Electromagnetic drop-on-demand (DOD) technology as an innovative platform for amorphous solid dispersion production

Abstract

Described are continuous manufacturing methods using 3D printing or any similar additive manufacturing technology to produce pharmaceutical ASDs. Manufacturing methods include preparing printing ink including API and polymeric carriers. The printing ink is accurately deposited onto a deposition surface by forming printing ink droplets by using an electromagnetic DoD 3D printing device to form an ASD printed product. The ASD printed product has improved solubility and bioavailability than the API in crystalline form.

Description

[0001] ELECTROMAGNETIC DROP-ON-DEMAND (DOD) TECHNOLOGY AS AN INNOVATIVE PLATFORM FOR AMORPHOUS SOLID DISPERSION PRODUCTION

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U.S. Provisional Patent Application No. 63 / 610,997, filed December 15, 2023, the disclosure of which is incorporated by reference herein in its entirety.

[0004] FIELD

[0005] The present disclosure relates generally to additive manufacturing technology including the production of pharmaceutical amorphous solid dispersions (ASDs) using drop-on- demand (DoD) systems.

[0006] BACKGROUND

[0007] Pharmaceuticals produced by amorphous solid dispersions (ASDs) are generally featured with improved solubility and bioavailability. Conventional ASD production technologies involving solvents or high processing temperatures tend to induce drug degradation and thus limit the variety of active pharmaceutical ingredients (API) that can be produced as ASDs.

[0008] The manufacturing of ASD-based pharmaceuticals is expanding quickly due to the enormous impact of ASD technology on boosting the bioavailability of drugs that have limited solubility, which is the case of most of the available active pharmaceutical agents (APIs). Three generations of ASD have been invented, primarily based on the polymeric carriers' crystalline state and the inclusion of other components such as surfactants (Bhujbal, S. V. et al., 2021, Acta Pharmaceutica Sinica B, 11, 2505; Vasconcelos, T. et al., 2016, Advanced Drug Delivery Reviews, 100, 85).

[0009] ASD manufacturing techniques are divided into two categories: solvent evaporation-based procedures and melting-based approaches. In both techniques, the crystalline structure of the drug material is disturbed either by melting or dissolving in the solvent, and subsequently converted into molecules that dissolve in the polymeric carrier. Spray drying is the most often used solvent evaporation-based technology. Electrospraying, electrospinning, freeze spray drying, fluidized bed technology, and supercritical fluids are also solvent evaporation- based techniques utilized on a lab or manufacturing scale. On the other hand, the fundamental advantage of melting-based procedures is that they do not require the use of organic solvents. The main downside of this category is the likelihood of drug degradation induced by the use of high temperatures in the manufacturing process, which limits their use for particular APIs (Repka, M. A. et al., 2012, Expert Opinion on Drug Delivery, 9, 105). The most common melting-based approach for generating ASDs is hot melt extrusion (Patil, H. et al., 2016, AAPS PharmSciTech, 17, 20). KinetiSol® technology, which uses high shear to make amorphous solid dispersions, is now evolving to broaden the application of melting-based techniques to a larger range of heat-sensitive APIs and polymers (Ellenberger, D. J. et al., 2018, AAPS PharmSciTech, 19, 1933).

[0010] Thus, there is a need in the art for novel methods of manufacturing ASDs that are amenable towards a broad array of APIs. The present invention addresses this need.

[0011] SUMMARY

[0012] The present invention relates to, in part, a method of manufacturing a printed product, the method comprising: providing a printing ink, wherein the printing ink comprises an active pharmaceutical ingredient (API) in crystalline form, a plurality of polymeric carriers, and a solvent; feeding the printing ink to an electro-magnetic (EMD) printhead; forming a printing droplet from the printing ink, wherein forming the printing droplet is characterized by a droplet size and a frequency of droplet discharge; and depositing the printing droplet on a deposition surface to form a printed product, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier.

[0013] In some embodiments, the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug. In some embodiments, the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In some embodiments, the API exhibits an aqueous solubility less than that of the ASD. In some embodiments, the API is thermostable, or the API is thermosensitive, or the API decomposes at temperatures over 65 °C, or the API decomposes at temperatures from 65 °C to 100 °C.

[0014] In some embodiments, the plurality of polymeric carriers comprises Eudragit L100-55 (EL100-55), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer. In some embodiments, the solvent is methanol, acetone, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, or a solvent that has a boiling point less than or equal to a temperature of the deposition surface.

[0015] In some embodiments, the deposition surface comprises a glass plate. In some embodiments, the glass plate has a tailored size. In some embodiments, the deposition surface is disposed on a heated printing stage. In some embodiments, the heated printing stage is set to a temperature of about 65 °C. In some embodiments, the deposition surface is a surface of a tablet. In some embodiments, the deposition surface is a blister pack. In some embodiments, the method further comprises drying the printed product so that the solvent is fully evaporated.

[0016] In some embodiments, the printhead further comprises a nozzle and a nozzle valve. In some embodiments, the nozzle valve is a magnetic valve. In some embodiments, the method further comprises the step of controlling the droplet size or the frequency of droplet discharge by adjusting a pressure of the nozzle or an open time of the nozzle valve. In some embodiments, the nozzle valve opens for extruding of the printing ink to form the printing droplet upon application of a magnetic field. In some embodiments, the printed product is deposited on the deposition surface at a printing pressure ranging from 1 to 200 kPa. In some embodiments, depositing the printing droplet on a deposition surface follows a grid, lines, a honeycomb pattern, or concentric deposition pattern.

[0017] The present invention further relates to, in part, a printed product comprising: a plurality of active pharmaceutical ingredient (API) molecules; and a plurality of polymeric carriers, wherein: the API molecules are dissolved in the plurality of polymeric carriers to form a plurality of particles; and the plurality of particles forms an amorphous solid dispersion (ASD), wherein each individual particle is coupled to another particle. In some embodiments, the printed product further comprises a second plurality of API molecules, wherein the second plurality of API molecules is different from the plurality of API molecules; and a second plurality of polymeric carriers, wherein: the second plurality of polymeric carriers is different from the plurality of polymeric carriers; the second plurality of API molecules are dissolved in the second plurality of polymeric carriers to form a second plurality of particles; and the second plurality of particles forms an ASD, wherein each individual particle of the second plurality of particles is coupled to another particle of the plurality of particles or the second plurality of particles.

[0018] In some embodiments, the plurality of API molecules forms a crystalline structure in solid state. In some embodiments, the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug. In some embodiments, the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In some embodiments, the API exhibits an aqueous solubility less than that of the ASD.

[0019] In some embodiments, the plurality of polymeric carriers comprise Eudragit L100-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), an ASD-forming anionic polymer, or an ASD-forming nonionic polymer. In some embodiments, the plurality of particles and the second plurality of particles are homogeneously dispersed in the printed product. In some embodiments, the printed product has a solubility greater than the solubility of the API in crystalline state. In some embodiments, the printed product further comprises a plurality of a second API molecules. In some embodiments, the printed product is in the form of a tablet or a pill.

[0020] In some embodiments, the printed product further comprises a plurality of components that are spatially separated. In some embodiments, the plurality of components comprises different APIs or API doses. In some embodiments, the plurality of components have different geometries. In some embodiments, the plurality of components comprises different polymeric carriers. In some embodiments, the concentration of the plurality of API molecules varies according to a geometric characteristic of the printed product.

[0021] The present invention further relates to, in part, a printing ink comprising: an active pharmaceutical ingredient (API); a plurality of polymeric carriers; and a solvent, wherein the printing ink is configured to: form a printing droplet when fed to an electro-magnetic (EMD) printhead, wherein the formed printing droplet is characterized by a droplet size and a frequency of droplet discharge; and form a printed product from a plurality of the printing droplets, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier. In some embodiments, the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug. In some embodiments, the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In some embodiments, the API, in pure form, exhibits an aqueous solubility less than that of the ASD. In some embodiments, the API is thermostable, or the API is thermosensitive, or the API decomposes at temperatures over 65 °C, or the API decomposes at temperatures from 65 °C to 100 °C.

[0022] In some embodiments, the plurality of polymeric carriers comprises Eudragit L100-55 (EL100-55), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

[0023] In some embodiments, the present invention further relates to, in part, a system comprising: a drop-on-demand (DoD) printing device; one or more processors; and one or more memory storing instructions that, upon execution by the one or more processors, configure the system to: receiving a print request, wherein the print request identifies an active pharmaceutical ingredient (API) and a plurality of polymeric carriers; providing the print request to a machine learning model, the machine learning model being trained to output a plurality of print parameters based on the API; generating, based on the plurality of print parameters output by the machine learning model, a print profile executable by the DoD printing device; and instructing the DoD printing device, based on the print profile, to form a printing droplet and use the printing droplet to deposit a printed product on a deposition surface.

[0024] In some embodiments, the plurality of print parameters comprises printing pressure, print speed, infill density, or print distance. In some embodiments, the printing pressure is from 1 to 200 kPa. In some embodiments, the print speed is from 1 to 20 mm / s. In some embodiments, the infill density is from 1 to 100%. In some embodiments, the DoD printing device further comprises a printhead that comprises a nozzle and a nozzle valve. In some embodiments, the print distance is the distance between the nozzle and the deposition surface, and the print distance is from 0.01 to 63.6 mm. In some embodiments, the plurality of print parameters comprises an open time of the nozzle valve. In some embodiments, the open time of the nozzle valve is from 1 ms to 20 ms. In some embodiments, the plurality of print parameters comprises a cycle time that the nozzle valve opens. In some embodiments, the cycle time is from 1 ms to 2000 ms. In some embodiments, the printed product is amorphous. The present invention further relates to, in part, medication made by the method of manufacturing or including the printed product.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 is a schematic illustration of an example amorphous solid dispersion (ASD).

[0027] FIG. 2 is a schematic illustration of an example manufacturing method for ASD printed products according to some examples.

[0028] FIG. 3 shows chemical structures of APIs and polymeric carriers according to some examples.

[0029] FIG. 4 comprises FIG. 4 A and FIG. 4B.

[0030] FIG. 4A provides data showing thermogravimetric analysis results of pure APIs according to some examples.

[0031] FIG. 4B provides data showing thermogravimetric analysis results of polymers according to some examples.

[0032] FIG. 5 comprises FIG. 5A, FIG. 5B, and FIG. 5C.

[0033] FIG. 5A provides data showing differential scanning calorimetry thermograms of efavirenz (EFZ) and ASD printed products including EFZ according to some examples.

[0034] FIG. 5B provides data showing differential scanning calorimetry thermograms of lumefantrine (LUM) and ASD printed products including LUM according to some examples.

[0035] FIG. 5C provides data showing differential scanning calorimetry thermograms of favipiravir (FAV) and ASD printed products including FAV according to some examples.

[0036] FIG. 6 provides polarized light microscopy images of pure APIs and ASD printed products according to some examples.

[0037] FIG. 7 comprises FIG. 7 A, FIG. 7B, and FIG. 7C.

[0038] FIG. 7A provides data showing powder X-ray diffraction (XRPD) analysis of pure EFZ and ASD printed products including EFZ according to some examples.

[0039] FIG. 7B provides data showing powder X-ray diffraction (XRPD) analysis of pure LUM and ASD printed products including LUM according to some examples. FIG. 7C provides data showing powder X-ray diffraction (XRPD) analysis of pure FAV and ASD printed product including FAV according to some examples. .

[0040] FIG. 8 comprises FIG. 8A, FIG. 8B, and FIG. 8C.

[0041] FIG. 8A provides data showing Fourier Transfer Infra-red (FT-IR) spectroscopy analysis data of pure EFZ, EL100-55, physical mixture (PM) of EFZ and EL100-55, and ASD printed product according to some examples.

[0042] FIG. 8B provides data showing FT-IR spectroscopy analysis data of pure LUM, HPMC-AS, PM of LUM and HPMC-AS, and ASD printed products according to some examples.

[0043] FIG. 8C provides data showing FT-IR spectroscopy analysis data of pure FAV, PAA, PM of FAV and PAA, and ASD printed products according to some examples.

[0044] FIG. 9 is a flowchart of using a machine learning model to deposit a printed product according to some examples.

[0045] DETAILED DESCRIPTION

[0046] The present invention relates generally to medication and pharmaceutical ASDs fabricated by DoD technologies. DoD systems are useful for precise and controlled dispensing of materials in small volumes. An electromagnetic DoD system can produce amorphous solid dispersions (ASDs) of drugs known for poor solubility or instability in a continuous manufacturing manner. As described in further detail herein, embodiments of the present technology relate to methods and systems for fabricating different types of medication, pharmaceutical dosage, or active pharmaceutical ingredients with various configurations.

[0047] Definitions

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0049] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0050] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate.

[0051] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0052] Methods of Making ASPs

[0053] The present invention provides, in part, various methods of making ASDs, including, but not limited to, methods for droplet on demand printing of ASDs, for example using an electro-magnetic printhead. The present invention further provides, in part, a method of manufacturing a printed product. Exemplary methods of this aspect may comprise providing a printing ink, such as a printing ink that comprises an active pharmaceutical ingredient (API) in crystalline form, a plurality of polymeric carriers, and a solvent; feeding the printing ink to an electro-magnetic (EMD) printhead; forming a printing droplet from the printing ink, such as a printing droplet that is characterized by a droplet size and a frequency of droplet discharge; and depositing the printing droplet on a deposition surface to form a printed product. In certain embodiments, the printed product is an amorphous solid dispersion (ASD), such as an ASD comprising molecules of the API surrounded by at least one polymeric carrier.

