MXPA06000809A - Small spherical particles of low molecular weight organic molecules and methods of preparation and use thereof - Google Patents

Abstract

The invention provides homogeneous small spherical particles of low molecular weight organic molecules, said small spherical particles having a uniform shape, a narrow size distribution and average diameter of 0.01-200µm. The invention further provides methods of preparation and methods of use of the small spherical particles. These small spherical particles are suitable for applications that require delivery of micron-size or nanosized particles with uniform size and good aerodynamic or flow characteristics. Pulmonary, intravenous, and other means of administration are among the delivery routes that may benefit from these small spherical particles.

Description

SMALL SPHERICAL PARTICLES OF ORGANIC MOLECULES OF LOW MOLECULAR WEIGHT AND METHODS OF PREPARATION AND USE OF THE SAME REFERENCE TO RELATED APPLICATION This application claims priority to provisional application Serial No. 60 / 489,292 filed on July 22, 2003, provisional application Serial No. 60 / 540,594 filed on January 30, 2004 and provisional application Serial No. 60 / 576, 91 8 filed on June 04, 2004, each of which is hereby incorporated in its entirety for reference and becomes a part of it.

DEVELOPMENT OR RESEARCH SPONSORED IN A WAY FEDERAL Not applicable.

BACKGROUND OF THE INVENTION TECHNICAL FIELD The present invention provides small, homogeneous spherical particles of low molecular weight active agents. These small spherical particles, in a preferred form of the invention, are characterized by a substantially uniform spherical shape, an average diameter of 0.01-200 μm, and a narrow size distribution. These small spherical particles are potentially advantageous for applications, for example, that require the supply of nano-sized or micron-sized particles with uniform size and good aerodynamic or flow characteristics. Pulmonary, intravenous, and other means of administration are among the delivery routes that can benefit from these small spherical particles.

BACKGROUND OF THE MATTER There is a growing number of organic compounds that are being formulated for therapeutic or diagnostic purposes that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges to be delivered by several routes of administration. Compounds that are insoluble in water can have important benefits when formulated as a stable suspension of particles. The control of the particle size is fundamental for the safety and effective use of these formulations. The particles must be less than seven microns in diameter to pass safely through the capillaries without causing embolisms (Alien et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981; ). One solution to this problem is the production of small particles of the candidate insoluble drug and the creation of a small particle suspension. In this manner, drugs that were previously incapable of being formulated in an aqueous-based system can be made convenient for intravenous administration. The particles suitable for intravenous administration will have a particle size of < 7 μm, low toxicity (as of components of toxic formulation or residual solvents), low excipient content, and preservation of the bioavailability of the active agent after being treated in the particle form. The present invention can lead to crystalline forms (polymorphic substances) having higher levels of dissolution. This can also result in particles having a high surface area for volume ratio and therefore may have higher levels of dissolution. Small particle preparations of water insoluble drugs may also be suitable for oral, pulmonary, topical, ophthalmic, nasal, buccal, rectal, vaginal, transdermal, ocular, infraocular, otic, or other routes of administration. Current proposals to increase the solubility of hydrophobic, low molecular weight agents are focused on increasing the surface area of the formulated particles mainly using micronization techniques, which increase the surface area for volume ratio by reducing the size of the surface. average particle of the particles. The agglomeration of micronized particles is a well-known limitation of the art for both liquid and powder formulations. The non-invasive supply of medications through the pulmonary route of administration plays an important role in the treatment of respiratory diseases and other diseases. The pulmonary route offers several clear advantages, among them the avoidance of first pass metabolism or degradation in the gastrointestinal tract, and access to a high concentration of narrow blood vessels with large surface area available for transport. This large surface area provides rapid systemic absorption when compared to the oral route of administration. Compared with other delivery routes, pulmonary delivery offers high levels of patient compliance. It is generally considered to be superior to implantable and injectable administration routes and is comparable to the nasal, transdermal and transmucosal routes. In an effort to increase patient compliance, pulmonary formulations of newer and older medications that were only available in injectable form are being developed for the treatment of serious diseases such as diabetes mellitus. The pulmonary supply also offers targeted delivery of the drug to the site of the disease for respiratory diseases such as asthma, rhinitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) and emphysema. The site-directed delivery allows for the most effective use of the medicament, and is particularly desirable when the bioavailability of the medicament is limited. Direct delivery of the drug to the site of the disease can potentially reduce toxicity, because the highest concentration of the drug reaches its target rather than being distributed throughout the body. Due to these unique characteristics, the pulmonary route is convenient both for systemic and topical drug delivery and is a permissive route for the supply of proteins and peptides. In recent years, medications such as insulin and human growth hormone (hGH), which were previously available only as injectables, have been formulated into solid dosage forms for pulmonary delivery and currently in advanced stages of clinical trials. The first lung medications developed were small molecule-based therapies for the treatment of diseases such as asthma and rhinitis. It was found that corticosteroids that have structures similar to cortisol produced naturally have powerful anti-inflammatory action. Pulmonary formulations of corticosteroids such as beclomethasone dipropionate, budesonide, and fluticasone propionate have been developed and have become a popular form of therapy for respiratory diseases that are associated with inflammation of the lungs. Advances in pharmaceutical research have led to the development of new formulations of existing drugs to treat diseases through the pulmonary route. For example, TOBI® (Chiron Corporation, Emeryville, CA) a pulmonary trobamycin solution for the treatment of cystic fibrosis, has been developed as an atomized dose form that can be delivered directly to the site of infection in the lungs, and is free of condom Although the pulmonary supply of small, organic molecules such as steroids and beta-combatants has been practiced since the invention of the first metered dose inhaler in the 50's, most efforts have been directed towards the discovery of new therapeutic agents and the development of new inhaler devices. Historically, little attention has been paid to the development of formulations with optimal aerodynamic characteristics; consequently, current formulations suffer from several disadvantages, including particles with large particle size distributions, an average particle size that is larger or smaller than required, and agglomerated particles. The development of small molecule compositions with a particle size precisely on the desired scale and with narrow particle size distribution is very desirable. Lung formulations are delivered by specific types of inhaler devices. The most popular devices are the metered dose inhaler (MDI), the dry powder inhaler (DPI) and the atomizer (US Food and Drug Administration, Center for Drug Evaluation and Research, 1998). An MDl can be used to deliver a solution or a suspension of the medicament with the aid of a propellant such as CFC or HFA. The activation of MIDs and DPIs often require patient motor skills as well as respiratory coordination, which can reduce the efficacy of the supply. An DPI can be used to deliver a dry powder of the medicament, and an atomizer often delivers a watery aerosol form of the medicament. The atomizers in general require little effort to inspire the patient in their operation. Sprayers tend to be large, and are mainly used by children or the elderly, whose level of inspiring flow is limited. These human factors, combined with non-optimized formulations, result in only a small fraction of the dose delivered that reaches the target area in the lungs. Most doses are typically placed in the throat and in the mouth, and do not reach the desired site, either higher airways or deep airways. In a radioactive qualified study of the deposit of salbutamol in the lungs, Melchor et al. (1993) reported 20-21% of the deposit with an MDl and only 12% of the deposit with an IPR. This is particularly undesirable for chronically occurring drugs, since large amounts of the drug are continuously deposited in non-target areas, mainly in the oropharynx. The high oropharyngeal deposit may have adverse local effects, such as oral thrush or candiasis. Due to the risk of adverse effects that result from the chronic use of corticosteroids is dose-dependent, a reduction in the dose delivered is predicted to reduce the risk of side effects (Corren et al., 2003). A dried powder of the medicament with particles on the scale of desired size and a narrow particle size distribution can result in reduced dose, because the portion of the drug reaching its destination is increased, therefore the administered dose can be decreased. This has been shown for fluticasone, budisonide, and beclomethasone by Corren et al. (ibid.) Conventional pulmonary formulations are the direct result of pharmaceutical cGMP manufacturing processes that typically have several phases. One of the final stages in many pharmaceutical processes is crystallization, which serves as a purification step, and as a method to precipitate solid out of solution. Current crystallization techniques lead to particles with various shapes and sizes, and most of the resulting powders have particles that are much larger than those required for pulmonary delivery. In addition, many active pharmaceutical agents are hydrophobic agents with limited solubility and thus limited bioavailability. The reduction in particle size reduces the energy barrier required for dissolution. Thus the size of the particles can be reduced and this is often achieved by adding a physical grinding or micronization stage during or after crystallization. For example, U.S. Pat. 5, 314,506 for Midler et al. , discloses a method for decreasing the particle size by the addition of a shock jet stage prior to the crystallization phase. The precipitation of the solution using an antisolvent system is one of the most common methods of crystallization (Wey et al., 2001). In this type of crystallization system a solute is crystallized from a primary solvent by the addition of a second solvent (antisolvent) in which the solute is relatively insoluble. A solution of the solute in a solvent, which is often saturated or closed for saturation, is formed initially. Then, an antisolvent is added that is miscible with the primary solvent. The antisolvent is selected so that the solute is relatively insoluble in the antisolvent. When the antisolvent is added to the solution, the solute is precipitated out of the binary mixture due to the reduction in solubility of the solute in the binary mixture compared to the solvent.

