WO2006076124A2

WO2006076124A2 - Stable, non-crystalline formulation comprising olanzapine

Info

Publication number: WO2006076124A2
Application number: PCT/US2005/045696
Authority: WO
Inventors: Sarma Duddu; Jiang Zhang; David Lechuga; Danforth Miller
Original assignee: Nektar Therapeutics
Priority date: 2004-12-16
Filing date: 2005-12-15
Publication date: 2006-07-20
Also published as: WO2006076124A3

Abstract

One or more embodiments of the invention provide various novel formulations comprising olanzapine that are non-crystalline, which exhibit desired or improved stability, and/or possesses desired micromeritic properties and/or are otherwise improvements over known olanzapine formulations. The olanzapine-containing formulations may be administered to a user to treat psychotic conditions, especially schizophrenia and schizophenic conditions, and/or mania.

Description

United States Patent Application for:

Stable Non-crystalline Formulation Comprising Olanzapine

RELATED APPLICATION

[0001] This application relates to U.S. Provisional Application No. 60/636,667, filed December 16, 2004, from which priority is claimed under 35 USC §119(e), and which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] One or more embodiments of the present invention relates to a formulation comprising olanzapine, to co-formulations of olanzapine with excipients, to methods for preparing the formulations, pharmaceutical compositions comprising the formulations and to their use in medical treatment. One or more embodiments of the present invention relates more particularly to co-formulations of olanzapine with one or more oligomeric and/or polymeric excipients, and to methods of making and methods of delivering, which result in desired, especially improved or enhanced, solubility or dissolution characteristics, resulting in desired, especially improved or enhanced, bioavailability and/or pharmacokinetics. Also provided are pharmaceutical compositions comprising the formulation, methods of administering the pharmaceutical compositions and methods of treating patients with the pharmaceutical compositions.

[0003] Olanzapine, 2-methyl-4-(4-methyl- 1 -piperazinyl)- 10H-thieno [2,3-6] [l,5]benzodiazepine, is a well known pharmaceutical agent. U.S. Patent 5,229,382 to Chakrabarti et al. which is incorporated herein by reference in its entirety, discloses that the compound has dopamine at D-I and D-2 receptor antagonizing properties, has antimuscarinic anti-cholinergic properties, and antagonist activity at noradrenergic α- receptors. One or more of these properties appear to play a role in making olanzapine effective in treating psychotic conditions, such as schizophrenia, schizophreniform diseases, and acute mania.

[0004] Olanzapine is commercially available in the United States from Eli Lilly and Company in Indianapolis, Indiana, under the trade name ZYPREXA®. According to the Eli Lilly product description, ZYPREXA® is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-l- piperazinyl)-10H-thieno[2,3-6] [l,5]benzodiazepine. The molecular formula is CnH₂₀N₄S, and the chemical structure is:

[0005] Commercially available olanzapine is a yellow crystalline powder, soluble in organic solvents, with limited solubility in water.

[0006] ZYPREXA® is available as orally administrable tablets in the following dosage amounts: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg of olanzapine. The ZYPREXA® tablets are said to contain the following inactive ingredients: carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red Iron Oxide (20 mg). The 2.5, 5.0, 7.5, and 10 mg tablets are imprinted with edible ink which contains FD&C Blue No. 2 Aluminum Lake. Olanzapine is also available in the form of an orally-disintegrating tablet under the trade name ZYPREXA® ZYDIS® which also contains the following inactive ingredients: gelatin, mannitol, aspartame, sodium methyl paraben and sodium propyl paraben. ZYPREXA® IntraMuscular is another form of olanzapine and is intended for intramuscular use. Each vial of ZYPREXA® IntraMuscular provides for the administration of 10 mg of olanzapine with inactive ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or sodium hydroxide are added during manufacturing to adjust _PH. Description of Related Art

[0007] In both the ZYPREXA® and ZYPREXA® ZYDIS® tablets, the olanzapine is in a crystalline form. The olanzapine described in U.S. Patent 5,229,382 {supra) is in the crystalline polymorphic Form I. U.S. Patent 5,736,541 to Bunnell et al., which is incorporated herein by reference in its entirety, describes the crystalline polymorphic Form II of olanzapine. U.S. Patent 5,736,541 describes Form I as being metastable and not well suited for commercial use in pharmaceutical formulations.

[0008] The existing crystalline forms of olanzapine have disadvantages. While the crystalline polymorphic Form II of olanzapine is relatively physically stable in that it does not easily convert to another form during storage or processing, the crystalline forms may be less bioactive than non-crystalline forms, such as amorphous forms. Noncrystalline forms of active agents generally have increased dissolution rates over crystalline forms. Accordingly, the non-crystalline forms may have increased bioavailability when administered to a user because of their ability to dissolve faster in the GI tract, as recognized in the art. This increased bioavailability can allow for the active agent to be taken up faster for systemic delivery. Also, the increased bioactivity can allow for a reduction in the amount of the active agent that needs to be administered to the user.

[0009] Prior art attempts to formulate non-crystalline (amorphous) olanzapine have met with only limited success. When pure amorphous olanzapine is formulated as described in U.S. Patent 5,985,864, to Imai et al, the formulation has limited physical stability, as discussed throughout the patent. Pure amorphous forms are thermodynamically less favored, thus under normal storage conditions, they tend to alter their form and convert to one or more crystalline forms. Because the degree of crystalline conversion at a particular time during storage is often unknown, it is difficult to assure that dosages are administered in a consistent solid form. As a result, the olanzapine must either be administered immediately after formulation or a sufficient amount of storage time must pass so that full conversion to a crystalline form takes place, in which case the advantages of having the olanzapine in amorphous form are lost. In addition, non- crystalline forms of active agents such as olanzapine are difficult to process for pharmaceutical compositions. PCT Application WO 03/007912 to Dekemper et al, which is incorporated herein by reference in its entirety, describes an amorphous form of olanzapine produced by dissolving olanzapine in a solvent and removing the solvent by freeze drying (lyophilization). This amorphous form is intended for reconstitution and subsequent parenteral delivery. PCT Application WO 03/007912 does not disclose that the olanzapine form is sufficiently stable for the amorphous form to be developed into an administrable tablet.

[0010] Therefore, it is desirable to be able to produce a non-crystalline, especially amorphous, form of olanzapine. It is further desirable to be able to produce a noncrystalline form of olanzapine that has a dissolution rate and/or profile indicative of desired bioavailability, especially bioavailability comparable to or better than commercially-available products. It is further desirable to be able to produce a noncrystalline form of olanzapine that has a dissolution rate and/or profile indicative of an improved bioavailability. It is further desirable to be able to produce a non-crystalline form of olanzapine that is physically stable, for example, by maintaining its noncrystalline state for an increased amount of time when compared to pure amorphous olanzapine. It is further desirable to be able to produce a non-crystalline form of olanzapine that is chemically stable. It is further desirable to be able to produce a noncrystalline form of olanzapine that possesses desired micromeritic properties, such as powder flowability and/or compressability, and/or post-handling ease. It is still further desirable to be able to produce a non-crystalline form of olanzapine that possesses two or more of the foregoing attributes.

Summary of the Invention

[0011] One or more embodiments of the present invention satisfies these one or more of these needs. The embodiments of the invention provide various novel formulations comprising olanzapine that are non-crystalline, stable, and/or possess desired micromeritic properties and/or otherwise improvements over known olanzapine formulations. [0012] In one aspect of the invention, a solid formulation comprises olanzapine wherein the formulation posseses desired, or improved, pharmaceutical and/or micromeritic properties, such as powder flow and compressibility.

[0013] In one aspect of the invention, a solid, non-crystalline formulation comprises olanzapine wherein the formulation is physically and chemically stable, and possesses desired or improved pharmaceutical and/or micromeritic properties, such as powder flow and compressibility.

[0014] In one aspect of the invention, a solid formulation comprises olanzapine wherein the formulation exhibits at least one of the characteristics of desired, especially commercially-desired, dissolution, solubility, stability, shelf life, or bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

[0015] In one aspect of the invention, a solid, non-crystalline formulation comprises olanzapine and an excipient, wherein the formulation exhibits at least one of the characteristics of desired (e.g. commercially comparable) or enhanced dissolution, solubility, stability, shelf life, bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

[0016] In another aspect of the invention, a solid, non-crystalline formulation comprises olanzapine wherein the formulation maintains its non-crystalline form when stored at about 25°C and about 60% relative humidity for a period of at least about one week, preferably at least about one month, more preferably at least about three months, and most preferably at least about six months, or about one year.

[0017] In another aspect of the invention, a solid, non-crystalline formulation comprises olanzapine wherein the formulation maintains its non-crystalline form when stored at about 40⁰C and about 75% relative humidity for a period of at least about one week, preferably at least about one month, more preferably at least about three months, and most preferably at least about six months.

[0018] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient.

[0019] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and a stabilizing excipient, wherein the formulation is more physically stable than a formulation without the stabilizing excipient.

[0020] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and a solubilizing excipient, wherein the formulation is more soluble than a formulation without the excipient.

[0021] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and a process-enhancing excipient, wherein the formulation exhibits improved processability compared to a formulation without the excipient.

[0022] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and a stabilizing excipient, wherein the formulation when stored at about 40⁰C and about 75% relative humidity converts to a crystalline form more slowly than a formulation without the stabilizing excipient.

[0023] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and a stabilizing excipient, wherein the formulation has a higher glass transition temperature (T_g) than a formulation without the stabilizing excipient.

[0024] In another aspect of the invention, a solid formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the particles exhibit desired micromeritic properties, such as powder flow and compressibility.

[0025] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine, a stabilizing excipient and at least one of a processing-enhancing excipient and a solubility-enhancing excipient, or both. [0026] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the excipient comprises a polymer or co-polymer of a cellulose, such as a hydroxypropyl alkylcellulose.

[0027] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the excipient comprises a polymer or co-polymer of a cellulose, such as an ethyl cellulose, a cellulose acetate, or derivatives thereof.

[0028] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the excipient comprises a polymer or co-polymer of a vinylpyrrolidone, such as polyvinylpyrrolidone.

[0029] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the excipient comprises a polymer or co-polymer of a vinylpyrrolidone and a vinyl acetate, such as a vinylpyrrolidone-vinyl acetate.

[0030] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise olanzapine and an excipient, and wherein the excipient comprises a polymer or co-polymer containing an amine or amide group.

[0031] In another aspect of the invention, a method of treating, slowing, mitigating or preventing conditions treatable by neuroleptic compounds, having at least one of relaxant, anxiolytic or anti-emetic properties, comprises administering to a user a noncrystalline formulation comprising olanzapine.

[0032] In another aspect of the invention, a method of treating, slowing, mitigating or preventing psychotic conditions, especially schizophrenia and schizophrenic conditions, and/or mania, comprises administering to a user a non-crystalline formulation comprising olanzapine. [0033] In another aspect of the invention, a method of treating, slowing, mitigating or preventing psychotic conditions, especially schizophrenia and schizophrenic conditions, and/or mania, comprises administering to a user a particulate formulation wherein the particles comprise olanzapine and an excipient.

[0034] In another aspect of the invention, a method of treating, slowing, mitigating or preventing psychotic conditions, especially schizophrenia and schizophrenic conditions, and/or mania, comprises administering to a user a non-crystalline, particulate formulation wherein the particles comprise olanzapine and a stabilizing excipient.

[0035] In another aspect of the invention, a method of treating, slowing, mitigating or preventing psychotic conditions, especially schizophrenia and schizophrenic conditions, and/or mania, comprises administering to a user a non-crystalline formulation comprising olanzapine following storage of the non-crystalline formulation.

[0036] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing a liquid containing olanzapine and spray drying the liquid to produce particles comprising olanzapine.

[0037] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing a liquid containing olanzapine and contacting the liquid with a supercritical or near supercritical fluid to remove the liquid to produce particles comprising olanzapine.

[0038] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing a liquid containing olanzapine and removing the liquid to produce particles comprising non-crystalline olanzapine.

[0039] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing a liquid containing olanzapine and an excipient and contacting the liquid with a supercritical or near critical fluid to remove the liquid to produce particles comprising non-crystalline olanzapine.

[0040] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing an aqueous liquid containing olanzapine and an excipient and removing the aqueous liquid to produce particles comprising olanzapine and the excipient.

[0041] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing an aqueous liquid containing olanzapine and an excipient and removing the aqueous liquid to produce particles comprising olanzapine and the excipient wherein the particles exhibit at least one of the characteristics of desired or enhanced dissolution, solubility, stability, shelf life, bioavailability, or manufacturing ease, manufacturing cost-effectiveness, or micromeritic properties.

[0042] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises providing an organic solvent containing olanzapine and an excipient and removing the organic solvent to produce particles comprising olanzapine and the excipient.

[0043] In another aspect of the invention, a method of making a formulation comprising olanzapine comprises spray drying a liquid containing olanzapine and an excipient to produce particles comprising non-crystalline olanzapine and the excipient.

[0044] In another aspect of the invention a method of making a formulation comprising olanzapine comprises providing a liquid and an olanzapine free compound and adding an acid in a manner that produces the acid salt of the olanzapine in solution. The liquid is then removed to form a non-crystalline olanzapine acid salt.

[0045] In another aspect of the invention, any two or more of the above aspects are combined.

