Nanosuspensions and amorphous solid dispersions of hydrophobic drugs and methods of use thereof - Patents.com

Abstract

In certain aspects, described herein are nanosuspensions comprising a plurality of nanoparticles comprising a hydrophobic drug suspended in an aqueous carrier having a desired viscosity. In other aspects, described herein are methods of use thereof, including methods of making dosage forms, components of the nanosuspension, dispensing cartridges and compositions therein, dosage forms, devices for dispensing the nanosuspension, and systems and applications of the embodiments described herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Applications Nos. 63 / 321,516 and 63 / 321,519, filed March 18, 2022, which are incorporated by reference herein in their entireties.

[0002] In certain aspects, the present disclosure relates to a nanosuspension comprising a plurality of nanoparticles comprising a hydrophobic drug suspended in an aqueous carrier having a desired viscosity. In other aspects, the present disclosure relates to an amorphous solid dispersion (ASD) comprising a drug prone to crystallization. Related methods (such as methods for identifying ASD-forming solutions and methods for producing a prepared dosage form comprising, for example, a hydrophobic drug and / or a drug prone to crystallization), compositions (e.g., compositions for use in and produced from the preparation methods), devices, and systems are also provided. [Background technology]

[0003] Traditionally, drug product development often takes a "one size fits all" approach with respect to dosage and image, most commonly exemplified by standard tablet sizes. This requires the development of a suitable bulk manufacturing approach and supply chain with appropriate quality control to deliver a specific dose of drug product to the target patient population. However, the increasing understanding of disease pathology and its relationship to genetics, as well as the increasing amount of statistical data that can be obtained for each patient, has generated great interest in personalized medicine approaches. Furthermore, the increase in highly potent drug molecules has placed a great emphasis on precise control over the delivery of small amounts of drug. Furthermore, the pharmaceutical industry is faced with an increasing number of poorly soluble drug candidates. This can cause significant issues with respect to obtaining sufficient absorption and bioavailability, risk of exposure variation, and difficulty in maintaining a safe therapeutic index. Current manufacturing approaches for solid dosage forms such as tablets face significant challenges with consistency and content uniformity for low dosages, which is particularly important for highly potent drugs as well as pediatric indications. As a result, there is great value in the ability to manufacture precise dosage forms on demand that can be tailored to individual patients while still handling small amounts of drug.

[0004] The crystalline form of a drug, such as a hydrophobic therapeutic drug, can have undesirable effects on attributes such as bioavailability, dissolution rate, solubility, and stability. This can cause significant problems with obtaining sufficient absorption and bioavailability, risk of exposure variation, and difficulty in maintaining a safe therapeutic index. The discovery and use of such drugs as non-crystalline solid forms, such as amorphous solid dispersions, can allow for more predictable and effective therapeutic use. Amorphous solid dispersions are combinations that include a ratio of drug and polymer that is susceptible to the formation of crystalline forms, and the drug is maintained in an amorphous form. Amorphous solid dispersions provide a form of the drug that has high solubility and sustained supersaturation. The identification and development of amorphous solid dispersions is difficult, costly, and requires large amounts of raw materials. In the context of drug development, such requirements impede the progress and identification of useful drug dosage forms, especially when only small amounts of the drug compound are available. Summary of the Invention

[0005] The present disclosure relates to a method for making a dosage form comprising a hydrophobic drug, the method comprising depositing a plurality of droplets of a formulation comprising a hydrophobic drug onto a substrate using a high frequency droplet dispenser to form a dosage form. In certain embodiments, the viscosity of the formulation is less than 3 cP.

[0006] In some embodiments, the high frequency droplet dispenser deposits multiple droplets using a thermal process. In some embodiments, the high frequency droplet dispenser deposits multiple droplets using a piezoelectric process. In some embodiments, the high frequency droplet dispenser comprises about 100 to about 1000 individual nozzles. In some embodiments, each nozzle comprises an opening having a diameter of about 20 μm to about 120 μm. In some embodiments, the high frequency droplet dispenser is a high frequency sub-nanoliter droplet dispenser. In some embodiments, the high frequency sub-nanoliter droplet dispenser dispenses droplets at greater than 3 kHz measured per nozzle. In some embodiments, the high frequency droplet dispenser dispenses droplets in a volume of 1 nanoliter or less.

[0007] In some embodiments, the average volume of each dispensed droplet of the plurality of droplets of the formulation is from about 1 picoliter to about 50 picoliters.

[0008] In some embodiments, droplets of a plurality of formulations are deposited on the substrate according to an average number of droplets per square inch. In some embodiments, the average number of droplets deposited per square inch of substrate is from about 1 droplet to about 500 droplets per square inch.

[0009] In some embodiments, the multiple droplets of the formulation deposited on the substrate have an average diameter of about 5 μm to about 100 μm.

[0010] In some embodiments, the multiple droplets of the formulation deposited on the substrate form a continuous layer.

[0011] In some embodiments, the viscosity of the formulation is between 0.5 cP and 3 cP. In some embodiments, the viscosity of the formulation is less than 2 cP and greater than 1 cP. In some embodiments, the viscosity of the formulation is between 1.2 cP and 1.8 cP.

[0012] In some embodiments, the formulation further comprises a viscosity modifier. In some embodiments, the viscosity modifier is a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol, and propylene glycerol. In some embodiments, the viscosity modifier is a viscosity reducing agent. In some embodiments, the viscosity reducing agent is a salt or an amino acid, or a combination thereof. In some embodiments, the amount of viscosity modifier in the mixture is based on the desired viscosity of the mixture. In some embodiments, the viscosity enhancing agent is present in the formulation at a concentration of about 1% to about 40% v / v of the formulation. In some embodiments, further comprising adding a viscosity enhancing agent to the formulation to achieve a viscosity of the formulation of about 1 cP to about 2 cP.

[0013] In some embodiments, the formulation is a suspension comprising an aqueous carrier and a plurality of nanoparticles suspended in the aqueous carrier, the nanoparticles comprising a hydrophobic drug. In some embodiments, the suspension is a nanosuspension. In some embodiments, the suspension is a colloidal suspension.

[0014] In some embodiments, the aqueous carrier comprises water and an organic solvent.

[0015] In some embodiments, the ratio of viscosity enhancing agent to aqueous carrier of the formulation is from about 1:1000 to about 1:2 by volume.

[0016] In some embodiments, the hydrophobic drug is not soluble in the aqueous carrier, hi some embodiments, the hydrophobic drug has a solubility in water of less than 1 mg / mL.

[0017] In some embodiments, the concentration of the hydrophobic drug in the suspension is from about 5 mg / mL to about 1,000 mg / mL.

[0018] In some embodiments, the suspension further comprises a stabilizing component. In some embodiments, the ratio of the stabilizing component to the aqueous carrier of the suspension is about 1:500 to about 1:10 by weight. In some embodiments, the stabilizing component comprises PVP and / or SDS.

[0019] In some embodiments, the average diameter of the nanoparticles is less than about 500 nm. In some embodiments, the nanoparticles have a D50 of about 100 nm to about 400 nm. In some embodiments, the nanoparticles have a D90 of about 250 μm to about 50 nm.

[0020] In some embodiments, at least a portion of the plurality of nanoparticles is deposited within a substrate. In some embodiments, at least a portion of the plurality of nanoparticles is deposited on top of a substrate.

[0021] In some embodiments, the formulation is an amorphous solid dispersion (ASD)-forming solution comprising a hydrophobic drug; an organic carrier; and a polymer, the ratio of polymer to hydrophobic drug inhibiting crystallization of the hydrophobic drug in the dry state on the substrate. In some embodiments, the ASD-forming solution is a colloid.

[0022] In some embodiments, the organic carrier of the ASD forming solution comprises any one or more components selected from the group consisting of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethyl sulfoxide.

[0023] In some embodiments, the ASD forming solution comprises at least 30% organic carrier by volume.

[0024] In some embodiments, the viscosity modifier has a ratio to organic carrier of from 1:100 to 40:100 by volume.

[0025] In some embodiments, the polymer of the ASD-forming solution is suitable for the formation of an amorphous solid dispersion (ASD) after deposition by a droplet dispenser. In some embodiments, the polymer is selected based on one or more properties of the hydrophobic agent. In some embodiments, the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PPVVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC acetate succinate (hypromellose acetate succinate or HPMC-AS), and Eudragit, or any combination thereof. In some embodiments, the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG, and HG. In some embodiments, the polymer is HPMC-AS-LF. In some embodiments, the ratio of the concentration of the polymer to the concentration of the hydrophobic agent is 1:20 to 20:1. In some embodiments, the ratio of the concentration of the polymer to the concentration of the hydrophobic agent is 1:2 to 2:1.

[0026] In some embodiments, the ASD forming solution further comprises a surfactant. In some embodiments, the surfactant is selected from Tween 80, Vit-E, TPGS, or SDS, or any combination thereof. In some embodiments, the ASD forming solution comprises 10% to 20% surfactant by volume. In some embodiments, the ASD forming solution comprises a ratio of surfactant to hydrophobic agent of 1:100 to 5:1.

[0027] In some embodiments, less than 5% of the hydrophobic drug crystallizes in the dry state after deposition by a droplet dispenser, hi some embodiments, substantially no crystallization of the hydrophobic drug occurs in the dry state.

[0028] In some embodiments, the ASD-forming solution is supersaturated with the hydrophobic agent, hi some embodiments, the concentration of the hydrophobic agent in the mixture is from about 5 mg / mL to about 1,000 mg / mL.

[0029] In some embodiments, at least a portion of the hydrophobic agent is within the substrate after deposition by the droplet dispenser. In some embodiments, at least a portion of the hydrophobic agent is on top of the substrate after deposition by the droplet dispenser.

[0030] In some embodiments, the hydrophobic agent is a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule drug. In some embodiments, the therapeutic agent is a biomolecule. In some embodiments, the therapeutic agent is a Biopharmaceutical Classification System (BCS) Class II or Class IV drug. In some embodiments, the therapeutic agent has a narrow therapeutic index. In some embodiments, the therapeutic agent is a high-potency drug. In some embodiments, the hydrophobic agent is an additive or adjuvant.

[0031] In some embodiments, the hydrophobic agent is a diagnostic compound.

[0032] In some embodiments, the hydrophobic agent is a reagent.

[0033] In some embodiments, the hydrophobic drug has a solubility in water of less than 0.1 mg / mL.

[0034] In some embodiments, the amount of hydrophobic agent is less than 0.1 mg.

[0035] In some embodiments, the substrate is a pharma- ceutically acceptable polymer.

[0036] In some embodiments, the substrate is selected from the group consisting of one or more of chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil, and polyacrylic acid derivatives. In some embodiments, the substrate is a thin film substrate.

[0037] In some embodiments, the dosage form is an oral dosage form. In some embodiments, the dosage form is a buccal dosage form. In some embodiments, the dosage form is a transdermal dosage form. In some embodiments, the dosage form is sterile.

[0038] In another aspect, provided herein is a suspension comprising an aqueous carrier and a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, wherein the viscosity of the suspension is less than 3 cP.

[0039] In some embodiments, the viscosity of the suspension is less than 2 cP and greater than 1 cP, hi some embodiments, the viscosity of the suspension is between 1.2 cP and 1.8 cP.

[0040] In some embodiments, the suspension further comprises a viscosity modifier. In some embodiments, the viscosity modifier is a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol, and propylene glycerol.

[0041] In some embodiments, the viscosity enhancing agent is present in the suspension at a concentration of about 1% to about 40% v / v of the suspension. In some embodiments, the ratio of viscosity enhancing agent to aqueous carrier of the suspension is about 1:1000 to about 1:2 by volume. In some embodiments, further comprising adding a viscosity enhancing agent to the suspension to achieve a viscosity of the suspension of about 1 cP to about 2 cP.

[0042] In some embodiments, the aqueous carrier comprises water and an organic solvent.

[0043] In some embodiments, the suspension is a colloidal suspension.

[0044] In some embodiments, the suspension further comprises a stabilizing component. In some embodiments, the ratio of the stabilizing component to the aqueous carrier of the suspension is about 1:500 to about 1:10 by weight. In some embodiments, the stabilizing component comprises PVP and / or SDS.

[0045] In some embodiments, the average diameter of the nanoparticles is less than about 500 nm. In some embodiments, the nanoparticles have a D50 of about 100 nm to about 400 nm. In some embodiments, the nanoparticles have a D90 of about 250 μm to about 50 nm.

[0046] In some embodiments, the hydrophobic drug is not soluble in the aqueous carrier, hi some embodiments, the hydrophobic drug has a solubility in water of less than 1 mg / mL.

[0047] In some embodiments, the hydrophobic agent is a therapeutic agent. In some embodiments, the therapeutic agent is a small molecule drug. In some embodiments, the therapeutic agent is a biomolecule. In some embodiments, the hydrophobic agent is a Biopharmaceutical Classification System (BCS) Class II or Class IV drug. In some embodiments, the therapeutic agent has a narrow therapeutic index. In some embodiments, the therapeutic agent is a high-potency drug.

[0048] In some embodiments, the hydrophobic agent is an additive or adjuvant.

[0049] In some embodiments, the concentration of the hydrophobic drug in the suspension is from about 5 mg / mL to about 1,000 mg / mL, hi some embodiments, the amount of the hydrophobic drug is less than 0.1 mg.

[0050] In another aspect, provided herein is an ASD-forming solution comprising an organic carrier, a hydrophobic drug, and a polymeric crystallization inhibitor, wherein the polymer inhibits crystallization of the drug in the dry state.

[0051] In some embodiments, the ASD forming solution has a viscosity of 0.5 cP to 3 cP. In some embodiments, the ASD forming solution has a viscosity of 1 cP to 2 cP. In some embodiments, the ASD forming solution has a viscosity of 1.2 cP to about 1.8 cP.

[0052] In some embodiments, the ASD forming solution includes a viscosity modifier. In some embodiments, the viscosity modifier is a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent is ethylene glycol, polyethylene glycol, glycerol, or propylene glycerol, or any combination thereof. In some embodiments, the viscosity modifier is a viscosity reducing agent. In some embodiments, the viscosity reducing agent is a salt or an amino acid, or a combination thereof. In some embodiments, the concentration of the viscosity modifier in the ASD forming solution is between 1% and 40%. In some embodiments, the viscosity modifier has a ratio to organic carrier of between 1:100 and 40:100 by volume. In some embodiments, the amount of viscosity modifier in the mixture is based on the desired viscosity of the mixture.

[0053] In some embodiments, the organic carrier of the ASD-forming solution comprises a component selected from the group consisting of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethylsulfoxide, hi some embodiments, the ASD-forming solution comprises at least 30% organic carrier by volume.

[0054] In some embodiments, the polymer is selected based on one or more properties of the hydrophobic agent.

[0055] In some embodiments, the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PPVVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC succinate acetate (hypromellose succinate or HPMC-AS), and Eudragit, or any combination thereof. In some embodiments, the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG, and HG. In some embodiments, the polymer is HPMC-AS-LF. In some embodiments, the ratio of the concentration of the polymer to the concentration of the drug in the ASD-forming solution is 1:20 to 20:1. In some embodiments, the ratio of the concentration of the polymer to the concentration of the drug in the ASD-forming solution is 1:2 to 2:1.

[0056] In other aspects, provided herein are compositions comprising a dry or lyophilized suspension, which upon reconstitution forms any of the suspensions described herein.

[0057] In another aspect, provided herein is a dosage form prepared by any method described herein.In some embodiments, the dosage form comprises a fixed amount of a hydrophobic drug that is a therapeutic agent and a fixed amount of a second hydrophobic drug.In some embodiments, the second hydrophobic drug is a therapeutic agent.In some embodiments, the second hydrophobic drug is a pharma-ceutically acceptable excipient.

[0058] In another aspect, provided herein is a plurality of dosage forms as described herein prepared as a batch of drug dosage forms, wherein the amount of hydrophobic drug in each drug dosage form of the batch does not vary by more than 5% from the average.

[0059] In another aspect, provided herein is a system for producing a dosage form, the system comprising: a suspension comprising a hydrophobic drug, the suspension comprising an aqueous carrier and a plurality of nanoparticles, each nanoparticle of the plurality of nanoparticles comprising a hydrophobic drug, and a viscosity of the suspension being less than 2 cP; and a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit at least one droplet of the suspension onto a substrate of the dosage form.

[0060] In some embodiments, each nozzle has an opening diameter of about 20 μm to about 120 μm.

[0061] In some embodiments, the droplets of the suspension are deposited on the substrate using a thermal process. In some embodiments, the droplets of the suspension are deposited on the substrate using a piezoelectric process.

[0062] In another aspect, a system for manufacturing a dosage form is provided herein, the system comprising: an amorphous solid dispersion (ASD) comprising a hydrophobic drug, the method comprising depositing droplets of an ASD-forming solution comprising the hydrophobic drug, an organic carrier, and a polymer onto a substrate using a droplet dispenser, the ratio of the polymer to the hydrophobic drug inhibiting crystallization of the hydrophobic drug in the dry state on the substrate, and the viscosity of the ASD-forming solution being less than 2 cP; and a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit at least one droplet of the solution onto the substrate of the dosage form. In some embodiments, each nozzle has an opening diameter of about 20 μm to about 120 μm. In some embodiments, the droplets of the solution are deposited onto the substrate using a thermal process. In some embodiments, the droplets of the solution are deposited onto the substrate using a piezoelectric process.

[0063] In another aspect, provided herein is a dispensing cartridge containing an ASD-forming solution as described herein.

[0064] In another aspect, provided herein is a dosage form comprising a nanosuspension of a hydrophobic drug deposited on a substrate via liquid droplets.

[0065] In another aspect, provided herein is a dosage form comprising an amorphous solid dispersion of a hydrophobic drug deposited on a substrate via liquid droplets.

[0066] In another aspect, provided herein is a method of determining a hydrophobic drug to polymer ratio forming an amorphous solid dispersion, comprising dispensing a quantity of a first precursor solution comprising a first organic carrier, a hydrophobic drug, and a first viscosity enhancing agent, and a quantity of a second precursor solution comprising a second organic carrier, a polymer, and a second viscosity enhancing agent onto a substrate to determine a hydrophobic drug to polymer ratio forming an amorphous solid dispersion of hydrophobic drug and polymer, the dispensing contacting the first precursor solution with the second precursor solution. In some embodiments, the dispensing mixes the first precursor solution and the second precursor solution on the substrate. In some embodiments, the dispensing mixes the first precursor solution and the second precursor solution before being applied to the substrate. In some embodiments, the amount of the first precursor solution and the amount of the second precursor solution are dispensed such that a gradient of drug to polymer ratio is formed in a region on the substrate. In some embodiments, an amount of the first precursor solution and an amount of the second precursor solution are dispensed such that an area on the substrate has a predetermined ratio of drug to polymer. In some embodiments, an amount of the first precursor solution is dispensed from a first sub-nanoliter droplet dispenser and an amount of the second precursor solution is dispensed from a second sub-nanoliter droplet dispenser. In some embodiments, the method further includes evaluating crystallization of the drug. In some embodiments, the first organic carrier and the second organic carrier are the same. In some embodiments, the first viscosity enhancing agent and the second viscosity enhancing agent are the same. In some embodiments, the substrate is a thin film.

[0067] In another aspect, provided herein is a droplet dispenser for producing a dosage form comprising a nanosuspension of a hydrophobic drug, the dispenser comprising: (a) a dispensing head comprising one or more nozzles; (b) a first cartridge containing a suspension comprising an aqueous carrier and a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, wherein the viscosity of the suspension is less than 3 cP, the first cartridge being operably coupled to the first dispensing head; and (c) a control system configured to dispense the mixture through the first dispensing head according to a dispensing pattern.

[0068] In some embodiments, the first dispensing head comprises about 100 to about 1000 nozzles. In some embodiments, each nozzle has an opening diameter of about 20 μm to about 120 μm. In some embodiments, the first dispensing head dispenses the droplets using a thermal process. In some embodiments, the first dispensing head dispenses the droplets using a piezoelectric process. In some embodiments, the method further comprises a second dispensing head operably coupled to a second cartridge, the second cartridge containing a second agent. In some embodiments, the method further comprises a third dispensing head operably coupled to a third cartridge, the third cartridge containing a protective coating agent. In some embodiments, the method further comprises a fourth dispensing head operably coupled to a fourth cartridge, the fourth cartridge containing an edible agent.

[0069] In another aspect, provided herein is a droplet dispenser for producing a dosage form comprising an amorphous solid dispersion of a hydrophobic drug, the dispenser comprising: (a) a first dispensing head comprising one or more nozzles; (b) a first mixture cartridge containing an ASD-forming solution comprising an organic carrier, a drug, a polymer, and a viscosity modifier, wherein the drug and polymer are present in the mixture in a ratio that inhibits crystallization of the drug in a dry state on a substrate, the first mixture cartridge being operably coupled to the first dispensing head; and (c) a control system configured to dispense the mixture through the dispensing head according to a dispensing pattern.

[0070] In some embodiments, the first dispensing head comprises about 100 to about 1000 nozzles. In some embodiments, each nozzle has an opening diameter of about 20 μm to about 120 μm. In some embodiments, the first dispensing head dispenses the droplets using a thermal process. In some embodiments, the first dispensing head dispenses the droplets using a piezoelectric process. In some embodiments, the method further comprises a second dispensing head operably coupled to a second mixture cartridge, the second mixture cartridge containing a second mixture including a second drug. In some embodiments, the method further comprises a third dispensing head operably coupled to a third mixture cartridge, the third mixture cartridge containing a protective coating mixture. In some embodiments, the method further comprises a fourth dispensing head operably coupled to a fourth mixture cartridge, the fourth mixture cartridge containing an edible mixture.

[0071] In other aspects, provided herein is a gradient of two components on a substrate, comprising: a first component comprising a hydrophobic drug; a second component comprising a polymeric crystallization inhibitor; and a ratio of the first component to the second component that varies across the gradient.

[0072] In some embodiments, the first component further comprises an organic carrier. In some embodiments, the first component further comprises a viscosity enhancing agent. In some embodiments, the second component further comprises an organic carrier. In some embodiments, the second component further comprises a viscosity enhancing agent. In some embodiments, the second component can inhibit crystallization of the hydrophobic drug. In some embodiments, the first and second components each comprise an organic carrier, and the organic carrier is the same. In some embodiments, the first and second components each comprise a viscosity enhancing agent, and the viscosity enhancing agents are the same. In some embodiments, the ratio is sufficiently low at a certain point on the gradient to prevent crystallization of the hydrophobic drug. In some embodiments, the first and second components are dispensed onto the substrate from a sub-nanoliter droplet dispenser. In some embodiments, the first component is dispensed onto the substrate from a first sub-nanoliter droplet dispenser, and the second component is dispensed onto the substrate from a second sub-nanoliter droplet dispenser. In some embodiments, the ratio changes at a consistent rate across the gradient. [Brief description of the drawings]

[0073] [Figure 1] FIG. 1 shows a microscope image of the nanosuspension.

[0074] [Diagram 2] FIG. 2 shows a microscope image of the nanosuspension dispensed onto a substrate.

[0075] [Diagram 3] FIG. 3 shows a microscope image of the nanosuspension dispensed onto a substrate.

[0076] [Figure 4A-4C] 4A-C each show a microscopic image of a dispensed nanosuspension on a substrate exposed to wetting by an advancing water line.

[0077] [Diagram 5]Figure 5 shows a microscopic image of the reconstituted nanosuspension obtained from a droplet of the nanosuspension deposited on a substrate. The resulting reconstituted nanosuspension was collected and analyzed by optical microscopy, which showed a uniform and well-dispersed suspension without significant aggregation.

[0078] [Figure 6A-6B] 6A and 6B show schematics of deposits with hydrophobic drug loading and / or polymer. Fig. 6A shows a schematic of a gradient deposit with various amounts of hydrophobic drug and / or polymer. Fig. 6B shows a schematic of a region with a deposit with a specific amount of hydrophobic drug relative to polymer.

[0079] [Figure 7A-7B] Figures 7A and 7B show schematics of deposition of a rapid crystallizing drug model (griseofulvin) and a polymer (HPMCAS-LF). Figure 7A further shows the crystalline drug form when the deposit is produced without polymer, and the amorphous polymer at 100% polymer loading. Figure 7B further shows the deposition of 20% drug loading resulting in an amorphous solid dispersion lacking the crystalline form of the drug. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] In certain aspects, provided herein are methods of making dosage forms, including dispensing multiple droplets of a formulation comprising a hydrophobic drug onto a substrate via a droplet dispenser, such as a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser, such as in a pattern or patterned layer. In other aspects, provided herein are embodiments, such as compositions, devices, and systems, useful with or produced from the methods described herein. In some embodiments, the methods described herein can be used to precisely prepare formulations such as nanosuspensions and ASDs (e.g., in personalized medicine), which can help improve drug absorption and bioavailability.

[0081] In certain aspects, provided herein are methods of making a dosage form comprising dispensing a plurality of droplets of a nanosuspension comprising a plurality of nanoparticles comprising a hydrophobic drug onto a substrate via a droplet dispenser, such as a radio frequency droplet dispenser or a radio frequency sub-nanoliter droplet dispenser, such as in a pattern or patterned layer. In other aspects, provided herein are embodiments such as compositions, devices, and systems useful with or produced from the methods described herein.

[0082] The disclosure of the present application is based on a unique perspective and insight into the deposition of droplets of nanosuspensions containing nanoparticles of hydrophobic drugs using a droplet dispenser (e.g., a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser) and the manufacture of related dosage forms. As described herein, the discoveries demonstrate that precise and reproducible amounts of hydrophobic drug-containing nanoparticles in nanosuspensions can be deposited onto substrates such as thin films over a wide range of concentrations without affecting the size of the nanoparticles or their chemical and physical stability during the process. Such deposition can be performed, for example, using a droplet dispenser that deposits the droplets using thermal and / or piezoelectric processes. Importantly, after the deposited droplets dry, the hydrophobic drug nanoparticles remain stable and can be successfully reconstituted by the addition of water. The suitability of using nanosuspension formulations as suitable "inks" allows such deposition techniques to be used as a general approach for poorly soluble drug molecules, significantly expanding the utility of the embodiments described herein. In some embodiments, the resulting material consists of a substrate such as a thin film containing ultra-low microgram amounts of nanoparticles (such as drug nanoparticles), making it suitable for the preparation of products with low dosages that are difficult for traditional solid dosage forms, with implications for products for highly potent molecules or pediatric formulations. Furthermore, in certain embodiments, the final deposition product allows for rapid dissolution and release of hydrophobic agents (such as drugs), allowing for rapid absorption and precise delivery. Such deposition also allows for custom tailoring of individual dosage forms on demand, through control of the initial concentration in the formulation as well as tailoring the deposition of materials to form the dosage form. Moreover, the results described herein demonstrate that this technique can be performed using common commercially available equipment with little custom modifications.

