WO2006063025A1

WO2006063025A1 - Stable non-crystalline formulation comprising donepezil

Info

Publication number: WO2006063025A1
Application number: PCT/US2005/044211
Authority: WO
Inventors: Chun Zhen; Sarma Duddu; David Lechuga; Jiang Zhang; Andreas Kordikowski
Original assignee: Nektar Therapeutics
Priority date: 2004-12-07
Filing date: 2005-12-07
Publication date: 2006-06-15

Abstract

One or more embodiment of the invention provide various novel formulations comprising donepezil that are non-crystalline, more stable, and/or otherwise improvements over known donepezil formulations. The donepezil-containing formulations may be administered to a user to treat senile dementila, especially the Alzheimer type.

Description

United States Patent Application for:

Stable Non-crystalline Formulation Comprising Donepezil

RELATED APPLICATION

[0001] This application relates to U.S. Provisional Application No. 60/633,990, filed December 7, 2004, from which priority is claimed under 35 USC §1 19(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 donepezil, to co-formulations of donepezil with excipients, to methods of preparing, pharmaceutical compositions comprising them and their use in medical treatment. The present invention relates more particularly to co-formulations of donepezil with one or more oligomeric and/or polymeric excipients, and to methods of making and methods of delivering, which result in improved or enhanced solubility or dissolution characteristics, resulting in 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] Donepezil, l-benzyl-4-[(5,6-dimethoxy-l -indanone)-2-yl] methylpiperidine, a cyclic amine compound having structural formula (Formula I):

Formula I

is a well known pharmaceutical agent.

[0004] U.S. Patent 4,895,841 to Sugimoto et al, which is incorporated herein by reference in its entirety, describes the acetylcholinesterase inhibitory action of cyclic amines, including the donepezil compound. This action makes the compound useful in treating and/or preventing the onset or progress of senile dementia, particularly senile dementia of the Alzheimer type.

[0005] Donepezil is commercially manufactured by Eisai Co., Ltd of Teaneck, New Jersey and is marketed in the United States by Eisai Co. and by Pfizer Inc. of New York, New York under the tradename ARICEPT®. According to the Eisai and Pfizer product description, ARICEPT® is donepezil hydrochloride, a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro- 5 ,6-dimethoxy-2- [ [ 1 -(phenylmethyl)-4-piperidiny l]methyl] - 1 H-inden- 1 -one hydrochloride. It has the empirical formulation C₂₄H₂₉NO₃HCl, a molecular weight of 415.96, and with the structural formula (Formula II):

Formula II

[0006] Donepezil hydrochloride is a white crystalline powder, soluble in chloroform, in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in hexane.

[0007] ARICEPT® is available as orally administrable tablets in the following dosage amounts: 5 mg and 10 mg of donepezil hydrochloride. The ARICEPT® tablets also contain the following inactive ingredients: lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The film coating contains talc, polyethylene glycol, hypromellose and titanium dioxide. Additionally, the 10 mg tablet contains yellow iron oxide (synthetic) as a coloring agent.

Description of Related Art

[0008] In the ARICEPT® tablets, the donepezil hydrochloride is in a crystalline form. Crystalline polymorphic Forms 1, II, III, IV, and V are described in U.S. Patents 5,985,864 and 6,140,321, both to Imai et at, both of which are incorporated herein by reference in their entireties. U.S. Patent 6,245,911 also to Imai et at, which is incorporated herein by reference in its entirety, describes various methods for making the crystalline polymorphic forms of donepezil hydrochloride by first making polymorphic crystalline donepezil free compound and then using the crystallines in the production of polymorphic crystalline donepezil hydrochloride.

[0009] The existing crystalline forms of donepezil have disadvantages. While the crystalline forms of donepezil are physically stable in that they do not easy convert to another form during storage or processing, the crystalline forms are, however, less bioactive than non-crystalline forms, such as amorphous forms. Moreover, crystalline forms of active agents generally have poorer dissolution rates than noncrystalline forms. While the free compound (i.e. base) form of donepezil is not very soluble, the acid salt form has acceptable solubility. The non-crystalline forms, however, often 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. Prior art attempts to formulate non-crystalline (amorphous) donepezil have met with only limited success. For example, U.S. Patent 5,985,864, which is referred to above, describes an amorphous form of donepezil hydrochloride produced by dissolving donepezil hydrochloride in water and freeze drying the solution for four days to form pure amorphous donepezil hydrochloride. However, when pure amorphous donepezil hydrochloride is formulated as described in 5,985,864, the formulation has limited physical stability, as discussed throughout the patent. Under normal storage conditions, the pure amorphous donepezil hydrochloride tends to alter its form and often converts to one or more of its crystalline forms. Because the degree of crystalline conversion at a particular time during the storage is often unknown, it is difficult to assure that dosages are administered in a consistent solid form. As a result, the donepezil 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 donepezil in amorphous form are lost. In addition, non-crystalline forms of active agents such as donepezil are difficult to process for pharmaceutical compositions.

