Analytical aspects of printed oral dosage forms

Accepted Manuscript Analytical aspects of printed oral dosage forms Magnus Edinger, Jette Jacobsen, Daniel Bar-Shalom, Jukka Rantanen, Natalja Genina PII: DOI: Reference:

S0378-5173(18)30765-8 https://doi.org/10.1016/j.ijpharm.2018.10.030 IJP 17848

To appear in:

International Journal of Pharmaceutics

Received Date: Revised Date: Accepted Date:

9 July 2018 30 August 2018 10 October 2018

Please cite this article as: M. Edinger, J. Jacobsen, D. Bar-Shalom, J. Rantanen, N. Genina, Analytical aspects of printed oral dosage forms, International Journal of Pharmaceutics (2018), doi: https://doi.org/10.1016/j.ijpharm. 2018.10.030

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Analytical aspects of printed oral dosage forms

Magnus Edinger1, Jette Jacobsen1, Daniel Bar-Shalom1, Jukka Rantanen1, Natalja Genina1* 1

Department of Pharmacy, Faculty of Health and Medical Sciences, University of

Copenhagen, Universitetsparken 2, DK-2100, Denmark *

Correspondence to: Natalja Genina, Department of Pharmacy, Universitetsparken 2, DK-

2100 Copenhagen, Denmark, Telephone: +45 35337923; E-mail: [email protected]

ABSTRACT Printing technologies, both 2D and 3D, have gained considerable interest during the last years for manufacturing of personalized dosage forms, tailored to each patient. Here we review the research work on 2D printing techniques, mainly inkjet printing, for manufacturing of filmbased oral dosage forms. We describe the different printing techniques and give an overview of film-based oral dosage forms produced using them. The main part of the review focuses on the non-destructive analytical methods used for evaluation of qualitative aspects of printed dosage forms, e.g., solid-state properties, as well as for quantification of the active pharmaceutical ingredient (API) in the printed dosage forms, with an emphasis on spectroscopic methods. Finally, the authors share their view on the future of printed dosage forms. Keywords: inkjet printing, personalized medicine, analytical methods, quantification

1 INTRODUCTION Personalized, precision or stratified medicine is gaining interest in the providing of an optimal treatment of diseases for each individual (EMA, 2017; NIH, 2018). Conceptually, personalized medicine is the opposite of the current “one-size-fits-all” strategy, where a standardized dose is prescribed to the majority of the population. In the case of precision medicine, treatment of a given disease is optimized for each specific patient, based on his or her expected/experienced response to the treatment. This, in turn, can be based on the patient’s age, gender, weight, lifestyle, genome, etc. For example, one patient may respond well to a low dose of a given medication, while another may have a faster drug metabolism, requiring administration of a higher dose. If both patients receive the same dose, one could experience side effects, while the other might not see a therapeutic response. A good example of a prescription drug with a narrow therapeutic window is zolpidem, prescribed to a patient for the treatment of insomnia. The patient did not experience an effect at a dose of 5 mg, but experienced adverse effects at a dose of 10 mg. No intermediate doses were available (Pies, 1995). A similar case could be seen with the anticoagulant warfarin, where the dose has to be thoroughly titrated for each patient (Vuddanda et al., 2018) . However, availability of different doses for this drug is limited in many countries, e.g., in Denmark only 2.5 mg tablets are available and the number of tablets taken is titrated to each patient (DLI, 2018). Potential co-morbidities can also be taken into account when optimizing the treatment for a specific patient, e.g., by incorporating multiple drugs into a single dosage unit. This strategy can help minimize the number of dosage units needed to be administered per day, and by that improve quality of life (Bryant et al., 2013; Williams et al., 2005). A fixed dose combination can also have a synergistic effect. For example, co-administration of lopinavir with a low dose of ritonavir would guarantee an adequate bioavailability of lopinavir and improve the effectiveness of antiretroviral treatment (Abbvie, 2018).

The prerequisite for the successful implementation of the concept of personalized medicine is the possibility of continuous monitoring of multiple parameters such as pharmacogenetic, physiological, psychological responses and so on, by a healthcare professional and/or a patient (Lind et al., 2017). Continuous collection of medical information combined with patients’ data about the diet, lifestyle and social network is needed to define the most appropriate treatment at a current time point. Therefore, the development of sensors for realtime detection of changes in multiple responses, together with the progress in applications to be used with smart devices, can be considered as an integral part of the concept of personalized medicine (Hayes et al., 2014). Additive manufacturing (AM) technology, by means of two-dimensional (2D) and threedimensional (3D) printing, has gained considerable interest in the manufacturing of personalized dosage forms, culminating with the recent FDA approval of the first 3D printed pharmaceutical product Spritam® (Aprecia® Pharmaceuticals) that is now commercially available (Di Prima et al., 2016). The main advantage of AM is the flexibility of the technology to adjust the dose of the dosage unit on-demand, for example, by either altering the physical dimensions and/or the geometry of the objects (Lind et al., 2017). Quick adjustment of the dose happens digitally by modifying the configuration of the dosage form in the computer software. As a result, the need of changing the formulation, its process parameters and/or the equipment is avoided; this would be a definite requirement if the manufacturing of dosage forms was done with the traditional manufacturing methods. While currently there is a lot of focus on 3D printing for additive manufacturing of personalized dosage forms, especially by Fused Deposition Modelling (FDM) (Trenfield et al., 2018), 2D printing technologies, such as inkjet (IJP) and flexographic printing, have also maintained interest in this regard (Scoutaris et al., 2016). These printing methods have been known for several decades in other industrial areas than the pharmaceutical, e.g., typography,

microelectronics, bioprinting, etc. Besides that, the food industry also has solutions for printing of edible materials, for example printers for cake decoration are available, using inks containing fruit colouring. Here, we attempt to give an overview of the most used printing methods in the production of personalized oral dosage forms such as oral films. The formulation strategies will be thoroughly discussed. The main focus of this review will be the description of the existing non-destructive systems to be used for quality control and assurance of the printed dosage forms. The prospects for continuous manufacturing of personalized medicine by printing will be mentioned and the authors’ predictions as to the future of printed medicine will be presented.

2 PRINTING METHODS Among 2D printing, IJP as a non-contact printing method and flexographic printing as a contact printing method have been proposed for the production of dosage forms (Alomari et al., 2015; Kolakovic et al., 2013; Scoutaris et al., 2016), while 3D printing, based on FDM, has been used for manufacture of film-based oral dosage forms (Ehtezazi et al., 2018; Goole and Amighi, 2016; Jamróz et al., 2017). The main difference between 2D printing and 3D printing for pharmacoprinting, i.e., printing of pharmaceuticals, is the need for a preproduced, edible carrier (substrate) in 2D printing that would hold/sorb the deposited ink in a digitally predefined pattern. Therefore, 2D printing is mostly limited to printing in the X and Y directions, while 3D printing possesses the geometry building potential as it enables printing in the Z direction by adding material layer-by-layer, resulting in a 3D dosage form. Despite this, inkjet printing has been used for manufacturing of 3D dosage forms (AcostaVélez et al., 2018; Clark et al., 2017; Kyobula et al., 2017), but nonetheless its main use has so far been in the 2D printing of pharmaceuticals on pre-manufactured substrates.