[0054] FIG. 1 is a schematic illustration of forming an amorphous solid dispersion (ASD) according to some examples. As illustrated by process 100, an API 110 in the form of a solid crystalline material may exhibit low solubility (e.g., aqueous solubility) and / or low bioavailability, which can make orally administered medications containing the API 110 difficult for systematic absorption by patients. Examples of the API 110 include, but are not limited to, favipiravir (FAV), efavirenz (EFZ), and lumefantrine (LUM), which are described in further detail herein. These example APIs are described as representative of different classes or types of APIs that are useful with the disclosed systems and methods. ASD improves the solubility of the API by kinetically stabilizing the more soluble amorphous phase of the API with a suitable amorphous polymer or polymeric carrier. Accordingly, the absorption challenges associated with the low solubility and bioavailability of the crystalline API 110 may be addressed by forming an ASD including the API 110.

[0055] To prepare the ASD of the API 110, a solvent 120 may be provided. The crystalline structure of the API 110 may be disturbed by the solvent 120. The solvent 120 may be a common solvent for both the API 110 and polymeric carriers 130. In some embodiments, the solvent 120 may be methanol, acetone, di chloromethane, chloroform, etc., though other solvents may be used. In some embodiments, the polymeric carriers 130 may be Eudragit L100- 55 (EL 100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or poly acrylic acid (PAA), etc., though other polymeric carriers may be used. In some embodiments, the API to polymeric carrier ratio may be 1 :9 and the total solid content may be 2% w / v, though other ratios and total solid contents may be used. Disturbed molecules of API 110 may subsequently dissolve in the polymeric carriers 130 and the solvent 120 to form dispersion particles 140, thereby resulting total miscibility of the API 110 molecules into matrixes of the polymeric carriers 130. The ionic interaction between the API 110 molecules and the polymeric carriers 130 can inhibit recrystallization of the API molecules throughout a following drying or evaporation process, generating a mixture 102. The mixture 102 may include the dispersion particles 140 and the solvent 120 and may be subject to further processing steps as desired.

[0056] In some embodiments, as further described in relation to FIG. 2, the mixture 102 may be used as a printing ink suitable for additive manufacturing or 3-D printing methods (e.g., DoD printing). In some embodiments, to form the ASD of API 110, the solvent 120 may be evaporated so that only the amorphous solid dispersion particles 140 in solid state are retained. The solvent 120 may be evaporated due to the pre-heated printbed’s set temperature.

[0057] FIG. 2 is a schematic illustration of an example manufacturing method for ASD printed products according to some examples. As workflow 200 illustrates, the method starts with step 210, where a printing ink 211 including at least one API and polymeric carriers in which the API can dissolve into is prepared. In some embodiments, the printing ink 211 may be the mixture 102 as discussed in relation to FIG. 1. The workflow 200 continues to step 220, where the printing ink 211 is fed into a DoD printer including an electromagnetic printhead 221. In some embodiments, multiple printing inks including different APIs may be mixed or combined prior to being fed or loaded into the DoD printer. The electromagnetic printhead 221 may include a nozzle valve 223 that is actuated and controlled by an external electromagnetic field to form one or more printing droplets 224. In some embodiments, an external electromagnetic field may trigger the opening and closing of the nozzle valve 223. The properties (e.g., droplet size) of the printing droplet 224 may depend on printing parameters. In some embodiments, the printing parameters may include printing pressure (e.g., the pressure being exerted on the printing ink 211), valve open time, cycle time (e.g., the frequency of forming a printing droplet), print speed, infill density, a deposition distance (e.g., the distance between the printhead and the deposition surface), etc. In some embodiments, the printing pressure may be in the ranges of 5-10 kPa, 10-15 kPa, 15-20 kPa, 20-25 kPa, or 25-30 kPa. In some embodiments, the open time may be in the ranges of 1-1.5 ms, 1.5-2 ms, and 2-2.5 ms. The cycle time may be in the ranges of 100-200 ms, 200-300 ms, 300-400 ms, 400-500 ms, and 500-600 ms. The print speed may be in the ranges of 5-10 mm / s, 10-15 mm / s, and 15-20 mm / s. The infill density may be 5-10%, 10-15%, 15-20%, 20-25%, and 25-30%. In some embodiments, by increasing the valve open time, the size of the printing droplet 224 may be increased. In some embodiments, when the valve open time is reduced while the cycle time remains unchanged, the size of the printing droplet 224 may be reduced. In some embodiments, when the cycle time is reduced and the rest of the printing parameters remain unchanged, the frequency of the printing droplet 224 being discharged from the nozzle valve 223 may be decreased, while the size of the printing droplet 224 remains unchanged.

[0058] The workflow 200 continues to step 230, at which the printing droplet 224 may be deposited on a deposition surface 225 to form a printed product 231 containing the API. The printed product may be an ASD including dispersion particles. The dispersion particles may include API molecules dissolved in polymeric carriers. In some embodiments, the deposition surface 225 may be a print bed or a printing stage. The deposition surface 225 may be heated to and / or maintained at a constant temperature to evaporate or dry out the extra solvent from the printed product 231. In some embodiments, the deposition temperature may be or may be as high as 65 °C, though other temperatures can be used. In some embodiments, the deposition surface 225 may be a blister pack, which can allow for preparation of a printed product directly in end-product packaging.

[0059] The printed product 231 may have any geometry or configuration as desired. The printed product 231 may have any size. In some embodiments, the printed product 231 may be circular, rectangular, triangular, or in any shape as desired. In some embodiments, the printed product 321 may have a core-shell structure, concentric structure (e.g., a plurality of ring or circular components assembled together, layer-by-layer structure, etc.). In some embodiments, the printed product 231 may include components that are spatially separated as a result of multiple rounds of printings. The properties of each component may vary or be adjusted as desired. In some embodiments, the printed product may include a first component including a first API and a second component including a second API, different from the first API. In some embodiments, the printed product may include a first component including a first polymeric carrier and a second component including a second polymeric carrier, different from the first polymeric carrier. In some embodiments, the printed product 231 may include components having different doses of the same API. In some embodiments, the printed product may include a first component including an API at a first concentration or loading and a second component including the API at a second concentration or loading, different from the first concentration or loading. In some embodiments, the API in the printed product 231 may have a concentration that distributes depending on a geometric characteristic of the printed product. For example, the printed product may be a circular tablet characterized by a diameter of x, the concentration of the API may have a bell distribution, a linear distribution, or an exponential distribution according to the value of x.

[0060] The workflow 200 continues to step 240, at which the printed product 231 is harvested. In some embodiments, mechanical arms or robotic devices may be used to harvest the printed product 231. In some embodiments, when the deposition surface 225 is a blister pack, a sealing component (e.g., a sealing mask) may be directly attached to the blister pack to finish the packaging of the printed product 231 without further manual or human labor involvements, thereby improving the efficiency of the manufacturing process and optionally maintaining sterile conditions.

[0061] The workflow 200 continues to step 250, at which the printed product 231 is subject to characterization analysis. It will be appreciated the characterization analysis is optional and not required for all embodiments or implementations. In some embodiments, the characterization analysis may include thermogravimetric analysis, differential scanning calorimetry analysis, microscopic or imaging analysis (e.g., polarized light microscopic imaging), property analysis (e.g., solubility analysis), X-Ray diffraction analysis (XRD), etc.

[0062] FIG. 3 shows chemical structures of APIs and polymeric carriers according to some examples. The APIs suitable for the systems and methods disclosed herein include, but are not limited to, favipiravir (FAV), efavirenz (EFZ), and lumefantrine (LUM). The polymeric carriers suitable for the systems and methods disclosed herein include Eudragit L1OO-55 (EL100- 55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyacrylic acid (PAA). These particular APIs are described to provide representative examples of APIs across a range of different types or with different compositions.

[0063] The present invention is amenable towards various APIs. Advantageously, methods of this aspect are useful for printing ASDs of APIs that are not typically soluble in aqueous solutions and so the APIs can benefit from use in the methods described herein. In certain embodiments, the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug. The Biopharmaceutics Classification System is used to characterize pharmaceutical ingredients based on solubility and permeability. In general class II or class IV drugs under the Biopharmaceutics Classification System have low solubility characteristics, such as where less than a single active dose will dissolve in about 250 mb of a solvent. Class II drugs are characterized as having high permeability, while class IV drugs are characterized as having low permeability. The techniques described herein for creating ASDs of class II and class IV drugs can be useful for generating forms of the drugs that are highly soluble despite the drugs, in their pure form, having low solubility. This can allow for a solubility enhancement to the class II and class IV drugs for a variety of dosage forms and particularly oral dosage forms, as the ASDs can exhibit high solubility, allowing the class II and class IV drugs to be more soluble than they otherwise would be in their pure and / or crystalline form. In some embodiments, the API may include, but is not limited to, favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In certain embodiments, the API in pure form may exhibit an aqueous solubility less than that of the ASD.

[0064] The present invention further provides methods for creating ASDs of APIs without having to subject the APIs to excessive temperatures. The disclosed techniques allow for generation of ASDs comprising an API at a temperature of about 65 °C or less, such as from 0 °C to 5 °C, from 5 °C to 10 °C, from 10 °C to 15 °C, from 15 °C to 20 °C, from 20 °C to 25 °C, from 25 °C to 30 °C, from 30 °C to 35 °C, from 35 °C to 40 °C, from 40 °C to 45 °C, from 45 °C to 50 °C, from 50 °C to 55 °C, from 55 °C to 60 °C, or from 60 °C to 65 °C. In other cases, the disclosed techniques can be useful for generating ASDs from APIs while subjecting the API to temperatures greater than 65 °C, such as from 65 °C to 100 °C. In some embodiments, the API is thermostable. In some embodiments, the API is thermosensitive or decomposes if subjected to temperatures of over 65 °C (e.g., from 65 °C to 100 °C).

[0065] A variety of polymeric carriers can be used, including an ASD-forming anionic polymer or an ASD-forming nonionic polymer. Exemplary polymeric carriers include, but are not limited to, Eudragit LI 00-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or povidone (PVP).

[0066] Exemplary solvents that can be used in any method of the present invention include, but are not limited to, methanol, acetone, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, or methyl tert-butyl ether. In certain embodiments, the solvent has a boiling point less than or equal to a temperature of the deposition surface or that will rapidly evaporate upon contact with the deposition surface. Methods of this aspect may further comprise drying the printed product so that the solvent is fully evaporated, such as by heating or allowing sufficient time for the solvent to evaporate.

[0067] Various deposition surfaces can be used. In certain embodiments, the deposition surface comprises a glass plate. In certain embodiments, the deposition surface is a tailored size. Optionally, the deposition surface is disposed on a heated printing stage. In examples, the heated printing stage may be set to a temperature of from 0 °C to 100 °C, such as a temperature of from 0 °C to 5 °C, from 5 °C to 10 °C, from 10 °C to 15 °C, from 15 °C to 20 °C, from 20 °C to 25 °C, from 25 °C to 30 °C, from 30 °C to 35 °C, from 35 °C to 40 °C, from 40 °C to 45 °C, from 45 °C to 50 °C, from 50 °C to 55 °C, from 55 °C to 60 °C, from 60 °C to 65 °C, from 65 °C to 70 °C, from 70 °C to 75 °C, from 75 °C to 80 °C, from 80 °C to 85 °C, from 85 °C to 90 °C, from 90 °C to 95 °C, or from 95 °C to 100 °C. In some embodiments, the deposition surface is a surface of a tablet or another dosage form. In some embodiments, the deposition surface is a blister pack. Printing directly into a blister pack can be useful for maintaining sterile conditions while generating a printed product directly into a blister pack that can be sealed immediately after printing.

[0068] In certain embodiments, the printhead comprises a nozzle and a nozzle valve. In some embodiments, the nozzle valve is a magnetic valve. In some embodiments, upon applying a magnetic field, the nozzle valve may open for extruding of the printing ink to form the printing droplet. Methods of this aspect may comprise or further comprise controlling the droplet size or the frequency of droplet discharge. In some embodiments, controlling the droplet size or the frequency of droplet discharge is achieved by adjusting a pressure of the nozzle and / or an open time of the nozzle valve. In some embodiments, the printed product is deposited on the deposition surface at a printing pressure ranging from 1 to 200 kPa.

[0069] Any suitable arrangement or deposition pattern can be used for depositing the printed product onto the deposition surface. In some embodiments, depositing the printing droplet on a deposition surface follows a grid, lines, a honeycomb pattern, or concentric deposition pattern. Advantageously, depositing according to a geometric configuration, such as a honeycomb pattern or concentric deposition pattern, can lessen the likelihood of recrystallization of the API. In addition, depositing according to a geometric configuration can aid in rapid or instantaneous solvent evaporation and subsequent development of ASD dispersion.

[0070] In some embodiments, a method comprises providing a printing ink, wherein the printing ink further comprise an active pharmaceutical ingredient (API) in crystalline form, a plurality of polymeric carriers, and a solvent, feeding the printing ink to an electro-magnetic (EMD) printhead, forming a printing droplet from the printing ink, wherein forming the printing droplet is characterized by droplet size and frequency of droplet discharge, and depositing the printing droplet on a deposition surface to form a printed product, wherein the printed product is an amorphous solid dispersion (ASD) of particles, wherein each of the particles comprises the API surrounded by and / or dissolved in the polymeric carrier.

[0071] Compositions

[0072] The present invention further provides compositions, such as printed products which may be generated using a droplet on demand printing technique, such as employing an electromagnetic print head. In certain embodiments, a printed product comprises a plurality of active pharmaceutical ingredient (API) molecules; and a plurality of polymeric carriers, where the API molecules are dissolved in the plurality of polymeric carriers to form a plurality of particles and the plurality of particles forms an amorphous solid dispersion (ASD), such as where each individual particle is coupled to another particle. In some embodiments, additional printed products are coupled together, such as where the printed product further comprises a second plurality of API molecules and a second plurality of polymeric carriers, such as where the second plurality of API molecules are dissolved in the second plurality of polymeric carriers to form a second ASD. Optionally, the plurality of particles and the second plurality of particles are homogeneously dispersed in the printed product.

