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

Abstract

The invention relates to a method for improving the bioavailability of organic small molecules and a deposited film manufactured by the method. Solid films and articles having a surface with discrete regions patterned with deposited low molecular weight organic compounds (e.g., pharmaceutically active substances and new chemical entities) are provided. The organic compound may be present at > = about 99 mass% in one or more discrete regions and may be crystalline or amorphous. The deposited organic compound may be deposited as a film having a high surface area. As a non-limiting example, the deposited organic compounds exhibit improved solubility and bioavailability. Methods of organic vapor jet printing deposition of such low molecular weight organic compounds in an inert gas stream are also provided.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of June 6, 2016, application number "201680040287.8", and invention name "Method for improving the bioavailability of organic small molecules and deposited films made therefrom". The original application is the Chinese national phase application of international application PCT / US2016 / 036009.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 171,702, filed on June 5, 2015. The entire disclosure of the above application is incorporated herein by reference. Technical Field

[0004] The present disclosure relates to pure deposited films of low molecular weight organic compounds (e.g., pharmaceutical active ingredients or new chemical entities), wherein such deposited low molecular weight organic compounds have improved bioavailability and solubility. Also provided are methods and apparatus for depositing low molecular weight organic compounds by deposition methods, such as organic vapor jet printing deposition methods and apparatus. Background Art

[0005] This section provides background information related to the present disclosure which is not necessarily prior art.

[0006] Solutions of small molecule organic compounds are widely used in many industries: as non-limiting examples, food, cosmetics / perfumes, pharmaceuticals, organic electronics, printing and paints. Water solubility is an especially important factor in controlling the bioavailability of active pharmaceutical ingredients (API). Therefore, the pharmaceutical industry faces many challenges. For example, more than 40% of newly discovered drugs / new chemical entities (NCE) have low solubility and dissolution rate, making them less favorable candidates for further research. 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 technology; chemical modifications: changing pH, using buffers, salt formation, complexation and other methods (such as using surfactants, cosolvency, hydrotrophy and new excipients).

[0007] Methods of reducing particle size take advantage of the fact that the solubility of a drug is intrinsically dependent on the size of the drug particles: as particle size decreases, the surface area to volume ratio increases, enhancing interactions with the solvent and leading to improved solvation. Common methods of reducing particle size (e.g., spray drying, pulverization, micronization, and nanonization) introduce physical stresses on the drug particles and potentially degrade sensitive NCE molecules and / or cause particle aggregation. In addition, these techniques typically require more complex processing techniques, including additional processing stages such as screening and fractionation into specific doses. Furthermore, reducing particle size is not necessarily feasible for high potency drugs that require sub-microgram doses or for newly developed drugs and drug candidates that are not yet available in large quantities (kilograms).

[0008] For example, nano-particles are known methods for improving the bioavailability of API powders. As mentioned above, because the dissolution process is controlled by the surface area to volume ratio of the solute, reducing the particle size leads to a larger surface area and a higher dissolution rate. However, nano-particles have many disadvantages. First, mechanical methods (such as grinding and high pressure homogenization (HPH)) are energy-consuming and time-consuming. Second, the resulting nanoparticles may lack storage stability and controlled release. Third, it is challenging to formulate with nanoparticles, because due to the changes in particle agglomeration and crystallinity, uniformity and stability are difficult to achieve.

[0009] In the initial discovery phase, these NCE compounds are typically added to cell cultures in organic solvent (e.g., dimethyl sulfoxide-DMSO) solutions. Initial drug testing involves dissolution of the drug in an organic solvent (e.g., DMSO), which can provide inaccurate assessments of drug efficacy 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 combined with limited drug amounts typically results in powders used "as is," leading to higher loss rates in drug discovery. Even after efficacy is established in vitro, the later stages of drug development still involve chemical or physical modifications to improve solubility limits and dissolution kinetics.

[0010] Therefore, in conventional methods, in order to achieve a given concentration of an organic solute in the original powder form, the desired 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 usually heated to increase the dissolution rate. This method can be both time-consuming and energy-consuming and potentially damaging to the compound / solvent.

[0011] Another disadvantage of immersing the powdered solute directly in the solvent is when the actual desired concentration of the compound or the volume of solution is very low. For example, if the desired concentration is micromolar, and the desired volume is 10 ml, the required weight of 200 g / mole of material is in micrograms. It is not feasible to accurately measure this weight of the precursor powder; therefore, a more concentrated solution is prepared and then diluted with an additional amount of solvent. This approach is not desirable from both an economic and safety perspective (when working with organic solvents).

[0012] New simplified methods for improving solubility and bioavailability and the ability to screen compounds for improved solubility and potency without the use of organic solvents would be highly desirable and significantly accelerate the drug development cycle and improve pharmaceutical compositions. Summary of the invention

[0013] This section provides a general summary of the disclosure, and is not a comprehensive disclosure of its full scope or all of its features.

[0014] In certain variations, the present disclosure provides a solid film comprising greater than or equal to about 99% by 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. The low molecular weight organic active ingredient compound may be a pharmaceutically active substance or a new chemical entity. The deposited low molecular weight organic compound has an increased solubility compared to the low molecular weight organic compound in a powdered non-deposited form.

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

[0016] In other variations, the present disclosure provides an article comprising a pharmaceutically acceptable substrate defining a surface. The article further comprises a deposited solid low molecular weight pharmaceutically active ingredient having a molecular weight of less than or equal to about 1,000 g / mol. 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 %.

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

[0018] In other variations, the present disclosure provides a solvent-free vapor deposition method comprising depositing, for example, a low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol on one or more discrete regions of a substrate in a substantially solvent-free method. The method may 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 one or more discrete regions at greater than or equal to about 99 mass %.

[0019] In other 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, passed by, or passed through the source. The low molecular weight organic compound is directed through a nozzle toward a cooled target. The low molecular weight organic compound is then condensed when it contacts the cooled target.

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

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

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

[0023] Figures 1(a) to 1(d) show schematic diagrams of organic vapor jet printing deposition techniques and equipment according to certain aspects of the present disclosure. Figure 1(a) shows an organic vapor jet deposition (OVJP) system for a small molecule drug deposition system. Figure 1(b) shows a mixed layer OVJP deposition method - the system includes multiple sources of materials to be evaporated that are subsequently mixed in a main jet stream. Figure 1(c) shows a multilayer method for forming OVJP deposition of different materials in one or more discrete areas on the surface of a substrate, where the different materials may overlap each other. Figure 1(d) shows a select patterning mode of OVJP deposition for depositing different materials.

[0024] Figures 2(a) to 2(b) show schematic diagrams of a specialized design of a source or organic material for OVJP deposition techniques according to certain aspects of the present disclosure. Figure 2(a) shows an evaporation source comprising an outer shell ("boat case") and a ceramic foam plug that can sublimate and carry evaporated molecules through a porous foam in a highly reproducible manner. Figure 2(b) shows an example of an evaporation source implementation. The boat case is made of quartz and the ceramic foam is silicon carbide with a porosity of 80 pores per inch (ppi) from Ultramet. The powder to be evaporated is placed between the porous foam disks or between the foam disks and a portion of quartz wool. The source can be reused after washing out the organic powder with an appropriate solvent.

[0025] Figure 3 Several examples of printed pharmaceutical organic compounds deposited by organic vapor jet printing deposition techniques according to certain aspects of the present disclosure are shown.

[0026] 4(a)-(b) show one example of a printed drug film with a deposited organic compound (BAY 11-7082) Comparative testing of deposited films according to certain aspects of the present disclosure compared to a comparative DMSO preparation for evaluation of bio-efficacy.

[0027] Figures 5(a) to 5(c) show schematic diagrams of organic vapor jet printing deposition techniques and equipment 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 spraying fluorescein molecules into 2 ml of phosphate buffered saline solution. Spraying 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 spray 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 microstructure of the compound powders.

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

[0030] Figures 8(a) to 8(d) show some examples of different coating forms of fluorescein on different substrates according to certain aspects of the present disclosure. Figure 8(a) shows a solid deposited film of fluorescein on an acrylic polymer wound care patch, Figure 8(b) shows a solid deposited film of fluorescein on a pullulan-based film, Figure 8(a) shows a solid deposited film of fluorescein on a stainless steel microneedle, and Figure 8(a) shows a solid deposited film of fluorescein on a borosilicate glass slide.

[0031] Figures 9(a) to 9(b) show the controlled release of printed fluorescein films prepared according to certain aspects of the present disclosure. Figure 9(a) shows the dissolution curves of printed fluorescein films with different thicknesses and constant area. The inset in Figure 9(a) shows the correlation of (1-exp(-kt)) with film thickness. Figure 9(b) shows the dissolution curves of printed fluorescein films with different diameters and constant thickness. The dotted lines are experimental. The solid lines are 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 fluorescein film and original powder in deionized water. The dashed line is the experimental value. The solid line is the theoretical prediction of the film and powder. Figure 10(b) shows the dissolution curves of ibuprofen film and original powder in HCl buffered pH 1.2 aqueous solution. The dashed line shows the experimental value. The solid line shows the theoretical prediction of the film and powder. Figure 10(c) shows the dissolution curves of tamoxifen film and original powder in acetate buffered pH 4.9 solution. The dashed line shows the experimental value. The solid line shows the theoretical prediction of the film and powder.

[0033] Fig.11 Schematic diagram showing drug administration for cancer cell growth studies.

[0034] Figures 12(a) to 12(d) show the improvement of the biological efficacy of 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).

[0035] Fig.13A graph showing the specific surface area of ​​the film as a function of the deposited film area for different printed film weights.

[0036] Corresponding reference characters indicate corresponding parts throughout the several views of the drawings. DETAILED DESCRIPTION

[0037] Some exemplary embodiments are provided so that the present disclosure is thorough and the scope is fully conveyed to those skilled in the art. A large 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 is obvious to those skilled in the art that specific details need not be used, and the exemplary embodiments can be embodied in many different forms and both should not be construed as limiting the scope of the present disclosure. In some exemplary embodiments, known methods, known device structures and known technologies are not described in detail.

[0038] The terms used herein are only for the purpose of describing specific exemplary embodiments, and are not intended to be restrictive. As used herein, unless the context clearly states otherwise, nouns modified by quantifiers represent one / kind or more / kind. The terms "comprise", "contain", "include" and "have" are inclusive, and therefore determine the presence of the features, elements, compositions, steps, integers, operations and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or their groups. Although the open term "comprise / include" should be understood as a non-limiting term for describing and claiming a plurality of embodiments set forth herein, in some aspects, the term can be alternatively understood as a more restricted term, such as "consisting of..." or "consisting essentially of...". Therefore, for any given embodiment of recording a composition, material, component, element, feature, integer, operation and / or processing step, the present disclosure also specifically includes an embodiment consisting of or essentially consisting of the composition, material, component, element, feature, integer, operation and / or processing step recorded in this way. 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 substantially 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 substantially affect the basic and novel features may be included in the embodiment.

[0039] Unless specifically determined as an order of performance, any method steps, processes, and operations described herein should not be construed as necessarily requiring their performance in the particular order discussed or illustrated. It should also be understood that alternative or additional steps may be employed unless otherwise specified.