BRIEF DESCRIPTION OF THE INVENTION The small spherical particles described herein have a uniform size, preferably in the 0.1-4 micron scale, and have a substantially uniform spherical shape. These particles have a higher ratio of surface area to volume, a reduced tendency to agglomerate compared to conventional micronized particles, and a uniform aerodynamic shape. An increase in the surface area of a formulated compound can increase the level of drug dissolution. Also described herein are methods for preparing small, homogeneous spherical particles comprising low molecular weight agents. These methods offer several advantages including low treatment temperatures, formation of small spherical particles on a scale of desired size, with a narrow size distribution and departure-to-match uniformity. These methods result in high yields when compared to conventional micronization techniques, and are provided for the recovery of substantially all of the starting material on the desired size scale. These methods do not require a separate stage and it requires a lot of sieving time to remove too large particles. Since the small spherical particles are substantially the same size and shape, game-to-game uniformity can be achieved. Additionally, these processes can significantly reduce manufacturing time and costs, when compared to conventional processes. The small spherical particles described herein are particularly convenient, for example, for targeted delivery to the lungs. For pulmonary delivery, the particles in general must have a MMAD of 5μm or less, depending on the lung area targeted for treatment (ie, deep lung, whole lung, etc.). Small spherical particles can be formed on a scale of size that is convenient for depositing in specific areas of the lungs. Pulmonary airway diseases, such as asthma, COPD, emphysema, and others, can be characterized by the area of the lung that is affected by the disease. Asthma is considered a disease of the entire lung, with inflammation of the central airways as well as the periphery of the lungs (Corren et al., 2003). It is known that in order to reach the periphery of the lung, the aerodynamic particle size of the drug should be 0.5 to 3.0 microns (Brown, 2002). This allows the target supply of the medication to the alveoli. In addition, systemic delivery through the lungs in general requires that the drug be delivered to the periphery of the lungs, ie, the alveoli. The small spherical particles described herein can be produced in a scale of size that allows effective deposition at the site of the disease, and since they are of substantially the same size, a high efficacy of medication delivery to the site of the lung wanted. These and other aspects and attributes of the present invention will be discussed with reference to the following drawings and the accompanying specification.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a scan electron microscopy (SEM) image of beclomethasone dipropionate (BDP), which is used as a starting material in the process described in example 1. This image presents the characteristics of many low molecular weight micronized drugs. The particle size of BDP varies between hundreds of nanometers up to 50 microns. The particle size distribution is wide and the particles have random shapes. FIG. 2 represents small spherical particles of beclomethasone dipropionate (BDP) prepared according to the method described in Example 1, below. These small spherical particles are characterized by a uniform shape, an average particle size of 2 microns, and an extremely narrow size distribution. The small spherical particles are substantially spherical, and are substantially of the same size. FIG. 3 presents Diffraction patterns of Dust with X-Rays (XRPD) of beclomethasone dipropionate start material (background), and XRPD patterns of two small spherical BDP particle batches made according to Example 1, below. FI G. 4 is a SEM image of micronized budesonide, which is used as starting material in example 2.

The particle size scales of budesonide between hundreds of nanometers up to 1 00 microns. The particle size distribution is wide, and the particles have random shapes. FIG. 5 represents small spherical particles of budesonide prepared according to the method described in example 2, below. These small spherical particles are characterized by a uniform shape, an average particle size of 2 microns, and an extremely narrow size distribution. The small spherical particles are substantially spherical, and are substantially of the same size. FIG. 6 presents an XRPD of micronized budesonide starting material (top), and XRPD patterns of small spherical budesonide (bottom) particles manufactured according to example 2, below. FIG. 7 presents the aerodynamic particle size distribution (PSD) of small spherical budesonide particles measured by an Aerocalibrator. The distribution is calculated based on time-of-trajectory. FIG. 8 is a SEM image of micronized itraconazole, which is used as the starting material in the example 3. The particle size scales of itraconazole between hundreds of nanometers to microns. The particle size distribution is wide, and the particles have random shapes. FIG. 9 represents small spherical particles of traconazole prepared according to the method described in Example 3, below. These small spherical particles are characterized by a uniform shape, an average particle size of 1 micron, and an extremely narrow size distribution. The small spherical particles are substantially spherical, and are substantially of the same size. FIG. 10 represents the particle size distribution of itraconazole microspheres by light scattering. The small spherical particles were suspended in deionized water with a surfactant. FIG. 1 1 is a schematic flow diagram that summarizes the process for making small spherical particles of beclametasone dipropionate (BDP). FIG. 12 is a schematic diagram of an apparatus for preparing small spherical particles. FIG. 13 is a schematic end view of an apparatus for preparing spherical particles. little. FIG. 14 is a schematic view of an apparatus for preparing small spherical particles.

DETAILED DESCRIPTION OF THE PREFERRED MODALITY Although this invention may have modalities in many different forms, the principles shown in the drawings, and which will be described herein in detail, have specific embodiments thereof with the understanding that the present discovery is for considered as an exemplification of the principles of the invention and is not intended to limit the invention to the specific embodiments illustrated.

The Particles The small spherical particles of the present invention preferably have an average particle size of from about 0.01 μm to about 200 μm, more preferably from about 0.1 μm to about 10 μm and more preferably 0.1 μm to about 4 μm, as Measures by dynamic light scattering methods eg, photo-correlation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), mid-angle laser light scattering (MALLS), or by light-dimming methods (Coulter method) , for example), or other methods, such as rheology, or microscopy (light or electron). The particles for pulmonary delivery will have an aerodynamic particle size determined by the trajectory measurement time by a TSI Corporation Aerocalibrator or Andersen Cascade Collider. The small spherical particles are substantially spherical. What is meant by substantially spherical is that the ratio of the lengths through the perpendicular axes of the particle cross section is from 0.5 to 2.0, more preferably from 0.8 to 1.2 and more preferably from 0.9 to 1.1. The surface contact is decreased between and between substantially substantially spherical particles which decreases the undesirable agglomeration of the particles. Shapes with facets and pieces have flat surfaces that present an opportunity for large contact areas between adjacent particles. For particles that have a large size distribution where there are both relatively large and relatively small particles, the smaller particles can fill in the gaps between the larger particles, thus creating new contact surfaces. Typically, the small spherical particles made by the process in this invention are substantially non-porous and have a density greater than 0.50 / cm3, more preferably greater than 0.750 / cm3 and more preferably greater than about 0.85 / cm3. A preferred scale for the density is from about 0.50 to about 2.00 g / cm3 and more preferably from about 0.75 to about 1.750 g / cm3 and even more preferably from about 0.85 g / cm3 to about 1.50 g / cm3. This is in contrast to low density, lung particles produced by spray drying that typically occur at approximately 0.4 g / cm3. Higher density particles are allowed for larger amounts of the active agent to be delivered to the patient compared to lower density particles. This is a particularly desirable feature for medications that are not very powerful, so larger amounts of the drug can be delivered, or for chronically occurring drugs, a decrease in the dosage size can decrease adverse effects and increase patient compliance . The small spherical particles may have a smooth surface profile or a textured surface profile. A smooth surface profile is generally smooth, which means that the distance from any point on the surface of the particle towards the center of the particle is the same distance. Textured surfaces refer to surface variations that have dimensions that are much smaller than the total diameter of the particle. The textured surface can take many forms including irregularly spaced or irregularly spaced protuberances or indentations in the particle surface, longitudinally or latitudinally extended lines or grooves or cracks or other surface rupture, or other forms or combinations of surface irregularities that can occur on a particle of medication. The texturization on a particle surface can be located on a single portion of the surface or on several portions of the surface of the particle or on substantially all the surface of the particle. The spherical shape of the small spherical particles combined with their uniform size provide a unique composition in which the particles are spheres of uniform size, which by definition is the physical form with the least amount of surface contact. It is well known that interactions between particles along surface contact areas, such as electrostatic, van der Waals and others, strongly depend on the distance between adjacent particles. Thus, a reduction in the contact area between the particles decreases the attractive interparticle forces and can lead to particles with a significantly reduced tendency for agglomeration. The reduced interparticle attraction between the small spherical particles results in powders with improved fluidity, and when in suspensions, they show reduced tendency to agglomerate. Compared with traditional powders of micronized medicaments, the small spherical particles described herein have a reduced tendency to agglomerate, settle or flocculate. The particles also preferably have substantially the same particle size. Particles that have a large size distribution where there are both relatively large and small particles allow smaller particles to fill in the gaps between the larger particles, thus creating new contact surfaces. A large size distribution can result in the creation of many contact opportunities for mandatory agglomeration. This invention creates spherical particles with a narrow size distribution, thereby reducing opportunities for contact agglomeration. What is meant by a narrow size distribution is a preferred particle size distribution would have a 90th percentile diameter ratio of small spherical particles for the diameter of 1 0th percentile less than or equal to 5. More preferably , the particle size distribution would have proportion of the 90th percentile diameter of the small spherical particles for the diameter of the 10th percentile less than or equal to 3. More preferably, the particle size distribution would have proportion of the 90th diameter of percentage of small spherical particles for the diameter of the 10th percentile less than or equal to 2. Geometric Standard Deviation (GSD) can also be used to indicate the narrow size distribution. The GSD calculations imply the determination of the effective cut diameter (ECD) in the cumulative mass less than the percentages of 15.9% and 84.1%. The GSD is equal to the square root of the proportion of the cumulative mass of ECD less than 84.17% for cumulative mass of ECD less than 15.9%. The GSD has a narrow size distribution when GSD <; 2.5, more preferably less than 1.8. The small spherical particles are preferably almost • 100% active agent or a combination or mixture of active agents that are substantially free of any of the excipients. What is meant by "substantially free of excipients" is that the active agent or active agents is present from about 70% to less than 1 00% by weight of the small spherical particles, excluding water. More preferably, the active agent (s) is greater than about 90% by weight of small spherical particles and more preferably the small spherical particles will have 95% or greater by weight of the active agent. These scales, as well as all other scales listed here, should include any scale, sub-scale, or combination of the scales in it. In some cases it may be desirable for the particle to include an optional volume agent or other surfactant as long as these additives do not substantially impact the effectiveness of the agent. Volume agents may include saccharides, disaccharides, polysaccharides and carbohydrates. The small spherical particles may be crystalline, semi-crystalline, or non-crystalline. The Active Agent The active agent of the present invention is a low molecular weight organic substance. A low molecular weight substance is one that has a molecular weight of equal to or less than about 1,500 Daltons. As stated above, the particles may have a single active agent or more than one active agent. The active agent can be hydrophobic or hydrophilic. In a preferred embodiment, the active agent is a poorly soluble compound in water. What is meant by little soluble in water is that the active agent has a solubility in water of less than 10 mg / mL, preferably less than 1 mg / mL. The active agent of the present invention is preferably a pharmaceutically active agent, which may be a therapeutic agent, a diagnostic agent, a cosmetic, a food supplement, or a pesticide. Examples of a suitable active agent for the present invention include but are not limited to steroids, beta-combatants, anti-microbials, antifungals, taxanes (antimitotic and antimicrotubule agents), amino acids, aliphatic compounds, aromatics and urea compound. In a preferred embodiment, the active agent is a therapeutic agent for treatment of pulmonary disorders. Examples of such agents include steroids, beta-combatants, antifungals, and anti-microbial combatants. Examples of steroids include but are not limited to beclomethe (including beclomethe dipropionate), flutice (including flutice propionate), budesonide, estradiol, fludrocortisone, flucinonide, triamcinolone (including triamcinolone acetonide), and flunisolide. Examples of beta-combatants include but are not limited to salmeterol xinafoate, formoterol fumarate, levoebuterol, bambuterol and tulobuterol. Examples of antifungal agents include but are not limited to traconazole, fluconazole, and amphotericin B. Numerous combinations of active agents may be desired including, for example, a combination of a spheroid and a beta-combatant, eg, flutice propionate. and salmeterol, budesonide and formeterol, etc. Also included are pharmaceutically accepted salts, esters, hydrates and solvates of these compounds. Also included in the above compounds are crystalline or a crystalline polymorphous substance or ponderous polymorphous substance of the small organic molecule. The present invention further provides additional steps to alter the crystal structure of the active agent to produce the agent both on the desired size scale and also on the desired crystal structure to optimize the level of dissolution of the agent. What is meant by the term crystal structure is the arrangement of the molecules within a glass lattice. The compounds that can be crystallized in different crystal structures are said to be polymorphic. The identification of polymorphous substances is an important step in the formulation of the medicine since the polymorphic substances different from the same medicine can show differences in level of dissolution, therapeutic activity, bioavailability and suspension stability. Therefore, it is important to ensure the consistency of the polymorphic form of the compound for split-to-batch reproducibility. In another form of the particles, the particles can include agents to vary the level of release of the agent or to provide for targeting the agent to a particular site for treatment. Examples of lung disorders include, but are not limited to, allergic rhinitis, bronchitis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, infectious disease, and cystic fibrosis.