2.1 Inkjet printing (IJP) IJP is widely implemented in common office printers for printing documents and images. IJP can furthermore be divided into two different techniques, continuous and drop-on-demand (DoD). In continuous inkjet printers, the liquid ink is directed through a nozzle using a highpressure pump, thereby forming a continuous stream of ink which is then broken up into a continuous stream of droplets using a piezoelectric transducer. An electrical charge is induced on the droplets in order to control their landing site to produce a usable pattern, while unneeded droplets are caught and recirculated through the printing system (Furlani, 2016). Continuous inkjet printers are widely used at different industrial settings, but they have not been used within the pharmaceutical field yet, likely due to the setup requiring a high recirculating ink volume (Daly et al., 2015). In contrast to continuous printing, the DoD printing technique only produces and ejects the precise amount of droplets when it is needed, according to the pre-programmed settings. This allows good control over the deposited amount of ink. The printing system consists of an ink reservoir and one or multiple nozzles equipped with a transducer. The type of the transducer subdivides DoD technology into piezoelectric inkjet (PIJ) and thermal inkjet (TIJ) printing. In PIJ, a piezoelectric element situated near the nozzle is actuated, whereby it deforms, ejecting a droplet of ink from the nozzle. The element then returns to its original shape, whereby the nozzle is filled with the ink from the reservoir, ready for ejecting a new droplet. PIJ has been widely used in the pharmaceutical development (Table 1). In contrast to PIJ, thermal inkjet printing (TIJ) includes a thermal actuation element in good contact with the ink. Rapid heating (within a few µs) of the element causes a vapor bubble to form, creating a fluid displacement that ejects a droplet from the nozzle. The heat source is then switched off, causing a rapid collapse of the bubble and the nozzle is again filled with ink from the reservoir (Yeates et al., 2012). TIJ has also been implemented within the pharmaceutical

research (Table 1). Due to the application of heat from the thermal element there may be a risk of degradation of thermolabile compounds such as proteins and biomacromolecules. However, multiple studies have shown that proteins and peptides show little to no degradation when printed using a TIJ system, likely due to the extremely short duration of the heating and ejection of the droplet (Goodall et al., 2002; Montenegro-Nicolini et al., 2017). PIJ and TIJ each has their advantages and disadvantages. TIJ requires the use of fluids which can be vaporized to eject the droplets. Both TIJ and PIJ operates with liquids within the proper viscosity range, as described in section 3.2.1. A main advantage of both methods is that they require low volumes of ink, making them suitable for research within the pharmaceutical field (Daly et al., 2015). 2.2 Other Drop-on-Demand printing techniques Multiple methods related to inkjet printing has been described, namely solenoid valve printing, where ink, held under pressure, is ejected by opening and closing a precisely controlled solenoid valve with a good droplet reproducibility (Planchette et al., 2016). Dropwise additive manufacturing (DAMPP) is another technique, where the ink is pumped through a single-channel, positive-displacement pump. The droplet volume is adjustable by regulating the displacement within the pump (Hirshfield et al., 2014). These methods have similar ink requirements as TIJ and PIJ (section 3.2.1) and both show good reproducibility. Electrohydrodynamic printing (EHD) is a printing method, where enough ink is filled into a nozzle to form a drop, but not enough to drip. A voltage is applied to an electrode placed under the substrate, stretching the ink from the nozzle to form a liquid bridge between the nozzle and the substrate. This bridge eventually breaks, leaving one droplet on the substrate and the remaining ink stays in the nozzle which is then used for another printing round. EHD can be used with higher-viscosity inks compared to the other printing methods, while still maintaining good drop reproducibility (Elele et al., 2010; Elele et al., 2012).

2.3 Flexographic printing Another technique primarily used in the graphical printing industry is flexographic printing, where the ink is first transferred from the ink tank by a fountain cylinder to the meter roll (anilox roll), which is in turn brought in contact with the plate cylinder with the relief pattern. The latter transfers the ink to the carrier (substrate), attached to the impression roll, in the shape, corresponding to the relief pattern (Kipphan, 2001). Flexographic printing is a highthroughput method, enabling printing of up to 16 m per minute (Janßen et al., 2013). However, it is challenging at achieving dosing precision as the amount of the ink deposited is dependent on a number of factors such as the ink viscosity and its adhesion to the substrate (De Micheli, 2000; Palo et al., 2015). Despite the limitations, flexographic printing has been successfully used for the development of orodispersible dosage forms (Table 1) 2.4 3D printing 3D printing has also been used for the manufacture of oral films. One of the most widely used 3D printing techniques in the pharmaceutical research is fused deposition modeling (FDM), where a strand of thermoplastic polymer is pushed into a nozzle using rollers. In the nozzle heat is applied, melting the polymer which is then deposited onto a build plate on which it solidifies. The sample is then built up layer by layer. The nozzle and the build plate are moved in a specified pattern during printing, creating samples of a specified geometry (Goole and Amighi, 2016). FDM have been used for the manufacture of orodispersible films containing aripiprazole, where 3D printed films had better dissolution rate compared to conventional cast films (Jamróz et al., 2017). Multi-layered fast dissolving oral films containing ibuprofen have been produced by FDM. It was possible to modify the release and the disintegration times based on the selection of the geometry (Ehtezazi et al., 2018). 3 PRINTED ORAL SOLID DOSAGE FORMs

In most research studies, manufacturing of oral solid dosage forms by 2D printing involves: (i) formulation of drug-containing inks; (ii) fabrication of edible carriers (substrate); (iii) printing of the ink onto the substrate; and (iv) drying. The review articles by Raijada et al. (2013) and Alomari et al. (2015) suggest formulations strategies for the development of printable dosage forms. Lind et al. give an overview of the approaches used to fabricate flexible doses by printing technologies (Lind et al., 2017). A very recent work suggests the modification of a commercially available TIJ printer to produce personalized medicine products (Vuddanda et al., 2018). In this review, we provide a further insight into the fabrication of drug products by 2D printing with a focus on non-destructive analytical techniques for real-time drug quantification of printed dosage forms. 3.1 The Active Pharmaceutical Ingredient (API) Potent APIs with a narrow therapeutic index are the best candidates for 2D printed personalized medicine, because they have to be precisely titrated to each patient, e.g., based on body weight (Ursan et al., 2013; Vuddanda et al., 2018). Therefore, hormones, biomacromolecules, psychoactive and anticancer drugs are the most obvious candidates to consider when 2D printing is in question (Lind et al., 2017). The reasons behind that are (i) flexible and at the same time precise dose adjustment is needed for these APIs; (ii) there is a limit in the amount of the API to be incorporated to the dosage form by printing; (iii) patientfriendly needle free dosage forms are possible to produce on-demand. 3.2 Ink formulation 3.2.1 Drop-on-Demand The most common ink formulations include API(s), solvents, co-solvents and humectant (Alomari et al., 2015; Kolakovic et al., 2013). Surface active agents, viscosity modifiers and

colorants can be also present. In general, the physicochemical properties of the API dictate the choice of the liquids to be used so that the liquid composition with the highest solubility of the selected API in it is normally preferred. If a poorly soluble API is chosen, nanosuspensions have been used as a way of formulating the ink with an acceptable concentration of the API (Cheow et al., 2015; Pardeike et al., 2011; Wickström et al., 2017a).

order to achieve reproducible doses when using DoD printing, it must be ensured that the droplets formed are of constant physical dimensions and that no “satellite droplets”, smaller drops separate from the main drop, are formed. Inconsistency in size and shape of jetted droplets may lead to variation in the deposited amount of API between the dosage units. Furthermore, one must ensure that the ink neither leaks from the nozzle nor accumulates at the nozzle. In DoD printing, the liquid is ejected from the nozzle in the form of a jet, consisting of preferably spherical single droplets that is deposited onto the substrate. Therefore, the viscosity and surface tension of the ink play a major role in the formation of regular droplets during printing and is related to the Ohnesorge number (Oh), defined by Eq. 1. Eq. 1

Where η is the viscosity, γ is the surface tension, ρ is the density of the fluid, while d is the characteristic length, usually equal to the diameter of the nozzle. An Ohnesorge number between approximately 1 and 0.1 is required for a successful printability. If it is too high, viscous forces within the ink will prevent the formation of a drop, while if it is too low, satellite droplets or leaking will be observed during printing (Derby, 2010). The velocity of

the ejected droplet must also be taken into account, which is described by the Reynolds number (Re), defined by Eq. 2.