[0040] When a component, element, or layer is referred to as being "on," "engaged," "connected," or "coupled" to another element or layer, it may be directly on, engaged, connected, or coupled to the other component, element, or layer, or there may be intervening elements or layers. Conversely, when an element is referred to as being directly "on," "directly engaged," "directly connected," or "directly coupled" to another element or layer, there may be no intervening elements or layers. Other words used to describe the relationship between elements should be interpreted in the same manner (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," etc.). As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0041] Unless otherwise stated, although the term first, second, third, etc. can be used to describe different steps, elements, components, regions, layers and / or parts in this article, these steps, elements, components, regions, layers and / or parts should not be limited by these terms. These terms can only be used to distinguish a step, element, component, region, layer and / or part from another step, element, component, region, layer and / or part. Unless the context clearly states, otherwise when used in this article, terms (such as "first", "second" and other numerical terms) do not mean order or sequence. Therefore, without departing from the teaching of exemplary embodiments, the first step, element, component, region, layer or part discussed below can be referred to as the second step, element, component, region, layer or part.

[0042] For ease of description herein, spatial or temporal relative 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 relative to other elements or features as shown in the drawings. The spatial or temporal relative terms may be intended to encompass different orientations of a device or system in use or operation in addition to the orientation depicted in the drawings.

[0043] Throughout this disclosure, numerical values ​​represent approximate measurements or limits of ranges to include smaller deviations from a given value and embodiments having approximately the values ​​mentioned as well as embodiments having the exact values ​​mentioned. 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 in all cases as being modified by the term "about", regardless of whether "about" actually appears before the numerical value. "Approximately" means that the numerical value allows some slight imprecision (using some methods to reach the value exactly; approximately or reasonably close to the value; almost). If the imprecision provided by "approximately" is not understood in this ordinary sense in the art, the "approximately" used herein at least represents the variation that can be caused by the ordinary methods of measuring and using these parameters.

[0044] Furthermore, disclosure of ranges includes disclosure of all values ​​within the entire range and further divided ranges, including the endpoints and sub-ranges stated in the ranges.

[0045] Some exemplary embodiments will now be described more fully with reference to the accompanying drawings.

[0046] The present disclosure provides new simplified methods for improving the solubility and bioavailability of organic compounds, especially those used in drug development or new chemical entities (NCEs) of drug compounds. In various aspects, the compositions, articles and methods of the present teachings provide the ability to screen compounds for improved solubility and potency without the use of organic solvents, which can significantly accelerate the drug development cycle and improve pharmaceutical compositions.

[0047] In some aspects, the present disclosure provides materials and methods for continuous manufacturing and personalized dosing methods of active ingredients. In many aspects, the present disclosure provides a solid film comprising a low molecular weight organic compound. In some aspects, the molecular weight of the low molecular weight compound may 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 optionally less than or equal to about 200 g / mol in some variations. 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 may include a variety 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 studied for potential pharmacological or biological activity), as will be further described below. However, in some alternative variations, as non-limiting examples, the low molecular weight organic compound can be a nutrient or food compound, a nutraceutical compound, a cosmetic or personal care compound, a fragrance compound, a colorant or dye, ink, a paint, etc.

[0048] Therefore, the present disclosure provides solid films, such as low molecular weight organic compounds (such as pharmaceutically active agents or new chemical entities) of patterned deposition on the surface of substrates. In some variations, the surface has a continuous organic compound surface coating or film, and in other variations, the organic compound can be applied to the selected discrete regions of the surface. The high-quality film or coating with a high purity level of low molecular weight organic compounds is formed by a method according to some aspects of the present disclosure. For example, in some variations, the purity level in one or more regions of the deposited low molecular weight compound 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 with the same purity level together or cumulatively. The deposited solid films can have surface feature morphologies ranging from molecularly flat to high surface areas (e.g., nanostructured surfaces) with feature sizes in the micrometer or nanometer range. Such surfaces patterned with organic compounds have improved the solubility of medical organic compounds and substances both in the initial research phase and at the production level.

[0049] In some aspects, a method for obtaining a solid film with a high level of purity and solubility is provided. For example, in some variations, a solvent-free vapor deposition method is provided, which includes depositing low molecular weight organic compounds on one or more discrete regions of a substrate in a method that is substantially free of solvent. "Substantially free of" means that there is no solvent compound or substance to the extent that undesirable and / or harmful effects can be ignored or do not exist. In some aspects, the substantially solvent-free vapor deposition method has less than or equal to about 0.5 weight %, optionally less than or equal to about 0.1 weight %, and in some preferred aspects, 0 weight % of undesirable solvent substances during the deposition process.

[0050] The deposited low molecular weight organic compound can then be present in one or more discrete regions at a high purity level (e.g., at greater than or equal to about 99 mass % as described above). The method 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).

[0051] In certain aspects, such methods may include entraining the low molecular weight organic compound in an inert gas stream or vacuum substantially free of any solvent prior to deposition. The inert gas stream may contain one or more generally non-reactive compounds, such as nitrogen, argon, helium, etc. In certain variations, the inert gas stream contains nitrogen.

[0052] Since many low molecular weight organic compounds (e.g., small molecule drugs) have sufficiently high vapor pressure (e.g., about 1 Pa to about 100 Pa) and relatively low vaporization enthalpy (e.g., 100 to 300 kJ / mol), even when evaporated under atmospheric pressure, a high vaporization rate (g / (sec*m)) can be achieved at a temperature of 100°C to 500°C. 2 ) without reaching a temperature range where compound degradation may occur. Any method / system capable of depositing molecular materials onto a substrate from a gas phase (where the molecular material source is an evaporated or sublimated solid) can be used to form a 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).

[0053] However, the method is not limited to a solid source of low molecular weight compounds. In some aspects, before entrainment, the low molecular weight organic compound is in a form selected from the following: powder, pressed particles, porous material and liquid. In some aspects, before entrainment, the low molecular weight organic compound is dispersed in the pores of the porous material. In other aspects, before entrainment, the low molecular weight organic compound is dispersed in a liquid bubbler through which an inert gas stream passes. In other aspects, the entrainment of the low molecular weight organic compound in an inert gas stream or 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 some variations, the deposition method results in a low molecular weight organic compound at a concentration greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / cm 2 The load density is deposited onto one or more discrete areas.

[0054] The parameters of the deposition process can be adjusted to control or influence the morphology, crystallinity, or both morphology and crystallinity of the deposited solid low molecular weight organic compound. The parameters are selected from the group consisting of: 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.

[0055] In certain aspects, the deposited low molecular weight organic compound has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m2 / g. The deposited low molecular weight organic compound can be amorphous. When the deposited low molecular weight organic compound is amorphous, it can also be limited to an average particle size (e.g., average particle diameter) of interconnected particles greater than or equal to about 2nm to less than or equal to about 200nm. In other aspects, the deposited low molecular weight organic compound is crystalline or polycrystalline. In some such variations, the average crystal size or crystalline domain can be greater than or equal to about 2nm to less than or equal to about 200nm.

[0056] In certain aspects, the one or more discrete regions on which the low molecular weight organic compound is deposited are continuous so that a solid film is formed on the surface of the substrate. In certain variations, the one or more discrete regions of the surface have a high surface area morphology, which may optionally define one or more nanostructures or microstructures. In certain variations, the average thickness of the low molecular weight organic compound deposited in the one or more discrete regions of the surface of the substrate may be less than or equal to about 300 nm, and the average surface roughness (R a ) may be less than or equal to about 100nm. Thus, for a solid deposited film having a thickness of 200±100nm, the film is flat (roughness <100nm). Starting from a thickness of about 200±100nm, undulations occur in the solid deposited film, which further produces and defines a nanostructure. As used herein, "nano-size" is generally understood by those skilled in the art to be at least one spatial dimension less than about 50μm (i.e., 50,000nm), and optionally less than about 10μm (i.e., 10,000nm). 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 300nm, and the deposited low molecular weight organic compound defines a nanostructured surface having a plurality of nanostructures, the main size of the nanostructure being greater than or equal to about 5nm to less than or equal to about 10μm. 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 may have a shape selected from the group consisting of needles, tubes or cylinders, rods, platelets, round particles (although they need not be perfectly round or annular), droplets, fronds, tree-like 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.

[0057] In certain variations, the purity level of the low molecular weight organic compound deposited in the 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 pharmaceutically active ingredients or new chemical entities) may include, as non-limiting examples: a variety of drugs or potential drugs (e.g., new chemical entities), including antiproliferative agents; 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; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic / anti-miotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof. The description of these suitable organic compounds / pharmaceutical active ingredients / new chemical entities is exemplary only and should not be considered to limit the scope of compounds or active ingredients that can be applied to a surface according to the present disclosure, as all organic molecules and / or active ingredients known to those skilled in the art that are suitable for use in these various types of compositions are contemplated. In addition, organic compounds may have multiple functions and therefore may be included in the above exemplary categories; however, may be classified in multiple different categories of active ingredients.

[0058] A wide variety of suitable active ingredients are listed in the Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals, Thirteenth Edition (2001), Merck Research Laboratories and International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition, 2004, Cosmetic Toiletry and Fragrance Association and in http: / / www.drugbank.ca / The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell. The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell. The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell. The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell. The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell. The invention relates to a method for treating a leukemia or leukemia in a human endothelial cell.

[0059] In some variations, the deposited low molecular weight organic compound has an increased dissolution rate compared to the same low molecular weight organic compound deposited in comparative powder or granular form. Thus, the dissolution rate of the deposited low molecular weight organic compound in aqueous solution (e.g., close to physiological conditions) is at least ten times greater than the comparative dissolution rate of the deposited low molecular weight organic compound in comparative powder or granular form. In some variations, the dissolution rate of the deposited low molecular weight organic compound in aqueous solution is at least fifteen times greater, optionally twenty times greater, and optionally thirty times greater than the comparative dissolution rate of the deposited low molecular weight organic compound in powder or granular form.

[0060] Since the biological processes of different drugs are different, increasing the dissolution rate also increases bioavailability, especially organic compounds where the difference in dissolution rate is limiting. Therefore, in some variations, the deposited low molecular weight organic compound has an increased bioavailability, such as the amount and / or rate at which the organic compound is absorbed into a living organism or system, compared to the same low molecular weight organic active ingredient in a comparative powder or granular form. In some variations, the bioavailability is increased regardless of whether it is measured by the amount or rate of uptake of the compound in a living organism or system. Such organisms or living systems may include (as non-limiting limitations): animals, such as mammals (e.g., humans) and companion animals; plants; bacteria; prokaryotic cells; eukaryotic cells; etc. In some instances, when the low molecular weight organic active ingredient compound is in a deposited solid form, its bioavailability may be increased, at least about 10% greater than the comparative bioavailability of the low molecular weight organic active ingredient in a comparative powder or granular form. When a low molecular weight organic active ingredient compound is deposited by the methods of the present disclosure, the bioavailability can be improved 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 improved by greater than about 100%, compared to a conventional powder or granular form of the low molecular weight organic active ingredient compound.

[0061] In some aspects, solid films with high surface area morphology can be formed by improved organic vapor jet printing (OVJP) methods, which eliminate the need for organic solvents and improve the dissolution rate of small molecule-based organic materials (e.g., APIs). Organic compounds that can be deposited by the OVJP method have relatively low molecular weights and are therefore considered to be low molecular weight organic compounds. The OVJP method utilizes a carrier gas (e.g., nitrogen) to transport sublimated organic vapors toward a cooling substrate or other target in the form of a focused gas jet. The OVJP method enables scalable patterning of relatively small molecular materials.