[0073] In certain embodiments, the APIs of the present invention include those that form a crystalline structure in solid state. In some embodiments, the APIs comprise Biopharmaceutics Classification System class II drugs or a Biopharmaceutics Classification System class IV drugs. Optionally, the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In some embodiments, the API, in pure form, exhibits an aqueous solubility less than that of the ASD. In some embodiments, the printed product may have a solubility greater than the solubility of the API in crystalline state. In some embodiments, the API comprises a plurality of APIs and / or API doses.

[0074] In some embodiments, the plurality of polymeric carriers may comprise Eudragit LI 00-55 (EL 100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

[0075] The printed product may take on any suitable form or shape. In some embodiments, the printed product is in the form of a tablet or a pill. In some embodiments, the printed product comprises or further comprises a plurality of components that are spatially separated. In some embodiments, the plurality of components comprises different APIs or API doses. In some embodiments, the plurality of components comprises different geometries. In some embodiments, the plurality of components comprises different polymeric carriers. In some embodiments, a concentration of the plurality of API molecules varies according to a geometric characteristic of the printed product.

[0076] In another aspect, compositions for use in preparing printed products are provided. In some embodiments, such compositions may correspond to or take the form of a printing ink. In some embodiments, the printing ink comprises an active pharmaceutical ingredient (API); a plurality of polymeric carriers; and a solvent. The printing ink may be configured to, adapted to, or formulated to form a printing droplet when being fed to an electromagnetic (EMD) printhead, such as where the formed printing droplet is characterized by a droplet size and a frequency of droplet discharge; and form a printed product, such as from a plurality of the printing droplets, such as where the printed product is an amorphous solid dispersion (ASD), optionally comprising molecules of the API surrounded by at least one polymeric carrier.

[0077] In certain embodiments, the printing inks described can use any suitable components of APIs, solvents, and / or polymeric carriers described herein. In some embodiments, the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug. In some embodiments, the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine. In some embodiments, the API, in pure form, exhibits an aqueous solubility less than that of the ASD. In some embodiments, the API is thermostable or the API is thermosensitive or decomposes at temperatures over 65 °C or from 65 °C to 100 °C. In some embodiments, the plurality of polymeric carriers comprises Eudragit LI 00-55 (EL 100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

[0078] Systems of Using Methods and Preparing Compositions

[0079] The present invention further provides, in part, systems of using the methods described herein and systems of using and / or preparing compositions described herein. Example systems may employ one or more machine learning models to adjust or determine printing parameters, such as to reliably generate ASDs comprising APIs. In some embodiments, a system of this method comprises a drop-on-demand (DoD) printing device; one or more processors; and one or more memory storing instructions that, upon execution by the one or more processors, cause the processors to perform operations, such as, but not limited to, receiving a print request, such as a print request that identifies an active pharmaceutical ingredient (API) and a plurality of polymeric carriers; providing the print request to a machine learning model, the machine learning model being trained to output a plurality of print parameters based on the API; generating, based on the plurality of print parameters output by the machine learning model, a print profile executable by the DoD printing device; and instructing and / or controlling the DoD printing device, based on the print profile, to form a printing droplet and use the printing droplet to deposit a printed product on a deposition surface. In some embodiments, the systems employ a machine learning model that is trained on known APIs and associated polymeric carriers and print parameters thereof.

[0080] FIG. 9 is a flowchart of using a machine learning model to generate a printed product according to some examples. The method 900 may be incorporated to a system including a drop-on-demand (DoD) printing device, one or more processors, and one or more memory or non-transitory data storage devices. The one or more memory or non-transitory data storage devices may store instructions that are executable by the system. The method 900 starts at step 902, at which the system may receive a print request. The print request identifies an active pharmaceutical ingredient (API) and a plurality of polymeric carriers. The API may be any suitable API, such as FAV, EFZ, LUM, etc. The polymeric carriers may be any suitable polymeric carrier, such as EL100-55, HPMC-AS, PAA, etc. In some embodiments, the print request may identify multiple APIs and / or a plurality of different polymeric carriers. The method 900 continues to step 904, at which the print request is provided to a machine learning model being trained to output a plurality of print parameters based on the API. In some embodiments, the print parameters may include printing pressure, valve open time, cycle time (e g., the frequency of forming a printing droplet), print speed, infill density, etc. In some embodiments, the print parameters may be manually adjusted by a user; for example, the instructions executable by the system may provide a query for user input and receive appropriate user input for adjusting parameters. The method 900 continues to step 906, at which the machine learning model generates a print profile executable by the DoD printing device based on the plurality of print parameters output by the machine learning model. In some embodiments, the print profile may be generated or stored in any suitable format (e.g., .g-code, . stl, .pdf, ,x3d, .dxf, .sat, etc.) that is executable by the DoD printing device. The method then continues to step 908, at which the DoD printing device is instructed to, based on the print profile, form a printing droplet and use the printing droplet to deposit a printed product on a deposition surface. In some embodiments, the size of the printing droplet and the frequency of generating the printing droplet may be adjusted by the print parameters such as printing pressure, valve open time, print speed, infill density, etc. In some embodiments, the deposition surface may be a print bed or a printing stage. The deposition surface may be heated to and / or maintained at a constant temperature to evaporate or dry out the extra solvent from the printed product. In some embodiments, the deposition temperature is 65 °C or may be less than 65 °C, for example. In some embodiments, the deposition surface may be a blister pack.

[0081] In some embodiments, the plurality of print parameters comprises printing pressure, print speed, infill density, or print distance. Example printing pressures may be from 1 to 200 kPa, such as from 1 kPa to 10 kPa, from 10 kPa to 20 kPa, from 20 kPa to 30 kPa, from 30 kPa to 40 kPa, from 40 kPa to 50 kPa, from 50 kPa to 60 kPa, from 60 kPa to 70 kPa, from 70 kPa to 80 kPa, from 80 kPa to 90 kPa, from 90 kPa to 100 kPa, from 100 kPa to 110 kPa, from 110 kPa to 120 kPa, from 120 kPa to 130 kPa, from 130 kPa to 140 kPa, from 140 kPa to 150 kPa, from 150 kPa to 160 kPa, from 160 kPa to 170 kPa, from 170 kPa to 180 kPa, from 180 kPa to 190 kPa, or from 190 kPa to 200 kPa. Example print speeds may be from 1 to 20 mm / s, such as from 1 mm / s to 2 mm / s, from 2 mm / s to 3 mm / s, from 3 mm / s to 4 mm / s, from 4 mm / s to 5 mm / s, from 5 mm / s to 6 mm / s, from 6 mm / s to 7 mm / s, from 7 mm / s to 8 mm / s, from 8 mm / s to 9 mm / s, from 9 mm / s to 10 mm / s, from 10 mm / s to 11 mm / s, from 11 mm / s to 12 mm / s, from 12 mm / s to 13 mm / s, from 13 mm / s to 14 mm / s, from 14 mm / s to 15 mm / s, from 15 mm / s to 16 mm / s, from 16 mm / s to 17 mm / s, from 17 mm / s to 18 mm / s, from 18 mm / s to 19 mm / s, or from

[0082] 19 mm / s to 20 mm / s. Example the infill density may be from 1 to 100%, such as from 1% to

[0083] 5%, from 5% to 10%, from 10% to 15%, from 15% to 20%, from 20% to 25%, from 25% to

[0084] 30%, from 30% to 35%, from 35% to 40%, from 40% to 45%, from 45% to 50%, from 50% to

[0085] 55%, from 55% to 60%, from 60% to 65%, from 65% to 70%, from 70% to 75%, from 75% to

[0086] 80%, from 80% to 85%, from 85% to 90%, from 90% to 95%, or from 95% to 100%.

[0087] In some embodiments, the DoD printing device comprises or further comprises a printhead that comprises a nozzle and a nozzle valve. In some embodiments, a print distance is the distance between the nozzle and the deposition surface. In some embodiments, the print distance is from 0.01 to 70 mm, 0.01 to 65 mm, 0.01 to 64 mm, 0.01 to 63 mm, 0.01 to 62 mm, 0.01 to 61 mm, and 0.01 to 60 mm, such as from 0.01 mm to 0.1 mm, from 0.1 mm to 0.5 mm, from 0.5 mm to 1 mm, from 1 mm to 5 mm, from 5 mm to 10 mm, from 10 mm to 20 mm, from

[0088] 20 mm to 30 mm, from 30 mm to 40 mm, from 40 mm to 50 mm, from 50 mm to 60 mm, from 60 mm to 65 mm, or from 60 mm to 70 mm. In some embodiments, the print distance is about 0.01 mm, about 1 mm, about 5 mm, about 10 mm, about 20 mm, about 30 mm, about 40 mm, about 50 mm, about 60 mm, about 65 mm, or about 70 mm. In some embodiments, the print distance is about 63.6 mm. In some embodiments, the plurality of print parameters comprises an open time of the nozzle valve. Example open time of the nozzle valve may be from 1 ms to 20 ms, such as from 1 ms to 2 ms, from 2 ms to 3 ms, from 3 ms to 4 ms, from 4 ms to 5 ms, from 5 ms to 6 ms, from 6 ms to 7 ms, from 7 ms to 8 ms, from 8 ms to 9 ms, from 9 ms to 10 ms, from 10 ms to 11 ms, from 11 ms to 12 ms, from 12 ms to 13 ms, from 13 ms to 14 ms, from 14 ms to 15 ms, from 15 ms to 16 ms, from 16 ms to 17 ms, from 17 ms to 18 ms, from 18 ms to 19 ms, or from 19 ms to 20 ms. In some embodiments, the plurality of print parameters comprises a cycle time that the nozzle valve opens. Optionally, the cycle time is from 1 ms to 2000 ms, such as from 1 ms to 5 ms, from 5 ms to 10 ms, from 10 ms to 20 ms, from 20 ms to 30 ms, from 30 ms to 40 ms, from 40 ms to 50 ms, from 50 ms to 60 ms, from 60 ms to 70 ms, from 70 ms to 80 ms, from 80 ms to 90 ms, from 90 ms to 100 ms, from 100 ms to 200 ms, from 200 ms to 300 ms, from 300 ms to 400 ms, from 400 ms to 500 ms, from 500 ms to 600 ms, from 600 ms to 700 ms, from 700 ms to 800 ms, from 800 ms to 900 ms, from 900 ms to 1000 ms, from 1000 ms to 1500 ms, or from 1500 ms to 2000 ms.

[0089] Other compositions described herein include medications, such as medications including the printed products described herein, including APIs in the form of ASDs. In examples, the medications may be manufactured according to any suitable method described herein.

[0090] EMBODIMENTS

[0091] 1. A method of manufacturing a printed product, the method comprising: providing a printing ink, wherein the printing ink comprises an active pharmaceutical ingredient (API) in crystalline form, a plurality of polymeric carriers, and a solvent; feeding the printing ink to an electro-magnetic (EMD) printhead; forming a printing droplet from the printing ink, wherein forming the printing droplet is characterized by a droplet size and a frequency of droplet discharge; and depositing the printing droplet on a deposition surface to form a printed product, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier. 2. The method of embodiment 1, wherein the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug.

[0092] 3. The method of any one of embodiments 1-2, wherein the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine.

[0093] 4. The method of any one of embodiments 1-3, wherein the API exhibits an aqueous solubility less than that of the ASD.

[0094] 5. The method of any one of embodiments 1-4, wherein the API is thermostable, or the API is thermosensitive, or the API decomposes at temperatures over 65 °C, or the API decomposes at temperatures from 65 °C to 100 °C.

[0095] 6. The method of any one of embodiments 1-5, wherein the plurality of polymeric carriers comprises Eudragit L100-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

[0096] 7. The method of any one of embodiments 1 -6, wherein the solvent is methanol, acetone, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, or a solvent that has a boiling point less than or equal to a temperature of the deposition surface.

[0097] 8. The method of any one of embodiments 1-7, wherein the deposition surface comprises a glass plate.

[0098] 9. The method of embodiment 8, wherein the glass plate has a tailored size.

[0099] 10. The method of any one of embodiments 1-9, wherein the deposition surface is disposed on a heated printing stage. 11. The method of embodiment 10, wherein the heated printing stage is set to a temperature of about 65 °C.

[0100] 12. The method of any one of embodiments 1-11, wherein the deposition surface is a surface of a tablet.

[0101] 13. The method of any one of embodiments 1-12, wherein the deposition surface is a blister pack.

[0102] 14. The method of any one of embodiments 1-13, further comprising drying the printed product so that the solvent is fully evaporated.

[0103] 15. The method of any one of embodiments 1-14, wherein the printhead further comprises a nozzle and a nozzle valve.

[0104] 16. The method of embodiment 15, wherein the nozzle valve is a magnetic valve.

[0105] 17. The method of any one of embodiments 1-16, further comprising the step of controlling the droplet size or the frequency of droplet discharge by adjusting a pressure of the nozzle or an open time of the nozzle valve.

[0106] 18. The method of any one of embodiments 1-17, wherein the nozzle valve opens for extruding of the printing ink to form the printing droplet upon application of a magnetic field.

[0107] 19. The method of any one of embodiments 1-18, wherein the printed product is deposited on the deposition surface at a printing pressure ranging from 1 to 200 kPa.

[0108] 20. The method of any one of embodiments 1-19, wherein depositing the printing droplet on a deposition surface follows a grid, lines, a honeycomb pattern, or concentric deposition pattern.