Eq. 2

Where V is the velocity of the ejected droplet. In order to achieve a printable ink formulation, where no satellite droplets or splashing on the substrate occur, an empirical relationship between the Reynolds and Ohnesorge numbers have been devised:

and

(McKinley and Renardy, 2011). These statements only apply to newtonian fluids. For more rheologically complex fluids such as suspensions or polymer solutions, where the rheological properties of the ink is dependent on the shearing forces exerted on the ink within the nozzle, the situation becomes more complex, making it difficult to print reproducible amounts of the ink (Clasen et al., 2012; Hoath et al., 2013; Hoath et al., 2012). It is evident that the ink formulation must be adapted to the chosen printer. 3.2.2 Flexography As the printing principle of the roll-to-roll printing is different from DoD, the requirements for the composition of the ink is also different. For example, the viscosity of the ink should be higher to allow a reproducible print (Kolakovic et al., 2013). Therefore, liquids of high viscosity (>40 mPa·s) or low viscosity liquids with solid viscosity modifiers are needed to make a printable ink. Inclusion of humectants is not crucial in flexographic printing (Raijada et al., 2013). 3.3 Substrates Besides the ink formulation, selection of the substrate is another important aspect in development of the successful drug product for 2D printing. Films, sheets, strips, solid foams with or without pre-incorporated drug are considered as suitable substrates for printing of the

drug-containing ink (Table 1). These substrates are often produced by solvent casting techniques, where the drying step is performed at ambient conditions or in an oven. Another method used is hot-melt extrusion, where excipients and, optionally, an API is mixed in a heated barrel with reciprocating screws, forced through a die and potentially downstreamprocessed in a film (Borges et al., 2015). Solid foams (also referred to as wafers) are usually produced by freeze-drying (Ayensu et al., 2012; Boateng et al., 2010; Iftimi et al., 2018) and/or vacuum-oven drying after being solvent-cast (Edinger et al., 2017). The selection of the most appropriate substrate for a printed dosage form depends on a number of factors, including the intended delivery route, the API(s), the dose(s), printing technique and the ink formulation. For example, the intended delivery route (oral, buccal, sublingual, cutaneous) dictates the composition of the substrates. For orodispersible delivery systems, fast disintegration/dissolution in the mouth is of high importance, therefore, substrates based on water soluble polymers with or without superdisintegrants are the primary choice (Janßen et al., 2013). Taste masking has to be considered as well (Douroumis, 2011). Buccal delivery would require the inclusion of mucoadhesive polymers in the formulation (MontenegroNicolini and Morales, 2017; Montenegro-Nicolini et al., 2018; Palo et al., 2017) and in case of systemic delivery via the cheeks, a water impermeable backing membrane can be added (Chinna Reddy et al., 2011). The pharmacokinetics of the chosen API affects the administration route. In case of extensive first-pass metabolism or in the case of biologics and macromolecules, oral administration should preferably be avoided, and e.g. buccal delivery might be selected (Morales et al., 2017). Early research work, related to printable pharmaceuticals, has been performed with non-edible substrates, such as paper (Genina et al., 2012), transparency films (Buanz et al., 2011) and fiberglass films (Meléndez et al., 2008) . However, these model substrates are usually regarded not acceptable for oral administration

of pharmaceuticals either due to them not being safe for patient administration, or due to low patient acceptance. The required mechanical properties of the substrates depend upon the chosen printing process. For instance, roll-to-roll printing would require a flexible and, at the same time, mechanically strong substrate (Raijada et al., 2013). In general, the substrates with adequate elasticity would be preferred for use with any printing technology. In case of a brittle material (e.g., a polymer), a sufficient addition of plasticizers in the substrate formulation would be required. Adaptable production of personalized medicine implies printing of varying doses of the API on-demand. However, solvent-cast oral films have a limited absorption capacity for the printing inks (Iftimi et al., 2018). Therefore, it is challenging to fabricate dosage forms with high doses of APIs due to insufficient penetration of the ink into the thin non-porous substrate. This in turn could cause crystallization of printed API at the surface of the substrate with potentially poor attachment to the carrier. Further, use of such dosage forms may be problematic due to a potential loss of API during handling, storage and transport resulting in non-compliance with the tests for mass and content uniformity (Raijada et al., 2013). The use of porous solid foams with a superior absorption capacity has been proposed as substrates addressing these problems (Elele et al., 2012; Iftimi et al., 2018). Introduction of porosity increasing agents in the composition of the oral films can be another solution to improve the absorption capacity of the substrate. An optimized porosity of the substrate, especially at its surface, could be required, when an easily distinguishable printed pattern, for example a pattern readable by smart devices, without edge bleeding and other defects is needed (Edinger et al., 2018). However, extensive absorption of the ink onto the substrate (in this case a colour agent is usually included) might minimize the contrast between the printed pattern and the substrate and make it impossible to recognize the printed pattern by a smart device.

The chosen combination of ink formulation and substrate composition should not induce any defects, such as warp, holes or significant thinning of the substrate during and after printing (Janßen et al., 2013; Planchette et al., 2016; Raijada et al., 2013). This is an important aspect to consider in order to minimize problems related to dose uniformity, and also during packaging and handling of the printed dosage forms. Furthermore, warping of the substrate can make it impossible to recognize a printed pattern of information-containing dosage forms (Edinger et al., 2018). These criteria make it challenging to find an optimal combination of the ink and substrate formulation. Patient acceptance of the final oral dosage forms is crucial, especially if the personalized medicine is to be designed for children and the elderly. Palatability, appearance and ease of administration are the key aspects to be considered when formulating paediatric dosage forms (Vakili et al., 2016). Finally, the properties of the substrate might impose limitations on the analytical techniques used to evaluate the quality of the printed dosage forms (Edinger et al., 2017), as discussed in more detail in the next section. 4 ANALYTICAL TOOLS FOR USE IN QUALITY SYSTEMS One of the main challenges in making inkjet printing a viable manufacturing method for personalized therapies is the lack of fast, reliable and robust non-destructive analytical techniques for real-time drug quantification of printed dosage forms. Well-known drug quantification methods such as ultraviolet-visible (UV) spectroscopy and high-performance liquid chromatography (HPLC), while very precise, they are destructive, meaning that a number of the produced dosage forms will be destroyed during the analysis, making the methods uneconomical. Furthermore, these methods are time- and labour-consuming. If/when pharmacoprinting is to be implemented for manufacturing of dosage forms, for example, in community pharmacies, the use of fast and small (potentially hand-held) non-destructive analytical devices for API quantification is a prerequisite. Other qualitative aspects of the