[0083] Thus, in some aspects, there is provided a method of making a dosage form comprising a hydrophobic drug, the method comprising depositing a plurality of droplets of a nanosuspension onto a substrate using a radio frequency droplet dispenser to form the dosage form, the nanosuspension comprising an aqueous carrier and a plurality of nanoparticles suspended in the aqueous carrier, the nanoparticles comprising the hydrophobic drug, and wherein the viscosity of the nanosuspension is less than 2 cP.

[0084] In another aspect, a nanosuspension is provided that comprises an aqueous carrier and a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, wherein the nanosuspension has a viscosity of less than 2 cP.

[0085] In other aspects, compositions are provided that include a dried or lyophilized nanosuspension, which upon reconstitution forms a nanosuspension as described herein.

[0086] In other aspects, the multiple dosage forms described herein are prepared as a batch of drug dosage forms, and the amount of hydrophobic drug in each drug dosage form of the batch does not vary by more than 5% from the average.

[0087] In another aspect, provided herein is a system for producing a dosage form, the system comprising: a nanosuspension comprising a hydrophobic drug, the nanosuspension comprising an aqueous carrier and a plurality of nanoparticles, each nanoparticle of the plurality of nanoparticles comprising a hydrophobic drug, and a viscosity of the nanosuspension being less than 2 cP; and a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit at least one droplet of the nanosuspension onto a substrate of the dosage form.

[0088] In certain aspects, provided herein are methods of making a dosage form comprising an amorphous solid dispersion (ASD), comprising depositing droplets of an ASD-forming solution onto a substrate using a droplet dispenser. In other aspects, further provided are methods of identifying an ASD-forming solution comprising a drug prone to crystallization, as well as embodiments encompassed by or produced using the methods described herein, such as ASD-forming solutions and / or precursor solutions thereof, drug dosage forms, devices, and systems.

[0089] The disclosure of this application is based on the inventor's unique perspective and findings regarding the low volume dispensing and deposition of droplets to form ASDs using a droplet dispenser. Such low volume dispensing and deposition significantly reduces the amount of crystallization-prone drugs, such as hydrophobic drugs, required to identify and / or generate ASDs. In contrast, current methodologies for studying ASDs include spray drying techniques, including microspray drying, which require at least about 100 mg of initial loading material. The techniques taught herein can identify and produce ASDs from microgram amounts or less of starting material. Furthermore, as taught herein, two or more precursor solutions can be dispensed from two or more droplet dispensers, thus enabling gradient deposition studies to identify the ratio of a crystallization-prone drug to one or more polymers that provide the ASD of that drug. Contributing to the discovery detailed herein is the discovery that a solution including an organic carrier can be formed to be compatible for use in a droplet dispenser, such as a sub-nanoliter droplet dispenser.

[0090] Thus, in some embodiments, a method is provided for making a dosage form comprising an amorphous solid dispersion (ASD) comprising a hydrophobic drug, the method comprising depositing droplets of an ASD-forming solution comprising the hydrophobic drug, an organic carrier, and a polymer onto a substrate using a droplet dispenser, the ratio of polymer to hydrophobic drug inhibiting crystallization of the hydrophobic drug in the dry state on the substrate.

[0091] In another aspect, provided herein is an ASD-forming solution comprising an organic carrier, a hydrophobic drug, a polymer, and a viscosity modifier, wherein the polymer inhibits crystallization of the drug in the dry state.

[0092] In another aspect, a dispensing cartridge containing the ASD-forming or precursor solutions described herein is provided.

[0093] In another aspect, a dosage form is provided that includes an amorphous solid dispersion of a hydrophobic drug deposited on a substrate via liquid droplets.

[0094] In another aspect, there is provided a dosage form prepared by the methods described herein.

[0095] In another aspect, a method is provided for determining a hydrophobic drug to polymer ratio that will form an amorphous solid dispersion, comprising dispensing onto a substrate a quantity of a first mixture comprising a first organic carrier, a hydrophobic drug, and a first viscosity enhancing agent, and a quantity of a second mixture comprising a second organic carrier, a polymer, and a second viscosity enhancing agent to determine the hydrophobic drug to polymer ratio that will form the amorphous solid dispersion, wherein the dispensing is performed such that the first and second mixtures are mixed on or before being applied to the substrate.

[0096] In another aspect, a droplet dispenser for producing a dosage form comprising an amorphous solid dispersion of a hydrophobic drug is provided, the dispenser comprising: (a) a dispensing head comprising one or more nozzles; (b) an ASD-forming solution comprising an organic carrier, a drug, a polymer, and a viscosity modifier, wherein the drug and polymer are present in the mixture in a ratio that inhibits crystallization of the drug in a dry state on a substrate, a mixture cartridge operably coupled to the dispensing head; and (c) a control system configured to dispense the mixture through the dispensing head according to a dispensing pattern.

[0097] In another aspect, a gradient on a substrate is provided, the gradient comprising a first location, a second location, and a third location, each comprising a mixture of a quantity of a first deposit and a quantity of a second deposit, the first deposit comprising a hydrophobic agent, the ratio of the amount of the first deposit to the amount of the second deposit at the first location being less than the ratio of the amount of the first deposit to the amount of the second deposit at the second location, the ratio of the amount of the first deposit to the amount of the second deposit at the second location being less than the ratio of the amount of the first deposit to the amount of the second deposit at the third location, and the interaction between the first deposit and the second deposit in the mixture at the first location, the second location, and the third location produces a measurable effect of the hydrophobic agent of the first deposit. In some embodiments, the difference in the ratio of the amount of the first deposit to the amount of the second deposit at each of the first location, the second location, and the third location is the same.

[0098] I. Definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or phraseology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0099] As used herein, the terms "polypeptide" and "protein" can be used interchangeably to refer to a polymer comprising amino acid residues, and are not limited to a minimum length. Such polymers can contain natural or non-natural amino acid residues, or combinations thereof, including, but not limited to, peptides, polypeptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Full-length polypeptides or proteins, and fragments thereof, are encompassed by this definition. The term also includes modified species thereof, such as post-translational modifications of one or more residues, such as methylation, phosphorylation, glycosylation, sialylation, or acetylation.

[0100] Throughout this disclosure, various aspects of the claimed subject matter are 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 claimed subject matter. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, when a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the disclosure, subject to any specifically excluded limit within the stated range. When a stated range includes one or both of the limits, a range excluding either or both of those included limits is also included in the disclosure. In some embodiments, two opposing open-ended ranges are provided for a feature, and such descriptions contemplate that a combination of those two ranges is provided herein. For example, in some embodiments, a feature may be described as being greater than about 10 units and the feature may be described (e.g., in a separate sentence) as being less than about 20 units, and thus a range of about 10 units to about 20 units is described herein.

[0101] The term "about" as used herein refers to the normal error range of each value, which is readily known in the art. Reference to a value or parameter herein as "about" includes (and describes) the variation that is directed to the value or parameter itself. For example, a statement that refers to "about X" includes the statement of "X".

[0102] As used in this specification and the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a" or "an" means "at least one" or "one or more." It is understood that aspects and variations described herein include embodiments that "consist of" and / or "consist essentially of" such aspects and variations.

[0103] As used herein, a "subject" or "individual," terms used interchangeably, is a mammal. In some embodiments, "mammals" include humans, non-human primates, farm and domestic animals, as well as zoo, sports, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, monkeys, etc. In some embodiments, the subject or individual is a human.

[0104] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present disclosure. The following description is illustrative of the disclosure and, of course, should not be construed as in any way limiting the scope of the invention described herein.

[0105] II. Methods of Making the Dosage Form In certain aspects, a method for making a dosage form comprising a plurality of nanoparticles comprising a hydrophobic drug is provided herein. As discussed herein, various aspects of the method are described in a modular manner in the subsequence section, and it will be readily understood that the method encompasses the embodiments described therein. Such a modular description is not intended to limit the scope of the present disclosure, and based on the teachings provided herein, a person skilled in the art will readily understand that a particular module can be at least partially integrated. Any section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0106] In some embodiments, the method includes dispensing a plurality of droplets of a nanosuspension comprising nanoparticles comprising a hydrophobic agent, such as according to a pattern or a patterned layer, onto a substrate via a droplet dispenser (such as a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser). In some embodiments, the nanosuspension is provided from a dispensing cartridge. In some embodiments, the method includes conveying the nanosuspension to a droplet dispenser or a component thereof, such as a dispensing head thereof. In some embodiments, the viscosity of the nanosuspension is from about 1 cP to about 5 cP, such as less than 2 cP, including from about 1 cP to less than 2 cp or from about 1.2 cP to about 1.8 cP.

[0107] In some embodiments, the method includes delivering a nanosuspension comprising a plurality of nanoparticles comprising a hydrophobic drug suspended in an aqueous carrier to a droplet dispenser (e.g., a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser) (the viscosity of the nanosuspension is less than 2 cP, e.g., from about 1 cp to less than 2 cp, or from about 1.2 cP to about 1.8 cP); and depositing a plurality of droplets of the nanosuspension onto a substrate using the droplet dispenser, e.g., according to a pattern or patterned layer, to form the dosage form.

[0108] In some embodiments, the droplet dispenser dispenses droplets toward the substrate to deposit the droplets thereon. Generally speaking, droplets dispensed from the droplet dispenser may undergo changes in morphology during the deposition process, such as (a) one droplet may merge with another droplet after being dispensed from the droplet dispenser (whether in air or on the substrate), and (b) the deposited droplets may dry on the substrate. Descriptions of droplets are provided herein and may be applicable to various conditions that occur during the deposition process. Such descriptions are not limited to only specific conditions unless otherwise specified. In some embodiments, depositing includes dispensing a large number of droplets of nanosuspension per square inch (also referred to herein as dots / inch). In some embodiments, the resulting pattern or patterned layer produced by the methods described herein includes, at least to some extent, merging of one or more dispensed droplets of nanosuspension. Such a pattern of droplets need not be regular, and in some embodiments, reflects the number of droplets applied to a set area of ​​the substrate. In some embodiments, the deposited droplets (whether merged before or on the substrate) resemble a pattern on a macroscale, such as a shape. In some embodiments, the dosage form includes one or more layers of droplets deposited on the substrate, such as formed from one or more passes of a droplet dispenser over an area of ​​the dosage form. In some embodiments, the patterned layer is a continuous layer of nanosuspension prior to drying, e.g., the deposited droplets are interconnected, at least to some extent. In some embodiments, the droplets of the nanosuspension are deposited at about 1 dots per inch (dpi) to about 1,000 dpi, e.g., at about 1 dpi to about 720 dpi, about 72 dpi to about 720 dpi, about 72 dpi to about 500 dpi, or about 72 dpi to about 300 dpi.In some embodiments, the droplets of the nanosuspension are deposited at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more. In some embodiments, droplets of the nanosuspension are deposited at about 1 dots per inch (dpi) to about 1,000 dpi, such as from about 1 dpi to about 720 dpi, from about 72 dpi to about 720 dpi, from about 72 dpi to about 500 dpi, or from about 72 dpi to about 300 dpi. In some embodiments, the droplets of the nanosuspension are deposited at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more.

[0109] In some embodiments, the dispensed or deposited droplets of the nanosuspension have a diameter of from about 1 nm to about 200 μm, such as from about 20 nm to about 800 nm, from about 100 nm to about 500 nm, or from about 10 μm to about 100 μm. In some embodiments, the dispensed or deposited droplets of the nanosuspension have a diameter of at least about 1 nm, e.g., at least about 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm, m, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 525 nm, 550 nm, 575 nm, 600 nm, 625 nm, 650 nm, 675 nm, 700 nm, 725 nm, 750 nm, 775 nm, 800 nm, 825 nm, 850 nm, 875 nm, 900 nm, 925 nm, 950 nm, 975 nm, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm in diameter. In some embodiments, the average of a population of dispensed or deposited droplets of a dosage form described herein meets the above criteria.

[0110] In some embodiments, the dispensed or deposited droplets of the nanosuspension comprise an average volume of about 1 picoliter (pL) to about 1 nL, e.g., about 1 pL to about 500 pL or about 1 pL to about 50 pL. In some embodiments, the dispensed or deposited droplets of the nanosuspension comprise an average volume of about 1 nL or less, e.g., about 950 pL or less, 900 pL or less, 850 pL or less, 800 pL or less, 750 pL or less, 700 pL or less, 650 pL or less, 600 pL or less, 550 pL or less, 500 pL or less, 450 pL or less, 400 pL or less, 350 pL or less, 300 pL or less, 250 pL or less, 200 pL or less, 150 pL or less, 100 pL or less, 75 pL or less, 50 pL or less, or 25 pL or less.

[0111] In some embodiments, the method further comprises coupling a cartridge containing the nanosuspension to a droplet dispenser (such as a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser). In some embodiments, the method further comprises selecting a cartridge containing the nanosuspension to generate a desired dosage form, for example, based on the desired properties of the final dosage form or one or more patterned layers thereon, such as the amount of hydrophobic drug deposited on the dosage form, the properties of the patterned layer (e.g., any of dpi, shape, size, and location on the dosage form), the release profile of the hydrophobic drug, and the characteristics of the final dosage form (e.g., structural integrity and / or protection of the patterned layer). In certain embodiments, the method comprises dispensing at least one nanosuspension and optionally another material (e.g., food-safe material for forming a label), the method encompassing the selection of each dispensed component. In some embodiments, the method comprises selecting a nanosuspension from a library of nanosuspensions (e.g., assembled in a kit). In some embodiments, the method further comprises making the nanosuspension.

[0112] In some embodiments, the method includes designing a pattern, e.g., characterized by dpi, of droplets of a nanosolution comprising a plurality of nanoparticles comprising a hydrophobic agent. In some embodiments, the method of designing includes determining (e.g., calculating) one or more settings based on any one or more of: the total amount of hydrophobic agent in the dosage form; the concentration of the hydrophobic agent in the nanosuspension; the desired surface area of ​​exposure of the nanosuspension of the dosage form or its dried form; the desired release profile of the hydrophobic agent; characteristics of (or use of) a sub-nanoliter droplet dispenser, such as aperture diameter, ejection frequency, and droplet size generated.

[0113] In some embodiments, the method includes creating and / or receiving instructions for controlling a droplet dispenser, such as to form a dosage form described herein. In some embodiments, the instructions are personalized for an individual.

[0114] In some embodiments, the method further comprises performing a drying period after dispensing the nanosuspension onto a substrate, e.g., to allow the nanosuspension to dry at least to some extent and / or to allow the nanosuspension to associate (e.g., be absorbed) with the substrate. In some embodiments, the method further comprises one or more processing steps after dispensing the nanosuspension onto a substrate, such as cutting the substrate into individual dosage forms and / or filling one or more dosage forms.

[0115] In some embodiments, the method further includes washing one or more dispensing heads of the droplet dispenser, e.g., by dispensing a non-drug-containing solvent. For example, such a washing step helps to ensure that the nanosuspension does not clog the nozzles of the dispensing heads and / or to reduce carryover of hydrophobic drugs.

[0116] III. Nanosuspensions In certain aspects, provided herein is a nanosuspension comprising a plurality of nanoparticles comprising a hydrophobic drug suitable for use in and / or with the embodiments described herein, including the methods, devices, dispensing cartridges, compositions, and systems disclosed herein. In some embodiments, the nanosuspension comprises a carrier (such as an aqueous carrier); and a plurality of nanoparticles comprising a hydrophobic drug suspended in the carrier, the nanosuspension having a viscosity suitable for use in the embodiments described herein, including the method of making a dosage form using a sub-nanoliter droplet dispenser. In some embodiments, the nanosuspension comprises a viscosity modifier, such as a viscosity enhancer. Without being bound by theory, the nanosuspension can stabilize low-solubility drugs as nanoparticles that can be rapidly absorbed by a patient or subject.

[0117] In some embodiments, provided herein is a nanosuspension comprising a carrier (such as an aqueous carrier), a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, and a stabilizing component. In some embodiments, the aqueous carrier comprises water (such as about 100% water). In some embodiments, the stabilizing component is a polymer (e.g., polyvinylpyrrolidone, PVP), a surfactant (e.g., sodium dodecyl sulfate, SDS), or a mixture thereof. In some embodiments, the polymeric stabilizing component comprises any one or more of polyvinylpyrrolidone (PVP), including any type and / or grade, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), poloxamer (including any type and / or grade), and polyethylene glycol (PEG, including any type and / or grade). In some embodiments, the surfactant stabilizing component comprises any one or more of polysorbate or Tween (including any type and / or grade), Vit-E TPGS, lecithin, alkyl sulfonic acid sodium salt, and cholic acid sodium salt. In some embodiments, the concentration of the hydrophobic drug in the nanosuspension (e.g., contained in a plurality of nanoparticles) is about 20 mg / mL to about 200 mg / mL, e.g., about 100 mg / mL. In some embodiments, the viscosity is less than 5 cP, e.g., less than about 4, 3 cP, or 2 cP, including about 1.2 cP to about 1.8 cP. In some embodiments, the nanosuspension includes a viscosity modifier, such as a viscosity enhancer.

[0118] In some embodiments, provided herein is a nanosuspension comprising an aqueous carrier, a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, and a stabilizing component, wherein the viscosity of the nanosuspension is less than 5 cP, e.g., any of about 4, cP, 3 cP, or less than 2 cP, including about 1 cP to less than 2 cP or about 1.2 cP to about 1.8 cP, and the concentration of the hydrophobic drug contained in, e.g., the plurality of nanoparticles in the nanosuspension is about 20 mg / mL to about 200 mg / mL, e.g., about 100 mg / mL. In some embodiments, the aqueous carrier comprises water (e.g., about 100% water). In some embodiments, the stabilizing component is a polymer (e.g., PVP), a surfactant (e.g., SDS), or a mixture thereof. In some embodiments, the nanosuspension comprises a viscosity modifier, such as a viscosity enhancer.

[0119] In some embodiments, provided herein is a nanosuspension comprising an aqueous carrier (water), a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, and a stabilizing component comprising a polymer (e.g., PVP), a surfactant (e.g., SDS) stabilizing component, or a mixture thereof, wherein the viscosity of the nanosuspension is less than 5 cP, e.g., any of about 4, cP, 3 cP, or less than 2 cP, including about 1 cP to less than 2 cP, or about 1.2 cP to about 1.8 cP, and the concentration of the hydrophobic drug contained in the nanosuspension, e.g., the plurality of nanoparticles, is about 20 mg / mL to about 200 mg / mL, e.g., about 100 mg / mL. In some embodiments, the nanosuspension comprises a viscosity modifier, such as a viscosity enhancer.

[0120] In some embodiments, a nanosuspension is provided that includes: (a) an aqueous carrier comprising about 100% water (wt%), (b) a plurality of nanoparticles comprising a hydrophobic drug, such as naproxen, suspended in the aqueous carrier, and (c) PVP and SDS, wherein the ratio of the hydrophobic drug, PVP, and SDS is about 1:0.25:0.01 (100:25:1), the concentration of the hydrophobic drug in the nanosuspension is about 100 mg / mL, and the viscosity of the nanosuspension is about 1 cP to about 3 cP, including about 2.1 cP. In some embodiments, the nanosuspension includes a viscosity modifier, such as a viscosity enhancer.

[0121] In some embodiments, there is provided a nanosuspension comprising: (a) an aqueous carrier comprising water; (b) a plurality of nanoparticles comprising a hydrophobic drug, such as naproxen, suspended in the aqueous carrier; (c) PVP and SDS; and (d) a viscosity modifier, such as a viscosity enhancer, e.g., ethylene glycol, wherein the ratio of the hydrophobic drug, PVP, and SDS is about 1:0.25:0.01 (100:25:1), the concentration of the hydrophobic drug in the nanosuspension is about 10 mg / mL, and the viscosity of the nanosuspension is about 1 cP to about 3 cP, including about 1.5 cP.

[0122] The following subsections provide additional description of various aspects of the nanosuspensions described herein. Such modular description is not intended to limit the scope of the present disclosure, and based on the teachings provided herein, one of ordinary skill in the art will readily appreciate that certain modules may be at least partially integrated. Any section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0123] A. Aqueous Carriers In some embodiments, the nanosuspension is a colloidal suspension of hydrophobic drug-containing nanoparticles in an aqueous carrier. In some embodiments, the aqueous carrier does not solubilize the hydrophobic drug-containing nanoparticles contained therein. In some embodiments, the aqueous carrier is a substantially aqueous solution, e.g., a solution comprising at least about 50% v / v, e.g., at least about 55% v / v, 60% v / v, 65% v / v, 70% v / v, 75% v / v, 80% v / v, 85% v / v, 90% v / v, 95% v / v, or 100% v / v of an aqueous medium, e.g., water. In some embodiments, the aqueous medium is water, including distilled water, double distilled water, deionized water, purified water, ultrapure water, DNase and / or RNase free water, protease free water, water suitable for injection, or pharmaceutical grade water.

[0124] In some embodiments, the aqueous carrier of the nanosuspension comprises water and an organic solvent. In some embodiments, the ratio of water to organic solvent in the aqueous carrier is about 6:4 to about 9.9:1, such as any of 6:4, 7:3, 8:2, or 9:1. In some embodiments, the ratio of water to organic solvent is greater than 10:1, greater than 100:1, greater than 1000:1, or greater than 10000:1. In some embodiments, the organic solvent is selected from the group consisting of acetonitrile, ethanol, isopropanol, DMSO, polyethylene glycol (PEG), and propylene glycol, or mixtures thereof. In some embodiments, the organic solvent is suitable for administration to an individual, such as a human. In some embodiments, the amount of organic solvent administered to an individual and remaining in a dosage form produced from the nanosuspension described herein is suitable for administration to an individual.

[0125] B. Viscosity The nanosuspensions provided herein have a viscosity suitable for use in the embodiments described herein, including the methods of making the dosage forms and droplet dispensers. In some embodiments, the viscosity of the nanosuspensions provided herein is such that they can be printed with a sub-nanoliter droplet dispenser. In some embodiments, the viscosity of the nanosuspensions provided herein is such that they do not leak from the dispensing cartridges described herein.

[0126] In some embodiments, the viscosity of the nanosuspension is about 0.5 cP to about 5 cP, e.g., about 0.5 cP to about 2.5 cP, about 1 cP to about 2.5 cP, about 1.5 to about 2.5, or about 1.2 cP to about 1.8 cP. In some embodiments, the viscosity of the nanosuspension is less than about 5 cP, e.g., about 4.9 cP, 4.8 cP, 4.7 cP, 4.6 cP, 4.5 cP, 4.4 cP, 4.3 cP, 4.2 cP, 4.1 cP, 4.0 cP, 3.9 cP, 3.8 cP, 3.7 cP, 3.6 cP, 3.5 cP, 3.4 cP, 3.3 cP, 3.2 cP, 3.1 cP, 3.0 cP, 2.9 cP, or less than about 5 cP. P, 2.8 cP, 2.7 cP, 2.6 cP, 2.5 cP, 2.4 cP, 2.3 cP, 2.2 cP, 2.1 cP, 2.0 cP, 1.9 cP, 1.8 cP, 1.7 cP, 1.6 cP, 1.5 cP, 1.4 cP, 1.3 cP, 1.2 cP, 1.1 cP, 1.0 cP, 0.9 cP, 0.8 cP, 0.7 cP, 0.6 cP or less than 0.5 cP. In some embodiments, the viscosity of the nanosuspension is less than about 2 cP, e.g., less than about any of 1.95 cP, 1.9 cP, 1.85 cP, 1.8 cP, 1.75 cP, 1.7 cP, 1.65 cP, 1.6 cP, 1.55 cP, 1.5 cP, 1.45 cP, 1.4 cP, 1.35 cP, 1.3 cP, 1.25 cP, 1.2 cP, 1.15 cP, 1.1 cP, 1.05 cP, 1 cP, 0.95 cP, 0.9 cP, 0.85 cP, 0.8 cP, 0.75 cP, 0.7 cP, 0.65 cP, 0.6 cP, 0.55 cP, or 0.5 cP. In some embodiments, the viscosity of the nanosuspension is at least about 0.5 cP, e.g., at least about 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, It is either less than 2.6 cP, 2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.1 cP, 3.2 cP, 3.3 cP, 3.4 cP, 3.5 cP, 3.6 cP, 3.7 cP, 3.8 cP, 3.9 cP, 4.0 cP, 4.1 cP, 4.2 cP, 4.3 cP, 4.4 cP, 4.5 cP, 4.6 cP, 4.7 cP, 4.8 cP, 4.9 cP, or 5.0 cP.In some embodiments, the viscosity of the nanosuspension is at least about 0.5 cP, e.g., at least about any of 0.55 cP, 0.6 cP, 0.65 cP, 0.7 cP, 0.75 cP, 0.8 cP, 0.85 cP, 0.9 cP, 0.95 cP, 1 cP, 1.05 cP, 1.1 cP, 1.15 cP, 1.2 cP, 1.25 cP, 1.3 cP, 1.35 cP, 1.4 cP, 1.45 cP, 1.5 cP, 1.55 cP, 1.6 cP, 1.65 cP, 1.7 cP, 1.75 cP, 1.8 cP, 1.85 cP, 1.9 cP, 1.95 cP, or 2.0 cP. In some embodiments, the viscosity of the nanosuspension is about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, 2.6 cP, Either 2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.1 cP, 3.2 cP, 3.3 cP, 3.4 cP, 3.5 cP, 3.6 cP, 3.7 cP, 3.8 cP, 3.9 cP, 4.0 cP, 4.1 cP, 4.2 cP, 4.3 cP, 4.4 cP, 4.5 cP, 4.6 cP, 4.7 cP, 4.8 cP, 4.9 cP, or 5.0 cP. In some embodiments, the viscosity of the nanosuspension is about any of 0.5 cP, 0.55 cP, 0.6 cP, 0.65 cP, 0.7 cP, 0.75 cP, 0.8 cP, 0.85 cP, 0.9 cP, 0.95 cP, 1 cP, 1.05 cP, 1.1 cP, 1.15 cP, 1.2 cP, 1.25 cP, 1.3 cP, 1.35 cP, 1.4 cP, 1.45 cP, 1.5 cP, 1.55 cP, 1.6 cP, 1.65 cP, 1.7 cP, 1.75 cP, 1.8 cP, 1.85 cP, 1.9 cP, 1.95 cP, or 2.0 cP. In the embodiments described herein, the viscosity of the nanosuspension is evaluated at about room temperature (e.g., about 20° C. to about 22° C., including any of about 20° C., 21° C., or 22° C.).

[0127] In some embodiments, various components may contribute to the viscosity of the nanosuspension, including the concentration of the hydrophobic drug and its nanoparticles. In some embodiments, the nanosuspension further comprises a viscosity modifier. In some embodiments, the viscosity modifier is a viscosity enhancer, e.g., increases the viscosity of the nanosuspension. In some embodiments, the viscosity modifier is a viscosity reducer, e.g., reduces the viscosity of the nanosuspension.