[0109] 21. A printed product comprising: a plurality of active pharmaceutical ingredient (API) molecules; and a plurality of polymeric carriers, wherein: the API molecules are dissolved in the plurality of polymeric carriers to form a plurality of particles; and the plurality of particles forms an amorphous solid dispersion (ASD), wherein each individual particle is coupled to another particle.

[0110] 22. The printed product of embodiment 21, further comprising: a second plurality of API molecules, wherein the second plurality of API molecules is different from the plurality of API molecules; and a second plurality of polymeric carriers, wherein: the second plurality of polymeric carriers is different from the plurality of polymeric carriers; the second plurality of API molecules are dissolved in the second plurality of polymeric carriers to form a second plurality of particles; and the second plurality of particles forms an ASD, wherein each individual particle of the second plurality of particles is coupled to another particle of the plurality of particles or the second plurality of particles.

[0111] 23. The printed product of any one of embodiments 21-22, wherein the plurality of API molecules forms a crystalline structure in solid state.

[0112] 24. The printed product of any one of embodiments 21-23, wherein the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug.

[0113] 25. The printed product of any one of embodiments 21-24, wherein the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine.

[0114] 26. The printed product of any one of embodiments 21-25, wherein the API exhibits an aqueous solubility less than that of the ASD. 27. The printed product of any one of embodiments 21-26, wherein the plurality of polymeric carriers comprise Eudragit L1OO-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), an ASD-forming anionic polymer, or an ASD-forming nonionic polymer.

[0115] 28. The printed product of any one of embodiments 21-27, wherein the plurality of particles and the second plurality of particles are homogeneously dispersed in the printed product.

[0116] 29. The printed product of any one of embodiments 21-28, wherein the printed product has a solubility greater than the solubility of the API in crystalline state.

[0117] 30. The printed product of any one of embodiments 21-29, wherein the printed product further comprises a plurality of a second API molecules.

[0118] 31. The printed product of any one of embodiments 21-30, wherein the printed product is in the form of a tablet or a pill.

[0119] 32. The printed product of any one of embodiments 21-31, wherein the printed product further comprises a plurality of components that are spatially separated.

[0120] 33. The printed product of embodiment 32, wherein the plurality of components comprises different APIs or API doses.

[0121] 34. The printed product of any one of embodiments 21-33, wherein the plurality of components have different geometries.

[0122] 35. The printed product of any one of embodiments 21-34, wherein the plurality of components comprises different polymeric carriers. 36. The printed product of any one of embodiments 21-35, wherein the concentration of the plurality of API molecules varies according to a geometric characteristic of the printed product.

[0123] 37. A printing ink comprising: an active pharmaceutical ingredient (API); a plurality of polymeric carriers; and a solvent, wherein the printing ink is configured to: form a printing droplet when fed to an electro-magnetic (EMD) printhead, wherein the formed printing droplet is characterized by a droplet size and a frequency of droplet discharge; and form a printed product from a plurality of the printing droplets, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier.

[0124] 38. The printing ink of embodiment 37, wherein the API comprises a Biopharmaceutics Classification System class II drug or a Biopharmaceutics Classification System class IV drug.

[0125] 39. The printing ink of any one of embodiments 37-38, wherein the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine.

[0126] 40. The printing ink of any one of embodiments 37-39, wherein the API, in pure form, exhibits an aqueous solubility less than that of the ASD.

[0127] 41. The printing ink of any one of embodiments 37-40, wherein the API is thermostable, or the API is thermosensitive, or the API decomposes at temperatures over 65 °C, or the API decomposes at temperatures from 65 °C to 100 °C.

[0128] 42. The printing ink of any one of embodiments 37-41, wherein the plurality of polymeric carriers comprises Eudragit L100-55 (EL1OO-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyacrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

[0129] 43. A system comprising: a drop-on-demand (DoD) printing device; one or more processors; and one or more memory storing instructions that, upon execution by the one or more processors, configure the system to: receiving a print request, wherein the print request identifies an active pharmaceutical ingredient (API) and a plurality of polymeric carriers; providing the print request to a machine learning model, the machine learning model being trained to output a plurality of print parameters based on the API; generating, based on the plurality of print parameters output by the machine learning model, a print profile executable by the DoD printing device; and instructing the DoD printing device, based on the print profile, to form a printing droplet and use the printing droplet to deposit a printed product on a deposition surface.

[0130] 44. The system of embodiment 43, wherein the plurality of print parameters comprises printing pressure, print speed, infill density, or print distance.

[0131] 45. The system of embodiment 44, wherein the printing pressure is from 1 to 200 kPa.

[0132] 46. The system of any one of embodiments 44-45, wherein the print speed is from 1 to 20 mm / s.

[0133] 47. The system of any one of embodiments 44-46, wherein the infill density is from 1 to 100%.

[0134] 48. The system of any one of embodiments 43-47, wherein the DoD printing device further comprises a printhead that comprises a nozzle and a nozzle valve. 49. The system of embodiment 48, wherein the print distance is the distance between the nozzle and the deposition surface, and the print distance is from 0.01 to 63.6 mm.

[0135] 50. The system of any one of embodiments 44-49, wherein the plurality of print parameters comprises an open time of the nozzle valve.

[0136] 51. The system of embodiment 50, wherein the open time of the nozzle valve is from 1 ms to 20 ms.

[0137] 52. The system of any one of embodiments 44-51, wherein the plurality of print parameters comprises a cycle time that the nozzle valve opens.

[0138] 53. The system of embodiment 52, wherein the cycle time is from 1 ms to 2000 ms.

[0139] 54. The system of any one of embodiments 43-53, wherein the printed product is amorphous.

[0140] 55. A medication made by the method of manufacturing of any one of embodiments 1-20 or including the printed product of any one of embodiments 21-36.

[0141] EXPERIMENTAL EXAMPLES

[0142] The methods disclosed herein may be used in the manufacture and fabrication of medications or pharmaceutical products that include active ingredients (e.g., active pharmaceutical ingredients, APIs) generally exhibiting or regarded as having poor solubility or bioavailability (e.g., poor solubility or bioavailability in their crystalline form). Specifically, the disclosed techniques include preparing printing ink containing target active ingredient(s) and polymeric carriers, such as a printing ink that is suitable for additive deposition technologies. The disclosed techniques further include using drop-on-demand (DoD) technology to form an amorphous solid dispersion (ASD) from the printing ink. The DoD system includes an electromagnetic component (e.g., an electromagnetic valve inside the printhead) that can be flexibly and accurately controlled to form printing ink droplets with desired properties so that the resultant active ingredients form an ASD during printing in order for the the active ingredients in the printed products to exhibit improved solubility or bioavailability, such as when compared to the crystalline form of the active ingredients.

[0143] Conventional ASD manufacturing techniques may be divided into two major categories: solvent evaporation-based approach and melting-based approach. In both approaches, the crystalline structure of API is disturbed by dissolving or melting in a solvent containing polymeric carriers, respectively. The disturbed API molecules are then converted into particles in which the API molecules are dissolved in polymeric carriers. Drying or evaporation steps may be subsequently used to remove the solvent. For example, under the evaporationbased approach, spray drying may be used to remove the solvent. Other drying or solventevaporation techniques such as electrospraying, electrospinning, freeze spray drying, fluidized bed technology, and supercritical fluids may also be used.

[0144] The melting-based approach usually does not require the use of organic solvents. However, as the melting-based approach generally relies on thermal processing steps such as hot melt extrusion, it causes degradations in thermosensitive APIs and the application of the meltingbased approach is thus limited.

[0145] Example 1 : Electromagnetic Drop-On-Demand (Pod) Technology

[0146] Three-dimensional (3D) printing technology, or additive manufacturing (AM) or additive deposition technologies, is a useful tool for pharmaceutics and bioengineering. 3D printing can be a cost-effective alternative technique compared to traditional pharmaceutical technologies for generating pharmaceutical delivery systems and supports the concept of personalized medication and customized polypills. Systems and methods described herein use 3D printing to provide an innovative manufacturing method for pharmaceutical ASDs, including for preparing ASDs of APIs that are thermosensitive. For example, the methods disclosed herein can employ a drop-on-demand (DoD) 3D printing technique. DoD is useful for allowing precise and well-controlled dispensing of liquids or materials in small volumes (e.g., as droplets). DoD involves forming droplets on-demand and depositing the formed droplets onto a target surface with high accuracy. In an example DoD system, droplets may be ejected from a printhead or a nozzle of the printhead according to various processing requirements or parameters, thereby enabling the printing inks to be deposited in a flexible and well-controlled manner. Example DoD systems include piezoelectric system, thermal inkjet system, and electromagnetic system. An example electromagnetic DoD system utilizes an external electromagnetic field to trigger a metal valve of the printhead to open and close. By adjusting printing parameters such as printing pressure, open time of the valve, cycle time of the valve, or the like, the DoD system can accurately control the size as well as the printing frequency of the printed droplet.

[0147] FIG. 4A provides data showing thermogravimetric analysis results of pure APIs according to some examples. The APIs disclosed herein include favipiravir (FAV), efavirenz (EFZ), and lumefantrine (LUM).

[0148] FIG. 4B provides data showing thermogravimetric analysis results of pure polymers according to some examples. The polymeric carriers disclosed herein include Eudragit L100-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyacrylic acid (PAA).

[0149] FIG. 5A provides data showing differential scanning calorimetric analysis results of efavirenz (EFZ) and ASD printed product including EFZ according to some examples. As shown in FIG. 5A, pure EFZ has a sharp endothermic peak at 138.82 °C, which indicates that pure EFZ has a crystalline structure. The ASD printed product including EFZ (EFZ-EL100-55 ASD) shows a shallow glass transition endothermic event on the plot at 83.6 °C, which indicates that the ASD printed product including EFZ has a glass transition temperature (Tg) of 83.6 °C. The absence of any minor endothermic peaks and / or multiple glass transition events in the plot of ASD printed product including EFZ verifies the homogenous dispersion of particles including EFZ at a molecular level and that the ASD printed product is amorphous.

[0150] FIG. 5B provides data showing differential scanning calorimetric analysis results of lumefantrine (LUM) and ASD printed product including LUM according to some examples. As shown in FIG. 5B, pure LUM has a sharp endothermic peak at 134.79 °C, which indicates that pure LUM has a crystalline structure. The ASD printed product including LUM (e.g., LUM- HPMC-AS ASD) shows a shallow glass transition endothermic event on the plot at 109.8 °C, which indicates that the ASD printed product including LUM has a glass transition temperature (Tg) of 109.8 °C. Similar to the ASD printed product including EFZ, the absence of any minor endothermic peaks and / or multiple glass transition events in the plot of ASD printed product including LUM verifies the homogenous dispersion of particles including LUM at a molecular level and that the ASD printed product is amorphous.

[0151] FIG. 5C provides data showing differential scanning calorimetric analysis results of favipiravir (FAV) and ASD printed product including FAV according to some examples. As shown in FIG. 5C, pure FAV has a sharp endothermic peak at 189.83 °C, which indicates that pure FAV has a crystalline structure. The ASD printed product including FAV (e.g., FAV-PAA ASD) shows a shallow glass transition endothermic event on the plot at 57.50 °C, which indicates that the ASD printed product including FAV has a glass transition temperature (Tg) of 57.50 °C. Similar to the ASD printed products including EFZ and LUM, the absence of any minor endothermic peaks and / or multiple glass transition events in the plot of ASD printed product including FAV verifies the homogenous dispersion of particles including FAV at a molecular level and that the ASD printed product is amorphous.

[0152] FIG. 6 provides polarized light microscopy images of pure APIs and ASD printed products according to some examples. As illustrated by FIG. 6, the images (a), (b), and (c) show polarized light microscopic images of pure EFZ, LUM, and FAV at 50x magnification, respectively. Images (a)-(c) display the existence of birefringence as polarization colors, which indicates the existence of EFZ, LUM and FAV as anisotropic crystalline structures. The images (d), (e), and (f) show polarized light microscopic images of ASD including EFZ (e.g., EFZ- EL100-55 ASD), LUM (e.g, LUM-HPMC-AS ASD), and FAV (e.g, FAV-PAA ASD) at lOx magnification, respectively. Compared with images (a)-(c), images (d)-(f) show nonbirefringence as evidenced by the absence of interference colors, which indicates the existence of isotropic solid particles made of randomly oriented molecules. Compared with images (e) and (I), image (d) showing the polarized light microscopy image of LUM-HPMC-AS ASD has a limited appearance of polarization colors. While the majority of LUM molecules exist in amorphous state, the limited appearance of polarization colors in image (d) may be caused by residual LUM molecules existing in crystalline form. The residual LUM molecules in crystalline form may be due to limited protonation of LUM. The limited protonation of LUM may be attributed to the low acidic group content (1 mmol / g) of HPMC-AS and the steric hindrance effect, which results in incomplete interaction between LUM and HPMC-AS in the printing ink and the incomplete amorphization of LUM inside HPMC-AS.

[0153] FIG. 7A provides data showing powder X-ray diffraction (XRPD) analysis of pure EFZ and ASD printed product including EFZ according to some examples. The ASD printed product may be made by using the electromagnetic DoD printing method and system disclosed herein. The X-ray diffractogram of pure EFZ 710 shows multiple sharp Bragg diffraction peaks at 20 angles of 14.1, 16.9, 20.3, 21.1, 26.1 and 32.4°, indicating the crystallinity of pure EFZ. The X-ray diffractogram of ASD including EFZ (e.g., EFZ-EL100-55 ASD) 720 shows broad halos with no distinctive Bragg diffraction peaks, which indicates that the ASD including EFZ is in an amorphous state.