Optional Excipients The system of the present invention may include one or more excipients. The excipient may bind the active agent or particles with additional characteristics such as increased stability of the particles or of the active agents or of the vehicle agents, controlled release of the active agent from the particles, or modified permeation of the active agent through biological tissues. Suitable excipients include, but are not limited to, carbohydrates (e.g., trehalose, sucrose, mannitol), cations (e.g., Zn2 +, Mg2 +, Ca2 +), anions (e.g., SO42"), amino acids (e.g., glycine), lipids, phospholipids, fatty acids, surfactants, triglycerides, bile acids and their salts (for example, cholate or its salts, such as sodium cholate, deoxycholic acid or its salts), fatty acid esters, and polymers (for example, amphiphiles) , hydrophilic polymers, such as polyethylene glycol or lipophilic polymers).

Live Delivery of the Particles The small spherical particles containing the active agent in the present invention are suitable for a live delivery to a subject in need of the agent by a convenient route, such as injectable, topical, oral, rectal, nasal, pulmonary, vaginal, buccal, sublingual, transdermal, transmucosal, otic, intraocular or ocular. The particles can be supplied as a stable liquid suspension, tablet, a dry powder, a powder suspended in a propellant such as CFC or HFA, or in an atomized form. A preferred delivery route is pulmonary delivery.

In this delivery route, the particles can be deposited to the deep lung, the central or peripheral area of the lung, or the upper respiratory tract of the subject in need of the therapeutic agent. The particles can be supplied as a dry powder by a dry powder inhaler, or they can be supplied in suspension by a metered dose inhaler or an atomizer. When delivered by the pulmonary route, the active agent can be used to treat local respiratory disorders to the lungs of the subject, or the active agent can be absorbed into the systemic circulation for the treatment of other diseases. Another preferred route of delivery is parenteral, which includes intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal, epidural, intra-arterial, intra-articular and the like.

The Process and Apparatus A method for preparing the small spherical particles of the present invention includes the following steps: (1) providing a solution of the active agent in a first solvent; (2) adding a second solvent to the solution to form a three-component solution of the two solvents and the active agent; the solubility of the active agent in the second solvent is lower than in the first solvent (3) spreading the three-component solution on a surface to form a thin film; and (4) evaporating the solvents by passing a stream of gas over the film to form small spherical particles of the active agent on the surface, where the gas does not react with the active agent. Small spherical particles are formed during the evaporation step, which also cools the thin film to facilitate the formation of small spherical particles. It is preferred that the steps are carried out at or below the ambient temperature of about 25 ° C. Any or all of the solvents, gas, agent and relevant portions of the apparatus used to make the particles can be cooled in order to facilitate particle formation and removal from the surface. The method may also include additional steps to dry the small spherical particles on the surface, remove the small spherical particles from the surface, and form a dry powder of the small spherical particles. The first solvent can be an organic solvent or an aqueous medium, depending on the active agent. Suitable organic solvents include but are not limited to N-methyl-2-pyrrolidinone (N-methyl-2-pyrrolidone), 2-pyrrolidinone (2-pyrrolidone), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide, dimethylacetamide, volatile acetones such as acetone, methyl ethyl acetone, acetic acid, lactic acid, acetonitrile, methanol, ethanol, isopropanol, 3-pentanol, n-propanol, benzyl alcohol, glycerol, tetrahydrofuran (THF), polyethylene glycol (PEG) ), PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG, 16, PEG-120, PEG-75, PEG-150, polyethylene glycol esters, PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmito-stearate, PEG-150 palmito-stearate, polyethylene glycol sorbitans, PEG-20 sorbitan isostearate, polyethylene glycol monoalkyl ethers, dimethyl ether PEG-3, dimethyl ether of PEG-4, polypropylene glycol (PPG), polypropylene alginate, butanediol of PPG-10, methyl glucose ether of PPG-10, r of methyl glucose of PPG-20, stearyl ether of PPG-15, dicaprylate / propylene glycol dicaprate, propylene glycol laurate, and glycofurol (polyethylene glycol ether of tetrahydrofurfuryl alcohol), propane, butane, pentane , hexane, heptane, octane, nonane, decane, or combinations thereof. In a preferred embodiment in which the active agent is a hydrophobic compound, the first solvent is an aqueous, miscible organic solvent, for example, an alcohol such as ethanol, and the second solvent is an aqueous medium. The three component system therefore comprises the hydrophobic active compound, ethanol and water. The first solvent or the second solvent or both the first solvent and the second solvent are preferably a volatile solvent. What is meant by volatile is that its vapor pressure is higher than that of water. In a preferred embodiment, the first solvent is more volatile than the second solvent, for example, ethanol is the first solvent and water is the second. In a process of the present invention, the step of providing the solution of the active agent in the first solvent includes the steps of adding the active agent to the first solvent and sonicating the first solvent to completely dissolve the agent in the first solvent. In a process of the present invention, the step of spreading the mixture on a surface to form a thin film includes the steps of transferring the mixture to a rotating evaporation flask and slowly turning the flask to coat the mixture on the surface of the flask. The gas used to evaporate the solvent from the thin film of the solution is preferably inert but may be non-inert. Examples of suitable gases that can be used to evaporate solvents from the thin film of the solution include but are not limited to nitrogen, hydrogen and inert gases such as helium and argon. The level of gas flow must be optimized according to the active agent, first solvent and / or the second solvent used in the process. The influx of gas can be stopped once the solvents evaporate completely. Optionally, the gas influx may continue at a reduced flow level for a short period of time (eg, about 3 minutes) to dry the small spherical particles on the surface. The method may also include additional steps of removing small spherical particles from the surface and forming dry powder from the small spherical particles. In one embodiment, the steps of removing the small spherical particles from the surface include adding a minimum amount of the second solvent to remove the small spherical particles from the surface. Preferably, the second solvent is ice water at about 4 ° C. Optionally, the second solvent can be sonicated, preferably on ice, to facilitate the removal process. The second solvent can also be further removed to form a dry powder by a process such as lyophilization.