printed dosage forms are also important such as the possible polymorphic transformations of the printed API after drying and during storage which may affect dissolution properties of the finished dosage form. Therefore there is a need for non-destructive process analysis and drug quantification methods in the area of printed dosage forms. Process Analytical Technology (PAT) in pharmaceutical manufacturing is a system designed to analyze and control the manufacturing process, ensuring the quality of the final dosage form. This is done by defining a quality target product profile (QTPP). In order to achieve this, the critical process parameters (CPP) and critical quality attributes (CQA) of the raw materials, intermediates, and end products are defined in a Quality-by-Design (QbD) framework in order to ensure the quality of the end product (Yu, 2008). The PAT framework was first outlined by the FDA in 2004 (FDA, 2004) and it conceptualizes the use of at-line, in-line or on-line integration of non-destructive measurement techniques supported by simultaneous data analysis tools, which provides control of the process during production. In order to make 2D printing viable as a close-to-the-end-user manufacturing method for pharmaceutical dosage forms, it is evident that implementation of PAT tools is crucial. Simplicity in use is often the key, and methods based on colour density measurements (colorimetry) have been successfully proposed (Vakili et al., 2016; Wickström et al., 2017b). Spectroscopic techniques such as infrared (IR), near-infrared (NIR) and Raman spectroscopy are other often used PAT methods due to their non-invasive nature and modest size of instrumentation, enabling easy implementation in a various process setups. 4.1 Techniques 4.1.1 Colorimetry Colorimetry is a technique where the colour intensity of the applied ink on the substrate is measured. Only a few APIs possess a distinguishable colour by themselves and therefore the

use of colorimetry requires the addition of colouring agent(s) to the ink. The colour density is then directly proportional to the amount of the ink deposited. The impression of colour is subjective between persons, therefore standardized colorimeters must be used to obtain empirical measurements which is based on the CIELAB international standard for colour measurements (Wickström et al., 2017b). Colorimetry has evident applications within the field of printable medicines, since 2D printers, particularly inkjet printers, were originally developed in order to print coloured inks. Variation due to colourants coming from different manufacturers, or the substrate having slight colour variation between batches can potentially induce errors when using this method. Furthermore, the penetration depth of the ink is of high importance, since an excessive penetration of the ink into the substrate may weaken the colour intensity and thereby invalidate the measurements. Therefore, oral films with a limited absorption capacity for the ink or paper-like substrates are a good choice when using colorimetry as an API quantification tool. 4.1.2 Infrared spectroscopy Infrared (IR) spectroscopy is an absorption technique that is based on the measurement of the fundamental vibrations of molecular bonds. In a given molecule, each bond vibrates with a specific resonant frequency that correlates to the absorption frequency of the mid-infrared light in the region between 4000-400 cm-1 (2.5-25 nm). The bands of an IR spectrum thus represent the structure-dependent frequency of the fundamental and overtone vibrations of molecules. A molecule hence has a distinct infrared spectrum that can be used for qualitative or quantitative modelling purposes. In a mixture of materials, each component will have a contribution of IR absorption that is linearly correlated to the amount of the component in the mixture. This enables modelling of the contributions and thereby quantification of the API in the mixture. IR spectroscopy is highly sensitive to water which can therefore be a limiting factor in the use of IR spectroscopy for printed dosage forms, since water-based inks are

often used. The instrumentation is based on an interferometer where infrared light is transmitted through or onto a sample. The infrared light interacts with the molecular bonds of the sample and the reflected or transmitted light is passed through a spectrograph onto a detector and formed into a spectrum using a Fourier-transform algorithm, a principle called Fourier-Transform Infrared Spectroscopy (FTIR). There are multiple variations of FTIR spectroscopy, and each technique has advantages and limitations. Transmission IR spectroscopy records the light that is transmitted through the sample and formed into a spectrum. Doing proper quantitative measurements require grinding of the sample and compression of it into a tablet with potassium bromide or combining it with liquid paraffin (nujol). Attenuated total reflectance (ATR) uses the phenomenon of total internal reflection. A beam is reflected onto a crystal that is in close contact with a sample and it will penetrate a fraction of the wavelength beyond the crystal surface into the sample. The beam will then lose energy at the specific wavelength at which the material absorbs. The resulting attenuated radiation can then be formed into a spectrum (Stuart, 2004). A disadvantage is the requirement of intimate contact between the sample and the ATR crystal. While IR spectroscopy shows potential as a tool for fast API quantification, the instrumentation for this purpose is not optimized for use in non-contact setups or requires destructive sample preparation. It can therefore be a challenge to implement as a fast and non-destructive analytical tool for printed dosage forms. 4.1.3 Near-Infrared spectroscopy Near-infrared spectroscopy (NIR) has been applied in quantitative studies of printed dosage forms. NIR is an absorption technique related to IR spectroscopy, where the overtones and combination bands of the fundamental infrared absorptions of molecules are observed and measured. The overtones and combination bands are highly overlapping, so it is difficult to assess the observed bands to specific molecular bonds of the studied compound(s). Each

compound in a formulation will have a linear contribution to the resulting NIR spectrum and can thereby be used for quantification purposes. Similar to IR spectroscopy, NIR is also sensitive to water, which can interfere with the spectrum of the studied compound, e.g. the API. The instrumentation of the NIR spectrometer is based on a visible/near-infrared light source that is directed onto the sample. The light interacts with the sample and the diffusely reflected or transmitted light is passed through a grating onto a detector and transformed into a spectrum. NIR spectroscopy can be used in both transmission and reflectance mode (Siesler et al., 2001). The choice of the technique depends on the nature of the dosage forms. The instrumentation allows easy implementation of probe setups and NIR is therefore highly useful as tool for API and excipient quantification (Simpson, 2010). 4.1.4 Near-Infrared Spectroscopy Chemical Imaging Near-infrared chemical imaging (NIR-CI) is an extension of NIR, where instead of taking a single spectrum, a number of spectra are taken over the area of the dosage form or its crosssection, creating a chemical image. Subsequent modelling of the data enables visualization of the distribution and concentration of e.g. the API on the surface of the dosage form. The instrumentation is similar to NIR with a light source directed onto the sample. Instead of forming a single spectrum, the diffusely reflected light passes through a slit, then through a dispersing filter and is then directed onto a line of detectors. The result is a line of spectra across the sample. By moving the sample along, multiple lines of spectra are gathered and formed into a NIR chemical image of the entire dosage form (Amigo, 2010). 4.1.5 Raman spectroscopy Raman spectroscopy is a technique that probes the same wavelength region as IR spectroscopy. While IR spectroscopy is absorption based, Raman is a scattering technique that probes the polarizability of molecular bonds. It relies on inelastic scattering of

monochromatic light. The instrumentation consists of a monochromatic laser (wavelengths often used are 532, 785 and 1064 nm) that is focused on the sample. Some of the laser photons will be absorbed by the sample turning the molecular bonds to a virtual energy state. The absorbed energy is mostly released with the same energy as the incident laser (Rayleigh scattering), but some photons will have shifted up (Stokes-Raman scattering) or down (AntiStokes Raman scattering) by the same amount as one level of the vibrational energy state of the molecular bond. A filter is used to remove the Rayleigh scattered photons, and the Raman shifted photons can then be directed through a spectrograph and transformed into a spectrum. The Stokes-Raman scattering is the stronger of the two and most instrumentations probe this part of the spectrum (Larkin, 2011a). Raman spectroscopy, being a scattering technique, is prone to various interfering effects, namely fluorescence that can entirely obscure the spectra (Larkin, 2011b). However, the instrumentation allows for in-line/at-line/on-line probe setups and Raman spectroscopy is therefore useful as a fast API quantification tool (Edinger et al., 2017). 4.1.6 Raman Chemical Imaging Raman chemical imaging is an extension of Raman spectroscopy, similar to NIR-CI in a way that a number of spectra are taken over an area of the dosage form. Most instrumentation is based on raster scanning the entire dosage form. However, line imagers (similar to the NIR line imagers described previously) do exist (Renishaw, 2018). The resulting Raman chemical image data can then be modelled to show qualitative properties such as drug distribution, or quantitative properties of the studied compounds in the dosage form (Amigo, 2010). 4.2 Preprocessing of spectroscopic data The obtained spectra by any of the spectroscopic techniques are often affected by multiple factors, mainly spectral noise and/or baseline drift due to scattering. Raman spectra can also