[0154] FIG. 7B provides data showing powder X-ray diffraction (XRPD) analysis of pure LUM and ASD printed product including LUM according to some examples. The ASD printed product may be made by using the electromagnetic DoD printing method and system disclosed herein. The X-ray diffractogram of pure LUM 730 shows multiple sharp Bragg diffraction peaks at 20 angles of 11.3, 15.1, 18.2, 20.3, 23.7, 25.8 and 27.2°, indicating the crystallinity of pure LUM. The X-ray diffractogram of ASD including LUM (e.g., LUM-HPMC-AS ASD) 740 shows broad halos with no distinctive Bragg diffraction peaks, which indicates that the ASD including LUM is in an amorphous state. Although the diffractogram of the ASD including LUM (e.g., LUM-HPMC-AS ASD) shows the existence of a low-intensity single sharp peak at 20 angle of about 15.6° which may indicate the existence of residual LUM molecules in crystalline form, the majority of LUM molecules is dissolved in HPMC-AS polymer carriers. It is worth noting that the absence of any thermal event in the DSC thermogram of the LUM- HPMC-AS ASD indicating this crystallinity is due to the limited DSC sensitivity for detecting small crystal content (Dedroog, S. et al., Journal of Pharmaceutical and Biomedical Analysis, 178, 112937), which may dissolve in the polymer during the test under the influence of heating (Bikiaris, D. et al., 2005, Thermochimical Acta, 439, 58).

[0155] FIG. 7C provides data showing powder X-ray diffraction (XRPD) analysis of pure FAV and ASD printed product including FAV according to some examples. The ASD printed product may be made by using the electromagnetic DoD printing method and system disclosed herein. The X-ray diffractogram of pure FAV 750 shows multiple sharp Bragg diffraction peaks at 20 angles of 11.9, 19.7, 20.2, 27.0 and 27.8°, indicating the crystallinity of pure FAV. The X- ray diffractogram of ASD including FAV (e.g., FAV-PAA ASD) 760 shows broad halos with no distinctive Bragg diffraction peaks, which indicates that the ASD including FAV is in amorphous state.

[0156] FIG. 8A provides data showing Fourier Transfer-Infrared (FT-IR) spectroscopy analysis data of pure EFZ, EL100-55, physical mixture (PM) of EFZ and EL100-55, and ASD printed product according to some examples. The FT-IR spectrum plot of EFZ shows characteristic stretching vibration bands of (C=O) and (-NH) groups at 1748 and 3318 cm'1, respectively. The plot shows a typical exocyclic triple bond stretching peak at 2251 cm-1and the tertiary amide stretching peak at 1603 cm'1. The plot exhibits a distinctive stretching vibration peak of (C = C) group of benzene ring at 1496 cm1, as well as three peaks at 1096, 1073, and 1055 cm'1characterizing the (C-O-C) group. The FT-IR spectrum plot of polymeric carrier EL100-55 shows that the characteristic stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups at 1731 and 1717 cm'1, respectively. Furthermore, the plot shows a distinctive peak at 2981 cm'1, which indicates the stretching vibration of the methylene (C-H) groups. The FT-IR spectrum plot of EFZ-EL100-55 PM shows all the characteristic peaks of EFZ and the characteristic stretching vibration band of-NH group of EFZ at 3318 cm'1and stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups at 1731 and 1717 cm'1, which indicates an absence of ionic interaction between EFZ and the acidic polymer EL-100-55. Due to dilution (e.g., ten-time dilution), the characteristic peaks of EFZ in the EFZ- EL 100-55 PM have lower intensities than the pure EFZ spectrum plot. The FT-IR spectrum plot of the ASD printed product EFZ-EL100-55 shows an absence of the stretching vibration band of (-NH) group of EFZ at 3318 cm'1and marked reduction in the intensity of the stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups of EL1OO-55 at 1731 and 1717 cm'1, which indicates the ionic interaction between the EFZ and the EL100-55 polymeric carriers.

[0157] FIG. 8B provides data showing FT-IR spectroscopy analysis data of pure LUM, HPMC-AS, PM of LUM and HPMC-AS, and ASD printed product according to some examples. The pure LUM spectrum plot demonstrates the characteristic stretching vibration band of the (- OH) group and the (C-H) group at 3402 and 2952 cm respectively. The peaks at 1085 and 1033 cm1correspond to the stretching vibrations of the (C-N) and (C-O) groups, respectively. The FT-IR spectrum plot of HPMC-AS shows the broad stretching vibration peak of the (-OH) group at 3446 cm'1. The plot shows a distinctive stretching vibration peak of the (C=O) group and the bending vibration peak of the (C-O) at 1734 and 1055 cm'1, respectively. The LUM- HPMC-AS PM spectrum plot displays variations in peak locations and intensities as compared to the pure LUM and HPMC-AS spectrum plots, suggesting the absence of ionic interactions between pure LUM and HPMC-AS in physically mixed state. The FT-IR spectrum plot of the ASD printed product shows a distinctive rise in intensity and widening of the (-OH) group peak, indicating an ionic interaction between the LUM and the polymeric carrier HPMC-AS. The ionic interaction is also supported by a decrease in the intensity of the HPMC-AS (C=O) group stretching vibration peak at 1734 cm'1, which indicates an extent of carboxyl group neutralization. FIG. 8C provides data showing FT-IR spectroscopy analysis data of pure FAV, PAA, PM of FAV and PAA, and ASD printed product according to some examples. The pure FAV spectrum plot shows stretching vibration bands of (-NH) group at 3357and 3224 cm'1, stretching vibration peak of (C=O) carbonyl group at 1655 cm1, and distinctive peaks of the (C-F) and (C-OH) groups at 1265 and 1183 cm'1, respectively. The FT-IR spectrum plot of polymeric carrier PAA exhibits bands at 3150 and 1715 cm'1, representing the stretching vibration of the (-OH) group and the carboxylic (C=O) group, respectively. The plot shows stretching vibration of (C~O) at 1266 cm'1, while the stretching vibrations of (C-H) for CH and CH2 groups are shown at 1456 and 2981 cm'1. The FT-IR spectrum plot of the FAV-PAA PM exhibits all the characteristic peaks of both pure FAV and PAA, which indicates the absence of chemical or ionic interactions. Mixing FAV with PAA (e.g., in a ratio of 1 :9) results in a marked reduction in the intensities of all FAV peaks due to dilution. The printed product ASD FAV- PAA has a different FT-IR spectrum than the physical mixture (e.g., FAV-PAA PM). The two stretching vibration bands of (~NH) group characterizing pure FAV are not detected at their positions (e.g., 3357and 3224 cm'1) in the physical mixture (e.g., FAV-PAA PM) plot, which indicates that the amino groups of pure FAV are completely consumed in the ionic interaction with PAA. The consumption of the amino groups in pure FAV is corroborated by the reduction in the intensity of the carboxylic (C=O) group of PAA.

[0158] Table 1 provides equilibrium solubility of pure APIs, physical mixtures including the APIs, and pinted product ASDs including the APIs in a phosphate buffer have a pH of 6.8. APIs include EFZ, LUM, and FAV. Polymeric carriers mixed with the APIs include ELI 00-55, HPMC, and PAA.

[0159] Table 1. Equilibrium solubilities API formulations used in the present invention.

[0160] Formulation Solubility (ug / nil) ± SD

[0161] EFZ pure drug 0.03 ± 0.04

[0162] EFZ-EL100-55 physical mixture 16.85 ± 5.95*

[0163] EFZ-EL100-55 ASD 21.18 ± 4.20**

[0164] LUM pure drug 1.26 ± 1.60

[0165] LUM-HPMC-AS physical mixture 1.40 ± 1.75

[0166] LUM-HPMC-AS ASD 20.21 ± 6.91** FAV pure drug 6674.34 ± 164.54

[0167] FAV-PAA physical mixture 2583.33 ± 1068.14**

[0168] FAV-PAA ASD 2109.65 ± 254.21**

[0169] The solubility results show the equilibrium solubility of EFZ is very limited (e.g., 0.026 ± 0.037 pg / ml). The physical mixture of EFZ and the polymeric carrier EL100-55 has an increased (p<0.005) solubility of 16.851 ± 5.945 pg / ml. The increase in solubility may be a result of the finer dispersion of EFZ molecules with the EL100-55 molecules, which provides improved wetting and prevents molecule aggregation. The printed product ASD including EFZ (e.g., EFZ-EL100-55 ASD) shows a significant (p<0.001) increase in EFZ solubility, which is more than 800 (e.g., 814) times higher than the solubility of pure EFZ. The substantial increase in EFZ solubility observed in the printed product ASD (e.g., EFZ-EL100-55 ASD) suggests a high degree of EFZ dispersion in the anionic polymeric carrier EL 100-55. As the polymeric carrier EL1OO-55 has a large number of acidic groups per unit mass (e.g., 5.8 mmol / g), a high- degree of drug protonation and a high-degree of amorphization can be achieved.

[0170] Pure LUM exhibits a low solubility (e g., 1.26 ± 1.60 pg / ml). The solubility of the LUM-HPMC-AS PM is 1.40 ± 1.75 pg / ml, which does not show a significant difference from the solubility of pure LUM. The small difference between pure LUM and LUM-HPMC- AS PM may be explained by the fact that HPMC-AS polymeric carriers are featured with steric hindrance restricting the accessibility to their anionic groups, which results in low LUM protonation by HPMC-AS in both the solid state as well as in an aqueous environment. The solubility of the printed product ASD (e.g., LUM-HPMC-AS ASD) has a solubility that is sixteen times higher (p<0.001) than that of the pure LUM, which indicates improved LUM protonation, efficient amorphization of LUM, and enhanced solubility.

[0171] Pure FAV has a solubility of 6674.3 ± 164.5 pg / ml. Significant reduction (p<0.001) in the solubility of FAV was observed for FAV-PAA PM and printed product ASD (e.g., FAV-PAA). The FAV-PAA PM has a solubility of 2583.3 ± 1068.1. The printed product ASD (e.g., FAV-PAA) has a solubility of 2109.64 ± 254.2 pg / ml. This unexpected reduction in solubility of FAV in both PM and ASD may be caused by the agglutination phenomenon which is described as the formation pseudo-gel layer by the polymer matrix and the pseudo-gel layer hinders the release of FAV into the medium. The strong FAV-PAA interaction, especially in the ASD state, may lead to the formation of insoluble drug-polymer complex that persists in the aqueous environment, which minimizes the hydration of the polymer and the dissociation of FAV molecules into the medium. Such decrease in solubility may be used to achieve controlled drug release (e.g., maintaining drug release over a sustained period).

[0172] Example 2: Electromagnetic Drop-On-Demand (Pod) Technology as an Innovative Platform for Amorphous Solid Dispersion Production

[0173] Production of amorphous solid dispersions (ASDs) is an invaluable technique to promote the solubility and bioavailability of medicinal substances. ASD is manufactured using a variety of classic and modern techniques, most of which rely on either melting or solvent evaporation. The present work is the first ever to introduce electromagnetic DoD as an alternative solvent evaporation-based method for producing ASD. Advanced DoD 3D printing of ASDs for three drug-polymer combinations (efavirenz-Eudragit L100-55, lumefantrine- hydroxypropyl methylcellulose acetate succinate, and favipiravir-polyacrylic acid) was investigated to ascertain the reliability of this technique. Polarized light microscopy, differential scanning calorimetry, X-ray powder diffraction, and Fourier transfer infrared spectroscopy results all supported the 3D printing of ASD for the three drugs, which significantly increases the equilibrium solubility of two of them compared to their pure states. Overall, the study's findings show how this new electromagnetic DoD technology has the potential to become a cutting-edge 3D printing solvent-evaporation technique for the continuous manufacturing of ASDs for a variety of drugs.

[0174] The ASD production technology provided herein has a significant impact on increasing the bioavailability of medications with limited solubility, which is the case for most active pharmacological agents (APIs) now available in the market. As a result, the production of ASD-based medicines is growing significantly. Conventionally, solvent-evaporation approach or melting-based approach were used for ASD manufacture, such as spray-drying, hot-melt extrusion, thin-film freezing etc. In both approaches, the crystalline structure of the drug material is broken down either by melting or dissolving in the solvent, and subsequently converted into separate drug molecules that are distributed randomly (amorphous) into the polymeric carrier.

[0175] 3D printing presents itself as a cost-effective alternative technique compared to traditional pharmaceutical technologies for advancing pharmaceutical delivery systems and promoting the concept of personalized medication. Electromagnetic drop-on-demand (DOD) technology was selected as a potential new contender for producing ASD based on the solvent evaporation approach. Electromagnetic DOD systems utilize an external electromagnetic field to trigger a metal valve to open and close, enabling droplet ejection at desired rate, which is a critical parameter in the production of ASD, particularly in the solvent-evaporation approach. By controlling the temperature of the 3D-printer printed and the other DOD parameters (such as the cycle time, infill density, and nozzle travel speed), the rate of evaporation of DOD printed solvent could be validated to assure the ASD formation. Accordingly, the present work provides electromagnetic drop-on-demand (DoD) printing technology as an innovative 3D-printing technique for manufacturing amorphous solid dispersion (ASD), and this innovated technology could potentially be categorized as a solvent-evaporation based method.

[0176] The present work describes, in part, the formation of ASD for three model poorly water-soluble model drugs was examined to confirm the validity of the invented technology. In brief, the ink solution for each of the three drugs were formed of drug, enteric polymer, and organic solvent at pre-examined composition ratio. Based on a computer aided design (CAD), the ink solutions were printed using the EMD, and the printing conditions were optimized to finally get solid ASD particles of each of the three drugs. To confirm the formation of ASDs, the necessary physicochemical characterization tests were carried out.