FIGS. 12 and 13 show a convenient apparatus for this process which includes a fluid supply device or system 12 (FIG.1-3) for supplying the three component solution from a source 14 to a surface 16, a driving device 1 8. to move the surface with respect to the source 14 to form a thin film 19 of the three component solution on the surface 16, and a gas supply device or system 20 for supplying gas under pressure to the surface 16 or the film 19 or both. In a process for continuously preparing the particles described herein, the fluid supply device includes the source 14 having a quantity of solution 22, a device 24 for supplying the solution to the surface 16, and in this case, it is a transfer roller. The transfer roller 24 is mounted for rotation about an axis and has an outer circumferential portion placed in contact with the solution which is then carried on an outer circumferential portion of the roller in encounter with the surface 16 to form a thin film 19 of the solution on the surface 16. It is contemplated that the delivery device 24 can take many forms and include many different types of applicators, such as applicators in spray or other type of applicator, as long as the applicator is capable of depositing the solution in a way controlled to the surface 16 to form a thin film 19 thereon. In a starting process, the solution can be added to the reaction vessel using standard laboratory techniques, such as pipetting or other techniques well known in the art. The surface 16 may have various shapes in cross section including flat, curved, round, elliptical, wavy, or irregular. As shown in FIGS. 12 and 13, in a preferred form of the invention, the surface is curved and preferably in general is cylindrical 26. It is contemplated that the curved surfaces may also be conical, frusto-conical, or spherical. As shown in FIGS. 12 and 13, the surface 16 is carried on an internal surface 1 6 or external 16 'of the glass cylinder 26. The glass cylinder, in a preferred form, is a 1 0 liter glass reagent vessel with a reactive head of optional glass 29, which can be clamped to seal the container. The surface 16 can have a smooth profile, which has a substantially constant height dimension across the surface, or the surface can be textured either to decrease the contact angle of the solution on the surface or to increase the wettability of the solution on the surface. Textured surfaces include those that have a surface profile that does not have a constant height for each point along the surface. Textured surfaces include but are not limited to a matt, frosted, embossed, or similar surface. In a preferred form of the invention, the surface is a smooth surface. Suitable surfaces are made of a material such as a polymer, metal, ceramic, or glass. The material can be rigid, semi-rigid or flexible. What is meant by flexible is that it has a modulus of elasticity of less than 20,000 psi. What is meant by rigid is that it has a modulus of elasticity of more than 40,000 psi. Semi-rigid materials have a modulus of elasticity between 20,000 psi and 40,000 psi. In a more preferred form of the invention, the surface is glass. Suitable polymers for forming the surface include those which do not react with the active agent and include polyolefins, cyclic olefins, bridged polycyclic hydrocarbons, polyamides, polyesters, polyethers, polyimides, polycarbonates, polystyrene, polyvinyl chloride, ABS, polytetrafluoroethylene (PTFE), esters and hydrocarbon copolymers, synthetic gums and the like. The term polyolefin used herein means including ethylene homopolymers and copolymers, propylene, butene, pentene, hexene, heptene, octene, noneneno, and decene. Suitable ethylene copolymers include: (a) ethylene copolymerized with monomers selected from the group of α-olefins having 3-10 carbons, substituted lower alkyl carboxylic acids and lower alkene and ester and anhydride derivatives thereof, ( b) ethylene propylene gums, (c) EPDM, (d) ethylene vinyl alcohol, and (e) ionomers. Preferably, the carboxylic acids have 3-10 carbons. Such carboxylic acids, therefore, include acetic acid, acrylic acid, and butyric acid. Suitable acrylic acid containing polymers include PMMA, sold under the trade name Plexiglas. The term lower alkene and lower alkyl means to include a carbon chain having 2-18 carbons, more preferably 2-10 and more preferably 2-8 carbons. Thus, a subgroup of this group of comonomers includes, as a representative but non-limiting example, vinyl acetates, vinyl acrylates, methyl acrylates, methyl methacrylates, acrylic acids, methacrylic acids, ethyl acrylates, and ethyl acrylic acids. . Suitable homopolymer and copolymers of cyclic olefins, bridged polycyclic hydrocarbons, and mixtures thereof can be found in Pat. from USA UU Nos. 4,874,808; 5,003,019; 5,008,356; 5,288,560; 5.21 8.049; 5,854,349; 5,863,986; 5,795,945; and 5,792,824, which are incorporated herein by reference in their entirety and become a part thereof. In a preferred form of the invention, these homopolymers, copolymers, and polymer blends will have a glass transition temperature of more than 50 ° C, more preferably from about 70 ° C to about 180 ° C, a density greater than 0.910 g. / cc, more preferably from 0.910 g / cc to about 1.3 g / cc and more preferably from 0.980 g / cc to about 1.3 g / cc, and will have at least about 20 mole% of a cyclic aliphatic or a polycyclic bridged in the main polymer element, more preferably from about 30-65 mole% and more preferably from about 30-60 mole%. In a preferred form of the invention, suitable cyclic olefin monomers are monocyclic compounds having from 5 to about 10 carbons in the chain. The cyclic olefins can be selected from the group consisting of unsubstituted and substituted cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene, cycloheptene, cycloheptadiene, cyclooctene, and cyclooctadiene. Suitable substituents include lower alkyl, acrylate derivatives and the like. In a preferred form of the invention, bridged polycyclic hydrocarbon monomers have two or more chains and more preferably contain at least 7 carbons. The chains can be replaced or not replaced. Suitable substitutes include lower alkyl, aryl, aralkyl, vinyl, allyloxy, (meth) acryloxy and the like. The bridged polycyclic hydrocarbons are selected from the group consisting of those described in the patents incorporated above and patent applications. A more preferred polycyclic hydrocarbon is a norbornene homopolymer or a copolymer of norbornene with ethylene. Suitable norbornene-containing polymers are sold by Ticona under the trade name TOPAS, by Nippon Zeon under the tradename ZEONEX and ZEONOR, by Daikyo Gomu Seiko under the trade name CZ resin, and by Mitsui Petrochemical Company under the tradename APEL. The polymeric material can be formed on the surface by extrusion, coextrusion, lamination, extrusion lamination, injection molding, blow molding, thermoforming, or other treatment technique. The material can be a flexible, semi-flexible or rigid. The material can be a single layer film or a multilayer film. The film may have a compatible surface for protein, such as the films described in U.S. Pat. UU No. 6,309,723 which is incorporated herein in its entirety for reference and is hereby incorporated herein by reference. The material can also be manufactured in numerous shapes and sizes as desired. Suitable metals include aluminum, stainless steel, vanadium, platinum, titanium, gold, beryllium, copper, molybdenum, osmium, nickel, or other suitable alloys or metals or metal compounds. Suitable ceramics include Cordierite, Albite (Feldspar NaAISi3O8), Augite (Iron Magnesium Silicate), Bite K (Mg, Fe) 3- (AISÍ3? 10), Hornablenda (Iron Magnesium Silicate), Hita KAI2 (AISi3O10) - (OH) 2, Kaolinite (AI2O3-2SiO2-4H2O), Labradorite (Feldspar, 60% CaAI2Si2O8 + 40% NaAISi3O8), Montmorillonite AI2O3-4SiÓ2-nH2O, Muscovite (Kal2 (AISi3O10) - (OH) 2), Orthoclase ( Feldspar KAISi3O8), Quartz (S¡O2), Mica (KAL2 (ALSi3O10) (OH) 2), Mica (K (Mg, Fe) 3 (AISi3O10) (OH) 2), Amphibole ((Ca-Na) 2- 3 (Mg, Fe, AI) 5Si6 (SiAI) 2O22 (OH) 2), Amphibole (CaMg5Si8O22 (OH) 2), Pyroxene (X2Si2O6), Olivine ((Mg, Fe) 2SiO4), Chlorates ((Mg, Fe, AI) 6 (AI, Si) 4O10 (OH) 8), Feldspar (K2O AI2O36SiO2), Feldspar (Na2O Al2O36SiO2, CaO AI2O32SiO2), Mulite, 3AI2O3-2SiO2, K0.5Na0.5NbO3, Fused Quartz, Fused Quartz, Steatite ( Magnesium Silicon Oxide), Vermiculite, Magnesium Aluminum Iron Silicate, Airgel of Silica, AREMCO Aremcolox ™ 502-1 100, Not Released, AREMCO Aremcolox ™ 502-1 100, Totally Launched, AREMCO 61 8 Cerama-bond ™, AREMCO 677 Pyro-Putty®, AREMCO 685 Cerama-bond ™, AREMCO Cerama-cast ™ 646, AREMCO Cerama-Fab ™ 665, AREMCO Cerama-cast ™ 674, AREMCO Cerama-bond ™ 3062, AREMCO Wax a-Dip ™ 538N, CeramTec Steatite Grade 645 (MgO-Si02), CeramTec Esteatatia Grade 665 (MgO-S02), Cordierite of CeramTec Grade 447 (2MgO-2AI2O3-5SiO2), Cordierite of CeramTec Grade 547 (2MgO-2AI2O3-5S¡O2), Cordierite of CeramTec 701 (2MgO-2AI203-5Si02), Steatite (Magnesium Silicon Oxide), Vermiculite, Magnesium Aluminum Iron Silicate, Single Magnesium Oxide (MgO) Glass Substrate, Single Spinel Crystal Substrate (MgAI2O4), AREMCO 571 Cerama-bond ™, AREMCO Cerama- cast ™ 583, AREMCO Cerama-cast ™ 584, AREMCO Cerama-cast ™ 672, CeramTec Steatite Grade 645 (MgO-SiO2), CeramTec Steatite Grade 665 (MgO-SiO2), Cordierite CeramTec Grade 477 (2MgO-2AI2O3-5SiO2), CeramTec Cordierite Grade 547 (2MgO-2AI2O3-5SiO2), CeramTec Cordierite Grade 701 (2MgO-2AI2O3-5SiO2), Steatite Du-Co DC-9-L-3, Steatite Du-Co DC-10-L-3, Steatite Du-Co DC-16-L-3, Steatite Du-Co CS-144-L-5, Fosterite Du-Co DC-200-L-5, Magnesium Oxide Du-Co DC-1 87, Lead Magnesium Niobate Piezoe EC-98 Ceramic EDO, Steatite GBC L3, ICE Steatite L-4, ICE Steatite L-5, Magnesia LUMINEX®, Steatite (Morgan Matroc), Magnesite NAPCO C90, Magnesite NAPCO C95, NAPCO H-98-Magnesite, NAPCO F96- Molten Magnesia, Sapeo C 221 Steatite, Sapeo C 220 Steatite, Sapeo C 410 Steatite, Magensium Oxide, MgO (Periclase), Magnesium Peroxide, Mg02, 99.6 % Alumina, thin film substrate, Cordierite, Albite (Feldspar NaAISi3O8), Biotite K (Mg, Fe) 3- (AISi3O10) (OH) 2, Hita KAI2 (A! Si3O10) - (OH) 2, Kaolinite (AI2O3) -2Si02-4H2O), Labradorite (Feldspar; 60% CaAI2Si2O8 + 40% NaAISi3O8), Montmorillonite AI203-4SiO2-nH2O, Muscovite (KAI2 (AISi3O10) - (OH) 2), Orthoclase (Feldspar KAISi3O8), Mulite, 3AI2O3-2SiO2, Germanium Mullite, 3AI203-2GeO2, Espinel, MgAI204, Aluminum Oxide Ceramic Substrate AO 95, 95% Purity, Aluminum Oxide Ceramic Substrate AO 98, 98% Purity, Individual Sapphire Crystal (Aluminum Oxide - AI2O3), Single Crystal Substrate (MgAI2O4) from Espinel, Individual Aluminum Lithium Oxide Crystal Substrate (LIOIO2), 96% Alumina-Aluminum Oxide Ceramic, 97.5% Alumina-Aluminum Oxide Ceramic, 98% Alumina-Aluminum Oxide Ceramic, 99.5% Alumina-Aluminum Oxide Ceramic, Individual Aluminum Lung Oxide Ceramic Substrate (LaAIO3), Individual Aluminum Oxide Crystal Substrate Doped with Thorium (Th: LaAIO3), Single Crystal Aluminate Substrate of Strontium (SrLaAIO3), Individual Crystal Substrate of Itrium Aluminate (YalO3), Berilia, 99.5 %; BeO, Calcium Hydroxyapatite, Ca10 (PO) 6 (OH) 2, Tetracalcium Phosphate, Ca4POg, Tricalcium Phosphate (TCP), CA3 (PO4) 2, Cordierite, Germanium Milite, 3AI2O32GeO2l Dy203, Er203, Yb203, Substrate Individual Lithium Aluminum Oxide Crystal (LIOIO2), Individual Lithium Gallium Oxide Crystal Substrate (LiGa02), Single Neodymium Gallium Oxide Crystal Substrate (NdGaO3), Individual Zinc Oxide Crystal Substrate ( ZnO), Individual Crystal Substrate of Strontium Titanate (SrTiO3), Individual Aluminum Oxide Crystal Substrate of Latano (LaAIO3), Individual Crystal Substrate of Aluminum Oxide of Latano Doped with Thorium (Th: LaAIO3), Substrate Single Crystal Aluminio Strontium (SrLaAIO3), Single Crystal Galato Strontium Lanthanum Substrate (SrLaGaO3), Single Itrium Aluminate Crystal Substrate (YA1O3), AREMCO Aremcolox ™ 502-1550, AREMCO Aremcolox ™ 502 -1550, Low Density, AREMCO Cerama-cast 674 of Medium Density, AREMCO Corr-Paint ™ CP3000, AREMCO Corr-Paint ™ CP301 0, AREMCO Corr-Paint ™ CP4000, Ceralloy 41 8, Beryllium Oxide, BeO, Chromium Carbide, Cr3C2, Hafnium Carbide, HfC, Carbide Molybdenum, Mo2C, Niobium Carbide, Silicon Carbide, CVD, Silicon Carbide, Alpha Sintered, Silicon Carbide, Sublimated, Tantalum Carbide, Titanium Carbide, TiC, Vanadium Carbide, Tungsten Carbide, W2C, Carbide Tungsten, WC, Zirconium Carbide, Silicon Carbide Individual Crystal Substrate (6H), GE Advanced Ceramic Tantalum Carbide (TaC) Coating, Advanced Ceramic Niobium Carbide (GE) Coating (NbC), Carbide Coating Advanced Ceramic Zirconia GE (ZrC), AREMCO Cerama-cast ™ 673, Ceralloy 546, Boron Carbide, B4C, Ceralloy 146, Silicon Carbide, SiC, Destech Silicon Carbide, Solid or Sparkling, Gouda Vuurvast CURON 140 K Denso Refractory , which can be melted, Gouda Vuurvast CURON 160 H GM SIC Denso Refractory, meltable, Gouda Vuurvast VI BRON 160 H SiC Denso, Refractory, meltable, Gouda Vuurvast VIBRON 160 K Dense, Refractory, meltable, Gouda Vuurvast VI BRON 160 K 50 Dense, Refractory, which can be melted, Gouda Vuurvast VI BRON 162 K Sp Dense, Refractory, which can be melted, Magnesium Fluoride, MgF2, (Sellaite), Biscofite (MgCI26H20), Taquidrite (2MgCI2-CaCI2-12H2O), Synthetic Material Criolite Powder Advanced Reade (Na3AIF6 or 3NaF AIF3), Copper Bromide, CuBr, Copper Bromide, CuBr, Hexagonal, Copper Chloride, CuCI, Cubic (Nantochite), Copper Chloride, CuCI, Hexagonal, Copper Fluoride, CuF, Iodide Copper, Cul, Cubic (Marshita), Copper Iodide, Cul, Hexagonal, Silver Bromide, AgBr (Bromirite), Silver Iodide, Agí, (Yodargirite), Silver Iodide, Agí, (Miersita), Actinium Bromide, AcBr3, Actinium Chloride, AcCl3, Actinium Fluoride, AcF3, Actinium Iodide, Acl3, Aluminum Bromide, AIBr3, Chloride of Aluminum, AICI3, Aluminum Fluoride, AIF3, Aluminum Iodide, AII3, Americium Bromide (II I), AmBr3, Americium Chloride (III), Americium Fluoride (III), AmF3, Americium Iodide (11), Aml3, Americium Fluoride (IV), AmF4, Antimony Bromide (III), SbBr3, Antimony Chloride (III) ), SbCI3, Zirconia, ZrO2, Zirconium Oxide Pottery, Zirconium Zirconium Stabilized, Zirconium Oxide Pottery, Stabilized Y2O3, Zirconium Oxide Pottery, Stabilized Y2O3, Zirconium Oxide Pottery, Stabilized Y2O3, Ceramic of Cirquita Deltada Ceraflex 3Y, Stabilized Itria, Ceramics Oxygen Ionizer Ceramics Slim Oxygen Ceraflex 8Y, Stabilized Itria, Individual Crystal Substrate of Itrium Stabilized Zirconia (YSZ), AREMCO 516 Ultra-temp, AREMCO Cerama-cast ™ 583, AREMCO Cerama-cast ™ 646, AREMCO Pyro-Paint ™ 640-ZO, CeramTec Hardened Alumina Grade 950 (AI2O3-ZrO2), Circona CeramTec Grade 848 (Zr02), Lead Zirconate Piezoelectric Piezoelectric Industries of Channel 5400, Piezoelectric of Titanato of Indium Lead Zirconate Ustrias de Canal 5500, Piezoelectric Piezoelectric Lead Lead Zirconia Industries 5600 Channel, AREMCO Pyro-Putty® 653, AREMCO Pyro-Putty® 1000, AREMCO Pyro-Putty® 2400, AREMCO Pyro-Putty® 2500, Boruro de Bario, BaB6 , Calcium Boride, Cerium Boride, CeB6, Advanced Ceramic Diboride / Boron Titanium Boron Nitrate Compound GE AC6043, Diboride Nitride / Titanium Advanced Ceramic Titanium Boron Metallization Boats GE, Diboride Powder Titanium (TiB2) Advanced Ceramic GE HCT-30, Titanium Diboride Powder (T¡B2) Advanced Ceramic GE HCT-40, Titanium Diboride Powder (TiB2) Advanced Ceramic GE HCT-30D, Diboride Powder Titanium (TiB2) Advanced Ceramic GE HCT-F, Titanium Diboride Powder (TiB2) Advanced Ceramic GE HCT-S, Ceralloy 225, Titanium Diboride, TiB2 and other ceramics commercially available. The drive device 18 is for moving the surface 16 with respect to the source 22, or with respect to an area of the surface where the solution is initially applied. The motor device can over the source of the solution with respect to the surface, the surface with respect to the source, or both. The movement can be rotatable, reciprocating in a vertical or horizontal direction, opposite side or vertical edges of the surface moving alternately up and down with respect to each other (ie, in a direction generally perpendicular to the surface), torsion, undulation, or any combination of these movements. In FIG. 12, the driving device 1 8 has a driving motor 27 and a shaft 28 for moving the surface with respect to the source of the solution. The driving motor 27 is capable of producing uniform rotating speeds at low RPM. The engine 27 has controls (not shown) for adjusting or selecting the rotation speed (RPM) and the time period of the rotation to enter a programmed series of rotations or directions of rotation (ie, in the direction of the needles). clockwise, or counter-clockwise or alternate between these two directions) or similar. The gas supply device or system 20 has a gas source 40 which supplies a gas manifold 42 for distributing a gas flow from the source in a controlled mode on the surface 16 using a gas controller 44. The gas source 40 includes a liquid nitrogen vaporizer 46 that converts liquid nitrogen to gaseous nitrogen. A fluid path 48 conveys the vaporizer gas 46, through the controller 44, and into the manifold 42.

