Method for improving bioavailability of organic small molecules and deposited film manufactured thereby

Abstract

A solid film and an article having a surface are provided, the surface having discrete regions patterned with deposited low molecular weight organic compounds (such as pharmaceutically active substances and new chemical entities). The organic compounds can be present in one or more discrete regions at ≥ about 99 mass % and can be crystalline or amorphous. The deposited organic compounds can be deposited as a film having a high surface area. As a non-limiting example, the deposited organic compounds exhibit improved solubility and bioavailability. Also provided is a method for depositing such low molecular weight organic compounds by organic vapor jet printing in an inert gas stream.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 171,702, filed on Jun. 5, 2015. The entire disclosure of the above application is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to pure deposited films of low - molecular - weight organic compounds (e.g., pharmaceutically active ingredients or new chemical entities), wherein such deposited low - molecular - weight organic compounds have improved bioavailability and solubility. Also provided are methods and apparatuses for depositing low - molecular - weight organic compounds by deposition methods, such as organic vapor jet printing deposition methods and apparatuses. Background Art

[0004] This section provides background information related to the present disclosure, which is not necessarily prior art.

[0005] Solutions of small - molecule organic compounds are widely used in many industries: by way of non - limiting examples, food, cosmetics / perfumes, pharmaceuticals, organic electronics, printing, and paint. Water solubility is an especially important factor in controlling the bioavailability of active pharmaceutical ingredients (APIs). Thus, the pharmaceutical industry faces many challenges. For example, more than 40% of newly discovered drugs / new chemical entities (NCEs) have low solubility and dissolution rates, making them less favorable candidates for further study. This problem is especially important for substances with low solubility and high permeability (class II type according to the Biopharmaceutics Classification System). Existing methods for improving solubility generally include physical modifications: reducing particle size, changing crystal habit, drug suspensions, solid dispersions, solid solutions, and cryogenic techniques; chemical modifications: changing pH, using buffers, salt formation, complexation, and other methods (e.g., using surfactants, cosolvency, hydrotrophy, and new excipients).

[0006] Methods for reducing particle size exploit the fact that the solubility of a drug depends inherently on the drug particle size: as the particle size decreases, the surface area to volume ratio increases, enhancing the interaction with the solvent and resulting in improved solvation. Conventional methods for reducing particle size (such as spray drying, milling, micronization, and nanosizing) introduce physical stress on the drug particles and potentially degrade sensitive NCE molecules and / or cause particle aggregation. In addition, these techniques generally require more complex processing techniques, including additional processing steps such as screening and dosing into specific dosages. Moreover, reducing particle size may not be feasible for high potency drugs requiring sub-microgram dosages or for newly developed drugs and drug candidates that are not yet available in large quantities (kilograms).

[0007] For example, nanosizing is a well-known method for improving the bioavailability of API powders. As described above, since the dissolution process is controlled by the surface area to volume ratio of the solute, reducing the particle size results in a larger surface area and a higher dissolution rate. However, nanosizing has many drawbacks. First, mechanical methods (such as ball milling and high pressure homogenization (HPH)) are energy-consuming and time-consuming. Second, the resulting nanoparticles may lack storage stability and controlled release. Third, formulating with nanoparticles is challenging because it is difficult to achieve uniformity and stability due to particle aggregation and changes in crystallinity.

[0008] In the initial discovery phase, these NCE compounds are typically added to cell cultures in solutions of organic solvents (such as dimethyl sulfoxide - DMSO). Initial drug testing involves dissolving the drug in an organic solvent (such as DMSO), which can provide an inaccurate assessment of drug potency and bioavailability. More specifically, solvents such as DMSO increase the solubility of drug molecules, affect cell membrane permeability, and potentially lead to the selection of "undruggable" NCEs. In addition, the lack of rapid phase screening methods in combination with limited amounts of drug often results in powders being used "as is", leading to a higher attrition rate in drug discovery. Even after establishing potency in vitro, later stages of drug development still involve chemical or physical modification to improve solubility limits and dissolution kinetics.

[0009] Thus, in conventional methods, to achieve a given concentration of an organic solute in its original powder form, the required amount of powder is directly immersed in a solvent and dissolved until all powder particles are separated into solvated molecules. This process is particularly challenging for low solubility substances with very slow dissolution rates. Therefore, the powder particle size can be reduced (by grinding or other methods), and the solution is typically heated to increase the dissolution rate. This method can be both time-consuming and energy-consuming and potentially damaging to the compound / solvent.

[0010] Another disadvantage of directly immersing a powdered solute in a solvent is when the actual desired concentration of the compound or the volume of the solution is very low. For example, if the desired concentration is in the micromolar range and the desired volume is 10 ml, the required weight of a 200 g / mol material is in the microgram range. It is not feasible to accurately measure this weight of the precursor powder; thus, a higher concentration solution is prepared and subsequently diluted with additional solvent. This method is not desirable from both economic and safety perspectives (when dealing with organic solvents).

[0011] A new simplified method for enhancing solubility and bioavailability, as well as the ability to screen the solubility and potency of compounds without using organic solvents, would be highly desirable and would significantly accelerate the drug development cycle and improve pharmaceutical compositions. SUMMARY OF THE INVENTION

[0013] This section provides an overview of the present disclosure, not an exhaustive disclosure of its full scope or all of its features.

[0014] In certain variations, the present disclosure provides a solid film that comprises a deposited low molecular weight organic active ingredient compound having a molecular weight less than or equal to about 1,000 g / mol and present in an amount greater than or equal to about 99 mass %. The low molecular weight organic active ingredient compound can be a pharmaceutical active or a new chemical entity. The deposited low molecular weight organic compound has enhanced solubility compared to the non-deposited powdered form of the low molecular weight organic compound.

[0015] In other variations, the present disclosure provides an article that comprises a surface of a solid substrate, the surface having one or more discrete regions patterned with a deposited low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol. In certain aspects, the deposited low molecular weight organic compound is present in the one or more discrete regions in an amount greater than or equal to about 99 mass %.

[0016] In other variations, the present disclosure provides an article that comprises a pharmaceutically acceptable substrate that defines a surface. The article further comprises a deposited solid low molecular weight pharmaceutical active ingredient having a molecular weight less than or equal to about 1,000 g / mol. The deposited solid low molecular weight pharmaceutical active ingredient is present in an amount greater than or equal to about 99 mass % in one or more discrete regions on the surface of the pharmaceutically acceptable substrate.

[0017] In other specific variations, the present disclosure provides an article that comprises a solid deposited film that contains a pharmaceutical composition. The pharmaceutical composition comprises at least one low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol.

[0018] In other variations, the present disclosure provides a solventless vapor deposition method that includes depositing a low molecular weight organic compound, such as one having a molecular weight less than or equal to about 1,000 g / mol, on one or more discrete regions of a substrate in a substantially solvent-free manner. The method can be selected from: vacuum thermal evaporation (VTE), organic vapor jet printing (OVJP), organic vapor phase deposition (OVPD), organic molecular beam deposition (OMBD), molecular jet printing (MoJet), organic vapor jet printing (OVJP), and organic vapor phase deposition (OVPD). The deposited low molecular weight organic compound is present in the one or more discrete regions in an amount greater than or equal to about 99 mass %.

[0019] In other specific variations, the present disclosure provides an organic vapor jet printing deposition method that includes entraining a low molecular weight organic compound in an inert gas stream by heating a solid low molecular weight organic compound source to sublime the low molecular weight organic compound. The inert gas stream is passed over, by, or through the source. The low molecular weight organic compound is directed through a nozzle toward a cooled target. Then, the low molecular weight organic compound condenses when it contacts the cooled target.

[0020] In other specific variations, the present disclosure provides a method for rapidly dissolving a low molecular weight organic compound. The method includes passing a gas stream containing an inert gas through a heated source of the low molecular weight organic compound. The low molecular weight organic compound volatilizes and is entrained in the gas stream. Then, the low molecular weight organic compound is deposited into a liquid containing one or more solvents by passing the gas stream through a nozzle toward the liquid. In this way, the deposited low molecular weight organic compound dissolves in the liquid.

[0021] Further application areas will become apparent from the description provided herein. The description and specific examples in the summary of the invention are intended for illustrative purposes only and are not intended to limit the scope of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The accompanying drawings described herein are for illustrative purposes only for the selected embodiments and not all possible implementations, and are not intended to limit the scope of the present disclosure.

[0023] Figures 1(a) through 1(d) illustrate schematic views of an organic vapor jet printing deposition technique and apparatus in accordance with certain aspects of the present disclosure. Figure 1(a) illustrates an organic vapor jet deposition (OVJP) system for a small molecule drug deposition system. Figure 1(b) illustrates a mixed layer OVJP deposition mode - the system includes multiple sources of materials to be evaporated that are subsequently mixed in a main jet stream. Figure 1(c) illustrates a multi-layer mode of OVJP deposition for forming different materials in one or more discrete regions on the surface of a substrate, where the different materials can overlap each other. Figure 1(d) illustrates a select patterning mode of OVJP deposition for depositing different materials.

[0024] Figures 2(a) through 2(b) illustrate schematic views of a dedicated design of a source or organic material for an OVJP deposition technique in accordance with certain aspects of the present disclosure. Figure 2(a) illustrates an evaporation source that includes a housing ("boat case") and a ceramic foam plug that can sublime and transport evaporated molecules in a highly reproducible manner through the porous foam. Figure 2(b) illustrates an example of an evaporation source implementation. The boat case is made of quartz, and the ceramic foam is silicon carbide from Ultramet with a porosity of 80 pores per inch (ppi). The powder to be evaporated is placed between the porous foam disks or between a foam disk and a portion of quartz wool. After washing away the organic powder with an appropriate solvent, the source can be reused.

[0025] Figure 3 Multiple examples of printed pharmaceutical organic compounds deposited by an organic vapor jet printing deposition technique are shown in accordance with certain aspects of the present disclosure.

[0026] Figures 4(a) through 4(b) illustrate an example of a printed drug film with a deposited organic compound (BAY 11-7082), and comparative tests of the deposited film compared to a comparative DMSO preparation are used to evaluate biological potency in accordance with certain aspects of the present disclosure.

[0027] Figures 5(a) to 5(c) show schematic diagrams of an organic vapor jet printing deposition technique and apparatus according to certain alternative aspects of the present disclosure. Figure 5(a) shows a schematic diagram of a rapid dissolution system for low molecular weight organic compounds according to certain aspects of the present disclosure. Figures 5(b) to 5(c) show an example of jetting fluorescein molecules into a 2 ml aqueous phosphate buffered saline solution. Jetting conditions: carrier gas: nitrogen. Carrier gas flow rate: 200 sccm. Source temperature: 300 °C; substrate temperature: 20 °C; nozzle tip inner diameter: 0.5 mm; nozzle tip - liquid surface spacing distance: 20 mm. In Figure 5(c), the concentration changes with the jetting duration. The concentration is measured by fluorescence spectroscopy calibrated with dissolved fluorescein powder.

[0028] Figures 6(a) to 6(r) show the surface morphology of solid printed films of caffeine, tamoxifen, BAY 11-7082, acetaminophen, ibuprofen, and fluorescein. Figures 6(a) to 6(f) show the chemical structures of the tested compounds. Figures 6(g) to 6(l) show the deposited film morphology after jetting according to certain aspects of the present teachings. Figures 6(m) to 6(r) show the original microstructures of the compound powders.

[0029] Figures 7(a) to 7(h) show drug films prepared according to certain aspects of the present disclosure and their structural characterization compared to powders of the same drugs. Figure 7(a) shows the ultra-performance liquid chromatography results (UPLC) of caffeine powder and a caffeine deposited film according to certain aspects of the present teachings. Figure 7(b) shows the UPLC of tamoxifen powder and the deposited film. Figure 7(c) shows the UPLC of BAY 11-7082 powder and the deposited film. Figure 7(d) shows the UPLC of acetaminophen powder and the deposited film. Figure 7(e) shows the X-Ray Diffraction (XRD) of caffeine powder and the deposited film, with the corresponding average crystal size. Figure 7(f) shows the XRD of tamoxifen powder and the deposited film, with the corresponding average crystal size. Figure 7(g) shows the XRD of BAY 11-7082 powder and the deposited film. Figure 7(h) shows the XRD of acetaminophen powder and the deposited film, with the corresponding average crystal size.

[0030] Figures 8(a) to 8(d) illustrate some examples of different coating forms of fluorescein on different substrates. Figure 8(a) shows a solid deposition film of fluorescein on an acrylic polymer wound care patch, Figure 8(b) shows a solid deposition film of fluorescein on a pullulan-based film, Figure 8(a) shows a solid deposition film of fluorescein on stainless steel microneedles, and Figure 8(a) shows a solid deposition film of fluorescein on a borosilicate glass slide.

[0031] Figures 9(a) to 9(b) illustrate the controlled release of a printed fluorescein film prepared according to certain aspects of the present disclosure. Figure 9(a) shows the dissolution curves of printed fluorescein films with different thicknesses and a constant area. The inset in Figure 9(a) shows the correlation of (1 - exp(-kt)) with the film thickness. Figure 9(b) shows the dissolution curves of printed fluorescein films with different diameters and a constant thickness. The dashed lines are experimental. The solid lines are the predicted theoretical values. The inset in Figure 9(b) shows the film dissolution rate relative to the film area.