be affected by the presence of fluorescence. Therefore the spectra are often pre-processed in order to reduce contributions arising from physical variation between samples, so that the resulting spectra only contain information related to the chemical nature of the samples. For IR and NIR spectra, Standard Normal Variate (SNV) transformation is an often used technique for correcting baseline drift. SNV corrects each spectrum to a mean value of zero and unit standard deviation (Barnes et al., 1989). Mean centering (Ctr) is also often applied in order to center the spectral data sets to have a mean value of zero. For Raman spectra, asymmetric least squares smoothing has been suggested as a baseline correction technique (He et al., 2014). Further noise reduction as well as enhancement of distinguishing spectral features can be done by Savitzky-Golay smoothing, which comprises fitting a smoothing window of the spectral channel to a polynomial function. First and second derivatives can be imposed on top of the smoothing window, which can enhance subtle spectral differences such as shoulders and small peaks (Savitzky and Golay, 1964). 4.3 Modelling of spectral data All the mentioned spectroscopic techniques yield spectra that can be difficult to interpret visually. Therefore modelling is needed in order to yield quantitative or qualitative information about the dosage forms. Principal components analysis (PCA) is an exploratory technique, where the data are decomposed into the main sources of variation (Kumar et al., 2014). This can be useful for qualitative analysis of chemical images, e.g., for visualizing the presence or distribution of the API and excipient(s), or the distribution of different polymorphs of the API. However, it cannot be used for quantification of these components. For instance, in order to quantify the content of an API in a dosage form, it is necessary to use multivariate regression techniques. Partial least squares regression (PLS, also called projection to latent structures) is an often-used linear method for quantitative modelling of spectral data. The PLS method works by maximizing the covariance between a set of

predictor variables (in this case the spectra) and a set of response variables (for example, the API content in the dosage form). In order to apply the regression technique, a calibration set must be prepared beforehand by using a well-known analytical technique. For example, HPLC can be used to quantify the concentration of the API in a series of samples which is then used in the calibration set. These concentration values are then correlated to the spectra obtained from those samples. After that, the amount of the API in the unknown samples can be already predicted from the calibration set. Often, spectral selection is also conducted in order to use only the spectral contribution of the relevant compound, e.g., the API. The resulting model contains a number of latent variables (LVs) used in the prediction of the response variable. The amount of variance explained by each LV shows its importance in the prediction of the response. The selection of the number of LVs is a complex task, as a higher number of LVs will always yield a better predictive model. However, one may risk overfitting the model, i.e. where random noise in the data set will be used for predicting the response variable (Abdi, 2010). Therefore, in order to validate a PLS model, cross-validation (CV) is often used, where multiple parallel models are developed, each time leaving out a small number of the samples testing the model. The resulting models are compared against each other resulting in the root mean square error of cross-validation (RMSECV). Together with the root mean square error of calibration (RMSEC), and the root mean square error of prediction (RMSEP) of the validation set, these values can be used to select the optimal number of LVs, which is highly dependent on the nature of the samples and the analysis used. In general, the smaller these values, the better is the model (Brereton, 2018). The goodnessof-fit of the model is usually assessed by the R2-value, denoting the upper bound of how well the model explains the data, and the Q2-value, denoting the lower bound (Wold et al., 2001). For more information on multivariate modeling and examples of other methods, the reader is referred to reviews and books (Brereton, 2018; Kumar et al., 2014).

4.4 Qualitative studies of printed pharmaceuticals Several of the mentioned spectroscopic techniques have been applied in quality assessment of inkjet-printed dosage forms. Meléndez et al. used Raman spectroscopy and Raman chemical imaging to assess the polymorphic form of prednisolone (formulated in 80/17/3 ethanol/water/glycerol) printed on polytetrafluoroethylene (PTFE) coated glass slides (Table 2). The distinction between different polymorphic forms of the printed API was done by selection of spectral features specific to each polymorphic form. The authors found that thermal IJP of prednisolone onto the substrates could result in crystallization of the API in two polymorphic forms: I and III (with form I being the commercially available). They concluded that the formation of the two polymorphs was not due to the IJP or interaction with the substrate, but rather a result of the drying process used (Meléndez et al., 2008). The polymorphic form produced is of importance, since different forms may exhibit different dissolution behaviors and therefore it must be ensured that only the intended form(s) are present. Kollamaram et al printed paracetamol on HPMC and PET films and used Raman spectroscopy to characterize the polymorphic form of the printed doses. They found that paracetamol crystallized exclusively into the stable form I when printing on the rough part of the HPMC substrate, while printing on the PET substrate resulted in crystallizing exclusively into form II. Printing on the smooth surface of the HPMC film gave a mixture of the polymorphic forms (Kollamaram et al., 2018). Thabet et al used confocal Raman microscopy to assess the distribution of enalapril maleate that was continuously inkjet-printed onto placebo and Hydrochlorothiazide-containing oral films. A confocal setup enabled the visualization of the distribution of the APIs both on the surface, but also inside the samples. The authors used a least squares fitting approach to generate intensity profiles of the components that was then visualized using a false-colour representation of each component. It was found that the printed enalapril maleate remained on the surface of the films for both

the placebo and the hydrochlorothiazide-containing films, possibly preventing potential incompatibilities between the APIs (Thabet et al., 2018a, b). NIR-CI was used by Janβen et al. to assess the API distribution on flexographically printed ODFs. Tadalafil and rasagiline mesylate were accurately deposited onto the placebo HPMC film using flexographic printing. NIR-CI was used in combination with partial least squares regression to assess the distribution of the printed API on the films, and compare this distribution with the distribution of the API incorporating in the films during solvent casting. They found that printed films had a more even distribution of API compared to films where the drug was incorporated during fabrication of the films (Janßen et al., 2013). Genina et al employed NIR-CI in combination with partial least squares regression for evaluating the distribution of rasagiline mesylate inkjet printedon ODF based on HPMC, as well as on copy paper and transparency films. Printing of multiple layers led to more uneven distribution of the API (Genina et al., 2013b). FTIR was used by Buanz et al. to assess the interaction of the API and the polymer when printing clonidine hydrochloride onto films made from polyvinyl alcohol (PVA) and carboxymethylcellulose sodium (SCMC). They found that the clonidine hydrochloride interacted by hydrogen bonding with PVA, but found no interactions with SCMC (Buanz et al., 2015). 4.5 Quantitative studies of printed pharmaceuticals For quantification of the API and other ingredients, each method has advantages and disadvantages, and the choice of the analytical technique depends on the nature of the printed dosage form. For an overview of methods used, refer to Table 3. Colorimetry has been used for quantification of vitamins B1, B2, B3 and B6 printed on copy paper, rice paper and sugar paper. The ink was formulated by dissolving the vitamins into a commercially available