IN THE DRAWINGS

[0046] These features, aspects, and advantages of one or more embodiments of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings which illustrate exemplary features of the invention. However, it is to be understood that each of the features can be used in the invention in general, not merely in the context of a particular example or drawing, and the invention includes any combination of these features, where:

[0047] Figure 1 is a graph showing an X-ray powder diffraction (XRPD) profile for a prior art, commercially-available form of olanzapine;

[0048] Figure 2 is a schematic block diagram of one embodiment of a spray-drying process according to one or more aspects of the present invention;

[0049] Figure 3 is a schematic diagram of an embodiment of an apparatus for carrying out a spray-drying process according to one or more aspects of the present invention;

[0050] Figure 4 is a schematic diagram of one embodiment of an apparatus for carrying out a particle precipitation process according to one or more aspects of the present invention;

[0051] Figure 5A is a graph showing an X-ray powder diffraction (XRPD) profile for pure non-crystalline olanzapine particles produced by spray drying olanzapine dissolved in an aqueous solution, in accordance with one or more aspects of the present invention. The graph was obtained immediately after preparation of the particles;

[0052] Figure 5B is a graph showing an X-ray powder diffraction (XRPD) profile for the pure non-crystalline olanzapine formulation analyzed in Figure 5A after the powder was exposed to 75% relative humidity at 4O⁰C for 1 week;

[0053] Figure 5C is a DVS isotherm plot showing change in mass (amount of water uptake) as a function of humidity for the pure non-crystalline formulation of Figure 5 A;

[0054] Figure 5D is a graph showing the glass transition temperature (T_g ) of the pure non-crystalline olanzapine of Figure 5 A as a function of temperature/relative humidity;

[0055] Figure 6 is a graph showing two X-ray powder diffraction (XRPD) profiles for a formulation comprising non-crystalline olanzapine and a stabilizing excipient, immediately after formulation (upper curve) and after the formulation was exposed to 75% relative humidity at 40⁰C for 1 week (lower curve); [0056] Figure 7 is a DVS Isotherm plot showing change in mass (amount of water uptake) as a function of humidity for particles comprising non-crystalline olanzapine and a stabilizing excipient of Fig 6;

[0057] Fig 8 is a graph showing the glass transition temperature (T_g ) of the noncrystalline olanzapine/excipient of Fig 6 as a function of temperature/relative humidity; and

[0058] Figure 9 is a graph showing X-ray powder diffraction (XRPD) profiles for three formulations comprising non-crystalline olanzapine and a stabilizing excipient (PVP) at varying ratios of olanzapinerPVP. For each of the three formulations, a profile was obtained immediately after formulation, and after the formulations were exposed to 60% relative humidity at 25 °C for 6 months.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

[0059] One or more embodiments of the present invention relates to a formulation comprising olanzapine, to a method of making a formulation comprising olanzapine, and to a method of administering a formulation comprising olanzapine. One or more embodiments of the present invention further relates to a pharmaceutical composition comprising olanzapine, to a method of making a pharmaceutical composition comprising olanzapine, and to a method of administering a pharmaceutical composition comprising olanzapine. Although the invention is illustrated in the context of a particulate formulation, one or more embodiments of the present invention can be used in other forms and for purposes other than for those specifically disclosed, and the invention should not be limited to the examples provided herein.

Definitions

[0060] Before describing one or more embodiments of the present invention in detail, it is to be understood that the invention is not limited to the particularly exemplified apparatus, systems, methods, or processes disclosed herein, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any manner.

[0061] All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

[0062] Reference herein to "one embodiment", "one version" or "one aspect" shall include one or more such embodiments, versions or aspects, unless otherwise clear from the context.

[0063] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include the plural unless the content clearly dictates otherwise.

[0064] The use of the term "about" or "approximately" to modify a numerical range or series means that all numerals in the range or series are so modified, unless otherwise clear from the context that only certain numerals are to be modified.

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. A number of methods and materials similar or equivalent to those described herein can be used in the practice of one or more embodiments of the present invention.

[0066] Amount of ingredients, materials or substances are listed as the ranges or levels of ingredients in the descriptions, which follow hereto.

[0067] "Therapeutically-effective amount" means that amount of active present in the composition that is needed to provide the desired level of drug in the subject to be treated to yield the expected physiological response.

[0068] "Drug" means any compound or composition which induces a desired pharmacologic and/or physiologic effect, when administered appropriately to the target organism (human or animal). Olanzapine is one example of a drug.

[0069] The term "vehicle" means a fluid which dissolves a solid or solids, to form a solution, or which forms a suspension of a solid or solids which do not dissolve or have a low solubility in the fluid. The vehicle can be composed of one or more fluids.

[0070] As used herein, a 'co-formulation' refers to two or more substances formulated at substantially the same time and/or formulated so that a particle comprising a co- formulation contains the two or more substances. For example, a co-formulation may comprise a solid dispersion of a first substance and a second substance, such as an intimate mixture of an active substance and an excipient. In one or more versions, the intimate mixture may comprise an active agent, especially a pharmaceutical ly-active agent, such as olanzapine, dispersed in a "matrix" of a carrier material, especially an excipient, such as an oligomeric and/or polymeric excipient. The co-formulations of one or more embodiments of the present invention with an excipient may advantageously modify the solubility and/or dissolution characteristics of the active substance. Unless otherwise clear from the context, a "formulation" includes a "co-formulation."

[0071] By "olanzapine" it is meant the compound 2-methyl-4-(4-methyl-l-piperazinyl)- 10H-thieno[2,3-6] [l,5]benzodiazepine or 2-methyl-10-(4-methyl-l-piperazinyl)-4H- thieno[2,3-6] [l,5]benzodiazepine and includes all compounds having the following chemical formula:

and which have anti-psychotic, anti-anxiety, and/or anti-agitation properties. The olanzapine compound may be in its free base form or in the form of any pharmaceutically acceptable salt, ester, or prodrug of olanzapine. The term "pharmaceutically acceptable salts" comprises cationic salts, such as alkali metal or alkaline earth metal salts such as sodium, potassium, calcium, lithium magnesium, zinc or the like.

[0072] Additional examples of pharmaceutically acceptable salts comprise anionic salts, such as salts of an inorganic acid, salts of an organic acid, and salts of an acidic amino acid. Examples of salts of inorganic acids are salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts of organic acids are salts of acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methansulfonic acid, and p-toluene sulfonic acid. Examples of salts of acidic amino acids are salts of aspartic acid and glutamic acid; preferable examples of salts of basic amino acids are salts of arginine, lysine, and ornithine.

[0073] The term "olanzapine" is further meant to include all forms, including stereoisomers, enantiomers, diastereomers, optically active forms, mixtures thereof, a racemic mixture, and a non-racemic mixture.

[0074] By "crystalline" it is meant any solid which gives a wide angle x-ray powder diffraction pattern showing one or more characteristic peaks that result from the solid's three dimensional structure, including pure compounds and mixtures which show such peaks. The x-ray powder diffraction may be performed by any suitable instrument, such as a D5000 XRD (Siemens, Germany) between 2 and 40° 2Θ, at a scan rate of 0.02 degrees per second.

[0075] By "non-crystalline" it is meant any solid which does not give rise to one or more characteristic peaks in wide angle x-ray powder diffraction indicative of crystallinity as defined above. This includes amorphous materials, which are disordered at the molecular level, and liquid crystals, such as frozen thermotropic liquid crystals, which can be distinguished from amorphous materials because they exhibit birefringence under polarized light, and microcrystalline forms which do not give rise to one or more characteristic peaks in wide angle x-ray diffraction. "Non-crystalline" also includes pure amorphous materials and amorphous mixtures of materials. In the case of a mixture, this includes molecular solid dispersions, which are comparable to liquid solutions in that there is a single phase which is disordered at the molecular level, non-molecular solid dispersions, which have one or more distinct amorphous phases, and to other homogeneous or non-homogeneous mixtures, provided there is no crystallinity as defined above.

[0076] One or more embodiments of the present invention provide an improved formulation comprising olanzapine. Among other improvements, the olanzapine- containing formulation described herein offers improvements over prior art formulations containing crystalline olanzapine in that the present formulation provides olanzapine in a form where it has a dissolution rate and/or profile which provides a desired, especially a commercially-desired, bioavailability. Additionally or alternatively, the present formulation is advantageous over known pure amorphous forms of olanzapine in that the present formulation has improved processability and/or improved physical stability and/or improved chemical stability, allowing the present formulation to be stored over longer periods of time and/or allowing the formulation more time for being processed into a solid dosage form, such as a tablet.

[0077] Solid olanzapine is conventionally present in one or more of its stable crystalline polymorphic forms. For example, as disclosed in U.S. Patent 5,736,541, olanzapine may be processed to be in its crystalline polymorphic Form II. This crystalline polymorphic form may be characterized by analyzing the X-ray powder diffraction pattern of the solid material. As described in the patent, Form II of olanzapine has a typical X-ray powder diffraction pattern as represented by the following interplanar spacings: 10.2689 8.S77 7.+72I 7.IiS

6.1*» 6fftt

&W9

5.2181

S.12S1

43*74

4,7*65

4.7138

44787

4.3307

4.2294

4.141

33S7J

3.7206

3.SM5 i,$m

3382* 3,2516 3.13*

3,0*43 3.O63S 3.0Ul 18739 1UO2 xnn

2-<H32

[0078] Commercially available olanzapine, supplied for example, by Sai Life Sciences Limited in Hyderabad, India, has been tested and analyzed and has the X-ray powder diffraction pattern shown in Figure 1. From observing the pattern shown in Figure 1 , it can be seen that the commercially available olanzapine is at least partially in crystalline form.

[0079] As discussed above, the crystalline form of olanzapine has proven to be stable and effective, however, a non-crystallline form with good stability and a desired dissolution rate (e.g. comparable to a commercially-available crystalline form) is commercially desirable. In the non-crystalline form, the olanzapine has a dissolution rate and/or profile that is generally comparable to, and may be higher than that of crystalline olanzapine. Accordingly, in one or more versions of the present invention, a formulation comprising olanzapine is provided in non-crystalline form, as are methods of making thereof. By providing non-crystalline olanzapine, the efficacy of the olanzapine is maintained while the dissolution rate and/or bioavailability are maintained and/or increased, and micromeritic properties may be improved, thereby providing an improved form of the pharmaceutical agent.

[0080] In one or more versions, the non-crystalline formulation is produced by spray drying. During the spray drying process the olanzapine is dissolved, dispersed or suspended within a liquid. This mixture is then passed through a nozzle, or other atomizer, which introduces droplets of the mixture into a chamber. As the droplets dry, the liquid is removed thereby producing solid particles comprising non-crystalline olanzapine. The particles are then collected, such as by filtration or cyclone separation, to provide a particulate composition that may be administered to a user or further processed into a dosage form.

[0081] By "spray drying" it is meant the process of producing a particulate solid from a solution, slurry, emulsion, or suspension, or the like, of the olanzapine in a liquid, such as an aqueous or organic liquid, by atomizing the liquid to form droplets and drying the droplets to form a particulate solid. Generally, the particles have a moisture content of less than about 10% by weight water, preferably less than about 5% by weight water and sometimes less than about 3% by weight water, and may be from about 3% to about 5%. The drying conditions are suitably chosen to provide the desired moisture levels. The particle size (mass mean diameter) may be tailored to be a particular size as dictated by the end usage. For tableting, the size may be about 10 μm to about 500 μm, and in one or more versions is in the range of about 10 μm to about 200 μm, or about 20 μm to about 100 μm, or about 20 μm to about 50 μm. Smaller particle sizes, for example about 10 μm or less, or larger particle sizes, for example about 500 or greater, may have applications in additional or alternative dosage forms.

[0082] During the spray drying process, atomization of the liquid may be performed using a conventional atomizer such as a centrifugal, sonic, pressure and/or rotary atomizer. In one or more versions, a rotary atomizer is used in which the liquid flows over the wheel surface as a thin film, and is sheared away into discrete droplets. Other suitable atomizers include two-fluid atomizers, wherein liquid and atomization gas stream are delivered concurrently. Typically, the atomization gas is pressurized to high pressure for delivery through an atomization nozzle. Often the gas is air although other gases such as nitrogen may also be used. An example of a suitable spray drying method is a method as described in The Spray Drying Handbook, by Keith Masters, Longman Publishing, 5th Ed., September 1991, the contents of which is incorporated herein by reference in its entirety. Other spray-drying references include US 6,592,904 and/or WO 03/037303, the contents of which are incorporated herein by reference in their entireties.

[0083] Alternatively or additionally, the liquid may be removed from the solution, slurry, emulsion, or suspension by other known techniques. For example, the liquid may be removed by freeze-drying (lyophilization), vacuum drying, spray-freeze drying, bubble drying, evaporation, or the like. However, spray drying is often advantageous in terms of its efficiency and reproducibility. Spray dried olanzapine tends to be less hygroscopic and has better flow properties. Spray drying also tends to produce particles having a high specific surface area, thus aiding in increasing a dissolution rate. The other techniques also have advantages, as known in the art.

[0084] In one or more embodiments of the present invention, and referring to Figure 2, a spray-drying process comprises an atomization operation 10 that produces droplets of a liquid medium, which are subsequently dried in a drying operation 20. The drying operation 20 may be a single drying chamber or a multi-stage operation. Drying of the liquid droplets results in formation of the discrete particles that form the dry powder compositions which are then collected in a separation operation 30. Each of these unit operations is described in greater detail below.