[0128] In some embodiments, the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol, propylene glycerol, and a cellulosic polymer, or a mixture thereof. In some embodiments, the cellulosic polymer is selected from methylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose, or a mixture thereof.

[0129] In some embodiments, the viscosity reducing agent is selected from the group consisting of salts and amino acids, or mixtures thereof.

[0130] In some embodiments, the viscosity modifier, such as a viscosity enhancing or reducing agent, has a concentration in the nanosuspension of about 0.1% v / v to about 40% v / v, such as about 1% v / v to about 10% v / v, about 5% v / v to about 15% v / v, about 10% v / v to about 20% v / v, about 15% v / v to about 25% v / v, about 20% v / v to about 30% v / v, about 25% v / v to about 35% v / v, or about 30% v / v to about 40% v / v. In some embodiments, the viscosity modifier, such as a viscosity enhancing or reducing agent, has a concentration in the nanosuspension of about 40% v / v or less, such as about any of 35% v / v, 30% v / v, 25% v / v, 20% v / v, 15% v / v, 10% v / v, 9% v / v, 8% v / v, 7% v / v, 6% v / v, 5% v / v, 4% v / v, 3% v / v, 2% v / v, 1% v / v, 0.9% v / v, 0.8% v / v, 0.7% v / v, 0.6% v / v, 0.5% v / v, 0.4% v / v, 0.3% v / v, 0.2% v / v, or 0.1% v / v. In some embodiments, the concentration of the viscosity modifier, such as a viscosity enhancing or reducing agent, in the nanosuspension is based on the desired viscosity of the nanosuspension.

[0131] In some embodiments, the ratio of viscosity modifier, such as viscosity enhancer or viscosity reducer, to the aqueous carrier of the nanosuspension is about 1:1000 to about 1:2, e.g., about 1:500 to about 1:2, about 1:100 to about 1:2, about 1:50 to about 1:2, about 1:20 to about 1:2, about 1:1000 to about 1:5, about 1:500 to about 1:5, about 1:100 to about 1:5, about 1:50 to about 1:5, about 1:20 to about 1:5, about 1:1000 to about 1:10, about 1:500 to about 1:10, about 1:100 to about 1:10, about 1:50 to about 1:10, or about 1:20 to about 1:10, or about 1:10 to about 1:5. In some embodiments, the ratio is about 1:5. In some embodiments, the ratio is about 1:10.

[0132] D. Hydrophobic Drugs and Nanoparticles Thereof The nanosuspensions described herein contain a hydrophobic drug in the form of nanoparticles. In the methods described herein, the nanosuspensions are deposited on a substrate using a droplet dispenser. In some embodiments, the droplet dispenser includes a dispensing head with a nozzle having established aperture size characteristics. In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension have characteristics such as size based on the aperture size characteristics such as diameter or maximum cross dimension.

[0133] In some embodiments, the nanoparticles of the nanosuspension, e.g., each nanoparticle of the plurality of nanoparticles, are about 500 μm or less, e.g., about 490 μm or less, 480 μm or less, 470 μm or less, 460 μm or less, 450 μm or less, 440 μm or less, 430 μm or less, 420 μm or less, 410 μm or less, 400 μm or less, 390 μm or less, 380 μm or less, 370 μm or less. Below, 360μm or less, 350μm or less, 340μm or less, 330μm or less, 320μm or less, 310μm or less, 300μm or less, 290μm or less, 280μm or less, 27 0μm or less, 260μm or less, 250μm or less, 240μm or less, 230μm or less, 220μm or less, 210μm or less, 200μm or less, 190μm or less, 180μm or less, and having a diameter (or maximum cross dimension) of any of the following: 170 μm or less, 160 μm or less, 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less, 30 μm or less, 20 μm or less, 10 μm or less, 1 μm or less, 950 nm or less, 900 nm or less, 850 nm or less, 800 nm or less, 750 nm or less, 700 nm or less, 650 nm or less, 600 nm or less, 550 nm or less, 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, or 50 nm or less.

[0134] In some embodiments, the nanoparticles of the nanosuspension have a D50 (Dv(50), also called the median diameter (or maximum intersection dimension) or midpoint of the particle size distribution) of about 250 μm to about 50 nm, e.g., 100 μm to about 1 μm, about 50 μm to about 500 nm, about 400 nm to about 100 nm, or about 250 nm to about 100 nm. In some embodiments, the nanoparticles of the nanosuspension are about 250 μm or less, e.g., about 240 μm or less, 230 μm or less, 220 μm or less, 210 μm or less, 200 μm or less, 190 μm or less, 180 μm or less, 170 μm or less, 160 μm or less, 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less. having a D50 of any of: D50 of 30 μm or less, 20 μm or less, 10 μm or less, 1 μm or less, 950 nm or less, 900 nm or less, 850 nm or less, 800 nm or less, 750 nm or less, 700 nm or less, 650 nm or less, 600 nm or less, 550 nm or less, 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, or 50 nm or less.

[0135] In some embodiments, the nanoparticles of the nanosuspension have a D90 (also referred to as Dv(90)) of about 250 μm to about 50 nm, e.g., 100 μm to about 1 μm, about 50 μm to about 500 nm, about 400 nm to about 100 nm, or about 250 nm to about 100 nm. In some embodiments, the nanoparticles of the nanosuspension have a D90 (also referred to as Dv(90)) of about 250 μm or less, e.g., about 240 μm or less, 230 μm or less, 220 μm or less, 210 μm or less, 200 μm or less, 190 μm or less, 180 μm or less, 170 μm or less, 160 μm or less, 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less. having a D90 of any of: 30 μm or less, 20 μm or less, 10 μm or less, 1 μm or less, 950 nm or less, 900 nm or less, 850 nm or less, 800 nm or less, 750 nm or less, 700 nm or less, 650 nm or less, 600 nm or less, 550 nm or less, 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, 100 nm or less, or 50 nm or less.

[0136] In some embodiments, the diameter (or maximum cross dimension) of the aperture of the droplet dispenser is at least about 20% larger, e.g., at least about 25% larger, 30% larger, 35% larger, 40% larger, 45% larger, 50% larger, 55% larger, 60% larger, 65% larger, 70% larger, 75% larger, 80% larger, 85% larger, 90% larger, 95% larger, 100% larger, 125% larger, 150% larger, 175% larger, 200% larger, 225% larger, 250% larger, 275% larger, 300% larger, 350% larger, 400% larger, 450% larger, or 500% larger than the diameter (or maximum cross dimension) of the nanoparticles of the nanosuspension, e.g., the diameter (or maximum cross dimension) of each nanoparticle of the plurality of nanoparticles.

[0137] There are numerous techniques known in the art for measuring particle characteristics such as nanoparticle size. The description provided herein encompasses all techniques for evaluating particle characteristics of nanosuspensions described herein. In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using dynamic light scattering (DLS). In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using disk centrifugation. In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using nanoparticle tracking analysis. In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using variable resistance pull sensing. In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using atomic force microscopy. In some embodiments, particle characteristics (such as size, e.g., diameter or maximum cross dimension) are measured using electron microscopy.

[0138] In some embodiments, the hydrophobic drug is poorly water soluble. In some embodiments, the drug has a solubility in a solvent, such as water, of about 1 mg / mL or less, such as about 750 μg / mL or less, 500 μg / mL or less, 250 μg / mL or less, 200 μg / mL or less, 150 μg / mL or less, 100 μg / mL or less, 50 μg / mL or less, 25 μg / mL or less, 1 μg / mL or less, 500 ng / mL or less, or 100 ng / mL. In some embodiments, the solvent is an aqueous solvent, such as water, bicarbonate buffer, biorelevant media, or a solvent containing a surfactant. In some embodiments, the hydrophobic drug is not soluble at the target concentration of the nanosuspension.

[0139] In some embodiments, a hydrophobic drug is sparingly soluble, slightly soluble, very slightly soluble, or substantially insoluble (insoluble) as defined by the United States Pharmacopeia-National Formulary (USP-NF). In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 30 parts of solvent required to 1 part of solute to about 100 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 100 parts of solvent required to 1 part of solute to about 1,000 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 1,000 parts of solvent required to 1 part of solute to about 10,000 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 10,000 parts of solvent required to 1 part of solute or more. In some embodiments, the solvent is an aqueous solvent, such as water, a bicarbonate buffer, a biorelevant medium, or a solvent that includes a surfactant.

[0140] In some embodiments, the hydrophobic agent is a Biopharmaceutical Classification System (BCS) Class II drug. In some embodiments, the hydrophobic agent is a BCS Class IV drug.

[0141] In some embodiments, the hydrophobic agent is a drug, such as a therapeutic agent, useful for treating and / or preventing a condition.

[0142] In some embodiments, the hydrophobic agent comprises or is a small molecule drug. In some embodiments, the small molecule drug is a synthetic small molecule drug. In some embodiments, the small molecule drug has a molecular weight of about 1,500 Da or less, for example about 1,250 Da or less, 1,000 Da or less, 750 Da or less, or 500 Da or less. In some embodiments, the small molecule drug meets one or more of Lipinski's rule of five (five or less hydrogen bond donors (total number of nitrogen-hydrogen and oxygen-hydrogen bonds), ten or less hydrogen bond acceptors (all nitrogen or oxygen atoms), molecular mass less than 500 Daltons, and octanol-water partition coefficient

[10] (logP) not exceeding 5).

[0143] In some embodiments, the hydrophobic agent comprises or is a biomolecule. In some embodiments, the biomolecule is a polypeptide, lipid, or nucleic acid. In some embodiments, the polypeptide is an antibody or a fragment thereof, including an antibody-drug-conjugate (ADC). In some embodiments, the polypeptide is a hormone. In some embodiments, the nucleic acid comprises RNA or DNA, including pDNA, siRNA, miRNA, mRNA, and lnRNA.

[0144] In some embodiments, the hydrophobic drug has a narrow therapeutic index, e.g., a drug that requires precise dosing for safety purposes. In some embodiments, the hydrophobic drug has a wide therapeutic index. In some embodiments, the hydrophobic drug is a high-potency drug, e.g., a drug that requires low dosing, e.g., less than about 1 mg.

[0145] In some embodiments, the hydrophobic drug is a regulatory approved compound, such as a drug approved for medical treatment by the U.S. Food and Drug Administration. In some embodiments, the hydrophobic drug is a prodrug. In some embodiments, the hydrophobic drug is a novel drug. In some embodiments, the hydrophobic drug is a fermentation product, a semi-synthetic product, a radiopharmaceutical, a biological, biotechnology-derived product, an herbal product, or a crude product of animal or plant origin.

[0146] In some embodiments, the concentration of the hydrophobic drug in the nanosuspensions described herein is from about 1 μg / mL to about 1,000 mg / mL, e.g., from about 0.1 mg / mL to about 1,000 mg / mL, from about 1 mg / mL to about 500 mg / mL, from about 5 mg / mL to about 1,000 mg / mL, or from about 5 mg / mL to about 1,000 mg / mL. In some embodiments, the concentration of hydrophobic drug in the nanosuspensions described herein is about 1,000 mg / mL or less, e.g., about 750 mg / mL or less, 500 mg / mL or less, 250 mg / mL or less, 200 mg / mL or less, 150 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 40 mg / mL or less, 30 mg / mL or less, 20 mg / mL or less, 10 mg / mL or less, 1 mg / mL or less, 900 μg / mL or less, 800 μg / mL or less, 700 μg / mL or less, 600 μg / mL or less, 500 μg / mL or less, 400 μg / mL or less, 300 μg / mL or less, 200 μg / mL or less, 100 μg / mL or less, 50 μg / mL or less, or 1 μg / mL or less. In some embodiments, the concentration of the hydrophobic drug in the nanosuspensions described herein is at least about 1 μg / mL, e.g., at least about any of 50 μg / mL, 100 μg / mL, 200 μg / mL, 300 μg / mL, 400 μg / mL, 500 μg / mL, 600 μg / mL, 700 μg / mL, 800 μg / mL, 900 μg / mL, 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 500 mg / mL, 750 mg / mL, or 1,000 mg / mL.

[0147] In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension described herein are stable for at least about 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, or 72 hours. In some embodiments, the nanosuspension has a dispersion index of about 0.5 or less, such as about 0.4 or less, 0.3 or less, 0.2 or less, or 0.1 or less. In some embodiments, the nanosuspension has an Ostwald ripening of about 20% or less, such as 15% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at about 12 hours. In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension have an aggregation of about 20% or less, such as 15% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at about 12 hours.

[0148] In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension described herein are produced by a milling technique. In some embodiments, the milling technique is selected from the group consisting of a ball mill, a wet media mill, a dry media mill, a jet mill (such as a fluidized bed jet mill), and a grinder. In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension described herein are produced by a hydrodynamic cavitation technique. In some embodiments, the hydrophobic drug-containing nanoparticles of the nanosuspension described herein are produced by an acoustic technique.

[0149] C. Stabilizing component In some embodiments, the nanosuspension comprises a stabilizing component, hi some embodiments, the stabilizing component is suitable for stabilizing the hydrophobic drug-containing nanoparticles in the nanosuspension described herein.

[0150] In some embodiments, the stabilization component comprises any one or more of PVP, SDS, HPC, HPMC, Pluronic (poloxamer), Tween (polysorbate), or Vit-E TPGS. In some embodiments, the stabilization component comprises PVP and / or SDS.

[0151] In some embodiments, the amount of stabilizing component in the nanosuspension described herein is at least about 0.1% w / w, such as at least about any of 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1.0% w / w, 1.5% w / w, 2.0% w / w, 2.5% w / w, 3.0% w / w, 3.5% w / w, 4.0% w / w, 4.5% w / w, 5.0% w / w, 6.0% w / w, 7.0% w / w, 8.0% w / w, 9.0% w / w, or 10% w / w. In some embodiments, the amount of stabilizing component in the nanosuspensions described herein is about 5% w / w or less, such as any of 4.5% w / w or less, 4.0% w / w or less, 3.5% w / w or less, 3.0% w / w or less, 2.5% w / w or less, 2.0% w / w or less, 1.5% w / w or less, 1.0% w / w or less, 0.9% w / w or less, 0.8% w / w or less, 0.7% w / w or less, 0.6% w / w or less, 0.5% w / w or less, 0.4% w / w or less, 0.3% w / w or less, 0.2% w / w or less, or 0.1% w / w or less.

[0152] In some embodiments, the amount of stabilizing component in the nanosuspensions described herein is based on the stabilizing component to drug weight ratio, in some embodiments, the stabilizing component to drug weight ratio is about 1:100 to about 2:1.

[0153] In some embodiments, the stabilizer component to drug weight ratio is at least about 1:100, e.g., at least about 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 11:100, 12:100, 13:100, 14:100, 15:100, 16:100, 17:100, 18:100, 19:100, 20:100, 21:100, 22:100, 23: The ratio is either 100, 24:100, 25:100, 30:100, 35:100, 40:100, 45:100, 50:100, 55:100, 60:100, 65:100, 70:100, 75:100, 80:100, 85:100, 90:100, 95:100, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, or 2:1.

[0154] In some embodiments, the amount of stabilizing component in the nanosuspension described herein is based on the ratio of stabilizing component to carrier. In some embodiments, the ratio of stabilizing component to carrier is less than about 1:10, 1:50, 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, or 1:1000. In some embodiments, the ratio of stabilizing component to carrier is greater than about 1:10,000, 1:1000, or 1:500. In some embodiments, the ratio of stabilizing component to carrier is about 1:10, 1:50, 1:100, 1:200, 1:300, 1:400, 1:500, 1:600, 1:700, 1:800, 1:900, or 1:1000. In some embodiments, the ratio of stabilizer component to carrier is about 1:50 to about 1:500. In some embodiments, the ratio of stabilizer component to carrier is about 1:50 or about 1:500.

[0155] IV. Nanosuspension Dispensing Cartridges and Compositions Therein In certain aspects, provided herein are dispensing cartridges that include (or are suitable for use with) the nanosuspensions described herein, or derivatives or precursors thereof. The dispensing cartridges described herein are generally suitable for holding one or more nanosuspensions described herein, such as in a reservoir of the dispensing cartridge, and are configured to interface with a dispensing head of a droplet dispenser such that the nanosuspensions can be delivered to the dispensing head. In some embodiments, the dispensing cartridge is a disposable cartridge. In some embodiments, the dispensing cartridge is suitable for one-time or limited time use.

[0156] In some embodiments, the dispensing cartridge comprises a material suitable for use with the nanosuspensions described herein, hi some embodiments, the dispensing cartridge comprises a material suitable for use in pharmaceutical applications, e.g., the material does not dissolve or leach its components in the presence of the nanosuspension.

[0157] In some embodiments, the dispensing cartridge includes one reservoir configured to hold a nanosuspension as described herein. In some embodiments, the dispensing cartridge includes more than one reservoir configured to hold a nanosuspension as described herein. In embodiments of a dispensing cartridge having more than one reservoir, in some examples, the dispensing cartridge includes one or more of the following: (i) a first nanosuspension including a hydrophobic drug and a second nanosuspension including another drug, such as a hydrophobic drug; (ii) a first nanosuspension including a hydrophobic drug and a second nanosuspension including a hydrophobic drug (e.g., the hydrophobic drug is at different concentrations in the first and second nanosuspensions and / or the first and second nanosuspensions include different non-drug components or concentrations thereof); (iii) a first nanosuspension including a hydrophobic drug and a second solution including a material useful for the embodiments described herein (wherein the material is not a nanosuspension as described herein). In some embodiments, a dispensing cartridge is provided that includes a material useful for the embodiments described herein, where the material is not a nanosuspension as described herein. For example, in some embodiments, the dispensing cartridge comprises a fluid suitable for deposition onto a substrate, such as to communicate a characteristic or identity (including a unique identity) of the dosage form via a logo and / or label. In some embodiments, the label is a machine-readable label, such as a QR code or a barcode. Also disclosed herein are kits comprising one or more dispensing cartridges described herein.

[0158] In some embodiments, the dispense cartridge includes a reservoir for containing a volume of the nanosuspension, e.g., as described herein. In some embodiments, the dispense cartridge includes a reservoir port, such as to facilitate flow of material(s) into or out of the reservoir. In some embodiments, the dispense cartridge includes a sponge material. In some embodiments, the sponge material is within the reservoir. In some embodiments, the dispense cartridge includes a dispense head interface configured to allow passage of the nanosuspension from the reservoir to a dispense head of the droplet dispenser.

[0159] In some embodiments, compositions are provided herein that include a nanosuspension form, including derivatives or precursors thereof. In some embodiments, the nanosuspension form is a frozen, dried, or lyophilized form of the nanosuspension. In some embodiments, the nanosuspension form can be processed to produce a nanosuspension as described herein, for example, by reconstitution. In some embodiments, the composition is contained within a dispensing cartridge.

[0160] V. Nanosuspension Dosage Forms In certain aspects, provided herein is a dosage form comprising a patterned layer comprising a plurality of nanoparticles comprising a hydrophobic drug. In some embodiments, the dosage form comprises a thin film substrate and a patterned layer comprising a plurality of nanoparticles, the nanoparticles comprising a hydrophobic drug.

[0161] In some embodiments, the dosage form is an oral dosage form (including oral drug dosage forms such as capsules comprising a thin film substrate, e.g., rolled and / or folded thin film substrate). In some embodiments, the dosage form is an intrabuccal dosage form. In some embodiments, the dosage form is a buccal dosage form. In some embodiments, the dosage form is a sublingual dosage form. In some embodiments, the dosage form is a vaginal dosage form. In some embodiments, the dosage form is a rectal dosage form. In some embodiments, the dosage form is an ophthalmic dosage form. In some embodiments, the dosage form comprises components derived from deposition of the described nanosuspensions using the methods provided herein. In some embodiments, the thin film substrate is suitable for human consumption. In some embodiments, the dosage form is suitable for contact-based delivery of hydrophobic drugs, e.g., transdermal dosage forms. In some embodiments, the dosage form is an ophthalmic dosage form. In some embodiments, the thin film substrate comprises a polymer (e.g., the thin film substrate is a polymeric film). In some embodiments, the thin film substrate comprises one or more of chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil, and polyacrylic acid derivatives.

[0162] The dosage forms described herein may have a patterned layer of any shape and / or size. In some embodiments, the characteristics of the patterned layer are based on the amount of hydrophobic drug in the dosage form. For example, such characteristics of the patterned layer may be based on the concentration of the hydrophobic drug in the nanosuspension and the desired total amount of hydrophobic drug deposited on the thin film substrate. In some embodiments, the characteristics of the patterned layer (e.g., any of the shape, size, and location on the dosage form) are based on the desired release profile of the hydrophobic drug (e.g., the patterned layer may be designed to increase the surface area to bodily fluids) and / or the characteristics of the final dosage form (e.g., the structural integrity and / or protection of the patterned layer). In some embodiments, the term layer should not be construed to mean only a single deposition from a droplet dispenser described herein. In some embodiments, the patterned layer is formed from many instances of droplet deposition from a droplet dispenser described herein (e.g., repeated printing of an area using a nanosuspension described herein). For example, in producing a dosage form including a patterned layer, the droplet dispenser may be controlled to deposit droplets of the nanosuspension in one or more passes to form the final patterned layer.

[0163] In some embodiments, the patterned layer is generated via a droplet dispenser that deposits the nanosuspension at about 1 dots per inch (dpi) to about 1,000 dpi, such as from about 1 dpi to about 720 dpi, from about 72 dpi to about 720 dpi, from about 72 dpi to about 500 dpi, or from about 72 dpi to about 300 dpi. In some embodiments, the patterned layer is generated via a droplet dispenser that deposits the nanosuspension at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more. In some embodiments, the patterned layer comprises a nanosuspension deposited at about 1 dots per inch (dpi) to about 1,000 dpi, such as from about 1 dpi to about 720 dpi, from about 72 dpi to about 720 dpi, from about 72 dpi to about 500 dpi, or from about 72 dpi to about 300 dpi. In some embodiments, the patterned layer comprises a nanosuspension deposited at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more.

[0164] In some embodiments, the deposited droplets of the nanosuspension have a diameter (or largest cross dimension) of from about 1 nm to about 200 μm, such as from about 20 nm to about 800 nm, from about 100 nm to about 500 nm, or from about 10 μm to about 100 μm. In some embodiments, the deposited droplets of the nanosuspension have a diameter of at least about 1 nm, e.g., at least about 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm, and having a diameter (or maximum cross dimension) of any of: 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 525 nm, 550 nm, 575 nm, 600 nm, 625 nm, 650 nm, 675 nm, 700 nm, 725 nm, 750 nm, 775 nm, 800 nm, 825 nm, 850 nm, 875 nm, 900 nm, 925 nm, 950 nm, 975 nm, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm. In some embodiments, the average of a population of droplets (such as a patterned layer(s)) described herein meets the above criteria.

[0165] In some embodiments, the patterned layer is at least partially within the thin film substrate (e.g., at least a portion of the nanosuspensions described herein permeate and / or are absorbed into the thin film substrate). In some embodiments, the patterned layer is at least partially on top of the thin film substrate (e.g., at least a portion of the nanosuspensions described herein are at or above the surface of the thin film substrate). In some embodiments, the patterned layer is at least partially within and at least partially on top of the thin film substrate.

[0166] In some embodiments, the dosage form comprises more than one patterned layer, for example a first patterned layer and a second patterned layer. In some embodiments, the first patterned layer comprises nanoparticles comprising a hydrophobic drug, and the second patterned layer comprises another drug. In some embodiments, the first patterned layer comprises nanoparticles comprising a hydrophobic drug, and the second patterned layer comprises nanoparticles comprising a hydrophobic drug. In some embodiments, the first patterned layer comprises nanoparticles comprising a hydrophobic drug, and the second patterned layer comprises nanoparticles comprising a second hydrophobic drug. In some embodiments, each patterned layer is produced by a layer-by-layer deposition technique.

[0167] In some embodiments, the dosage form comprises the hydrophobic drug in an amount of about 1 ng to about 1 mg, e.g., about 100 ng to about 500 ng, about 250 ng to about 750 ng, about 500 ng to about 1 μg, about 750 ng to about 1.25 μg, about 1 μg to about 2 μg, about 1 μg to about 10 μg, about 10 μg to about 50 μg, or about 25 μg to about 100 μg.

[0168] In some embodiments, the dosage form contains at least about 1 ng, e.g., at least about 5 ng, 10 ng, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, 100 ng, 125 ng, 150 ng, 175 ng, 200 ng, 225 ng, 250 ng, 275 ng, 300 ng, 325 ng, 350 ng, 375 ng, 400 ng, 425 ng, 450 ng, 475 ng, 500 ng, 525 ng, 550 ng, 575 ng, 600 ng, 625 ng, 650 ng, 675 ng, ng, 700ng, 725ng, 750ng, 775ng, 800ng, 825ng, 850ng, 875ng, 900ng, 925ng, 950ng, 975ng, 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, or 100 μg of a hydrophobic drug.

[0169] In some embodiments, the dosage form further comprises a marking and / or label. For example, in certain embodiments, the dosage form may contain printed information regarding any one or more of the following: active agent, amount of active agent, date of manufacture, the individual for which the dosage form is manufactured, time of manufacture, traceable identification code, expiration date, instructions for use, storage instructions, or company name and / or logo. In some embodiments, the marking and / or label is suitable for consumption, for example, includes a food-safe dye.

[0170] In some embodiments, the dosage form includes a protective coating, for example, applied over the patterned layer. In some embodiments, the protective coating is applied to the dosage form via a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser. In some embodiments, the dosage form includes a film coating.

[0171] In some embodiments, the dosage form is suitable for human use and / or consumption, hi some embodiments, the dosage form is sterile.

[0172] In some embodiments, the dosage form is manufactured according to any of the methods described herein. For example, in some embodiments, a dosage form is provided that is produced by dispensing a patterned layer of a nanosuspension comprising a plurality of nanoparticles comprising a hydrophobic drug onto a substrate via a droplet dispenser (e.g., a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser).

[0173] In certain aspects, a batch of dosage forms described herein is provided.In some embodiments, the batch of dosage forms comprises at least 5 dosage forms, for example, any of 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 dosage forms.In some embodiments, the batch of drug dosage forms described comprises individual dosage forms with an amount of hydrophobic drug that does not vary more than 5% from the average.

[0174] VI. DEVICES FOR DISPENSING NANOSUSPENSIONS DETAILED HEREIN In certain aspects, provided herein is a device for dispensing and depositing droplets of the nanosuspension described herein. In some embodiments, the device comprises a sub-nanoliter droplet dispenser. In some embodiments, the device comprises a high frequency sub-nanoliter droplet dispenser. Sub-nanoliter droplet dispensers, including sub-nanoliter high frequency droplet dispensers, are known in the art, including those described in U.S. Patent Nos. 7,585,038, 7,963,635, and 6,851,786, the entireties of which are incorporated herein by reference.