[0062] Therefore, in certain aspects, the OVJP deposition method is performed using an OVJP system 100 as shown in FIG. 1 (a). A cylindrical reactor 102 includes a low molecular weight organic compound source 110. The source 110 is a low molecular weight organic compound in solid form (e.g., powder or pressed particles). The source 110 may hold or contain a low molecular weight organic compound, for example, a porous material having a low molecular weight organic compound distributed in the pores. The reactor 102 has an inlet 112 for an inert carrier gas stream 120 to enter. The heater 114 is disposed around the outside, or may be otherwise integrated into the reactor 102. The material in the evaporation source 110 sublimates or evaporates and is carried by the inert carrier gas 120. Therefore, the method includes entraining the low molecular weight organic compound in the inert carrier gas stream 120 by heating the source 110 to sublimate or evaporate the low molecular weight organic compound 130, so 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, through 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 Figure 1(a), a low molecular weight organic compound 130 in an inert carrier gas flow 120 is directed through a nozzle 132 to focus a jet 134 toward a cooling target 140. The nozzle 132 is translated over the substrate by an xyz motion controller, and any desired deposition pattern can be printed.

[0063] The cooling target 140 can be a solid or a liquid. The cooling target 140 can be a substrate made of, for example, 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, a medical device, an implant, a membrane, a gel, a patch, a dressing, a fabric, a bandage, a sponge, a stent, a contact lens, a subretinal implant prosthesis, a denture, a brace, a wearable device, a bracelet, and a combination thereof. When the cooling target 140 is a liquid, it can be a polar or non-polar liquid, including an aqueous liquid. The liquid can contain one or more solvents.

[0064] The method also includes condensing the low molecular weight organic compound 130 as it contacts the cooling target 140 on one or more discrete regions. In this manner, the surface of the cooling target 140 can be selectively patterned by directing the jet 134 toward the desired region (or the surface can be temporarily masked). In the variation shown in FIG. 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 certain aspects, the loading density of the condensed low molecular weight organic compound deposited onto the one or more discrete regions of the cooling target 140 by OVJP can be greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / cm 2 In certain variations, 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 1000m 2 / g. Fig.13 A graph showing the specific surface area of ​​the film as a function of the deposited film area for different printed film weights (100 μg, 200 μg, 300 μg, 400 μg and 1000 μg). The specific surface area of ​​the deposited film is higher for samples with lower mass, and the specific surface area decreases with higher mass. As the printed film area increases, the surface area increases. When nanoparticles are grown on the deposited film, the surface area increases further (approximately 2 to 10 times, depending on the particle shape and size). For comparison, powdered organic particles are typically 1 μm to 100 μm in size with a surface area of ​​0.1 m 2 / g to 1m 2 / g. Therefore, the increase in surface area can be several orders of magnitude larger (e.g. Fig.13 The curve in ).

[0065] The thickness may vary depending on the amount of time the jet 134 is directed at a particular region of the surface of the cooling target 140 where the condensed low molecular weight organic compound condenses. In certain variations, 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 a) (a two-dimensional profile of the surface taken perpendicular to the layer, if any) is less than or equal to about 100 nm. As described above, for a solid film 150 having a thickness of 200±100 nm, the film is generally flat, with a surface roughness of less than about 100 nm. Starting from a thickness of about 200±100 nm, undulations appear in the solid film 150, which further create and define a plurality of nanostructures 152. In this manner, the surface of the solid film 150 is nanostructured.

[0066] When the average thickness of the solid film is greater than or equal to about 300 nm, the average surface roughness (R a ) may be greater than or equal to about 100 nm. In addition, 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 may define a nanostructured surface having a plurality of nanostructures 152, wherein the major dimension (e.g., the largest dimension, as indicated by the length of the nanorods or nanocylinders) of the nanostructures 152 may be greater than or equal to about 5 nm to less than or equal to about 10 μm.

[0067] Depending on the OVJP conditions used and the chemical nature of the condensed low molecular weight organic compound, the nanostructures 152 may have different shapes. See, e.g., Figure 3 7(a) to 7(h). In some aspects, the plurality of nanostructures 152 have a shape selected from the group consisting of needles, tubes, rods, or cylinders, platelets, round particles, droplets, leaves, tree structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

[0068] While solid film 150 may have any of the purity levels previously described above, in certain variations, the condensed low molecular weight organic compounds are present at greater than or equal to about 99.5 mass %.

[0069] Two variations of the OVJP apparatus and method are described herein. In one variation, the deposition of the organic compound is performed under atmospheric pressure conditions, rather than drawing a moderate vacuum (10 -3 Torr). This method can be carried out in a glove box with suitable ventilation. In the case of oxygen or moisture sensitive organic compounds, the method can be carried out in a glove box with an inert gas environment. In other variations, entrainment and introduction are carried out under reduced pressure conditions, for example, at greater than or equal to about 0.1 Torr to less than or equal to about 500 Torr.

[0070] In other aspects, the 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 compound. The parameters can be 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. The morphology may include formed nanostructures. The condensed low molecular weight organic compound in the solid film 150 may be amorphous. In other aspects, the condensed low molecular weight organic compound in the solid film 150 is crystalline or polycrystalline. The low molecular weight organic compound may be any of those previously described above.

[0071] FIG. 1( b) shows another OVJP system 160 for performing an OVJP deposition method, which is similar to that shown in FIG. 1( a), except that two different low molecular weight organic compounds are co-deposited. For the sake of simplicity, unless specifically discussed herein, components identical to those in the OVJP system 100 in FIG. 1( a) will not be reintroduced or discussed. In the OVJP system 160, a first cylindrical reactor 162 includes 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. A second cylindrical reactor 172 includes 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 may be the same as the source 110 in FIG. 1( a). A first inert carrier gas stream 182 enters the first cylindrical reactor 162, and a second inert carrier gas stream 192 enters the second cylindrical reactor 172. A third inert carrier gas stream 194 may pass through a conduit 196. Thus the method includes entraining the 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. Notably, the first source 164 in the first cylindrical reactor 162 and the second source 174 in the second cylindrical reactor 172 may 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 comprising the first low molecular weight organic compound 200 and the second low molecular weight organic compound 202 in vapor phase are combined and mixed together to form a mixed stream 214, which exits the nozzle 216 of the main cylindrical reactor 210 to form a jet stream 218. As in FIG. 1( a), the jet stream 218 comprising the first low molecular weight organic compound 200 in vapor phase and the second low molecular weight organic compound 202 in vapor phase is directed through the nozzle 216 toward a cooling target 220. The cooling target 220 may be the same as the cooling target 140 in FIG. 1( a).

[0072] The method also includes condensing the first low molecular weight organic compound 200 and the second low molecular weight organic compound 202 when they contact the cooling target 220 in one or more discrete regions. In this way, the surface of the cooling target 220 can be selectively patterned by directing the jet 218 toward the desired area (or the surface can be temporarily masked). In the variation shown in Figure 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 may have the same properties as described in the context of the solid film 150 in Figure 1 (a), except that it is a uniform 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 comprises any of the purity levels previously described above, with the cumulative amount of the condensed low molecular weight organic compounds being present in certain variations at greater than or equal to about 99 mass % and optionally greater than 99.5 mass % in certain variations. As will be appreciated by those skilled in the art, more than two different low molecular weight organic compounds may be applied in the OVJP method and system as shown.

[0073] FIG. 1( c) shows another OVJP system for 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 sprayed directly on a cooling substrate, so that a first low molecular weight organic compound or a 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 may overlap and form a multilayer system in one or more regions. FIG. 1( d) shows a patterning method of an OVJP system like FIG. 1( c), in which a first low molecular weight organic compound or a second low molecular weight organic compound is applied to discrete regions of a surface simultaneously, but does not overlap each other to form a predetermined pattern (e.g., a dot array). Any pattern can be made by independently translating the nozzles.

[0074] Therefore, Figure 1 (a) to Figure 1 (d) show multiple schematic diagrams of OVJP systems / devices for manufacturing films according to some variations of the present disclosure. Therefore, the method for manufacturing a surface patterned with an organic compound (e.g., a pharmaceutically active agent) may include sublimating or otherwise volatilizing the organic compound contained in the source / target. A single source or target may be used, or multiple sources or targets using a variety of different organic compounds (using different configurations shown in Figures 1 (c) and 1 (d)) may also be used. Similarly, multiple devices may be used in parallel. The system may include one or more sources of a small molecule drug that is heated in powder form. An inert carrier gas (e.g., nitrogen, argon, or helium) is introduced into the device and directed toward the source / target of the organic material. In some variations, the organic compound is in solid form, such as powder form. Heat is also applied in the system (e.g., by a heater) so that the organic compound is sublimated or volatilized into a gas / fluid phase and carried by a passing inert carrier gas flow. The carrier gas with the entrained gaseous organic compound is then ejected from the nozzle in the form of a focused jet and directed toward the substrate with a controlled temperature (e.g., it may be cooled), where the entrained small organic molecules condense. -4 g / cm 2 To 0.1g / cm 2 Deposited in precisely controlled amounts within a highly controlled weight range.

[0075] Such a manufacturing method is highly controllable. In such an OVJP system, multiple parameters can be controlled, including, for example, pressure and flow (including carrier gas flow (sccm)), inert carrier gas type, evaporation source temperature (°C), and substrate composition, substrate surface texture, and substrate temperature (°C). Changes in each parameter can 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 organic materials can be printed in any pattern (including a variety of preselected deposition patterns). The resolution of the pattern formed depends on the nozzle geometry, the type of inert gas, and the flow conditions. In order to obtain large-area deposits, adjacent deposit lines can be printed with one nozzle or with multiple nozzles. This achieves the scalability of the process under robust processing conditions. In addition, in some aspects, such a method ideally eliminates the need for liquid solvents, vacuum, or a large number of post-processing steps to obtain the desired particle size of one or more organic compounds. Importantly, such an OVJP works without the need for liquid solvents or vacuum, and allows controlled crystallinity in organic films.

[0076] In addition, the present disclosure contemplates a new evaporation source / target for a vapor deposition method of low molecular weight organic compounds. As shown in Figures 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 (Figure 2(a)) made of porous ceramic (e.g., meshed) foam used as a 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 contain oxides, nitrides, carbides, borides, silicides, or any combination thereof, provided that the organic material to be deposited does not interact harmfully with the foam (e.g., chemically decompose). The foam is then cut into the desired container shape. Due to the high thermal and mechanical stability of ceramic foam, the container with the foam can be compressed and heated to ensure the tight placement of the foam, thereby ensuring the reproducibility of the process when the powder is replaced and preventing powder from overflowing during the process. A variation of such an organic material source is shown in Figure 2(b). The hull is made of quartz, and the foam is made of silicon carbide from Ultramet. The powder to be deposited is an organic molecular substance Alq 3 , and its sublimation point is about 300°C.

[0077] One or more non-limiting advantages and / or features of the methods 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. Variations in 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) a wide range of small molecule organic drugs with molecular weights up to 1000 g / mol can be deposited; (iv) the amount of the drug can be precisely controlled (up to 1e -9 g) depositing low molecular weight organic materials; (v) low molecular weight organic materials can be printed in any pattern; (vi) the resolution of the pattern depends on the nozzle geometry, the type of inert gas and the 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 a mixture of multiple compounds; (viii) continuous operation in roll-to-roll manufacturing; (ix) printing of personalized doses of substances or substance mixtures is possible; and (x) the deposition device can be highly compact, enabling device mobility and use in a modular manner (many nozzles arranged in any desired manner), as well as incorporation into the system as a manufacturing module.

