115.

A

114.

M

113.

D

112.

TE

111.

Gao, L., et al., Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs. Pharmaceutical Research, 2013. 30(2): p. 307-324. Shen, L.J., Nanomedicines in renal transplant rejection–focus on sirolimus. International journal of nanomedicine, 2007. 2(1): p. 25-32. Wu, Y., et al., The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. International Journal of Pharmaceutics, 2004. 285(1–2): p. 135-146. Hoy, S.M., L.J. Scott, and G.M. Keating, Intramuscular paliperidone palmitate. CNS drugs, 2010. 24(3): p. 227-244. He, Y. and C. Ho, Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development. Journal of Pharmaceutical Sciences, 2015. 104(10): p. 3237-3258. Kawabata, Y., et al., Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. International Journal of Pharmaceutics, 2011. 420(1): p. 1-10. Vasconcelos, T., et al., Amorphous solid dispersions: Rational selection of a manufacturing process. Advanced Drug Delivery Reviews, 2016. 100: p. 85101. Huang, S. and R.O. Williams, Effects of the Preparation Process on the Properties of Amorphous Solid Dispersions. AAPS PharmSciTech, 2017. Chen, B., et al., Chapter 31 - Process Development and Scale-Up: Twin-Screw Extrusion, in Developing Solid Oral Dosage Forms (Second Edition). 2017, Academic Press: Boston. p. 821-868. Rumondor, A.C.F., S.S. Dhareshwar, and F. Kesisoglou, Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption. Journal of Pharmaceutical Sciences, 2016. 105(9): p. 2498-2508. Maviret. 2017, European Medicines Agency. p. 126. Klein, C.E., et al., The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2007. 44(4): p. 401-410. Sherman, E.M. and J.G. Steinberg, Heat-stable ritonavir tablets: a new formulation of a pharmacokinetic enhancer for HIV. Expert Opinion on Pharmacotherapy, 2011. 12(1): p. 141-148. Chemburkar, S.R., et al., Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development. Organic Process Research & Development, 2000. 4(5): p. 413-417. Verreck, G., et al., Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion—part I. International Journal of Pharmaceutics, 2003. 251(1–2): p. 165-174.

EP

110.

A

123. 124.

52

127. 128. 129. 130.

135.

M

CC

136.

D

134.

TE

133.

EP

132.

A

N

131.

SC RI PT

126.

Lee, S., et al., Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability. Archives of Pharmacal Research, 2005. 28(7): p. 866-874. Six, K., et al., Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion, part II. Pharmaceutical Research, 2003. 20(7): p. 1047-1054. Shah, N., et al., Development of Novel Microprecipitated Bulk Powder (MBP) Technology for Manufacturing Stable Amorphous Formulations of Poorly Soluble Drugs. International Journal of Pharmaceutics, 2012. Harmon, A., A Roller Coaster Chase for a Cure, in The New York Times. 2010. Harmon, A., After Long Fight, Drug Gives Sudden Reprieve, in The New York Times. 2010. Hurter, P., et al., SOLID FORMS OF N-[2,4-BIS(1,1-DIMETHYLETHYL)-5HYDROXYPHENYL]-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE, V. Pharmaceuticals, Editor. 2011. Miller, D.A., D. Ellenberger, and M. Gil, Spray-Drying Technology, in Formulating Poorly Water Soluble Drugs, R.O. Williams III, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International: Cham, Switzerland. p. 437525. Wiederhold, N.P., Pharmacokinetics and safety of posaconazole delayedrelease tablets for invasive fungal infections. Clinical Pharmacology : Advances and Applications, 2016. 8: p. 1-8. Krishna, G., et al., Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers. Antimicrobial Agents and Chemotherapy, 2009. 53(3): p. 958-966. Walsh, T.J., et al., Treatment of Invasive Aspergillosis with Posaconazole in Patients Who Are Refractory to or Intolerant of Conventional Therapy: An Externally Controlled Trial. Clinical Infectious Diseases, 2007. 44(1): p. 2-12. Courtney, R., et al., Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. British Journal of Clinical Pharmacology, 2004. 57(2): p. 218-222. Kraft, W.K., et al., Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrobial agents and chemotherapy, 2014. 58(7): p. 4020-4025. Cornely, O.A., et al., Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. Journal of Antimicrobial Chemotherapy, 2016. 71(3): p. 718-726. Duarte, R.F., et al., Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia. Antimicrobial agents and chemotherapy, 2014. 58(10): p. 5758-5765.

U

125.

A

137. 138.

53

140. 141.

142.

A

CC

EP

TE

D

M

A

N

U

143.

Haser, A., et al., Melt Extrusion, in Formulating Poorly Water Soluble Drugs, R.O. Williams III, A.B. Watts, and D.A. Miller, Editors. 2016, Springer International: Cham, Switzerland. p. 383-435. Harmon, P.A. and N. Variankaval, Solid dosage formulations of an orexin receptor antagonist. 2013, Merck Sharp & Dohme Corp. Kesisoglou, F., et al., Development of In Vitro–In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls. Journal of Pharmaceutical Sciences, 2015. 104(9): p. 2913-2922. Grabowski, H., Patents, Innovation and Access to New Pharmaceuticals. Journal of International Economic Law, 2002. 5(4): p. 849-860. Lehman, B. The Pharmaceutical Industry and the Patent System. 2003.