The manifold 42 can take many forms, depending on whether the surface 16 is placed on an internal or external surface. FIG 12 shows the surface 16 on an inner surface of the cylinder 26, and FIG. 13 shows the surface 1 6 placed on an external surface of the cylinder 26. The manifold 42 shown in FIG. 12 is a tube 50 having a plurality of perforations 52. The tube may be a rigid, semi-rigid, or flexible tube. FIG. 1 3 shows a mode of the manifold 42 for transporting gas to the external surface 16 'and includes a filled space pierced with a flexible, rigid or semi-rigid material and, in a preferred form of the invention, has an external hemi-cylindrical portion which is generally follow the curvature of the outer surface 16 '. The motor 27 is mounted to a support structure 56 having a vertical riser 58, which, in a preferred form of the apparatus, can be adjusted to an angle a, with respect to a horizontal surface such as a floor. In a preferred form of the apparatus, the angle a will be from 20 degrees to 160 degrees, more preferably from 45 degrees to 135 degrees, still more preferably from 75 degrees to 1 15 degrees, and more preferably from 80 to 100 degrees (or any scale or combination of scales in it). A second cylinder 30 is mounted to the shaft 28 by a flange and defines a sleeve that is sized to coaxially receive the first cylinder 26. The second cylinder can be manufactured from any of the materials described herein that are suitable for the first cylinder . In a preferred form, the second cylinder is made of a polymeric material such as a COC, a polyester, a polycarbonate, a polyolefin, a polystyrene, or a substituted or unsubstituted acrylic acid, methacrylic acid, or polymers containing ethacrylic acid. A more preferred form of the apparatus is a poly (methyl acrylate) or PMMA, sold under the trade name Plexiglas. The apparatus is capable of making particles described above in a starting mode (FIG 12) or in a continuous mode (FIG 13). For starting mode treatment, an amount of the three component solution is added to an interior of the first cylinder 26. The first cylinder 26 is leveled using stop 56, so that the liquid level of the solution is approximately the same level of the upper part and the bottom of the glass container (a glass rim in the mouth of the container prevents the solution from escaping). The motor 27 then rotates the second cylinder 26 and the glass container 26 for several seconds, until a uniform coating 19 is formed on the internal surface 16 of the container. In a controlled manner, nitrogen gas is then allowed to flow into the manifold 42 so that the perforations 52 in the manifold distribute the gas evenly over the surface of the thin layer 19 of solution coating the glass. This causes a laminar flow of nitrogen gas to flow over the liquid surface, reducing the boundary layer effects and causing efficient evaporation without heating. There may be some beneficial turbulent mixing of the nitrogen on the surface of the thin film that facilitates evaporation, but the net effect is laminar flow of the gas on the surface of the thin film and out of an open end of the container. Nitrogen gas, which contains solvent vapors, exists in a container mouth and is discharged into an appropriate hood or exhaust system or solvent recovery system. Within a short period, such as one minute, the thin layer of solution 1 9 becomes opaque and then dries like a cloudy film on the surface of the glass. The nitrogen is allowed to flow at a reduced level for several minutes in order to completely dry the resulting small spherical particles. Then the gas flow stops, and the nitrogen collector is removed. Afterwards, samples can easily be obtained from any part of the container. The container can then be tilted backward and the microspheres thrown to the bottom of the container where they are easily collected. For continuous operation, FIG. 13 shows the solution 22 in a holding tank and is continuously applied to the surface 16 'by the roller 24. A pressure washer 60 sprays the dry film with a cleaning fluid, such as water, and a removal device 62 which continuously removes particles by engaging the surface with a member having a smooth blade such as a squeegee, scraper or knife with a smooth blade. FIG. 14 shows a portion of another apparatus for continuously forming particles and includes the surface 16 ', movable in the direction indicated by the arrows. The surface is carried by a conveyor belt. The conveyor belt travels around the driving rollers 66. One or both of the driving rollers are connected to a driving source such as a motor described above having motor controls. The apparatus includes the roller 24, which applies the solution to the surface 16 '. The conveyor is activated to move the surface to cause a thin film of the solution to form. The film is then exposed to the gas, washed, and removed by the squeegee 62. The conveyor can be modified to have the solution applied and removed from the same side of the conveyor belt.