[0078] Figure 3Multiple examples of printing pharmaceutical materials (e.g., organic compounds) according to the organic vapor jet deposition printing method of the present teachings are shown. 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 performed in an inert nitrogen environment (<1 ppm of O 2 and H 2 O) was carried out under atmospheric pressure. Figure 3 Electron micrographs are included in the table showing the refinement of the original powder microstructure due to the deposition / printing process. Although not shown, the X-ray diffraction pattern further demonstrates 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 film indicate high material purity after deposition.

[0079] 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 liquids. In some aspects, the liquid can be an aqueous solution, showing how accurate drug concentrations can be rapidly achieved 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, in order to obtain a given concentration of an organic solute in the form of an original powder, 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 materials with very slow dissolution rates. In order to increase the dissolution rate, the powder particle size is reduced (by grinding or other methods), and the solution is usually heated. This method can be both time-consuming and energy-consuming, and potentially damages the solvent.

[0080] Another disadvantage of the conventional technique of immersing the powdered solute directly in the 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 micromolar, the required volume is 10 ml, and the weight required for 200 g / mole of material is micrograms. It is not feasible to accurately measure this weight of the precursor powder; therefore, a more concentrated solution is prepared and then diluted with an additional amount of solvent. This method is not desirable from both an economic and safety perspective (when processing with organic solvents).

[0081] Also provide the method for dissolving low molecular weight organic compound rapidly, it comprises making the gas stream containing inert gas pass through the source of heating of low molecular weight organic compound, as shown in Fig. 5 (a).Low molecular weight organic compound volatilizes and is entrained in the gas stream.Then, by making the gas stream pass through nozzle towards the liquid containing one or more solvents low molecular weight organic compound is sprayed into this liquid.In this way, the low molecular weight organic compound of deposition is dissolved in liquid as expected.Liquid can be polar or non-polar liquid, comprises aqueous liquid containing water or aqueous liquid miscible with water.Therefore, liquid can comprise one or more solvents.

[0082] The heated source may include a porous ceramic container containing a low molecular weight organic compound that receives heat transferred from a heater, such as the porous ceramic container described above in the context of FIG. 2( a) to FIG. 2( b). In certain 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 may be greater than or equal to about 15 mm to less than or equal to about 25 mm from the surface of the liquid. The inert gas may be nitrogen. After dissolution, the concentration of the low molecular weight organic compound is optionally greater than or equal to about 1×10 -11 In some embodiments, the amount of the low molecular weight organic compound deposited is less than or equal to about 100 μ g. In other embodiments, the volume of the liquid deposited / sprayed to the gas stream containing the low molecular weight organic compound is less than or equal to about 100 ml. The deposition is carried out to be greater than or equal to about 1 minute to be less than or equal to about 120 minutes. The low molecular weight organic compound can be any of those previously mentioned, and as a non-limiting example, the low molecular weight organic compound can be selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

[0083] Therefore, the present disclosure contemplates new dissolution methods and apparatus for carrying out such methods, as shown in Figures 5(a) to 5(c). The apparatus shown in Figure 5(a) comprises a heated organic powder evaporation source in a ceramic tube, similar to those previously described above. The temperature of the source is high enough to cause evaporation / volatilization / sublimation of the organic material. An inert carrier gas is flowed through the powder, the volatilized / evaporated molecules are obtained and delivered to the solution. Using this method, precise and controlled amounts of organic materials can be sprayed into submicromolar concentration solutions. Figure 5(b) shows an example of spraying fluorescein (molecular weight 332g / mole) into a micromolar concentration of phosphate buffered saline solution. In Figure 5(c), the concentration of fluorescein in the solution is shown to be changed by the spray duration (e.g., spraying 0 minutes to 100 minutes). The concentration is measured by fluorescence spectroscopy calibrated with dissolved fluorescein powder.

[0084] In certain aspects, the present disclosure therefore contemplates a solid film comprising greater than or equal to about 99% by 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-mentioned low molecular weight compounds. For example, the deposited low molecular weight organic active ingredient compounds can be selected from: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; 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); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic 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 the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

[0085] In certain aspects, the solid film has a solid film specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g. In certain variations, the deposited low molecular weight organic active ingredient compound in the solid film is amorphous. The solid film may also define particles having an average particle size of 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.

[0086] 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 ) is less than or equal to about 100 nm.

[0087] In other variations, the average thickness of the solid film is greater than or equal to about 300 nm. 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 having a major dimension of 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 may have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

[0088] Figures 6(a) to 6(r) show the surface morphology of solid printed films of caffeine, tamoxifen, BAY 11-7082, acetaminophen, ibuprofen and fluorescein deposited with OVJP. Figures 6(a) to 6(f) show the chemical structures of the compounds. Figures 6(g) to 6(l) show the deposited film morphology after spraying according to certain aspects of the present teaching. Figures 6(m) to 6(r) show the original microstructure of the powder of the compound. All materials were deposited while raster scanning the nozzle at a speed of 0.2mm / s, with adjacent lines 0.2mm apart from each other. The nozzle tip diameter in all tests was 0.5mm. All depositions were performed in an inert nitrogen environment (<1ppm O 2 and H 2 Electron micrographs show that the original powder microstructure is refined due to the printing process.

[0089] Table 1 lists the OVJP deposition conditions for the printed films.

[0090] Table 1

[0091]

[0092] The source temperature was determined by thermogravimetry and adjusted to obtain a local deposition rate of approximately 0.5 μg / min. The temperature range and carrier gas flow rate may vary depending on system size and configuration.

[0093] In certain embodiments, the solid film may include a deposited low molecular weight organic compound containing caffeine. A 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. FIG. 6( a) shows a chemical structure; FIG. 6( g) shows a micrograph of the morphology of a deposited film of a nanostructure in the form of a needle shape or a tube shape; and FIG. 6( m) shows the morphology of a conventional powder.

[0094] In other specific embodiments, the solid film may include a deposited low molecular weight organic compound containing (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile (BAY 11-7082). The plurality of nanostructures have a platelet 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. FIG. 6( c ) shows the chemical structure, FIG. 6( i ) shows a micrograph of the morphology of a deposited film of nanostructures in the form of platelets, and FIG. 6( o ) shows the morphology of a conventional powder.

[0095] In other embodiments, the solid film may include 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. FIG. 6( f ) shows the chemical structure, FIG. 6( l ) shows a micrograph of the morphology of a deposited film of nanostructures in the form of circular nanostructures, and FIG. 6( r ) shows the morphology of a conventional powder.

[0096] In other embodiments, the solid film may include a deposited low molecular weight organic compound containing acetaminophen. 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 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. FIG. 6( d ) shows a chemical structure, FIG. 6( j ) shows a micrograph of the morphology of a deposited film of nanostructures in the form of a droplet shape, and FIG. 6( p ) shows the morphology of a conventional powder.

[0097] Figure 6(b) shows the chemical structure of Tamoxifen. Figure 6(h) shows a micrograph of the morphology of a deposited film having nanostructures in the form of continuous platelet-like shapes, while Figure 6(n) shows the morphology of a conventional powder.

[0098] Figure 6(e) shows the chemical structure of ibuprofen. Figure 6(k) shows a micrograph of the morphology of a deposited film with nanostructures in droplet-like form, the solids have aggregated, while Figure 6(q) shows the morphology of a conventional powder.

[0099] The X-ray diffraction patterns (FIG. 7(e) to FIG. 7(h)) show 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. 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 film shown in FIG. 7(a) to FIG. 7(d) indicate the high material purity after deposition.

[0100] In other aspects, the deposited low molecular weight organic compound according to the present teachings has an increased dissolution rate compared to a comparative powder or granular form of a low molecular weight organic active ingredient. The dissolution rate of the deposited low molecular weight organic active ingredient compound in the solid film in aqueous solution is at least ten times greater than the comparative dissolution rate of the low molecular weight organic active ingredient in the comparative powder or granular form. The dissolution rate enhancement may be any of those previously discussed above.

[0101] The dissolution process in a finite volume can be described by the Noyes-Whitney equation (Eq. 1), where C is the solute concentration, t is the time, D is the diffusion coefficient in the solvent, V is the solvent volume, δ is the boundary layer thickness, Cs is the solubility in a given solvent, and A is the surface area of ​​the solute:

[0102]

[0103] When comparing dissolution from a powder form and a film form of the same material and the same crystal structure, D, V, Cs are constant and the initial dissolution rate is proportional to A / δ. For dissolution from a film, δ and A are constant because the area of ​​the film does not change during dissolution. In a powder, δ and A vary because the particle size and shape vary. In addition, the particles tend to agglomerate during dissolution, which does not occur when dissolving from a film form. Therefore, only the initial rates between powders and films can be compared.

[0104] The degree of improvement in dissolution rate is similar to the degree of improvement in surface area. In a specific non-limiting example, the initial dissolution rate of 25 μg of fluorescein powder in deionized water is 8.9 e -5 μg ml -1 Second -1 , while the printed film is 1.61e -3 μgml -1 Second -1 , which is 18 times higher. The membrane surface area is 6.4e -5 m 2 , and the powder surface area is 3.6e -6 m 2 , 17 times higher.

[0105] The initial dissolution rate of 30 μg powder of ibuprofen in buffered HCl 1.3 was 0.0004 μg ml -1 Second -1 , while the initial dissolution rate of the printed film was 0.04 μg ml -1 Second -1 , about 10 times higher. The membrane surface area is 6.4e -5 m 2 , and the powder surface area is 1.5e -5 m2 , about 5 times higher.

[0106] The initial dissolution rate of 30 μg of tamoxifen powder in buffered acetate 4.9 was 2e -4 μgml -1 Second -1 , while the initial dissolution rate of the printed film is 2e -3 μg ml -1 Second -1 , 10 times higher. The membrane surface area is 6.4e -5 m 2 , and the powder surface area is 9e - 6 m 2 , 7 times higher. It is worth noting that these are merely illustrative examples, but the surface area of ​​the membrane is related to the printing surface area, which is not limiting according to the present teachings.

[0107] Likewise, the deposited low molecular weight organic compounds according to the present teachings have an increased bioavailability compared to the low molecular weight organic active ingredients in comparative powder or granule form. The increased bioavailability is associated with 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 low molecular weight organic active ingredient in comparative powder or granule form. The level of bioavailability increase can be any of those previously described above.

[0108] In certain aspects, the solid film is substantially free of any binder or impurity. A solid film substantially free of binders or impurities has less than or equal to about 0.5% by weight, optionally less than or equal to about 0.1% by weight, and in certain preferred aspects, 0% by weight of undesirable binders or impurities present in the solid film composition. In certain variations, the solid film comprises greater than or equal to about 99.5% by mass of deposited low molecular weight organic active ingredient compounds; however, any purity level discussed above can also be obtained in the solid film.

[0109] 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 manufactured. The deposited low molecular weight organic compound shows improved solubility and bioavailability.

[0110] In other variations, the present disclosure contemplates a solid film comprising 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 compound is preferably a pharmaceutically active substance or a new chemical entity. The low molecular weight organic active ingredient compound is any of the low molecular weight compounds described above. The common amount of the plurality of low molecular weight organic active ingredient compounds in the solid film may be greater than or equal to about 99% by mass. The solid film may have any of the compositions or features just described, which will not be repeated here for the sake of brevity.