[0032] Figures 10(a) to 10(c) show comparative dissolution curves of films and powders. Figure 10(a) shows the dissolution curves of a fluorescein film and the original powder in deionized water. The dashed lines are experimental values. The solid lines are the theoretical predictions for the film and the powder. Figure 10(b) shows the dissolution curves of an ibuprofen film and the original powder in an HCl buffered aqueous solution at pH 1.2. The dashed lines show the experimental values. The solid lines show the theoretical predictions for the film and the powder. Figure 10(c) shows the dissolution curves of a tamoxifen film and the original powder in an acetate buffered solution at pH 4.9. The dashed lines show the experimental values. The solid lines show the theoretical predictions for the film and the powder.

[0033] Figure 11 Shows a schematic diagram of drug application for cancer cell growth studies.

[0034] Figures 12(a) to 12(d) illustrate the improvement in biological potency of deposition films prepared according to certain aspects of the present disclosure compared to conventional formulations. Figure 12(a) shows the MCF7 cell treatment curve using tamoxifen (solid line - eye guide). Figure 12(b) shows the OVCAR3 cell treatment curve using tamoxifen (solid line - eye guide). Figure 12(c) shows the MCF7 cell treatment curve using BAY 11-7082 (solid line - eye guide). Figure 12(d) shows the OVCAR3 cell treatment curve using BAY 11-7082 (solid line - eye guide).

[0035] Figure 13A graph showing the membrane specific surface area of different printing film weights as a function of the deposited film area.

[0036] Corresponding reference numerals in the various views throughout the drawings indicate corresponding parts. DETAILED DESCRIPTION OF THE INVENTION

[0038] Some exemplary embodiments are provided so that the present disclosure is thorough and conveys the full scope to those skilled in the art. A number of specific details (such as examples of specific compositions, components, devices, and methods) are set forth to provide a thorough understanding of the embodiments of the present disclosure. It will be apparent to those skilled in the art that specific details need not be used and that the exemplary embodiments may be embodied in many different forms and neither should be construed as limiting the scope of the present disclosure. In some exemplary embodiments, well-known methods, well-known device structures, and well-known technologies are not described in detail.

[0039] The terms used herein are for the purpose of describing particular exemplary embodiments only and are not intended to be limiting. As used herein, unless the context clearly dictates otherwise, a noun without a quantifier means one or more. The terms "comprising," "containing," "including," and "having" are inclusive and thus specify the presence of the stated features, elements, compositions, steps, integers, operations, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. Although the open-ended term "comprising / including" should be understood as a non-limiting term for describing and claiming the various embodiments set forth herein, in some aspects, the term may alternatively be understood as a more restrictive term, such as "consisting of" or "consisting essentially of." Thus, for any given embodiment that recites a composition, material, component, element, feature, integer, operation, and / or processing step, the present disclosure also specifically includes embodiments consisting of or consisting essentially of such recited composition, material, component, element, feature, integer, operation, and / or processing step. In the case of "consisting of," alternative embodiments exclude any additional composition, material, component, element, feature, integer, operation, and / or processing step, while in the case of "consisting essentially of," any additional composition, material, component, element, feature, integer, operation, and / or processing step that materially affects the basic and novel features is excluded from the embodiment, but any composition, material, component, element, feature, integer, operation, and / or processing step that does not materially affect the basic and novel features may be included in the embodiment.

[0040] Unless specifically determined to be carried out in a particular order, any method steps, processes, and operations described herein should not be construed as necessarily requiring them to be carried out in the particular order discussed or illustrated. It should also be understood that, unless otherwise stated, alternative or additional steps may be employed.

[0041] When a component, element, or layer is referred to as being "on", "engaged with", "connected to", or "coupled to" another element or layer, it can be directly on, engaged with, connected to, or coupled to another component, element, or layer, or intervening elements or layers may be present. In contrast, when an element is referred to as being "directly on", "directly engaged with", "directly connected to", or "directly coupled to" another element or layer, intervening elements or layers may not be present. Other words used to describe the relationship between elements should be interpreted in the same manner (e.g., "between" relative to "directly between", "adjacent" relative to "directly adjacent", etc.). As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0042] Unless otherwise stated, although the terms first, second, third, etc. may be used herein to describe different steps, elements, components, regions, layers, and / or parts, these steps, elements, components, regions, layers, and / or parts should not be limited by these terms. These terms may be used only to distinguish one step, element, component, region, layer, and / or part from another step, element, component, region, layer, and / or part. Unless the context clearly indicates otherwise, the terms (e.g., "first", "second", and other numerical terms) used herein do not imply an order or sequence. Thus, without departing from the teachings of the exemplary embodiments, the first step, element, component, region, layer, or part discussed below may be referred to as the second step, element, component, region, layer, or part.

[0043] For convenience of description herein, spatial or time-related terms (e.g., "before", "after", "inside", "outside", "below", "beneath", "lower", "above", "upper", etc.) may be used to describe the relationship of one element or feature to another element or feature as shown in the figures. Spatial or time-related terms may be intended to include different orientations of the device or system in use or operation in addition to the orientation depicted in the figures.

[0044] Throughout this disclosure, approximate measures or limitations of numerical ranges are intended to include deviations that are less than the given value and embodiments that have about the recited value and embodiments that have exactly the recited value. Except in the working examples provided at the end of the detailed description of the invention, all numerical values of parameters (e.g., amounts or conditions) in this specification (including the appended claims) should be understood to be modified in all instances by the term "about", whether or not the term "about" actually appears before the numerical value. "About" means that the recited numerical value allows some slight imprecision (with some methods achieving the value precisely; approximating or reasonably approaching the value; nearly). If the imprecision provided by "about" is not understood in this ordinary sense in the art, then "about" as used herein means at least the variation that can be caused by the ordinary methods of measuring and using these parameters.

[0045] In addition, the disclosure of a range includes the disclosure of all values within the entire range and further divided ranges, including the endpoints and sub-ranges given by the range.

[0046] Some exemplary embodiments will now be described more fully with reference to the accompanying drawings.

[0047] This disclosure provides new and simplified methods for enhancing the solubility and bioavailability of organic compounds, particularly those new chemical entities (NCEs) used in drug development or drug compounds. In various aspects, the compositions, articles, and methods of this teaching provide the enhanced ability to screen the solubility and potency of compounds without the use of organic solvents, which can significantly accelerate the drug development cycle and improve drug compositions.

[0048] In some aspects, the present disclosure provides materials and methods for the continuous manufacture and personalized administration of active ingredients. In various aspects, the present disclosure provides solid films comprising low molecular weight organic compounds. In some aspects, the molecular weight of the low molecular weight compound can be less than or equal to about 1,000 g / mol, optionally less than or equal to about 900 g / mol, optionally less than or equal to about 800 g / mol, optionally less than or equal to about 700 g / mol, optionally less than or equal to about 600 g / mol, optionally less than or equal to about 500 g / mol, optionally less than or equal to about 400 g / mol, optionally less than or equal to about 300 g / mol, and in some variations optionally less than or equal to about 200 g / mol. In some variations, the molecular weight of the low molecular weight compound can be greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol. The solid film can comprise a plurality of low molecular weight organic compounds. In some variations, the low molecular weight organic compound is an active compound, such as a pharmaceutically active compound or a new chemical entity (a compound being investigated for potential pharmacological or biological activity), as will be further described below. However, in some alternative variations, by way of non-limiting example, the low molecular weight organic compound can be a nutritional or food compound, a nutraceutical compound, a cosmetic or personal care compound, an aromatic compound, a colorant or dye, an ink, a paint, etc.

[0049] Accordingly, the present disclosure provides solid films, such as deposited low molecular weight organic compounds (e.g., pharmaceutical active agents or novel chemical entities) patterned on the surface of a substrate. In some variations, the surface has a continuous organic compound surface coating or film, while in other variations, the organic compound can be applied to selected discrete regions of the surface. High-quality films or coatings of low molecular organic compounds with high purity levels are formed by methods according to certain aspects of the present disclosure. For example, in some variations, the purity level in one or more regions where the low molecular weight compound is deposited can be greater than or equal to about 90 mass% of the low molecular weight compound, optionally greater than or equal to about 95 mass%, optionally greater than or equal to about 97 mass%, optionally greater than or equal to about 98 mass%, and in some preferred aspects, optionally greater than or equal to about 99 mass%, optionally greater than or equal to about 99.5 mass%, optionally greater than or equal to about 99.7 mass%, and in some variations, greater than or equal to about 99.99 mass% purity concentration. In some variations, there are multiple low molecular weight compounds that together or cumulatively have the same purity level. The deposited solid film can have surface feature morphologies ranging from molecularly flat to high surface area (e.g., nanostructured surfaces) with characteristic dimensions in the micron or nanometer range. Such surfaces patterned with organic compounds enhance the solubility of medical organic compounds and substances both at the initial research stage and at the production level.

[0050] In some aspects, methods are provided for obtaining solid films with high levels of purity and solubility. For example, in some variations, a solvent-free vapor deposition method is provided that includes depositing a low molecular weight organic compound on one or more discrete regions of a substrate in a substantially solvent-free manner. "Substantially solvent-free" means that no solvent compounds or substances are present to an extent where undesired and / or harmful effects are negligible or absent. In some aspects, the substantially solvent-free vapor deposition method has less than or equal to about 0.5 wt%, optionally less than or equal to about 0.1 wt%, and in some preferred aspects, 0 wt% of undesired solvent substances during the deposition process.

[0051] The then deposited low molecular weight organic compound can be present in one or more discrete regions at a high purity level (e.g., greater than or equal to about 99 mass% as described above). The methods for depositing the low molecular weight organic compound can be selected from vacuum thermal evaporation (VTE), organic vapor jet printing (OVJP), organic vapor phase deposition (OVPD), organic molecular beam deposition (OMBD), molecular jet printing (MoJet), organic vapor jet printing (OVJP), and organic vapor phase deposition (OVPD).

[0052] In some aspects, such a method can include entraining a low molecular weight organic compound in an inert gas stream or in a vacuum that is substantially free of any solvent prior to deposition. The inert gas stream can contain one or more compounds that are generally non-reactive, such as nitrogen, argon, helium, etc. In certain variations, the inert gas stream contains nitrogen.

[0053] Because many low molecular weight organic compounds (such as small molecule drugs) have a sufficiently high vapor pressure (e.g., from about 1 Pa to about 100 Pa) and a relatively low enthalpy of evaporation (e.g., 100 to 300 kJ / mol), even when evaporating at atmospheric pressure, a high evaporation rate (on the order of grams / (second * m 2 ) can be achieved at temperatures from 100 °C to 500 °C without reaching a temperature range where compound degradation can occur. Any method / system capable of depositing molecular material from the gas phase onto a substrate (where the molecular material source is an evaporating or subliming solid) can be used to form the deposited low molecular weight organic compound pharmaceutical substance. This includes, but is not limited to: vacuum thermal evaporation (VTE), organic vapor phase deposition (OVPD), organic molecular beam deposition (OMBD), and molecular jet printing (MoJet).

[0054] However, the method is not limited to solid sources of low molecular weight compounds. In some aspects, prior to entrainment, the low molecular weight organic compound is in a form selected from: powder, pressed granules, porous material, and liquid. In some aspects, prior to entrainment, the low molecular weight organic compound is dispersed in the pores of a porous material. In other aspects, prior to entrainment, the low molecular weight organic compound is dispersed in a liquid bubbler through which the inert gas stream passes. In other aspects, the entrainment of the low molecular weight organic compound in the inert gas stream or in a vacuum is carried out by heating a solid low molecular weight organic compound source to sublime or evaporate the low molecular weight organic compound. In certain variations, the deposition method results in the low molecular weight organic compound being deposited onto one or more discrete regions with a loading density greater than or equal to about 1×10 -4 g / cm 2 and less than or equal to about 1 g / cm 2 of the deposited low molecular weight organic compound pharmaceutical substance.

[0055] The parameters of the deposition process can be adjusted to control or affect the morphology, crystallinity, or both the morphology and crystallinity of the deposited solid low molecular weight organic compound. The parameters are selected from: system pressure, flow rate of the inert gas stream, composition of the inert gas, temperature of the low molecular weight organic compound source, composition of the substrate, surface texture of the substrate, temperature of the substrate, and combinations thereof.

[0056] In some aspects, the specific surface area of the deposited low molecular weight organic compound is greater than or equal to about 0.001 m 2 / g and less than or equal to about 1,000 m2 / g. The deposited low molecular weight organic compound can be amorphous. When the deposited low molecular weight organic compound is amorphous, it can also define interconnected particles with an average particle size (e.g., average particle diameter) of greater than or equal to about 2 nm to less than or equal to about 200 nm. In other aspects, the deposited low molecular weight organic compound is crystalline or polycrystalline. In some such variations, the average crystal size or crystal domain can be greater than or equal to about 2 nm to less than or equal to about 200 nm.

[0057] In certain aspects, one or more discrete regions on which the low molecular weight organic compound is deposited are continuous, such that a solid film is formed on the surface of the substrate. In certain variations, one or more discrete regions of the surface have a high surface area morphology, which can optionally define one or more nanostructures or microstructures. In certain variations, the average thickness of the low molecular weight organic compound deposited in one or more discrete regions of the surface of the substrate can be less than or equal to about 300 nm, and the average surface roughness (R a ) can be less than or equal to about 100 nm. Thus, for a solid deposited film with a thickness of 200 ± 100 nm, the film is flat (roughness < 100 nm). Starting from a thickness of about 200 ± 100 nm, undulations appear in the solid deposited film, which further generate and define nanostructures. As used herein, "nanoscale" is generally understood by those skilled in the art to mean that at least one spatial dimension is less than about 50 μm (i.e., 50,000 nm), and optionally less than about 10 μm (i.e., 10,000 nm). In certain aspects, the average thickness of the low molecular weight organic compound deposited in one or more discrete regions is greater than or equal to about 300 nm, and the deposited low molecular weight organic compound defines a nanostructured surface having a plurality of nanostructures, the main dimensions of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm. The resulting morphology depends on the thermophysical properties of the low molecular weight organic compound, the substrate material, and the deposition conditions. The plurality of nanostructures can have shapes selected from: needles, tubes or cylinders, rods, platelets, circular particles (although they need not be perfectly circular or annular), droplets, fronds, dendritic or fern-like structures, fractals, hemispheres, puddles, interconnected puddles, islands, interconnected islands, and combinations thereof. The shape of the nanostructures formed depends on the low molecular weight organic compound being deposited as well as the deposition process conditions and film thickness.