yellow ink containing tartrazine as the colourant. Basically the amount of the colouring agent was quantified, and the amount of the printed APIs was predicted based on those values. The authors achieved acceptable prediction accuracy for the vitamins, but some deviations were observed. A degree of the variation was also found to be related to the substrates. The authors noted that the colour saturation was quickly achieved, making measurements less precise (Wickström et al., 2017b). Vakili et al. used colorimetry to quantify propranolol hydrochloride printed on edible icing sheets and rice paper, as well as custom-made HPC coated rice paper. The ink was coloured by the addition of a commercially available red ink. The best prediction accuracy of the API content was achieved for the porous edible rice paper, while it was lower for edible icing sheets and coated rice paper. The deviation of the two last substrates was found to be due to a smearing effect caused by the feeding rollers, because the ink did not penetrate into the substrate (Vakili et al., 2016). These two examples show colorimetry as a usable method for the API quantification of inkjet printed film-based dosage forms. The advantage of the method is its simplicity and the use of a simple hand-held device. One downside of the method is that the API quantification is indirect, because it actually measures the amount of the added colourant. Therefore, in order to ensure the quantification of the correct dose, the API content must be correlated to the colour density of the ink by a separate method before printing as a part of the process setup. Furthermore, colour saturation can be a problem at high doses and has to be taken into account when printing. The colour saturation problem could potentially be circumvented by increasing the area printed. Attenuated total reflectance infrared (ATR-FTIR) spectroscopy was applied by Palo et al. for the quantification of loperamide hydrochloride (0.1-2.5 mg) and caffeine (0.05-1.2 mg) printed on polyethylene terephthalate (PET) films. The amount of the drug printed was linearly correlated with the signal intensity of the specific peaks of the IR spectrum

originating from the present APIs. The authors tested multiple modeling approaches, but found that the best prediction accuracy was achieved using PLS regression (Table 3) (Palo et al., 2016a). While this shows the applicability of IR spectroscopy for quantification of printed APIs, the substrate used (PET films) is for proof of concept purposes only and unsuitable for pharmaceutical applications. Furthermore, the nature of the IR setup requires intimate contact between the ATR window and the substrate, which may lead to smearing of the printed ink, resulting in determination of the incorrect dose. The penetration depth of the light in ATR is between 2-15 µm (Larkin, 2011b), therefore it can be used only with substrates with little to no penetration of the ink, such as thin films. Vakili et al have used both NIR spectroscopy and NIR-CI for quantitative studies of the API in the inkjet-printed dosage forms. Using a hand-held NIR spectrometer, the content of levothyroxine sodium and prednisolone as the model APIs was assessed on commercially available edible icing sheets and on in-house prepared oral films. Areas of 2 by 2 cm were printed for both APIs. The small handheld device measured the NIR absorbance spectra of the printed dosage forms in the spectral range between 1550-1950 nm. The authors used Orthogonal Partial Least Squares regression (OPLS) to model the data (Table 3) (Vakili et al., 2017). OPLS uses the PLS algorithm for modelling, but with the addition that data in the spectra which are orthogonal to the response variable (i.e. unrelated data), is reduced resulting in an easier to interpret model compared to PLS. However, the prediction accuracy is similar to PLS (Trygg and Wold, 2002). The handheld NIR spectrometer measured only a 1 mm diameter circle on the printed dosage form (compared to a printed area of 4 cm2), and it can therefore be prone to sampling error and variation within the printed dosage form This can potentially be circumvented by measuring on multiple points of each printed dosage form to obtain an average.

Raman spectroscopy has been employed for the quantification of haloperidol printed on inorganic compacts and commercially available paracetamol tablets (Table 3). The same technique was tested on solid foams, but quantification was not possible due to the highly porous nature of the substrates. For the inorganic compacts there was a good agreement between the calibration and validation sets. For the paracetamol tablets, a slightly lower model accuracy was achieved. The authors suspected a high penetration depth of the ink into the substrate and Raman interference from the substrate (paracetamol is a strongly Raman scattering compound) to be the reasons for the lower accuracy on the paracetamol tablets as compared to the inorganic compacts. The penetration depth of the ink was assessed to be between 250-500 µm, while the laser penetration was only 50-100 µm (Edinger et al., 2017). Some APIs show fluorescence, making Raman spectroscopy unsuitable for API quantification. 4.6 Printing technologies for continuous manufacturing of oral dosage forms Continuous manufacturing, as opposed to batch manufacturing, is the maintenance of a process in which material is continuously fed into a production line where it is processed and monitored, resulting in a final product. Continuous manufacturing affords multiple advantages compared to conventional batch manufacturing such as easy up- and downscaling, enabling easy switching from pilot-scale to full-scale manufacturing, or accomodating market demand. A precondition for a continuous manufacturing line is a constant monitoring of all unit operations within the process in order to ensure the quality of the final dosage form (Rantanen and Khinast, 2015). The schematic representation of a continuous manufacturing setup employing inkjet-printing is shown in Fig. 2. (i) The process starts with feeding the raw materials, e.g., the API powder and solvent (s), into the system and combining in the right proportions to form a printable ink. Before or during each process step control tools must be employed, starting with ensuring the quality and purity of the raw materials. The ink

preparation can also be done as a semi-batchwise process, i.e., a portion of ink is prepared and used at specific intervals during the printing process. The rheological properties of the ink is crucial for droplet formation and droplet size, therefore it must be measured for each portion of ink. This can be done with a capillary rheometer, which calculates the viscosity of the liquid based on measurement of the volumetric flux of liquid and pressure drop through a calibrated channel (Malkin and Isayev, 2017). The ink is then loaded into the print head. Here the jetting properties of the formed ink and droplet size produced in the printer must be continuously assessed to ensure a smooth printing process and guarantee a correct dose of the API printed onto the dosage form. The assessment of the jetting properties of the ink can be done with a stroboscopic camera attached at or near the print head. (ii) Besides feeding the raw materials for the ink, a substrate must be fed into the system. Depending on the desired nature of the substrate, it can be pre-produced or it can be directly manufactured from the raw materials as well. However, as printing is often conducted on planar films, preparation of the films by thorough mixing of the starting ingredients, casting and subsequent drying, within a continuous line can be challenging. However, if the printing is done on compacts or tablets, compaction of those can be more easily included in the continuous manufacturing line. (iii) After loading the ink into the print head and preparing the substrate, printing can be commenced. The printing settings should be adapted continuously based on the measurement of the ink viscosity, the droplet size and jetting properties, especially if the variation in the starting materials is observed. Furthermore, the printer should be continuously checked for clogging of nozzles or other problems related to the printing process (iv). A drying step can be included after printing, if necessary. (v) Optional coating processes of the printed API can also be conducted during or after this step with subsequent drying (Genina et al., 2012). Finally, the finished dosage forms must be controlled for the API content using one the aforementioned spectroscopic methods or the colorimetric technique. Other potentially

critical quality attributes of the printed dosage forms must also be assessed before they can be packed and distributed to patients. Printing technologies have been already suggested for the use in continuous manufacturing (Daly et al., 2015), but only a few papers have shown an actual continuous production. Janßen et al proved flexographic printing to be a feasible technique for semi-continuous manufacturing of ODF. Placebo films of up to 100 m in length were produced and flexographic printing was used to deposit two model APIs tadalafil and rasagiline mesylate onto the substrates. The APIs were printed in multiple layers, reusing the same printing setup, making the process non-continuous, but the technique has the potential to be used for fully continuous manufacturing of printable medicine (Janßen et al., 2013). Recently, Thabet et al. showed for the first time the use of inkjet printing as an applicable method for continuous manufacturing. Placebo and hydrochlorothiazide-containing oral films were pre-produced and an enalapril-containing ink was continuously printed on the films at a speed of 125 mm/min using water-based and methanol-based inks. 6 cm2 of the printed films was used for dose testing. Doses containing 0.04 ± 0.02 mg enalapril were produced using the water-based ink, while doses containing 0.5 ± 0.02 mg were produced using the methanol-based ink (Thabet et al., 2018a). While the process was not fully continuous from raw material to end product, it serves as a proof-of-concept that inkjet printing can potentially be implemented in a fully continuous manufacturing line. It is evident that a fully continuous manufacturing line employing, for example inkjet printing, requires a complex interplay of instruments and equipment. However, given that a continuous tableting line does already exist (Simonaho et al., 2016), it is only a matter of time and necessity before a continuous inkjet manufacturing line can become a reality. That said, if the end product is considered “compounding”, the requirements might be less demanding (Minghetti et al., 2014). 5 FUTURE VISION