[0175] In some embodiments, a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser, for producing a dosage form is provided, the dispenser comprising: (a) a dispensing head operatively connected to a reservoir for a nanosuspension, and (b) a control system configured to control deposition of the nanosuspension through the dispensing head. In some embodiments, a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser, for producing a dosage form is provided, the dispenser comprising: (a) a dispensing head, (b) a nanosuspension dispensing cartridge receiving space configured to operatively couple a nanosuspension dispensing cartridge to the dispensing head, and (c) a control system configured to control deposition of the nanosuspension through the dispensing head according to a dispensing pattern. In some embodiments, a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser, for producing a dosage form is provided, the dispenser comprising: (a) a dispensing head; (b) a nanosuspension dispensing cartridge comprising a nanosuspension comprising a hydrophobic drug, the nanosuspension dispensing cartridge being operably coupled to the dispensing head, the nanosuspension comprising an aqueous carrier and a plurality of nanoparticles, each nanoparticle of the plurality of nanoparticles comprising a hydrophobic drug; and (c) a control system configured to deposit the nanosuspension through the dispensing head according to a dispensing pattern. In some embodiments, the viscosity of the nanosuspension is less than 2 cP, e.g., between about 1 cp and less than 2 cp, or between 1.8 cP and about 1.2 cP.

[0176] In some embodiments, the dispensing head comprises between about 10 and about 1000 individual nozzles. In some embodiments, the dispensing head includes at least about 10, e.g., at least about any of 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 individual nozzles.

[0177] In some embodiments, each nozzle of the dispensing head has an opening (through which the nanosuspension is dispensed) having a maximum cross-section (e.g., diameter) of about 20 μm to about 120 μm, e.g., about 20 μm to about 70 μm or about 30 μm to about 60 μm. In some embodiments, the nozzles of the dispensing head have an opening having a maximum cross-section (e.g., diameter) of at least about 20 μm, e.g., at least about any of 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 75 μm, 100 μm, or 120 μm.

[0178] In some embodiments, each nozzle of the dispensing head is configured to dispense droplets of the nanosuspension having a volume of about 1 to about 500 picoliters (pL). In some embodiments, the nozzles of the dispensing head are configured to dispense droplets of the nanosuspension having a volume of about 500 pL or less, e.g., about 450 pL or less, 400 pL or less, 350 pL or less, 300 pL or less, 250 pL or less, 200 pL or less, 150 pL or less, 100 pL or less, 75 pL or less, 50 pL or less, or 25 pL or less.

[0179] In some embodiments, the dispense head is a continuous dispense head. In some embodiments, the dispense head is a drop-on-demand printhead. In some embodiments, the dispense head is a thermal inkjet printhead. In some embodiments, the dispense head is a piezoelectric inkjet printhead. In some embodiments, the dispense head is a solenoid valve printhead. In some embodiments, the dispense head is an electrostatic printhead. In some embodiments, the dispense head is an acoustic printhead.

[0180] In some embodiments, the dispensing head is a sub-nanoliter dispensing head. In some embodiments, the dispensing head is a high frequency sub-nanoliter dispensing head (e.g., a dispensing head operating at a dispensing frequency of greater than 2,000 Hz, such as greater than about 2.5 kHz, 3 kHz, 3.5 kHz, 4 kHz, 4.5 kHz, or 5 kHz).

[0181] In some embodiments, the dispensing device comprises more than one dispensing head. In some embodiments, the dispensing device further comprises a second dispensing head operably coupled to a second dispensing cartridge. In some embodiments, the dispensing device further comprises a third dispensing head operably coupled to a third dispensing cartridge. In some embodiments, the dispensing device further comprises a fourth dispensing head operably coupled to a fourth dispensing cartridge. In configurations with more than one dispensing head, the dispensing device is configured to be operably coupled to a dispensing cartridge that includes any of a variety of materials, such as nanosuspensions, protective coatings, and label and / or marking materials (such as edible inks).

[0182] VII. Systems and Uses Including Nanosuspension Embodiments Described Herein In certain aspects, systems and applications utilizing methods of making the dosage forms described herein and associated features are provided herein. In some embodiments, systems are provided that include a dispensing device configured to receive instructions for printing the dosage forms described herein. In some embodiments, the system is established at the point of care, such as a hospital, a nursing home, a pharmacy, or a home. In some embodiments, the dosage form is an individualized dosage form designed for an individual based on the characteristics of the dosage form, such as, for example, the amount of hydrophobic drug.

[0183] In some embodiments, the methods and dispensing devices described herein are suitable for personalized medicine. In some embodiments, the methods and dispensing devices described herein are suitable for point-of-care applications. In some embodiments, the methods and dispensing devices described herein are suitable for rapid dosage form production (including on a small scale, such as less than 100 dosage forms). In some embodiments, the methods and dispensing devices described herein are suitable for producing dosage forms with accurate and precise amounts of hydrophobic drugs (e.g., required for hydrophobic drugs with narrow therapeutic index, high potency, and / or pediatric use). In some embodiments, the methods and dispensing devices described herein are suitable for producing dosage forms with hydrophobic drugs that are less stable (e.g., not stable for extended periods of time after production, e.g., more than 24 hours). In some embodiments, the methods and dispensing devices described herein are suitable for non-pharmaceutical applications, such as dietary supplements.

[0184] VIII. ASD-forming solutions and their precursor solutions In certain aspects, amorphous solid dispersion (ASD)-forming solutions and precursor solutions thereof are provided herein. Such ASD-forming solutions and precursor solutions thereof are useful for forming ASDs and / or for studying and identifying conditions that result (or do not result) in the formation of ASDs, including drugs that are prone to crystallization, such as hydrophobic drugs. As taught herein, the ASD-forming solution, including its components and precursors, can be dispensed and deposited in several ways. In some embodiments, the ASD-forming solution is dispensed in the form of a single solution from a droplet dispenser. In some embodiments, the ASD-forming solution is dispensed from two or more droplet dispensers, and the ASD-forming solution is formed after dispensing from the two or more droplet dispensers (e.g., precursor solutions from two or more droplet dispensers are mixed before and / or on the substrate to form the ASD-forming solution and / or ASD). In some embodiments, the ASD-forming solution is in the form of a single solution. In some embodiments, the precursor solutions described herein are combined to form the ASD-forming solution. For example, the ASD-forming solution may be formed from two precursor solutions, such as a first precursor solution containing at least one component of the ASD-forming solution (e.g., a drug that is prone to crystallization, such as a hydrophobic drug) and a second precursor solution containing at least one component of the ASD-forming solution (e.g., a polymer). In some embodiments, the ASD-forming solution is formulated such that upon dispensing and / or depositing the precursor solution, and / or thereafter, the ASD-forming solution produces an ASD containing a drug that is prone to crystallization, e.g., a hydrophobic drug. In certain aspects described herein, one or more of the precursor solutions as deposited (e.g., at a deposition ratio between drug and polymer) do not form an ASD. Without being bound by theory, it is believed that the ASD converts the crystalline drug material into amorphous material, which increases solubility and therefore enhances absorption.

[0185] In some aspects, the ASD-forming solution provided herein comprises a precursor solution comprising an organic carrier, a polymer, and an agent that is prone to crystallization, such as a hydrophobic agent, and at least one component of the ASD-forming solution. As discussed herein, various aspects of the ASD-forming solution and its precursor solution are described in a modular manner in the sections provided herein, and it will be readily understood that the ASD-forming solution and its precursor solution encompasses the embodiments described therein and any combination thereof. Such a modular description is not intended to limit the scope of the disclosure, and based on the teachings provided herein, one of ordinary skill in the art will readily understand that certain modules can be at least partially integrated. Any section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0186] A. Organic Carriers In some aspects, the present specification provides an ASD-forming solution or a precursor solution thereof that includes an organic carrier. In some embodiments, the organic carrier improves the solubility of drugs that tend to crystallize, such as hydrophobic drugs, and / or improves carrier evaporation during the deposition process of the droplet dispenser. In some embodiments, the precursor solution does not include a precursor solution that includes a component that is compatible with an organic carrier, such as an aqueous carrier.

[0187] In some embodiments, the organic carrier of the ASD forming solution comprises any one or more of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethylsulfoxide, or a combination thereof.

[0188] In some embodiments, the ASD-forming solution or precursor solution thereof comprises at least about 30% by volume of the organic carrier, e.g., at least about 35% by volume of the organic carrier, 40% by volume of the organic carrier, 45% by volume of the organic carrier, 50% by volume of the organic carrier, 55% by volume of the organic carrier, 60% by volume of the organic carrier, 65% by volume of the organic carrier, 70% by volume of the organic carrier, 75% by volume of the organic carrier, 80% by volume of the organic carrier, 85% by volume of the organic carrier, 90% by volume of the organic carrier, 95% by volume of the organic carrier, or 100% by volume of the organic carrier.

[0189] In some embodiments, the organic carrier comprises water. In some embodiments, the organic carrier comprises less than 30% water by volume, less than 20% water by volume, less than 10% water by volume, less than 5% water by volume, less than 2% water by volume, less than 1% water by volume, or less than 0.5% water by volume. In some embodiments, the organic carrier does not contain water. In some embodiments, the organic carrier contains only trace amounts of water.

[0190] In some embodiments, the ASD-forming solution or its precursor solution may include an aqueous carrier and a solubilizing agent. In such cases, the aqueous carrier replaces the organic carrier in the ASD-forming solution or its precursor solution. The aqueous carrier can replace the organic carrier in any of the embodiments presented herein. In some embodiments, the solubilizing agent is selected from the group consisting of a surfactant, an emulsifier, polyethylene glycol, propylene glycol, polysorbate, cyclodextrin, or a metal chelating agent (e.g., ethylenediamine-tetraacetic acid).

[0191] B. Polymer In some aspects, the present specification provides an ASD forming solution or its precursor solution, which comprises a polymer suitable for forming an ASD with a drug that is prone to crystallization, such as a hydrophobic drug.Generally speaking, a certain concentration or ratio of polymer to a drug that is prone to crystallization inhibits the formation of the crystalline form of the drug.In some embodiments, the precursor solution does not include a polymer, for example, the polymer is contained in a separate precursor solution.

[0192] In some embodiments, the polymer of the ASD-forming solution is suitable for forming an amorphous solid dispersion (ASD) after deposition by a droplet dispenser. In some embodiments, the polymer adjusts the viscosity of the ASD-forming solution or its precursor solution.

[0193] In some embodiments, the polymer is selected based on one or more properties of the drug that is prone to crystallization, such as a hydrophobic drug. In some embodiments, the polymer is selected based on the interaction with the drug that is prone to crystallization, such as a hydrophobic drug. For example, in some embodiments, the interaction between the polymer and the drug comprises one or more of van der Waals forces, ionic interactions, or hydrogen bonds.

[0194] In some embodiments, the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PPVVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC acetate succinate (hypromellose acetate succinate or HPMC-AS), and Eudragit, or any combination thereof. In some embodiments, the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG, and HG.

[0195] In some embodiments, the polymer is HPMC-AS-LF.

[0196] In some embodiments, the weight ratio of polymer to drug prone to crystallization, such as hydrophobic drug, in the ASD forming solution is 1:20 to 20:1, e.g., 1:20 to 1:15, 1:10, 1:5, 1:2, 1:1, 2:1, 5:1, 10:1.15:1, or 20:1. In some embodiments, the weight ratio is 1:15 to 1:10, 1:5, 1:2, 1:1, 2:1, 5:1, 10:1.15:1, or 20:1. In some embodiments, the weight ratio is 1:10 to 1:5, 1:2, 1:1, 2:1, 5:1, 10:1.15:1, or 20:1. In some embodiments, the weight ratio is 1:5 to 1:2, 1:1, 2:1, 5:1, 10:1, 15:1, or 20:1. In some embodiments, the weight ratio is 1:2 to 1:1, 2:1, 5:1, 10:1, 15:1, or 20:1. In some embodiments, the weight ratio is 1:1 to 2:1, 5:1, 10:1, 15:1, or 20:1. In some embodiments, the weight ratio is 2:1 to 5:1, 10:1, 15:1, or 20:1. In some embodiments, the weight ratio is 5:1 to 10:1, 15:1, or 20:1. In some embodiments, the weight ratio is 10:1 to 15:1 or 20:1. In some embodiments, the weight ratio is 15:1 to 20:1.

[0197] In some embodiments, the weight ratio of the concentration of polymer to the concentration of the crystallization-prone drug, such as a hydrophobic drug, in the ASD-forming solution is 1:2 to 2:1.

[0198] In some embodiments, the polymer loading of the ASD-forming solution or its precursor solution is about 1% to about 99% (w / w), such as about 5% to about 15%, about 15% to about 25%, about 25% to about 25%, about 35% to about 45%, about 45% to about 55%, about 55% to about 65%, about 65% to about 75%, about 75% to about 85%, or about 85% to about 95%. In some embodiments, the polymer loading of the ASD-forming solution or its precursor solution is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0199] C. Drugs that are prone to crystallization The ASD-forming solutions described herein include one or more agents that are prone to crystallization, e.g., hydrophobic agents, including hydrophobic drugs. In some embodiments, the agents are prone to crystallization during handling and / or manufacturing of the dosage form, e.g., spray drying and / or deposition by a droplet dispenser as described herein. In some embodiments, the agents are prone to crystallization at a desired concentration in the final product, such as a drug dosage form, as described herein. Techniques for measuring crystallization are well known in the art, e.g., microscopy and polarized light microscopy, Raman spectroscopy, and imaging such as differential scanning calorimetry. In some embodiments, crystallization is assessed upon manufacturing the ASD (e.g., after deposition of the ASD-forming solution by the methods described herein). In some embodiments, crystallization is assessed at a period of time after manufacturing the ASD, e.g., about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 9 months, or 1 year after manufacturing the ASD. In some embodiments, the ASD is held at a temperature higher than room temperature, e.g., at a temperature of 37° C. or higher, for a period of time.

[0200] In some embodiments, the drug prone to crystallization is a hydrophobic drug. In some embodiments, the hydrophobic drug is poorly water soluble. In some embodiments, the hydrophobic drug has a solubility in a solvent, such as pure water, of about 1 mg / mL or less, such as about 750 μg / mL or less, 500 μg / mL or less, 250 μg / mL or less, 200 μg / mL or less, 150 μg / mL or less, 100 μg / mL or less, 50 μg / mL or less, 25 μg / mL or less, 1 μg / mL or less, 500 ng / mL or less, or 100 ng / mL. In some embodiments, the solvent for evaluating solubility is an aqueous solvent, such as water, bicarbonate buffer, biorelevant medium, or a solvent containing a surfactant. In some embodiments, the hydrophobic drug is not soluble at the target concentration of the ASD-forming solution.

[0201] In some embodiments, a hydrophobic drug is sparingly soluble, slightly soluble, very slightly soluble, or substantially insoluble (insoluble) as defined by the United States Pharmacopeia-National Formulary (USP-NF). In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 30 parts of solvent required to 1 part of solute to about 100 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 100 parts of solvent required to 1 part of solute to about 1,000 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 1,000 parts of solvent required to 1 part of solute to about 10,000 parts of solvent required to 1 part of solute. In some embodiments, a hydrophobic drug is classified as sparingly soluble if it has a solubility of about 10,000 parts of solvent required to 1 part of solute or more. In some embodiments, the solvent is an aqueous solvent, such as water, a bicarbonate buffer, a biorelevant medium, or a solvent that includes a surfactant.

[0202] In some embodiments, the hydrophobic agent is a Biopharmaceutical Classification System (BCS) Class II drug. In some embodiments, the hydrophobic agent is a BCS Class IV drug.

[0203] In some embodiments, the hydrophobic agent is a drug, such as a therapeutic agent, useful for treating and / or preventing a condition.

[0204] In some embodiments, the hydrophobic agent comprises or is a small molecule drug. In some embodiments, the small molecule drug is a synthetic small molecule drug. In some embodiments, the small molecule drug has a molecular weight of about 1,500 Da or less, for example about 1,250 Da or less, 1,000 Da or less, 750 Da or less, or 500 Da or less. In some embodiments, the small molecule drug meets one or more of Lipinski's rule of five (five or less hydrogen bond donors (total number of nitrogen-hydrogen and oxygen-hydrogen bonds), ten or less hydrogen bond acceptors (all nitrogen or oxygen atoms), molecular mass less than 500 Daltons, and octanol-water partition coefficient

[10] (logP) not exceeding 5).

[0205] In some embodiments, the hydrophobic agent comprises or is a biomolecule. In some embodiments, the biomolecule is a polypeptide, lipid, or nucleic acid. In some embodiments, the polypeptide is an antibody or a fragment thereof, including an antibody-drug-conjugate (ADC). In some embodiments, the polypeptide is a hormone. In some embodiments, the nucleic acid comprises RNA or DNA, including pDNA, siRNA, miRNA, mRNA, and lnRNA.

[0206] In some embodiments, the hydrophobic drug has a narrow therapeutic index, e.g., a drug that requires precise dosing for safety purposes. In some embodiments, the hydrophobic drug has a wide therapeutic index. In some embodiments, the hydrophobic drug is a high-potency drug, e.g., a drug that requires low dosing, e.g., less than about 1 mg.

[0207] In some embodiments, the hydrophobic drug is a regulatory approved compound, such as a drug approved for medical treatment by the U.S. Food and Drug Administration. In some embodiments, the hydrophobic drug is a prodrug. In some embodiments, the hydrophobic drug is a novel drug. In some embodiments, the hydrophobic drug is a fermentation product, a semi-synthetic product, a radiopharmaceutical, a biological, biotechnology-derived product, an herbal product, or a crude product of animal or plant origin.

[0208] In some embodiments, the concentration of the hydrophobic agent in the ASD forming solution or precursor thereof described herein is from about 1 μg / mL to about 1,000 mg / mL, e.g., from about 0.1 mg / mL to about 1,000 mg / mL, from about 1 mg / mL to about 500 mg / mL, from about 5 mg / mL to about 1,000 mg / mL, or from about 5 mg / mL to about 1,000 mg / mL. In some embodiments, the concentration of the hydrophobic agent in the ASD-forming solution or precursor thereof described herein is about 1,000 mg / mL or less, such as about 750 mg / mL or less, 500 mg / mL or less, 250 mg / mL or less, 200 mg / mL or less, 150 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, 40 mg / mL or less, 30 mg / mL or less, 20 mg / mL or less, 10 mg / mL or less, 1 mg / mL or less, 900 μg / mL or less, 800 μg / mL or less, 700 μg / mL or less, 600 μg / mL or less, 500 μg / mL or less, 400 μg / mL or less, 300 μg / mL or less, 200 μg / mL or less, 100 μg / mL or less, 50 μg / mL or less, or 1 μg / mL or less. In some embodiments, the concentration of the hydrophobic agent in the ASD-forming solution or precursor solution described herein is at least about 1 μg / mL, such as at least about 50 μg / mL, 100 μg / mL, 200 μg / mL, 300 μg / mL, 400 μg / mL, 500 μg / mL, 600 μg / mL, 700 μg / mL, 800 μg / mL, 900 μg / mL, 1 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 500 mg / mL, 750 mg / mL or 1,000 mg / mL.

[0209] In some embodiments, the loading of the crystallization-prone drug, e.g., hydrophobic drug, of the ASD-forming solution or its precursor solution is about 1% to about 99% (w / w), e.g., about 5% to about 15%, about 15% to about 25%, about 25% to about 25%, about 35% to about 45%, about 45% to about 55%, about 55% to about 65%, about 65% to about 75%, about 75% to about 85%, or about 85% to about 95%. In some embodiments, the drug loading of the ASD-forming solution or its precursor solution is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0210] The ASD-forming solutions described herein can prevent one or more drugs prone to crystallization from crystallizing indefinitely or for a finite period of time, hi some embodiments, the ASD-forming solutions form an ASD in which the drug prone to crystallization never crystallizes.

[0211] D. Viscosity and viscosity modifiers The ASD-forming solution and its precursor solution provided herein have a viscosity such that the solution is suitable for use in the embodiments described herein, including the methods of making dosage forms and droplet dispensers. In some embodiments, the viscosity of the solution provided herein (e.g., the ASD-forming solution or its precursor solution, e.g., the solution dispensed from the ASD-forming solution) is such that it can be dispensed with a droplet dispenser, e.g., a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser. In some embodiments, the viscosity of the ASD-forming solution or its precursor solution provided herein is such that it does not leak from the dispensing cartridge or droplet dispenser described herein.

[0212] In some embodiments, the viscosity of the ASD-forming solution or its precursor solution is about 0.5 cP to about 5 cP, such as about 0.5 cP to about 3 cP, about 0.5 cP to about 2.5 cP, about 1 cP to about 2.5 cP, about 1.5 to about 2.5, about 1 cP to about 2 cP, or about 1.2 cP to about 1.8 cP. In some embodiments, the viscosity of the ASD-forming solution or its precursor solution is less than about 5 cP, such as about 4.9 cP, 4.8 cP, 4.7 cP, 4.6 cP, 4.5 cP, 4.4 cP, 4.3 cP, 4.2 cP, 4.1 cP, 4.0 cP, 3.9 cP, 3.8 cP, 3.7 cP, 3.6 cP, 3.5 cP, 3.4 cP, 3.3 cP, 3.2 cP, 3.1 cP, 3.0 cP, 3.2 ... P, 2.9 cP, 2.8 cP, 2.7 cP, 2.6 cP, 2.5 cP, 2.4 cP, 2.3 cP, 2.2 cP, 2.1 cP, 2.0 cP, 1.9 cP, 1.8 cP, 1.7 cP, 1.6 cP, 1.5 cP, 1.4 cP, 1.3 cP, 1.2 cP, 1.1 cP, 1.0 cP, 0.9 cP, 0.8 cP, 0.7 cP, 0.6 cP or less than 0.5 cP. In some embodiments, the viscosity of the ASD forming solution or precursor solution thereof is less than about 2 cP, e.g., less than about any of 1.95 cP, 1.9 cP, 1.85 cP, 1.8 cP, 1.75 cP, 1.7 cP, 1.65 cP, 1.6 cP, 1.55 cP, 1.5 cP, 1.45 cP, 1.4 cP, 1.35 cP, 1.3 cP, 1.25 cP, 1.2 cP, 1.15 cP, 1.1 cP, 1.05 cP, 1 cP, 0.95 cP, 0.9 cP, 0.85 cP, 0.8 cP, 0.75 cP, 0.7 cP, 0.65 cP, 0.6 cP, 0.55 cP, or 0.5 cP.In some embodiments, the viscosity of the ASD forming solution or precursor solution thereof is at least about 0.5 cP, e.g., at least about 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, It is either less than 2.5 cP, 2.6 cP, 2.7 cP, 2.8 cP, 2.9 cP, 3.0 cP, 3.1 cP, 3.2 cP, 3.3 cP, 3.4 cP, 3.5 cP, 3.6 cP, 3.7 cP, 3.8 cP, 3.9 cP, 4.0 cP, 4.1 cP, 4.2 cP, 4.3 cP, 4.4 cP, 4.5 cP, 4.6 cP, 4.7 cP, 4.8 cP, 4.9 cP, or 5.0 cP. In some embodiments, the viscosity of the ASD forming solution or precursor solution thereof is at least about 0.5 cP, e.g., at least about any of 0.55 cP, 0.6 cP, 0.65 cP, 0.7 cP, 0.75 cP, 0.8 cP, 0.85 cP, 0.9 cP, 0.95 cP, 1 cP, 1.05 cP, 1.1 cP, 1.15 cP, 1.2 cP, 1.25 cP, 1.3 cP, 1.35 cP, 1.4 cP, 1.45 cP, 1.5 cP, 1.55 cP, 1.6 cP, 1.65 cP, 1.7 cP, 1.75 cP, 1.8 cP, 1.85 cP, 1.9 cP, 1.95 cP, or 2.0 cP. In some embodiments, the viscosity of the ASD forming solution or precursor solution thereof is about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP, 2.2 cP, 2.3 cP, 2.4 cP, 2.5 cP, Either 2.6cP, 2.7cP, 2.8cP, 2.9cP, 3.0cP, 3.1cP, 3.2cP, 3.3cP, 3.4cP, 3.5cP, 3.6cP, 3.7cP, 3.8cP, 3.9cP, 4.0cP, 4.1cP, 4.2cP, 4.3cP, 4.4cP, 4.5cP, 4.6cP, 4.7cP, 4.8cP, 4.9cP, or 5.0cP.In some embodiments, the viscosity of the ASD forming solution or precursor solution thereof is about 0.5 cp, 0.55 cp, 0.6 cp, 0.65 cp, 0.7 cp, 0.75 cp, 0.8 cp, 0.85 cp, 0.9 cp, 0.95 cp, 1 cp, 1.05 cp, 1.1 cp, 1.15 cp, 1.2 cp, 1.25 cp, 1.3 cp, 1.35 cp, 1.4 cp, 1.45 cp, 1.5 cp, 1.55 cp, 1.6 cp, 1.6 5 cp, 1.7 cp, 1.75 cp, 1.8 cp, 1.85 cp, 1.9 cp, 1.95 cp, 2.0 cp, 2.05 cp, 2.1 cp, 2.15 cp, 2.2 cp, 2.25 cp, 2.3 cp, 2.35 cp, 2.4 cp, 2.45 cp, 2.5 cp, 2.55 cp, 2.6 cp, 2.65 cp, 2.7 cp, 2.75 cp, 2.8, 2.85 cp, 2.9 cp, 2.95 cp, or 3 cp. In embodiments described herein, the viscosity of the ASD-forming solution or its precursor solution is evaluated at about room temperature (e.g., about 20° C. to about 22° C., including any of about 20° C., 21° C., or 22° C.). In some embodiments in which the ASD-forming solution is generated from two or more precursor solutions thereof, at least two of the two or more precursor solutions have the same viscosity. In some embodiments in which the ASD-forming solution is formed from two or more precursor solutions, at least two of the two or more precursor solutions have different viscosities.

[0213] In some embodiments, various components, including the type and / or concentration of hydrophobic agents and / or polymers, may contribute to the viscosity of the ASD-forming solution or its precursor solution. In some embodiments, the ASD-forming solution or its precursor solution further comprises a viscosity modifier. In some embodiments, the viscosity modifier is a viscosity enhancer, e.g., increases the viscosity of the ASD-forming solution or its precursor solution. In some embodiments, the viscosity modifier is a viscosity reducer, e.g., reduces the viscosity of the ASD-forming solution or its precursor solution.

[0214] In some embodiments, the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol, propylene glycerol, and a cellulosic polymer, or a mixture thereof. In some embodiments, the cellulosic polymer is selected from methylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose, or a mixture thereof. In some embodiments, the viscosity enhancing agent is a polymer useful for forming an ASD, as discussed in other sections of this application.

[0215] In some embodiments, the viscosity reducing agent is selected from the group consisting of salts and amino acids, or mixtures thereof.