[0058] In certain variations, the purity level of the low molecular weight organic compound deposited in one or more discrete regions is any of those previously described, such as greater than or equal to about 99.5 mass %. Suitable low molecular weight organic compounds (which may be drug active ingredients or new chemical entities) can include (as non-limiting examples): a variety of drugs or potential drugs (e.g., new chemical entities), including anti-proliferatives; anti-rejection drugs; anti-thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; anti-progesterones; anti-androgens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); anti-microbial agents; anti-viral agents; anti-fungal agents; antibiotics; chemotherapeutic agents; anti-neoplastic / anti-miotic agents; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof. The description of these suitable organic compounds / drug active ingredients / new chemical entities is merely exemplary and should not be considered as limiting the scope of compounds or active ingredients that can be applied to the surface according to the present disclosure, as all organic molecules and / or active ingredients known in the art that are suitable for these various types of compositions are contemplated. In addition, an organic compound can have multiple functions and can thus be included in the above exemplary categories; however, it can be classified in multiple different categories of active ingredients.

[0059] A variety of suitable active ingredients are described in the Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Edition (2001), Merck Research Laboratories and the International Cosmetic Ingredient Dictionary and Handbook, 10th Edition, 2004, Cosmetic Toiletry and Fragrance Association and in http: / / www.drugbank.ca / is disclosed above, and the relevant parts of each of them are incorporated herein by reference. Each additional reference cited or described herein is hereby expressly incorporated by reference in its entirety. In certain variations, the low molecular weight organic compound is an active ingredient compound selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof. BAY 11-7082 ((E)-3-(4-methylphenylsulfonyl)-2-propenenitrile) selectively and irreversibly inhibits the activation of the transcription factor NF-κB (which otherwise regulates the expression of inflammatory cytokines, chemokines, immune receptors, and cell adhesion molecules) and can inhibit the surface expression of TNF-α-induced adhesion molecules ICAM-1, VCAM-1, and E-selectin in human endothelial cells.

[0060] In certain variations, the deposited low molecular weight organic compound has an increased dissolution rate compared to the same low molecular weight organic compound deposited in a comparative powder or particulate form. Thus, the dissolution rate of the deposited low molecular weight organic compound in an aqueous solution (e.g., near physiological conditions) is at least ten times greater than the comparative dissolution rate of the deposited low molecular weight organic compound in a comparative powder or particulate form. In certain variations, the dissolution rate of the deposited low molecular weight organic compound in an aqueous solution is at least fifteen times greater than the comparative dissolution rate of the deposited low molecular weight organic compound in a powder or particulate form, optionally twenty times greater, and optionally thirty times greater.

[0061] Due to the different biological processes of different drugs, increasing the dissolution rate also increases the bioavailability, especially for organic compounds where the dissolution rate difference is limiting. Thus, in certain variations, the deposited low molecular weight organic compounds have increased bioavailability compared to the same low molecular weight organic active ingredient in a comparative powder or particulate form, such as the amount and / or rate at which the organic compound is absorbed into a living organism or system. In certain variations, the bioavailability is increased, whether measured by the amount or rate of uptake of the compound in a living organism or system. Such organisms or living systems can include (by way of non-limiting example): animals, such as mammals (e.g., humans) and companion animals; plants; bacteria; prokaryotic cells; eukaryotic cells; and the like. In certain instances, when the low molecular weight organic active ingredient compound is in a deposited solid form, its bioavailability can be increased, being at least about 10% greater than the comparative bioavailability of the low molecular weight organic active ingredient in a comparative powder or particulate form. When the low molecular weight organic active ingredient compound is deposited by the methods of the present disclosure, the bioavailability can be increased by at least about 20%, optionally at least about 30%, optionally at least about 40%, optionally at least about 50%, optionally at least about 60%, optionally at least about 70%, optionally at least about 80%, optionally at least about 90%, and in certain variations, the bioavailability is increased by more than about 100%.

[0062] In certain aspects, solid films having a high surface area morphology can be formed by an improved organic vapor jet printing (OVJP) method that eliminates the need for organic solvents and increases the dissolution rate of small molecule-based organic materials (such as APIs). Organic compounds that can be deposited by the OVJP method have a relatively low molecular weight and are thus considered low molecular weight organic compounds. The OVJP method utilizes a carrier gas (e.g., nitrogen) to transport the sublimed organic vapor in the form of a focused gas jet towards a cooled substrate or other target. The OVJP method enables scalable patterning of relatively small molecular materials.

[0063] Thus, in some aspects, the OVJP deposition method is performed using the OVJP system 100 shown in FIG. 1(a). The cylindrical reactor 102 contains a source 110 of low molecular weight organic compounds. The source 110 is a low molecular weight organic compound in solid form (e.g., powder or pressed pellets). The source 110 may hold or contain a low molecular weight organic compound, e.g., a porous material having a low molecular weight organic compound distributed within pores. The reactor 102 has an inlet 112 through which an inert carrier gas stream 120 enters. A heater 114 is disposed externally around or may otherwise be integrated into the reactor 102. The material in the evaporation source 110 sublimes or evaporates and is carried by the inert carrier gas 120. Thus, the method includes entraining a low molecular weight organic compound in the inert carrier gas stream 120 by heating the source 110 to sublime or evaporate the low molecular weight organic compound 130 such that it is in vapor form and entrained in the inert carrier gas stream 120. Entrainment may occur by passing the inert carrier gas stream 120 over, past, or through the source 120. Controllable system parameters include carrier gas flow rate (sccm), evaporation source temperature (° C.), and substrate temperature (° C.). As shown in FIG. 1(a), the low molecular weight organic compound 130 in the inert carrier gas stream 120 is directed through a nozzle 132 as a focused jet stream 134 toward a cooling target 140. The nozzle 132 is translated above the substrate by an xyz motion controller and is capable of printing any desired deposition pattern.

[0064] The cooling target 140 can be solid or liquid. The cooling target 140 can be a substrate made of, for example, materials such as glass, metal, silicone, polymer, hydrogel, organogel, natural fiber, synthetic fiber, and any combination thereof. As will be further described below, the cooling target 140 can be a microneedle, medical device, implant, membrane, gel, patch, dressing, fabric, bandage, sponge, scaffold, contact lens, subretinal implantable prosthesis, denture, brace, wearable device, bracelet, and combinations thereof. When the cooling target 140 is liquid, it can be a polar or nonpolar liquid, including aqueous liquids. The liquid may contain one or more solvents.

[0065] The method also includes condensing the low molecular weight organic compound 130 when it contacts the cooling target 140 in one or more discrete regions. In this way, the surface of the cooling target 140 can be selectively patterned by directing the spray jet 134 towards the desired region (or the surface can be temporarily masked). In the variant shown in Figure 1(a), one or more discrete regions in the surface of the cooling target 140 are continuous, and the condensed low molecular weight organic compound forms a solid film 150 on the surface of the cooling target 140. In some aspects, the loading density of the condensed low molecular weight organic compound deposited onto one or more discrete regions of the cooling target 140 can be greater than or equal to about 1×10 -4 g / cm 2 to less than or equal to about 1 g / cm 2 . In some variants, the specific surface area of the condensed low molecular weight organic compound on the surface of the cooling target 140 is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1000 m 2 / g. Figure 13 A graph is shown of the specific surface area of films of different printed film weights (100 μg, 200 μg, 300 μg, 400 μg, and 1000 μg) as a function of the deposited film area. For samples of smaller mass, the specific surface area of the deposited film is higher, and as the mass increases, the specific surface area decreases. As the printed film area increases, the surface area increases. When nanoparticles are grown on the deposited film, the surface area increases further (by about 2 to 10 times, depending on the particle shape and size). For comparison, powdered organic particles typically have a size of 1 μm to 100 μm and a surface area of 0.1 m 2 / g to 1 m 2 / g. Thus, the increase in surface area can be several orders of magnitude greater according to the printed area (as shown by the curves in Figure 13 ).

[0066] The thickness can be varied according to the amount of time the spray jet 134 is directed at a specific region of the surface of the cooling target 140 where the condensed low molecular weight organic compound condenses. In some variants, when the average thickness of the solid film 150 of the condensed low molecular weight organic compound in one or more discrete regions is less than or equal to about 300 nm, the average surface roughness (R aThe two-dimensional profile, if any, taken perpendicular to the surface of the layer is less than or equal to about 100 nm. As described above, for the solid film 150 having a thickness of 200 ± 100 nm, the film is generally flat, with a surface roughness less than about 100 nm. Starting from a thickness of about 200 ± 100 nm, undulations appear in the solid film 150, which further give rise to and define a plurality of nanostructures 152. In this way, the surface of the solid film 150 is nanostructured.

[0067] When the average thickness of the solid film is greater than or equal to about 300 nm, the average surface roughness (R a ) can be greater than or equal to about 100 nm. Additionally, in the case where the average thickness of the solid film 150 is greater than or equal to about 300 nm, the condensed low molecular weight organic compound can define a nanostructured surface having a plurality of nanostructures 152, and the major dimension (e.g., the maximum dimension, as shown by the length of a nanorod or nanocylinder) of the nanostructures 152 can be greater than or equal to about 5 nm to less than or equal to about 10 μm.

[0068] Depending on the OVJP conditions used and the chemical nature of the condensed low molecular weight organic compound, the nanostructures 152 can have different shapes. See, for example, Figure 3 and FIGS. 7(a) to 7(h). In some aspects, the plurality of nanostructures 152 have a shape selected from: needles, tubes, rods, or cylinders, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

[0069] Although the solid film 150 can have any purity level as previously described above, in some variations, the condensed low molecular weight organic compound is present at greater than or equal to about 99.5 mass %.

[0070] Two variations of the OVJP apparatus and method are described herein. In one variation, the deposition of the organic compound is carried out under atmospheric pressure conditions rather than pumping medium vacuum (10 -3 torr). This method can be carried out in a glove box with a suitable ventilation device. In the case of oxygen or moisture-sensitive organic compounds, this method can be carried out in a glove box with an inert gas environment. In other variations, the entrainment and guidance are carried out under reduced pressure conditions, e.g., at greater than or equal to about 0.1 torr to less than or equal to about 500 torr.

[0071] In other aspects, parameters of the OVJP process can be adjusted to affect the morphology, crystallinity, or both the morphology and crystallinity of the condensed low molecular weight organic compounds. The parameters can be selected from: system pressure, flow rate of the inert gas stream, inert gas composition, source temperature, target substrate composition, surface texture of the target substrate, target substrate temperature, and combinations thereof. The morphology can include the formed nanostructures. The condensed low molecular weight organic compounds in the solid film 150 can be amorphous. In other aspects, the condensed low molecular weight organic compounds in the solid film 150 are crystalline or polycrystalline. The low molecular weight organic compounds can be any of those previously described above.

[0072] Figure 1(b) shows another OVJP system 160 for performing an OVJP deposition method, which is similar to that shown in Figure 1(a), except that two different low molecular weight organic compounds are co-deposited. For the sake of brevity, components that are the same as those in the OVJP system 100 in Figure 1(a) will not be re-introduced or discussed unless specifically addressed herein. In the OVJP system 160, the first cylindrical reactor 162 contains a first source 164 of a first low molecular weight organic compound. The first cylindrical reactor 162 also has a heater 166 and a nozzle 168. The second cylindrical reactor 172 contains a second source 174 of a second low molecular weight organic compound. The second cylindrical reactor 172 also has a heater 176 and a nozzle 178. The first and second sources 164, 174 can be like the source 110 in Figure 1(a). A first inert carrier gas stream 182 enters the first cylindrical reactor 162, while a second inert carrier gas stream 192 enters the second cylindrical reactor 172. A third inert carrier gas stream 194 can pass through the conduit 196. Thus the method includes entraining a first low molecular weight organic compound in the first inert carrier gas stream 180 in the first cylindrical reactor 162 by heating the first source 164 to sublime or evaporate the first low molecular weight organic compound 200 so that it is in vapor form and entrained in the inert carrier gas stream 180. The second low molecular weight organic compound 202 is also entrained in the second inert carrier gas stream 192 in the second cylindrical reactor 172 by heating the second source 174 to sublime or evaporate the second low molecular weight organic compound 202 so that it is in vapor form and entrained in the second inert carrier gas stream 192. It is noted that the first source 164 in the first cylindrical reactor 162 and the second source 174 in the second cylindrical reactor 172 can be heated to different temperature ranges to sublime or evaporate different low molecular weight compounds having different thermodynamic properties. The inert carrier gas stream 180 having the entrained first low molecular weight organic compound 200, the second inert carrier gas stream 192 having the entrained second low molecular weight organic compound 202, and the third inert carrier gas stream 194 all enter the main cylindrical reactor 210 having a heater 212. The three streams containing the vapor phase of the first low molecular weight organic compound 200 and the second low molecular weight organic compound 202 are combined and mixed together to form a mixed stream 214, and the mixed stream 214 exits the nozzle 216 of the main cylindrical reactor 210 to form a jet stream 218. As in Figure 1(a), the jet stream 218 containing the vapor phase of the first low molecular weight organic compound 200 and the vapor phase of the second low molecular weight organic compound 202 is directed through the nozzle 216 towards the cooling target 220. The cooling target 220 can be like the cooling target 140 in Figure 1(a).