[0111] In other variations, the article comprises a solid deposited film comprising a pharmaceutical composition comprising at least one low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol. The solid deposited film may have any of the above-described compositions or features, which are not repeated here for the sake of brevity.

[0112] In other specific variations, an article is provided, which comprises a surface of a solid substrate, the surface of the solid substrate 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 low molecular weight organic compound is any of the above-mentioned low molecular weight compounds. The deposited low molecular weight organic compound is present in one or more discrete regions with a mass % greater than or equal to about 99%. In some aspects, one or more discrete regions on the surface are continuous, and the deposited solid low molecular weight organic compound forms a solid film on the surface of a pharmaceutically acceptable substrate. Any of the above-mentioned solid films comprising any of the above-mentioned compositions or features may be disposed on the surface of a solid substrate. The deposited film may be applied to a variety of solid substrates having any type of substrate geometry, including flat substrates, microneedles, balls, tubes, curved surfaces, meshes, fabrics, and combinations thereof.

[0113] In other specific variations, an article is provided, which comprises a surface of a 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 compound is any of the low molecular weight compounds described above. The plurality of deposited low molecular weight organic compounds are cumulatively present in one or more discrete regions at greater than or equal to about 99 mass %. Therefore, any of the above-mentioned solid films may be disposed on the surface of the solid substrate. In addition, the solid substrate may be those just described above.

[0114] In other aspects, the present disclosure provides articles comprising a pharmaceutically acceptable substrate with a defined surface. The material selected for the substrate is preferably pharmaceutically acceptable or biocompatible, in other words, substantially nontoxic to the cells and tissues of living organisms. The pharmaceutically acceptable material can be a material suitable for contacting with the tissues of humans and other animals without causing excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit / risk ratio. The article also comprises a solid low molecular weight pharmaceutical active ingredient deposited with a molecular weight less than or equal to about 1,000 g / mol. The pharmaceutical active ingredient is a drug or other compound that can be used to prevent or treat a disease or disorder in humans or other animals, prevent or treat a physiological disorder or disease, or provide a benefit that exceeds potential harmful effects in a conventional risk-benefit assessment. The low molecular weight organic active ingredient can be any of those described above. Therefore, the articles and compositions of the present disclosure can be used to treat or prevent systemic diseases, such as cancer, autoimmune diseases, cardiovascular diseases, stroke, diabetes, severe respiratory infections, inflammation, pain control, etc.

[0115] 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. Therefore, any solid film having a low molecular weight pharmaceutically active ingredient as described above can be disposed on the surface of a solid substrate.

[0116] In some aspects, pharmaceutically acceptable substrates are biodegradable. Biodegradable means that the material forming the substrate dissolves or erodes when exposed to a solvent (e.g., serum, growth or culture medium, blood, body fluid, or saliva) containing a high concentration of water. In some variations, the substrate can be split into small pieces or can disintegrate to form a colloid or gel together. In some variations, the pharmaceutically acceptable substrate includes a pharmaceutically acceptable material selected from glass, metal, siloxane, polymer, hydrogel, organogel, organic material, natural fiber, synthetic fiber, ceramic, biological tissue, and combinations thereof. In other variants, the pharmaceutically acceptable material is selected from glass, metal, siloxane, polymer, hydrogel, organogel, natural fiber, synthetic fiber, and combinations thereof. The deposited solid low molecular weight pharmaceutical active ingredient can be formed on any type of substrate geometry, including flat substrates, microneedles, balls, tubes, curved surfaces, meshes, etc. In addition, the substrate can be any size. In certain non-limiting variations, the pharmaceutically acceptable substrate is selected from: microneedles, medical devices, implants, films (e.g., dissolvable films or films with removable backings), gels, patches, dressings (e.g., gauze, non-adhesive mesh, bandages, films, foils, foams, or tissue adhesives), fabrics (e.g., woven, non-woven, or knitted), sponges, stents, contact lenses, subretinal implants, dentures, braces, wearable devices, bracelets, and combinations thereof.

[0117] Figures 8(a) to 8(d) show examples of different coating forms on different substrates. TM Acrylic polymer TEGADERM for sale TM Patch (Figure 8(a)) and pullulan-based 8(b)), fluorescein was deposited onto the tip of a stainless steel microneedle (Fig. 8(c)), and tamoxifen was deposited onto a borosilicate glass slide (Fig. 8(d)).

[0118] In other aspects, the present disclosure contemplates an article comprising a solid deposited film containing a pharmaceutical composition. The pharmaceutical composition comprises at least one low molecular weight organic compound having a molecular weight of 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 a plurality of low molecular weight organic compounds are co-deposited to form a solid deposited film. Thus, the pharmaceutical composition may 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 deposited film at greater than or equal to about 99 mass %.

[0119] The article can be a multilayer stack, and the solid deposited film comprising the pharmaceutical composition is the first layer and the multilayer stack comprises a second layer with a different chemical composition. The second layer may comprise a second pharmaceutical composition different from the pharmaceutical composition in the first layer. In other aspects, the second layer comprises a material that minimizes the dissolution rate of the pharmaceutical composition in the first layer. In other variations, the second layer may comprise a material having a solubility controlled by the presence of a trigger, the trigger being selected from: light, radiation, magnetism, radio waves, pH of the surrounding medium, and combinations thereof. In this way, such an external force or trigger can be used to increase or minimize the solubility of the pharmaceutical composition. The pharmaceutical composition can be any compound and is attributed to those discussed previously. In addition, the solid deposited film may have any features or characteristics discussed previously.

[0120] Example

[0121] The OVJP nozzle used was made of 0.5" OD quartz tube with a 0.5mm ID nozzle tip at 15° from the nozzle axis. All nozzles used were identical. The inert gas used during deposition was 99.99% pure nitrogen.

[0122] The nozzle was cleaned with acetone and isopropyl alcohol solvents, dried and then re-cleaned with a power density of 8.6 W·in -2 A 36" heavy-duty insulated tape heater (Omega Engineering, Inc.) was wrapped around the source. The heating tape leads were connected to a temperature controller (Digi-Sense Benchtop Temperature Controller, Cole Palmer Instruments Co.) and a 1 / 16" K-type thermocouple was used to maintain the temperature of the source. The source contained approximately 0.15 g of powder embedded in 100 DPI porous SiC ceramic foam and placed in the heated source portion of the tube. Gas flow was maintained using a mass flow controller (C100 MFC, Sierra Instruments).

[0123] The process parameters that were kept constant were: nozzle-substrate spacing (1.5 mm), substrate temperature (20°C). 2 was performed in a purged glove box.

[0124] Thermogravimetry of pharmaceutical substances

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

[0126] Areal deposits were printed by raster scanning adjacent overlapping lines at a distance of 0.2 mm. This distance was determined to allow deposits of uniform thickness for a nozzle of 0.5 mm inner diameter set 1.5 mm from the substrate surface. The fluorescein film on the microneedles was deposited through a flexible mask. The same process can be performed without a mask when using a nozzle with appropriate printing resolution.

[0127] In some aspects, the OVJP method performed according to some aspects of this teaching can deliver a variety of compounds (e.g., caffeine, ibuprofen, doxorubicin, BAY 11-7082) of controlled amounts to a variety of substrates in the form of films. Then further observe how the film dissolves in an aqueous solution. Use a fluorescent substance (e.g., fluorescein) to monitor the film dissolution process.

[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) tested for biological efficacy. Figure 3 The films were tested by applying OVCAR3 cell solutions directly to the printed films of BAY 11-7082, compared to BAY 11-7082 drug in powder form dissolved in DMSO. No significant differences in potency were observed, indicating that the films have enhanced solubility properties.

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

[0130] Figures 10(a) through 10(c) illustrate the improvement in dissolution rate of a drug film printed from the vapor phase relative to the drug in powder form, according to certain aspects of the present teachings. 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 conducted at a temperature of 19 ± 1 °C.

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

[0132]

[0133] In the case of sink conditions, C << Cs, the dissolution rate is substantially constant and can thus be precisely controlled by the film area. The dissolution process of the powder form is more uncontrollable than that of the film form. In contrast to the film form, in the case of the powder, the effective dissolution area changes during the process and is affected by changes in particle size and shape, wettability, and 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, Mp 0 —average initial weight of the particles, 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 in crystalline organic solids. The powder micronization technique for improving dissolution rate is limited by processing conditions and powder agglomeration. When the drug is deposited in film form, these limitations are substantially absent. The deposited film can be as thin as a single layer of the material.

[0136] Here, the dissolution behavior in film and powder forms was studied in three poorly soluble materials—fluorescein in deionized water, ibuprofen in aqueous hydrochloride (HCl) buffer pH 1.2 solution, and tamoxifen in aqueous acetate buffer solution (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 experiment, 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 9 mm diameter drug film was used. The film weight was 5 to 80 μg. First, the intrinsic dissolution rate (IDR) of the film was studied and compared with the dissolution of a compressed powder in the form of 1.57 mm diameter particles. IDR is defined as equation (4):

[0138]

[0139] In this case, (dm / dt) max is the maximum slope of the dissolution curve evaluated at the beginning of the dissolution process (m - mass of solute dissolved). The glass substrate with the deposited film was connected to a stirring bar with the same diameter as the pressed pellet bar (20 mm) to ensure the same thickness of the hydrodynamic boundary layer for the pressed powder and the deposited film. The solution volume was kept constant in all experiments, about 10 ml, and the temperature was 20 ± 1 °C. In all cases, the intrinsic dissolution of the film was comparable to that of the pressed pellets (3 × 10 -5 ±5×10 -6 , for ibuprofen it is 1×10 -3 ±3×10 -4 , for tamoxifen, 6 × 10 -4 ±1×10 -4 All values ​​are expressed 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 study.

[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. Further dissolution rate reduction is mainly due to the reduction of 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, for ibuprofen (Figure 10(b)), it is about 30 times, and for tamoxifen (Figure 10(c)), it is about 10 times. Since the IDR or solubility is unchanged, the initial increase in dissolution rate is mainly attributed to the increase in the film surface area. The magnitude of the increase is well consistent with the magnitude of the increase in the powder surface area. Importantly, this embodiment only represents the dissolution improvement that can be obtained when forming a pharmaceutical composition of a deposited film according to the present teaching. 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. Furthermore, film dissolution is accurately predicted until almost complete dissolution, whereas in the case of powders, predicting the dissolution rate is more complicated due to changes in particle shape and agglomeration, as can be seen in the dissolution of ibuprofen powder in Figure 10(b).

[0141] Pharmaceutical substances (e.g., tamoxifen and BAY 11-7082) printed from the vapor phase also further enhance bioefficacy. To test the effectiveness of drugs in deposited film form, cancer cell lines in culture were exposed to tamoxifen films and BAY films deposited on glass slides. See Fig.11 , which shows the application of drugs in the form of films. Ovarian cancer cell line OVCAR3 and breast cancer cell line MCF7 were used to study growth inhibition in the presence of tamoxifen and BAY-27. The following controls were also used to generate growth inhibition curves: i) clean glass slides without deposited drug films as sham controls; 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 so that for tamoxifen (4.5 μg / film), the nominal concentration was treated to be 5 μM (1.8 μg / ml), and for BAY 117082 (0.25 μg / film), it was 500 nM (0.1 μg / ml).