[0085] The atomization process 10 may utilize any one of several conventional forms of atomizers. The atomization process increases the surface area of the starting liquid. Due to atomization there is an increase in the surface energy of the liquid, the magnitude of which is directly proportional to the surface area increase. The source of this energy increase depends on the type of atomizer used. Any atomizer (rotary, centrifugal, sonic, pressure, two fluid) which is capable of producing droplets with a mass median diameter of less than about 100 microns, is suitable. [0086] If, a two fluid atomizer is used, the atomization gas may be nitrogen which has been filtered or otherwise cleaned to remove particulates and other contaminants. Alternatively, other gases, such as air may be used. The atomization gas will be pressurized for delivery through the atomization nozzle, typically to a pressure above 5 psig, preferably being above 10 psig. The atomization conditions, including atomization gas flow rate, atomization gas pressure, liquid flow rate, and the like, are controlled to produce liquid droplets having a desired particle diameter as known to the art.

[0087] The feedstock for the process may comprise a solution, suspension, colloidal system, or other dispersion of an active agent in a suitable solvent, or co-solvent system. The active agent comprises a drug, pharmaceutical, compound, formulation or substance, which is desired to be spray-dried. Olanzapine thus comprises one example of an active agent. In one or more embodiments, the active agent is present as an aqueous or nonaqueous solution. Aqueous solvents, non-aqueous solvents, mixtures of solvents and combinations thereof according to this invention may be employed. Choice of solvent or solvents is preferably determined by solubility parameters of the materials, known solvent/solute relationships and process parameters. The total dissolved solids, including the insoluble active agent and other carriers, excipients, etc., that may be present in the final dried particle, may be present at a wide range of concentrations, typically being present at from about 0.1% by weight to about 50% by weight, and often about 1% to about 25% by weight. It will thus be understood that the term "feedstock" as used herein is used broadly and encompasses mixtures such as solutions, slurries, suspensions, emulsions, microemulsions, multiple emulsions, and reverse emulsions.

[0088] The drying operation 20 is performed next to evaporate liquid from the droplets produced by the atomization operation 10. In one or more embodiments, the drying comprises introducing energy to the droplets, typically by mixing the droplets with a heated gas which causes evaporation of the water or other liquid medium. In one or more embodiments, the mixing is done in a spray dryer or equivalent chamber where a heated gas stream has been introduced. In one or more embodiments, the heated gas stream may flow concurrently with the atomized liquid; in other embodiments a counter- current flow, cross-current flow, or other flow pattern of the heated gas is employed. It is also possible to perform the drying operation in multiple stages as described, for example, in more detail in WO 01/00312 the disclosure of which is incorporated by reference in its entirety, and in particular with regard to drying apparatus, steps methods and conditions.

[0089] The drying rate may be controlled based on a number of variables, including the droplet size distribution, the inlet temperature of the gas stream, the outlet temperature of the gas stream, the inlet temperature of the liquid droplets, and the manner in which the atomized spray and hot drying gas are mixed. In one embodiment, the drying gas stream has an inlet temperature of at least about 70⁰C, and may be at least about 12O⁰C, at least about 135°C, at least about 145⁰C, and may often be over about 175°C, or even as high as about 200⁰C, depending on the active agent being dried. At least in part, the inlet temperature of the heated gas drying stream depends on the lability of the active agent being treated. The outlet temperature is usually in the range of about 50-100⁰C. The drying gas may be moved through the system using conventional blowers or compressors.

[0090] The separation operation 30 is selected to achieve high efficiency collection of the particles produced by the drying operation 20. Any of several conventional separation operations may be used, although in some cases they could be modified to assure collection of a specified particle size range. In one or more embodiments, separation is achieved using a cyclone separator. Other separators, such as filters, for example, a membrane medium (bag filter), a sintered metal fiber filter, or the like may also be used. The separation operation should achieve collection of at least about 70% of all particles, and in some embodiments collects more than about 85%, more than about 90%, or even more than about 95% of such particles.

[0091] Referring now to Figure 3, one embodiment of a spray-dryer system is described. The system includes a spray dryer 50, which may be a commercial spray dryer such as those available from suppliers such as Buchi, Niro, APV, Yamato Chemical Company, Okawara Kakoki Company, and others. The spray dryer 50 is provided with a feedstock as described above through a supply pump 52, filter 54, and supply line 56. The supply line 56 is connected to a multi-nozzle two-fluid atomizer 57. Atomizing air is supplied from a compressor 58, a filter 60, and line 62 to the atomizer 57. Drying air is also provided to the spray dryer 50 through a heater 65 and a filter 66.

[0092] In this embodiment, dried particles from the spray dryer 50 are carried by the air flow through conduit 70 to a separator 72. In some embodiments, the separator 72 comprises a cyclone. Alternatively, the separator 72 may be a filter, with filter media such as bag filters, cloth filters, and cartridge filters. The dried particles comprising powder are collected in a particle collection canister 76, which may be periodically be removed and replaced. The dry powder in the canister 76 may be used for packaging in unit dosage or other forms. The carrier gas passes out from the top of the separator 72 through line 80 and an exhaust fan 84.

[0093] As one alternative to spray drying, the liquid may be removed from the solution, slurry, emulsion, or suspension by other known techniques. For example, the liquid may be removed by freeze drying (lyophilization), vacuum drying, spray-freeze drying, evaporation, bubble drying, or the like. In one or more embodiments, spray drying is advantageous because it permits the manipulation of a surface composition and/or topology of theϊesulting particles which can result in desired, especially improved, pharmaceutical and/or micromeritic properties. Additionally, spray drying is advantageous in terms of its efficiency and reproducibility.

[0094] In other embodiments of the present invention, the non-crystalline formulation comprising olanzapine may be produced by a supercritical (or near critical) solvent extraction or particle precipitation method which comprises contacting the liquid containing the olanzapine with an anti-solvent. For example, in one or more versions, the liquid may comprise one or more organic solvents in which the olanzapine is dissolved or suspended. The liquid may be contacted by a compressed gas, such as a supercritical or near supercritical anti-solvent gas, to rapidly remove the organic solvent and thereby extract particles comprising olanzapine. In one particular version, the anti- solvent gas may be supercritical carbon dioxide, for example.

[0095] A solvent removal process using a supercritical or near-critical fluid involves contacting a solution or suspension containing olanzapine in a fluid (the "olanzapine solution/suspension") with a compressed fluid (generally a supercritical or near-critical fluid) anti-solvent under conditions which allow the anti-solvent to extract the fluid from the olanzapine solution/suspension and to cause particles comprising olanzapine to precipitate from the solution/suspension. The conditions are such that the fluid mixture formed between the anti-solvent and the extracted fluid is still in a compressed (generally supercritical or near-critical) state. The anti-solvent fluid should generally be a nonsolvent for the olanzapine and be miscible with the fluid.

[0096] In one or more versions, the solvent removal process is a supercritical fluid particle formation process, such as the process known as the "SEDS™" (Solution Enhanced Dispersion by Supercritical fluids) process of Nektar Therapeutics in San Carlos, California and in Bradford, United Kingdom. In one or more versions, this process involves using the anti-solvent fluid substantially simultaneously both to extract the vehicle from, and to disperse, the olanzapine solution/suspension. In this context, 'disperse' refers generally to the transfer of kinetic energy from one fluid to another, usually implying the formation of droplets, or of other analogous fluid elements, of the fluid to which the kinetic energy is transferred. Examples of Nektar Therapeutics' supercritical fluid processes are described in PCT Publications WO 95/01221, WO 96/00610, WO 98/36825, WO 99/44733, WO 99/59710, WO 01/03821, WO 01/15664, WO 02/38127 and WO 03/008082. Other suitable processes are described in PCT Publications WO 99/52507, WO 99/52550, WO 00/30612, WO 00/30613, WO 00/67892 and WO 02/058674. All of these documents are incorporated herein by reference in their entireties. The target solution/suspension and the anti-solvent are preferably contacted with one another in the manner described in WO 95/01221 and/or WO 96/00610, being co-introduced into a particle formation vessel using a fluid inlet which allows the mechanical energy (typically the shearing action) of the anti-solvent flow to facilitate intimate mixing and dispersion of the fluids at the point where they meet. The target solution/suspension and the anti-solvent preferably meet and enter the particle formation vessel at substantially the same point, for instance via separate passages of a multi- passage coaxial nozzle. Alternatively or additionally, the supercritical fluid process may be of the type described in WO 03/008082, which is incorporated herein by reference in its entirety, in which the target solution/suspension and the anti-solvent enter the vessel at separate, although close, locations.

[0097] Reference to an anti-solvent fluid being in a compressed state means that, at the relevant operating temperatures, it is above its vapor pressure, preferably above atmospheric pressure, more preferably from about 50 to about 250 bar. The anti-solvent fluid is preferably a fluid which is a gas at atmospheric pressure and ambient temperature. Preferably, "compressed" means close to, at or more preferably above the critical pressure P_c for the fluid concerned. The anti-solvent is preferably a supercritical or near-critical fluid or may alternatively be a compressed liquid. A "supercritical fluid" is a fluid at or above its critical pressure (P_c) and its critical temperature (T_c) simultaneously. A "near-critical fluid" is either (a) above its T_c but slightly below its P_c or (b) above its P_c but slightly below its T₀ or (c) slightly below both its P_c and T. The terms "compressed fluid", "supercritical fluid" and "near-critical fluid" each encompass a mixture of fluid types, so long as the overall mixture is in the compressed, supercritical or near-critical state respectively.

[0098] Various anti-solvents, solvents, and process conditions may be used. The anti- solvent should be a non-solvent to the olanzapine, and miscible with the olanzapine solution/suspension fluid. The ant-solvent preferably comprises supercritical, near- critical or liquid CO₂, especially supercritical CO₂. Preferred solvents include one or more of methanol, ethanol, isopropylalcohol, acetone, tetrahydrofuran, ethylacetate, dimethylformamide, dichloromethane, MeCN (acetonitrile), N,N-dimethylacetamide (DMA). The processing conditions are preferably chosen to produce particles of desired sizes and/or to reduce residual solvent levels. If olanzapine is co-formulated with an excipient, and the SCF™ particle precipitation process is used, the excipient is preferably soluble or miscible with the solvent. Excipients with varying degrees of hydrophilicity may thus be suitable depending upon the solvent employed in the SCF™ process.

[0099] By "sonic velocity" and "supersonic velocity" is meant respectively that the velocity of the anti-solvent fluid as it enters the vessel is the same as or greater than the velocity of sound in that fluid at that point. By "near-sonic velocity" is meant that the anti-solvent velocity on entry into the vessel is slightly lower than, but close to, the velocity of sound in that fluid at that point—for instance its "Mach number" M (the ratio of its actual speed to the speed of sound) is greater than about 0.8, preferably greater than about 0.9 or 0.95. Generally speaking, in the method of the invention, the Mach number for the anti-solvent fluid on entering the particle formation vessel may be between about 0.8 and 1.5, preferably between about 0.9 and 1.3.

[00100] In one or more embodiments, the method of the present invention comprises a method for forming a substance, or co-forming two or more substances, in particulate form, the method comprising introducing into a particle formation vessel (a) a solution or suspension of the target substance in a fluid vehicle (the "target solution/suspension") and (b) a compressed fluid anti-solvent for the substance, and allowing the anti-solvent fluid to extract the vehicle from the target solution/suspension so as to form particles of the target substance, wherein (i) the pressure in the particle formation vessel is Pi which is preferably greater than the critical pressure P₀ of the anti- solvent, (ii) the anti-solvent is introduced through a restricted inlet so as to have a back pressure of P₂, where P₂ is greater than Pi, (iii) the temperature in the particle formation vessel is Ti which is preferably greater than the critical temperature T₀ of the anti- solvent, (iv) the anti-solvent is introduced into the vessel at a temperature T₂, where T₂ is greater than Ti, (v) Ti and T₂ are such that Joule-Thomson cooling of the anti-solvent as it enters the vessel does not reduce the anti-solvent temperature to below that required of it at the point of particle formation (and are preferably such that the anti-solvent temperature does not fall below T_c within the vessel) and (vi) Pi, P₂, Ti and T₂ are such that the anti-solvent fluid has a sonic, near-sonic or supersonic velocity as it enters the particle formation vessel.

[00101] The use of near-sonic, sonic or supersonic anti-solvent velocities can allow achievement of smaller particle sizes and narrower size distributions in a supercritical fluid-based particle formation processes. In particular it can allow the formation of small micro- or even nano-particles, for instance of volume mean diameter less than about 5 microns, preferably less than about 2 microns, more preferably less than 1 micron. Such particulate products preferably have narrow size distributions, such as with a standard deviation of about 2.5 or less, more preferably about 2.0 or less, most preferably about 1.9 or even about 1.8 or less.

[00102] The use of near-sonic, sonic or supersonic anti-solvent velocities also appears to lead to more efficient vehicle extraction, thus potentially yielding particles with lower residual solvent levels, less agglomeration and generally improved handling properties.

[00103] Preferably the two fluids meet immediately downstream of the point of anti-solvent entry. "Immediately" in this context implies a sufficiently small time interval (between the anti-solvent entering the particle formation vessel and its contact with the target solution/suspension) as preferably still to allow transfer of mechanical energy from the anti-solvent to the solution/suspension so as to achieve dispersion. Nevertheless, there is still preferably a short interval of time between anti-solvent entry and fluid contact so as to eliminate, or substantially eliminate or at least reduce, the risk of apparatus blockage due to particle formation at the point of anti-solvent entry. The timing of the fluid contact will depend on the nature of the fluids, the target substance and the desired end product, as well as on the size and geometry of the particle formation vessel and the apparatus used to introduce the fluids and on the fluid flow rates. The contact may occur within about 0.0001 to about 50 milliseconds, or within about 0.001 to 25 milliseconds. The contact preferably occurs within about 0.001 to 20 milliseconds, such as within about 0.01 to 10 milliseconds, of the anti-solvent entering the particle formation vessel.