[0216] In some embodiments, the viscosity modifier, such as a viscosity enhancer or viscosity reducer, has a concentration in the ASD forming solution or its precursor solution of about 0.1% v / v to about 40% v / v, e.g., about 1% v / v to about 10% v / v, about 5% v / v to about 15% v / v, about 10% v / v to about 20% v / v, about 15% v / v to about 25% v / v, about 20% v / v to about 30% v / v, about 25% v / v to about 35% v / v, or about 30% v / v to about 40% v / v. In some embodiments, the viscosity modifier, such as a viscosity enhancing or reducing agent, has a concentration of about 40% v / v or less in the ASD-forming solution or its precursor solution, such as about 35% v / v, 30% v / v, 25% v / v, 20% v / v, 15% v / v, 10% v / v, 9% v / v, 8% v / v, 7% v / v, 6% v / v, 5% v / v, 4% v / v, 3% v / v, 2% v / v, 1% v / v, 0.9% v / v, 0.8% v / v, 0.7% v / v, 0.6% v / v, 0.5% v / v, 0.4% v / v, 0.3% v / v, 0.2% v / v, or 0.1% v / v. In some embodiments, the concentration of the viscosity modifier, such as a viscosity enhancing or reducing agent, in the ASD-forming solution or its precursor solution is based on the desired viscosity of the ASD-forming solution or its precursor solution.

[0217] In some embodiments, the ratio of the viscosity modifier, such as a viscosity enhancer or viscosity reducer, to the organic carrier of the ASD-forming solution or its precursor solution is about 1:1000 to about 1:2, e.g., about 1:500 to about 1:2, about 1:100 to about 1:2, about 1:50 to about 1:2, about 1:20 to about 1:2, about 1:1000 to about 1:5, about 1:500 to about 1:5, about 1:100 to about 1:5, about 1:50 to about 1:5, about 1:20 to about 1:5, about 1:1000 to about 1:10, about 1:500 to about 1:10, about 1:100 to about 1:10, about 1:50 to about 1:10, or about 1:20 to about 1:10, or about 1:10 to about 1:5. In some embodiments, the ratio is about 1:5. In some embodiments, the ratio is about 1:10.

[0218] E. Precursor solution In certain aspects, a precursor solution for the ASD-forming solution is provided herein. As described herein, a method of depositing an ASD-forming solution on a substrate includes dispensing an ASD-forming solution or its components from one or more droplet dispensers. In some embodiments, the ASD-forming solution is formed by dispensing two or more precursor solutions containing the components. For example, in some embodiments, the ASD-forming solution may be formed by dispensing a first precursor solution containing a drug prone to crystallization and a second precursor solution containing a polymer, and the first precursor solution and the second precursor solution are mixed to form the ASD-forming solution after dispensing. Thus, the precursor solution may contain the components of the ASD-forming solution in any configuration and / or concentration such that mixing of the two or more precursor solutions results in an ASD-forming solution.

[0219] In some embodiments, the precursor solution does not contain a component of the ASD-forming solution. For example, in some embodiments, the ASD-forming solution includes an organic carrier, a polymer, and a drug prone to crystallization, and the ASD-forming solution inhibits, e.g., prevents, crystallization of the drug in the dry state. In some embodiments, the ADS-forming solution optionally includes a viscosity modifier, such as a viscosity modifier different from the polymer. In some embodiments, the precursor solution does not contain an organic carrier. In some embodiments, the precursor solution does not contain a drug prone to crystallization. In some embodiments, the precursor solution does not contain a drug prone to crystallization. In some embodiments, the precursor solution does not contain a viscosity modifier.

[0220] In some embodiments where the precursor solution does not contain an organic carrier, the precursor solution comprises any carrier suitable for use in a droplet dispenser, hi some embodiments, the precursor solution comprises an aqueous carrier.

[0221] In some aspects provided herein, one or more precursor solutions are deposited on a substrate and do not form an ASD. For example, in some embodiments, a first precursor solution containing a drug that is prone to crystallization and a second precursor solution containing a polymer are deposited on a substrate to form a gradient containing two or more different drug-to-polymer ratios. In such embodiments, not all or none of the drug-to-polymer ratios result in an ASD. In light of the disclosure provided herein, the term precursor solution is not intended to limit the scope of such solutions to those that form an ASD-forming solution.

[0222] IX. METHODS FOR IDENTIFYING ASD AND / OR ASD-FORMING SOLUTIONS, AND PRODUCTS THEREOF In certain embodiments, methods are provided herein for identifying ASDs and / or ASD-forming solutions. ASDs are generally optimized to balance the amount of polymer required to inhibit drug crystallization with the amount of polymer required to provide a particular property(s) associated with the drug, such as drug release from a drug dosage form that includes the ASD. Traditional identification of ASDs and their component ratios is a laborious process that requires large amounts of raw materials and high costs. In certain embodiments, methods provided herein include, for example, deposition of ASD-forming solutions and / or precursor solutions from one or more droplet dispensers, allowing both ASD-forming conditions and identification of ASDs with desired characteristics (e.g., drug to polymer ratio with desired release).

[0223] FIG. 6A and FIG. 6B are provided for purposes of illustrating techniques for identifying ASDs and / or ASD-forming solutions. As shown in FIG. 6A, in some embodiments, a precursor solution containing a crystallization-prone drug, e.g., a hydrophobic drug, and a precursor solution containing a polymer suitable for ASD formation are dispensed from separate droplet dispensers. The amount of the first precursor solution dispensed from the first droplet dispenser and the amount of the second precursor solution dispensed from the second droplet dispenser can be varied across a region such that gradient deposition occurs. The degree of variation can be controlled as desired. In FIG. 6A, the left side of the gradient deposition contains 100% loading of the crystallization-prone drug, and the right side of the gradient deposition contains 100% polymer loading. The amount of each precursor solution deposited in the gradient deposition is indicated by black (drug) and white (polymer) triangles. The resulting gradient deposition can then be evaluated to identify conditions suitable for forming an ASD containing the drug. In some embodiments, products of the described methods, such as gradient depositions containing various ratios of crystallization-prone drug to polymer, are provided herein. 6B illustrates another technique encompassed by the methods provided herein. Using a precursor solution containing a drug that is prone to crystallization, e.g., a hydrophobic drug, and a precursor solution containing an appropriate polymer, deposition of regions (e.g., the illustrated circle) can be performed to generate a specific drug loading. The resulting regions can then be evaluated to identify suitable conditions for forming an ASD containing the drug.

[0224] In some aspects, provided herein is a method for determining the ratio of a drug prone to crystallization, such as a hydrophobic drug, to a polymer that forms an ASD, the method comprising dispensing a quantity of a first precursor solution including the drug and a quantity of a second precursor solution including the polymer onto a substrate to determine the ratio of the drug to the polymer that forms the ASD, the dispensing being performed such that the first precursor solution and the second precursor solution are mixed on or before being applied to the substrate. In some embodiments, the method comprises generating a plurality of regions on the substrate, each having a different ratio of drug to polymer from the precursor solution. In some embodiments, the different regions form a gradient of drug and polymer ratio, such as from 0% drug and 100% polymer to 100% drug and 0% polymer. In some embodiments, the first precursor solution comprises an organic carrier and the drug. In some embodiments, the first precursor solution further comprises a polymer. In some embodiments, the first precursor solution further comprises a viscosity enhancing agent. In some embodiments, the second precursor solution comprises a polymer and another carrier, such as an organic carrier. In some embodiments, the second precursor solution comprises another viscosity enhancing agent.

[0225] In some embodiments, the first precursor solution is dispensed from a first droplet dispenser, such as a sub-nanoliter droplet dispenser, e.g., a radio frequency sub-nanoliter dispenser. In some embodiments, the second precursor solution is dispensed from a second droplet dispenser, such as a sub-nanoliter droplet dispenser, e.g., a radio frequency sub-nanoliter dispenser.

[0226] In some embodiments, the method includes mixing components of a first precursor solution and a second precursor solution, e.g., to obtain an ASD-forming solution or candidate thereof, and dispensing the ASD-forming solution or candidate thereof onto a substrate using a droplet dispenser to determine whether an ASD is formed. In some embodiments, multiple ADS-forming solutions are independently deposited onto a substrate to determine the ratio of a crystallization-prone agent, e.g., a hydrophobic agent, to a polymer that forms an ASD.

[0227] In some embodiments, the method further comprises assessing the crystallization of a drug that is susceptible to crystallization, such as a hydrophobic drug.

[0228] In some embodiments, the substrate is a thin film, such as a pharmaceutical thin film substrate described herein.

[0229] In certain aspects, a gradient is provided on a substrate, the gradient comprising a first location, a second location, and a third location, each comprising a mixture of a quantity of a first deposit and a quantity of a second deposit, the first deposit comprising an agent that is prone to crystallization, such as a hydrophobic agent, the ratio of the amount of the first deposit to the amount of the second deposit at the first location being less than the ratio of the amount of the first deposit to the amount of the second deposit at the second location, the ratio of the amount of the first deposit to the amount of the second deposit at the second location being less than the ratio of the amount of the first deposit to the amount of the second deposit at the third location, and the interaction between the first deposit and the second deposit in the mixture at the first location, the second location, and the third location produces a measurable effect of the agent of the first deposit. In some embodiments, the difference between the ratio of the amount of the first deposit to the amount of the second deposit at each of the first location, the second location, and the third location is the same.

[0230] In some embodiments, the first deposit comprises a hydrophobic deposit and the second deposit comprises a polymer. In some embodiments, the first deposit further comprises a first organic carrier and a first viscosity enhancer, and the second deposit further comprises a second organic carrier and a second viscosity enhancer. In some embodiments, the first organic carrier and the second organic carrier are the same. In some embodiments, the first viscosity enhancer and the second viscosity enhancer are the same. In some embodiments, the amount of the first deposit and the amount of the second deposit are concentrations. In some embodiments, the measurable effect of the hydrophobic agent is crystallinity. In some embodiments, the first deposit is dispensed from a first droplet dispenser, such as a sub-nanoliter droplet dispenser, and the second deposit is dispensed from a second droplet dispenser, such as a sub-nanoliter droplet dispenser.

[0231] X. Methods of Making Dosage Forms Containing ASD In some aspects, provided herein is a method of making a dosage form comprising an amorphous solid dispersion (ASD) comprising a drug prone to crystallization, e.g., a hydrophobic drug, comprising depositing droplets of an ASD-forming solution comprising a drug, an organic carrier, and a polymer onto a substrate using a droplet dispenser, the ratio of polymer to drug inhibiting crystallization of the drug in the dry state on the substrate. In some embodiments, depositing the droplets of the ASD-forming solution onto the substrate comprises dispensing the ASD-forming solution from a droplet dispenser. In some embodiments, depositing the droplets of the ASD-forming solution onto the substrate is performed by dispensing the ASD-forming solution and / or its precursor solution from more than one droplet dispenser, the ASD-forming solution being formed on the substrate and / or during transfer from the droplet dispenser(s) to the substrate. In some embodiments, the ASD-forming solution precursor comprises a subset of the components of the ASD-forming solution. In some embodiments, the ASD-forming solution precursor comprises the components of the ASD-forming solution at a different concentration than in the resulting ASD-forming solution. In some embodiments, different ASD-forming solutions and / or precursor solutions thereof may be dispensed from different droplet dispensers.

[0232] In the methods provided herein, the droplet dispenser ejects droplets that travel to the substrate. Many configurations of the methods are provided herein, for example, based on the configuration of one or more droplet dispensers and the ASD-forming solution. In some embodiments, the ASD-forming solution is formed during transfer from the droplet dispenser to the substrate. In some embodiments, the ASD-forming solution is formed when deposited on the substrate by the droplet dispenser. In some embodiments, the ASD-forming solution is formed during transfer from the droplet dispenser to the substrate and when deposited on the substrate by the droplet dispenser. In some embodiments, the ASD is formed during transfer from the droplet dispenser to the substrate. In some embodiments, the ASD is formed when deposited on the substrate by the droplet dispenser. In some embodiments, the ASD is formed during transfer from the droplet dispenser to the substrate and when deposited on the substrate by the droplet dispenser.

[0233] In some embodiments, the method includes depositing an ASD-forming solution onto a substrate, the ASD-forming solution being identified using the methods described herein. The methods provided herein may utilize any of the components described herein, such as the ASD-forming solution and / or its precursor solution, a droplet dispenser, and a substrate. The modular description is not intended to limit the scope of the teachings provided herein, and one of ordinary skill in the art will readily appreciate that the method encompasses the embodiments described herein and any combination thereof.

[0234] In some embodiments, the method includes depositing droplets of an ASD-forming solution, including a drug prone to crystallization, such as a hydrophobic drug, an organic carrier, and a polymer, onto a substrate using a droplet dispenser, where the ratio of the polymer to the drug prone to crystallization inhibits crystallization of the drug in a dry state on the substrate. In some embodiments, depositing the droplets of the ASD-forming solution includes dispensing the ASD-forming solution from a droplet dispenser. In some embodiments, depositing the droplets of the ASD-forming solution includes dispensing a precursor solution from a droplet dispenser. In some embodiments, the ASD-forming solution, or a precursor solution thereof, has a viscosity of about 0.5 cp to about 5 cP, including less than about 1 cp to 2 cp, or about 1.2 cP to about 1.8 cP. In some embodiments, the droplet dispenser is a sub-nanoliter droplet dispenser. In some embodiments, the droplet dispenser is a high frequency sub-nanoliter droplet dispenser. In some embodiments, the ASD-forming solution, or a precursor solution thereof, is dispensed from a dispensing cartridge. In some embodiments, the method includes delivering an ASD-forming solution, or a precursor solution thereof, to a droplet dispenser or a component thereof, such as a dispensing head thereof.

[0235] In some embodiments, the droplet dispenser dispenses droplets toward the substrate to deposit the droplets thereon. Generally speaking, droplets dispensed from the droplet dispenser may undergo changes in morphology during the deposition process, such as (a) one droplet may merge with another droplet after being dispensed from the droplet dispenser (whether in air or on the substrate), (b) the deposited droplet may dry on the substrate, and (c) solvent may be lost during transfer from the droplet dispenser to the substrate. Descriptions of droplets are provided herein and may be applicable to various conditions that occur during the deposition process. Such descriptions are not limited to only a particular condition unless otherwise stated. In some embodiments, depositing includes dispensing a number of droplets of the ASD-forming solution per square inch (also referred to herein as dots / inch). In some embodiments, the resulting pattern or patterned layer produced by the methods described herein includes, at least to some extent, merging of one or more dispensed droplets of the ASD-forming solution. Such a pattern of droplets need not be regular, and in some embodiments reflects the number of droplets applied to a set area of ​​the substrate. In some embodiments, the deposited droplets (whether merged before or on the substrate) resemble a pattern on a macroscale, such as a printed feature. In some embodiments, the dosage form includes one or more layers of droplets deposited on the substrate, such as formed from one or more passes of a droplet dispenser over an area of ​​the dosage form. In some embodiments, the patterned layer is a continuous layer of ADS-forming solution prior to drying, e.g., the deposited droplets are, at least to some extent, interconnected. In some embodiments, the droplets of ADS-forming solution are deposited at about 1 dots per inch (dpi) to about 1,000 dpi, e.g., at any of about 1 dpi to about 720 dpi, about 72 dpi to about 720 dpi, about 72 dpi to about 500 dpi, or about 72 dpi to about 300 dpi.In some embodiments, droplets of ASD forming solution are deposited at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more. In some embodiments, droplets of the ASD-forming solution are deposited at about 1 dots per inch (dpi) to about 1,000 dpi, such as from about 1 dpi to about 720 dpi, from about 72 dpi to about 720 dpi, from about 72 dpi to about 500 dpi, or from about 72 dpi to about 300 dpi. In some embodiments, droplets of ASD forming solution are deposited at about 1 dpi or more, e.g., any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more.

[0236] In some embodiments, the dispensed or deposited droplets of the ASD-forming solution or its precursor solution have a diameter of about 1 nm to about 200 μm, such as about 20 nm to about 800 nm, about 100 nm to about 500 nm, or about 10 μm to about 100 μm. In some embodiments, the dispensed or deposited droplets of the ASD forming solution or its precursor solution have a diameter of at least about 1 nm, e.g., at least about 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm, 550 nm, 560 nm, 570 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm, 770 nm, 780 nm, 790 nm, 800 nm, m, 390 nm, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 525 nm, 550 nm, 575 nm, 600 nm, 625 nm, 650 nm, 675 nm, 700 nm, 725 nm, 750 nm, 775 nm, 800 nm, 825 nm, 850 nm, 875 nm, 900 nm, 925 nm, 950 nm, 975 nm, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm in diameter. In some embodiments, the average of a population of dispensed or deposited droplets of a dosage form described herein meets the above criteria.

[0237] In some embodiments, the dispensed or deposited droplets of the ASD-forming solution or its precursor solution comprise an average volume of about 1 picoliter (pL) to about 1 nL, e.g., about 1 pL to about 500 pL or about 1 pL to about 50 pL. In some embodiments, the dispensed or deposited droplets of the ASD-forming solution or its precursor solution comprise an average volume of about 1 nL or less, e.g., about 950 pL or less, 900 pL or less, 850 pL or less, 800 pL or less, 750 pL or less, 700 pL or less, 650 pL or less, 600 pL or less, 550 pL or less, 500 pL or less, 450 pL or less, 400 pL or less, 350 pL or less, 300 pL or less, 250 pL or less, 200 pL or less, 150 pL or less, 100 pL or less, 75 pL or less, 50 pL or less, or 25 pL or less.

[0238] As described in more detail in other sections herein, in some embodiments, the droplet dispenser dispenses the ASD forming solution or a precursor solution thereof using a thermal process. In some embodiments, the droplet dispenser dispenses the ASD forming solution or a precursor solution thereof using a piezoelectric process. In some embodiments, the droplet dispenser is a sub-nanoliter droplet dispenser. In some embodiments, as described in more detail in other sections herein, the sub-nanoliter droplet dispenser is a high frequency sub-nanoliter droplet dispenser. In some embodiments, the droplet dispenser comprises about 100 to about 1000 individual nozzles. In some embodiments, each nozzle comprises an opening having a diameter of about 20 μm to about 120 μm. In some embodiments, the high frequency sub-nanoliter droplet dispenser dispenses droplets at greater than 3 kHz measured per nozzle.

[0239] In some embodiments, the method further comprises coupling a cartridge containing the ASD-forming solution or its precursor solution to a droplet dispenser (such as a high frequency droplet dispenser or a high frequency sub-nanoliter droplet dispenser). In some embodiments, the method further comprises selecting a cartridge containing the ASD-forming solution or its precursor solution to generate a desired dosage form based on, for example, a desired property of the final dosage form or one or more patterned layers thereon, such as the amount of hydrophobic drug deposited on the dosage form, the amount of polymer deposited on the dosage form, the properties of the patterned layer (e.g., any of dpi, shape, size, and location on the dosage form), the release profile of the hydrophobic drug, and one or more characteristics of the final dosage form (e.g., structural integrity and / or protection of the patterned layer). In certain embodiments, the method comprises dispensing or depositing at least one ASD-forming solution and optionally another material (e.g., a food-safe material for forming a label), the method encompassing the selection of each dispensed component. In some embodiments, the method comprises selecting an ASD-forming solution or its precursor solution from a library (e.g., compiled in a kit). In some embodiments, the method further comprises producing an ASD-forming solution and / or a precursor solution thereof.

[0240] In some embodiments, the method includes designing a pattern, characterized, for example, by dpi, of droplets of an ASD-forming solution that includes a drug that is prone to crystallization, such as a hydrophobic drug. In some embodiments, the method includes determining (e.g., calculating) one or more settings based on any one or more of the total amount of drug in the dosage form, such as a hydrophobic drug; the concentration of the drug in the ASD-forming solution or its precursor solution; the desired surface area of ​​exposure of the resulting ASD or its dried form of the dosage form; the desired release profile of the drug; the amount of polymer relative to the drug; and the characteristics of the droplet dispenser (or its use), such as aperture diameter, ejection frequency, and droplet size to be generated.

[0241] In some embodiments, the method includes creating and / or receiving instructions for controlling a droplet dispenser, such as to form a dosage form described herein. In some embodiments, the instructions are personalized for an individual.

[0242] In some embodiments, the method further comprises performing a drying period after depositing the ASD-forming solution on the substrate, e.g., to allow the ASD-forming solution to at least partially dry and / or form an ASD. In some embodiments, the method further comprises one or more processing steps after depositing the ASD-forming solution on the substrate, such as cutting the substrate into individual dosage forms and / or filling one or more dosage forms.

[0243] In some embodiments, the method further includes washing one or more dispensing heads of the droplet dispenser, e.g., by dispensing a non-drug-containing solvent. For example, such a washing step helps to ensure that the ASD-forming solution or its precursor solution does not clog the nozzles of the dispensing heads and / or to reduce carryover of components dispensed therefrom.

[0244] XI. ASD DISPENSING CARTRIDGES AND COMPOSITIONS THEREIN In certain aspects, provided herein are dispensing cartridges that contain (or are suitable for use with) the ASD-forming solutions and / or precursor solutions thereof described herein, or derivatives or precursors thereof. The dispensing cartridges described herein are generally suitable for holding one or more ASD-forming solutions and / or precursor solutions thereof described herein, such as in a reservoir of the dispensing cartridge, and are configured to interface with a dispensing head of a droplet dispenser such that the contents of the dispensing cartridge can be delivered to the dispensing head. In some embodiments, the dispensing cartridge is a disposable cartridge. In some embodiments, the dispensing cartridge is suitable for one-time or limited time use.

[0245] In some embodiments, the dispensing cartridge comprises a material suitable for use with the ASD-forming solutions and / or precursor solutions thereof described herein, in some embodiments, the dispensing cartridge comprises a material suitable for use in pharmaceutical applications, e.g., the material does not dissolve or leach its components in the presence of the ASD-forming solutions and / or precursor solutions thereof.

[0246] In some embodiments, the dispensing cartridge includes one reservoir configured to hold the ASD-forming solution and / or precursor solution thereof described herein. In some embodiments, the dispensing cartridge includes more than one reservoir configured to hold the ASD-forming solution(s) and / or precursor solution(s) thereof described herein. In some embodiments, a dispensing cartridge is provided that includes a material useful for the embodiments described herein, where the material is not the ASD-forming solution and / or precursor solution(s) thereof described herein. For example, in some embodiments, the dispensing cartridge includes a fluid suitable for deposition on a substrate, such as to communicate a characteristic or identity (including a unique identity) of the dosage form via a logo and / or label. In some embodiments, the label is a machine-readable label, such as a QR code or a bar code. Also disclosed herein are kits that include one or more dispensing cartridges described herein.

[0247] In some embodiments, the dispense cartridge includes a reservoir for containing a volume of the ASD-forming solution and / or precursor solution thereof, e.g., as described herein. In some embodiments, the dispense cartridge includes a reservoir port, such as to facilitate flow of material(s) into or out of the reservoir. In some embodiments, the dispense cartridge includes a sponge material. In some embodiments, the sponge material is within the reservoir. In some embodiments, the dispense cartridge includes a dispense head interface configured to enable passage of the ASD-forming solution and / or precursor solution thereof from the reservoir to a dispense head of the droplet dispenser.

[0248] In some embodiments, compositions are provided herein that include a form of ASD-forming solution and / or its precursor solution, including derivatives or precursors thereof. In some embodiments, the form of the ASD-forming solution and / or its precursor solution is in a frozen, dried, or lyophilized form. In some embodiments, the form of the ASD-forming solution and / or its precursor solution can be processed to generate the desired ASD-forming solution and / or its precursor solution described herein, for example, by reconstitution. In some embodiments, the composition is contained within a dispensing cartridge.

[0249] XII. ASD Dosage Form In certain aspects, provided herein is a dosage form comprising an ASD that comprises a drug that is prone to crystallization, such as a hydrophobic drug, deposited on a substrate. In some embodiments, provided herein is a dosage form that is manufactured according to the methods provided herein. In some embodiments, the dosage form has different mechanical properties compared to dosage forms manufactured by conventional means, such as solvent casting.

[0250] In some embodiments, the drug prone to crystallization is present in the dosage form at less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the drug in crystalline form. In some embodiments, the drug prone to crystallization is present in the dosage form at less than 5% of the drug in crystalline form. In some embodiments, the crystalline form of the drug prone to crystallization is substantially absent from the dosage form.

[0251] In some embodiments, the dosage form is an oral dosage form (including oral drug dosage forms such as capsules comprising a thin film substrate, e.g., rolled and / or folded thin film substrate). In some embodiments, the dosage form is an intrabuccal dosage form. In some embodiments, the dosage form is a buccal dosage form. In some embodiments, the dosage form is a sublingual dosage form. In some embodiments, the dosage form is a vaginal dosage form. In some embodiments, the dosage form is a rectal dosage form. In some embodiments, the dosage form is an ophthalmic dosage form. In some embodiments, the dosage form comprises components derived from deposition of the described ASD-forming solution using the methods provided herein. In some embodiments, the thin film substrate is suitable for human consumption. In some embodiments, the dosage form is suitable for contact-based delivery of hydrophobic drugs, e.g., transdermal dosage forms. In some embodiments, the dosage form is an ophthalmic dosage form. In some embodiments, the thin film substrate comprises a polymer (e.g., the thin film substrate is a polymeric film). In some embodiments, the thin film substrate comprises one or more of chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil, and polyacrylic acid derivatives.

[0252] The dosage forms described herein may have a patterned layer of any shape and / or size. In some embodiments, the characteristics of the patterned layer are based on the amount of crystallization-prone drug, e.g., hydrophobic drug, in the dosage form. For example, such characteristics of the patterned layer may be based on the concentration of the hydrophobic drug in the ASD-forming solution and the desired total amount of hydrophobic drug to be deposited on a substrate, such as a thin film substrate. In some embodiments, the characteristics of the patterned layer (e.g., any of the shape, size, and location on the dosage form) are based on the desired release profile of the crystallization-prone drug, e.g., hydrophobic drug (e.g., the patterned layer may be designed to increase the surface area to bodily fluids) and / or the characteristics of the final dosage form (e.g., the structural integrity and / or protection of the patterned layer). In some embodiments, the term layer should not be construed to mean only a single deposition from a droplet dispenser described herein. In some embodiments, the patterned layer is formed from many instances of droplet deposition from a droplet dispenser described herein (e.g., repeated printing of areas using the ASD-forming solution and / or precursor solutions thereof described herein). For example, in producing a dosage form including a patterned layer, a droplet dispenser may be controlled to deposit droplets of the ASD-forming solution and / or its precursor solution in one or more passes to form the final patterned layer.