[0142] Figures 12(a) to 12(d) show cancer cell count curves treated with different drug forms to demonstrate that the bioefficacy of deposited films prepared according to certain aspects of the present disclosure is improved compared to conventional preparations. 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 film-form drugs showed a viability almost similar to that of drugs dissolved in DMSO. The tamoxifen in film form showed significantly better effectiveness than the powdered drugs dissolved in the growth medium. For film form, the MCF7 cancer cell viability after 48 hours was 58%, and for powder form, it was 79% (Figure 12 (a)), and for film form, the OVCAR3 cancer cell viability after 48 hours was 44%, and for powder form, it was 68% (Figure 12 (b)). The BAY in film form showed effectiveness similar to the powdered drugs dissolved in the growth medium (Figure 12 (c) to Figure 12 (d)).

[0144] The reason for the difference between the powder form and the film of tamoxifen is believed to be due to the higher dissolution rate of the film compared to the powder form. Since the actual concentration of the dissolved powder is less than 5 μM, the growth cell inhibition rate is lower. The difference in behavior between tamoxifen and BAY is mainly due to 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 many aspects, the present disclosure contemplates high surface area films of small molecule organic compounds (e.g., pharmaceutical substances) with precise weight and high purity made using organic vapor jet printing deposition techniques and equipment. In addition, certain organic compounds (e.g., BAY 11-7082 drug) can be dissolved directly by spraying into a solution, and the drug dissolves with an efficacy similar to that of the same drug dissolved in DMSO. Similarly, the rapid and accurate dissolution of small molecule pharmaceutical substances has been demonstrated by spraying fluorescein directly into a phosphate buffered saline solution. These results indicate 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 the optional features of the inventive materials and inventive methods discussed and listed above and herein as the present disclosure are specifically disclosed as embodiments. In many aspects, the present disclosure contemplates a solid film comprising greater than or equal to about 99% by mass of a deposited low molecular weight organic active ingredient compound. The molecular weight of the low molecular weight organic active ingredient compound is less than or equal to about 1,000 g / mol. In addition, the low molecular weight organic active ingredient compound is a pharmaceutically active substance or a new chemical substance. Also specifically disclosed is a combination of the solid film optionally having any one or more than one of the listed features (1) to (17).

[0147] The solid film of the first embodiment optionally has any one or any combination of more than one 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 1,000m 2 / g; (2) the deposited low molecular weight organic active ingredient compound in the solid film is amorphous; (3) the amorphous solid film further 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; (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 the group consisting of: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; Nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic 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 deposited low molecular weight organic compound has a molecular weight of 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, wherein the major dimension of the nanostructures is 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, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, dendritic structures, and fractals, wherein the plurality of nanostructures have a shape selected from the group consisting of 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 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;

[0149] b. the deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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;

[0150] c. the deposited low molecular weight organic compound comprises 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

[0151] d. the deposited low molecular weight organic compound comprises acetaminophen, 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;

[0152] (14) the deposited low molecular weight organic compound has an increased dissolution rate compared to a comparative powder or granular 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 low molecular weight organic active ingredient in the comparative powder or granular form; (15) the deposited low molecular weight organic compound has an increased bioavailability compared to a comparative powder or granular 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 low molecular weight organic active ingredient in the comparative powder or granular form; (16) the solid film is substantially free of any binders 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 of less than or equal to about 1,000 g / mol. The deposited low molecular weight organic compound is present in one or more discrete regions at a concentration of greater than or equal to about 99 mass %. Also specifically disclosed is a combination of the article optionally having any one or more of the listed features (18) to (34) or any combination of any of the previously listed features (1) to (17).

[0154] The article of the second embodiment optionally has any one or any combination of the following features: (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 to less than or equal to about 1,000m 2 / g; (19) the deposited low molecular weight organic compound is amorphous; (20) the amorphous low molecular weight organic compound is further defined as particles having an average particle size of greater than or equal to about 2 nm to 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 to less than or equal to about 200 nm; (24) the deposited low molecular weight organic compound is selected from the group consisting of: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); anti microbial agent; antiviral agent; antifungal agent; antibiotic; chemotherapeutic agent; antineoplastic agent / anti-miotic agent; anesthetic, analgesic or analgesic; antipyretic agent, prostaglandin inhibitor; platelet inhibitor; DNA demethylating agent; cholesterol lowering agent; vasodilator; endogenous vasoactive disruptor; angiogenic substance; heart failure active ingredient; targeted toxin agent; 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 deposited low molecular weight organic compound has a molecular weight of greater than or equal to about 100 g / mol to 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 deposited low molecular weight organic compound has an average thickness of greater than or equal to about 300 nm, and the film defines a nanostructured surface comprising a plurality of nanostructures, wherein the major dimension of the nanostructures is greater than or equal to about 5 nm to 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, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, dendrites, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (30) comprises one of the following:

[0155] a. The deposited low molecular weight organic compound 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;

[0156] b. the deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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;

[0157] c. the deposited low molecular weight organic compound comprises 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 comprises acetaminophen, 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;

[0159] (31) the deposited low molecular weight organic compound has an increased dissolution rate compared to a comparative powder or granular 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 low molecular weight organic active ingredient in the comparative powder or granular form; (32) the deposited low molecular weight organic compound has an increased bioavailability compared to a comparative powder or granular 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 low molecular weight organic active ingredient in the comparative powder or granular form; (33) the deposited low molecular weight organic compound is substantially free of any binders or impurities; 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 pharmaceutically active ingredient having a molecular weight of less than or equal to about 1,000 g / mol. 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 %.

[0161] Also specifically disclosed is a combination of the product optionally comprising any one or any combination of more than one of the enumerated features (35) to (55) or any of the previously enumerated features (1) to (34).

[0162] The article of the third embodiment optionally has any one or more of the following features in any combination: (35) one or more discrete regions in 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; (36) the pharmaceutically acceptable substrate is biodegradable; (37) the pharmaceutically acceptable substrate comprises a pharmaceutically acceptable material selected from the group consisting of 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 the group consisting of microneedles, medical devices, implants, membranes, gels, patches, dressings, fabrics, bandages, sponges, stents, contact lenses, subretinal implant prostheses, dentures, braces, wearable devices, bracelets, and combinations thereof; (39) the solid low molecular weight pharmaceutically active ingredient deposited in one or more discrete regions has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 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 is further limited to particles with an average particle size of 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: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); Antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic 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-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (47) the deposited solid low molecular weight pharmaceutical active ingredient has a molecular weight of 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 (Ra ) is less than or equal to about 100 nm; (49) the average thickness of the deposited solid low molecular weight pharmaceutically active ingredient in one or more discrete regions is greater than or equal to about 300 nm, and the deposited solid low molecular weight pharmaceutically active ingredient defines a nanostructured surface comprising a plurality of nanostructures, wherein the major dimension of the nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm; (50) the deposited solid low molecular weight pharmaceutically active ingredient defines a nanostructured surface having a plurality of nanostructures, wherein the plurality of nanostructures have a shape selected from the following: needles, tubes, rods, platelets, round particles, droplets, leaves, tree structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (51) comprising one of the following: 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;

[0163] b. the deposited solid low molecular weight pharmaceutically active ingredient comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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;

[0164] c. the deposited solid low molecular weight pharmaceutically active ingredient 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

[0165] d. the deposited solid low molecular weight pharmaceutically active ingredient comprises acetaminophen, 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;

[0166] (52) The deposited solid low molecular weight pharmaceutical active ingredient has an enhanced dissolution rate compared to a comparative powder or granular form of the low molecular weight pharmaceutical active ingredient, wherein the dissolution rate of the deposited solid low molecular weight pharmaceutical active ingredient in an aqueous solution is at least ten times greater than the comparative dissolution rate of the low molecular weight pharmaceutical active ingredient in the comparative powder or granular form; (53) The deposited solid low molecular weight pharmaceutical active ingredient has an enhanced bioavailability compared to a comparative powder or granular form of the low molecular weight pharmaceutical 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 low molecular weight pharmaceutical active ingredient in the comparative powder or granular form; (54) The deposited solid low molecular weight pharmaceutical active ingredient is substantially free of any binders or impurities; 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 pharmaceutical active ingredient.

[0167] In other aspects, the present disclosure contemplates a fourth embodiment, which is an article comprising a solid deposited film containing a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol. Also specifically disclosed is a combination of the article optionally having any one or more of the listed features (56) to (68) or any of the previously listed features (1) to (55).

[0168] The article of the fourth embodiment optionally has any one or any combination of 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 deposited film at a concentration of greater than or equal to about 99 mass %; (59) the article is a multilayer stack, and the solid deposited film comprising the pharmaceutical composition is the first layer and the multilayer 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 the group consisting of light, radiation, magnetism, radio waves, pH of the surrounding medium, and combinations thereof; (63) the specific surface area of ​​the solid deposited film is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 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 pharmaceutical active ingredient or new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (66) low molecular weight The amount of organic compound is selected from: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof; (67) the low molecular weight organic compound in the pharmaceutical composition has improved solubility compared to a comparative powder or granular form of the low molecular weight organic compound, 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 the comparative powder or granular form; (68) the deposited low molecular weight organic compound in the pharmaceutical composition has improved bioavailability compared to a comparative powder or granular form of the low molecular weight organic active ingredient, 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 the comparative powder or granular form.

[0169] In other aspects, the present disclosure contemplates a fifth embodiment of a method for solvent-free vapor deposition. The method includes depositing a low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol on one or more discrete regions of a substrate in a substantially solvent-free method. 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 with greater than or equal to about 99 mass %.

[0170] Also specifically disclosed is a combination of the method comprising optionally having any one or more of the enumerated steps or features (69) to (91) or any of the previously enumerated features (1) to (68) in the context of the first to fourth embodiments. The method for solventless vapor deposition optionally has any one or more of the following steps or features: (69) also includes entraining the low molecular weight organic compound in an inert gas flow or 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 the following: powder, pressed particles, porous material and liquid; (71) wherein prior to entrainment, the low molecular weight organic compound is dispersed in the porous material; (72) wherein prior to entrainment, the low molecular weight organic compound is dispersed in a liquid bubbler through which the inert gas flow passes; (73) the entrainment of the low molecular weight organic compound in the inert gas flow or vacuum is performed by heating a solid low molecular weight organic compound source to cause the low molecular weight organic compound to sublime or evaporate; (74) the low molecular weight organic compound is in a form greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / 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 1,000m 2 / g; (77) the deposited low molecular weight organic compound is amorphous; (78) the deposited low molecular weight organic compound is also limited to particles with an average particle size of greater than or equal to about 2nm to less than or equal to about 200nm; (79) the deposited low molecular weight organic compound is crystalline or polycrystalline; (80) the average crystal size is greater than or equal to about 2nm to less than or equal to about 200nm; (81) the deposited low molecular weight organic compound is a pharmaceutically active ingredient or new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof; (82) the low molecular weight organic compound is selected from the group consisting of: 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) is less than or equal to about 100 nm; (85) the average thickness of the deposited low molecular weight organic compound 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, wherein the major dimension of the nanostructures is 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, platelets, round particles, droplets, leaves, dendritic structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (87) the purity level of the deposited low molecular weight organic compound 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 granular 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 deposited low molecular weight organic compound in the comparative powder or granular form; (91) the deposited low molecular weight organic compound has an increased bioavailability compared to a comparative powder or granular form of a 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 low molecular weight organic active ingredient in the comparative powder or granular form.

[0171] 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, through, or through the source. The low molecular weight organic compound is entrained in the inert gas stream through a nozzle toward a cooled target. The low molecular weight organic compound is condensed when it contacts the cooled target.