SC RI PT

139.

54

SC RI PT

Three energies that determine solubility of the solid solute [21](reproduced with permission).

EP

TE

D

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N

U

Figure 1:

‘Spring & Parachute’ concept for supersaturation stability [46] (adapted, reproduced with permission).

A

CC

Figure 2:

55

SC RI PT U N

A

Phase diagram for a drug-polymer system using Flory-Huggins theory. Regions A and B demonstrate a stable amorphous dispersion, Regions C and D suggest a metastable amorphous dispersion, and Regions E and F demonstrate an instable amorphous dispersion [65](reproduced with permission).

A

CC

EP

TE

D

M

Figure 3:

56

SC RI PT U N

A

Free energy of mixing as a function of composition at different interaction parameters [69](reproduced with permission).

A

CC

EP

TE

D

M

Figure 4:

57

SC RI PT U

Dose proportionality of compound 3 in 10% Tween (-▲-) as the crystalline form; in 0.5% Methocel/0.24% SLS as the amorphous form (■-) and in solid dispersion at 50% drug loading in HPMC-AS given as suspension in Methocel (-●-) from 10 mpk to 750 mpk dosed at 5 ml/kg in Sprague Dawley rats (n=4) [103] (corrected, reproduced with permission).

A

CC

EP

TE

D

M

A

N

Figure 5:

58

SC RI PT U N A M D

Timeline of FDA-approved products for amorphous solid dispersions and nanocrystals.

A

CC

EP

TE

Figure 6:

59

SC RI PT U N A M D

TE

Timeline of patent applications filed for amorphous solid dispersions and nanocrystals.

A

CC

EP

Figure 7:

60

Generic Name Sirolimus Aprepitant Fenofibrate Fenofibrate Megestrol acetate Paliperidone palmitate

Processing Technology NanoCrystal® NanoCrystal® NanoCrystal® IDD-P™ NanoCrystal® NanoCrystal®

Company Pfizer (Wyeth) Merck Fournier Pharma (AbbVie) Sciele Pharma, SkyePharma PAR Pharmaceuticals Janssen

A

CC

EP

TE

D

M

A

N

U

Trade Name Rapamune® Emend® TriCor® Triglide® Megace® ES Invega Sustenna®

Examples of FDA-approved nanocrystal products (adapted) [72, 110]

61

FDA Approval 2000 2003 2004 2005 2005 2009

SC RI PT

Table 1:

Examples of FDA-approved products that are based on amorphous solid dispersions. Citations

Meda Pharmaceuticals Ranbaxy Laboratories Janssen Astellas Pharma Merck

FDA Approval 1985 1987 1992 1994 2001

Melt extrusion Spray drying

AbbVie Janssen

2007 2008

Tacrolimus Everolimus

Spray drying Spray drying

Astellas Pharma Novartis

2009 2010

Norvir® Tablet

Ritonavir

Melt extrusion

AbbVie

2010

[114-119] [114-117, 119] [116, 117] [114-117, 119] [114-119]

Onmel®

Itraconazole

Melt extrusion

U

Table 2:

Generic Name

Processing Technology

Company

Cesamet® ISOPTIN® SR Sporanox® Prograf® NuvaRing®

Solvent evaporation Melt extrusion Fluid bed bead layering Spray drying Melt extrusion

Kaletra® Intelence®

Nabilone Verapamil Itraconazole Tacrolimus Etonogestrel/Ethinyl Estradiol Lopinavir/Ritonavir Etravirin

Modigraf® Zortress®

Merz Pharma

2010

INCIVEK™

Telaprevir

Spray drying

Vertex

2011

Zelboraf®

Vemurafenib

Roche

2011

Kalydeco®

Ivacaftor

Solvent/anti-solvent precipitation Spray drying

Vertex

2012

Noxafil® DelayedRelease Tablet

Posaconazole

Melt extrusion

Merck

2013

Astagraf XL®

Tacrolimus

Wet granulation

Astellas Pharma

2013

[114, 119]

Belsomra® Harvoni® Viekira XR™

Suvorexant Ledipasvir/Sofosbuvir Dasabuvir/Ombitasvir/ Paritaprevir/Ritonavir Sofosbuvir/Velpatasvir Lumacaftor/Ivacaftor Venetoclax Elbasvir/Grazoprevir Glecaprevir/Pibrentasvir

Melt extrusion Spray drying Melt extrusion

Merck Gilead Sciences AbbVie

2014 2014 2014

[117-119] [117, 119] [116-119]

Spray drying Spray drying Melt extrusion Spray drying Melt extrusion

Gilead Sciences Vertex AbbVie Merck AbbVie

2016 2016 2016 2016 2017

[117, 119] [116, 117] [117, 118] [118] [120]

N

A

M

D

TE

EP

A

CC

Epclusa® Orkambi® Venclexta™ Zepatier® Mavyret™

62

[114-116] [114, 117] [114-117] [114-117] [117, 118]

SC RI PT

Trade Name

[114, 116119] [114, 116, 117, 119] [114, 116, 117, 119] [114, 116, 117, 119] [114, 116119]