[0073] The method further includes condensing a first low molecular weight organic compound 200 and a second low molecular weight organic compound 202 when they contact a cooling target 220 in one or more discrete regions thereof. In this way, the surface of the cooling target 220 can be selectively patterned by directing the jet stream 218 towards a desired region (or the surface can be temporarily masked). In the variant shown in Fig. 1(b), one or more discrete regions in the surface of the cooling target 220 are continuous, and the condensed low molecular weight organic compounds form a solid film 230 on the surface of the cooling target 220. The solid film 230 can have the same properties as described in the context of the solid film 150 in Fig. 1(a), except that it is a homogeneous mixture of two different low molecular weight organic compounds. As shown, the solid film 230 has a nanostructure 232 in the form of nanorods or nanocylinders. When considering the cumulative amounts of both the first low molecular weight organic compound 200 and the second low molecular weight organic compound 202, the solid film 230 contains any of the purity levels described above, and in some variants, the cumulative amount of the condensed low molecular weight organic compounds is present in some variants at greater than or equal to about 99 mass% and optionally greater than 99.5 mass%. As will be understood by those skilled in the art, more than two different low molecular weight organic compounds can be applied in the OVJP method and system as shown.

[0074] Fig. 1(c) shows another OVJP system for the multilayer deposition of different low molecular weight organic compounds, in which two different cylindrical reactors similar to those described in Fig. 1(b) are independently directly sprayed onto a cooling substrate such that the first low molecular weight organic compound or the second low molecular weight organic compound condenses on one or more selected regions of the cooling substrate. Thus, different deposited solid films are formed on the cooling target. These films can overlap and form a multilayer system in one or more regions. Fig. 1(d) shows the patterning mode of the OVJP system as in Fig. 1(c), where the first low molecular weight organic compound or the second low molecular weight organic compound is respectively simultaneously applied to discrete regions of the surface, but do not overlap with each other to form a predetermined pattern (e.g., a dot array). Any pattern can be fabricated by translating the nozzles independently of each other.

[0075] Accordingly, FIGS. 1(a) through 1(d) illustrate various schematic views of an OVJP system / apparatus for fabricating films in accordance with certain variations of the present disclosure. A method of fabricating a surface patterned with an organic compound (such as a pharmaceutical active agent) may include sublimating or otherwise volatilizing the organic compound contained in a source / target. A single source or target may be used, or multiple sources or targets employing multiple different organic compounds (using the different configurations shown in FIGS. 1(c) and 1(d)) may also be used. Similarly, multiple apparatuses may be used in parallel. The system may include one source or multiple sources holding a heated small molecule drug in powder form. An inert carrier gas (e.g., nitrogen, argon, or helium) is introduced into the apparatus and directed toward the source / target of the organic material. In certain variations, the organic compound is in solid form, such as in powder form. Heat is also applied within the system (e.g., via a heater) such that the organic compound sublimates or volatilizes into a gas / fluid phase and is carried by the passing inert carrier gas stream. The carrier gas with the entrained gaseous organic compound is then ejected from a nozzle in the form of a focused jet and directed toward a substrate having a controlled temperature (e.g., can be cooled), where the entrained small organic molecules condense. For example, the material may be deposited in a precisely controlled amount at a highly controlled weight range of 1×10 -4 g / cm 2 to 0.1 g / cm 2 of the substrate.

[0076] Such a fabrication method is highly controllable. Multiple parameters may be controlled in such an OVJP system, including: for example, pressure and flow rate (including carrier gas flow rate (sccm)), inert carrier gas type, evaporation source temperature (° C.), and substrate composition, substrate surface texture, and substrate temperature (° C.). Variations in each parameter may affect film morphology (e.g., feature type, size, and distribution) and crystallinity. The nozzle is translated above the substrate by an xyz motion controller and is capable of printing the organic material in any pattern (including multiple preselected deposition patterns). The resolution of the pattern formed depends on nozzle geometry, inert gas type, and flow conditions. To obtain large area deposits, adjacent deposit lines may be printed with one nozzle or with multiple nozzles. This enables scalability of the process under robust processing conditions. Additionally, in certain aspects, such a method desirably eliminates the need for liquid solvents, vacuum, or extensive post-processing steps to obtain a desired particle size of one or more organic compounds. Importantly, such OVJP operates without liquid solvents or vacuum and allows for controlled crystallinity in the organic film.

[0077] In addition, the present disclosure contemplates new evaporation sources / targets for vapor deposition methods of low molecular weight organic compounds. As shown in FIGS. 2(a) to 2(b), a ceramic porous powder holder is provided. The evaporation / volatilization source includes an outer container made of thermally or mechanically deformable glass or metal and a disk (FIG. 2(a)) made of porous ceramic (e.g., reticulated) foam that serves as the powder holder. The powder of the organic material is covered by another ceramic foam disk or ceramic wool (glass / quartz). The porous ceramic foam may comprise oxides, nitrides, carbides, borides, silicides, or any combination thereof, provided that the organic material to be deposited does not interact detrimentally (e.g., chemically decompose) with the foam. The foam is then cut into the desired container shape. Due to the high thermal and mechanical stability of the ceramic foam, the container with the foam can be compressed and heated to ensure a tight placement of the foam, thus ensuring the reproducibility of the process when changing the powder and preventing powder spillage during the process. A variant of such an organic material source is shown in FIG. 2(b). The hull is made of quartz and the foam is made of silicon carbide from Ultramet. The powder to be deposited is the organic molecular substance Alq3, which has a sublimation point of about 300 °C.

[0078] One or more non-limiting advantages and / or features of the method according to the present disclosure include: (i) the method is highly controllable. As described above, the control parameters include: evaporation source temperature, inert carrier gas type, pressure and flow rate, substrate composition, surface texture and temperature. Variation of each parameter can affect film morphology (e.g., feature type, size, distribution) and crystallinity; (ii) the need for solvents or extensive post-processing steps to obtain the desired particle size is eliminated; (iii) the ability to deposit a wide range of small molecule organic drugs with molecular weights up to 1000 grams per mole; (iv) low molecular weight organic materials can be deposited in precisely controlled amounts (up to 1e -9 grams); (v) low molecular weight organic materials can be printed in any pattern; (vi) the resolution of the pattern depends on nozzle geometry, inert gas type and flow conditions. To obtain large area deposits, adjacent deposit lines can be printed with one nozzle or with multiple nozzles. This enables scalability of the process under robust processing conditions; (vii) low molecular weight organic materials can be co-printed as mixtures of multiple compounds; (viii) it can be carried out continuously in roll-to-roll manufacturing; (ix) printing of personalized doses of substances or mixtures of substances can be achieved; and (x) the deposition equipment can be highly compact, enabling equipment mobility and use in a modular manner (many nozzles arranged in any desired way), and incorporation into the system as a manufacturing module.

[0079] Figure 3Shows multiple examples of printing pharmaceutical materials (e.g., organic compounds) by an organic vapor jet deposition printing method according to the present teachings. All materials were deposited while rastering the nozzle at a speed of 0.2 mm / s, with adjacent lines spaced 0.2 mm apart from each other. The nozzle tip diameter in all tests was 0.5 mm. All depositions were carried out at atmospheric pressure in an inert nitrogen environment (<1 ppm of O2 and H2O). Figure 3 The table of Figure 3 includes electron micrographs showing the refinement of the original powder microstructure due to the deposition / printing process. Although not shown, X-ray diffraction patterns further demonstrate that the crystal structure of the film is comparable to that of the original source material, indicating that the crystal structure was not altered during deposition. HPLC results of the original powder and the film show high material purity after deposition.

[0080] In other aspects, the present disclosure contemplates methods for rapidly dissolving low molecular weight organic compounds. Small molecule organic vapor compounds can be directly sprayed into a liquid. In certain aspects, the liquid can be an aqueous solution, demonstrating how precisely drug concentrations can be achieved rapidly without the need for additional solvents and / or powder preparations. Solutions of small molecule organic compounds are widely used in many industries: food, cosmetics / perfumes, pharmaceuticals, printing, and paints. As background, conventionally, to obtain a given concentration of an organic solute in its original powder form, the required amount of powder is directly immersed in a solvent and dissolved until all powder particles are separated into solvated molecules. This method is particularly challenging for low solubility substances with very slow dissolution rates. To increase the dissolution rate, the powder particle size is reduced (by grinding or other methods), and the solution is typically heated. This method can be both time-consuming and energy-consuming, and potentially damaging to the solvent.

[0081] Another disadvantage of the conventional technique of directly immersing a powder solute in a solvent is when the actual desired concentration of the compound or the solution volume is very low. For example, if the desired concentration is in the micromolar range and the required volume is 10 ml, the weight required for a 200 g / mol material is in the microgram range. It is not feasible to accurately measure this weight of the precursor powder; therefore, a higher concentration solution is prepared and subsequently diluted with additional amounts of solvent. This method is not desirable from both economic and safety perspectives (when dealing with organic solvents).

[0082] Also provided is a method for rapidly dissolving low molecular weight organic compounds, which includes passing a gas stream containing an inert gas through a heated source of the low molecular weight organic compound, as shown in FIG. 5(a). The low molecular weight organic compound volatilizes and is entrained in the gas stream. Then, the low molecular weight organic compound is sprayed into the liquid by passing the gas stream through a nozzle towards a liquid containing one or more solvents. In this way, the deposited low molecular weight organic compound is dissolved in the liquid as desired. The liquid can be a polar or non-polar liquid, including aqueous liquids containing water or aqueous liquids miscible with water. Thus, the liquid can contain one or more solvents.

[0083] The heated source can include a porous ceramic container containing the low molecular weight organic compound that receives heat transferred from a heater, such as the above-mentioned porous ceramic container in the context of FIGS. 2(a) to 2(b). In some aspects, the temperature of the heated source is greater than or equal to about 250 °C, and the liquid is at ambient temperature. The nozzle can be greater than or equal to about 15 mm to less than or equal to about 25 mm from the liquid surface. The inert gas can be nitrogen. After dissolution, the concentration of the low molecular weight organic compound is optionally greater than or equal to about 1×10 -11 mol / L to less than or equal to about 20 mol / L. In some variations, the amount of the deposited low molecular weight organic compound is less than or equal to about 100 μg. In other variations, the volume of the liquid into which the gas stream containing the low molecular weight organic compound is deposited / sprayed is less than or equal to about 100 ml. The deposition is carried out for greater than or equal to about 1 minute to less than or equal to about 120 minutes. The low molecular weight organic compound can be any of those previously mentioned above. As non-limiting examples, the low molecular weight organic compound can be selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

[0084] Accordingly, the present disclosure contemplates new dissolution methods and apparatuses for carrying out such methods, as shown in FIGS. 5(a) to 5(c). The apparatus shown in FIG. 5(a) includes a heated organic powder evaporation source in a ceramic tube, similar to those previously mentioned above. The temperature of the source is high enough to cause evaporation / volatilization / sublimation of the organic material. An inert carrier gas is passed through the powder to obtain volatilized / evaporated molecules and deliver them to the solution. Using this method, an accurate and controlled amount of organic material can be sprayed into a solution at submicromolar concentrations. FIG. 5(b) shows an example of spraying fluorescein (molecular weight 332 g / mol) into a micromolar concentration of phosphate buffered saline solution. In FIG. 5(c), it is shown that the concentration of fluorescein in the solution changes with the spraying duration (e.g., spraying for 0 minutes to 100 minutes). The concentration is measured by fluorescence spectroscopy calibrated with dissolved fluorescein powder.

[0085] In some aspects, the present disclosure thus contemplates solid films that comprise greater than or equal to about 99 mass % of a deposited low molecular weight organic active ingredient compound having a molecular weight less than or equal to about 1,000 g / mol. For example, the molecular weight of the deposited low molecular weight organic compound can be greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol. The low molecular weight organic active ingredient compound is preferably a pharmaceutically active substance or a new chemical entity. The low molecular weight organic active ingredient is any of the above low molecular weight compounds. For example, the deposited low molecular weight organic active ingredient compound can be selected from: antiproliferatives; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); antimicrobials; antivirals; antifungals; antibiotics; chemotherapeutic agents; antitumor agents / antimiotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof. In certain variations, the deposited low molecular weight organic active ingredient compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

[0086] In some aspects, the solid film specific surface area of the solid film is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000 m z / g. In certain variations, the deposited low molecular weight organic active ingredient compound in the solid film is amorphous. The solid film can also define particles having an average particle size greater than or equal to about 2 nm to less than or equal to about 200 nm. In the case where the solid film is amorphous, the deposited low molecular weight organic active ingredient compound in the solid film is stable for greater than or equal to about 1 month, optionally greater than or equal to about 2 months, optionally greater than or equal to about 3 months, optionally greater than or equal to about 6 months, optionally greater than or equal to about 9 months, and in certain variations, optionally greater than or equal to about 1 year.

[0087] In other variations, the deposited low molecular weight organic active ingredient compound in the solid film is crystalline or polycrystalline. The average crystal size can be greater than or equal to about 2 nm to less than or equal to about 200 nm. The average thickness of the solid film can be less than or equal to about 300 nm, and the average surface roughness (R a ) of the solid film is less than or equal to about 100 nm.