Examples All active agents were purchased from Spectrum, Chemicals & Laboratory Products, unless otherwise specified.

Example 1: Small Spherical Particles of Beclomethasone Dipropionate (BDP) USP of Micronized Beclomethasone Dipropionate (BDP) was weighed and dissolved in USP ethanol to form 10 mg / ml of a BDP-ethanol solution. 1.2 ml of the BDP-ethanol solution was mixed with 0.8 ml of deionized water to form 3: 2 vol / vol of BDP-ethanol / water solution. The solution was transferred to a Pyrex® 1000 ml round flask of a modified rotary evaporator (complete modified Rotavapor-R, Buchi), and turned in the flask for a few seconds to form a thin film on the inner surface of the flask. After the thin film stabilized, an influx of controlled pure nitrogen was allowed to enter the flask at a flow level LPM 65-75. When the liquid phase evaporated, the solubility of the drug in the remaining mixed solvent rapidly diminished, and thus a translucent layer was formed on the surface of the flask. After the drug was precipitated, the rotation of the flask and the influx of nitrogen continued for several minutes to ensure complete evaporation of the liquid phase and the dryness of the small spherical particles. The resulting small spherical particles were collected by resuspending them in a small amount of iced deionized water and by sonicating the suspension to facilitate separation of the small spherical particles from the inner surface of the flask. The final stages were instant freezing and lyophilization. The particle morphology for the following examples was obtained using Exploration Electron Microscopy (SEM, FEI Quanta 200, Hilsboro, OR). The sample was prepared for analysis by placing a small amount on double carbon adhesive tape secured to an aluminum sample base. The sample was then coated with crackling using a Cressington 108 Auto sizzling coater for 90 seconds and 20 mA. A second SEM instrument (Amray, 1000, Bedford, MA) was used to obtain additional images of the small spherical particles, due to their higher resolution capabilities. FIG. 1 present SEM micrographs of the micronized BDP starting material. FIG. 2 presents micrographs of the resulting small spherical BDP particles. The starting material of micronized BDP varies in shape and size and has a wide size distribution of 5-50 microns, although some of the particles are larger than 50 microns (F1G.1). In contrast, the small BDP spherical particles have a uniform spherical shape, have a narrow particle size distribution and have an average diameter of about 1-2 microns. The small spherical particles have smooth surfaces compared to the rough surface of the micronized starting material (FIG 2). X-ray powder diffraction measurements (XRPD) were carried out on the BDP starting material (BDP # 1) and on two batches of small BDP spherical particles (BDP # 2 and BDPJM0710) to ensure the degree of crystallinity of the starting material and to compare it with the crystallinity of the small spherical BDP particles. The XRPD standards were obtained using an X-ray powder diffractometer (Shimadzu XRD-6000) with a rotating anode. The powders were scanned on a 2T scale by continuous scanning at 3 ° / min (0.4 sec / 0.02o stage) from 2.5 to 40 degrees, using Cu K to radiation. The diffracted radiation was detected by a Nal scintillation detector and analyzed using XRD-6000 v. 4.1. The XRPD pattern for the BDP starting material (FIG 3, background) exhibits reflectance resolution, indicating that the sample is crystalline. The XRPD patterns of the two BDP microsphere batches (FIG 3, middle and top) also exhibit reflectance resolution, indicating crystalline samples. However, the XRPD patterns for the small spherical particle samples are different from the XRPD patterns of the micronized start material in terms of maximum positions in 2, suggesting that the samples are composed of different shapes or mixtures of shapes than the material Of start. The two batches of small spherical particles showed identical maxima, which suggests that these independent batches were prepared according to the method described above are small spherical particles, homogeneous in terms of their degree of crystallinity. In addition, it shows that the process is reproducible.

Example 2: Budesonide USP Small Spherical Particles of Micronized Beclomethasone Dipropionate (BDP) was weighed and dissolved in USP ethanol to form 10 mg / ml of budesonide-ethanol solution. 1.2 ml of the budesonide-ethanol solution was mixed with 0.8 ml of deionized water to form 3: 2 vol / vol of budesonide-ethanol / water solution. The solution was transferred to a Pyrex® 1000 ml round flask of a modified rotary evaporator (complete modified Rotavapor-R, Buchi) and the process was continued as described in Example 1 for small spherical particles comprising BDP. Particle morphology for the following examples was obtained using Exploration Electron Microscopy (SEM, FEl Quanta 200, Hilsboro, OR). FIG. 4 presents SEM of micronized budesonide starting material and FIG. 5 presents SEM of the resulting small spherical budesonide particles. Similar to Example 1, the starting material of micronized budesonide varies in shape and size and has a broad size distribution of 5-100 microns. Some of the particles are larger than 100 microns (FIG 4). In contrast, the small spherical budesonide particles have a uniform spherical shape, have a narrow size distribution and are 1 -2 microns in average size (FIG 5). XRPD measurements were performed on the budesonide starting material (RN0020) and on a batch of small spherical particles of budesonide to examine the degree of crystallinity of the starting material and to compare it with the crystallinity of small spherical particles of budesonide ( FIG 6). The XRPD pattern of budesonide starting material showed distinctive maxima, characteristic of crystalline state. In contrast, the XRPD of the small spherical budesonide particles was continuous and typical of the non-crystalline or amorphous state.

The aerodynamic particle size distribution was measured by a time-of-trajectory method, using a TSI Corporation Aerocalibrator (TSI, St. Paul, MN). The F1G 7 shows an aerodynamic particle size distribution with 90% 5 of particles less than 2.4 microns.

Example 3: Small spherical particles of Itraconazole USP of micronized itraconazole (Wycoff, I nc), weight and a USP volume of acetone were added to form 10 mg / ml of an acetone-itraconazole suspension. The suspension was formed in a glass flask with a return cover to prevent the rapid evaporation of acetone. The sealed vial was vortexed and then placed in a water bath preheated to 70 ° C. The bottle was left in the bath for 5-10 minutes, which allowed the dissolution of itraconazole and the formation of an itraconazole-acetone solution. The bottle was removed from the bath at 70 ° C and allowed to cool to room temperature. After cooling, 2.48 ml of the itraconazole-acetone solution was mixed with 1.52 ml of a 10% ethanol in deionized water solution to form a 38% ethanol-water / 62% acetone-itraconazole solution vol. vol. The total volume of the ethanol-water / acetone-itraconazole solution was 4 ml. The solution was transferred to a Pyrex® 1000 ml round flask of a modified rotary evaporator (complete modified Rotavapor-R, Buchi), and the process was continued as described in Example 1 for small spherical BDP particles.

FIG. 8 presents SEMs of micronized itraconazole starting material and FIG. 9 presents SEMs of the resulting small spherical particles of itraconazole. The starting material of micronized itraconazole varies in shape and size and has a broad particle size distribution of 0.1-20 microns. Some of the particles are larger than 20 microns (FIG 8). In contrast, the small spherical particles of itraconazole have a uniform spherical shape, a narrow particle size distribution and an average diameter of 0.5-2 microns (FIG 9). The particle size distribution was measured by light scattering using a Coulter instrument (Beckman Coulter LS 230, Miami, FL). The normalized number, normalized surface area, and normalized volume size distribution of small spherical particles of itraconazole are presented in FIG. 10. The three normalized distributions overlap, which demonstrates the monodispersity of the particles. It also shows that the microparticles are distributed homogeneously in aqueous solution in the presence of surfactant, and that they do not tend to agglomerate.

Example 4: Small Spherical Particles of Estradiol USP from micronized estradiol (Akzo Nobel) was weighed and inserted into a glass tube with back cover. The USP of ethanol was added to the tube to form 5 mg / ml of an estradiol in ethanol solution.