[00104] At the point where the target solution/suspension and the anti-solvent meet, the angle between their axes of flow may be from about 0 degrees (i.e., the two fluids are flowing in parallel directions) to about 180 degrees (i.e., oppositely-directed flows). In one or more embodiments of the present invention, they meet at a point where they are flowing in approximately perpendicular directions, i.e., the angle between their axes of flow is from about 70 to about 110 degrees, more preferably from about 80 to about 100 degrees, such as about 90 degrees. In other embodiments of the present invention, the flows of target solution/suspension and the anti-solvent meet at a point where they are flowing in approximately parallel directions, i.e., the angle between their axes of flow is from about 0 to about 70 degrees, more preferably from about 0 to about 30 degrees, such as about 0 degrees.

[00105] When carrying out an embodiment of the present invention, the particle formation vessel temperature and pressure are ideally controlled so as to allow particle formation to occur at or substantially at the point where the target solution/suspension meets the anti-solvent fluid. The conditions in the vessel must generally be such that the anti-solvent fluid, and the solution which is formed when it extracts the vehicle, both remain in the compressed (preferably supercritical or near-critical, more preferably supercritical) form whilst in the vessel. For the supercritical, near-critical or compressed solution, this means that at least one of its constituent fluids (usually the anti-solvent fluid, which in general will be the major constituent of the mixture) should be in a compressed state at the time of particle formation. There should at that time be a single- phase mixture of the vehicle and the anti-solvent fluid, otherwise the particulate product might be distributed between two or more fluid phases, in some of which it might be able to redissolve. This is why the anti-solvent fluid preferably is miscible or substantially miscible with the vehicle.

[00106] The flow rate of the anti-solvent fluid relative to that of the target solution/suspension, and its pressure and temperature, should be sufficient to allow it to accommodate the vehicle, so that it can extract the vehicle and hence cause particle formation. The anti-solvent flow rate will generally be higher than that of the target solution/suspension—typically, the ratio of the target solution/suspension flow rate to the anti-solvent flow rate (both measured at or immediately prior to the two fluids coming into contact with one another) will be about 0.001 or greater, preferably from about 0.01 to 0.2, more preferably from about 0.03 to 0.1. The anti-solvent flow rate will also generally be chosen to ensure an excess of the anti-solvent over the vehicle when the fluids come into contact, to minimize the risk of the vehicle re-dissolving and/or agglomerating the particles formed. [00107] Figure 4 shows one embodiment of an apparatus suitable for carrying out methods in accordance with the present invention. Reference numeral 100 denotes a particle formation vessel, within which the temperature and pressure can be controlled by means of a heating jacket 102 and back a pressure regulator 103. The vessel 100 contains a particle collection device (not shown) such as a filter, filter basket or filter bag. A fluid inlet assembly 104 allows introduction of a compressed (typically supercritical or near- critical) fluid anti-solvent from source 105 and one or more target solutions/suspensions from sources such as 106 and 107. The elements labeled 108 are pumps, and 109 is a cooler. A recycling system 110 allows solvent recovery.

[00108] The fluid inlet assembly 104 may for example take the forms shown in

U.S. Patent 6,063,138 and/or U.S. Patent 5,851,435, the disclosures of which are incorporated by reference in their entireties, and in particular with regard to apparatus, steps, methods and conditions. The fluid inlet assembly 104 includes a nozzle (not shown) for introduction of the anti-solvent fluid. The nozzle may comprise a single passage of circular cross section, with a circular outlet, or may alternatively comprise a multi-component nozzle, with anti-solvent introduced through one or more of its passages and the remaining passages either closed off or else used to introduce additional reagents. (For example, a multi-passage nozzle of the type described in WO-95/01221 and/or corresponding U.S. Patent 5,851,453 or WO-96/00610 may be used). Such nozzles have two or more concentric (coaxial) passages, the outlets of which are typically separated by a short distance to allow a small degree of internal mixing to take place between fluids introduced through the respective passages before they exit the nozzle. The anti-solvent could for instance be introduced through the inner passage of such a nozzle, traversing a small "mixing" zone as it exits that inner passage and then passing through the main nozzle outlet into the particle formation vessel).

[00109] Preferably, the opening at the outlet end (tip) of the nozzle will have a diameter in the range of about 0.05 to 2 mm, more preferably between about 0.1 and 0.3 mm, typically about 0.2 mm. The outlet end of the nozzle may be tapered depending upon the desired velocity of the fluids introduced through the nozzle; an increase in the angle may be used, for instance, to increase the velocity of the supercritical fluid introduced through the nozzle and hence to increase the amount of physical contact between the supercritical fluid and the vehicle.

[00110] Figure 5 A shows the x-ray powder diffraction pattern of pure olanzapine particles produced by spray drying olanzapine dissolved in an aqueous solution (absent any excipient). By "pure olanzapine" it is meant that a majority of the particles consist of olanzapine. While peaks indicative of crystallinity exist, the formulation is nonetheless stable, and the particles may possess desired micromeritic properties, therefore the formulation is within the scope of the present invention. Stability is confirmed by Figure 5 B, which shows the x-ray powder diffraction pattern of the pure olanzapine shown in Figure 5 A following storage of the particles at about 75% relative humidity and at about 60⁰C for 1 week. As can be seen, the pure olanzapine made by spray drying advantageously maintains its solid form. This pure non-crystalline formulation may be administered to a user immediately, or soon after preparation; may be formulated immediately, or soon after preparation, into a stable form; may be stored under controlled environments; or may be allowed to convert to another solid state form. Figure 5C is a DVS isotherm plot, and Figure 5D is a graph of glass transition temperature, both for the pure olanzapine analyzed in Figure 5A.

[00111] The pure olanzapine, as shown in Figures 5A and 5B, produced by spray drying in accordance with one or more embodiments of the present invention is advantageously physically stable, and the spray-drying process permits manipulation of the surface composition and/or topology to provide desired, especially improved, pharmaceutical and/or micromeritic properties. It has been found that in accordance with one or more embodiments of the present invention, olanzapine which has been spray-dried from a nitrile solution, such as an acetonitrile, is initially non-crystalline, and may retain substantially its non-crystalline character for a period of time, especially when stored under cool and/or dry conditions. In one or more versions, the cool conditions comprise a storage temperature of about 10⁰C or less, and the dry conditions comprise a relative humidity of about 25% or less.

[00112] Accordingly, in one or more versions of the present invention, a non- crystalline formulation comprising olanzapine is formulated so as to improve its physical stability, and/or micromeritic properties. For example, the improved stability may be provided by combining the non-crystalline olanzapine with a stabilizing excipient. The stabilizing excipient is provided in a sufficient quantity to reduce the tendency of the non-crystalline olanzapine to convert to a crystalline form. The olanzapine and a stabilizing excipient may be formulated together by conventional methods such as blending the two ingredients together. Preferably, the stabilizing excipient is in intimate contact with the non-crystalline olanzapine. The stabilizing excipient may be either noncrystalline or crystalline, as long as it serves to maintain the olanzapine in a noncrystalline form. In one or more versions of the present invention, a non-crystalline formulation comprising olanzapine is formulated so as to improve its pharmaceutical and/or micromeritic properties, while retaining a desired, or a sufficient, especially a commercially-sufficient, physical stability. In other versions of the present invention, a non-crystalline formulation comprising olanzapine is formulated to improve its physical stability as well as its pharmaceutical and/or micromeritic properties. Desired micromeritic properties, for example, powder flow, compressibility or post-handling ease, of a particle of olanzapine may be obtained by employing one or more solvent removal processes of the present invention, especially spray-drying, which can permit the manipulation of the surface composition of the olanzapine formulation or olanzapine and excipient co-formulation produced thereby. In one or more versions, the increase in physical stability may comprise a longer storage life of the formulation before crystallization, or may comprise a higher formulation glass transition temperature (T_g) at a particular relative humidity, or may comprise a lower hygroscopicity, or may comprise other physical stability determinants, or combinations thereof. In one or more versions, a higher T_g is higher than room, or ambient temperature, and preferably is significantly higher.

[00113] In one or more versions, the formulation is made up of particles, and the particles comprise non-crystalline olanzapine and an excipient, i.e. both the olanzapine and the stabilizing excipient are present in the same formulated particle, as by co- formulating, for example. By providing the stabilizing excipient and the olanzapine in the same particle, the excipient and the olanzapine are in greater contact and the stabilizing excipient is better able to assert its stabilizing influence on the olanzapine. In one version, the olanzapine and the excipient are formulated so that there is provided a solid dispersion of one component in another, such as an intimate mixture of olanzapine dispersed in a matrix of the stabilizing excipient, or a solid solution of the components, whereby an intimate association results. In one version, the particles comprising noncrystalline olanzapine and excipient may be formulated by adding the excipient to the liquid in the product methods described above. For example, olanzapine and a stabilizing excipient may be dissolved or suspended in an aqueous or organic solvent and the particles may be formed by removing the solvent by spray drying, freeze drying, spray freeze drying, bubble drying, evaporation, supercritical fluid extraction, or other solvent removal techniques.

[00114] The stabilizing excipient may be any excipient that serves to reduce the conversion of non-crystalline olanzapine to crystalline olanzapine when compared to non-crystalline olanzapine in the absence of the stabilizing excipient. For example, the excipient may comprise one or more polymeric or oligomeric excipients, such as polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), vinylpyrrolidone/vinyl acetate copolymer in a VP: VA of 60:40 (PVP-VA 64), poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; carbohydrates; polyols; sugars; oligosaccharides such as cyclodextrins; proteins, peptides and amino acids; lipids and modified lipids such as lipid-PEG and lipid-sugar esters; salts; citric acid; citrates (including alkali metal or alkaline earth metal citrates); known glass formers; or the like. Some stabilizing excipients are described in U.S. Patent 6,582,728, and in PCT WO 01/15664, the entire disclosures of which are incorporated herein by reference in their entireties, and in particular those portions relating to oligomers, polymers and/or excipients.

[00115] In one or more versions, the stabilizing excipient comprises an excipient which serves to reduce the hygroscopicity of the formulation. In one or more versions, excipients suitable for this purpose comprise non-sugar and/or non-carbohydrate excipients, such as natural and synthetic polymers, proteins, polyhydroxic acids, cellulose derivatives, lipid derivitives combinations thereof and mixtures thereof.

[00116] In one or more versions, a process-enhancing excipient is formulated or co-formulated with the olanzapine to improve processability of the resulting powder. Such process-enhancing excipient comprises one or more which serves to improve the flowability of a particulate formulation. Suitable process-enhancing excipients comprise amino acids, espcially neutral amino acids, such as leucine or trileucine, and high melting point lipids, such as dipalmitoyl phosphatidylcholine (DPPC) or distearoylphosphatidylcholine (DSPC). Cellulosic polymers and co-polymers, and derivatives thereof, and polyvinylpyrrolidone (PVP), co-polymers of vinyl pyrrolidone with other monomers, such as vinyl acetate, and derivatives thereof, and combinations thereof can act to reduce a static charge on processing equipment, thereby increasing efficiency, throughput and yield. Polymers and co-polymers, such as these may additionally or alternatively increase yield by virtue of a relatively low viscosity and/or low molecular weight, which can be used to increase particle size. The process- enhancing excipient may comprise the sole excipient, or may comprise a formulation or co-formulation with other excipients. In one or more versions, the olanzapine formulation comprises a process-enhancing excipient and at least one of a stabilizing excipient or a solubility-enhancing excipient. In one or more versions, the olanzapine formulation comprises a a stabilizing excipient, and at least one of a process-enhancing excipient and a solubility-enhancing excipient. In one or more versions, a process- enhancing excipient and/or a stabilizing excipient, and/or a solubility-enhancing excipient may be blended (such as dry blended) with a particulate non-crystalline olazapine powder formed in accordance with any embodiment or example herein.

[00117] Additional or alternative examples of polymeric or oligomeric excipients for formulation with olanzapine according to one or more embodiments of the invention comprise other celluloses and cellulose derivatives, such as alkyl (for example, methyl or ethyl) cellulose, hydroxyalkyl celluloses, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), carboxymethylcelluose, sodium carboxymethyl cellulose, microcrystalline cellulose, microfϊne cellulose, or mixtures thereof; traditional "natural" source materials, their derivatives and their synthetic analogues, such as acacia, tragacanth, alginates (for instance calcium alginate), alginic acid, starch, agar, carrageenan, xanthan gum, chitosan, gelatin, guar gum, pectin, amylase or lecithin; homo- and co-polymers of hydroxy acids such as lactic and glycolic acids; hydrated silicas, such as bentonite or magnesium aluminium silicate; polymeric surfactants, such as polyoxyethylene or polyoxypropylene, or polyalkylene oxides such as polyethylene oxides;phospholipids, such as DMPC (dimyristoyl phosphatidyl choline), DMPG (dimyristoyl phosphatidyl glycerol) or DSPC (distearyl phosphatidyl choline); carbohydrates, such as lactose, sucrose, dextrans, cyclodextrins or cyclodextrin derivatives; mannitol; dendrimeric polymers, such as those based on 3,5 hydroxy benzyl alcohol;poly(ε-caprolactones), DL-lactide-co-caprolactones and their derivatives;poly(orthoester)s and poly(orthoester)/poly(ethylene glycol) copolymers, including block copolymers, such as are described in US-5,968,543 and US-5,939,453, the entire disclosures of which are incorporated herein by reference in their entireties, and in particular those portions relating to oligomers, polymers and/or excipients. Derivatives of such polymers, such as polymers with incorporated esters of short chain α-hydroxy acids or glycolic-co-lactic acid copolymers; or mixtures thereof, are additionally suitable.