[0088] In some variations, the average thickness of the solid film is greater than or equal to about 300 nm. The average surface roughness (R a ) is greater than or equal to about 100 nm. A film having such a thickness defines a nanostructured surface comprising a plurality of nanostructures, the primary dimensions of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm. In one such embodiment, the plurality of nanostructures can have a shape selected from: needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

[0089] Figures 6(a) through 6(r) show the surface morphology of solid printed films of caffeine, tamoxifen, BAY11-7082, acetaminophen, ibuprofen, and fluorescein deposited by OVJP. Figures 6(a) through 6(f) show the chemical structures of the compounds. Figures 6(g) through 6(l) show the deposited film morphology after jetting according to certain aspects of the present teachings. Figures 6(m) through 6(r) show the original microstructures of the powders of the compounds. All materials were deposited while raster scanning the nozzle at a speed of 0.2 mm / s, with adjacent lines spaced 0.2 mm apart from each other. The nozzle tip diameter was 0.5 mm in all tests. All depositions were carried out at atmospheric pressure in an inert nitrogen environment (<1 ppm O2 and H2O). The electron micrographs show refinement of the original powder microstructure due to the printing process.

[0090] Table 1 lists the OVJP deposition conditions for the printed films.

[0091] Table 1

[0092]

[0093] The source temperature was determined by thermogravimetry and adjusted to obtain a local deposition rate of about 0.5 μg / minute. The temperature range and carrier gas flow rate can be varied depending on the system size and configuration.

[0094] In certain embodiments, the solid film can comprise a deposited low molecular weight organic compound containing caffeine. The plurality of nanostructures have a needle shape or a tube shape. The average diameter of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm, and the average length is greater than or equal to about 5 nm to less than or equal to about 100 μm. Figure 6(a) shows the chemical structure; Figure 6(g) shows a micrograph of the morphology of the deposited film having nanostructures in the form of a needle shape or a tube shape; and Figure 6(m) shows the morphology of the conventional powder.

[0095] In some other specific embodiments, the solid film may comprise a deposited low molecular weight organic compound containing (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile (BAY 11-7082). The plurality of nanostructures have a flake shape, wherein the average height of the plurality of nanostructures is greater than or equal to about 10 nm to less than or equal to about 10 μm. The average width of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm. The average length is greater than or equal to about 5 nm to less than or equal to about 100 μm. Figure 6(c) shows the chemical structure, Figure 6(i) shows a micrograph of the morphology of the deposited film with nanostructures in the form of flakes, and Figure 6(o) shows the morphology of the conventional powder.

[0096] In some other embodiments, the solid film may comprise a deposited low molecular weight organic compound containing fluorescein. The plurality of nanostructures have a circular shape. The average radius of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm. Figure 6(f) shows the chemical structure, Figure 6(l) shows a micrograph of the morphology of the deposited film with nanostructures in the form of circular nanostructures, and Figure 6(r) shows the morphology of the conventional powder.

[0097] In some other embodiments, the solid film may comprise a deposited low molecular weight organic compound containing acetaminophen. The plurality of nanostructures have a shape selected from the following: microdroplets, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof, wherein the average major dimension of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 20 μm. Figure 6(d) shows the chemical structure, Figure 6(j) shows a micrograph of the morphology of the deposited film with nanostructures in the form of microdroplet shapes, and Figure 6(p) shows the morphology of the conventional powder.

[0098] Figure 6(b) shows the chemical structure of tamoxifen. Figure 6(h) shows a micrograph of the morphology of the deposited film with nanostructures in the form of continuous flake shapes, and Figure 6(n) shows the morphology of the conventional powder.

[0099] Figure 6(e) shows the chemical structure of ibuprofen. Figure 6(k) shows a micrograph of the morphology of the deposited film with nanostructures in the form of microdroplet-like shapes, where the solid has aggregated, and Figure 6(q) shows the morphology of the conventional powder.

[0100] The X-ray diffraction patterns (Figures 7(e) to 7(h)) show that the crystal structure of the film is comparable to that of the original source material, indicating that the crystal structure has not changed during deposition. The crystal size of the deposited compound is substantially refined, from tens of nanometers for the powder to a few nanometers for the film. The UPLC results of the initial powder and the film shown in Figures 7(a) to 7(d) indicate high material purity after deposition.

[0101] In other aspects, the deposited low-molecular-weight organic compounds according to the present teachings have an improved dissolution rate compared to comparative powders or granules of low-molecular-weight organic active ingredients. The dissolution rate of the deposited low-molecular-weight organic active ingredient compounds in the solid film in an aqueous solution is at least ten times greater than the comparative dissolution rate of the comparative powders or granules of low-molecular-weight organic active ingredients. The improved dissolution rate can be any of those discussed previously above.

[0102] The dissolution process in a finite volume can be described by Noyes-Whitney (Equation 1), where C is the solute concentration, t is the time, D is the diffusion coefficient in the solvent, V is the volume of the solvent, δ is the boundary layer thickness, Cs is the solubility in the given solvent, and A is the surface area of the solute:

[0103]

[0104] When comparing dissolution from powder and film forms of the same material and the same crystal structure, D, V, and Cs are constant, and the initial dissolution rate is proportional to A / δ. For dissolution from the film, δ and A are constant because the area of the film remains unchanged during dissolution. In the powder, δ and A are variable because the particle size and shape are variable. Additionally, the particles tend to agglomerate during dissolution, which does not occur when dissolving from the film form. Therefore, only the initial rates between the powder and the film can be compared.

[0105] The degree of improvement in the dissolution rate is similar to the degree of improvement in the surface area. In a specific non-limiting example, the initial dissolution rate of 25 μg of fluorescein powder in deionized water is 8.9e -5 μg ml -1 second -1 , while for the printed film it is 1.61e -3 μgml -1 second -1 , which is 18 times higher. The film surface area is 6.4e -5 m 2 , while the powder surface area is 3.6e -6 m 2 , 17 times higher.

[0106] The initial dissolution rate of 30 μg of ibuprofen powder in buffered HCl 1.3 is 0.0004 μg ml -1 second -1 , while the initial dissolution rate of the printed film is 0.04 μg ml -1 second -1 , approximately 10 times higher. The film surface area is 6.4e -5 m 2 , while the powder surface area is 1.5e -5 m2 , about 5 times higher.

[0107] The initial dissolution rate of 30 μg of powder of tamoxifen in buffered acetate 4.9 was 2e -4 μg ml -1 second -1 , while the initial dissolution rate of the printed film was 2e -3 μg ml -1 second -1 , 10 times higher. The film surface area was 6.4e -5 m 2 , while the powder surface area was 9e - 6 m 2 , 7 times higher. It should be noted that these are merely illustrative examples, but the surface area of the film is related to the printed surface area, which is not limiting according to the present teachings.

[0108] Similarly, compared to a comparative powder or particulate form of a low molecular weight organic active ingredient, the deposited low molecular weight organic compound according to the present teachings has improved bioavailability. The improved bioavailability is related to an increased dissolution rate. The bioavailability of the deposited low molecular weight organic active ingredient compound in the solid film is at least about 10% greater than the comparative bioavailability of the comparative powder or particulate form of the low molecular weight organic active ingredient. The level of improved bioavailability can be any of those previously described above.

[0109] In some aspects, the solid film is substantially free of any binder or impurity. The solid film substantially free of binder or impurity has less than or equal to about 0.5 wt%, optionally less than or equal to about 0.1 wt%, and in some preferred aspects, 0 wt% of the undesired binder or impurity present in the solid film composition. In some variations, the solid film comprises greater than or equal to about 99.5 mass% of the deposited low molecular weight organic active ingredient compound; however, any of the purity levels discussed above can also be obtained in the solid film.

[0110] In some aspects, the deposited low molecular weight organic compound on the surface is crystalline or polycrystalline. In other aspects, the deposited low molecular weight organic compound is amorphous. In this way, a substantially pure molecular drug film with a high surface area morphology is fabricated. The deposited low molecular weight organic compound exhibits increased solubility and bioavailability.

[0111] In other variations, the present disclosure contemplates solid films that comprise a plurality of deposited low molecular weight organic active ingredient compounds each having a molecular weight less than or equal to about 1,000 g / mol. The low molecular weight organic active ingredient compounds are preferably pharmaceutical active substances or new chemical entities. The low molecular weight organic active ingredient compounds are any of the aforementioned low molecular weight compounds. The combined amount of the plurality of low molecular weight organic active ingredient compounds in the solid film can be greater than or equal to about 99 mass %. The solid film can have any of the compositions or characteristics just above, which are not repeated here for the sake of brevity.

[0112] In other variations, the article comprises a solid deposited film containing a pharmaceutical composition that comprises at least one low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol. The solid deposited film can have any of the compositions or characteristics above, which are not repeated here for the sake of brevity.

[0113] In other specific variations, an article is provided that comprises a surface of a solid substrate, the surface of the solid substrate having one or more discrete regions patterned with deposited low molecular weight organic compounds having a molecular weight less than or equal to about 1,000 g / mol. The low molecular weight organic compounds are any of the aforementioned low molecular weight compounds. The deposited low molecular weight organic compounds are present in the one or more discrete regions in an amount greater than or equal to about 99 mass %. In some aspects, one or more of the discrete regions in the surface are continuous and the deposited solid low molecular weight organic compounds form a solid film on the surface of a pharmaceutically acceptable substrate. Any of the solid films containing any of the compositions or characteristics above can be disposed on the surface of the solid substrate. The deposited film can be applied to a variety of solid substrates having any type of substrate geometry, including flat substrates, microneedles, spheres, tubes, curved surfaces, meshes, fabrics, and combinations thereof.

[0114] In other specific variations, an article is provided that comprises a surface of a solid substrate, the surface of the solid substrate having one or more discrete regions patterned with a plurality of deposited low molecular weight organic compounds each having a molecular weight less than or equal to about 1,000 g / mol. The low molecular weight organic compounds are any of the aforementioned low molecular weight compounds. The plurality of deposited low molecular weight organic compounds are cumulatively present in the one or more discrete regions in an amount greater than or equal to about 99 mass %. Accordingly, any of the solid films above can be disposed on the surface of the solid substrate. Additionally, the solid substrate can be those just above.

[0115] In other aspects, the present disclosure provides articles that include a pharmaceutically acceptable substrate defining a surface. The material selected for the substrate is preferably pharmaceutically acceptable or biocompatible, in other words, substantially non-toxic to the cells and tissues of a living organism. A pharmaceutically acceptable material can be a material that is suitable for contact with the tissues of humans and other animals without causing undue toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. The article also includes a deposited solid low molecular weight pharmaceutically active ingredient having a molecular weight less than or equal to about 1,000 g / mol. The pharmaceutically active ingredient is a drug or other compound that can be used to prevent or treat a disease or disorder, prevent or treat a physiological disorder or condition, or provide a benefit over potential harmful effects in a conventional risk-benefit assessment in humans or other animals. The low molecular weight organic active ingredient can be any of those described above. Thus, the articles and compositions of the present disclosure can be used to treat or prevent systemic conditions such as cancer, autoimmune diseases, cardiovascular diseases, stroke, diabetes, severe respiratory infections, inflammation, pain control, and the like.

[0116] The deposited solid low molecular weight pharmaceutically active ingredient is present in one or more discrete regions on the surface of the pharmaceutically acceptable substrate at greater than or equal to about 99 mass %. The one or more discrete regions of the surface are continuous, and the deposited solid low molecular weight pharmaceutically active ingredient forms a solid film on the surface of the pharmaceutically acceptable substrate. Thus, any solid film having a low molecular weight pharmaceutically active ingredient as described above can be disposed on the surface of a solid substrate.

[0117] In some aspects, the pharmaceutically acceptable substrate is biodegradable. Biodegradable means that the material forming the substrate dissolves or erodes when exposed to a solvent containing a high concentration of water (such as serum, growth or culture medium, blood, body fluid or saliva). In some variations, the substrate may break into small pieces or may disintegrate to collectively form a colloid or gel. In certain variations, the pharmaceutically acceptable substrate comprises a pharmaceutically acceptable material selected from: glass, metal, silicone, polymer, hydrogel, organogel, organic material, natural fiber, synthetic fiber, ceramic, biological tissue, and combinations thereof. In other alternative embodiments, the pharmaceutically acceptable material is selected from: glass, metal, silicone, polymer, hydrogel, organogel, natural fiber, synthetic fiber, and combinations thereof. The deposited solid low molecular weight drug active ingredient can be formed on any type of substrate geometry, including flat substrates, microneedles, spheres, tubes, curved surfaces, meshes, etc. Additionally, the substrate can be of any size. In certain non-limiting variations, the pharmaceutically acceptable substrate is selected from: microneedles, medical devices, implants, membranes (such as soluble membranes or membranes with removable backing), gels, patches, dressings (such as gauze, non-adhesive mesh, bandage, membrane, foil, foam or tissue adhesive), fabrics (such as textiles, non-woven or knitted fabrics), sponges, scaffolds, contact lenses, subretinal implantable prostheses, dentures, braces, wearable devices, bracelets, and combinations thereof.

[0118] Figures 8(a) through 8(d) illustrate examples of different coating forms on different substrates. The low molecular weight compound fluorescein was patterned onto an acrylic polymer TEGADERM TM patch sold by 3M TM (Figure 8(a)) and a pullulan-based membrane (Figure 8(b)), fluorescein was deposited onto the tips of stainless steel microneedles (Figure 8(c)), and tamoxifen was deposited onto a borosilicate glass slide (Figure 8(d)).

[0119] In other aspects, the present disclosure contemplates articles that comprise a solid deposition membrane containing a pharmaceutical composition. The pharmaceutical composition comprises at least one low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol. In certain variations, the pharmaceutical composition further comprises at least one additional deposited compound different from the low molecular weight organic compound such that multiple low molecular weight organic compounds are co-deposited to form a solid deposition membrane. Thus, the pharmaceutical composition can comprise at least two low molecular weight organic compounds. In certain variations, the pharmaceutical composition has at least one low molecular weight organic compound present in the solid deposition membrane in an amount greater than or equal to about 99 mass %.