[0172] Also specifically disclosed is a combination of the method comprising optionally having any one or more of the steps or features (92) to (108) or any combination of the previously listed features (1) to (91). The method for organic vapor jet printing deposition optionally has any one or more of the following steps or features: (92) cooling the surface of the target substrate and depositing the condensed low molecular weight organic compound in one or more discrete areas of the surface; (93) the condensed low molecular weight organic compound is greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / cm2 The loading 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 the one or more discrete regions is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1000m 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) is 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, wherein the major dimension of the nanostructures is 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 the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, dendrites, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; (98) the one or more discrete regions in the surface are continuous, and the condensed low molecular weight organic compound defines a nanostructured surface having a plurality of nanostructures, wherein the nanostructures have a major dimension greater than or equal to about 5 nm to less than or equal to about 10 μm; (99) the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, dendrites, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof; The 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) the entrainment and the directing are performed under atmospheric pressure conditions; (102) wherein the entrainment and the directing are performed under reduced pressure conditions of greater than or equal to about 0.1 Torr to less than or equal to about 500 Torr; (103) adjusting parameters 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 flow, composition of the inert gas, 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 new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antitumor agents / Antimiotics; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic 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 has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

[0173] In other aspects, the present disclosure contemplates a seventh embodiment of a method for rapidly dissolving a low molecular weight organic compound. The method comprises passing a gas stream comprising an inert gas through a heated source of the low molecular weight organic compound. The low molecular weight organic compound is volatilized and entrained in the gas stream. The method further involves depositing the low molecular weight organic compound into a liquid comprising one or more solvents by passing the gas stream through a nozzle, such that the deposited low molecular weight organic compound is dissolved in the liquid.

[0174] Also specifically disclosed is a combination of the method comprising optionally having any one or more of the steps or features (109) to (121) or any combination of any of the previously listed features (1) to (108). The method for rapidly dissolving a low molecular weight organic compound optionally comprises any one or more of the following steps or features: (109) the heating source comprises a porous ceramic container containing a low molecular weight organic compound that receives heat transferred from a heater; (110) the temperature of the heating 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 comprises nitrogen; (113) the liquid is an aqueous liquid comprising water; (114) the concentration of the low molecular weight organic compound is greater than or equal to about 1×10 -11mol / 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 performed 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 new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, Analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive interfering agents; angiogenic 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 pharmaceutical active ingredient 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 pharmaceutical active ingredient 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.

[0175] The above description of the embodiments is provided for illustration and description 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 the particular embodiment, but are interchangeable and can be used in a selected embodiment where applicable, even if not specifically shown or described. The same can also be changed in a variety of ways. Such variations are not considered to be deviating from the present disclosure, and all such modifications are intended to be included within the scope of the present disclosure.

Claims

1. A solid film comprising greater than or equal to about 99 mass % of a deposited low molecular weight organic active ingredient compound having a molecular weight of less than or equal to about 1,000 g / mol, wherein the low molecular weight organic active ingredient compound is a pharmaceutically active substance or a new chemical entity.

2. The solid film of claim 1, wherein the solid film has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g.

3. The solid film of claim 1, wherein the deposited low molecular weight organic active ingredient compound in the solid film is amorphous.

4. The solid film of claim 3, wherein the solid film further 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.

5. The solid film of claim 3, wherein the deposited low molecular weight organic active ingredient compound in the solid film is stable for greater than or equal to about 1 month.

6. The solid film of claim 1, wherein the deposited low molecular weight organic active ingredient compound in the solid film is crystalline or polycrystalline.

7. The solid film of claim 6, wherein the average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm.

8. The solid film of claim 1, wherein the deposited low molecular weight organic active ingredient compound is selected from the group consisting of: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobials; antivirals; antifungals; antibiotics; chemotherapeutics; antineoplastic / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

9. The solid film of claim 1, wherein the deposited low molecular weight organic active ingredient compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

10. The solid film of claim 1, wherein the deposited low molecular weight organic compound has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

11. The solid film of claim 1, wherein the film has an average thickness of less than or equal to about 300 nm and an average surface roughness (R a ) is less than or equal to about 100 nm.

12. The solid film of claim 1, wherein the film has an average thickness greater than or equal to about 300 nm and defines a nanostructured surface comprising a plurality of nanostructures having a major dimension of greater than or equal to about 5 nm to less than or equal to about 10 μm.

13. The solid film of claim 12, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

14. The solid film of claim 13, comprising one of the following: a. the deposited low molecular weight organic compound 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; b. the deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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; c. the deposited low molecular weight organic compound comprises 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 d. The deposited low molecular weight organic compound comprises acetaminophen, 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.

15. The solid film of claim 1, wherein the deposited low molecular weight organic compound has an enhanced dissolution rate compared to a comparative powder or granular 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 aqueous solution is at least ten times greater than the comparative dissolution rate of the low molecular weight organic active ingredient in the comparative powder or granular form.

16. The solid film of claim 1, wherein the deposited low molecular weight organic compound has an enhanced bioavailability compared to a comparative powder or granular 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 low molecular weight organic active ingredient in the comparative powder or granular form.

17. The solid film of claim 1, being substantially free of any binders or impurities.

18. The solid film of claim 1 comprising greater than or equal to about 99.5 mass % of the deposited low molecular weight organic active ingredient compound.

19. A product comprising: A surface of a solid substrate having one or more discrete regions patterned with a deposited low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol, wherein 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 %.

20. The article of claim 19, wherein the deposited low molecular weight organic compound in the one or more discrete regions has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g.

21. The article of claim 19, wherein the deposited low molecular weight organic compound is amorphous.

22. The article of claim 21, wherein the deposited low molecular weight organic compound further 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.

23. The article of claim 21, wherein the deposited low molecular weight organic compound is stable for greater than or equal to about 1 month.

24. The article of claim 19, wherein the deposited low molecular weight organic compound is crystalline or polycrystalline.

25. The article of claim 24, wherein the average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm.

26. The article of claim 19, wherein the deposited low molecular weight organic compound is a pharmaceutically active ingredient or new chemical entity selected from the group consisting of antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

27. The article of claim 19, wherein the deposited low molecular weight organic compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

28. The article of claim 19, wherein the deposited low molecular weight organic compound has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

29. The article of claim 19, wherein the average thickness of the deposited low molecular weight organic compound in the 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.

30. The article of claim 19, wherein the average thickness of the deposited low molecular weight organic compound in the 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 comprising a plurality of nanostructures having a major dimension of greater than or equal to about 5 nm to less than or equal to about 10 μm.

31. The article of claim 30, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

32. The article of claim 31, comprising one of the following: a. the deposited low molecular weight organic compound 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; b. the deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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; c. the deposited low molecular weight organic compound comprises 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 d. The deposited low molecular weight organic compound comprises acetaminophen, 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.

33. The article of claim 19, wherein the deposited low molecular weight organic compound in the one or more discrete regions has a purity level greater than or equal to about 99.5 mass %.

34. The article of manufacture of claim 19, wherein the low molecular weight organic compound is a pharmaceutically active ingredient or a new chemical entity.

35. The article of claim 19, wherein the one or more discrete regions of the surface are continuous and the deposited low molecular weight organic compound forms a solid film on the surface of the substrate.

36. The article of claim 19, wherein the deposited low molecular weight organic compound has an enhanced solubility compared to a comparative powder or granular form of the low molecular weight organic compound, wherein the dissolution rate of the deposited low molecular weight organic compound in aqueous solution is at least ten times greater than the comparative dissolution rate of the low molecular weight organic compound in the comparative powder or granular form.

37. The article of manufacture of claim 19, wherein the deposited low molecular weight organic compound has an enhanced bioavailability compared to a comparative powder or granular form of the low molecular weight organic compound, wherein the bioavailability of the deposited low molecular weight organic compound is at least about 10% greater than the comparative bioavailability of the low molecular weight organic compound in the comparative powder or granular form.

38. A product comprising: a pharmaceutically acceptable substrate defining a surface; and A deposited solid low molecular weight pharmaceutically active ingredient having a molecular weight of less than or equal to about 1,000 g / mol, wherein 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 %.

39. The article of claim 38, wherein 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.

40. The article of claim 38, wherein the pharmaceutically acceptable substrate is biodegradable.

41. The article of claim 38, wherein the pharmaceutically acceptable substrate comprises a pharmaceutically acceptable material selected from the group consisting of glass, metals, silicones, polymers, hydrogels, organogels, organic materials, natural fibers, synthetic fibers, ceramics, biological tissues, and combinations thereof.

42. The article of claim 38, wherein the pharmaceutically acceptable substrate is selected from the group consisting of microneedles, medical devices, implants, films, gels, patches, dressings, fabrics, bandages, sponges, stents, contact lenses, subretinal implants, dentures, braces, wearable devices, bracelets, and combinations thereof.

43. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient in the one or more discrete regions has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g.

44. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient is amorphous.

45. The article of claim 43, wherein the deposited solid low molecular weight pharmaceutically active ingredient further 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.

46. ​​The article of claim 43, wherein the deposited solid low molecular weight pharmaceutically active ingredient is stable for greater than or equal to about 1 month.

47. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient is crystalline or polycrystalline.

48. The article of claim 47, wherein the average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm.

49. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutical active ingredient is selected from the group consisting of: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

50. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

51. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

52. The article of claim 38, wherein the average thickness of the deposited solid low molecular weight pharmaceutically active ingredient in the 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.

53. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient in the one or more discrete regions has an average thickness of greater than or equal to about 300 nm, and the deposited solid low molecular weight pharmaceutically active ingredient defines a nanostructured surface comprising a plurality of nanostructures having a major dimension of greater than or equal to about 5 nm to less than or equal to about 10 μm.

54. The article of claim 53, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

55. The article of claim 54, comprising one of the following: a. the deposited low molecular weight organic compound 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; b. the deposited low molecular weight organic compound comprises (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, and the plurality of nanostructures have a platelet 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, 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; c. the deposited low molecular weight organic compound comprises 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 d. The deposited low molecular weight organic compound comprises acetaminophen, 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.

56. The article of claim 38, wherein the deposited solid low molecular weight pharmaceutically active ingredient in the one or more discrete regions has a purity level of greater than or equal to about 99.5% by mass.

57. The article of claim 38, wherein the deposited low molecular weight pharmaceutical active ingredient has an enhanced dissolution rate compared to a comparative powder or granular form of the low molecular weight pharmaceutical active ingredient, wherein the dissolution rate of the deposited low molecular weight pharmaceutical active ingredient in an aqueous solution is at least ten times greater than the comparative dissolution rate of the low molecular weight pharmaceutical active ingredient in the comparative powder or granular form.

58. The article of manufacture of claim 38, wherein the deposited low molecular weight pharmaceutical active has improved bioavailability compared to a comparative powder or granular form of the low molecular weight pharmaceutical active, wherein the bioavailability of the deposited low molecular weight pharmaceutical active is at least about 10% greater than the comparative bioavailability of the low molecular weight pharmaceutical active in the comparative powder or granular form.

59. An article comprising a solid deposited film comprising a pharmaceutical composition comprising at least one low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol.

60. The article of manufacture of claim 59, wherein the pharmaceutical composition further comprises at least one additional deposited compound different from the low molecular weight organic compound.

61. The article of manufacture of claim 59, wherein the pharmaceutical composition comprises at least two low molecular weight organic compounds.