[00118] In one version, the stabilizing excipient may comprise one or more polymeric or oligomeric compounds having at least one amine group and/or amide group, or other nitrogen-containing group, or a combination thereof. Examples comprise polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone and copolymers containing vinylpyrrolidone monomer units.

[00119] In one or more versions of the formulation according to the invention, an oligomeric or polymeric stabilizing excipient is present in an amount by weight sufficient, following formulation with olanzapine, to provide improved stability to the olanzapine, such as the non-crystalline olanzapine. In one or more embodiments, the improved stability comprises physical stability which is at least comparable to, and preferably better than, that attained by a crystalline form of olanzapine. In one or more embodiments, the improved stability comprises chemical stability which is at least comparable to, and preferably better than, that attained by a crystalline form of olanzapine. In one or more embodiments, the improved stability comprises a formulation that maintains its non-crystalline form when stored at about 25°C and about 60% relative humidity for a period of at least about 1 week, more preferably at least about 1 month, more preferably at least about three months. In one or more embodiments, the improved stability comprises a formulation that maintains its noncrystalline form when stored at about 40°C and about 75% relative humidity for a period of at least about 1 week, more preferably at least about 1 month, more preferably at least about three months. In one or more embodiments, the improved stability comprises a formulation maintains its non-crystalline form when stored under either of the foregoing accelerated storage conditions for a period of at least about 1 week, more preferably at least about 1 month, more preferably at least about three months.

[00120] Generally, in terms of weight percentage, one or more excipients are present at a concentration in the range of from about 0.1 to about 99.9% w/w, preferably from about 5% to about 70%, more preferably from about 10% to about 50% w/w of the formulation. The olanzapine may be present in the complementary (to the excipient) amount, and in one or more versions is present in an amount of between about 0.1 to about 99.9% by weight, and often is present from about 1 to about 50%, typically from about 5% to about 25% by weight.

[00121] The formulation according to the invention is preferably in particulate form, especially in the form of particles having a volume mean diameter (VMD) of about 5 to about 200 μm preferably about 10 μm to about 100 μm more preferably from about 10 μm to about 50 μm, or about 15 μm to about 30 μm. In some embodiments, particle sizes are about 20 or 25 μm, or in a range thereof. Particle sizes may be measured for instance using a laser diffraction sensor such as the Helos™ system available from Sympatec GmbH, Germany (which provides a geometric projection equivalent (mass mean diameter, MMD)). Volume mean diameters may be obtained using commercially available software packages. [00122] In one or more versions, the formulation may comprise a solubility enhancing excipient. The commercially available olanzapine is sufficiently soluble in an aqueous liquid that has a pH less than about 6. Accordingly, in one or more versions, the solubility enhancing excipient comprises an acid that may be added to a water solution to lower the pH of the solution thereby increasing the solubility of the olanzapine. In one or more versions, the solubility enhancing excipient comprises an organic acid, which may be monoprotic, diprotic or multiprotic, such as carboxylic and sulfonic acids. Examples include formic, citric, ascorbic, benzoic, malic, and maleic acids. In one particular version, the solubility enhancing excipient comprises citric acid. Alternatively or additionally, a different acid or other solubility enhancer may be used. For example, suitable acids comprise inorganic mineral acids such as HCl and H₂SO₄, and organic acids such as glycolic acid, lactic acid, and tartaric acid. The solution may then undergo a solvent removal process to produce particles comprising olanzapine.

[00123] Following formulation with at least one excipient, the olanzapine will have improved physical stability with respect to reversion to crystalline form, for at least about one week, more preferably at least about one month, and most preferably at least about three months. By "stable" is meant that over the specified time period, there is no significant change in the X-ray diffraction (XRD) pattern of the formulation and, where measurable, in its differential scanning calorimetry (DSC) profile. Preferably there is no significant change in the dissolution profile of the olanzapine formulation over time. Preferably there is little or no change in degree of crystallinity of the olanzapine within the formulation with respect to the initial amount. In one or more embodiments, for example, there is less than about 50% or 40% or 30% or 20%, preferably less than about 10%, or less than about 5%, more preferably less than about 3% or 2% or % 1% change in degree of crystallinity of the olanzapine within the formulation with respect to the initial amount. Preferably there is no detectable crystalline olanzapine present in the formulation either before or after storage. Stability may be assessed by storing the formulation according to the invention at ambient temperature, for example from about 18 to 25⁰C, or from about 20 to 23⁰C, such as about 22⁰C, or at the accepted industrial standard temperature of about 25°C, and at up to about 20% or 30% or 40% or 60% or even about 75% relative humidity (RH). In one particular assessment, the temperature is about 25°C and the relative humidity is about 60%. Higher storage temperatures and/or humidities may be used, in conventional manner, to mimic longer term storage periods, as may conventional thermal cycling procedures such as freeze/thaw cycling. For example, an accelerated storage assessment may be performed at about 4O⁰C and about 75% relative humidity. The formulation according to the invention is preferably stable, for the periods mentioned above, when stored at about 25⁰C and up to about 60% RH for a period of at least about one week, preferably at least about one month, more preferably at least about three months, most preferably at least about six months. Even more preferably, the formulation is considered stable when stored at about 4O⁰C, most preferably at about 4O⁰C and up to about 75% RH for a period of at least about one week, preferably at least about one month, more preferably at least about three months, and most preferably at least about six months. As a general guide, a formulation tested as stable under accelerated storage conditions for three months will be stable under ambient storage conditions for at least about two years.

[00124] The degree of crystallinity of the formulation may be assessed by conventional techniques, for example using X-ray powder diffraction (XRPD) techniques, particularly high resolution X-ray powder diffraction using a synchrotron radiation source. Levels of non-crystalline or amorphous phase may also be assessed by reference to its moisture uptake at any given temperature and humidity.

[00125] Bioavailability may be assessed, according to standard procedures, with reference to the release profile of the active substance, with time, into the patient's bloodstream. It may be measured for example as either the maximum plasma concentration of active achieved following administration (C_max), or as the area under the plasma concentration curve (AUC) integrated from time zero (the point of administration) to a suitable endpoint or to infinity. Bioavailabilty can also be estimated using standard dissolution rate tests.

[00126] The formulations according to one or more embodiments of the present invention may be further formulated into a pharmaceutical composition. A pharmaceutical composition according to the invention may take the form of any delivery form conventional in the art. The composition may take the form of a solid composition such as a powder, granulate or tablet, for example, or a liquid form such as a solution or suspension (including more viscous forms such as pastes and gels) suitable for oral delivery. Alternatively, pharmaceutical compositions according to one or more embodiments of the invention may be presented in a form suitable for topical application (for instance as a gel or paste), as a solution or suspension for parenteral, subcutaneous or transdermal administration, or as injection or suppository. In other versions, the formulations and co-formulations comprising non-crystalline olanzapine can be blended with sugars and/or effervescent systems, such as bicarbonates/citric acid, to produce orally disintegrating tablets. One or more particulatate formulations or co-formulations of the present invention comprising non-crystalline olanzapine can also be administered as an aerosol. In one or more versions, a small particle size and/or low density particle is desired for such aerosol versions. In one or more versions, spray-drying is a preferred solvent removal technique for its ability to produce such small and/or low density particles.

[00127] Also there are provided methods of treatment using a pharmaceutical composition according to the present invention. The invention thus further comprises methods of treating psychotic conditions, especially schizophrenia and schizophrenic conditions, and/or mania, in a patient (human or animal) by administering an effective amount of a pharmaceutical composition according to the present invention.

[00128] The formulations according to one or more embodiments of the present invention may be further formulated into a pharmaceutical composition. A pharmaceutical composition according to the invention may take any delivery form known in the art. The composition may take the form of a solid composition such as a powder, granulate or tablet, for example, or a liquid form such as a solution or suspension (including more viscous forms such as pastes and gels) suitable for oral delivery. Alternatively, pharmaceutical compositions according to the invention may be presented in a form suitable for topical application (for instance as a gel or paste), as a solution or suspension for injection or as a suppository. [00129] Pharmaceutical compositions according to the invention may comprise additional active substances and/or excipients, which may or may not be included along with the olanzapine and the excipient as part of the formulation of the invention. For example, the pharmaceutical composition may comprise the olanzapine formulation of one or more embodiments of the present invention plus an active agent that is added to the composition. Alternatively, the additional active agent may be formulated to be in the same particle as the olanzapine by adding the additional active agent to the liquid containing the olanzapine during the processing of the olanzapine. The pharmaceutical compositions according to the invention may include other additives such as those typically used in pharmaceutical dosage formulations, for instance flavorings and sweeteners, colors, bulking agents, tablet lubricants and disintegrating agents. The pharmaceutical compositions according to the invention may include other additives such as those typically used in pharmaceutical dosage formulations, for instance flavorings and sweeteners, colors, bulking agents, tablet lubricants and disintegrating agents.

[00130] In one or more embodiments of the present invention, a pharmaceutical composition comprises a olanzapine formulation or co-formulation of olanzapine and excipient as described in any formulation, co-formulation, composition and method herein, together with additional excipients. A non-crystalline form of olanzapine may be made by spray-drying a solution of olanzapine and PVP-VA, in accordance with one or more embodiments of the present invention. The spray-dried powder may then be formulated, with additional excipients, into an appropriately-sized tablet dosage form, for example, containing about 2.5 mg, 5 mg, 7.5 mg or more of olanzapine per tablet. A dry granulation process, such as roller compaction, may be used to make the granules. Alternatively or additionally, a wet granulation process as known in the art, may be used to make the granules. In either case, the granules can than be compressed into tablets, also by means as known in the art. In one or more embodiments, a tablet dissolution profile is preferably comparable to, on a dose per dose basis (at least parity or near parity with), a commercially-available dosage form, especially ZYPREXA®. In other embodiments, a tablet dissolution profile is preferably better than commercially-available dosage form, especially ZYPREXA®. The tablet formulations may be made as described herein to be preferably chemically and physically stable for at least one year, preferably two years at room temperature, and/or preferably stable for at least one year under accelerated storage conditions. The formulations additionally may be scaled to production-sized batches.

[00131] The non-crystalline form of olanzapine may be formed by adding the olanzapine to a liquid and removing the liquid in a manner that produces particles comprising non-crystalline olanzapine, such as by using one or more of the solvent removal or solid extraction techniques discussed above. In one or more versions, the free compound, e.g. base, of olanzapine is the starting material for the process embodiments herein. The commercially-available form of olanzapine is often the free- base form. To improve solubility, the free-base can be reacted with a substantially equal mole of an acid, for example hydrochloric acid, to produce an olanzapine acid salt. This olanzapine acid salt may then be introduced into a liquid, such as by dissolving the olanzapine in the liquid, and the liquid may be removed, using one or more process embodiments described herein and in a manner which produces the desired form of olanzapine, such as non-crystalline olanzapine. Alternatively, the olanzapine free base and the acid can both be added to a liquid in a manner where the reaction to olanzapine takes place in the liquid, and the liquid can then be removed to produce the particles of olanzapine. In other versions, the olanzapine free base may be in solution in a liquid, such as a mother liquor from the synthesis process, and the acid may be added to this liquid, and the liquid may then be removed to produce non-crystalline olanzapine. When an excipient is to be included in the produced particles, the excipient may be added to the solution containing the olanzapine or the olanzapine free base and the acid. In an alternative version, a crystalline form of olanzapine may be used as the starting material that is added to the liquid. The crystalline olanzapine, for example, is dissolved in the solvent and the solvent is removed by a process that produces the non-crystalline olanzapine.

[00132] The following examples illustrate the formation of non-crystalline and/or stable versions of a formulation comprising olanzapine. These examples are not intended to limit the scope of the invention. EXAMPLE 1

[00133] A first example according to the present invention involves the formulation of pure olanzapine by removing a solvent to produce solid particles comprising olanzapine. In some embodiments, commercially available olanzapine comprises a crystalline powder with low solubility in water at pH above 6. Olanzapine tends to have a higher solubility in organic solvents, such as nitriles. Accordingly, the olanzapine may be dissolved, for example, in low concentrations in an oaqueous solvent or in higher concentrations in a solvent containing a liquid in which olanzapine is more soluble than it is in water. For example, non-aqueous solvents may include organic solvents, such as nitriles, acetonitrile, alcohols such as ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents. The solution may then be removed to produce particles comprising pure olanzapine, which may have beneficial pharmaceutical and/or micromeritic properties. Additionally, the particles of pure olanzapine may be processed under conditions which result in a physical stability acceptable for certain purposes. The solvent removal may be performed, for example, by spray-drying, freeze-drying, spray-freeze drying, vacuum drying, evaporation, and supercritical fluid extraction. In one version, the olanzapine is prepared under conditions, such as by being formed sufficiently quickly, that produce the olanzapine in a form that is at least partially non-crystalline for at least a period of time. Additioanlly or alternatively, instead of dissolving the olanzapine, solid particles of the olanzapine may be suspended in a liquid, such as an aqueous liquid, and the suspension may be dried to produce solid particles comprising olanzapine.