[0177] The present work is characterized by a number of novel features including, but not limited to, the lack of introduction of high temperatures to avoid drug degradation, its application towards a wide range of drugs and solvents, a tailorable droplet size and amount of drug loading, the ability to load multiple drugs at once, having a confined area and portable device enabling printing at a point-of-care, and lower energy consumption. The present work addresses multiple problems, such as thermal sensitivity of several medications that cannot be employed in other melting-based ASD methods. The present method is straightforward, being a single-step manufacturing process, and outperforms the complexity of existing ASD generation procedures. Further, the present technology is an innovative alternative solvent-evaporation method for manufacturing ASDs. It fills the gap that currently formulating thermosensitive drugs does not have a single-step manufacturing approach. The electromagnetic DoD system offers the advantages of taking up less space, utilizing less energy, and not requiring the presence of an external gas cylinder, making it a more environmentally friendly system. It also could produce multi-drug formulation with the same polymer and solvent. It allows tailored dose adjustment and gives flexibility for dose titration. Future applications of the present invention include inks which could be printed directly into a package, sealed, and applied to patients with an individualized dosing.

[0178] Three-dimensional (3D) printing technology, as additive manufacturing (AM) technology, has emerged as the one of most promising tools for pharmaceutics and bioengineering. 3D printing presents itself as a cost-effective alternative technique compared to traditional pharmaceutical technologies for advancing pharmaceutical delivery systems and supporting the concept of personalized medication and customized polypills (Maniruzzaman, M., 2018, 3D and 4D printing in biomedical applications: process engineering and additive manufacturing, Wang, J. et al., 2021, Advanced Drug Delivery Reviews, 174, 294).

[0179] The breakthrough upgrades in various 3D-printing techniques motivated researchers to investigate the use of 3D printing technology in ASD production. To that goal, for the first time, the selective laser sintering (SLS) technique was adopted to 3D print ritonavir- Kollidon® VA64 ASD (Davis, D. A. et al., 2021, Journal of Pharmaceutical Sciences, 110, 1432). Further research was conducted on the SLS of indomethacin- Kollidon® VA64 ASD to investigate the mechanism of ASD formation by SLS, as well as the impact of processing parameters on ASD production. The findings proposed that during the laser sintering process, the drug particles spread and ultimately disintegrate in the polymeric matrix. As a result, this process could be classified as a melting-based method for ASD production (Thakkar, R. et al., 2021, Pharmaceutics, 13; Santitewagun, S. et al., 2022, Molecular Pharmaceutics, 19, 2380).

[0180] Hot melt extrusion together with fused deposition modelling was also examined for the 3D printing of tablets encapsulating itraconazole and ketoconazole ASDs (Parulski, C. et al., 2022, International Journal of Pharmaceutics, 626; Gottschalk, N. et al., 2023, International Journal of Pharmaceutics, 5, 100179). So recently, the drop-on-powder (binder jetting) technique was explored for the 3D printing of ASD-containing tablets. Gottschalk et al. milled the ASD formed by hot melt extrusion and use it as the powder bed for tablets prepared by binder jetting (Gottschalk, N. et al., 2023, International Journal of Pharmaceutics, 5, 100151). In another study, both the medicine and the polymer were mixed in a hydroalcoholic solvent to formulate the binder ink, then printed the ink onto the surface of the powder bed to produce tablets containing ketoconazole-copovidone ASD. The qualities of the produced ASD were considerably affected by formulation parameters such as drug loading and ink-to-powder ratio. This work could be considered the first endeavor for developing a 3D-printing method to produce ASD adopting the solvent evaporation approach. Electromagnetic drop-on-demand (DOD) technology was selected as the 3D printing technique that could serve as a potential new contender for producing ASD based on the solvent evaporation approach. Drop-on-demand (DOD) technology is a widely used method in various industries for precise and controlled dispensing of liquids or materials in small volumes. It involves generating individual droplets on-demand and depositing them onto a target surface with high accuracy. This technology finds applications in various fields, including printing, pharmaceuticals, electronics, biotechnology, and more.

[0181] In DOD systems, droplets are ejected from a nozzle or printhead based on specific requirements, providing flexibility in material deposition. There are three main types of DOD systems: piezoelectric, thermal inkjet and electromagnetic (Luo, Z. et al, 2017, Materials Letters, 188, 184; Zikulnig, J., 2021, Fabrication Technologies for Flexible Printed Sensors). Electromagnetic DOD systems utilize an external electromagnetic field to trigger a metal valve to open and close. The printing variables that affect droplet size involve pressure and open time. On the other hand, the cycle time would affect the printing frequency.

[0182] The applications of DOD technology are vast and diverse. In pharmaceutical manufacturing, DOD technology is employed for precise dispensing of active ingredients, allowing for accurate dosage and drug formulation (Lu, A. et al., 2022, Pharmaceutical Research, 39, 2905). It also finds applications in biotechnology for the controlled deposition of biological fluids and reagents in protein microarray printing and biofabrication processes (Zaugg, F. G., 2003, MRS Bulletin, 28, 837).

[0183] The present work exploits electromagnetic DOD technology as an innovative 3D- printing technique for manufacturing ASD. The offered technique could be positioned as an alternate solvent evaporation-based method. Three poorly soluble drug substances from distinct chemical and therapeutic categories were utilized as model drugs: favipiravir (FAV), efavirenz (EFZ), and lumefantrine (LUM).

[0184] FAV is a slightly soluble pyrazine derivative that is very potent against numerous RNA viruses, including influenza and, more recently, COVID-19 (Gattani, V., 2023, Journal of Drug Delivery Science and Technology, 79, 104082; Joshi, S. et al., 2021, International Journal of Infectious Diseases, 102, 501). Efavirenz is a widely used antiretroviral medicine that is a specific non-nucleoside reverse transcriptase inhibitor (NNRTI). Lumefantrine is an anti-malarial drug that is used together with artemether. Because of their limited water solubility, both EFZ and LUM exhibit poor and fluctuating oral bioavailability (Bhujbal, S. V. et al., 2021, Journal of Pharmaceutical Sciences, 110, 2423; Pawar, J. et al., 2016, European Journal of Pharmaceutical Sciences, 88, 37). A variety of techniques were investigated, including spray drying, kneading methods, and hot melt extrusion vacuum compression molding, to manufacture ASDs of EFZ with various polymers such as Soluplus® and HPMCAS, polyvinyl alcohol, and polyvinyl pyrrolidone (Costa, B. L. A. et al., 2019, European Journal of Pharmaceutics and Biopharmaceutics, 142, 300; Jorgensen, J. R. et al., 2023, International Journal of Pharmaceutics, 632, 122564; Sarabu, S. et al., 2020, Carbohydrate Polymers, 233, 115828; Alves, L. D. S. et al., 2014, Carbohydrate Polymers, 104, 166). Spray anti-solvent precipitation, spray drying, and HME methods were used to create LUM ASDs (Hiew, T. N. et al., 2022, Molecular Pharmaceutics, 19, 392; Song, Y. et al., 2016, International Journal of Pharmaceutics, 514, 456).

[0185] In the present work, Eudragit L100-55 (EL100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), Polyacrylic acid (PAA), and were used as polymeric carriers for the ASD of EFZ, LUM, and FAV, respectively. The amorphization of the three drugs is investigated, and the impact of ASD formation on the equilibrium solubility of each drug is evaluated to establish the reliability of this presented technique.

[0186] Materials

[0187] Efavirenz, Lumefantrine were provided by TCI America (Tokyo Chemical Industry Co., Portland, Oregon, USA). Favipiravir was provided by Hangzhou Longshine Biotech Co., Ltd. (Hangzhou, Zhejiang province, China). AquaSolve™ HPMC-AS MG was provided by Ashland™ (Wilmington, Delaware, United States). Eudragit LI 00-55 was purchased from Evonik nutrition & care GmbH (Kirschenalle, Darmstadt, Germany). PAA and HPLC grade methanol and acetone of were provided by Sigma-Aldrich Inc (St. Louis, Missouri, USA). HPLC grade acetonitrile was purchased from Fischer Scientific (Pittsburg, Pennsylvania, USA).

[0188] Preparation of 3D Printed ASD

[0189] To prepare the ink solution of each drug with its carrier polymer, EFZ and EL100-55 were completely dissolved in methanol, LUM and HPMC-AS in acetone, and FAV and PAA in methanol. In all inks, the drug: polymer ratio was 1 :9 and the total solid content was 2%w / v. A computer aided design (CAD) measuring 7 cm in width, 11 cm in length, and 1 cm in thickness was created using Microsoft 3D Builder® software. For the printing process, the ink solution was loaded into a three cc Optimum® syringe barrel. The syringe barrel was then attached to an electro-magnetic (EMD) printhead (Cellink, BICO, Gothenburg, Sweden). Subsequently, the printhead was installed onto the Cellink Bio X printer (BICO, Gothenburg, Sweden). To receive the printed object, a glass plate with a tailored size was placed on the heated printing stage, set at a temperature of 65°C. The distance between the nozzle and the glass plate was maintained at 63.6 mm. The printing parameters were configured as follows: a concentric pattern was used for printing, with a printing pressure ranging from 10 to 30 kPa. The open time was set to 2 ms, the cycle time to 500 ms, and the print speed to 10 mm / s. The infill density was set at 25%. After the printing process and allowing sufficient time for drying, the printed objects (ASDs) were carefully harvested using blades. These harvested ASDs were then stored for future characterizations and analysis.

[0190] Thermogravimetric Analysis (TGA)

[0191] The thermal properties of the pure active agents, the polymers and physical mixtures o were investigated using Mettler-Toledo TGAZDSC1 analyzer (Mettler-Toledo, Schwerzenbach, Switzerland). In ceramic crucibles, the samples were placed and ramped from 35 to 500 °C at 20 °C / min rate. Ultra-purified nitrogen / air was used to purge the furnace at a flow rate of 50 mL / min. The STAR software was used to operate the instrument and collect the data, while data were analyzed using GraphPad Prism® version 5.00 for Windows (San Diego, California, USA).

[0192] Differential Scanning Calorimetric (DSC) studies

[0193] The DSC analysis of the pure drugs (EFZ, LUM and FAV), the polymers (EL100- 55, HPMC-AS and PAA), the physical mixtures (EFZ-EL100-55, LUM-HPMC-AS and FAV- PAA), and the 3-D printed ASDs (EFZ-EL1OO-55, LUM-HPMC-AS and FAV-PAA) was carried out using DSC Q20 (TA® instruments, New Castle, DE, USA). Samples of about 3 mg were placed in T-zero aluminum DSC pans and sealed with standard aluminum lids (DSC consumables incorporated, Austin, MN, USA) using a calibrated balance. The samples were ramped from 20 to 200 °C at a 3 °C / min rate and ultra-purified nitrogen was purged at a 50 mL / min flow rate for all samples. The data were collected by TA advantage software (Q series, Version 2007 build 13029.20308). The results were presented as a plot of temperature (°C) versus heat flow (W / g) using GraphPad Prism® version 5.00 for Windows (San Diego, California, USA).

[0194] Polarized light microscopy (PLM)

[0195] The crystallinity of the pure drugs (EFZ, LUM and FAV), as well as the 3-D printed ASDs (EFZ-EL100-55, LUM-HPMC-AS and FAV-PAA) was examined using the Olympus BX53 polarizing photomicroscope (Olympus America Inc., Webster, TX, USA). The samples were evenly spread out on glass slides, and any extra powder was brushed off. After compensation with a 530 nm compensator (U-TP53O, Olympus® corporation, Japan), snapshots were taken with a QIC AM Fast 1394 digital camera (Qlmaging, Tucson, AZ, USA) using 10X and 20X magnification lenses to determine the state of the samples. Linksys 32 software® (Linkam sci ins Ltd., Tadworth, UK) was used to analyze the captured images.

[0196] X-ray Powder Diffraction (XRPD) Studies

[0197] The X-ray powder diffraction patterns of pure active agents (EFZ, LUM and FAV), the polymers (EL100-55, HPMC-AS and PAA), the physical mixtures (EFZ-EL100-55, LUM-HPMC-AS and FAV-PAA), and the 3-D printed ASDs (EFZ-EL100-55, LUM-HPMC-AS and FAV-PAA) were investigated using MinFlex 600 XRPD instrument (Rigaku Corporation, Tokyo, Japan) with Cu Ka X-ray source ( = 1.5418 A). The prepared samples were placed into the magnetic sample cell in the sample holder and scanned from a 20 angle of 10 to 45 degrees, with a scan speed 5° / min and a scan step of 0.04°. The voltage and current applied were 40 kV and 15 mA, respectively. GraphPad Prism® version 5.00 for Windows (San Diego, California, USA), was used to plot the data as a plot of 20 (degree) versus intensity.

[0198] Fourier Transfer Infrared (FT-IR) Spectroscopy

[0199] Fourier Transform Infrared (FTIR) spectroscopic analysis of the pure drugs (EFZ, LUM and FAV), the physical mixtures (EFZ-EL100-55, LUM-HPMC-AS and FAV-PAA), as well as the 3-D printed ASDs (EFZ-EL1OO-55, LUM-HPMC-AS and FAV-PAA) was carried out using a modular NicoletTM iSTM 50 FTIR system (ThermoFisher Scientific, Waltham, Massachusetts, USA). For analysis, few milligrams of each sample were used to measure the transmittance over a the range of 4000 to 700 cm ’, at a resolution of 4 cm’1(64 scans / run). The integrated OMNICTM series software (Version 9.0 ThermoFisher Scientific, Waltham, MA, USA) was used to collect and analyze the spectra and the GraphPad Prism® version 5.00 for Windows (San Diego, California, USA) was used to plot the data.