[0253] In some embodiments, the dosage form comprises an ASD-forming solution deposited on a substrate at about 1 dots per inch (dpi) to about 1,000 dpi, e.g., about 1 dpi to about 720 dpi, about 72 dpi to about 720 dpi, about 72 dpi to about 500 dpi, or about 72 dpi to about 300 dpi. In some embodiments, the dosage form comprises an ASD-forming solution deposited on a substrate at about 1 dpi or more, e.g., at any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more. In some embodiments, the dosage form comprises an ASD-forming solution deposited on a substrate at about 1 dots per inch (dpi) to about 1,000 dpi, e.g., about 1 dpi to about 720 dpi, about 72 dpi to about 720 dpi, about 72 dpi to about 500 dpi, or about 72 dpi to about 300 dpi. In some embodiments, the dosage form comprises an ASD-forming solution deposited on a substrate at about 1 dpi or more, e.g., at any of about 20 dpi or more, 50 dpi or more, 72 dpi or more, 100 dpi or more, 120 dpi or more, 150 dpi or more, 200 dpi or more, 250 dpi or more, 300 dpi or more, 350 dpi or more, 400 dpi or more, 450 dpi or more, 500 dpi or more, 550 dpi or more, 600 dpi or more, 650 dpi or more, 700 dpi or more, 720 dpi or more, 750 dpi or more, 800 dpi or more, 850 dpi or more, 900 dpi or more, 950 dpi or more, or 1,000 dpi or more.

[0254] In some embodiments, the deposited droplets of the ASD-forming solution have a diameter (or largest cross dimension) of from about 1 nm to about 200 μm, e.g., from about 20 nm to about 800 nm, from about 100 nm to about 500 nm, or from about 10 μm to about 100 μm. In some embodiments, the deposited droplets of the ASD forming solution have a diameter of at least about 1 nm, e.g., at least about 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm, 400 nm , 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm, 490 nm, 500 nm, 525 nm, 550 nm, 575 nm, 600 nm, 625 nm, 650 nm, 675 nm, 700 nm, 725 nm, 750 nm, 775 nm, 800 nm, 825 nm, 850 nm, 875 nm, 900 nm, 925 nm, 950 nm, 975 nm, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, or 100 μm. In some embodiments, the average of a population of droplets (such as a patterned layer(s)) described herein meets the above criteria.

[0255] In some embodiments, the patterned layer is at least partially within a substrate, such as a thin film substrate (e.g., at least a portion of the ASDs described herein are permeated and / or absorbed into the thin film substrate). In some embodiments, the patterned layer is at least partially on top of a substrate, such as a thin film substrate (e.g., at least a portion of the ASDs described herein are on or above the surface of the thin film substrate). In some embodiments, the patterned layer is at least partially within and at least partially on top of a substrate, such as a thin film substrate.

[0256] In some embodiments, the dosage form comprises more than one patterned layer, for example a first patterned layer and a second patterned layer. In some embodiments, the first patterned layer comprises an ASD comprising a drug prone to crystallization, for example a hydrophobic drug, and the second patterned layer comprises another drug. In some embodiments, the first patterned layer comprises an ASD comprising a drug prone to crystallization, for example a hydrophobic drug, and the second patterned layer comprises an ASD comprising a drug. In some embodiments, the first patterned layer comprises an ASD comprising a drug prone to crystallization, for example a hydrophobic drug, and the second patterned layer comprises an ASD comprising a second drug prone to crystallization, for example a second hydrophobic drug. In some embodiments, each patterned layer is produced by a layer-by-layer deposition technique.

[0257] In some embodiments, the dosage form comprises an amount of a drug prone to crystallization, e.g., a hydrophobic drug, from about 1 ng to about 1 mg, e.g., from about 100 ng to about 500 ng, from about 250 ng to about 750 ng, from about 500 ng to about 1 μg, from about 750 ng to about 1.25 μg, from about 1 μg to about 2 μg, from about 1 μg to about 10 μg, from about 10 μg to about 50 μg, or from about 25 μg to about 100 μg.

[0258] In some embodiments, the dosage form comprises at least about 1 ng, e.g., at least about 5 ng, 10 ng, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, 100 ng, 125 ng, 150 ng, 175 ng, 200 ng, 225 ng, 250 ng, 275 ng, 300 ng, 325 ng, 350 ng, 375 ng, 400 ng, 425 ng, 450 ng, 475 ng, 500 ng, 525 ng, 550 ng, 575 ng, 600 ng, 625 ng, 650 ng, 675 ng, 700 ng, g, 725 ng, 750 ng, 775 ng, 800 ng, 825 ng, 850 ng, 875 ng, 900 ng, 925 ng, 950 ng, 975 ng, 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, or 100 μg of a crystallizable drug, e.g., a hydrophobic drug.

[0259] In some embodiments, the dosage form further comprises a marking and / or label. For example, in certain embodiments, the dosage form may contain printed information regarding any one or more of the active agent, the amount of active agent(s), the date of manufacture, the individual for which the dosage form is manufactured, the time of manufacture, a traceable identification code, an expiration date, instructions for use, storage instructions, or a company name and / or logo. In some embodiments, the marking and / or label is suitable for consumption, for example, includes a food-safe dye.

[0260] In some embodiments, the dosage form includes a protective coating, for example, applied over the deposited ASD or a portion thereof. In some embodiments, the protective coating is applied to the dosage form via a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser. In some embodiments, the dosage form includes a film coating.

[0261] In some embodiments, the dosage form is suitable for human use and / or consumption, hi some embodiments, the dosage form is sterile.

[0262] In certain aspects, a batch of dosage forms described herein is provided.In some embodiments, the batch of dosage forms comprises at least 5 dosage forms, for example, any of 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 dosage forms.In some embodiments, the batch of drug dosage forms described comprises individual dosage forms having an amount of drug prone to crystallization, e.g., hydrophobic drug, that does not vary more than 5% from the average.

[0263] XIII. Device for dispensing and depositing ASD In certain aspects, provided herein are devices for dispensing and depositing droplets, such as droplets of the ASD-forming solutions and / or precursor solutions described herein. In some embodiments, the devices include a sub-nanoliter droplet dispenser. In some embodiments, the devices include a high frequency sub-nanoliter droplet dispenser. Sub-nanoliter droplet dispensers, including sub-nanoliter high frequency droplet dispensers, are known in the art, including those described in U.S. Pat. Nos. 7,585,038, 7,963,635, and 6,851,786, the entireties of which are incorporated herein by reference.

[0264] In some embodiments, a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser, for manufacturing a dosage form is provided, the dispenser comprising: (a) a dispensing head operably connected to a reservoir for an ASD-forming solution or its precursor solution, and (b) a control system configured to control deposition of the ASD-forming solution or its precursor solution through the dispensing head. In some embodiments, a droplet dispenser, such as a sub-nanoliter droplet dispenser or a high frequency sub-nanoliter droplet dispenser, for manufacturing a dosage form is provided, the dispenser comprising: (a) a dispensing head, (b) an ASD-forming solution or its precursor solution dispensing cartridge receiving space configured to operably couple a dispensing cartridge to the dispensing head, and (c) a control system configured to control deposition of the ASD-forming solution or its precursor solution through the dispensing head according to a dispensing configuration, such as a dpi profile. In some embodiments, the viscosity of the ASD-forming solution or its precursor solution is about 0.5 cp to about 5 cp, such as about 1 cp to about 2 cp or about 1.8 cP and about 1.2 cP.

[0265] In some embodiments, the dispensing head comprises between about 10 and about 1000 individual nozzles. In some embodiments, the dispensing head includes at least about 10, e.g., at least about any of 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 individual nozzles.

[0266] In some embodiments, each nozzle of the dispensing head has an opening (through which the nanosuspension is dispensed) having a maximum cross-section (e.g., diameter) of about 20 μm to about 120 μm, e.g., about 20 μm to about 70 μm or about 30 μm to about 60 μm. In some embodiments, the nozzles of the dispensing head have an opening having a maximum cross-section (e.g., diameter) of at least about 20 μm, e.g., at least about any of 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 75 μm, 100 μm, or 120 μm.

[0267] In some embodiments, each nozzle of the dispensing head is configured to dispense droplets of the ASD-forming solution or its precursor solution having a volume of about 1 to about 500 picoliters (pL). In some embodiments, the nozzles of the dispensing head are configured to dispense droplets of the ASD-forming solution or its precursor solution having a volume of about 500 pL or less, e.g., about 450 pL or less, 400 pL or less, 350 pL or less, 300 pL or less, 250 pL or less, 200 pL or less, 150 pL or less, 100 pL or less, 75 pL or less, 50 pL or less, or 25 pL or less.

[0268] In some embodiments, the dispensing head is a continuous dispensing head. In some embodiments, the dispensing head is a drop-on-demand printhead. In some embodiments, the droplet dispenser dispenses droplets using a thermal process. In some embodiments, the droplet dispenser dispenses droplets using a piezoelectric process. In some embodiments, the dispensing head is a thermal inkjet printhead. In some embodiments, the dispensing head is a piezoelectric inkjet printhead. In some embodiments, the dispensing head is a solenoid valve printhead. In some embodiments, the dispensing head is an electrostatic printhead. In some embodiments, the dispensing head is an acoustic printhead.

[0269] In some embodiments, the dispensing head is a sub-nanoliter dispensing head. In some embodiments, the dispensing head is a high frequency sub-nanoliter dispensing head (e.g., a dispensing head operating at a dispensing frequency of greater than 2,000 Hz, such as greater than about 2.5 kHz, 3 kHz, 3.5 kHz, 4 kHz, 4.5 kHz, or 5 kHz).

[0270] In some embodiments, the dispensing device comprises more than one dispensing head. In some embodiments, the dispensing device further comprises a second dispensing head operably coupled to a second dispensing cartridge. In some embodiments, the dispensing device further comprises a third dispensing head operably coupled to a third dispensing cartridge. In some embodiments, the dispensing device further comprises a fourth dispensing head operably coupled to a fourth dispensing cartridge. In configurations with more than one dispensing head, the dispensing device is configured to be operably coupled to a dispensing cartridge that includes any of a variety of materials, such as nanosuspensions, protective coatings, and label and / or marking materials (such as edible inks).

[0271] XIV. Systems and Uses Including ASD Embodiments Described Herein In certain aspects, systems and applications utilizing methods of making the dosage forms described herein and associated features are provided herein. In some embodiments, systems are provided that include a dispensing device configured to receive instructions for printing the dosage forms described herein. In some embodiments, the system is established at the point of care, such as a hospital, a nursing home, a pharmacy, or a home. In some embodiments, the dosage form is an individualized dosage form designed for an individual based on the characteristics of the dosage form, such as, for example, the amount of hydrophobic drug.

[0272] In some embodiments, the methods and dispensing devices described herein are suitable for personalized medicine. In some embodiments, the methods and dispensing devices described herein are suitable for point-of-care applications. In some embodiments, the methods and dispensing devices described herein are suitable for rapid dosage form production (including on a small scale, such as less than 100 dosage forms). In some embodiments, the methods and dispensing devices described herein are suitable for producing dosage forms having an accurate and precise amount of a drug prone to crystallization, such as a hydrophobic drug (e.g., required for drugs with a narrow therapeutic index, high potency, and / or pediatric use), in the form of an ASD. In some embodiments, the methods and dispensing devices described herein are suitable for producing dosage forms having a drug prone to crystallization, such as a hydrophobic drug, that is less stable in the form of an ASD (e.g., not stable for an extended period of time after production, such as more than 24 hours). In some embodiments, the methods and dispensing devices described herein are suitable for non-pharmaceutical applications, such as dietary supplements.

[0273] XV. EMBODIMENTS HAVING AND / OR DETERMINED FROM A COMBINATION OF A NANOSUSPENSION AND ASD In certain aspects, embodiments are provided herein that have and / or are derived from the nanosuspension formulations described herein and the amorphous solid dispersion (ASD) formulations described herein.For example, in some embodiments, methods of making a dosage form are provided herein, the methods comprising depositing a plurality of droplets of the nanosuspension formulations described herein onto a substrate using a high frequency droplet dispenser, and depositing a plurality of droplets of the ASD formulations described herein onto a substrate using a high frequency droplet dispenser, thereby making a dosage form.In some embodiments, the devices, systems, and / or dispensing cartridges disclosed herein may comprise the nanosuspension formulations described herein, and the ASD formulations described herein.For example, in some embodiments, the devices and / or systems comprise a first dispensing cartridge comprising the nanosuspension formulations described herein, and a second dispensing cartridge comprising the ASD formulations described herein.

[0274] It should be understood that in all embodiments involving an amorphous solid dispersion (ASD), embodiments are also envisioned in which the ASD is a nanoparticle-forming ASD. Such nanoparticle-forming ASDs can, in some embodiments, be further defined by the teachings provided herein on nanosuspensions and products produced therefrom, such as particle size. In some embodiments, the nanosuspension is an ASD formulation (as described herein). In one embodiment, the ASD formulation is a nanoparticle-forming ASD (as described herein).

[0275] The present invention is not intended to be limited in scope to the specific disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods described will become apparent from the descriptions and teachings herein. Such variations can be made without departing from the true scope and spirit of the present disclosure, and are intended to fall within the scope of the present disclosure. Enumerated embodiments Embodiment 1. A method of making a dosage form containing a hydrophobic drug, comprising: forming a dosage form by depositing a plurality of droplets of a nanosuspension onto a substrate using a radio frequency droplet dispenser, the nanosuspension comprising: An aqueous carrier; a plurality of nanoparticles suspended in the aqueous carrier, the nanoparticles comprising a hydrophobic drug; The method, wherein the viscosity of the nanosuspension is less than 3 cP. Embodiment 2. The method of embodiment 1, wherein the radio frequency droplet dispenser deposits the plurality of droplets using a thermal process. Embodiment 3. The method of embodiment 1, wherein the high frequency droplet dispenser deposits multiple droplets using a piezoelectric process. Embodiment 4. The method of any one of embodiments 1 to 3, wherein the high frequency droplet dispenser comprises about 100 to about 1000 individual nozzles. Embodiment 5. The method of embodiment 4, wherein each nozzle comprises an opening having a diameter of about 20 μm to about 120 μm. Embodiment 6. The method of any one of embodiments 1 to 5, wherein the high frequency droplet dispenser is a high frequency sub-nanoliter droplet dispenser. Embodiment 7. The method of any one of embodiments 1-6, wherein the radio frequency droplet dispenser dispenses droplets in a volume of 1 nanoliter or less. Embodiment 8. The method of embodiment 7, wherein the average volume of each dispensed droplet of the plurality of droplets of the nanosuspension is from about 1 picoliter to about 50 picoliters. Embodiment 9. The method of embodiment 7 or 8, wherein a plurality of nanosuspension droplets are deposited on the substrate according to an average number of droplets per square inch. Embodiment 10. The method of embodiment 9, wherein the average number of droplets deposited per square inch of substrate is from about 1 droplet to about 500 droplets per square inch. Embodiment 11. The method of embodiment 9 or 10, wherein the plurality of droplets of the nanosuspension deposited on the substrate have an average diameter of about 5 μm to about 100 μm. Embodiment 12. The method of any one of embodiments 1 to 11, wherein the multiple droplets of the nanosuspension deposited on the substrate form a continuous layer. Embodiment 13. The method of any one of embodiments 1 to 12, wherein the viscosity of the nanosuspension is less than 2 cP and greater than 1 cP. Embodiment 14. The method of any one of embodiments 1 to 13, wherein the viscosity of the nanosuspension is between 1.2 cP and 1.8 cP. Embodiment 15. The method of any one of embodiments 1 to 14, wherein the nanosuspension further comprises a viscosity modifier. Embodiment 16. The method of embodiment 15, wherein the viscosity modifier is a viscosity enhancer. Embodiment 17. The method of embodiment 16, wherein the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol and propylene glycerol. Embodiment 18. The method of embodiment 16 or 17, wherein the viscosity enhancing agent is present in the nanosuspension at a concentration of about 1% to about 40% v / v of the nanosuspension. Embodiment 19. The method of any one of embodiments 16 to 18, wherein the ratio of viscosity enhancing agent to aqueous carrier of the nanosuspension is from about 1:1000 to about 1:2 by volume. Embodiment 20. The method of any one of embodiments 16 to 19, further comprising adding a viscosity enhancing agent to the nanosuspension to achieve a viscosity of the nanosuspension of about 1 cP to about 2 cP. Embodiment 21. The method of any one of embodiments 1 to 20, wherein the aqueous carrier comprises water and an organic solvent. Embodiment 22. The method of any one of embodiments 1 to 21, wherein the nanosuspension is a colloidal suspension. Embodiment 23. The method of any one of embodiments 1 to 22, wherein the nanosuspension further comprises a stabilizing component. Embodiment 24. The method of embodiment 23, wherein the ratio of stabilizing component to aqueous carrier of the nanosuspension is from about 1:500 to about 1:10 by weight. Embodiment 25 The method of embodiment 23, wherein the stabilizing component comprises PVP and / or SDS. Embodiment 26. The method of any one of embodiments 1 to 25, wherein the average diameter of the nanoparticles is less than about 500 nm. Embodiment 27. The method of any one of embodiments 1 to 26, wherein the plurality of nanoparticles has a D50 of about 100 nm to about 400 nm. Embodiment 28. The method of any one of embodiments 1 to 27, wherein the plurality of nanoparticles has a D90 of about 250 μm to about 50 nm. Embodiment 29. The method of any one of embodiments 1 to 28, wherein the hydrophobic drug is not soluble in the aqueous carrier. Embodiment 30. The method of embodiment 29, wherein the hydrophobic drug has a solubility in water of less than 1 mg / mL. Embodiment 31 The method of embodiment 29, wherein the hydrophobic agent is a therapeutic agent. Embodiment 32 The method of embodiment 31, wherein the therapeutic agent is a small molecule drug. Embodiment 33 The method of embodiment 31, wherein the therapeutic agent is a biomolecule. Embodiment 34. The method of embodiment 31, wherein the therapeutic agent is a Biopharmaceutic Classification System (BCS) Class II or Class IV drug. Embodiment 35. The method of any one of embodiments 32-34, wherein the therapeutic agent has a narrow therapeutic index. Embodiment 36. The method of any one of embodiments 32-35, wherein the therapeutic agent is a high-potency drug. Embodiment 37 The method of embodiment 29 or 30, wherein the hydrophobic agent is an additive or adjuvant. Embodiment 38. The method of any one of embodiments 1 to 37, wherein the concentration of the hydrophobic drug in the nanosuspension is from about 5 mg / mL to about 1,000 mg / mL. Embodiment 39. The method of any one of embodiments 1 to 38, wherein the amount of the hydrophobic drug is less than 0.1 mg. Embodiment 40. The method of any one of embodiments 1 to 39, wherein the substrate is a pharma- ceutically acceptable polymer. Embodiment 41. The method of any one of embodiments 1 to 40, wherein the substrate is selected from the group consisting of one or more of chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil, and polyacrylic acid derivatives. Embodiment 42 The method of any one of embodiments 1 to 41, wherein the pharma- ceutically acceptable substrate is a thin film substrate. Embodiment 43 The method of any one of embodiments 1 to 42, wherein at least a portion of the plurality of nanoparticles is within a substrate. Embodiment 44 The method of any one of embodiments 1 to 43, wherein at least a portion of the plurality of nanoparticles is on top of a substrate. Embodiment 45. The method of any one of embodiments 1 to 44, wherein the dosage form is an oral dosage form. Embodiment 46. The method of any one of embodiments 1 to 44, wherein the dosage form is a buccal dosage form. Embodiment 47. The method of any one of embodiments 1 to 44, wherein the dosage form is a transdermal dosage form. Embodiment 48. The method of any one of embodiments 1 to 47, wherein the dosage form is sterile. Embodiment 49. A nanosuspension comprising: An aqueous carrier; and a plurality of nanoparticles comprising a hydrophobic drug suspended in an aqueous carrier, wherein the viscosity of the nanosuspension is less than 3 cP. Embodiment 50. A nanosuspension according to embodiment 49, wherein the viscosity of the nanosuspension is less than 2 cP and greater than 1 cP. Embodiment 51. A nanosuspension according to embodiment 49 or 50, wherein the viscosity of the nanosuspension is between 1.2 cP and 1.8 cP. Embodiment 52. A nanosuspension according to any one of embodiments 49 to 51, wherein the nanosuspension further comprises a viscosity modifier. Embodiment 53. A nanosuspension according to embodiment 52, wherein the viscosity modifier is a viscosity enhancer. Embodiment 54. A nanosuspension according to embodiment 53, wherein the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol and propylene glycerol. Embodiment 55. The nanosuspension of embodiment 52 or 53, wherein the viscosity enhancing agent is present in the nanosuspension at a concentration of about 1% to about 40% v / v of the nanosuspension. Embodiment 56. A nanosuspension described in any one of embodiments 53 to 55, wherein the ratio of viscosity enhancing agent to aqueous carrier of the nanosuspension is from about 1:1000 to about 1:2 by volume. Embodiment 57. The nanosuspension of any one of embodiments 53 to 56, further comprising adding a viscosity enhancing agent to the nanosuspension to achieve a viscosity of the nanosuspension of about 1 cP to about 2 cP. Embodiment 58. A nanosuspension according to any one of embodiments 49 to 57, wherein the aqueous carrier comprises water and an organic solvent. Embodiment 59. A nanosuspension according to any one of embodiments 49 to 58, wherein the nanosuspension is a colloidal suspension. Embodiment 60. A nanosuspension according to any one of embodiments 49 to 59, wherein the nanosuspension further comprises a stabilizing component. Embodiment 61. The nanosuspension of embodiment 60, wherein the ratio of stabilizing component to aqueous carrier of the nanosuspension is from about 1:500 to about 1:10 by weight. Embodiment 62. A nanosuspension according to embodiment 60, wherein the stabilizing component comprises PVP and / or SDS. Embodiment 63. A nanosuspension according to any one of embodiments 49 to 62, wherein the average diameter of the nanoparticles is less than about 500 nm. Embodiment 64. A nanosuspension described in any one of embodiments 49 to 63, wherein the plurality of nanoparticles has a D50 of about 100 nm to about 400 nm. Embodiment 65. A nanosuspension described in any one of embodiments 49 to 64, wherein the plurality of nanoparticles has a D90 of about 250 μm to about 50 nm. Embodiment 66. A nanosuspension according to any one of embodiments 49 to 65, wherein the hydrophobic drug is not soluble in the aqueous carrier. Embodiment 67. A nanosuspension according to embodiment 66, wherein the hydrophobic drug has a solubility in water of less than 1 mg / mL. Embodiment 68. The nanosuspension of embodiment 66, wherein the hydrophobic drug is a therapeutic agent. Embodiment 69. The nanosuspension of embodiment 68, wherein the therapeutic agent is a small molecule drug. Embodiment 70. The nanosuspension of embodiment 68, wherein the therapeutic agent is a biomolecule. Embodiment 71. The nanosuspension of embodiment 66, wherein the hydrophobic drug is a Biopharmaceutical Classification System (BCS) Class II or Class IV drug. Embodiment 72. A nanosuspension according to any one of embodiments 69 to 71, wherein the therapeutic agent has a narrow therapeutic index. Embodiment 73. A nanosuspension according to any one of embodiments 67 to 72, wherein the therapeutic agent is a high-potency drug. Embodiment 74. A nanosuspension according to embodiment 66 or 67, wherein the hydrophobic agent is an additive or adjuvant. Embodiment 75. A nanosuspension according to any one of embodiments 49 to 74, wherein the concentration of the hydrophobic drug in the nanosuspension is from about 5 mg / mL to about 1,000 mg / mL. Embodiment 76. A nanosuspension form according to any one of embodiments 49 to 75, wherein the amount of hydrophobic drug is less than 0.1 mg. Embodiment 77. A composition comprising a dried or lyophilized nanosuspension, which upon reconstitution forms a nanosuspension according to any one of embodiments 49 to 76. Embodiment 78. A dosage form prepared by the method of embodiment 1. Embodiment 79. The dosage form of embodiment 78, wherein the dosage form comprises a fixed amount of a hydrophobic drug that is a therapeutic agent and a fixed amount of a second hydrophobic drug. Embodiment 80 The dosage form of embodiment 79, wherein the second hydrophobic agent is a therapeutic agent. Embodiment 81 The dosage form of embodiment 79, wherein the second hydrophobic agent is a pharma- ceutically acceptable excipient. Embodiment 82. A plurality of dosage forms according to any one of embodiments 78-81 prepared as a batch of drug dosage forms, wherein the amount of hydrophobic drug in each drug dosage form of the batch does not vary by more than 5% from the average. Embodiment 83. A system for producing a dosage form, comprising: a nanosuspension comprising a hydrophobic drug, the nanosuspension comprising an aqueous carrier and a plurality of nanoparticles, each nanoparticle of the plurality of nanoparticles comprising a hydrophobic drug, the nanosuspension having a viscosity of less than 2 cP; a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit at least one droplet of the nanosuspension onto a substrate of the dosage form; Including, the system. Embodiment 84. The system of embodiment 83, wherein each nozzle has an opening diameter of about 20 μm to about 120 μm. Embodiment 85. The system of embodiment 83 or 84, wherein the droplets of the nanosuspension are deposited on the substrate using a thermal process. Embodiment 86. The system of embodiment 83 or 84, wherein droplets of the nanosuspension are deposited on the substrate using a piezoelectric process.