[00134] The spray drying (or other solvent removal) process is performed under conditions selected to result in the formation of a desired form of olanzapine, such as a non-crystalline form. Such conditions generally comprise those that result in the formation of at least a partially non-crystalline form of olanzapine, as a free-flowing powder, and/or having a T_g of above about 40⁰C, or a dry T_g of the olanzapine (without any residual solvents) of above about 90°C, or both.

EXAMPLE 2 [00135] Example 2 is a specific version of Example 1. In this version, particles comprising olanzapine are produced by spray drying as described herein and/or as additionally described in U.S. Patent 6,051,256, which is incorporated herein by reference in its entirety, with particular reference to spray drying processes. The starting material may be one or more of the crystalline polymorphs of olanzapine.

[00136] Specifically, the olanzapine of Example 2 can be made by performing the following steps:

[00137] 1. Starting with a commercially available olanzapine, the material is dissolved in a solvent comprising acetonitrile, at a solids content of about 0.01 to 20%, preferably about 0.1 to 20% and more preferably about 5-10%.

[00138] 2. The solution is spray-dried, for example, in a Buchi spray dryer with a solution feed rate at about 5 ml/min, an inlet temperature of about 100⁰C and an outlet temperature of about 6O⁰C. In one or more embodiments, the processing conditions result in the formation of at least a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above room temperature, especially above about 40°C, 50°C or 60⁰C, or a dry T_g of the pure olanzapine (without any residual solvents) of above about 90⁰C, or both.

[00139] 3. The particles are collected and are placed in a dry box.

[00140] The solution of step 1 can alternatively or additionally be made into powder using technologies known in the art, such as by freeze-drying, spray-freeze drying, vacuum drying, evaporation, bubble drying or extraction. This process can be performed in solvents other than water, such as organic solvents. For example, useful solvents comprise ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 3

[00141] Example 3 is another specific version of Example 1. In this version, particles comprising olanzapine are produced by spray drying. The particles were analyzed and the data from the analysis is shown in Figures 5A and 5B discussed above. The starting material may be one or more of the crystalline polymorphs of olanzapine.

[00142] Specifically, the olanzapine of Example 3 was be made by performing the following steps:

[00143] 1. Starting with a commercially available olanzapine, the material is dissolved in a solvent comprising water, at a solids content of about 0.01 to 20%, preferably about 0.1 to 20% and more preferably about 5-10%.

[00144] 2. The solution was spray-dried, for example, in a Buchi spray dryer with a solution feed rate at about 5 ml/min, an inlet temperature of about 100⁰C and an outlet temperature of about 6O⁰C. In one or more embodiments, the processing conditions result in the formation of at least a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40°C, or a dry T_g of the pure olanzapine (without any residual solvents) of above about 90⁰C, or both.

[00145] 3. The particles are collected and are placed in a dry box.

[00146] The solution of step 1 can alternatively or additionally be made into powder using technologies known in the field, such as by freeze drying, spray freeze drying, vacuum drying, bubble drying, evaporation, or extraction. This process can be performed in other organic solvents. For example, useful solvents comprise ethanol, iso- propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 4

[00147] In a fourth Example, a spray drying process is used to produce particles comprising non-crystalline olanzapine and a stabilizing excipient. Using this version, a non-crystalline form of olanzapine can be produced that remains non-crystalline over a period of time, especially a commercially-preferred period of time. In this version, the stabilizing excipient can be any excipient that increases the physical stability of the non- crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient.

[00148] Specifically, the non-crystalline olanzapine and excipient of this Example can be made by performing the following steps:

[00149] 1. Starting with a commercially available olanzapine, the material is dissolved in water at about 0.01 to 20%, preferably at about 0.1 to 20%, and more preferably at about 5-10% solid content. Particularly at the higher solid content ranges, solubility enhancers may be preferred. At lower concentrations, the olanzapine can be dissolved using an energy input, comprising, for example, mechanical agitation, sonication, vigorous stirring or the like. Alternatively, a solvent in which the olanzapine is more soluble, such as ethanol, may comprise the solvent.

[00150] 2. A stabilizing excipient is added to the solution of step 1 solution in a weight ratio of stabilizing excipientolanzapine of from about 0.1:10 to 10:0.1, more preferably from about 1 : 10 to 10:1, and most preferably about 1 :1. Steps 1 and 2 may be reversed or combined.

[00151] 3. The solution is spray dried under conditions selected to result in the formation of non-crystalline olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100-120⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40 or 50⁰C, or a dry T_g of the particles (without any residual solvents) of above about 60 or 70 or 80⁰C, or both. Alternatively or additionally, other solvent removal techniques, as described herein, may be used.

[00152] The stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient. The excipient preferably is partly or wholly miscible with the olanzapine in the noncrystalline state. This increase in physical stability may comprise a longer storage life of the formulation before crystallization, or may comprise a higher formulation glass transition temperature (T_g) at a particular relative humidity, or may comprise a lower hygroscopicity, or may comprise other physical stability determinants, or combinations thereof. In one or more versions, the stabilizing excipient is selected that has a higher T_g than that of the non-crystalline olanzapine, and the resulting formulation thus has a higher Tg than that of the non-crystalline olanzapine. In other versions, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline olanzapine, and the resulting formulation thus has a lower hygroscopicity than that of the non-crystalline olanzapine. In other versions, the stabilizing excipient may be selected so that it has both a higher glass transition temperature than that of the non-crystalline olanzapine and a lower hygroscopicity than that of the non-crystalline olanzapine (such as olanzapine). In one or more embodiments, suitable excipients comprise polyvinylpyrrolidone (PVP), a polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), a vinylpyrrolidone/vinyl acetate copolymer in a VA:VP of 60:40 (PVP-VA 64). Other preferred ratios of vinyl pyrrolidone: vinyl acetate may be about 80:20, 70:30, 50:50, 30:70, 40:60 and 20:80. Other useful excipients comprise poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; carbohydrates; polyols; sugars; oligo saccharides such as cyclodextrins; proteins, peptides and amino acids; lipids and modified lipids such as lipid-PEG and lipid-sugar esters; salts; citric acid; citrates; known glass formers; or the like.

[00153] Additional stabilizing excipients include cellulose polymers especially enteric cellulose polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit E, hydroxypropyl cellulose and hydroxypropyl beta cyclodextrin and combinations and mixtures of the above. More than one excipient, for example, more than one stabilizing excipient, may be formulated or co-formulated with the olanzapine in accordance with one or more embodiments of the present invention.

[00154] The solvent of this example (or other examples) can be removed by other aqueous solvent removal processes, such as freeze drying, spray freeze drying, evaporation, vacuum drying, bubble drying, or combinations thereof. The solvent of this example may alternatively or additionally comprise solvents other than water, such as organic solvents. For example, the solvent may comprise ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 5

[00155] In a fifth example, a spray drying process is used to produce particles comprising non-crystalline olanzapine and solubility-enhancing excipient. In this version, the excipient can be any excipient that increases the solubility of the noncrystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient. The commercially available olanzapine is sufficiently soluble in an aqueous liquid that has a pH less than about 6. Accordingly, in one version, the solubility enhancing excipient comprises an acid that may be added to a water solution to lower the pH of the solution thereby increasing the solubility of the olanzapine. In one particular version, the solubility enhancing excipient comprises citric acid.

[00156] Specifically, the non-crystalline olanzapine and excipient of this Example

5 can be made by performing the following steps:

[00157] 1. Starting with a commercially available olanzapine, the material is dissolved in water at about 0.01 to 20%, preferably about 0.1 to 20% and more preferably about 5-10% solids content.

[00158] 2. Citric acid is added to the water at a weight ratio of citric acid:olanzapine of from about 0.1 :10 to 10:0.1, preferably from about 0.5:5 to 5:0.5, more preferably from about 1:2 to 2:1, and most preferably of about 1:2. Alternatively or additionally, a different acid or other solubility enhancer may be used. For example, suitable acids include HCl, H₂SO₄, glycolic acid, lactic acid, and tartaric acid. Steps 1 and 2 may be reversed or combined.

[00159] 3. The solution is spray dried under conditions selected to result in the formation of a non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100-120⁰C. In one or more embodiments, the preferred processing conditions result in the formation of at least a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of the particles (without any residual solvents) of above about 70⁰C, or both. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, and wherein in one or more embodiments, a residual moisture level is about 3-5%. Alternatively or additionally, other solvent removal techniques may be used.

EXAMPLE 6

[00160] Example 6 is a specific version of Example 4. In this Example, a spray drying process is used to produce particles comprising non-crystalline olanzapine and a stabilizing excipient, wherein the stabilizing excipient comprises a non-carbohydrate, especially non-sugar polymeric or oligomeric excipient. Using this version, a noncrystalline form of olanzapine can be produced that remains stable with respect to the non-crystalline form over a period of time. In addition, because carbohydrate or sugar excipients tend to be hygroscopic, the particles produced in accordance with these and other Examples are less hygroscopic than particles comprising non-crystalline olanzapine and a sugar. In this version, the stabilizing excipient can be any non-sugar, non- carbohydrate excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient.

[00161] Specifically, the non-crystalline olanzapine and excipient of Example 6 can be made by performing the following steps:

[00162] 1. Starting with a commercially available crystalline olanzapine, the material is dissolved in water at about 0.01 to 20%, more preferably at about 0.1 to 20%, and more preferably at about 5-10% solid content. Particularly at the higher solid content ranges, solubility enhancers may be preferred. At lower concentrations, the olanzapine is sufficiently soluble to be dissolved using an energy input comprising mechanical agitation, sonication, vigorous stirring or the like. Alternatively, a solvent in which the olanzapine is more soluble, such as ethanol, may comprise the solvent.

[00163] 2. A stabilizing non-sugar excipient, such as a PVP, or a PVTWA copolymer is added to the solution of step 1 solution in a weight ratio of stabilizing excipientolanzapine of from about 0.1 :10 to 10:0.1, more preferably from about 1:10 to 10:1, and most preferably about 1:1. Steps 1 and 2 may be reversed or combined.

[00164] 3. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a noncrystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40°C, or a dry T_g of the particles (without any residual solvents) of above about 70°C, or both. Alternatively or additionally, other solvent removal techniques may be used.

[00165] The stabilizing excipient may be selected to comprise any excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient. This increase in physical stability may comprise a longer storage life of the formulation before crystallization, or may comprise a higher formulation glass transition temperature (T_g) at a particular relative humidity, or may comprise a lower hygroscopicity, or may comprise other physical stability determinants, or combinations thereof. In one or more versions, the stabilizing excipient is selected that has a higher glass transition temperature than that of the non-crystalline olanzapine, and the resulting formulation thus has a higher T_g than that of the non-crystalline olanzapine. In other versions, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline olanzapine, and the resulting formulation thus has a lower hygroscopicity than that of the non-crystalline olanzapine. In other versions, the stabilizing excipient may be selected so that it has both a higher glass transition temperature than that of the non-crystalline olanzapine and a lower hygroscopicity than that of the non-crystalline olanzapine (such as olanzapine). Useful excipients comprise polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), sodium citrate, citric acid, ethyl cellulose, and mixtures thereof. Other stabilizing excipients that may be used comprise vinylpyrrolidone/vinyl acetate copolymer, such as PVP-VA 64, poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; proteins, peptides and amino acids; lipids and modified lipids such as lipid-PEG esters; salts; citric acid; citrates; known non-sugar glass formers; or the like.

EXAMPLE 7

[00166] Example 7 represents yet another specific version of Example 4. In the production of Example 7, the following steps were carried out:

[00167] 1. Starting with a commercially available olanzapine, the material was dissolved in water at 1-25% solids content.

[00168] 2. Hydroxypropyl cellulose (HPC) was then added to the solution in a weight ratio of from about 0.1 :10 to 10:0.1, more preferably from about 1 :10 to 10:1, more preferably from about 1 : 1 to about 6:1 and most preferably about 1:1.

[00169] 3. The solution is spray dried under conditions selected to result in the formation of particles comprising least partially non-crystalline form olanzapine and HPC. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100-120⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a non-crystalline form of olanzapine comprising a free-flowing powder with a T_g above about 40⁰C, or a dry T_g of the particles (without any residual solvents) of above about 9O⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used.

[00170] The solvent of this example can be removed by other aqueous solvent removal processes, such as freeze drying, spray freeze drying, evaporation, or vacuum drying. The solvent of this example may alternatively or additionally comprise solvents other than water, such as organic solvents. For example, suitable solvents comprise ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 8

[00171] Example 8 represents yet another specific version of Example 4. In the production of Example 8, the following steps were carried out:

[00172] 1. Starting with a commercially available olanzapine, the material was dissolved in water at 1-25% solids content.

[00173] 2. Ethyl cellulose was then added to the solution in a weight ratio of from about 0.1:10 to 10:0.1, more preferably from about 1:10 to 10:1, more preferably from about 1 : 1 to about 6: 1 and most preferably about 1 :1.

[00174] 3. The solution is spray dried under conditions selected to result in the formation of particles comprising least partially non-crystalline form olanzapine and ethyl cellulose. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100-120⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40°C, or a dry T_g of the particles (without any residual solvents) of above about 70°C, or both. Alternatively or additionally, other solvent removal techniques may be used.

[00175] The solvent of this example can be removed by other aqueous solvent removal processes, such as freeze drying, spray freeze drying, evaporation, or vacuum drying. The solvent of this example may alternatively or additionally comprise solvents other than water, such as organic solvents. For example, suitable solvents comprise ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 9

[00176] Example 9 represents an example comprising a process-enhancing excipient. In the production of Example 9, the following steps are carried out:

[00177] 1. Leucine is added slowly to a solution containing water and ethanol co-solvents and the mixture is stirred and/or sonicated to dissolve the excipient.