[0120] The article can be a multilayered stack, and the solid deposition film containing the pharmaceutical composition is the first layer and the multilayered stack includes a second layer having a different chemical composition. The second layer may contain a second pharmaceutical composition different from the pharmaceutical composition in the first layer. In other aspects, the second layer contains a material that minimizes the dissolution rate of the pharmaceutical composition in the first layer. In other variations, the second layer may contain a material having solubility controlled by the presence of a trigger selected from: light, radiation, magnetism, radio waves, the pH of the surrounding medium, and combinations thereof. In this way, such external forces or triggers can be used to increase or minimize the solubility of the pharmaceutical composition. The pharmaceutical composition can be any compound as previously discussed. Additionally, the solid deposition film can have any of the characteristics or properties previously discussed. Examples

[0121] The OVJP nozzle used was made of a 0.5” outer diameter quartz tube with a 0.5 mm inner diameter nozzle tip 0.5 mm from the nozzle axis at 15 °C. All nozzles used were the same. The inert gas used during deposition was 99.99% pure nitrogen.

[0122] The nozzle was cleaned with acetone and isopropyl alcohol solvents, dried and wrapped with a 36” heavy-duty insulated strip heater (Omega Engineering, Inc.) with a power density of 8.6 W·in -2 The heating tape leads were connected to a temperature controller (Digi-Sense Benchtop temperature controller, Cole Palmer Instruments Co.), and a 1 / 16” type K thermocouple was used to maintain the temperature of the source. The source contained approximately 0.15 g of powder embedded in a 100 DPI porous SiC ceramic foam and placed in the heated source section of the tube. A mass flow controller (C100MFC, Sierra Instruments) was used to maintain the gas flow.

[0123] The process parameters kept constant were: nozzle-substrate spacing distance (1.5 mm), substrate temperature (20 °C). The process was carried out in a glove box purged with 99.99% pure N2.

[0124] Thermogravimetry of pharmaceutical substances

[0125] To determine the evaporation temperature of the powder and subsequently the source temperature in the system, thermogravimetric analysis was used. All measurements were carried out using a TA Instruments thermogravimetric analyzer (TGA) Q500 system (0.01% accuracy), where the nitrogen sample purge flow rate was 60 ml / min and the balance purge flow rate was 40 ml / min. The heating rate was 5 °C / min.

[0126] The area deposits are printed by raster scanning adjacent overlapping lines at a distance of 0.2 mm. For a nozzle with an inner diameter of 0.5 mm set 1.5 mm from the substrate surface, this distance is determined to allow for a uniform thickness of the deposit. The fluorescein film on the microneedles is deposited through a flexible mask. When using a nozzle with an appropriate printing resolution, the same process can be carried out without a mask.

[0127] In some aspects, the OVJP method carried out according to certain aspects of the present teachings can deliver a controlled amount of a variety of compounds (e.g., caffeine, ibuprofen, doxorubicin, BAY 11-7082) onto a variety of substrates in the form of a film. Then further observe how the film dissolves in an aqueous solution. The film dissolution process is monitored using a fluorescent substance (e.g., fluorescein).

[0128] Figures 4(a) to 4(b) show an example of a printed drug film of the deposited organic compound BAY 11-7082 (CAS 19542-67-7) for testing the biological potency. The film was deposited under the conditions shown in Figure 3 The film was tested by directly applying the OVCAR3 cell solution onto the printed film of BAY 11-7082 and comparing it with the BAY 11-7082 drug in powder form dissolved in DMSO. No significant difference in potency was observed, indicating that the film has enhanced solubility characteristics.

[0129] Figures 9(a) to 9(b) show how the dissolution (or release) rate of the film can be controlled by membrane patterning. In the first case, the deposited film thickness is changed while the film area remains constant (Figure 9(a)). Here the dissolution rate remains constant and an exact final concentration is reached. The concentration-dissolution time correlation is shown in the inset of Figure 9(a). Figure 9(b) shows the dissolution from films with different deposited areas. Here the dissolution rate is proportional to the film area. In both cases, the Noyes-Whitney theory well predicts the correlation.

[0130] Figures 10(a) to 10(c) show the improvement in the dissolution rate of drug films printed from the vapor phase according to certain aspects of the present teachings relative to the drug in powder form. To compare the dissolution behavior of the film form relative to the original powder, loose powder having the same weight as the film was introduced into 10 ml of solution without any pretreatment and stirred using a stir bar having the same shape and diameter as that used for the film. All experiments were carried out at a temperature of 19 ± 1 °C.

[0131] In the case of dissolution from the film, the exposed dissolution area and the boundary layer thickness remain constant, and the solution of Equation (1) is Equation (2):

[0132]

[0133] Under sink conditions, C << Cs, the dissolution rate is essentially constant and can thus be precisely controlled by the membrane area. The dissolution process in powder form is more uncontrollable than in membrane form. In contrast to the membrane form, in the case of powder, the effective dissolution area changes during the process and is affected by changes in particle size and shape, wettability, and the tendency to agglomerate. The simplified solution of Equation 1 is described by the Hixson and Crowell model (Equation (3)), where N is the number of powder particles, Mp0 is the average initial weight of the particles, and ρ is the density of the solute material.

[0134]

[0135] This model does not account for effects such as changes in particle shape, boundary layer thickness, tendency to agglomerate, and wettability, and assumes a spherical particle shape, which is not a common shape for crystalline organic solids. The powder micronization technique for enhancing dissolution rate is limited by processing conditions and powder agglomeration. These limitations are essentially absent when depositing the drug in membrane form. The deposited membrane can be as thin as a single layer of the material.

[0136] Here, the dissolution behavior in membrane and powder forms was investigated in three poorly soluble materials - fluorescein in deionized water, ibuprofen in aqueous hydrochloride (HCl) buffer at pH 1.2, and tamoxifen in aqueous acetate buffer (pH 4.9). First, the solubility of the different compounds in the respective solvents was measured at a temperature of 20 ± 1 °C. The solubility of fluorescein in deionized water was 10 ± 0.5 μg / ml, that of ibuprofen in HCl 1.2 solution was 22.5 ± 0.5 μg / ml, and the solubility of tamoxifen in acetate pH 4.9 was 23.6 ± 0.5 μg / ml.

[0137] For the dissolution rate experiments, a USP 2 stirring device with a stirring speed of 100 rpm was used. The concentration was monitored using a UV-VIS spectrometer equipped with a dipping probe. For example, a glass slide substrate with a deposited drug membrane of 9 mm diameter was used. The membrane weight was 5 to 80 μg. First, the intrinsic dissolution rate (IDR) of the membrane was investigated and compared with the dissolution of the compressed powder in the form of 1.57 mm diameter particles. The IDR is defined by Equation (4):

[0138]

[0139] In this case, (dm / dt) maxis the maximum slope evaluated at the start of the dissolution process (m is the mass of solute dissolved). A glass substrate with a deposited film was connected to a stir bar having the same diameter (20 mm) as the compacted pellet rod, ensuring the same hydrodynamic boundary layer thickness for the compacted powder and the deposited film. The solution volume was kept constant at about 10 ml in all experiments, and the temperature was 20 ± 1 °C. In all cases, the intrinsic dissolution of the film was comparable to that of the compacted particles (3 × 10 -5 ± 5 × 10 -6 for fluorescein, 1 × 10 -3 ± 3 × 10 -4 for ibuprofen, and 6 × 10 -4 ± 1 × 10 -4 for tamoxifen, all values in (μg s -1 mm -2 ). Since the IDR depends on the crystal structure and crystallinity of the compound, this indicates that there is no change in the crystallinity and structure of the film, as also observed in the XRD studies.

[0140] Figures 10(a) to 10(c) show the dissolution behavior of the deposited film relative to the original loose powder. It can be seen that the initial dissolution rate of the film is very rapid and constant until about 80% of the film is dissolved. The further dissolution rate decreases, mainly due to the decrease in the film surface area. For fluorescein (Figure 10(a)), the initial dissolution rate of the film is increased by about 10 times relative to the loose powder, about 30 times for ibuprofen (Figure 10(b)), and about 10 times for tamoxifen (Figure 10(c)). Since the IDR or solubility remains unchanged, the initial increase in the dissolution rate is mainly attributed to the increase in the film surface area. The magnitude of the increase is in good agreement with the magnitude of the increase in the powder surface area. Importantly, this example only represents the dissolution improvement that can be obtained when forming a drug composition in the form of a deposited film according to the present teachings. For example, if the film dissolves from a soluble polymer substrate, the rate can be further doubled because dissolution occurs from both sides of the film. In addition, the film dissolution can be accurately predicted until almost complete dissolution, whereas in the case of powder, predicting the dissolution rate is more complex due to changes in particle shape and agglomeration, as can be seen in the dissolution of ibuprofen powder in Figure 10(b).

[0141] Medicinal substances printed from the gas phase (such as tamoxifen and BAY 11-7082) further enhance the biological potency. To test the drug efficacy in the form of a deposited film, cancer cell lines in culture were exposed to tamoxifen films and BAY films deposited on glass slides. See Figure 11, which shows drug application in the form of a film. The ovarian cancer cell line OVCAR3 and the breast cancer cell line MCF7 were used to study growth inhibition in the presence of tamoxifen and BAY-27. Growth inhibition curves were also generated using the following controls: i) a clean glass slide without a deposited drug film as a sham control; ii) 5 μM tamoxifen or 500 nM BAY dissolved in dimethyl sulfoxide (DMSO; conventional drug dose); and iii) tamoxifen or BAY powder directly dissolved in sterile supplemented growth medium. In all cases, the amount of drug introduced was calculated such that for tamoxifen (4.5 μg / film), the nominal concentration was 5 μM (1.8 μg / ml), and for BAY 117082 (0.25 μg / film) was 500 nM (0.1 μg / ml).

[0142] Figures 12(a) to 12(d) show the cancer cell count curves treated with different drug forms to demonstrate the increased biological potency of the deposited films prepared according to certain aspects of the present disclosure compared to conventional formulations. Figure 12(a) shows the MCF7 cell treatment curve using tamoxifen (solid line - eye guide). Figure 12(b) shows the OVCAR3 cell treatment curve using tamoxifen (solid line - eye guide). Figure 12(c) shows the MCF7 cell treatment curve using BAY 11-7082 (solid line - eye guide). Figure 12(d) shows the OVCAR3 cell treatment curve using BAY 11-7082 (solid line - eye guide).

[0143] In both cases, the cells treated with the film form of the drug showed viability almost similar to that of the drug dissolved in DMSO. The film form of tamoxifen showed significantly better efficacy than the powdered drug dissolved in the growth medium. For the film form, the viability of MCF7 cancer cells after 48 hours was 58%, and for the powdered form was 79% (Figure 12(a)), and for the film form, the viability of OVCAR3 cancer cells after 48 hours was 44%, and for the powdered form was 68% (Figure 12(b)). The film form of BAY showed similar efficacy to the powdered drug dissolved in the growth medium (Figures 12(c) to 12(d)).

[0144] The reason for the difference between the powdered form and the film of tamoxifen is thought to be due to the higher dissolution rate of the film compared to the powdered form. Since the actual concentration of the dissolved powder is lower than 5 μM, the growth cell inhibition rate is lower. The behavioral difference between tamoxifen and BAY is mainly due to the differences in compound solubility and dissolution rate - the solubility of tamoxifen at pH 7.4 is less than 5 μg / ml, while the solubility of BAY is 29.25 ± 0.05 μg / ml.

[0145] In various aspects, the present disclosure contemplates high surface area films of small molecule organic compounds (such as pharmaceutical substances) having precise weights and high purities, made using organic vapor jet printing deposition techniques and equipment. Additionally, certain organic compounds (such as the BAY 11-7082 drug) can be dissolved directly by jetting into a solution, and the drug dissolves with a potency similar to that of the same drug dissolved in DMSO. Similarly, jetting fluorescein directly into a phosphate buffered saline solution demonstrated the rapid and accurate dissolution of small molecule pharmaceutical substances. These results suggest that organic vapor jet printing deposition techniques can be used to produce drug films and particle morphologies with enhanced solubility characteristics.

[0146] All possible combinations of those discussed and listed above, as well as those optionally characterized as materials and methods of the invention in this disclosure, are specifically disclosed as embodiments. In various aspects, the present disclosure contemplates solid films that comprise a deposited low molecular weight organic active ingredient compound in an amount greater than or equal to about 99 mass %. The low molecular weight organic active ingredient compound has a molecular weight less than or equal to about 1,000 g / mol. Additionally, the low molecular weight organic active ingredient compound is a pharmaceutically active substance or a novel chemical substance. Combinations of such solid films are also specifically disclosed, optionally having any combination of one or more of the enumerated features (1) to (17).