[0200] Solubility studies

[0201] The equilibrium solubilities of the pure drugs (EFZ, LUM and FAV), the physical mixtures (EFZ-EL100-55 (1 :9), LUM-HPMC-AS (1 :9) and FAV-PAA (1 :9)), and the 3-D printed ASDs (EFZ-EL100-55 (1 :9), LUM-HPMC-AS (1 :9) and FAV-PAA (1 :9)) were determined in a pH 6.8 phosphate buffer at 37.0 ± 0.5 °C. For efavirenz and lumefantrine, 0.5 mg of the pure drugs or equivalent amounts of the physical mixture or the 3-D printed ASDs were added to 1.0 ml of buffer in Eppendorf tubes, while, for favipiravir, an equivalent of 5 mg of drug or equivalent weights were added to the tube samples (Sarabu, S. et al., 2020, Carbohydrate Polymers, 233, 115828). The tubes were placed in a glass shaker incubator, stirred at 100 rpm and maintained at 37.0 ± 0.5 °C of 96 h. After reaching equilibrium, the solutions were centrifuged (Eppendorf centrifuge 5804r, Hamburg, Germany) at 15,000 rpm speed for 20 min, and the supernatants were analyzed and the drugs concentrations, were determined (Sections 0). All sample series were performed in triplicate.

[0202] Quantitation of Efavirenz, lumefantrine and favipiravir

[0203] The amounts of efavirenz dissolved were quantified using a reverse-phase high- performance liquid chromatography (RP-HPLC) method. The RP-HPLC system comprises an HPLC apparatus (ThermoFisher Vanquish HPLC system, Thermo Fisher, Waltham, MA, USA), connected with a C-18 column of L*I.D =250*4.6 mm, 5-pm particle size (Discovery® C-18 HPLC column, Supelco™, Millipore Sigma, MA, USA). The instrumentation and chromatographic data were controlled by Thermo Scientific Chromeleon™ chromatography data system. The sample solutions were also diluted with the same diluent, if necessary, and then injected to the HPLC system. The mobile phase consists of a 45:55 (v / v) mixture of Phosphate buffer (pH 5.6) and acetonitrile, respectively. The mobile phase was eluted at an isocratic rate of 1 ml / min, for 15-min run time. The detector's wavelength was set to 247 nm and the chromatographic analysis was carried out at room temperature. All measurements were carried out in triplicate. For the quantitation of lumefantrine and favipiravir, spectrophotometric analysis of the samples was carried out using Synergy Hl multi-mode plate reader (Biotek Instruments Inc., USA) at 300 and 360 nm, respectively. Dilution of samples was carried when necessary and the quantity dissolved of each drug was calculated based on standard calibration curves.

[0204] Statistical analysis

[0205] For multiple comparisons between formulations in terms of equilibrium solubility, one ay analysis of variance (ANOVA) with Tukey post-hoc test was carried out. The statistical analysis was performed using GraphPad Prism® version 5.00 for Windows (San Diego, California, USA), for Windows (San Diego, California, USA). All solubility data were expressed as the mean ± standard deviation (SD). Statistical significance was set at / ? < 0.05.

[0206] Results and Discussion

[0207] Preparation of the 3D-Printed ASDs

[0208] The ink solution was chosen based on the idea that the occurrence of certain drug- polymer intermolecular interactions promotes the formation and stability of ASDs (Hiew, T. N., 2022, Journal of Controlled Release, 352, 47). The acid-base interaction approach is of great interest in enhancing the quality of the produced ASD in terms of high solid-state dispersion stability and increased dissolving rate (Song, Y. et al., 2016, International Journal of Pharmaceutics, 514, 456; Nguyen, H. T. et al., 2023, International Journal of Pharmaceutics, 642, 123139). The anionic polymers ELI 00-55, HPMC AS, and PAA were chosen for this work because they are sufficiently acidic to form bonds with the hydrogen acceptor groups of EFZ, LUM, and FAV (Rabel, S. R. et al., 1996, Pharmaceutical Development and Technology, 1, 91).

[0209] A preliminary investigation was conducted to choose appropriate formulation and processing parameters for the 3D printing of ASD using electromagnetic DOD technology. As is well recognized in solvent-evaporation-based approaches for ASD formation, the solvent system must be carefully chosen. Different solvents (e.g., methanol, acetone, dichloromethane, and chloroform) with boiling points less than the highest possible temperature of the print bed (65°C) were screened for printability, and they demonstrated good printability. This observation indicates the practicability of this proposed technique for various organic solutions rather than being restricted to only particular ink components (i.e. ethanol -water mixture) like in binder jetting technology. Methanol was chosen for dissolving EFZ-EL100-55 and FAV-PAA combinations, and acetone for LUM-PAA, for two reasons. The primary reason is safety, as methanol and acetone are classified as classes III and II, respectively, by the International Council for Harmonization. The second reason is that sufficient solubility of drug and polymer in the solvent of choice provides an appropriate environment for drug-polymer interaction, preventing the formation of non-homogenous ASDs and the quick precipitation of selective components.

[0210] Furthermore, in the early screening investigation, several drug-polymer ratios and total solid content (c.a. 1-10%) were investigated to obtain the most printable and ASD-forming compositions. The ideal concentration was chosen to be 2%w / v because ink solutions with higher total solid contents are too viscous to be printed smoothly by the EMD printhead. Furthermore, lesser viscosity ink solutions effectively enhance the likelihood of basic and acidic groups being close to each other (Song, Y. et al., 2016, International Journal of Pharmaceutics, 514, 456). Considering the mass action effect, the drug: polymer ratio of 1 :9 was adopted in this work because the presence of weak acids in stoichiometric excess offers an environment that favors complete protonation of the medicines and, as a result, more efficient drug-polymer interaction (Trasi, N. S. et al., 2020, International Journal of Pharmaceutics, 2, 100052).

[0211] In terms of the 3D printing process, in addition to the formulation parameters, adjusting the DOD printing parameters is critical to the success of this technology. During the preliminary study, various parameters c.a. printing pressure, print nozzle-to-print bed distance, infill density, infill speed, infill pattern, and EMD printhead open time and cycle time) were investigated, and the printed materials were evaluated visually or via PLM. Eventually, the parameters were tuned towards achieving the smallest droplet size, quick solvent evaporation, and, as a result, the formation of ASD.

[0212] Solid State Characterization of the ASD Thermogravimetric Analysis (TGA)

[0213] 3D printing of the drug-polymer solution on hot print bed may cause the thermal degradation of the drug substances; EFZ, LUM and FAV and the polymers; EL1OO-55, HPMC- AS and PAA. The TGA analysis was conducted TGA analysis to elucidate the thermal degradation profile of the drug substances and the polymer prior to the printing, and to determine the ideal print bed temperature. For all the samples of drug substances and polymers, the weight loss percentage was measured at a range of temperatures. Evaporation of physiosorbed water causes the initial weight loss, and further weight loss steps imply compounds’ decomposition (Saadatkhah, N. et al., 2020, The Canadian Journal of Chemical Engineering, 98, 34). The thermal degradation curves show that all the drug substances and the polymers are stable at a temperature below 100 °C (FIG. 4A). The results show the onset of degradation for the drug substances EFZ, LUM and FAV are 181, 230 and 141 °C, respectively, and the maximum decomposition rates were observed at 263, 351 and 216 °C, respectively, in accordance with previously reported results (Braga, S. S. et al., 2021, Molecules, 26, 519). FIG. 4 shows the decomposition of EL1OO-55 and HPMC-AS starts at 341 and 238 °C reached the maximum decomposition rate at 399 and 364 °C, respectively (Seo, Y. et al., 2022, Soft Matter, 18, 8331). The thermal degradation curve of PAA (FIG. 4B) shows the characteristic three decompositions of the low molecular weight PAA, starting at 171, 323 and 414 °C and reaches maximum decomposition rates at 261, 363 and 445 °C (Cardenas, G. et al., 2000, European Polymer Journal, 36, 1091). The print bed temperature of the current DoD printing studies was maintained at 65 °C which is much less than the minimum temperature causes thermal degradation for any of the drug substances or the polymers.

[0214] Differential Scanning Calorimetric (DSC) studies

[0215] The thermal behavior and solid-state characteristics of the 3D printed ASD were examined to investigate the practicability of the present 3D printing technique to produce typical ASDs. FIG. 5 shows the DSC thermograms of EFZ-EL100-55 ASD, LUM-HPMC-AS ASD and FAV-PAA ASD as compared to the neat drugs. Sharp endothermic peaks of EFZ, LUM and FAV can be seen at 138.82, 134.79 and 189.83 °C, respectively, indicating that the three neat drugs exist in crystalline state (FIG 5A-5C). Single glass transition endothermic event at each thermogram was demonstrated indicating glass transition temperature (Tg) values of 83.6, 109.8, and 57.5 °C for EFZ-EL100-55 ASD, LUM-HPMC-AS ASD and FAV-PAA ASD, respectively. The absence of any minor endothermic peaks and / or multiple glass transition events in all the 3D printed ASD thermograms represent homogenous dispersion of the drugs molecules within the counter polymers at the molecular level, thereby minimizing drugs’ crystallinity (Thakore, S. D. et al., 2021, Molecular Pharmaceutics, 18, 2835; Baird, J. A., 2012, Advanced Drug Delivery Reviews, 64, 396).

[0216] Polarized Light Microscopy (PLM) The optical properties of solid substances are commonly utilized to distinguish between the crystalline or amorphous states (Ma, X., 2019, Journal of Drug Delivery Science and Technology, 50, 113; Liu, X. et al., 2018, Journal of Pharmaceutical Investigation, 48, 19). FIG. 6 demonstrates the optical properties of pure active substances, displaying the existence of birefringence as polarization colors and thus underlining the existence of EFZ, LUM and FAV as anisotropic crystalline structures. On the other hand, the PLM images of the 3D-print EFZ- EL 100-55 ASD, LUM-HPMC-AS ASD and F AV-PAA ASD show non-birefringence as evidenced by the absence of interference colors, revealing the production of isotropic solid particles made of randomly oriented molecules (FIG. 6D-6F). The PLM image of LUM-HPMC- AS ASD displays only a limited appearance of polarization colors, which could be due to the reason that a few of the LUM molecules exist in crystalline form, while nearly all LUM molecules exist in an amorphous state (FIG. 6E). The limited protonation of LUM attributed to the low acidic group content (1 mmol / g) of HPMCAS and the steric hindrance effect, which results in incomplete interaction between LUM and HPMC-AS in the ink solution, are the most likely explanations for the incomplete amorphization of LUM inside HPMC-AS.

[0217] X-ray Powder Diffraction (XRPD) Studies.

[0218] X-ray powder diffraction has long been regarded as one of the most preferred quick analytical techniques used for the analysis of the crystal structures of pharmaceutical powders (Ma, X., 2019, Journal of Drug Delivery Science and Technology, 50, 113). PXRD measurements were performed for the pure active agents; EFZ, LUM and FAV, as well as their 3D-printed amorphous solid dispersions EFZ-EL100-55, LUM-HPMC-AS, and FAV-PAA (FIG. 7A). The X-ray diffractogram of EFZ (FIG. 7A) displays multiple sharp Bragg diffraction peaks at 20 angles of 14.1, 16.9, 20.3, 21.1, 26.1 and 32.4°, indicating the crystallinity of EFZ (Sathigari, S. et al., 2009, AAPS PharmSciTech, 10, 81; Sathigari, S. K. et al., 2012, Journal of Pharmaceutical Sciences, 101, 3456). LUM crystals’ X-ray diffractogram (FIG. 7B) also shows the characteristic sharp diffraction peak at 11.3, 15.1, 18.2, 20.3, 23.7, 25.8 and 27.2° 26 angles LUM (Fule, R. et al., 2013, Journal of Pharmaceutical Investigation, 43, 305). FIG. 7C emphasizes the crystalline structure of FAV by the existence of Bragg diffraction peaks at 29 angles of 11.9, 19.7, 20.2, 27.0 and 27.8° (Wong, S. N. et al., 2022, Pharmaceutics, 14, 300). The formation of 3D printed ASD of the three drugs with the counter polymer was demonstrated in FIG. 7A-7C. The X-ray diffractograms (FIG. 7A-7C) of the 3D-printed EFZ-EL100-55 ASD, LUM-HPMC-AS ASD and FAV-PAA ASD displayed three broad halos with no distinctive Bragg diffraction peaks at any of the diffractograms. The ionic interaction of the drugs EFZ, LUM, and FAV with the acidic polymers EL100-55, HPMC-AS, and PAA, respectively, results in total miscibility of the drug molecules into the polymeric matrixes, inhibiting recrystallization of the drug molecules throughout the drying process. Ultimately, these results demonstrate that the ASD prepared by the proposed DoD technique are in an amorphous state, which is consistent with the thermal and the PLM data presented above. However, the diffractogram (FIG. 7B) of the LUM-HPMC-AS ASD shows the existence of a low-intensity single sharp peak at 20 angle of 15.6°, indicating the existence of some LUM molecules in crystalline form, while the bulk of molecules is completely dissolved in HPMC-AS polymer (Dedroog, S. et al., 2020, Journal of Pharmaceutical and Biomedical Analysis, 178, 112).