[0276] A second enumerated list of embodiments: Embodiment 1A. A method of making a dosage form comprising an amorphous solid dispersion (ASD) comprising a hydrophobic drug, comprising depositing droplets of an ASD-forming solution comprising the hydrophobic drug, an organic carrier, and a polymer onto a substrate using a droplet dispenser; A method wherein the ratio of polymer to hydrophobic drug inhibits crystallization of the hydrophobic drug in the dry state on the substrate. Embodiment 2A. The method of embodiment 1A, wherein the droplet dispenser dispenses multiple droplets using a thermal process. Embodiment 3A. The method of embodiment 1A, wherein the droplet dispenser dispenses multiple droplets using a piezoelectric process. Embodiment 4A. The method of any one of Embodiments 1A-3A, wherein the droplet dispenser comprises about 100 to about 1000 individual nozzles. Embodiment 5A. The method of embodiment 4A, wherein each nozzle comprises an opening having a diameter of about 20 μm to about 120 μm. Embodiment 6A. The method of any one of Embodiments 1A-5A, wherein the droplet dispenser is a sub-nanoliter droplet dispenser. Embodiment 7A. The method of embodiment 6A, wherein the sub-nanoliter droplet dispenser is a high frequency sub-nanoliter droplet dispenser. Embodiment 8A. The method of embodiment 7A, wherein the high frequency sub-nanoliter droplet dispenser dispenses droplets at greater than 3 kHz, measured per nozzle. Embodiment 9A. The method of any one of embodiments 1A-8A, wherein the droplet dispenser dispenses droplets in a volume of 1 nanoliter or less. Embodiment 10A. The method of embodiment 9A, wherein the average volume of the dispensed droplets of the ASD-forming solution is from about 1 picoliter to about 50 picoliters. Embodiment 11A. The method of any one of embodiments 1A-10A, wherein the droplets of the ASD-forming solution are deposited on the substrate according to an average number of droplets per square inch. Embodiment 12A. The method of embodiment 11A, wherein the average number of droplets of the ASD-forming solution deposited per square inch of substrate is from about 1 droplet to about 500 droplets per square inch. Embodiment 13A. The method of any one of embodiments 9A-12A, wherein the droplets of the ASD-forming solution dispensed from the droplet dispenser have an average maximum cross dimension of about 5 μm to about 100 μm. Embodiment 14A. The method of any one of Embodiments 1A-13A, wherein the droplets of the ASD-forming solution deposited on the substrate form a continuous layer. Embodiment 15A. The method of any one of embodiments 1A-14A, wherein the ASD-forming solution has a viscosity of 0.5 cP to 3 cP. Embodiment 16A. The method of any one of embodiments 1A-15A, wherein the ASD-forming solution has a viscosity of 1 cP to 2 cP. Embodiment 17A. The method of any one of embodiments 1A-16A, wherein the ASD-forming solution has a viscosity of 1.2 cP to about 1.8 cP. Embodiment 18A. The method of any one of embodiments 1A-17A, wherein the ASD-forming solution further comprises a viscosity modifier. Embodiment 19A. The method of embodiment 18A, wherein the viscosity modifier is a viscosity enhancer. Embodiment 20A. The method of embodiment 19A, wherein the viscosity enhancing agent is ethylene glycol, polyethylene glycol, glycerol, or propylene glycerol, or any combination thereof. Embodiment 21A. The method of embodiment 18A, wherein the viscosity modifier is a viscosity reducer. Embodiment 22A. The method of embodiment 21A, wherein the viscosity reducing agent is a salt or an amino acid, or a combination thereof. Embodiment 23A. The method of any one of embodiments 18A to 22A, wherein the concentration of the viscosity modifier in the ASD-forming solution is 1% to 40%. Embodiment 24A. The method of any one of Embodiments 18A to 23A, wherein the viscosity modifier has a ratio to organic carrier of from 1:100 to 40:100 by volume. Embodiment 25A. The method of any one of Embodiments 18A-24A, wherein the amount of viscosity modifier in the mixture is based on the desired viscosity of the mixture. Embodiment 26A. The method of any one of embodiments 1A-25A, wherein the organic carrier of the ASD-forming solution comprises any one or more of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethyl sulfoxide. Embodiment 27A. The method of any one of embodiments 1A-26A, wherein the ASD-forming solution comprises at least 30% by volume of an organic carrier. Embodiment 28A. The method of any one of embodiments 1A-27A, wherein the polymer of the ASD-forming solution is suitable for forming an amorphous solid dispersion (ASD) after deposition by a droplet dispenser. Embodiment 29A. The method of any one of embodiments 1A-28A, wherein the polymer is selected based on one or more properties of the hydrophobic drug. Embodiment 30A. The method of any one of embodiments 1A-29A, wherein the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PPVVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC acetate succinate (hypromellose acetate succinate or HPMC-AS), and Eudragit, or any combination thereof. Embodiment 31A. The method of any one of embodiments 1A-30A, wherein the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG and HG. Embodiment 32A. The method of any one of embodiments 1A-31A, wherein the polymer is HPMC-AS-LF. Embodiment 33A. The method of any one of embodiments 1A to 32A, wherein the ratio of the concentration of polymer to the concentration of drug in the ASD-forming solution is 1:20 to 20:1. Embodiment 34A. The method of any one of embodiments 1A to 33A, wherein the ratio of the concentration of polymer to the concentration of drug in the ASD-forming solution is 1:2 to 2:1. Embodiment 35A. The method of any one of Embodiments 1A-34A, wherein less than 5% of the hydrophobic drug crystallizes in the dry state following deposition by a droplet dispenser. Embodiment 36A. The method of any one of embodiments 1A-35A, wherein substantially no crystallization of the hydrophobic drug occurs in the dry state. Embodiment 37A. The method of any one of embodiments 1A-36A, wherein the ASD-forming solution is supersaturated with the hydrophobic drug. Embodiment 38A. The method of any one of embodiments 1A-37A, wherein the hydrophobic agent is a drug. Embodiment 39A. The method of embodiment 38A, wherein the drug is a small molecule drug. Embodiment 40A. The method of embodiment 38A or 39A, wherein the agent is a Biopharmaceutic Classification System (BCS) Class II or IV drug. Embodiment 41A. The method of embodiment 38A, wherein the drug is a biomolecule. Embodiment 42A. The method of embodiment 41A, wherein the biological molecule is a polypeptide. Embodiment 43A. The method of any one of embodiments 38A-42A, wherein the drug has a narrow therapeutic index. Embodiment 44A. The method of any one of embodiments 38A to 43A, wherein the drug is a high-potency drug. Embodiment 45A. The method of any one of embodiments 1A-37A, wherein the hydrophobic agent is a diagnostic compound. Embodiment 46A. The method of any one of embodiments 1A to 37A, wherein the hydrophobic agent is a reagent. Embodiment 47A. The method of any one of embodiments 1A to 37A, wherein the hydrophobic agent is an adjuvant or additive. Embodiment 48A. The method of any one of embodiments 1A-47A, wherein the agent has a solubility in water of less than 0.1 mg / mL. Embodiment 49A. The method of any one of embodiments 1A to 48A, wherein the concentration of the drug in the mixture is from about 5 mg / mL to about 1,000 mg / mL. Embodiment 50A. The method of any one of embodiments 1A-49A, wherein the ASD-forming solution further comprises a surfactant. Embodiment 51A. The method of embodiment 50A, wherein the surfactant is selected from Tween 80, Vit-E, TPGS, or SDS, or any combination thereof. Embodiment 52A. The method of embodiment 50A or 51A, wherein the ASD-forming solution comprises 10% to 20% surfactant by volume. Embodiment 53A. The method of any one of embodiments 50A-52A, wherein the ASD-forming solution comprises a ratio of surfactant to hydrophobic agent of 1:100 to 5:1. Embodiment 54A. The method of any one of embodiments 1A-53A, wherein the substrate is a pharma- ceutically acceptable polymer. Embodiment 55A. The method of any one of embodiments 1A-54A, wherein the substrate comprises chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil or a polyacrylic acid derivative, or any combination thereof. Embodiment 56A. The method of any one of embodiments 1A-55A, wherein the substrate is a thin film substrate. Embodiment 57A. The method of any one of embodiments 1A-56A, wherein at least a portion of the hydrophobic drug is within the substrate after deposition by the droplet dispenser. Embodiment 58A. The method of any one of embodiments 1A-57A, wherein at least a portion of the hydrophobic drug is on top of the substrate after deposition by the droplet dispenser. Embodiment 59A. The method of any one of embodiments 1A-58A, wherein the dosage form is an oral dosage form. Embodiment 60A. The method of any one of embodiments 1A-58A, wherein the dosage form is a buccal dosage form. Embodiment 61A. The method of any one of embodiments 1A to 58A, wherein the dosage form is a transdermal dosage form. Embodiment 62A. The method of any one of embodiments 1A to 61A, wherein the dosage form is sterile. Embodiment 63A. The method of any one of embodiments 1A-62A, wherein the ASD-forming solution is a colloid. Embodiment 64A. The method of any one of embodiments 1A to 63A, further comprising forming an ASD-forming solution. Embodiment 65A. An ASD forming solution comprising: An organic carrier; A hydrophobic drug; and a polymer crystallization inhibitor, An ASD-forming solution in which the polymer inhibits drug crystallization in the dry state. Embodiment 66A. An ASD formulation solution described in embodiment 65A, wherein the ASD forming solution has a viscosity of 0.5 cP to 3 cP. Embodiment 67A. An ASD forming solution described in any one of embodiments 65A to 66A, wherein the ASD forming solution has a viscosity of 1 cP to 2 cP. Embodiment 68A. An ASD forming solution described in any one of embodiments 65A to 67A, wherein the ASD forming solution has a viscosity of 1.2 cP to about 1.8 cP. Embodiment 69A. An ASD-forming solution described in any one of embodiments 65A to 68A, wherein the ASD-forming solution comprises a viscosity modifier. Embodiment 70A. An ASD-forming solution according to any one of embodiments 65A to 68A, wherein the viscosity modifier is a viscosity enhancer. Embodiment 71A. The ASD-forming solution of any one of embodiments 65A-70A, wherein the viscosity enhancing agent is ethylene glycol, polyethylene glycol, glycerol, or propylene glycerol, or any combination thereof. Embodiment 72A. An ASD-forming solution according to any one of embodiments 65A to 69A, wherein the viscosity modifier is a viscosity reducer. Embodiment 73A. The ASD-forming solution of any one of embodiments 65A-69A or 72A, wherein the viscosity-reducing agent is a salt or an amino acid, or a combination thereof. Embodiment 74A. An ASD-forming solution described in any one of embodiments 65A to 73A, wherein the concentration of the viscosity modifier in the ASD-forming solution is 1% to 40%. Embodiment 75A. The ASD-forming solution of any one of embodiments 65A to 74A, wherein the viscosity modifier has a ratio to organic carrier of 1:100 to 40:100 by volume. Embodiment 76A. The ASD-forming solution of any one of embodiments 6A5-75A, wherein the amount of viscosity modifier in the mixture is based on the desired viscosity of the mixture. Embodiment 77A. An ASD-forming solution described in any one of embodiments 65A to 76A, wherein the organic carrier of the ASD-forming solution comprises any one or more of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethyl sulfoxide. Embodiment 78A. An ASD-forming solution according to any one of embodiments 65A-77A, wherein the ASD-forming solution comprises at least 30% by volume of an organic carrier. Embodiment 79A. An ASD-forming solution of any one of embodiments 65A-78A, wherein the polymer is selected based on one or more properties of the hydrophobic drug. Embodiment 80A. The ASD-forming solution of any one of embodiments 65A-79A, wherein the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PPVVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC acetate succinate (hypromellose acetate succinate or HPMC-AS), and Eudragit, or any combination thereof. Embodiment 81A. An ASD-forming solution described in any one of embodiments 65A to 80A, wherein the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG and HG. Embodiment 82A. An ASD-forming solution according to any one of embodiments 65A to 81A, wherein the polymer is HPMC-AS-LF. Embodiment 83A. An ASD-forming solution described in any one of embodiments 65A to 82A, wherein the ratio of the concentration of polymer to the concentration of drug in the ASD-forming solution is 1:20 to 20:1. Embodiment 84A. An ASD-forming solution described in any one of embodiments 65A to 83A, wherein the ratio of the concentration of polymer to the concentration of drug in the ASD-forming solution is 1:2 to 2:1. Embodiment 85A. A dispensing cartridge containing an ASD-forming solution described in any one of embodiments 61A to 84A. Embodiment 86A. A dosage form comprising an amorphous solid dispersion of a hydrophobic drug deposited on a substrate via liquid droplets. Embodiment 87A. A dosage form prepared by the method of any one of embodiments 1A-64A. Embodiment 88A. The dosage form of embodiment 87A, wherein the dosage form comprises a fixed amount of a hydrophobic drug that is a therapeutic agent and a fixed amount of a second hydrophobic drug. Embodiment 89A. The dosage form of embodiment 87A, wherein the second hydrophobic agent is a therapeutic agent. Embodiment 90A. The dosage form of embodiment 87A, wherein the second hydrophobic agent is a pharma- ceutically acceptable excipient. Embodiment 91A. A method for determining a ratio of hydrophobic drug to polymer that forms an amorphous solid dispersion, comprising dispensing onto a substrate a quantity of a first precursor solution comprising a first organic carrier, a hydrophobic drug, and a first viscosity enhancing agent, and a quantity of a second precursor solution comprising a second organic carrier, a polymer, and a second viscosity enhancing agent, wherein the dispensing contacts the first precursor solution with the second precursor solution. Embodiment 92A. The method of embodiment 91A, wherein the dispensing mixes the first and second precursor solutions on the substrate. Embodiment 93A. The method of embodiment 91A, wherein the dispensing mixes the first and second precursor solutions before being applied to the substrate. Embodiment 94A. The method of any one of embodiments 91A-93A, wherein an amount of the first precursor solution and an amount of the second precursor solution are dispensed such that a gradient of the drug to polymer ratio is formed in a region on the substrate. Embodiment 95A. The method of embodiment 94A, wherein an amount of a first precursor solution and an amount of a second precursor solution are dispensed such that an area on the substrate has a predetermined ratio of drug to polymer. Embodiment 96A. The method of any one of embodiments 91A-95A, wherein a first amount of precursor solution is dispensed from a first sub-nanoliter droplet dispenser and a second amount of precursor solution is dispensed from a second sub-nanoliter droplet dispenser. Embodiment 97A. The method of any one of embodiments 91A-96A, further comprising assessing crystallization of the agent. Embodiment 98A. The method of any one of Embodiments 91A-97A, wherein the first organic carrier and the second organic carrier are the same. Embodiment 99A. The method of any one of embodiments 91A-98A, wherein the first viscosity enhancing agent and the second viscosity enhancing agent are the same. The method of any one of embodiments 91A-99A, wherein the substrate is a thin film. Embodiment 101A. A drop dispenser for producing a dosage form comprising an amorphous solid dispersion of a hydrophobic drug, comprising: (a) a dispensing head comprising one or more nozzles; (b) an ASD-forming solution comprising an organic carrier, a drug, a polymer, and a viscosity modifier, the drug and polymer are present in the mixture in a ratio that inhibits crystallization of the drug in the dry state on the substrate; a mixture cartridge operably coupled to the first dispensing head; and (c) a control system configured to dispense the mixture via the dispensing head according to a dispensing pattern. Embodiment 102A. A dispenser as described in embodiment 101A, wherein the dispensing head comprises about 100 to about 1000 nozzles. Embodiment 103A. The dispenser of embodiment 101A or 102A, wherein each nozzle has an opening diameter of about 20 μm to about 120 μm. Embodiment 104A. A dispenser of any one of embodiments 101A-103A, wherein the dispensing head dispenses droplets using a thermal process. Embodiment 105A. A dispenser according to any one of embodiments 101A to 104A, wherein one head dispenses droplets using a piezoelectric process. Embodiment 106A. A dispenser described in any one of embodiments 101A to 105A, further comprising a second dispensing head operably connected to a second mixture cartridge, the second mixture cartridge containing a second mixture including a second drug. Embodiment 107A. The dispenser of embodiment 106A, further comprising a third dispensing head operably coupled to a third mixture cartridge, the third mixture cartridge containing the protective coating mixture. Embodiment 108A. The dispenser of embodiment 107A, further comprising a fourth dispensing head operably coupled to a fourth dispensing cartridge, the fourth mixture cartridge containing an edible mixture. Embodiment 109A. A gradient of two components on a substrate, comprising: a first component comprising a hydrophobic drug; a second component comprising a polymer crystallization inhibitor; a ratio of the first component to the second component, the ratio varying across the gradient. Embodiment 110A. The gradient of embodiment 109A, wherein the first component further comprises an organic carrier. Embodiment 111A. The gradient of embodiment 109A or 110A, wherein the first component further comprises a viscosity enhancing agent. Embodiment 112A. The gradient of any one of embodiments 109A-111A, wherein the second component further comprises an organic carrier. Embodiment 113A. The gradient of any one of embodiments 109A to 112A, wherein the second component further comprises a viscosity enhancer. Embodiment 114A. A gradient according to any one of embodiments 109A to 113A, wherein the second component is capable of inhibiting crystallization of a hydrophobic drug. Embodiment 115A. The gradient of embodiment 109A, wherein the first and second components each comprise an organic carrier, and the organic carriers are the same. Embodiment 116A. The gradient of embodiment 109A, wherein the first and second components each comprise a viscosity enhancing agent, and the viscosity enhancing agents are the same. Embodiment 117A. A gradient of any one of embodiments 109A-116A, wherein the ratio is sufficiently low at certain points on the gradient to prevent crystallization of the hydrophobic drug. Embodiment 118A. The gradient of any one of embodiments 109A-117A, wherein the first and second components are dispensed onto the substrate from a sub-nanoliter droplet dispenser. Embodiment 119A. The gradient of any one of embodiments 109A to 117A, wherein a first component is dispensed onto the substrate from a first sub-nanoliter droplet dispenser and a second is dispensed onto the substrate from a second sub-nanoliter droplet dispenser. Embodiment 120A. A gradient according to any one of embodiments 109A-119A, wherein the ratio changes at a consistent rate across the gradient. EXAMPLES

[0277] The following examples are included for illustrative purposes and are not intended to limit the scope of the teachings provided in this application. Reagents and materials were obtained from commercial sources and used as received unless otherwise noted. Loadings and concentrations are reported as weight percent (wt%) unless otherwise noted.

[0278] Example 1: Preparation of nanosuspension Naproxen was used as obtained commercially. A 20 mL glass scintillation vial was charged with 45.6 grams of yttria-stabilized zirconia powder grinding beads. Naproxen solid (0.876 g) was weighed into the vial. In another 20 mL vial, water (2.628 mL) and a stock solution of 5% polyvinylpyrrolidone (PVP, 4.380 mL) and 1% sodium dodecyl sulfate (SDS, 0.876 mL) were mixed. The aqueous solution was then transferred to the vial containing naproxen to form a slurry with a naproxen:PVP:SDS ratio of 1:0.25:0.01 and an overall drug concentration of 100 mg / mL. The vial was sealed with a polytetrafluoroethylene cap and then placed in a resonant acoustic mixer for grinding at 40 G intensity for 2 hours.

[0279] The resulting liquid nanosuspension samples were removed from the milling beads by extraction with a syringe equipped with a 26-gauge needle, giving an average yield of approximately 7 grams (80%). The resulting nanosuspension appeared as a white, opaque mixture with well-dispersed and suspended nanoparticles, visible only under high magnification with an optical microscope (see Figure 1). The nanosuspension at 100 mg / mL drug concentration was diluted with an appropriate volume of water to obtain formulation samples at 10 mg / mL and 1 mg / mL drug concentrations. Ethylene glycol was added to some formulation samples as a viscosity enhancer.

[0280] Example 2: Viscosity measurements and inkjet printing of nanosuspensions The viscosity of the naproxen formulations was measured using a viscometer. A recirculating water bath was used to maintain the temperature of the sample chamber at 25° C. An aliquot (0.5 mL) of the formulation sample was added to the sample chamber and the viscosity was recorded after the measurement stabilized to less than 0.1% variation.

[0281] A commercial inkjet photoprinter with a standard thermal inkjet printhead was used to print patterns of the nanosuspension. Refillable ink cartridges were used as received and loaded with the liquid formulation for printing. The nanosuspension was introduced into the cartridge through an opening at the top to fill the internal reservoir. The cartridge had a sponge-like material used to help control the release rate of the liquid through a large opening at the bottom of the cartridge where it enters the inkjet printhead for final dispensing. Adobe Photoshop was used to create simple print patterns consisting of circles with a diameter of 100 pixels and a resolution of 72 dots per inch (dpi) using an ink color from a single cartridge source (e.g., cyan). Commercially available 8.5" x 11" acetate transparency film was used as the print substrate. The print output was allowed to air dry for several hours before analysis. Between print runs, the inkjet printhead was carefully washed with deionized water and acetone to remove any residual formulation. Results for the four formulation samples are shown in Table 2.

[0282] The 1 and 10 mg / mL nanosuspension formulations were not retained within the cartridge and therefore could not be printed effectively. The 10 mg / mL formulation with 10% ethylene glycol had a viscosity of approximately 1.5 cP. This higher viscosity formulation printed better, consistent with measurements of commercially available inks that have a viscosity of approximately 1-5 cP. Further measurements were performed to determine the effect of ethylene glycol on the stability of the formulations. [Table 1]

[0283] Example 3: Particle size analysis of nanosuspensions using dynamic light scattering The particle size distribution of the naproxen formulations prepared in Example 1 was determined. A 10 μL aliquot of each nanosuspension sample was taken and diluted in 90 μL of water for analysis using a dynamic light scattering instrument. A 40 μL aliquot of the diluted suspension was dispensed into a low volume black polystyrene 384-well plate for analysis. The particle size of each sample was reported as the average of 10 acquisitions at 25° C. with an acquisition time of 3 seconds. The autocorrelation curve was fitted using either the cumulant or regularization method to obtain and report the D50 radius measurements. The normalized polydispersity (%Pd) was calculated as the polydispersity divided by the estimated hydrodynamic radius from the cumulant fit of the autocorrelation function multiplied by 100. The D50 radius results are shown in Table 2. The addition of ethylene glycol to the formulation increased the size of the nanoparticles in the nanosuspension. [Table 2]

[0284] Example 4: Drug concentration analysis of printed patterns by high performance liquid chromatography Drug concentration analysis was performed on the printed nanosuspension patterns from Example 2 using a high performance liquid chromatography (HPLC) system equipped with a quaternary pump, a photodiode array UV-Vis detector, and a reversed phase alkylsilane column (particle size 3.5 μm, dimensions 50×4.6 mm). The printed patterns from Example 2 were cut, then washed, and completely dissolved in 1:1 acetonitrile:water. The resulting solutions were then analyzed by HPLC with drug concentrations compared to standards of known concentration. The mobile phase for the HPLC process consisted of 0.05% trifluoroacetic acid in water and acetonitrile. Gradient elution was utilized, with the acetonitrile mobile phase increasing from 2 to 65% over 6.5 minutes at a flow rate of 1.25 mL / min. The column was heated at 30° C., and detection was performed at 254 nm. Analysis of multiple printed patterns (n=3) demonstrated that the deposition of microgram amounts of drug onto transparent films was highly reproducible with low variability. The results are shown in Table 3. [Table 3] For a naproxen nanosuspension formulation with a drug concentration of 100 mg / mL, the 2 Considering the measured deposition of and the target print resolution of 72 dpi in the pattern, a droplet size of 16.6 picoliters was calculated, which is well within the expected range for droplet sizes dispensed by similar inkjet printheads. This also indicates that there was no major disruption of the droplet formation or significant loss or degradation of the drug formulation during the printing process, consistent with the HPLC analysis results.

[0285] These results are consistent with expectations of the inkjet printing process as a precise method for controlling droplet deposition and demonstrate that no significant issues arose despite the replacement of traditional printer inks with drug formulation "inks," allowing for the production of consistent dosage forms with good content uniformity. Furthermore, the amount of drug deposited was directly proportional to the initial concentration of the nanosuspension ink. Reducing the initial concentration from 100 mg / mL to 10 mg / mL reduced the amount of naproxen deposited on the transparent film by 10-fold. Furthermore, HPLC analysis showed no presence of degradants or other impurities, suggesting that the drug remained stable throughout the inkjet printing process despite the flash heating required for deposition.

[0286] Example 5: Optical analysis and reconstruction of printed patterns Optical microscopy analysis of the printed nanosuspension patterns from Example 2 was performed using a microscope equipped with a camera. Commercial acetate transparency films used for inkjet printing the nanosuspension formulations were directly analyzed by bright-field transmission optical microscopy at various magnification scales. The results are shown in Figures 2 and 3.

[0287] The reconstitution of the printed nanosuspension after drying was then investigated. A drop of water was placed on the transparent film holding the dried and printed nanosuspension from Example 3. The wetting and redispersion of the nanosuspension droplets was observed in real time by monitoring the advancing water line with an optical microscope (see Figures 4A-4C). Upon exposure to water, the dried nanosuspension droplets immediately hydrated and released the drug nanoparticles into solution. The resulting reconstituted nanosuspension was collected and analyzed by optical microscopy, which showed a uniform and well-dispersed suspension with no significant aggregation (see Figure 7). Dynamic light scattering analysis of the reconstituted sample showed particles consisting of 114 nm in diameter and showed no significant aggregation after drying and redispersion, confirming that the stability of the nanosuspension during this process was maintained.

[0288] Example 6: Dispensing and Deposition of Organic Carriers by Inkjet Printer This example demonstrates the dispensing and deposition of an organic carrier using a droplet dispenser that dispenses droplets using a thermal process, thereby enabling the dispensing of drugs that are prone to crystallization, such as hydrophobic drugs, and polymers to produce amorphous solid dispersions containing the drug.

[0289] The solvent mixture was made according to Table 4. A refillable inkjet printer cartridge was used as received to load the solvent mixture for printing. A commercial inkjet photoprinter equipped with a standard thermal inkjet printhead was used to dispense and deposit droplets of the solvent mixture onto the thin film substrate. [Table 4]

[0290] It was observed that the solvent mixture leaked in certain droplet dispensers and from certain dispenser cartridges if the solvent mixture was too fluid (low viscosity), whereas dispensing of the solvent mixture was impossible or unreliable if the solvent mixture was too viscous. A 40% ethylene glycol in acetone mixture with a 1.659 cp viscosity was successfully dispensed and deposited onto a thin film substrate, thereby demonstrating that the high concentration organic carrier is a suitable solution for use in a droplet dispenser.

[0291] Example 7: Preparation of amorphous solid dispersions using an inkjet printer This example demonstrates the identification of an ASD-forming solution using two precursor solutions, as well as the fabrication and optimization of ASDs therefrom using a droplet dispenser.

[0292] A first precursor solution was created containing 2% griseofulvin (a fast crystallizer model drug; 20 mg / mL), acetone organic carrier, and ethylene glycol. Various amounts of ethylene glycol, a viscosity modifier, were evaluated, including 30%, 35% and 40%. Only the 35% and 40% ethylene glycol precursor solutions had viscosities between 1 cp and 2 cp (1.200 and 1.702, respectively), and the 40% ethylene glycol precursor solution was used to evaluate dropwise dispensing.

[0293] A second precursor solution was made containing 2% HPMCAS-LF (polymer; 20 mg / mL) in an acetone organic carrier and, optionally, ethylene glycol. Various amounts of ethylene glycol, a viscosity modifier, were evaluated, including 0% (pure acetone), 5%, 20%, 30% and 40%. Only the 0% and 5% ethylene glycol precursor solutions had viscosities between 1 cp and 2 cp (1.208 and 1.365, respectively), and the 5% ethylene glycol precursor solution was used to evaluate dropwise dispensing. Note that the polymer HPMCAS-LF also serves to modulate the viscosity of the precursor solution.