Small spherical particles of estradiol were formed by two methods. In the first method, a drop of estradiol-ethanol solution was placed on a glass slide, and ambient air was blown onto the slide to dryness. When the ethanol was evaporated from the drop, the estradiol precipitated out of the solution and a translucent film formed on the slide. The slide was left on the laboratory bench for an additional 20 minutes to allow complete evaporation of the ethanol. In the second method, a drop of the solution was placed on a glass slide that rested on a layer of ice. The slide was covered with aluminum foil to prevent soaking. Ambient air was blown on the slide to dryness. When the ethanol was evaporated from the drop, the strariol precipitated out of the solution and a translucent film formed on the slide. The slide was left on the ice layer for an additional 20 minutes to allow complete evaporation of the ethanol. The slides were examined under a light microscope to verify the existence of small spherical particles and to estimate the size distribution of the resulting small spherical particles of estradiol. Small spherical particles were formed on both slides, one was left at ambient air temperature and the other was placed on the ice bath.

Example 5: Small Fludrocortisone USP Spherical Particles of micronized fludrocortisone was weighed and inserted into a glass tube with back cover. The USP of ethanol was added to the tube to form a 5 mg / ml fludrocortisone in ethanol solution. Small spherical particles of fludrocortisone were formed by two methods. In the first method, a drop of fludrocortisone-ethanol solution was placed on a glass slide, and ambient air was blown onto the slide to dryness. When the ethanol was evaporated from the drop, the fludrocortisone precipitated out of the solution and a translucent film formed on the slide. The slide was left on the laboratory bench for an additional 20 minutes to allow complete evaporation of the ethanol. In the second method, one drop of the fludrocrotisone-ethanol solution was placed on a glass slide that rested on a layer of ice. The slide was covered with aluminum foil to prevent soaking. Ambient air was blown on the slide to dryness. A translucent film of fludrocortisone was formed on the slide. The slide was left on the ice layer for an additional 20 minutes to allow complete evaporation of the ethanol. The slides were examined under a light microscope to verify the existence of small spherical particles and to estimate the size distribution of the resulting small spherical particles of fludrocortisone. Small spherical particles were formed on both slides, one was left at ambient air temperature and the other was placed on the ice bath.

Example 6: Flucinonide USP Small Spherical Particles of micronized flucinonide was weighed and inserted into a back cover glass tube. A relative volume of USP of ethanol was added to the tube to form a 5 mg / ml flucinonide in ethanol suspension. The tube with the suspension was placed in a thermal bath, preheated to 45 ° C. Some of the flucinonide did not dissolve at that elevated temperature, however, additional heating was avoided. One drop of the flucinonide-ethanol suspension was placed on a glass slide. Ambient air was blown onto the slide until complete dryness. A translucent film of flucinonide It was formed on the slide. The slide was left on the laboratory bench for an additional 20 minutes to allow complete evaporation of the ethanol. The slide was examined under a light microscope to verify the existence of small spherical particles and to estimate the size distribution of the resulting small spherical particles of flucinonide. The resulting small spherical particles of flucinonide had a uniform particle size distribution and an average diameter of 1 -1 .15 microns.

Example 7: Effect of Several First and Second Solvents on Small Spherical Steroid Particle Formation The ability to form small spherical particles of two steroids, beclomethasone dipropionate (BDP) and fluticasone propionate (FP) was examined in matrix experiments using acetone , ethanol, methanol, and methyl ethyl acetone (MEK) individually as the first solvents and water and heptane individually as the second solvents. The amount of the second solvent added to the first solvent / steroid solution was varied as 0%, 10%, 20%, 30%, and 40% (v / v). MEK is not miscible with water and methanol is not miscible with heptane, so these combinations were not included in the experiment. Either BDP or FP was weighed in a glass tube with back cover and the solvent of choice was added (w / v) to give a final concentration of 2 mg / mL. The tubes were vortexed and sonicated to completely dissolve the spheroid. The sealed tubes containing these solutions were used as reserve solutions for subsequent mixtures with the appropriate second solvent. Immediately before use, an appropriate amount of the second solvent was slowly added to the first solvent / steroid solution while mixing to avoid premature precipitation. After adding the second solvent, the solutions were examined visually to ensure that premature precipitation had not occurred. An apparatus was constructed so that an orifice nozzle 0.3175 cm in diameter was placed 4,445 cm above a standard glass microscope slide. Nitrogen gas was allowed to flow at 5 liters per minute through the nozzle and onto the slide so that the flow direction of the gas was perpendicular to the surface of the slide. One or two gobs of the test solution were placed on the slide directly below the hole, and the flow of nitrogen continued until the slide dried (one to three minutes depending on the composition of the solution). Each slide was then examined under a polarized light microscope (Leica EPISTAR, Buffalo, NY) using incident illumination. Each slide was graded for the presence of predominantly small spherical particles (+), a mixture of small spherical particles and non-spherical particles (+/-). And predominantly non-spherical particles (-). Variations in size and size distribution were observed between different test solutions. The results are arranged in the table below.

Table 1: Formation of small spherical particles of Benclometasone dipropionate Table 2: Formation of small spherical particles of Fluticasone Propionate of small spherical particles and non-spherical particles; (-) = predominantly non-spherical particles, N / A = test not carried out due to non-miscible solvents; and ppp = the steroid precipitated during the addition of second solvent.

Although no water was added at the 0% concentrations, some water could have been absorbed from the air during the experiment. However, the amount of water absorbed by the solvent is assumed to be well below 10%. The results indicate that the ability to form small spherical particles varies according to: 1) the small organic molecule used, 2) the first solvent composition, 3) the second solvent composition, and 4) the amount of the second solvent in the final formulation. Also noteworthy is the fact that several first solvents and second solvents other than water can be used to create small spherical particles by this method. In this case the alkane heptane was replaced by water as the second solvent and was successfully used to make small spherical particles of BDP and FP. Example 8: Evaporative Cooling During the Training of BDP Small Spherical Particles Small spherical BDP particles were made on glass slides by the same method as Example 7 using acetone as the first solvent and water as the second solvent, except that the nitrogen gas flow level was 2.5 liters per minute. When the solvent was evaporated, the temperature of the droplets on the slide was measured using a non-contact infrared sensor (Cole-Parmer, Vernon Hills, IL, Model # A39671-22). The time interval between placing the drop on the slide under the flow of nitrogen gas and the lowest temperature recorded was noted. Samples containing 10% water and 40% water (v / v) were compared. The temperature measured on the surface of the dry slide with nitrogen flow was a constant 21.8 ° C measured for several minutes before the start of each experimental run. Consequently, the nitrogen gas itself was not changing temperature during the test period. When the water / acetone / 10% BDP solution was evaporated, the temperature dropped from 21.8DC to 9.6 ° C in 7 seconds. A repeat run resulted in a drop in temperature to 9.8 ° C in 7 seconds, so that the test method was reproducible. In contrast, when the 40% water / acetone / BDP solution was evaporated, the temperature dropped from 21.8 ° C to 11.6 ° C in 12 seconds. The reduction in the amount of the temperature drop and the increased time to reach the coldest temperature can be explained by the decreased amount of acetone in the 40% water sample. Small spherical particles of BDP were observed using the light microscope (described in Example 7) on all glass slides, where the 40% water gave a uniform size distribution of particles estimated at 1 to 2 micrometers in diameter. In contrast, 10% water slides gave a larger size distribution of microspheres estimated at 0.5 to 10 micrometers in diameter. These results indicate that evaporative cooling occurs using this method to manufacture BDP microspheres and different cooling levels and absolute temperature changes are associated with different size distributions of small spherical particles. Although specific modalities have been illustrated and described, additional modifications can be envisaged without departing from the spirit of the invention and the scope of protection is limited only by the scope of the accompanying claims.

Claims (80)