In order for 2D printing techniques to be established as useful methods for manufacturing of oral dosage forms, the gaps of conventional manufacturing methods should be identified and unique possibilities of the printing technology should be highlighted. It is well-known that traditional manufacturing methods for solid dosage forms are limited in the provision of personalized medicine: patient-tailored dose, surface design, colour, etc. Printing technology can fill this niche, and be as a recognizable method for production of customized dosage forms that patients would find more acceptable (Goyanes et al., 2017; Scoutaris et al., 2018). In addition, the advent of generic dosage forms with few, if any, distinguishing (or confusing) characteristics, imposes problems related to their recognition by patients. In other words, endusers can have difficulties in identifying their own medicine. IJP enables fabrication of the medicine in a unique pattern of e.g. quick response (QR) codes, that contain the drug itself and information relevant to the consumer (Edinger et al., 2018). A regular smartphone equipped with a barcode scanner can be used by end-users to identify and trace the medicine, and by that improve medicine safety and adherence (Mira et al., 2015; Tseng and Wu, 2014), and minimize visits to healthcare professionals (Rathbone and Prescott, 2017). Another deficiency of conventional tablets or capsules, is their simple design that can be easy to counterfeit. Circulation of counterfeit medications is a world-wide problem nowadays (WHO, 2017). Manufacturing of dosage forms by IJP close to the end-user in a unique pattern, e.g., barcode, can improve the tracking of medicines from the manufacturing to the end-users with a reduced risk for counterfeiting (Preis et al., 2015). This is also important for online ordering of medicines, where the cases of delivering counterfeit drug products were detected. The barcode, such as QR code or other mobile device readable patterns, can actually encode a password protected URL that would require the key to confirm the originality of medicine, and give access to the required information. The key could be sent to

end users’ personal mobile device after ordering the medicine (McGuigan, 2018). This would ensure that original and correct medicine was received by the end-user.

The concept of personalized medicine includes the production of the medicine in flexible doses on-demand and preferably at settings close to end-users (Alomari et al., 2015; Lind et al., 2017). Printing technology is more beneficial in this regard as compared to conventional manufacturing methods, because it is (i) automated with the dose adjustment in the computer software (for IJP); (ii) precise and easily scalable; (iii) requires a small footprint, enabling incorporating it in the pharmacy or even patient’s home. In those settings, validated state of the art quality control systems are needed (Crommelin and Bouwman-Boer, 2016). The authors believe that a near future research will be focused on the development of miniaturized handheld non-destructive quality control methods and data management tools (e.g. machine vision) for quality control purposes of printable medicine, among others (Rantanen and Khinast, 2015; Vakili et al., 2017; Wickström et al., 2017b). As the world is increasingly driven by digital devices interconnected through the Internet of Things (IoT), the use of personal mobile devices and applications will be used with the printable medicine beyond the idea of QR-encoded smart dosage forms. Interconnection between portable spectroscopic/colorimetric devices and personal mobile devices can be established, in a way that the healthcare professionals/end-users themselves can perform quality control of the printable medicine. It will potentially be possible especially when the operation of the printing equipment to manufacture dosage forms is performed remotely, e.g., by technical staff (Alhnan et al., 2016; Lind et al., 2017).

The authors here believe that the printing technology is ready for implementation for ondemand production of personalized medicine. However, it is difficult to predict when flexible

manufacturing of drug products could be implemented. The regulations covering manufacturing of medicine on patient demand are still developing. The patient attitude towards a new role in decision-making, including unintended consequences, is of concern (Kaae et al., 2018). However, there is a lot of interest and need for production of personalized medicine, and therefore the changes with regards to manufacturing of personalized medicine can be dramatic in the coming years.

6 CONCLUSION The present review has examined the analytical aspects of the printed dosage forms. We have attempted to present the most recent literature regarding analytical aspects, with an emphasis on non-destructive spectroscopic analytical methods for API quantification, and there is a number of techniques that show promise for this purpose, namely colorimetry, near-infrared spectroscopy and Raman spectroscopy. Semi-continuous manufacturing using inkjet-printing has been performed, however, there is still a some way until a fully continuous manufacturing line can be established. We have outlined likely requirements for a continuous manufacturing line to be commercially viable and there is a need for research focusing on scaling up towards commercial fabrication of printed dosage forms. The trends identified will potentially help to drive towards upscaling into an industrial environment.

Acknowledgements This work was supported by The Danish Council for Independent Research (DFF), Technology and Production Sciences (FTP), grant number 12-126515/0602-02670B; the Drug Research Academy (University of Copenhagen).

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Figure captions

Fig. 1. NIR-CI applied for quantification of theophylline printed on copy paper. Left: PCA contour plot of the printed doses (each square is 1 cm2). Red corresponds to a higher concentration of theophylline, while blue is lower. Right: The predicted theophylline content vs the measured theophylline content. Reprinted with permission from Vakili et al. (2015).

Fig. 2. Schematic of the process steps of a continuously operating inkjet printing line.

Table 1. Overview of the composition of substrates and inks used in 2D printing of film-like drug delivery systems. Substrate

Ink

Subst

Preparat Polysacch

Other

Solv

API,

Ink

rate

ion

aride or

compon

ent

[concentrati

‘base’

type

method

other

ents

on in ink]

Printi

Referen

ng

ce

metho d

matrix former, [ ] (grade) Oral

Commer

Potato

film

cially

starch

Olive oil

Wate

Salbutamol

Glycerol:

r

sulphate,

water

al.

[30 mg/ml]

(10:90)

(2011)

Sodium

Water

available

TIJ

Buanz et

(CA) Oral

CA

films

HPMC,

--

N/A

PIJ

Wimmer

HPMC

picosulfate,

-

with TiO2

[200 mg/ml]

Teubenb

, gelatin,

acher et

gelatin

al.

with TiO2

(2018)

Rapidfilm ® (Tesa Labtec); nonporous & porous MCC films; Listerine® PocketPaks Oral

Solvent

HPMC,

films

casting

--

1%

Naproxen

PVP (K-

5% (w/v)

aceti

[30 & 70

90), EtOH IJP

(E50) /

c

mg/ml]

Chitosan,

acid

3% (w/v)

in wate r

Drop

Hsu et al. (2013)

Oral

Solvent

HPC, 5%

--

films

casting/C

(w/w)

Icing

A

sheets

Wate

Caffeine [20

PG:Water

PIJ

Genina

/multiple r

mg/ml]

(30:70)

et al.

Klucel LF/

ingredie

Loperamide

PG:EtOH

(2013a)

Corn

ns.

HCl [50

(40:60)

starch

(Raijada

mg/ml]

et al., 2013) Icing

CA

sheets

Corn

Multiple

Wate

Piroxicam [5

PEG400:

PIJ &

Raijada

starch

ingredie

r

mg/ml & 14

EtOH

Flexo

et al.

mg/ml]

(40:60)

ns

(2013)

PEG 400 Oral

Solvent

films

casting

HPMC

--

Wate

Naproxen,

PVP K90

DoD

Hirshfiel

r

70 mg/ml

in EtOH

(DAM

d et al.