[0219] Fourier Transfer Infra-red (FT-IR) Spectroscopy

[0220] FT-IR Spectrum of EFZ (FIG. 8A) shows the characteristic stretching vibration bands of (C=O) and (-NH) groups at 1748 and 3318 cm’1, respectively. The typical exocyclic triple bond stretching peak is demonstrated at 2251 cm’1, as is the tertiary amide stretching peak at 1603 cm’1. The spectrum exhibits the distinctive stretching vibration peak of (C=C) group of benzene ring at 1496 cm’1, as well as the three peaks at 1096, 1073, 1055 cm’1characterizing the (C-O-C) group (Da Costa, M. A. et al., 2012, Pharmaceutics, 5, 1; Okafor, N. I. et al., 2020, Journal of Pharmaceutical Investigation, 50, 201). The FT-IR spectrum of EL 100-55 demonstrates the characteristic stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups at 1731 and 1717 cm’1, respectively. Furthermore, a distinctive peak at 2981 cm’1is seen indicating the stretching vibration of the methylene (C-H) groups (Liu, X. et al., 2018, International Journal of Pharmaceutics, 547, 291; Moustafine, R. I. et al., 2008, European Journal of Pharmaceutics and Biopharmaceutics, 70, 215). In the FT-IR spectrum of the EFZ-EL1OO-55 PM shows all the characteristic peaks of EFZ and, particularly the characteristic stretching vibration band of-NH group of EFZ at 3318 cm’1and stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups at 1731 and 1717 cm’1, the indicating the absence of ionic interaction between the drug and the acidic polymer. Mention worthy, the characteristic peaks of EFZ in the EFZ-EL 100-55 PM show lower intensities than the pure drug spectrum because of ten-times dilution. On the other hand, the FT-IR spectrum of the 3D-printed EFZ-EL100-55 ASD exhibits total absence of the stretching vibration band of (- NH) group of EFZ at 3318 cm'1and marked reduction in the intensity of the stretching vibration bands of the carboxylic and esterified carboxylic (C=O) groups of EL100-55 at 1731 and 1717 cm'1, revealing the ionic interaction between them (Jha, D. K. et al., 2021, Carbohydrate Polymer Technologies and Applications, 2, 100137).

[0221] The FT-IR spectra of the neat LUM and HPMC-AS, the LUM-HPMC-AS PM, and the LUM-HPMC-AS ASD are shown in FIG. 8B. The LUM spectrum demonstrates the characteristic stretching vibration band of the (-OH) group and the (C-H) group at 3402 and 2952 respectively. The peaks at 1085 and 1033 cm1correspond to the stretching vibrations of the (C-N) and (C-O) groups, respectively (Takale, N. R. et al., 2022, International Journal of Pharmaceutics, 628, 122354). The FT-IR spectrum of HPMC-AS shows the broad stretching vibration peak of the (-OH) group at 3446 cm'1. In addition, the distinctive stretching vibration peak of the (C=O) group and the bending vibration peak of the (C-O) can bees seen at 1734 and 1055 cm'1, respectively (Du, Y. et al., 2020, Materials Chemistry and Physics, 249, 122963). The LUM-HPMC-AS PM spectrum displays no noteworthy variations in peak locations and intensities as compared to the neat LUM and HPMC-AS spectra, suggesting the absence of interactions between both in the physical mixing state (FIG. 8B). On the other hand, the Fourier transform infrared spectrum of the 3D-printed LUM-HPMC-AS ASD shows a distinct rise in intensity and widening of the (-OH) group peak, indicating an interaction between the drug and the polymer (Takale, N. R. et al., 2022, International Journal of Pharmaceutics, 628, 122354). This is supported by a decrease in the intensity of the HPMC-AS (C=O) group stretching vibration peak (at 1734 cm'1), pointing to an extent of carboxyl group neutralization (Du, Y. et al., 2020, Materials Chemistry and Physics, 249, 122963).

[0222] FIG. 8C presents the FT-IR spectrum of the pure FAV demonstrating the characteristic peaks FAV. The stretching vibration bands of (-NH) group are seen at 3357and 3224 cm'1. The figure also shows the stretching vibration peak of (C=O) carbonyl group at 1655 cm'1and the distinctive peaks of the (C~F), and (C~OH) groups at 1265 and 1183 cm'1, respectively (Tulbah, A. S., 2021, Pharmaceuticals, 14, 1059). The FT-IR spectrum of PAA exhibits bands at 3150 and 1715 cm'1representing the stretching vibration of the (-OH) group and the carboxylic (C=O) group, respectively (FIG. 8C). The stretching vibration of (C-O) is seen at 1266 cm'1, while the stretching vibration of (C-H) for both the CH and CH2 groups is demonstrated at 1456 and 2981 cm'1(Dong, J. et al., 1997, Journal of Polymer Science Part B: Polymer Physics, 35, 507). The FT-IR of the FAV-PAA PM exhibits all the characteristic peaks of both the FAV pure drug and the PAA naive polymer, pointing out the absence of chemical interactions. Mixing FAV with PAA in (1 :9) ratio results in a marked reduction in the intensities of all FAV peaks due to dilution. The 3D-printed FAV-PAA ASD has a different FT-IR spectrum than the physical mixture (FIG. 8C). The two stretching vibration bands of (-NH) group that characterize FAV are completely disappeared and cannot not be detected at their positions (c.a. 3357and 3224 cm’1), indicating that the amino groups of FAV are completely consumed in the ionic interaction with the acidic PAA polymer. This conclusion is strengthened by the reduction in the intensity of the carboxylic (C=O) group of PAA (Kirwan, L. J. et al., 2003, Langmuir, 19, 5802).

[0223] Solubility studies

[0224] Drug solubility is an important attribute in drug product development. Table 1 shows the solubility of the three pure drug substances, EFZ, LUM and FAV in simulated intestinal medium (pH 6.8) compared to their physical mixtures with the acidic polymers and the 3D-printed ASDs. The results show the equilibrium solubility of EFZ in buffer pH 6.8 is very limited (c.a. 0.026 ± 0.037 pg / ml) EFZ (Cristofoletti, R. et al., 2013, Journal of Pharmaceutical Sciences, 102, 318). The physical mixing of EFZ with the acidic polymer EL100-55 resulted in a significant increase (p<0.005) in EFZ solubility which became 16.851 ± 5.945 pg / ml. This observed improvement in EFZ solubility could be due to the finer dispersion of drug particles with the polymer particles, which improved wetting and prevented aggregation (Dong, W. Y. et al., 2007, International Journal of Pharmaceutics, 331, 84). On the other hand, a highly significant ( / ?<0.001) increase in EFZ solubility is obtained by the production of the 3D-printed EFZ-EL1OO-55 ASD, as the solubility became more than 814 times the raw drug substance solubility. The substantial increase in EFZ solubility caused by the 3D printed ASD suggests a high degree of drug dispersion in the anionic polymer EL1OO-55, which has a large amount of acidic groups per unit mass (5.8 mmol / g), allowing for a high degree of drug protonation and, as a result, amorphization.

[0225] LUM exhibits a low solubility (c.a. 1.26 ± 1.60 pg / ml) in phosphate buffer pH 6.8, which is consistent with the reported findings (Yao, X. et al., 2021, Journal of Pharmaceutical Sciences, 110, 3670). The solubility of the LUM-HPMC-AS PM is 1.40 ± 1.75 pg / ml which is not significantly different from that of plain LUM. This result may be explained by the fact that HPMCAS polymer features steric hindrance that restricts the accessibility to their anionic groups, resulting in little LMN protonation by HPMCAS both in the solid state as well as within the aqueous environment. On the other hand, the solubility of the 3D-printed LUM- HPMC-AS ASD is sixteen times higher (p<0.001) than that of pure LUM, revealing that LUM protonation within the ink solution has been significantly improved, resulting in efficient amorphization of LUM and subsequent solubility enhancement.

[0226] The results show that the equilibrium solubility of plain FAV is 6674.3 ± 164.5 pg / ml, similar to the published data (Moshikur, R. M. et al., 2021, Molecular Pharmaceutics, 18, 3108). Significant reduction (p<0.001) in the solubility of FAV was observed with FAV-PAA PM and FAV-PAA ASD, to 2583.3 ± 1068.1 and 2109.64 ± 254.2 pg / ml, respectively. This unexpected reduction in solubility of FAV in both PM and ASD could be explained by the agglutination phenomenon which is described as the formation pseudo-gel layer by the polymer matrix, that hinder the drug release into the medium. Furthermore, the strong FAV-PAA interaction, especially in the ASD state, could leads to the formation of an insoluble drug- polymer complex that persist even in the aqueous environment, minimizing the hydration of the polymer and the dissociation of FAV molecules into the medium.

[0227] Conclusions

[0228] The present work is the first to demonstrate electromagnetic DOD technology as a cutting-edge 3D printing method for creating ASDs. The creation of ASDs for three different pharmacological compounds in combination with three different enteric polymers underlines the validity of this technique. Electromagnetic DOD could be classified as a solvent-evaporationbased ASD manufacturing approach that is an alternative to existing techniques. The electromagnetic DoD system offers the advantages of taking up less space, utilizing less energy, and not requiring the presence of an external gas cylinder, making it a more environmentally friendly system. By automating the collection step and upgrading the print bed's heating limits, this method can serve as a continuous manufacturing process that accommodates a wider spectrum of solvents, drugs, and polymers. The 3D-printing parameters are important to the success of this technology's ASD formation.

[0229] All references throughout this application, for example patent documents, including issued or granted patents or equivalents and patent application publications, and non- patent literature documents or other source material are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference.

[0230] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art, in some cases as of their filing date, and it is intended that this information can be employed herein, if needed, to exclude (for example, to disclaim) specific embodiments that are in the prior art.

Claims

CLAIMSWe claim:

1. A method of manufacturing a printed product, the method comprising: providing a printing ink, wherein the printing ink comprises an active pharmaceutical ingredient (API) in crystalline form, a plurality of polymeric carriers, and a solvent; feeding the printing ink to an electro-magnetic (EMD) printhead; forming a printing droplet from the printing ink, wherein forming the printing droplet is characterized by a droplet size and a frequency of droplet discharge; and depositing the printing droplet on a deposition surface to form a printed product, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier.2 The method of claim 1, wherein the API comprises favipiravir (FAV), efavirenz (EFZ), lumefantrine (LUM), pyrazine, a pyrazine derivative, posaconazole, vemurafenib, fenofibrate, or duloxetine.

3. The method of claim 1, wherein the API is thermostable, or the API is thermosensitive, or the API decomposes at temperatures over 65 °C, or the API decomposes at temperatures from 65 °C to 100 °C.

4. The method of claim 1, wherein the plurality of polymeric carriers comprises Eudragit LI 00-55 (EL 100-55), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly acrylic acid (PAA), povidone-vinyl acetate (PVP-VA), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), povidone (PVP), or an ASD-forming anionic polymer or an ASD-forming nonionic polymer.

5. The method of claim 1, wherein the solvent is methanol, acetone, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, or a solvent that has a boiling point less than or equal to a temperature of the deposition surface.

6. The method of claim 1, wherein the deposition surface comprises a glass plate.

7. The method of claim 1, wherein the deposition surface is disposed on a heated printing stage set to a temperature of about 65 °C.

8. The method of claim 1, wherein the deposition surface is a surface of a tablet or a blister pack.

9. The method of claim 1, further comprising drying the printed product so that the solvent is fully evaporated.

10. The method of claim 1, wherein the printhead further comprises a nozzle and a nozzle valve.

11. The method of claim 1, wherein the printed product is deposited on the deposition surface at a printing pressure ranging from 1 to 200 kPa.

12. The method of claim 1, wherein depositing the printing droplet on a deposition surface follows a grid, lines, a honeycomb pattern, or concentric deposition pattern.

13. A pri nted product compri si n : a plurality of active pharmaceutical ingredient (API) molecules; and a plurality of polymeric carriers, wherein: the API molecules are dissolved in the plurality of polymeric carriers to form a plurality of particles; and the plurality of particles forms an amorphous solid dispersion (ASD), wherein each individual particle is coupled to another particle.

14. The printed product of claim 13, further comprising:a second plurality of API molecules, wherein the second plurality of API molecules is different from the plurality of API molecules; and a second plurality of polymeric carriers, wherein: the second plurality of polymeric carriers is different from the plurality of polymeric carriers; the second plurality of API molecules are dissolved in the second plurality of polymeric carriers to form a second plurality of particles; and the second plurality of particles forms an ASD, wherein each individual particle of the second plurality of particles is coupled to another particle of the plurality of particles or the second plurality of particles.

15. The printed product of claim 13, wherein the printed product is in the form of a tablet or a pill.

16. A printing ink comprising: an active pharmaceutical ingredient (API); a plurality of polymeric carriers; and a solvent, wherein the printing ink is configured to: form a printing droplet when fed to an electro-magnetic (EMD) printhead, wherein the formed printing droplet is characterized by a droplet size and a frequency of droplet discharge; and form a printed product from a plurality of the printing droplets, wherein the printed product is an amorphous solid dispersion (ASD), wherein the ASD comprises molecules of the API surrounded by at least one polymeric carrier.

17. A system comprising: a drop-on-demand (DoD) printing device; one or more processors; and one or more memory storing instructions that, upon execution by the one or more processors, configure the system to:receiving a print request, wherein the print request identifies an active pharmaceutical ingredient (API) and a plurality of polymeric carriers; providing the print request to a machine learning model, the machine learning model being trained to output a plurality of print parameters based on the API; generating, based on the plurality of print parameters output by the machine learning model, a print profile executable by the DoD printing device; and instructing the DoD printing device, based on the print profile, to form a printing droplet and use the printing droplet to deposit a printed product on a deposition surface.

18. The system of claim 17, wherein the plurality of print parameters comprises printing pressure, print speed, infill density, or print distance.

19. The system of claim 18, wherein the print distance is the distance between the nozzle and the deposition surface, and the print distance is from 0.01 to 63.6 mm.

20. A medication made by the method of manufacturing of any one of claims 1-12 or including the printed product of any one of claims 13-15.

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