62. The article of claim 59, wherein the pharmaceutical composition has at least one low molecular weight organic compound present in the solid deposited film at greater than or equal to about 99 mass %.

63. The article of claim 59, wherein the article is a multilayer stack and the solid deposited film comprising the pharmaceutical composition is a first layer and the multilayer stack comprises a second layer having a different chemical composition.

64. The article of claim 63, wherein the second layer comprises a second pharmaceutical composition that is different from the pharmaceutical composition in the first layer.

65. The article of claim 63, wherein the second layer comprises a material that minimizes the dissolution rate of the pharmaceutical composition in the first layer.

66. The article of claim 63, wherein the second layer comprises a material having a solubility controlled by the presence of a trigger selected from the group consisting of light, radiation, magnetism, radio waves, pH of the surrounding medium, and combinations thereof.

67. The article of claim 59, wherein the solid deposited film has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g.

68. The article of claim 59, wherein the solid deposited film is stable for greater than or equal to about 1 month.

69. The article of manufacture of claim 59, wherein the low molecular weight organic compound is a pharmaceutically active ingredient or a new chemical entity selected from the group consisting of antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

70. The article of claim 59, wherein the low molecular weight organic compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

71. The article of manufacture of claim 59, wherein the low molecular weight organic compound in the pharmaceutical composition has improved solubility compared to a comparative powder or granular form of the low molecular weight organic compound, 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 the comparative powder or granular form.

72. The article of manufacture of claim 59, wherein the at least one low molecular weight organic compound in the pharmaceutical composition has an enhanced bioavailability compared to a comparative powder or granular form of the low molecular weight organic compound, wherein the bioavailability of the at least one low molecular weight organic compound in the pharmaceutical composition is at least about 10% greater than the comparative bioavailability of the low molecular weight organic compound in the comparative powder or granular form.

73. A solvent-free vapor deposition method comprising: A low molecular weight organic compound having a molecular weight of less than or equal to about 1,000 g / mol is deposited on one or more discrete regions of a substrate by a substantially solvent-free method selected from the group consisting of 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), wherein 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 %.

74. The solventless vapor deposition method of claim 73, further comprising entraining the low molecular weight organic compound in a flow of an inert gas or vacuum substantially free of any solvent prior to said depositing.

75. The solventless vapor deposition process of claim 74, wherein prior to said entraining, said low molecular weight organic compound is in a form selected from the group consisting of: a powder, a pressed particle, a porous material, and a liquid.

76. The solventless vapor deposition method of claim 74, wherein the low molecular weight organic compound is dispersed in a porous material prior to the entrainment.

77. The solventless vapor deposition process of claim 74, wherein prior to said entraining, said low molecular weight organic compound is dispersed in a liquid bubbler through which said inert gas stream passes.

78. The solventless vapor deposition method of claim 74, wherein the entrainment of the low molecular weight organic compound in the inert gas stream or vacuum is performed by heating a solid low molecular weight organic compound source to sublime or evaporate the low molecular weight organic compound.

79. The solventless vapor deposition method of claim 74, wherein the low molecular weight organic compound is present in an amount greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / cm 2 A load density of 100% is deposited onto the one or more discrete areas.

80. The solvent-free vapor deposition method of claim 74, wherein parameters are adjusted 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 flow, 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.

81. The solventless vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound has a specific surface area of ​​greater than or equal to about 0.001 m 2 / g to less than or equal to about 1,000m 2 / g.

82. The solventless vapor deposition process of claim 73, wherein the deposited low molecular weight organic compound is amorphous.

83. The solventless vapor deposition method of claim 82, wherein the deposited low molecular weight organic compound further 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.

84. The solventless vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound is crystalline or polycrystalline.

85. The solventless vapor deposition process of claim 84, wherein the average crystal size is greater than or equal to about 2 nm to less than or equal to about 200 nm.

86. The solvent-free vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound is a pharmaceutically active ingredient or new chemical entity selected from the group consisting of antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

87. The solventless vapor deposition method of claim 73, wherein the low molecular weight organic compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-propenenitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

88. The solventless vapor deposition method of claim 73, wherein the deposited low molecular weight organic active ingredient compound has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

89. The solvent-free vapor deposition method of claim 73, wherein the average thickness of the deposited low molecular weight organic compound in the 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.

90. The solvent-free vapor deposition method of claim 73, wherein the average thickness of the deposited low molecular weight organic compound in the 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, wherein a major dimension of the nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm.

91. The solvent-free vapor deposition method of claim 90, wherein the plurality of nanostructures have a shape selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

92. The solventless vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound in the one or more discrete regions has a purity level greater than or equal to about 99.5 mass %.

93. The solventless vapor deposition method of claim 73, wherein the low molecular weight organic compound is a pharmaceutical active ingredient or a new chemical entity.

94. The solventless vapor deposition method of claim 73, wherein the 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.

95. The solvent-free vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound has an enhanced dissolution rate compared to a comparative powder or granular form of the deposited low molecular weight organic compound, wherein the dissolution rate of the deposited low molecular weight organic compound in aqueous solution is at least ten times greater than the dissolution rate of the deposited low molecular weight organic compound in the comparative powder or granular form.

96. The solvent-free vapor deposition method of claim 73, wherein the deposited low molecular weight organic compound has an enhanced bioavailability compared to a comparative powder or granular form of the low molecular weight organic compound, wherein the bioavailability of the deposited low molecular weight organic compound is at least about 10% greater than the comparative bioavailability of the low molecular weight organic compound in the comparative powder or granular form.

97. An organic vapor jet printing deposition method comprising: entraining the low molecular weight organic compound in the inert gas stream by heating a solid low molecular weight organic compound source to sublime the low molecular weight organic compound and passing the inert gas stream over, through or through the source; directing the low molecular weight organic compound in the inert gas stream through a nozzle toward a cooling target; and The low molecular weight organic compound is caused to condense when it contacts the cooled target.

98. The organic vapor jet printing deposition method of claim 97, wherein the cooling target is a surface of a substrate and the condensed low molecular weight organic compound is deposited on one or more discrete regions of the surface.

99. The organic vapor jet printing deposition method of claim 98, wherein the condensed low molecular weight organic compound has a concentration of greater than or equal to about 1×10 -4 g / cm 2 To less than or equal to about 1g / cm 2 A load density of 200 is deposited onto the one or more discrete areas of the surface.

100. The organic vapor jet printing deposition method of claim 98, wherein the specific surface area of ​​the condensed low molecular weight organic compound in the one or more discrete regions is greater than or equal to about 0.001 m 2 / g to less than or equal to about 1000m 2 / g.

101. The organic vapor jet printing deposition method of claim 98, wherein the average thickness of the condensed low molecular weight organic compound in the 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.

102. The organic vapor jet printing deposition method of claim 98, wherein the average thickness of the condensed low molecular weight organic compound in the 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, wherein a major dimension of the nanostructures is greater than or equal to about 5 nm to less than or equal to about 10 μm.

103. The organic vapor jet printing deposition method of claim 102, wherein the plurality of nanostructures have shapes selected from the group consisting of needles, tubes, rods, platelets, round particles, droplets, leaves, tree-like structures, fractals, hemispheres, pits, interconnected pits, islands, interconnected islands, and combinations thereof.

104. The organic vapor jet printing deposition method of claim 98, wherein the 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.

105. The organic vapor jet printing deposition method of claim 97, wherein the condensed low molecular weight organic compound has a purity level greater than or equal to about 99.5 mass %.

106. The organic vapor jet printing deposition method of claim 97, wherein the cooling target is a liquid comprising one or more solvents.

107. The organic vapor jet printing deposition method of claim 97, wherein the entraining and directing are performed under atmospheric pressure conditions.

108. The organic vapor jet printing deposition method of claim 97, wherein the entraining and directing are performed under reduced pressure conditions of greater than or equal to about 0.1 Torr to less than or equal to about 500 Torr.

109. The organic vapor jet printing deposition method of claim 97, wherein 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 flow, 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.

110. The organic vapor jet printing deposition method of claim 97, wherein the condensed low molecular weight organic compound is amorphous.

111. The organic vapor jet printing deposition method of claim 97, wherein the condensed low molecular weight organic compound is crystalline or polycrystalline.

112. The organic vapor jet printing deposition method of claim 97, wherein the low molecular weight organic compound is a pharmaceutically active substance or new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; sugars; nutrients; hormones; cytotoxins; hormone agonists; hormone antagonists; inhibitors of hormone biosynthesis and processing; antiprogestins; antiandrogens; anti-inflammatory agents; nonsteroidal anti-inflammatory agents (NSAIDs); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antitumor agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

113. The organic vapor jet printing deposition method of claim 97, wherein the low molecular weight organic compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

114. The organic vapor jet printing deposition method of claim 97, wherein the low molecular weight organic compound is a pharmaceutically active substance or a new chemical entity and has a molecular weight of greater than or equal to about 100 g / mol to less than or equal to about 900 g / mol.

115. A method for rapidly dissolving low molecular weight organic compounds, the method comprising: passing a gas stream comprising an inert gas through a heated source of the low molecular weight organic compound, wherein the low molecular weight organic compound is volatilized and entrained in the gas stream; as well as The low molecular weight organic compound is deposited into a liquid comprising one or more solvents by passing the gas stream through a nozzle toward the liquid, such that the deposited low molecular weight organic compound is dissolved in the liquid.

116. The method of claim 115, wherein the source of heating comprises a porous ceramic container containing the low molecular weight organic compound that receives heat transferred from a heater.

117. The method of claim 115, wherein the temperature of the heated source is greater than or equal to about 250°C and the liquid is at ambient temperature.

118. The method of claim 115, wherein 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.

119. The method of claim 115, wherein the inert gas comprises nitrogen.

120. The method of claim 119, wherein the liquid is an aqueous liquid comprising water.

121. The method of claim 115, wherein the concentration of the low molecular weight organic compound is greater than or equal to about 1×10 -11 mol / L to less than or equal to about 20 mol / L.

122. The method of claim 115, wherein the amount of low molecular weight organic compound deposited is less than or equal to about 100 μg.

123. The method of claim 115, wherein the volume of the liquid is less than or equal to about 100 ml.

124. The method of claim 115, wherein the depositing is performed for greater than or equal to about 1 minute to less than or equal to about 120 minutes.

125. The method of claim 115, wherein the low molecular weight organic compound is a pharmaceutically active substance or new chemical entity selected from the following: antiproliferative agents; anti-rejection drugs; antithrombotic agents; anticoagulants; antioxidants; free radical scavengers; nucleic acids; carbohydrates; 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); antimicrobial agents; antiviral agents; antifungal agents; antibiotics; chemotherapeutic agents; antineoplastic agents / antimiotic agents; anesthetics, analgesics or analgesics; antipyretics, prostaglandin inhibitors; platelet inhibitors; DNA demethylating agents; cholesterol-lowering agents; vasodilators; endogenous vasoactive disruptors; angiogenic substances; heart failure active ingredients; targeted toxin agents; and combinations thereof.

126. The method of claim 115, wherein the low molecular weight organic compound is selected from the group consisting of: caffeine, (E)-3-(4-methylphenylsulfonyl)-2-acrylonitrile, fluorescein, acetaminophen, ibuprofen, tamoxifen, and combinations thereof.

127. The method of claim 115, wherein the low molecular weight organic compound is a pharmaceutically active ingredient 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.

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