[0147] The solid film of the first embodiment optionally has any combination of one or more of the following features: (1) The specific surface area of the solid film is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000 m 2 / g; (2) The deposited low-molecular-weight organic active ingredient compound in the solid film is amorphous; (3) The amorphous solid film also defines particles with an average particle size of greater than or equal to about 2 nm to less than or equal to about 200 nm; (4) The deposited low-molecular-weight organic active ingredient compound in the amorphous solid film is stable for greater than or equal to about 1 month; (5) The deposited low-molecular-weight organic active ingredient compound in the solid film is crystalline or polycrystalline; (6) The average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm; (7) The deposited low-molecular-weight organic active ingredient compound is selected from: anti-proliferative agents; anti-rejection drugs; anti-thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; anti-progesterones; anti-androgens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); anti-microbial agents; anti-viral agents; anti-fungal agents; antibiotics; chemotherapeutic agents; anti-tumor agents / anti-miotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (8) The deposited low-molecular-weight organic active ingredient compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (9) The molecular weight of the deposited low-molecular-weight organic compound is greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol; (10) The average thickness of the film is less than or equal to about 300 nm, and the average surface roughness (R a ) is less than or equal to about 100 nm; (11) The average thickness of the film is greater than or equal to about 300 nm, and the film defines a nanostructured surface comprising a plurality of nanostructures, the main dimensions of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm; (12) The film defines a nanostructured surface comprising a plurality of nanostructures having shapes selected from: needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, the plurality of nanostructures having shapes selected from: droplets, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (13) Comprising one of the following:

[0148] a. The deposited low-molecular-weight organic compound contains caffeine, and the plurality of nanostructures have a needle shape or a tube shape, wherein the average diameter of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm, and the average length is greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0149] b. The deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, and the plurality of nanostructures have a flake shape, wherein the average height of the plurality of nanostructures is greater than or equal to about 10 nm to less than or equal to about 10 μm, the average width of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm, and the average length is greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0150] c. The deposited low molecular weight organic compound comprises fluorescein, and the plurality of nanostructures have a circular shape, wherein the average radius of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm; or

[0151] d. The deposited low molecular weight organic compound comprises acetaminophen, and the plurality of nanostructures have a shape selected from the following: droplets, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof, wherein the average major dimension of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 20 μm;

[0152] (14) The deposited low molecular weight organic compound has an increased dissolution rate compared to a comparative powder or particulate form of the low molecular weight organic active ingredient, wherein the dissolution rate of the deposited low molecular weight organic active ingredient compound in the solid film in an aqueous solution is at least ten times greater than the comparative dissolution rate of the comparative powder or particulate form of the low molecular weight organic active ingredient; (15) The deposited low molecular weight organic compound has an increased bioavailability compared to a comparative powder or particulate form of the low molecular weight organic active ingredient, wherein the bioavailability of the deposited low molecular weight organic active ingredient compound in the solid film is at least about 10% greater than the comparative bioavailability of the comparative powder or particulate form of the low molecular weight organic active ingredient; (16) The solid film is substantially free of any binder or impurities; and / or (17) The solid film comprises greater than or equal to about 99.5 mass% of the deposited low molecular weight organic active ingredient compound.

[0153] In other aspects, the present disclosure contemplates a second embodiment, which is an article comprising a solid substrate surface having one or more discrete regions patterned with a deposited low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol. The deposited low molecular weight organic compound is present in the one or more discrete regions at greater than or equal to about 99 mass%. Also specifically disclosed is the article including any combination of any one or more than one of the optionally listed features (18) to (34) or any of the previously listed features (1) to (17).

[0154] The article of the second embodiment optionally has any one or more than one of the following features in any combination: (18) The specific surface area of the low-molecular-weight organic compound deposited in one or more discrete regions is greater than or equal to about 0.001 m 2 / g and less than or equal to about 1,000 m 2 / g; (19) The deposited low-molecular-weight organic compound is amorphous; (20) The amorphous low-molecular-weight organic compound also defines particles with an average particle size greater than or equal to about 2 nm and less than or equal to about 200 nm; (21) The deposited low-molecular-weight organic compound is stable for greater than or equal to about 1 month; (22) The deposited low-molecular-weight organic compound is crystalline or polycrystalline; (23) The average crystal size is greater than or equal to about 2 nm and less than or equal to about 200 nm; (24) The deposited low-molecular-weight organic compound is selected from: anti-proliferative agents; anti-rejection drugs; anti-thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; anti-progesterones; anti-androgens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); anti-microbial agents; anti-viral agents; anti-fungal agents; antibiotics; chemotherapeutic agents; anti-tumor agents / anti-miotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (25) The deposited low-molecular-weight organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (26) The molecular weight of the deposited low-molecular-weight organic compound is greater than or equal to about 100 g / mol and less than or equal to about 900 g / mol; (27) The average thickness of the deposited low-molecular-weight organic compound is less than or equal to about 300 nm, and the average surface roughness (R a ) is less than or equal to about 100 nm; (28) The average thickness of the deposited low-molecular-weight organic compound is greater than or equal to about 300 nm, and the film defines a nanostructured surface comprising a plurality of nanostructures, the main dimensions of the nanostructures being greater than or equal to about 5 nm and less than or equal to about 10 μm; (29) The deposited low-molecular-weight organic compound defines a nanostructured surface comprising a plurality of nanostructures having shapes selected from: needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (30) Comprising one of the following:

[0155] a. The deposited low-molecular-weight organic compound contains caffeine, and the plurality of nanostructures have a needle shape or a tube shape, wherein an average diameter of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm, and an average length is greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0156] b. The deposited low-molecular-weight organic compound contains (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, and the plurality of nanostructures have a flake shape, wherein an average height of the plurality of nanostructures is greater than or equal to about 10 nm to less than or equal to about 10 μm, an average width of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm, and an average length is greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0157] c. The deposited low-molecular-weight organic compound contains fluorescein, and the plurality of nanostructures have a circular shape, wherein an average radius of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm; or

[0158] d. The deposited low-molecular-weight organic compound contains acetaminophen, and the plurality of nanostructures have a shape selected from the following: droplet, hemisphere, pit, interconnected pits, island, interconnected islands, and combinations thereof, wherein an average major dimension of the plurality of nanostructures is greater than or equal to about 5 nm to less than or equal to about 20 μm;

[0159] (31) Compared with a comparative powder or particulate form of the low-molecular-weight organic active ingredient, the deposited low-molecular-weight organic compound has an increased dissolution rate, wherein a dissolution rate of the deposited low-molecular-weight organic active ingredient compound in a solid film in an aqueous solution is at least ten times greater than a comparative dissolution rate of the comparative powder or particulate form of the low-molecular-weight organic active ingredient; (32) Compared with a comparative powder or particulate form of the low-molecular-weight organic active ingredient, the deposited low-molecular-weight organic compound has an increased bioavailability, wherein a bioavailability of the deposited low-molecular-weight organic active ingredient compound in a solid film is at least about 10% greater than a comparative bioavailability of the comparative powder or particulate form of the low-molecular-weight organic active ingredient; (33) The deposited low-molecular-weight organic compound is substantially free of any binder or impurity; and / or (34) One or more discrete regions contain greater than or equal to about 99.5 mass% of the deposited low-molecular-weight organic active ingredient compound.

[0160] In other aspects, the present disclosure contemplates a third embodiment, which is an article comprising a pharmaceutically acceptable substrate defining a surface and a deposited solid low molecular weight pharmaceutical active ingredient having a molecular weight less than or equal to about 1,000 g / mol. The deposited solid low molecular weight pharmaceutical active ingredient is present in one or more discrete regions on the surface of the pharmaceutically acceptable substrate at greater than or equal to about 99 mass %.

[0161] Also specifically disclosed is a combination of such articles including any combination of any one or more than one of the recited features (35) to (55) or any of the previously recited features (1) to (34).

[0162] The article of the third embodiment optionally has any combination of any one or more than one of the following features: (35) one or more discrete regions in the surface are continuous and the deposited solid low molecular weight pharmaceutical active ingredient forms a solid film on the surface of the pharmaceutically acceptable substrate; (36) the pharmaceutically acceptable substrate is biodegradable; (37) the pharmaceutically acceptable substrate comprises a pharmaceutically acceptable material selected from: glass, metal, silicone, polymer, hydrogel, organogel, organic material, natural fiber, synthetic fiber, ceramic, biological tissue, and combinations thereof; (38) the pharmaceutically acceptable substrate is selected from: microneedles, medical devices, implants, membranes, gels, patches, dressings, fabrics, bandages, sponges, scaffolds, contact lenses, subretinal implantable prostheses, dentures, braces, wearable devices, bracelets, and combinations thereof; (39) the specific surface area of the deposited solid low molecular weight pharmaceutical active ingredient in one or more discrete regions is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000 m 2 / g; (40) The deposited solid low molecular weight pharmaceutical active ingredient is amorphous; (41) The amorphous deposited solid low molecular weight pharmaceutical active ingredient further defines particles with an average particle size greater than or equal to about 2 nm to less than or equal to about 200 nm; (42) The amorphous deposited solid low molecular weight pharmaceutical active ingredient is stable for greater than or equal to about 1 month; (43) The deposited solid low molecular weight pharmaceutical active ingredient is crystalline or polycrystalline; (44) The average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm; (45) The deposited solid low molecular weight pharmaceutical active ingredient is selected from: anti - proliferative agents; anti - rejection drugs; anti - thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; anti - androgens; anti - inflammatory agents; non - steroidal anti - inflammatory agents (NSAIDs); antimicrobials; antivirals; antifungals; antibiotics; chemotherapeutic agents; anti - tumor agents / anti - miotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol - lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (46) The deposited solid low molecular weight pharmaceutical active ingredient is selected from: caffeine, (E) - 3 - (4 - methylphenylsulfonyl) - 2 - acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (47) The molecular weight of the deposited solid low molecular weight pharmaceutical active ingredient is greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol; (48) The average thickness of the deposited solid low molecular weight pharmaceutical active ingredient in one or more discrete regions is less than or equal to about 300 nm, and the average surface roughness (R a ) is less than or equal to about 100 nm; (49) The average thickness of the deposited solid low molecular weight pharmaceutical active ingredient in one or more discrete regions is greater than or equal to about 300 nm, and the deposited solid low molecular weight pharmaceutical active ingredient defines a nanostructured surface comprising a plurality of nanostructures, the major dimensions of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm; (50) The deposited solid low molecular weight pharmaceutical active ingredient defines a nanostructured surface having a plurality of nanostructures having shapes selected from: needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (51) Comprising one of the following:

[0163] a. The deposited solid low molecular weight pharmaceutically active ingredient comprises caffeine, and the plurality of nanostructures have a needle shape or a tube shape, wherein the plurality of nanostructures have an average diameter of greater than or equal to about 5 nm to less than or equal to about 10 μm, and an average length of greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0164] b. The deposited solid low molecular weight pharmaceutically active ingredient comprises (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, and the plurality of nanostructures have a flake shape, wherein the plurality of nanostructures have an average height of greater than or equal to about 10 nm to less than or equal to about 10 μm, the plurality of nanostructures have an average width of greater than or equal to about 5 nm to less than or equal to about 10 μm, and an average length of greater than or equal to about 5 nm to less than or equal to about 100 μm;

[0165] c. The deposited solid low molecular weight pharmaceutically active ingredient comprises fluorescein, and the plurality of nanostructures have a circular shape, wherein the plurality of nanostructures have an average radius of greater than or equal to about 5 nm to less than or equal to about 10 μm; or

[0166] d. The deposited solid low molecular weight pharmaceutically active ingredient comprises paracetamol, and the plurality of nanostructures have a shape selected from the group consisting of: droplets, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof, wherein the plurality of nanostructures have an average major dimension of greater than or equal to about 5 nm to less than or equal to about 20 μm;

[0167] (52) The deposited solid low molecular weight pharmaceutically active ingredient has an improved dissolution rate as compared to a comparative powder or particulate form of the low molecular weight pharmaceutically active ingredient, wherein the dissolution rate of the deposited solid low molecular weight pharmaceutically active ingredient in an aqueous solution is at least ten times greater than the comparative dissolution rate of the comparative powder or particulate form of the low molecular weight pharmaceutically active ingredient; (53) The deposited solid low molecular weight pharmaceutically active ingredient has an improved bioavailability as compared to a comparative powder or particulate form of the low molecular weight pharmaceutically active ingredient, wherein the bioavailability of the deposited low molecular weight organic active ingredient compound in the solid film is at least about 10% greater than the comparative bioavailability of the comparative powder or particulate form of the low molecular weight pharmaceutically active ingredient; (54) The deposited solid low molecular weight pharmaceutically active ingredient is substantially free of any binder or impurity; and / or (55) One or more discrete regions contain greater than or equal to about 99.5 mass % of the deposited solid low molecular weight pharmaceutically active ingredient.

[0168] In other aspects, the present disclosure contemplates a fourth embodiment, which is an article comprising a solid deposition film containing a pharmaceutical composition, the pharmaceutical composition comprising at least one low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol. Also specifically disclosed is a combination of such articles including any combination of one or more than one of the optionally listed features (56) to (68) or any of the previously listed features (1) to (55).

[0169] The article of the fourth embodiment optionally has any combination of one or more than one of the following features: (56) the pharmaceutical composition further comprises at least one additional deposited compound different from the low molecular weight organic compound; (57) the pharmaceutical composition comprises at least two low molecular weight organic compounds; (58) the pharmaceutical composition has at least one low molecular weight organic compound present in the solid deposition film in an amount greater than or equal to about 99% by mass; (59) the article is a multi-layer stack, and the solid deposition film containing the pharmaceutical composition is the first layer and the multi-layer stack comprises a second layer having a different chemical composition; (60) the second layer comprises a second pharmaceutical composition different from the pharmaceutical composition in the first layer; (61) the second layer comprises a material that minimizes the dissolution rate of the pharmaceutical composition in the first layer; (62) the second layer comprises a material having a solubility controlled by the presence of a trigger selected from: light, radiation, magnetism, radio waves, the pH of the surrounding medium, and combinations thereof; (63) the specific surface area of the solid deposition film is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000 m 2 / g; (64) the solid deposited film is stable for greater than or equal to about 1 month; (65) the low molecular weight organic compound is a pharmaceutically active ingredient or a new chemical entity selected from: anti-proliferatives; anti-rejection drugs; anti-thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; anti-progesterones; anti-androgens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); anti-microbial agents; anti-viral agents; anti-fungal agents; antibiotics; chemotherapeutic agents; anti-tumor agents / anti-miotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (66) the low molecular weight organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (67) compared to the low molecular weight organic compound in a comparative powder or particulate form, the low molecular weight organic compound in the pharmaceutical composition has increased solubility, wherein the dissolution rate of the low molecular weight organic compound in an aqueous solution is at least ten times greater than the dissolution rate of the low molecular weight organic compound in a comparative powder or particulate form; (68) compared to the low molecular weight organic active ingredient in a comparative powder or particulate form, the deposited low molecular weight organic compound in the pharmaceutical composition has increased bioavailability, wherein the bioavailability of the deposited low molecular weight organic active ingredient compound in the pharmaceutical composition is at least about 10% greater than the comparative bioavailability of the low molecular weight organic active ingredient in a comparative powder or particulate form.