[0294] The first and second precursor solutions were added to separate refillable inkjet printer cartridges. A commercially available inkjet photoprinter with a standard thermal inkjet printhead was used to dispense and deposit droplets of the first and second precursor solutions onto a substrate according to the desired ratio of griseofulvin to HPMCAS-LF and the methods described herein. Specifically, gradient deposition was performed using two droplet dispensers (printheads) as shown in FIG. 7A. The amount of the first precursor solution dispensed from the first droplet dispenser and the amount of the second precursor solution dispensed from the second droplet dispenser can be varied across the area to produce a gradient deposition. The gradient can be varied as desired, and in this example a uniform gradient was produced, where on the left side of the gradient deposition the deposit contains 100% loading of griseofulvin and on the right side of the gradient deposition the deposit contains 100% HPMCAS-LF. Images were captured to show the crystallization of griseofulvin at 100% loading of griseofulvin and amorphous polymer at 100% loading of HPMCAS-LF. Areas of set loading of griseofulvin were also created for HPMCAS-LF (100%, 50%, 40%, 30%, 20%, 10%, 0%) as shown in FIG. 7B. Images captured of areas with 20% loading of griseofulvin and corresponding 20% ​​loading of griseofulvin on gradient deposition demonstrated that ASD of griseofulvin was produced using the droplet dispensing technique taught herein. 20% griseofulvin loading is known to produce ASD by conventional large-scale spray drying technique. The results demonstrated herein show that the droplet dispenser technique can reproduce known ASD characteristics at a small scale.

Claims

1. 1. A method of making a dosage form containing a hydrophobic drug, comprising:

16. A method comprising depositing a plurality of droplets of a formulation comprising the hydrophobic drug onto a substrate using a radio frequency droplet dispenser to form a dosage form, wherein the formulation has a viscosity of less than 3 cP.

2. The method of claim 1 , wherein the radio frequency droplet dispenser deposits the plurality of droplets using a thermal process.

3. The method of claim 1 , wherein the radio frequency droplet dispenser deposits the plurality of droplets using a piezoelectric process.

4. The method of any one of claims 1 to 3, wherein the high frequency droplet dispenser comprises from about 100 to about 1000 individual nozzles.

5. The method of claim 4, wherein each nozzle comprises an opening having a diameter of about 20 μm to about 120 μm.

6. The method of any one of claims 1 to 6, wherein the high frequency droplet dispenser is a high frequency sub-nanoliter droplet dispenser.

7. 7. The method of claim 6, wherein the high frequency sub-nanoliter droplet dispenser dispenses droplets at greater than 3 kHz measured per nozzle.

8. The method of any one of claims 1 to 7, wherein the radio frequency droplet dispenser dispenses droplets in a volume of 1 nanoliter or less.

9. 10. The method of claim 8, wherein an average volume of each dispensed droplet of the plurality of droplets of the formulation is from about 1 picoliter to about 50 picoliters.

10. 9. The method of claim 7 or 8, wherein the plurality of droplets of the formulation are deposited on the substrate according to an average number of droplets per square inch.

11. The method of claim 10, wherein the average number of droplets deposited per square inch of the substrate is from about 1 droplet per square inch to about 500 droplets per square inch.

12. 12. The method of claim 10 or 11, wherein the plurality of droplets of the formulation deposited on the substrate have an average diameter of about 5 μm to about 100 μm.

13. The method of any one of claims 1 to 12, wherein the plurality of droplets of the formulation deposited on the substrate form a continuous layer.

14. 14. The method of any one of claims 1 to 13, wherein the ASD forming solution has a viscosity of from 0.5 cP to 3 cP.

15. 15. The method of any one of claims 1 to 14, wherein the viscosity of the formulation is less than 2 cP and greater than 1 cP.

16. 16. The method of any one of claims 1 to 15, wherein the viscosity of the formulation is between 1.2 cP and 1.8 cP.

17. The method of any one of claims 1 to 15, wherein the formulation further comprises a viscosity modifier.

18. 17. The method of claim 16, wherein the viscosity modifier is a viscosity enhancer.

19. 18. The method of claim 17, wherein the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol and propylene glycerol.

20. 20. The method of claim 18, wherein the viscosity modifier is a viscosity reducer.

21. 21. The method of claim 20, wherein the viscosity reducing agent is a salt or an amino acid, or a combination thereof.

22. The method of any one of claims 17 to 21, wherein the amount of the viscosity modifier in the mixture is based on a desired viscosity of the mixture.

23. 19. The method of claim 17 or 18, wherein the viscosity enhancing agent is present in the formulation at a concentration of about 1% to about 40% v / v of the formulation.

24. 21. The method of any one of claims 17 to 20, further comprising adding the viscosity enhancing agent to the formulation to achieve a viscosity of the formulation of about 1 cP to about 2 cP.

25. The method according to any one of claims 1 to 24, wherein the formulation comprises: An aqueous carrier; and a plurality of nanoparticles suspended in the aqueous carrier, the nanoparticles comprising the hydrophobic drug.

26. The method according to any one of claims 1 to 25, wherein the suspension is a nanosuspension.

27. The method according to any one of claims 1 to 26, wherein the suspension is a colloidal suspension.

28. The method of any one of claims 1 to 27, wherein the aqueous carrier comprises water and an organic solvent.

29. 20. The method of any one of claims 18 to 19, wherein the ratio of the viscosity enhancing agent to the aqueous carrier of the formulation is from about 1:1000 to about 1:2 by volume.

30. 30. The method of any one of claims 25 to 29, wherein the hydrophobic drug is not soluble in the aqueous carrier.

31. 31. The method of any one of claims 1 to 30, wherein the hydrophobic drug has a solubility in water of less than 1 mg / mL.

32. 32. The method of any one of claims 25 to 31, wherein the concentration of the hydrophobic drug in the suspension is from about 5 mg / mL to about 1,000 mg / mL.

33. The method of any one of claims 1 to 32, wherein the suspension further comprises a stabilizing component.

34. 34. The method of claim 33, wherein the ratio of said stabilizing component to said aqueous carrier of said suspension is from about 1:500 to about 1:10 by weight.

35. 35. The method of claim 33 or claim 34, wherein the stabilizing component comprises PVP and / or SDS.

36. 26. The method of claim 25, wherein the plurality of nanoparticles has an average diameter of less than about 500 nm.

37. 26. The method of claim 25, wherein the plurality of nanoparticles has a D50 of about 100 nm to about 400 nm.

38. 26. The method of claim 25, wherein the plurality of nanoparticles has a D90 of about 250 μm to about 50 nm.

39. The method of claim 25 , wherein at least a portion of the plurality of nanoparticles are deposited within the substrate.

40. The method of claim 25 , wherein at least a portion of the plurality of nanoparticles are deposited on top of the substrate.

41. The method according to any one of claims 1 to 24, wherein the formulation comprises: The hydrophobic drug; An organic carrier; and a polymer, wherein the ratio of said polymer to said hydrophobic drug inhibits crystallization of said hydrophobic drug in the dry state on said substrate.

42. 42. The method of claim 41, wherein the ASD forming solution is a colloid.

43. 43. The method of claim 41 or 42, wherein the organic carrier of the ASD forming solution comprises any one or more components selected from the group consisting of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethyl sulfoxide.

44. 44. The method of any one of claims 41 to 43, wherein the ASD-forming solution comprises at least 30% by volume of an organic carrier.

45. 45. The method of any one of claims 44, wherein the viscosity modifier has a ratio to the organic carrier of from 1:100 to 40:100 by volume.

46. 46. ​​The method of any one of claims 41 to 45, wherein the polymer of the ASD-forming solution is suitable for forming an amorphous solid dispersion (ASD) after deposition by the droplet dispenser.

47. The method of any one of claims 41 to 46, wherein the polymer is selected based on one or more properties of the hydrophobic drug.

48. 48. The method of any one of claims 41-47, wherein the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PVPVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC succinate acetate (hypromellose succinate or HPMC-AS), and Eudragit, or any combination thereof.

49. 49. The method of any one of claims 41 to 48, wherein the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG and HG.

50. 50. The method of any one of claims 41 to 49, wherein the polymer is HPMC-AS-LF.

51. 51. The method of any one of claims 41 to 50, wherein the ratio of the concentration of the polymer to the concentration of the hydrophobic drug is from 1:20 to 20:

1.

52. 52. The method of any one of claims 41 to 51, wherein the ratio of the concentration of the polymer to the concentration of the hydrophobic drug is from 1:2 to 2:

1.

53. 53. The method of any one of claims 41 to 52, wherein the ASD-forming solution further comprises a surfactant.

54. 54. The method of claim 53, wherein the surfactant is selected from Tween 80, Vit-E, TPGS, or SDS, or any combination thereof.

55. 55. The method of claim 53 or 54, wherein the ASD forming solution comprises 10% to 20% of the surfactant by volume.

56. 56. The method of any one of claims 53 to 55, wherein the ASD forming solution comprises a ratio of the surfactant to the hydrophobic drug of 1:100 to 5:

1.

57. 57. The method of any one of claims 41 to 56, wherein less than 5% of the hydrophobic drug crystallizes in the dry state following deposition by the droplet dispenser.

58. 58. The method of any one of claims 41 to 57, wherein substantially no crystallization of the hydrophobic drug occurs in the dry state.

59. 59. The method of any one of claims 41 to 58, wherein the ASD forming solution is supersaturated with the hydrophobic drug.

60. 60. The method of any one of claims 41-59, wherein the concentration of the hydrophobic drug in the mixture is from about 5 mg / mL to about 1,000 mg / mL.

61. The method of any one of claims 41 to 60, wherein at least a portion of the hydrophobic agent is within the substrate after deposition by the droplet dispenser.

62. 62. The method of any one of claims 41 to 61, wherein at least a portion of the hydrophobic agent is on top of the substrate after deposition by the droplet dispenser.

63. The method of any one of claims 1 to 62, wherein the hydrophobic agent is a therapeutic agent.

64. 64. The method of claim 63, wherein the therapeutic agent is a small molecule drug.

65. 64. The method of claim 63, wherein the therapeutic agent is a biomolecule.

66. 64. The method of claim 63, wherein the therapeutic agent is a Biopharmaceutic Classification System (BCS) Class II or Class IV drug.

67. 67. The method of any one of claims 63 to 66, wherein the therapeutic agent has a narrow therapeutic index.

68. 68. The method of any one of claims 63 to 67, wherein the therapeutic agent is a high-potency drug.

69. The method of any one of claims 1 to 62, wherein the hydrophobic agent is an additive or adjuvant.

70. 63. The method of any one of claims 1 to 62, wherein the hydrophobic agent is a diagnostic compound.

71. The method of any one of claims 1 to 62, wherein the hydrophobic agent is a reagent.

72. 72. The method of any one of claims 1 to 71, wherein the hydrophobic drug has a solubility in water of less than 0.1 mg / mL.

73. 73. The dosage form of any one of claims 1 to 72, wherein the amount of hydrophobic drug is less than 0.1 mg.

74. The method of any one of claims 1 to 73, wherein the substrate is a pharma- ceutically acceptable polymer.

75. 75. The method of any one of claims 1 to 74, wherein the substrate is selected from the group consisting of one or more of chitosan, ethylenediaminetetraacetic acid, polyvinylpyrrolidone, polyvinyl alcohol, alginate, agar, carrageenan, guar gum, xanthan gum, polycarbophil, and polyacrylic acid derivatives.

76. The method of any one of claims 1 to 75, wherein the substrate is a thin film substrate.

77. 77. The method of any one of claims 1 to 76, wherein the dosage form is an oral dosage form.

78. 77. The method of any one of claims 1 to 76, wherein the dosage form is a buccal dosage form.

79. 77. The method of any one of claims 1 to 76, wherein the dosage form is a transdermal dosage form.

80. The method of any one of claims 1 to 79, wherein the dosage form is sterile.

81. A suspension comprising: An aqueous carrier; a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier; wherein the viscosity of the suspension is less than 3 cP.

82. 82. The suspension of claim 81, wherein the viscosity of the suspension is less than 2 cP and greater than 1 cP.

83. 83. The suspension according to claim 81 or 82, wherein the viscosity of the suspension is between 1.2 cP and 1.8 cP.

84. 84. A suspension according to any one of claims 81 to 83, wherein the suspension further comprises a viscosity modifier.

85. 85. The suspension of claim 84, wherein the viscosity modifier is a viscosity enhancing agent.

86. 86. The suspension of claim 85, wherein the viscosity enhancing agent is selected from the group consisting of ethylene glycol, polyethylene glycol, glycerol and propylene glycerol.

87. 87. The suspension of claim 85 or 86, wherein the viscosity enhancing agent is present in the suspension at a concentration of from about 1% to about 40% v / v of the suspension.

88. 88. A suspension according to any one of claims 81 to 87, wherein the ratio of the viscosity enhancing agent to the aqueous carrier of the suspension is from about 1:1000 to about 1:2 by volume.

89. 89. A suspension according to any one of claims 81 to 88, further comprising adding said viscosity enhancing agent to said suspension to achieve a viscosity of said suspension of from about 1 cP to about 2 cP.

90. 90. The suspension of any one of claims 81 to 89, wherein the aqueous carrier comprises water and an organic solvent.

91. 91. The suspension of any one of claims 81 to 90, wherein the suspension is a colloidal suspension.

92. 92. The suspension of any one of claims 81 to 91, wherein the suspension further comprises a stabilizing component.

93. 93. The suspension of claim 92, wherein the ratio of said stabilizing component to said aqueous carrier of said suspension is from about 1:500 to about 1:10 by weight.

94. 94. The suspension of claim 92 or 93, wherein the stabilizing component comprises PVP and / or SDS.

95. 95. The suspension of any one of claims 81 to 94, wherein the average diameter of the nanoparticles is less than about 500 nm.

96. 96. The suspension of any one of claims 81 to 95, wherein the plurality of nanoparticles has a D50 of about 100 nm to about 400 nm.

97. 97. The suspension of any one of claims 81 to 96, wherein the plurality of nanoparticles has a D90 of about 250 μm to about 50 nm.

98. 98. The suspension of any one of claims 81 to 97, wherein the hydrophobic drug is not soluble in the aqueous carrier.

99. 99. The suspension of any one of claims 81 to 98, wherein the hydrophobic drug has a solubility in water of less than 1 mg / mL.

100. 100. The suspension of any one of claims 81 to 99, wherein the hydrophobic drug is a therapeutic agent.

101. The suspension of claim 100, wherein the therapeutic agent is a small molecule drug.

102. The suspension of claim 100, wherein the therapeutic agent is a biomolecule.

103. 101. The suspension of claim 100, wherein the hydrophobic drug is a Biopharmaceutical Classification System (BCS) Class II or Class IV drug.

104. 104. The suspension of any one of claims 100 to 103, wherein the therapeutic agent has a narrow therapeutic index.

105. 105. The suspension of any one of claims 100 to 104, wherein the therapeutic agent is a high-potency drug.

106. 100. The suspension of any one of claims 81 to 99, wherein the hydrophobic agent is an additive or adjuvant.

107. 107. The suspension of any one of claims 81-106, wherein the concentration of the hydrophobic drug in the suspension is from about 5 mg / mL to about 1,000 mg / mL.

108. 108. The suspension form of any one of claims 81-107, wherein the amount of the hydrophobic drug is less than 0.1 mg.

109. 1. An ASD forming solution, comprising: An organic carrier; A hydrophobic drug; Polymer crystallization inhibitors and wherein the polymer inhibits crystallization of the drug in a dry state.

110. 110. The ASD formulation solution of claim 109, wherein the ASD formulation solution has a viscosity of 0.5 cP to 3 cP.

111. The ASD forming solution of any one of claims 109 to 110, wherein the ASD forming solution has a viscosity of 1 cP to 2 cP.

112. 112. The ASD forming solution of any one of claims 109 to 111, wherein the ASD forming solution has a viscosity of 1.2 cP to about 1.8 cP.

113. The ASD forming solution according to any one of claims 109 to 112, wherein the ASD forming solution comprises a viscosity adjusting agent.

114. 114. The ASD forming solution of claim 113, wherein the viscosity modifier is a viscosity enhancer.

115. 115. The ASD forming solution of claim 114, wherein the viscosity enhancing agent is ethylene glycol, polyethylene glycol, glycerol, or propylene glycerol, or any combination thereof.

116. 114. The ASD forming solution of claim 113, wherein the viscosity modifier is a viscosity reducer.

117. 117. The ASD formation solution of claim 116, wherein the viscosity reducing agent is a salt or an amino acid, or a combination thereof.

118. The ASD forming solution according to any one of claims 114 to 117, wherein the concentration of the viscosity modifier in the ASD forming solution is 1% to 40%.

119. 119. The ASD forming solution of any one of claims 114 to 118, wherein the viscosity modifier has a ratio to the organic carrier of from 1:100 to 40:100 by volume.

120. 120. The ASD forming solution of any one of claims 114 to 119, wherein the amount of viscosity modifier in the mixture is based on the desired viscosity of the mixture.

121. 121. The ASD forming solution of any one of claims 109 to 120, wherein the organic carrier of the ASD forming solution comprises a component selected from the group consisting of acetone, dimethylformamide, ethanol, methanol, pentane, hexane, heptane, ethyl acetate, isopropyl alcohol, ethylene glycol, and dimethyl sulfoxide.

122. 122. The ASD forming solution of any one of claims 109 to 121, wherein the ASD forming solution comprises at least 30% by volume of an organic carrier.

123. 123. The ASD forming solution of any one of claims 109 to 122, wherein the polymer is selected based on one or more properties of the hydrophobic drug.

124. 124. The ASD forming solution of any one of claims 109-123, wherein the polymer is selected from the group consisting of cellulose derivatives, poly(vinylpyrrolidinone) (PVP), poly(vinylpyrrolidinone-co-vinyl acetate) (copovidone, or PVPVA), hydroxypropyl methylcellulose (hypromellose, or HPMC), and HPMC succinate acetate (hypromellose succinate or HPMC-AS), and Eudragit, or any combination thereof.

125. 124. The ASD forming solution of any one of claims 109 to 123, wherein the polymer is a grade selected from the group consisting of LF, MF, HF, LMP, MMP, HMP, LG, MG and HG.

126. 124. The ASD-forming solution of any one of claims 109 to 123, wherein the polymer is HPMC-AS-LF.

127. The ASD forming solution according to any one of claims 109 to 126, wherein the ratio of the concentration of the polymer to the concentration of the drug in the ASD forming solution is 1:20 to 20:

1.

128. The ASD forming solution according to any one of claims 109 to 127, wherein the ratio of the concentration of the polymer to the concentration of the drug in the ASD forming solution is 1:2 to 2:

1.

129. 109. A composition comprising a dry or lyophilized suspension, which upon reconstitution forms a suspension according to any one of claims 81 to 108.

130. A dosage form prepared by the method of any one of claims 1 to 80.

131. 131. The dosage form of claim 130, wherein the dosage form comprises a fixed amount of the hydrophobic drug that is a therapeutic agent and a fixed amount of a second hydrophobic drug.

132. The dosage form of claim 131, wherein the second hydrophobic drug is a therapeutic agent.

133. The dosage form of claim 131, wherein the second hydrophobic agent is a pharma- ceutically acceptable excipient.

134. 134. The multiple dosage form of any one of claims 130-133 prepared as a batch of drug dosage forms, wherein the amount of the hydrophobic drug in each drug dosage form of the batch does not vary by more than 5% from the average.

135. 1. A system for producing a dosage form, comprising: a. a suspension comprising a hydrophobic drug, the suspension comprising an aqueous carrier and a plurality of nanoparticles, each nanoparticle of the plurality of nanoparticles comprising the hydrophobic drug, the suspension having a viscosity of less than 2 cP; b. a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit at least one droplet of a suspension onto a substrate of said dosage form; Including, the system.

136. 136. The system of claim 135, wherein each nozzle has an opening diameter of about 20 μm to about 120 μm.

137. 137. The system of claim 135 or 136, wherein droplets of the suspension are deposited on the substrate using a thermal process.

138. 137. The system of claim 135 or 136, wherein droplets of the suspension are deposited on the substrate using a piezoelectric process.

139. 1. A system for producing a dosage form, comprising: an amorphous solid dispersion (ASD) comprising a hydrophobic drug, the method comprising depositing droplets of an ASD-forming solution comprising the hydrophobic drug, an organic carrier, and a polymer onto a substrate using a droplet dispenser, the ratio of the polymer to the hydrophobic drug inhibiting crystallization of the hydrophobic drug in the dry state on the substrate, and the viscosity of the ASD-forming solution is less than 2 cP; a radio frequency droplet dispenser comprising about 100 to about 1000 individual nozzles, each nozzle configured to deposit droplets of at least one solution onto a substrate of said dosage form; Including, the system.

140. 140. The system of claim 139, wherein each nozzle has an opening diameter of about 20 μm to about 120 μm.

141. 141. The system of claim 139 or 140, wherein the droplets of the solution are deposited on the substrate using a thermal process.

142. 141. The system of claim 139 or 140, wherein droplets of the solution are deposited on the substrate using a piezoelectric process.

143. A dispensing cartridge comprising an ASD forming solution according to any one of claims 109 to 128.

144. A dosage form comprising a nanosuspension of a hydrophobic drug deposited on a substrate via droplets.

145. A dosage form comprising an amorphous solid dispersion of a hydrophobic drug deposited on a substrate via droplets.

146. 1. A method for determining a ratio of a hydrophobic drug to a polymer that forms an amorphous solid dispersion, comprising dispensing onto a substrate a quantity of a first precursor solution comprising a first organic carrier, the hydrophobic drug, and a first viscosity enhancing agent, and a quantity of a second precursor solution comprising a second organic carrier, a polymer, and a second viscosity enhancing agent, wherein the dispensing contacts the first precursor solution with the second precursor solution.

147. 147. The method of claim 146, wherein the dispensing mixes the first precursor solution and the second precursor solution on the substrate.

148. 147. The method of claim 146, wherein the dispensing mixes the first and second precursor solutions before being applied to the substrate.

149. 149. The method of any one of claims 146-148, wherein the amount of the first precursor solution and the amount of the second precursor solution are dispensed such that a gradient of the ratio of the drug to the polymer is formed in a region on the substrate.

150. 149. The method of any one of claims 146-148, wherein the amount of the first precursor solution and the amount of the second precursor solution are dispensed such that an area on the substrate has a predetermined ratio of the drug to the polymer.

151. 151. The method of any one of claims 146 to 150, wherein the amount of the first precursor solution is dispensed from a first sub-nanoliter droplet dispenser and the amount of the second precursor solution is dispensed from a second sub-nanoliter droplet dispenser.

152. 152. The method of any one of claims 146-151, further comprising assessing crystallization of the agent.

153. 153. The method of any one of claims 146 to 152, wherein the first organic carrier and the second organic carrier are the same.

154. 154. The method of any one of claims 146-153, wherein the first viscosity enhancing agent and the second viscosity enhancing agent are the same.

155. The method of any one of claims 143 to 154, wherein the substrate is a thin film.

156. 1. A droplet dispenser for producing a dosage form comprising a nanosuspension of a hydrophobic drug, comprising: (a) a dispensing head comprising one or more nozzles; (b) an aqueous carrier; and a first cartridge containing a suspension comprising a plurality of nanoparticles comprising a hydrophobic drug suspended in the aqueous carrier, wherein the viscosity of the suspension is less than 3 cP; a first cartridge, the first cartridge being operably coupled to a first dispensing head; and (c) a control system configured to dispense the mixture through the first dispensing head according to a dispensing pattern.

157. 157. The dispenser of claim 156, wherein the first dispensing head comprises from about 100 to about 1000 nozzles.

158. A dispenser according to claim 156 or 157, wherein each nozzle has an opening diameter of from about 20 μm to about 120 μm.

159. The dispenser of any one of claims 156 to 158, wherein the first dispensing head dispenses droplets using a thermal process.

160. The dispenser of any one of claims 156 to 159, wherein the first dispensing head dispenses droplets using a piezoelectric process.

161. 161. The dispenser of any one of claims 156 to 160, further comprising a second dispensing head operably connected to a second cartridge, the second cartridge containing a second medicament.

162. 162. The dispenser of claim 161, further comprising a third dispensing head operably coupled to a third cartridge, the third cartridge containing a protective coating.

163. 163. The dispenser of claim 162, further comprising a fourth dispensing head operably coupled to a fourth cartridge, the fourth cartridge containing an edible agent.

164. 1. A drop dispenser for producing a dosage form comprising an amorphous solid dispersion of a hydrophobic drug, comprising: (a) a first dispensing head comprising one or more nozzles; (b) a first mixture cartridge containing an ASD-forming solution comprising an organic carrier, the drug, a polymer, and a viscosity modifier, the drug and the polymer are present in the mixture in a ratio that inhibits crystallization of the drug upon drying on the substrate; a first mixture cartridge, the first mixture cartridge being operably coupled to the first dispensing head; and (c) a control system configured to dispense the mixture through the dispensing head according to a dispensing pattern.

165. 165. The dispenser of claim 164, wherein the first dispensing head comprises from about 100 to about 1000 nozzles.

166. 163. A dispenser according to claim 161 or 162, wherein each nozzle has an opening diameter of from about 20 μm to about 120 μm.

167. The dispenser of any one of claims 164 to 166, wherein the first dispensing head dispenses droplets using a thermal process.

168. The dispenser of any one of claims 164 to 167, wherein the first dispensing head dispenses droplets using a piezoelectric process.

169. A dispenser according to any one of claims 164 to 168, further comprising a second dispensing head operably connected to a second mixture cartridge, the second mixture cartridge containing a second mixture comprising a second drug.

170. 170. The dispenser of claim 169, further comprising a third dispensing head operably coupled to a third mixture cartridge, the third mixture cartridge containing a protective coating mixture.

171. 171. The dispenser of claim 170, further comprising a fourth dispensing head operably coupled to a fourth mixture cartridge, the fourth mixture cartridge containing an edible mixture.

172. A gradient of two components on a substrate, a first component comprising a hydrophobic drug; a second component comprising a polymer crystallization inhibitor; the ratio of the first component to the second component; and wherein the ratio varies across the gradient.

173. 173. The gradient of claim 172, wherein the first component further comprises an organic carrier.

174. 174. The gradient of claim 172 or 173, wherein the first component further comprises a viscosity enhancing agent.

175. 175. The gradient of any one of claims 172 to 174, wherein the second component further comprises an organic carrier.

176. 176. The gradient of any one of claims 172 to 175, wherein the second component further comprises a viscosity enhancing agent.

177. 177. The gradient of any one of claims 172-176, wherein the second component is capable of inhibiting crystallization of the hydrophobic drug.

178. 178. The gradient of any one of claims 172 to 177, wherein the first and second components each comprise an organic carrier, and the organic carriers are the same.

179. 179. The gradient of any one of claims 172 to 178, wherein the first and second components each comprise a viscosity enhancing agent, and the viscosity enhancing agents are the same.

180. 180. The gradient of any one of claims 172-179, wherein the ratio becomes sufficiently low at certain points on the gradient to prevent crystallization of the hydrophobic drug.

181. The gradient of any one of claims 172 to 180, wherein the first and second components are dispensed onto the substrate from a sub-nanoliter droplet dispenser.

182. 182. The gradient of any one of claims 172 to 181, wherein the first component is dispensed onto the substrate from a first sub-nanoliter droplet dispenser and the second component is dispensed onto the substrate from a second sub-nanoliter droplet dispenser.

183. 183. The gradient of any one of claims 172 to 182, wherein the ratio changes at a consistent rate across the gradient.

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