[00178] 2. 5 g of crystalline olanzapine is added to the solution of step 1 and dissolved by stirring and/or sonication. The weight ratio of leucine:olanzapine may be from about 10:90 to about 90: 10, and in one or more versions is between about 20:80 and 80:20, or any range therebetween. The order of steps 1 and 2 may be reversed.

[00179] 3. The solution is spray-dried under conditions selected to result in the formation of particles comprising a non-crystalline form of olanzapine and leucine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100-120⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein a residual moisture level comprises about 3-5%. In one or more embodiments, the processing conditions result in the formation of a non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of the particles (without any residual solvents) of above about 70°C, or both. In one or more embodiments, the processing conditions result in the formation of a non-crystalline form of olanzapine comprising a free-flowing powder possessing desired or enhanced micromeritic properties. Alternatively, or additionally, other solvent removal techniques, as described herein, may be used. Leucine (as well as other amino- acids) are particularly useful for their contribution to the micromeritic properties of the powder formulation. For example, leucine may be used to produce a particulate formulation comprising olanzapine which is in the form of a dispersible powder, suitable for aerosols, or a powder ready for compression into a table dosage form. When co- formulated with the olanzpine as described herein, the leucine appears to form a coating on the formulated particles, providing good handling qualities. In this, or any other example, the leucine or other amino acid may be spray-blended with the olanzapine to produce a particle with desired or improved micromeritic properties.

EXAMPLE 10

[00180] Example 10 is another specific version of Example 4. In this Example, a spray drying process is used to produce particles comprising non-crystalline olanzapine and a stabilizing excipient, wherein the stabilizing excipient comprises a polymeric or oligomeric excipient other than a sugar and wherein the particle and/or the formulation further comprises a sugar. In this version, the non-sugar excipient comprises the primary stabilizer, and the sugar excipient comprises primarily a non-stabilizing purpose, such as a processing aid to facilitate downstream processing (such as mixing or tableting), and/or serves to reduce a static charge on processing equipment.

EXAMPLE 11

[00181] Example 11 is a specific version of Examples 4 and 5. In this Example, a spray drying process is used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient. Using this version, a noncrystalline form of olanzapine can be produced that remains non-crystalline over a period of time. In this version, the stabilizing excipient comprises any excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient.

[00182] Specifically, the non-crystalline olanzapine and excipient of Example 11 can be made by performing the following steps:

[00183] 1. Starting with a commercially available crystalline olanzapine, the material is dissolved in water at about 0.1 to 20%, and preferably at about 5-10% solid content.

[00184] 2. Citric acid is added to the water at a weight ratio of citric acid: olanzapine of from about 0.1 :10 to 10:0.1, more preferably from about 0.5:5 to 5:0.5, more preferably from about 1:2 to 2:1, and most preferably of about 1:2. Alternatively or additionally, a different acid or other solubility enhancer may be used.

[00185] 3. A stabilizing excipient is added to the solution of step 2 in a weight ratio of stabilizing excipientolanzapine of from about 0.1 :10 to 10:0.1, preferably from about 1 : 10 to 10:1, and more preferably about 1 :1. Steps 1 , 2 and 3 may be reversed or combined.

[00186] 4. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a noncrystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 4O⁰C, or a dry T_g of the powder (without any residual solvents) of above about 70⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used.

[00187] The stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient. This increase in physical stability may be in terms of the formulations storage life before crystallization and/or may be in terms of its glass transition temperature at a particular relative humidity and/or other physical stability determinants. In one version, the stabilizing excipient is selected that has a higher glass transition temperature than the non-crystalline olanzapine. In another version, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline olanzapine. In another version, the stabilizing excipient may be selected so that it has both a higher glass transition temperature and a lower hygroscopicity. For example, useful types of excipients comprise polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), sodium citrate, citric acid, ethyl cellulose, and mixtures thereof. Other stabilizing excipients that may be used comprise a vinylpyrrolidone/vinyl acetate copolymer in a VP: VA ratio of 60:40 (PVP-VA 64), or in ratios of 80:20, 70:30, 50:50, 40:60, 30:70, 20:80 or others, poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; carbohydrates; polyols; sugars; oligo saccharides such as cyclodextrins; proteins, peptides and amino acids; lipids and modified lipids such as lipid-PEG and lipid-sugar esters; salts; citric acid; citrates; known glass formers; or the like.

EXAMPLE 12

[00188] Example 12 is a specific version of Example 11. In this example, a spray drying process is used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient, wherein the stabilizing excipient comprises a polymeric or oligomeric excipient other than a sugar. Using this version, a non-crystalline form of olanzapine can be produced that remains physically stable (non-crystalline) over a period of time, such as at least about one month, preferably at least about three months, more preferably at least about six months. In addition, because sugar excipients tend to be hygroscopic, the particles produced in accordance with this Example are less hygroscopic than particles comprising noncrystalline olanzapine and a sugar. In this version, the stabilizing excipient can be any non-sugar excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient.

[00189] Specifically, the non-crystalline olanzapine and excipient of Example 12 can be made by performing the following steps:

[00190] 1. Starting with a commercially available crystalline olanzapine, the material is dissolved in water at about 0.1 to 20%, and more preferably at about 5-10% solid content.

[00191] 2. Citric acid is added to the water at a weight ratio of citric acidiolanzapine of from about 0.1 :10 to 10:0.1, more preferably from about 0.5:5 to 5:0.5, more preferably from about 1 :2 to 2: 1 , and most preferably of about 1 :2. Alternatively or additionally, a different acid or other solubility enhancer may be used.

[00192] 3. A stabilizing excipient other than a sugar or carbohydrate is added to the solution of step 2 in a weight ratio of stabilizing excipient: olanzapine of from about 0.1:10 to 10:0.1, preferably from about 1 : 10 to 10:1, and more preferably about 1:1. Steps 1 , 2 and 3 may be reversed or combined.

[00193] 4. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of the powder (without any residual solvents) of above about 70⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used. [00194] The stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline olanzapine when compared to a formulation of non-crystalline olanzapine substantially absent the excipient. This increase in physical stability may be in terms of the formulations storage life before crystallization and/or may be in terms of its glass transition temperature at a particular relative humidity and/or other physical stability determinants. In one version, the stabilizing excipient is selected that has a higher glass transition temperature than the non-crystalline olanzapine. In another version, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline olanzapine. In another version, the stabilizing excipient may be selected so that it has both a higher glass transition temperature and a lower hygroscopicity. For example, suitable excipients comprise polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), PVP-VA 64, sodium citrate, citric acid, ethyl cellulose, poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; proteins, peptides and amino acids; lipids and modified lipids such as lipid- PEG esters; salts; citric acid; citrates; known non-sugar glass formers; or the like.

EXAMPLE 13

[00195] Example 13 is a specific version of Example 11. In this example, a spray drying process is used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient, wherein the stabilizing compound is a polymeric compound containing an amino group or an amido group. For example, the stabilizing excipient may comprise one or more of polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA). Preferred are PVP30, PVP90, PVPVA64, and PVPV A28 (VP: VA ratio of 2:8). Using this version, a non-crystalline form of olanzapine can be produced that remains physically stable (non-crystalline) over a period of time, such as at least about one month, preferably at least about three months, more preferably at least about six months, with low hygroscopicity. [00196] Specifically, the non-crystalline olanzapine and excipient of Example 13 can be made by performing the following steps:

[00197] 1. Starting with a commercially available crystalline olanzapine, the material is dissolved in water at about 0.1 to 20%, and more preferably at about 5-10% solid content.

[00198] 2. Citric acid is added to the water at a weight ratio of citric acid:olanzapine of from about 0.1:10 to 10:0.1, more preferably from about 0.5:5 to 5 :0.5, more preferably from about 1 :2 to 2: 1 , and most preferably of about 1 :2. Alternatively, a different acid or other solubility enhancer may be used.

[00199] 3. A stabilizing excipient comprising one or more polymers having an amine group or an amide group is added to the solution of step 2 in a weight ratio of stabilizing excipienfcolanzapine of from about 0.1:10 to 10:0.1, more preferably from about 1:10 to 10:1, and most preferably about 1:1. Steps 1, 2 and 3 may be reversed or combined.

[00200] 4. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a noncrystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of the powder (without any residual solvents) of above about 70⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used.

EXAMPLE 14

[00201] Example 14 is a specific version of Example 11. In this example, a spray drying process is used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient comprising PVPVA. Using this version, a non-crystalline form of olanzapine can be produced that remains physically stable (non-crystalline) over a period of time, such as at least about one month, preferably at least about three months, more preferably at least about six months, with low hygroscopicity.

[00202] Specifically, the non-crystalline olanzapine and excipient of Example 14 can be made by performing the following steps:

[00203] 1. Starting with a commercially available crystalline olanzapine, the material is dissolved in water at about 0.1 to 20%, and more preferably at about 5-10% solid content.

[00204] 2. Citric acid is added to the water at a weight ratio of citric acid:olanzapine of from about 0.1:10 to 10:0.1, more preferably from about 0.5:5 to 5:0.5, more preferably from about 1:2 to 2:1, and most preferably of about 1:2. Alternatively, a different acid or other solubility enhancer may be used.

[00205] 3. PVPVA is added to the solution of step 2 in a weight ratio of stabilizing excipientolanzapine of from about 0.1:10 to 10:0.1, more preferably from about 1 : 10 to 10:1, and most preferably about 1 :1. Steps 1 , 2 and 3 may be reversed or combined.

[00206] 4. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 4O⁰C, or a dry T_g of the powder (without any residual solvents) of above about 70⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used.

EXAMPLE 15

[00207] Example 15 is a specific version of Example 14. In this example, a spray drying process was used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient comprising PVPVA. Using this version, a non-crystalline form of olanzapine can be produced that remains physically stable (non-crystalline) over a period of time, such as at least about one month, preferably at least about three months, more preferably at least about six months, with low hygroscopicity.

[00208] Specifically, the non-crystalline olanzapine and excipient of Example 15 can be made by performing the following steps:

[00209] 1. 5 g of PVPVA64 and 2.5g citric acid were dissolved in 87.5 g of water and stirred.

[00210] 2. 5 g of crystalline olanzapine was added to the solution of step 1 and dissolved by stirring. Steps 1 and 2 can be reversed.

[00211] 3. The solution was spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40°C, or a dry T_g of the powder (without any residual solvents) of above about 7O⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used. [00212] The particles comprising non-crystalline olanzapine and stabilizing excipient made in accordance with Example 15 have been analyzed and have been found to be non-crystalline with improved physical stability. An X-ray powder diffraction pattern of the powder particles is shown in Figure 6 (as shown by the upper curve). The X-ray pattern shows the powder to be non-crystalline in that no crystallinity-indicative peaks are present. The powder particles were then stored for 1 week at 75% relative humidity at 4O⁰C. The particles were X-rayed again and the X-ray powder diffraction pattern is also shown in Figure 6 (as shown by the lower curve). As can be seen, there is no indication of the conversion of the non-crystalline form to a crystalline form. To further illustrate the improvement in stability over pure non-crystalline forms of olanzapine, Figure 7 shows a graph of the water uptake into the non-crystalline formulation of Example 15 as a function of relative humidity, and Figure 8 shows a graph of the glass transition temperature of the particles as a function of relative humidity at about 4O⁰C. It should be noted that the T_g is only one possible determinant of the desired physical qualities of the resulting particles, and other determinants, such as hygroscopicity, empirical physical stability, chemical stability, powder flowability, handling properties, and micromeritic properties may be important as well.

EXAMPLE 16

[00213] Example 16 is a specific version of Example 14. In this example, a spray drying process is used to produce particles comprising non-crystalline olanzapine, a solubility enhancing excipient, and a stabilizing excipient comprising PVPVA. Using this version, a non-crystalline form of olanzapine can be produced that remains noncrystalline stable over a period of time with low hygroscopicity.

[00214] Specifically, the non-crystalline olanzapine and excipient of Example 16 can be made by performing the following steps:

[00215] 1. 4 g of PVPVA64 and 4 g citric acid are dissolved in 87.5 g of water and stirred.

[00216] 2. 4 g of crystalline olanzapine is added to the solution of step 1 and dissolved by stirring. Steps 1 and 2 can be reversed.

[00217] 3. The solution is spray dried under conditions selected to result in the formation of an at least partially non-crystalline form of olanzapine. For example, in one version, the solution is spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a partially non-crystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of the powder (without any residual solvents) of above about 70⁰C, or both. Alternatively or additionally, other solvent removal techniques may be used.

EXAMPLE 17

[00218] In this Example, three concentration ratios of olanzapine:excipient were prepared and spray dried from an acetonitrile solution. Specifically, formulations of noncrystalline olanzapine and excipient of were made by performing the following steps:

[00219] 1. Crystalline olanzapine and PVP-Cl 5 were dissolved in acetonitrile to form three different solutions, having ratios (w/w) of olanzapine:PVP-C15 of 10:90, 25:75 and 50:50, respectively.

[00220] 2. Each solution was spray dried under conditions selected to result in the formation of an at least partially noncrystalline powder form of olanzapine. The result was a free-flowing powder, with good handling qualities. For example, in one or more versions, the solution was spray dried in a conventional Buchi 190 spray dryer at a solution feed rate of about 5-10 ml/min and with an inlet temperature of about 100- 12O⁰C. The conditions may be adjusted for other spray dryers and/or other sized spray dryers, wherein in one or more embodiments, a residual moisture level is about 3-5%. In one or more embodiments, the processing conditions result in the formation of a noncrystalline form of olanzapine comprising a free-flowing powder and/or having a T_g above about 40°C, or a dry T_g of the powder (without any residual solvents) of above about 70°C, or both. Alternatively or additionally, other solvent removal techniques may be used.