1. CLAIMS 1. Small spherical particles, comprising an organic molecule with a molecular weight of less than 1500 Daltons, with a narrow particle size distribution, characterized in that the organic molecule is at least 70% and less than or equal to 100% by weight of the particle.
2. 2. The particles according to claim 1, characterized in that the organic molecule is 90% or greater by weight of the particle.
3. 3. The particles according to claim 1, characterized in that the organic molecule is 95% or greater by weight of the particle.
4. 4. The particles according to claim 1 having an average particle size of from about 0.01 μm to about 200 μm.
5. 5. The particles according to claim 1 having an average particle size of from about 0.1 μm to about 10 μm.
6. 6. The particles according to claim 1 having an average particle size of from about 0.1 μm to about 5 μm.
7. 7. The particles according to claim 1, characterized in that the organic molecule is hydrophobic.
8. 8. The particles according to claim 1, characterized in that the organic molecule is hydrophilic.
9. 9. The particles according to claim 1, characterized in that the organic molecule is poorly soluble in water. 1.
10. The particles according to claim 1 characterized in that the organic molecule has a solubility in water of less than 10 mg / mL. eleven .
11. The particles according to claim 1 characterized in that the organic molecule has a solubility in water of less than 1 mg / mL.
12. 12. The particles according to claim 1, characterized in that the active agent is selected from the group consisting of pharmaceutically therapeutic agents, diagnostic agents, cosmetics, food supplements, and pesticides.
13. The particles according to claim 12 characterized in that the pharmaceutically therapeutic agent is selected from the group consisting of: steroids, beta-combatants, antifungal and antomicrobial agents, bacteriostatic agents, taxanes, amino acids, aliphatic compounds, aromatic compounds, and compound of urea.
14. 14. The particles according to claim 13 characterized in that the spheroid is selected from the group consisting of: beclomethasone, budesonide, fluticasone, flunisolide, flucinolone, betamethasone, mometasone, ciclesonide, prednisolone, prednisone, hydrocortisone, dexamethasone, triamcinolone, mometasone, and salts pharmaceutically accepted, esters, hydrates and solvates of these compounds.
15. 15. The particles according to claim 13 characterized in that the beta-combatant is a short-acting beta-adrenergic fighter or a long-acting beta-adrenergic fighter.
16. 16. The particles according to claim 15 characterized in that the short acting beta adrenergic is selected from the group consisting of: salbutamol, pirbutenol, metaproterenol, terbutaline and fenoterol.
17. 17. The particles according to claim 15 characterized in that the long acting beta adrenergic is selected from the group consisting of: salmeterol, formoterol, bambuterol, clenbuterol, procaterol, bitoleterol, broxaterol and tulobuterol, and pharmaceutically accepted salts, esters, hydrates and solvates of these compounds.
18. 18. The particles according to claim 1, characterized in that the small spherical particles contain a combination of two or more active agents.
19. 19. The particles according to claim 1 further comprising a bulking agent.
20. 20. The particles according to claim 13, characterized in that the antifungal agent is selected from the group consisting of: itraconazole, fluconazole, posoconazole. twenty-one .
21. The particles according to claim 1 having a density greater than 0.5 / cm3.
22. 22. The particles according to claim 1 having a density greater than 0.75 / cm3.
23. 23. The particles according to claim 1 having a density greater than 0.85 / cm3.
24. 24. The particles according to claim 1 having a density of about 0.5 to about 2 g / cm3.
25. 25. The particles according to claim 1 having a density of about 0.75 to about 1.75 g / cm3.
26. 26. The particles according to claim 1 having a density of about 0.85 g / cm3 to about 1.5 g / cm3.
27. 27. The particles according to claim 1, characterized in that the organic molecule further comprises a polymorphic substance or pseudo-polymorphic substance of the organic molecule.
28. 28. The particles according to claim 1 characterized in that the particles are crystalline, semi-crystalline or non-crystalline.
29. 29. The particles according to claim 1, wherein the particles are modified to result in controlled release of the organic molecule.
30. 30. The particles according to claim 1, characterized in that the particles are suitable for routes of administration selected from the group consisting of parenteral, topical, oral, rectal, nasal, pulmonary, vaginal, buccal, sublingual, transdermal, transmucosal, ocular, transocular. , and otic.
31. 31 The particles according to claim 1, characterized in that the particles are suitable for pulmonary delivery.
32. 32. The particles according to claim 31, characterized in that the pulmonary delivery includes delivery to upper airways of the lung, the average airways of the lung and / or to the periphery of the lung.
33. 33. The particles according to claim 1 characterized in that the particles are suitable for oral delivery to the gastrointestinal tract.
34. 34. The particles according to claim 1, characterized in that the particles are suitable for delivery by a device selected from the group consisting of a dry powder inhaler, a metered dose inhaler, and an atomizer.
35. 35. The particles according to claim 1, characterized in that the small spherical particles are suitable for local treatment or systemic treatment.
36. 36. The particles according to claim 1, characterized in that the particles are suitable for transdermal delivery.
37. 37. The particles according to claim 1, characterized in that the particles are suitable for intravenous delivery, intramuscular delivery, or subcutaneous delivery.
38. 38. A method for preparing small spherical particles of a low molecular weight organic molecule active agent, the method comprising the steps of: preparing a solution of the active agent in a first solvent, the active agent having solubility in the first solvent; adding a second solvent to the solution to form a solution of three components of the two solvents and the active agent, characterized in that the solubility of the active agent in the second solvent is lower than in the first solvent; spreading the solution on a surface to form a thin film of the solution on the surface; and evaporating the solvents from the solution to form small spherical particles of the active agent on the surface as a stream of gas passes over the film to form small spherical particles that are coated on the surface, where the gas does not react with the active agent.
39. 39. The method according to claim 38 further comprising the step of removing small spherical particles from the surface.
40. 40. The method according to claim 39, characterized in that the step of removing comprises the step of adding a third solvent to the surface.
41. 41 The method according to claim 39 characterized in that the third solvent is a single solvent or a mixture of solvents.
42. 42. The method according to claim 41 characterized in that the third solvent is the same as the first solvent or the second solvent.
43. 43. The method according to claim 41 characterized in that the third solvent is the same as the second solvent.
44. 44. The method according to claim 3 further comprising the step of removing the second solvent to form dry powder from the small spherical particles.
45. 45. The method according to claim 38, characterized in that the step of preparing the solution of the active agent in the first solvent is by adding the agent to the first solvent and sonicating the mixture to dissolve the agent in the first solvent.
46. 46. The method according to claim 38 characterized in that the surface is a material selected from a polymer, metal, ceramic, or glass.
47. 47. The method according to claim 38 characterized in that the surface is a glass surface.
48. 48. The method according to claim 38 characterized in that the surface is a polymer selected from the group consisting of: polyolefins, cyclic olefins, bridged polycyclic hydrocarbons, polyamides, polyesters, polyethers, polyimides, polycarbonates, polystyrene, polyvinyl chloride, ABS, polytetrafluoroethylene (PTFE), styrene and hydrocarbon copolymers, and synthetic gums.
49. 49. The method according to claim 38 characterized in that the surface is a metal selected from the group consisting of: aluminum, stainless steel, vanadium, platinum, titanium, gold, beryllium, copper, molybdenum, osmium, nickel, or other suitable alloys or metals or metal compounds.
50. 50. The method according to claim 38, characterized in that the surface is a ceramic.
51. 51 The method according to claim 50 characterized in that the ceramic is a metal oxide.
52. 52. The method according to claim 38, characterized in that the material can be rigid, semi-rigid or flexible.
53. 53. The method according to claim 38 characterized in that the step of spreading the mixture on a surface further comprises the step of moving the surface.
54. 54. The method according to claim 53 characterized in that the surface is moved in a manner selected from the group consisting of rotating, reciprocating in a vertical or horizontal direction, opposite side or vertical edges of the surface that alternately move upwards and downwards with respect to each other torsion, undulation, or any combination of these movements.
55. 55. The method according to claim 38 characterized in that the surface has a smooth surface or a textured surface.
56. 56. The method according to claim 38 characterized in that the surface has a cross sectional shape selected from the group consisting of: flat, curved, wavy or irregular.
57. 57. The method according to claim 38, characterized in that the step of spreading the solution on a surface to form a thin film comprises the step of transferring the solution to a rotating evaporation flask and slowly turning the flask to form a coating of the solution on the inner surface of the flask.
58. 58. The method according to claim 38 characterized in that the gas is selected from the group consisting of; nitrogen, hydrogen, helium, and argon.
59. 59. The method according to claim 38, characterized in that the gas is nitrogen.
60. 60. The method according to claim 38 further comprising the step of continuing the inflow of gas at a reduced flow level after the formation of small spherical particles was initiated in order to dry the small spherical particles.
61. 61 The method according to claim 38 characterized in that the second solvent is cooled to a temperature that reduces the solubility of the active agent.
62. 62. The method according to claim 39 characterized in that removing the small spherical particles from the surface further comprises the step of sonicating the solution.
63. 63. The method according to claim 62, characterized in that the sonication step is carried out on ice.
64. 64. The method according to claim 44, characterized in that the step of removing the second solvent comprises the step of lyophilizing.
65. 65. The method according to claim 38 characterized in that the first solvent is an organic solvent and is selected from the group consisting of: N-methyl-2-pyrrolidinone (N-methyl-2-pyrrolidone), 2-pyrrolidinone (2-pyrrolidone) ), 1,3-dimethyl-2-imidazolidinone (DMl), dimethylsulfoxide, dimethylacetamide, volatile ketones such as acetone, ethyl acetone methyl, acetic acid, lactic acid, acetonitrile, methanol, ethanol, isopropanol, 3-pentanol, n- propanol, benzyl alcohol, glycerol, tetrahydrofuran (THF), polyethylene glycol (PEG), PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG, 16, PEG-120, PEG-75 , PEG-150, polyethylene glycol esters, PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmito-stearate, PEG-150 palmito-stearate, polyethylene glycol sorbitans, sorbitan isostearate of PEG-20, monoalkyl ethers of polyethylene glycol, dimethyl ether of PEG-3, dimethyl ether of PEG-4, polypropylene glycol (PPG), algin polypropylene butoxide, PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether, glycol propylene dicaprylate / dicaprate, propylene glycol laurate , and glycofurol (polyethylene glycol ether of tetrahydrofurfuryl alcohol), propane, butane, pentane, hexane, heptane, octane, nonane, decane, or combinations thereof.
66. 66. The method according to claim 38, characterized in that the first solvent or the second solvent both the first solvent and the second solvent are volatile.
67. 67. The method according to claim 38 characterized in that the first solvent is ethanol and the second solvent is water.
68. 68. The method according to claim 38, characterized in that the second solvent is an alkane selected from the group consisting of hexane, heptane, octane, nonane and decane.
69. 69. The method according to claim 38 characterized in that the steps are carried out at about 25 ° C or below.
70. 70. An apparatus for forming small spherical particles of a solution containing a low molecular weight agent comprising: a surface mounted for movement; a fluid supply device for applying the solution to an area of the surface; a drive device connected to the surface to move the area with respect to the fluid supply device; and a space filled with gas placed close to the surface to provide gas under pressure to the surface.
71. 71 The apparatus according to claim 70, characterized in that the surface has a cross-sectional shape selected from the group consisting of: flat, curved, corrugated or irregular.
72. 72. The apparatus according to claim 70, characterized in that the cross-sectional shape of the surface is curved.
73. 73. The apparatus according to claim 72, characterized in that the driving device is a motor that has a shaft for rotating the curved surface.
74. 74. The apparatus according to claim 73, characterized in that the curved surface is placed on an external surface or an internal surface of a cylinder.
75. 75. The apparatus according to claim 74 characterized in that the cylinder is made of a material selected from the group consisting of a polymer, metal, ceramic or glass.
76. 76. The apparatus according to claim 75, characterized in that the gas filled space has a length and has a plurality of perforations along the length.
77. 77. The apparatus according to claim 75 further comprising an applicator for applying the solution to the surface.
78. 78. The apparatus according to claim 77, characterized in that the applicator sprays the solution on the surface or applies it by direct contact with the surface.
79. 79. The apparatus according to claim 77, characterized in that the applicator is a roller having a first portion that comes into contact with the solution and a second portion that comes into contact with the surface.
80. 80. The apparatus according to claim 77 further comprising a squeegee to remove the film from the surface.