[0170] In other aspects, the present disclosure contemplates a fifth embodiment of a method for solventless vapor deposition. The method includes depositing a low molecular weight organic compound having a molecular weight less than or equal to about 1,000 g / mol on one or more discrete regions of a substrate in a substantially solvent-free manner. The method is selected from vacuum thermal evaporation (VTE), organic vapor jet printing (OVJP), organic vapor phase deposition (OVPD), organic molecular beam deposition (OMBD), molecular jet printing (MoJet), and organic vapor jet printing (OVJP), and organic vapor phase deposition (OVPD). The deposited low molecular weight organic compound is present in one or more discrete regions at greater than or equal to about 99 mass %.

[0171] Also specifically disclosed is a combination of the method comprising any combination of any one or more than one of the recited steps or features (69) to (91), or any of the previously recited features (1) to (68) in the context of the first to fourth embodiments. The method for solventless vapor deposition optionally has any combination of any one or more than one of the following steps or features: (69) further comprising entraining a low molecular weight organic compound in an inert gas stream or in a vacuum substantially free of any solvent prior to deposition; (70) wherein prior to entrainment, the low molecular weight organic compound is in a form selected from: powder, pressed granules, porous material, and liquid; (71) wherein prior to entrainment, the low molecular weight organic compound is dispersed in a porous material; (72) wherein prior to entrainment, the low molecular weight organic compound is dispersed in a liquid bubbler through which the inert gas stream passes; (73) entrainment of the low molecular weight organic compound in the inert gas stream or in a vacuum is effected by heating a solid low molecular weight organic compound source to sublime or evaporate the low molecular weight organic compound; (74) the low molecular weight organic compound is deposited onto one or more discrete regions at a loading density greater than or equal to about 1×10 -4 g / cm 2 to less than or equal to about 1 g / cm 2 ; (75) adjusting parameters to affect the morphology, crystallinity, or both the morphology and crystallinity of the deposited low molecular weight organic compound, wherein the parameters are selected from: system pressure, flow rate of the inert gas stream, composition of the inert gas, temperature of the low molecular weight organic compound source, composition of the substrate, surface texture of the substrate, temperature of the substrate, and combinations thereof; (76) the specific surface area of the deposited low molecular weight organic compound is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000 m 2 / g; (77) The deposited low molecular weight organic compound is amorphous; (78) The deposited low molecular weight organic compound also defines particles having an average particle size of greater than or equal to about 2 nm to less than or equal to about 200 nm; (79) The deposited low molecular weight organic compound is crystalline or polycrystalline; (80) The average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm; (81) The deposited low molecular weight organic compound is a pharmaceutically active ingredient or a new chemical entity selected from the following: anti-proliferative agents; anti-rejection drugs; anti-thrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; anti-progesterones; anti-androgens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); anti-microbial agents; anti-viral agents; anti-fungal agents; antibiotics; chemotherapeutic agents; anti-tumor agents / anti-miotics; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (82) The low molecular weight organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (83) The molecular weight of the deposited low molecular weight organic active ingredient compound is greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol; (84) The average thickness of the deposited low molecular weight organic compound in one or more discrete regions is less than or equal to about 300 nm, and the average surface roughness (R a)Less than or equal to about 100 nm; (85) The average thickness of the low molecular weight organic compound deposited in one or more discrete regions is greater than or equal to about 300 nm, and the deposited low molecular weight organic compound defines a nanostructured surface having a plurality of nanostructures, the major dimension of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm; (86) The plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (87) The purity level of the low molecular weight organic compound deposited in one or more discrete regions is greater than or equal to about 99.5 mass%; (88) The low molecular weight organic compound is a pharmaceutically active ingredient or a new chemical entity; (89) One or more discrete regions are continuous, and the deposited low molecular weight organic compound forms a solid film on the surface of the substrate; (90) The deposited low molecular weight organic compound has an increased dissolution rate compared to a comparative powder or particulate form of the deposited low molecular weight organic compound, wherein the dissolution rate of the deposited low molecular weight organic compound in an aqueous solution is at least ten times greater than the dissolution rate of the comparative powder or particulate form of the deposited low molecular weight organic compound; (91) The deposited low molecular weight organic compound has an increased bioavailability compared to a comparative powder or particulate form of the low molecular weight organic active ingredient, wherein the bioavailability of the deposited low molecular weight organic active ingredient compound is at least about 10% greater than the comparative bioavailability of the comparative powder or particulate form of the low molecular weight organic active ingredient.

[0172] In other aspects, the present disclosure contemplates a sixth embodiment of a method for organic vapor jet printing deposition. The method includes entraining a low molecular weight organic compound in an inert gas stream by heating a solid low molecular weight organic compound source to sublime the low molecular weight organic compound. The inert gas stream is passed over, past, or through the source. The low molecular weight organic compound is entrained in the inert gas stream and directed towards a cooled target through a nozzle. The low molecular weight organic compound is condensed when it contacts the cooled target.

[0173] Also specifically disclosed is the method including any combination of any one or more of the optional steps or features (92) to (108) or any combination of the previously recited features (1) to (91). The method for organic vapor jet printing deposition optionally has any combination of any one or more of the following steps or features: (92) The cooled target is the surface of a substrate, and the condensed low molecular weight organic compound is deposited in one or more discrete regions of the surface; (93) The condensed low molecular weight organic compound is deposited at a rate greater than or equal to about 1×10 -4 g / cm 2 to less than or equal to about 1 g / cm2 The load density is deposited onto one or more discrete regions of the surface; (94) the specific surface area of the condensed low molecular weight organic compound in one or more discrete regions is greater than or equal to about 0.001 m 2 / g and less than or equal to about 1000 m 2 / g; (95) the average thickness of the condensed low molecular weight organic compound in one or more discrete regions is less than or equal to about 300 nm, and the average surface roughness (R a)Less than or equal to about 100 nm; (96) The average thickness of the condensed low-molecular-weight organic compound in one or more discrete regions is greater than or equal to about 300 nm, and the condensed low-molecular-weight organic compound defines a nanostructured surface having a plurality of nanostructures, the main dimensions of the nanostructures being greater than or equal to about 5 nm to less than or equal to about 10 μm; (97) The plurality of nanostructures have a shape selected from: needles, tubes, rods, flakes, circular particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (98) One or more discrete regions in the surface are continuous, and the condensed low-molecular-weight organic compound forms a solid film on the surface of the substrate; (99) The purity level of the condensed low-molecular-weight organic compound is greater than or equal to about 99.5 mass%; (100) The cooling target is a liquid containing one or more solvents; (101) Entrainment and guiding are carried out under atmospheric pressure conditions; (102) wherein entrainment and guiding are carried out under reduced pressure conditions of greater than or equal to about 0.1 Torr to less than or equal to about 500 Torr; (103) Parameters are adjusted to affect the morphology, crystallinity, or both the morphology and crystallinity of the condensed low-molecular-weight organic compound, wherein the parameters are selected from: system pressure, flow rate of the inert gas stream, inert gas composition, temperature of the source, composition of the target substrate, surface texture of the target substrate, temperature of the target substrate, and combinations thereof; (104) wherein the condensed low-molecular-weight organic compound is amorphous; (105) wherein the condensed low-molecular-weight organic compound is crystalline or polycrystalline; (106) wherein the low-molecular-weight organic compound is a pharmaceutically active substance or a new chemical entity selected from: antiproliferatives; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogesterones; antiandrogens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); antimicrobials; antivirals; antifungals; antibiotics; chemotherapeutic agents; antitumor agents / antimiosis agents; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (107) wherein the low-molecular-weight organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; and / or (108) wherein the low-molecular-weight organic compound is a pharmaceutically active substance or a new chemical entity, and the molecular weight is greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

[0174] In other aspects, the present disclosure contemplates a seventh embodiment of a method for rapidly dissolving low molecular weight organic compounds. The method includes passing a gas stream containing an inert gas over a heated source of the low molecular weight organic compound. The low molecular weight organic compound volatilizes and is entrained in the gas stream. The method further involves depositing the low molecular weight organic compound into a liquid containing one or more solvents by passing the gas stream through a nozzle towards the liquid such that the deposited low molecular weight organic compound dissolves in the liquid.

[0175] Also specifically disclosed is a combination of the method including any combination of any one or more of the recited steps or features (109) to (121) or any combination of any of the previously recited features (1) to (108). The method for rapidly dissolving low molecular weight organic compounds optionally has any combination of any one or more of the following steps or features: (109) the heated source includes a porous ceramic container containing the low molecular weight organic compound that receives heat transferred from a heater; (110) the temperature of the heated source is greater than or equal to about 250 °C and the liquid is at ambient temperature; (111) the nozzle is greater than or equal to about 15 mm to less than or equal to about 25 mm from the surface of the liquid; (112) the inert gas includes nitrogen; (113) the liquid is an aqueous liquid containing water; (114) the concentration of the low molecular weight organic compound is greater than or equal to about 1×10 -11from about 1 mol / L to less than or equal to about 20 mol / L; (115) the amount of the deposited low-molecular-weight organic compound is less than or equal to about 100 μg; (116) the volume of the liquid is less than or equal to about 100 ml; (117) the deposition is carried out for greater than or equal to about 1 minute to less than or equal to about 120 minutes; (118) the low-molecular-weight organic compound is a pharmaceutically active substance or a new chemical entity selected from the following: antiproliferatives; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; saccharides; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; non-steroidal anti-inflammatory agents (NSAIDs); antimicrobials; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antitumor agents / antimiosis agents; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (119) the low-molecular-weight organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (120) the low-molecular-weight organic compound is a pharmaceutically active substance or a new chemical entity having a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 1,000 g / mol; and / or (121) the low-molecular-weight organic compound is a pharmaceutically active substance or a new chemical entity having a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

[0176] The above description of the embodiments is for illustrative and descriptive purposes. It is not intended to be exhaustive or to limit the present disclosure. The individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but are interchangeable and usable in a selected embodiment where applicable, even if not specifically shown or described. Similarly, it can also be changed in many ways. Such variations are not considered to depart from the present disclosure, and all such modifications are intended to be included within the scope of the present disclosure.

Claims

1. An organic vapor jet printing deposition method, comprising: entraining an organic compound having a molecular weight less than or equal to 1,000 g / mol in an inert gas stream by heating a solid organic compound source to sublime the organic compound and passing an inert gas stream over, through, or across the source; directing the organic compound in the inert gas stream through a nozzle toward a cooling target; and condensing the organic compound when it contacts the cooling target, wherein the entraining and directing are carried out under atmospheric pressure conditions, and wherein the cooling target is a liquid containing one or more solvents.

2. The organic vapor jet printing deposition method according to claim 1, wherein the organic compound is deposited on one or more discrete regions of the cooling target.

3. The organic vapor jet printing deposition method according to claim 2, wherein the organic compound is deposited onto the one or more discrete regions of the cooling target at a loading density greater than or equal to 1×10 -4 g / cm 2 and less than or equal to 1 g / cm 2 .

4. The organic vapor jet printing deposition method according to claim 1, wherein the purity level of the condensed organic compound is greater than or equal to 99.5 mass%.

5. The organic vapor jet printing deposition method according to claim 1, wherein the cooling target contains a polar liquid.

6. The organic vapor jet printing deposition method according to claim 1, wherein the cooling target contains an aqueous solution.

7. The organic vapor jet printing deposition method according to claim 1, wherein the cooling target contains a non-polar liquid.

8. The organic vapor jet printing deposition method according to claim 1, wherein the cooling target contains one solvent.

9. The organic vapor jet printing deposition method according to claim 1, wherein the cooling target contains more than one solvent.

10. The organic vapor jet printing deposition method according to claim 1, wherein the organic compound is a pharmaceutically active substance or chemical entity selected from: antiproliferatives; anti-rejection drugs; antithrombotic agents; antioxidants; free radical scavengers; nucleic acids; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; anti-inflammatory agents; antimicrobials; chemotherapeutic agents; antitumor agents / antimiosis agents; anesthetics, analgesics or painkillers; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenesis substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

11. The organic vapor jet printing deposition method according to claim 1, wherein the organic compound is a pharmaceutically active substance or chemical entity selected from: anticoagulants; saccharides; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; non-steroidal anti-inflammatory agents (NSAIDs); antiviral agents; antifungal agents; antibiotics; and combinations thereof.

12. The organic vapor jet printing deposition method according to claim 1, wherein the organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen; and combinations thereof.

13. The organic vapor jet printing deposition method according to claim 1, wherein the organic compound is a pharmaceutically active substance or chemical entity and has a molecular weight greater than or equal to 100 g / mol to less than or equal to 900 g / mol.

Images