[00221 ] X-ray powder diffraction patterns of the olanzapine/P VP-C 15 powder formulations were taken immediately after formulation and following storage for six months at 60% relative humidity and 25⁰C. These diffraction patterns are shown in Figure 9. As can be seen, all formulations were initially non-crystalline, and remained non-crystalline for at least six months. In the Figure, the upper two curves represent a 10:90 ratio of olanzapine:PVP, the next two curves represent a 25:75 ratio of olanzapine:PVP, and the lower two curves represent a 50:50 ratio of olanzapine:PVP. In each case, the upper curve of the pair is the T₀ analysis, and the lower curve is the analysis after storage for six months.

EXAMPLE 18

[00222] To any of the above examples, an additional active agent or agents may be added to the solution to allow for the production of particles comprising non-crystalline olanzapine, the additional active agent, and optionally a stabilizing excipient. The relative weight proportion of olanzapine to the additional active agent will vary depending on the active agent and the desired therapeutic profile.

[00223] Another example according to the present invention involves the formation of pure non-crystalline olanzapine by a Solution Enhanced Dispersion by Supercritical fluids (SEDS™) particle precipitation process, such as the one described in U.S. Patent 5,851,453 and U.S. Patent 6,063,138, both of which are incorporated herein by reference in their entireties, with particular reference to methods, apparatus and conditions for supercritical particle precipitation. Olanzapine is dissolved in a suitable non-aqueous solvent, such as an organic solvent. The solution is then contacted, in a particle precipitation process, by supercritical carbon dioxide which removes the solvent to produce particles comprising olanzapine. The starting material may be one or more of the crystalline polymorphs of olanzapine. The process is performed under conditions selected to result in the formation of a non-crystalline form of olanzapine. Such conditions generally comprise a reactor vessel temperature of about 35-80⁰C and a reactor vessel pressure of about 85-200 bar. In functional terms, it is preferred that the formation of a non-crystalline form of olanzapine comprise a free-flowing powder and/or having a T_g above about 40⁰C, or a dry T_g of above about 90⁰C, or both.

[00224] Specifically, the non-crystalline olanzapine of this Example 4 can be made by performing the following steps:

[00225] 1. Starting with a commercially available crystalline olanzapine, the salt is dissolved in a suitable solvent, at a solids content of about 0.01 to 20%, preferably about 0.1 to 20% and more preferably about 5-10%. In one or more versions, the suitable solvent comprises a nitrile, such as acetonitrile.

[00226] 2. The solution is then contacted, in a particle precipitation process, with a supercritical or near critical fluid anti-solvent, such as supercritical CO₂, which removes the solvent from the solution to produce non-crystalline olanzapine.

[00227] The solution of step 1 can alternatively or additionally be made into powder as described above.

EXAMPLE 19

[00228] In any of the above examples, the free compound, e.g. base, of olanzapine may be used as the starting material. For example, equal molar amounts of olanzapine free compound and hydrochloric acid may be added. The olanzapine and the hydrochloric acid react to form olanzapine hydrochloride that may then be processed into non-crystalline olanzapine. Alternatively, the starting material may be a liquid that contains olanzapine free compound, such as a mother liquor from the synthesis process, and the hydrochloric acid may be added to the liquid under conditions that will produce olanzapine. Additionally, a salt form may be used as the starting material.

EXAMPLE 20

[00229] In this example the solvent obtained as described in any other example herein can additionally or alternatively be removed by other aqueous solvent removal processes, such as freeze drying, spray freeze drying, evaporation, vacuum drying, bubble drying, or combinations thereof. The solvent of one or more examples herein may alternatively or additionally comprise solvents other than water, such as organic solvents. For example, the solvent may comprise ethanol, iso-propanol, methanol, other short chain alcohols, esters, ethers, and other low boiling point solvents.

EXAMPLE 21

[00230] A formulation, especially a pharmaceutical composition in accordance with any of the above examples may be administered to a patent (human or animal), for a condition treatable thereby, such as a psychotic disorder, and particularly to treat a patient having schizophrenia or schizophreniform disorders or conditions, and mania. For example, the formulations described herein may be formulated into a tablet containing 2 mg, 5 mg, 10 mg, or more of non-crystalline olanzapine. These amounts may be altered in order to achieve a desired therapeutic profile.

Analytical Methods

[00231] The analytical techniques employed in some of the examples are more fully described below.

[00232] X-ray powder diffraction (XRD/XRPD)

[00233] XRD/XRPD is used to characterize the nature of a sample or samples. An amorphous sample is indicated by the lack of diffraction peaks in the diffraction pattern which is characteristic of crystalline materials. Samples are analysed (on a D5000 XRD (Siemens, Germany) between 2 and 40° 2Θ, at a scan rate of 0.02 degrees per second, unless indicated otherwise.

[00234] Differential scanning calorimetry (DSC)

[00235] DSC is used to determine glass transition temperatures. This technique provides a measure of the glass transition characteristics of amorphous materials. In addition, the absence of a melting point is indicative of the lack of three dimensional order characteristic of crystalline materials. A Perkin-Elmer ™ DSC 7 (Perkin-Elmer Ltd, UK) is used. 1-5 mg samples are examined in sealed, crimped aluminium pans, under an atmosphere of nitrogen. Samples are measured using a TA DSC-2920 instrument (TA Instruments, New Castle, Delaware). About 5-10 mg sample is packed into an aluminum DSC pan and gently tapped to get the powder to form a uniform layer on the bottom of the pan (Catalog numbers 900 793.901 for pans and 900 794.901 for lids). The DSC pan is hermetically sealed using a sample encapsulation press (part # 900680.902). Helium is used as the DSC purge gas at 30 ml/min. A Refrigerated Control System (RCS) provides the heat sink for the DSC, with helium as the circuit gas run at -110 ml/min. In modulated DSC experiments, the sample is first cooled to about 0°C, held isothermally for 10 minutes, and then heated at 2°C/minute to ~200°C. The heating rate is modulated by superimposing a sinusoidal heating profile at ±0.318°C/min.

[00236] Dynamic Vapor Sorption

[00237] The moisture sorption isotherm of a powder at 25°C is measured using a dynamic vapor sorption (DVS) instrument made by Surface Measurement Systems, UK. Sample masses between 5 and 20 mg are used. Samples were loaded in a dry box to avoid moisture sorption. In the first step of the experimental run, the sample is dried at 25°C and 0%RH for at least 300 minutes, in an attempt to bring the sample to near zero wt% water. Then, the instrument is programmed to increase the RH in steps of 5% RH from 0% to 90% RH and decrease the RH in steps of 5%RH from 90% to 0% RH. A criterion of dm/dt =0.0001%/min is chosen for the system to hold at each RH step before proceeding to the next RH step.

[00238] High Performance Liquid Chromatography

[00239] A Hypersil model BDS C 18 (25 cm X 4.6 mm) column is used at ambient temperature. The mobile phase contained 30:70 acetonitrile : phosphate buffer (ammonium dihydrogen phosphate), with pH adjusted to 2.3 using Ortho-phosphoric acid. The flow rate is 1 ml/min and effluent is monitored at 254 run, in isocratic mode. Injection volume is 50 μl, with olanzapine target concentration about 40μg/ml. [00240] Materials

[00241] Crystalline olanzapine was obtained, for example from by Sai Life

Sciences Limited in Hyderabad, India.

[00242] PVPVA is commercially available from BASF, for example, under the trademark Kollidone®

[00243] HPC/HPMC is commercially available from Dow Chemical for example, under the trademark Methocel®.

[00244] Other chemicals, reagents and materials were obtained from various commercial sources, such as Sigma.

[00245] Although the present invention has been described in considerable detail with regard to certain preferred versions thereof, other versions are possible, and alterations, permutations and equivalents of the version shown will become apparent to those skilled in the art upon a reading of the specification. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention. Therefore, any appended claims should not be limited to the description of the preferred versions contained herein and should include all such alterations, permutations, and equivalents as fall within the true spirit and scope of the present invention.

Claims

IN THE CLAIMS

1. A particulate composition comprising non-crystallineolanzapine, wherein the composition is physically and chemically stable for at least one month at 25° C and 65% RH.

2. A pharmaceutical or nutraceutical composition comprising a formulation according to claim 1.

3. The composition of claim 1 wherein the olanzapine is produced by the steps of

(a) preparing a solution comprising olanzapine and solvent;

(b) removing the solvent from the solution of step (a); wherein a plurality of particles, in the form of a free-flowing powder, result.

4. The composition of claim 3 wherein the solvent removal step further comprises the steps of

(i) atomizing the solution comprising olanzapine and solvent; and (ii) spray-drying the olanzapine and solvent solution.

5. The composition of claim 4 wherein the solution of olanzapine and solvent further comprises an excipient, and wherein the resulting particles comprise olanzapine and excipient.

6. The composition of claim 5 wherein the excipient comprises a stability-enhancing excipient, a solubility-enhancing excipient, a process-enhancing excipient, or a combination thereof.

7. The composition of claim 6 wherein the stability-enhancing excipient is selected from polymers and copolymers of cellulose and derivatives thereof, and polymers and co-polymers of vinylpyrrolidone; the solubility-enhancing excipient is selected from organic and inorganic acids; and the process-enhancing excipient is selected from non-sugars and non-carbohydrates.

8. The composition of claim 6 wherein the composition has a higher T_g, a lower hygroscopicity, or both, compared to the olanzapine alone

9. The composition of claim 6 wherein the excipient comprises PVP, PVPVA, HMPC, HPC, alkyl cellulose, derivatives thereof and mixtures thereof.

10. The composition of claim 6 wherein the excipient comprises an amine or amide containing polymer or oligomer, or a combination thereof.

11. The composition of claim 1 wherein the olanzapine is produced by the steps of

(a) preparing a solution comprising olanzapine and solvent;

(b) atomizing the solution comprising olanzapine and solvent; and

(c) removing the solvent, under supercritical conditions, to produce noncrystalline olanzapine; wherein a plurality of particles, in the form of a free-flowing powder, result.

12. The composition of claim 11 wherein the solution of olanzapine and solvent further comprises an excipient, and wherein the resulting particles comprise olanzapine and excipient.

13. The composition of claim 12 wherein the composition has a higher T_g, a lower hygroscopicity, or both, compared to the olanzapine alone.

14. The composition of claim 12 wherein the excipient comprises a stability-enhancing excipient, a solubility-enhancing excipient, a process-enhancing excipient, or a combination thereof.

15. The composition of claim 14 wherein the stability-enhancing excipient is selected from polymers and copolymers of cellulose and derivatives thereof, and polymers and co-polymers of vinylpyrrolidone; the solubility-enhancing excipient is selected from organic and inorganic acids; and the process-enhancing excipient is selected from non-sugars and non-carbohydrates.

16. A particulate co-formulation comprising an olanzapine and excipient, the co- formulation prepared by a solvent removal method comprising

(a) providing a solution comprising solution or suspension of olanzapine and a polymeric or co-polymeric excipient in a solvent; and

(b) atomizing and spray-drying the solution so as to cause particles of a co- formulated non-crystalline olanzapine and excipient to precipitate from the solution.

17. The co-formulation of claim 16 wherein the excipient comprises a hydroxyalkylcellulose, an alkyl cellulose, a vinylpyrrolidone, a vinylpyrrolidone- vinyl acetate co-polymer, or a combination thereof.

18. The co-formulation of claim 17, wherein a ratio of olanzapine to excipient is about 1:1.

19. A method of preparing a particulate co-formulation comprising olanzapine and a stabilizing excipient, the method comprising

(a) providing a solution or suspension of olanzapine and a stabilizing excipient in a solvent; and

(b) removing the liquid from the solution or suspension so as to cause particles of co-formulated olanzapine and stabilizing excipient to precipitate, wherein a plurality of particles result, the particles the form of a free-flowing powder, and having a T_g of about 40°C or greater, a residual moisture of about 3-5%, and a volume mean diameter of about 5-200 microns.

20. A solid, non-crystalline formulation comprising particles of olanzapine and a stabilizing excipient, wherein the formulation is more physically stable than a formulation without the stabilizing excipient, and wherein the formulation is in the form of a free-flowing powder.

21. The formulation of claim 20 wherein the stabilizing excipient comprises one which serves to reduce the glass transition temperature of the formulation, or which serves to reduce the hygroscopicity of the formulation, or both.

22. The formulation of claim 20 and further including a solubility-enhancing excipient.

23. The formulation of claim 22 wherein the solubility-enhancing excipient comprises an organic acid, an inorganic acid, or both.

24. A solid, non-crystalline formulation comprising particles of olanzapine, a stabilizing excipient, and at least one of a solubility-enhancing excipient and a process- enhancing excipient, wherein the formulation is more physically stable than a formulation without the stabilizing excipient, and wherein the formulation is in the form of a free-flowing powder.

25. The formulation of claim 24 wherein the formulation includes a process-enhancing excipient, and wherein the formulation exhibits improved micromeritic properties.

26. The formulation of claim 25 wherein the process-enhancing excipient comprises an amine or amide containing compound.

27. The formulation of claim 26 wherein the improved micromeritic properties comprise at least one of powder flowability, powder compressability, powder handling, powder particle size and powder density.