(0.3 g in

PP)

(2014)

10 ml) Oral

Freeze-

HPMC,

films

drying &

5% (w/w)

Solvent casting

--

Wate

Ibuprofen,

PEG400

DoD

Elele et

r

20%

SLS:PEG

(EHD)

al.

(Methocel

(w/w)/Griseo

400 (2%

E15LV)

fulvin, 20%

w/w)

(2010)

(w/w) Oral

Solvent

HPMC,

Mesopor

Wate

Haloperidol.

Lactic

film

casting

10%

ous

r

160 mg/ml

acid:

et al.

(w/w),

fumed

EtOH

(2018)

(Metolose®

silica,

(14:86)

60 SH-50)

glycerol

colorants

--

Oral

Solvent

HPC

films,

casting/C

(Klucel

bilaye

A rice

red

sheets

PIJ

PIJ

Edinger

Wate

levothyroxin

PG:DMS

Wickströ

r

e sodium salt

O (50:50)

m et al.

EXF)/potat

pentahydrate

+ CA

(2017b)

o starch

, 20 mg/ml

yellow edible ink

Easybake®

Oral

CA rice

sheet

sheet/rice edible rice

and

paper

paper

paper/Blue Dragon Spring Roll

®

--

Wate

Indomethaci

Poloxame

r

n 145.1

r 407

al.

mg/ml/

(60% w/w

(2015)

intraconasol

of API

112.2 mg/ml

content) +Water

Flexo

Palo et

Wrappers

(20 ml)

Oro-

Electro-

Gelatin,

Glucose

10M

Lidocaine

mucos

spinning

20-25%

+/-

Aceti hydrochlorid

al

(w/v),

piroxica

c

e

fibrou

(Type A

m

acid

monohydrate

s

from

aq.

, 350 mg/ml

substr

porcine

solut

ate

skin)

ion

PG:Water

PIJ

(40:60)

Palo et al. (2017)

+/DMF in 1:4 (v/v) ratio Orodis

CA icing

HPC/HPM

-

sheet/sol

C,

persibl

vent

e film

casting

(ODF)

Glycerol

Wate

Levothyroxi

PG:EtOH:

PIJ

Vakili et

r

ne sodium

DMSO

al.

7.5%/7.5%

salt

(10:45:45

(2017)

(w/w),

pentahydrate

)

(Klucel

, 20 mg/ml /

EXF/Phar

prednisolone

macoat

, 40 mg/ml

606) ODF

Solvent

HPMC,

Glycerol

Wate

Rasagine

HPC:EtO

Flexo

Janßen et

casting

13.88%

,

r

mesylate/Ta

H

al.

(w/w)

crospovi

dalafil

(5:90

(2013)

(Pharmaco

done

w/w)

at 606)

HPC:Wat er (10:90 w/w)+ coloring agent

ODF

Solvent

HPMC,

Glycerol

Wate

Rasagiline

PG:Water

casting

13.88%

,

r

mesylate

(30:70)

(w/w)

crospovi

TIJ

Genina et al. (2013b)

(Pharmaco

done

at 606) ODF

ODF

CA

Rapidfilm

--

--

Sodium

Water

PIJ

Planchett

® (Tesa

picosulfate,

and

e et al.

Labtec),

200 mg/ml

soleno

(2016)

nonporous

id

& porous

valve

MCC films

IJ

Solvent

HPMC,

casting

20%

Glycerol

Wate

Warfarin

r

sodium, 300

a et al.

mg/ml

(2018)

(w/w),

Water

TJP

Vuddand

(Pharmaco at 606) Icing

CA with

Corn/

Multiple

Wate

Propranolol

Glycerol:

TIJ

Vakili et

sheet/r

extra

potato

ingredie

r+

hydrochlorid

Water

al.

ice

polymer

starch

nts

ethan e, 50 mg/ml

(10:90) +

(2016)

sheet

and

Raijada

ol

CA red

sugar

et al.

coating

(2013) +

edible ink

coating with HPC + sacchari n sodium salt hydrate Solid

Vacuum

HPMC,

foam

oven

6.7%

drying

SLS

Wate

Haloperidol

Lactic

PIJ

Edinger

r

162 mg/ml

acid:Etha

et al.

(w/w)

nol

(2017)

(Metolose®

(14:86)

60 SH4000) Solid

Freeze-

HPMC,

PEG400

Wate

Propranolol

PG:Water

foam

drying

5% (w/v)

0,

r

hydrochlorid

(30:70)

(Metolose®

glycerol,

e, 50 mg/ml

PIJ

Iftimi et al. (2018)

60 SH-

Tween

4000)

20®, poloxam er, SLS

Table 2. Qualitative studies of printed dosage forms. API

Analytical method

Property assessed

Substrate

Modeling

Reference

Prednisolone

Raman chemical imaging

Polymorphic form (I and III)

PTFE fiberglass film

Signal-tobaseline intensity

Meléndez et al. (2008)

Rasagiline mesylate Tadalafil

NIR-CI

Drug distribution on printed films

HPMC film

PLS2

Janßen et al. (2013)

Rasagiline mesylate

NIR-CI

Drug distribution on the printed substrates

HPMC film Copy paper Transparency film

PLS

Genina et al. (2013b)

Enalapril maleate

Confocal Raman microscopy

Drug distribution on printed films

Hydrochlorothiazide Least squares containing films fitting Placebo films

Thabet et al. (2018a) Thabet et al. (2018b)

Clonidine hydrochloride

FTIR

API interaction with film materials

Polyvinyl alcohol/ sodium carboxymethylcellulose films

(Buanz et al., 2015)

-

Table 3. Overview of methods used for quantitative assessment of inkjet printed dosage forms.

API

Analytical Method

Propranolol Hydrochlori de

Colorimetr y

Dose(s )

Substrate

Modeling

R2 (predictio n)

Validatio n method

Referenc e

Rice paper

-

0.9767

UV

Vakili et al. (2016)

-

0.9609 (RP)

LC-MS

Wickströ m et al. (2017b)

0.944 (IS) 0.944 (PF)

HPLC

Vakili et al. (2017)

0.926 (IS)

UV

Icing sheets Coated Rice paper

Vitamin B1, B2, B3 and B6 (combined)

Levothyroxi ne sodium (LS)

Colorimetr y

NIR

B1 (570 µg), B2 (570 µg), B3 (25160 µg) B6 (7-90 µg)

Rice paper (RP)

0.150.8 mg

Icing sheet (IS) Polymer film (PF)

Sugar paper (SP)

0.9918 (SP)

Copy paper (CP)

0.9496 (CP)

Orthogona l-PLS Ctr, SG 3rd derivative. 1+2 component s

Prednisolone (P)

NIR

0.42.0 mg

Icing sheet (IS) Polymer film (PF)

Orthogona l-PLS

0.874 (PF) Ctr, SG 3rd derivative. 1+1 component s

Theophyllin e

NIR-CI

25240 µg/cm

Copy paper

Undisclose 0.9767 d

UV

Vakili et al. (2015)

Palo et al. (2016b)

2

Loperamide Hydrochlori de

ATRFTIR

0.12.5 mg

PTFE film

PLS, spectral selection 4001750cm-1, SNV + Ctr, 5 LVs

0.99

HPLC

Caffeine

ATRFTIR

0.051.2 mg

PTFE film

PLS, spectral selection 4001750cm-1, SNV + Ctr, 5 LVs

0.99

UV

Haloperidol

Raman

Inorganic compacts (IC)

PLS, SG + SNV, spectral selection, 720-760 cm-1, 1 LV (IC), 2LVs (PT)

0.99 (IC)

HPLC

Paracetam ol tablets (PT)

0.97 (PT)

Edinger et al. (2017)

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