[0010] Therefore, it is desirable to be able to produce a non-crystalline, especially amorphous, form of donepezil. It is further desirable to be able to produce a noncrystalline form of donepezil that is physically stable, for example, by maintaining its non-crystalline state for an increased amount of time when compared to pure amorphous donepezil. It is further desirable to be able to produce a non-crystalline form of donepezil that is chemically stable. It is still further desirable to be able to produce a non-crystalline form of donepezil that is both physically and chemically stable. Non-crystalline forms may have other advantages, such as handling advantages.

Summary of the Invention

[0011] One or more embodiments of the present invention satisfies these needs. The embodiments of the invention provide various novel formulations comprising donepezil that are non-crystalline, more stable, and/or otherwise improvements over known donepezil formulations.

[0012] In one aspect of the invention, a solid, non-crystalline formulation comprises donepezil wherein the formulation is physically stable. [0013] In one aspect of the invention, a solid formulation comprises donepezil wherein the formulation exhibits at least one of the characteristics of acceptable, or parity, dissolution, solubility, stability, shelf life, or bioavailability, when compared to a commercially-available formulation, or manufacturing ease or manufacturing cost-effectiveness.

[0014] In one aspect of the invention, a solid, non-crystalline formulation comprises donepezil and an excipient, wherein the formulation exhibits at least one of the characteristics of enhanced dissolution, solubility, stability, shelf life, bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

[0015] In another aspect of the invention, a solid, non-crystalline formulation comprises donepezil wherein the formulation maintains its non-crystalline form when stored at 25°C and 60% relative humidity for a period of at least one week, more preferably at least one month, more preferably at least three months.

[0016] In another aspect of the invention, a solid, non-crystalline formulation comprises donepezil wherein the formulation maintains its non-crystalline form when stored at 40°C and 75% relative humidity for a period of at least one week, more preferably at least one month, more preferably at least three months.

[0017] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and an excipient.

[0018] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and a stabilizing excipient, wherein the formulation is more physically stable than a formulation without the stabilizing excipient.

[0019] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and a stabilizing excipient, wherein the formulation when stored at 40°C and 75% relative humidity converts to a crystalline form more slowly 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 donepezil and a stabilizing excipient, wherein the formulation has a higher glass transition temperature (T_g) than a formulation without the stabilizing excipient.

[0021] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and a stabilizing excipient, wherein the formulation has a glass transition temperature (T_g) of above about 40°C.

[0022] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and a stabilizing excipient, wherein the formulation has a lower hygroscopicity 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 donepezil and an excipient, and wherein the excipient comprises a polymer or co-polymer of a cellulose, such as a hydroxypropyl alkylcellulose

[0024] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and an excipient, and wherein the excipient comprises a polymer or co-polymer of a vinylpyrrolidone, such as polyvinylpyrrolidone.

[0025] In another aspect of the invention, a solid, non-crystalline formulation comprises particles, wherein the particles comprise donepezil and an excipient, and wherein the excipient comprises a co-polymer of a a vinylpyrrolidone and a vinyl acetate, such as a vinylpyrrolidone-vinyl acetate.

[0026] In another aspect of the invention, a method of treating, slowing, mitigating or preventing conditions for which an excess of acetylcholinesterase is present, comprises administering to a user a non-crystalline formulation comprising donepezil.

[0027] In another aspect of the invention, a method of treating, slowing, mitigating or preventing the onset of senile dementia, such as Alzheimer-type senile dementia, comprises administering to a user a non-crystalline formulation comprising donepezil.

[0028] In another aspect of the invention, a method of treating, slowing, mitigating or preventing the onset of senile dementia, such as Alzheimer-type senile dementia, comprises administering to a user a formulation comprising non-crystalline donepezil following storage of the formulation.

[0029] In another aspect of the invention, a method of treating, slowing, mitigating or preventing the onset of senile dementia, such as Alzheimer-type senile dementia, comprises administering to a user a particulate formulation wherein the particles comprise non-crystalline donepezil and an excipient.

[0030] In another aspect of the invention, a method of treating, slowing, mitigating or preventing the onset of senile dementia, such as Alzheimer-type senile dementia, comprises administering to a user a non-crystalline, particulate formulation wherein the particles comprise non-crystalline donepezil and a stabilizing excipient.

[0031] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing a liquid containing donepezil and spray drying the liquid to produce particles comprising non-crystalline donepezil.

[0032] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing a liquid containing donepezil and contacting the liquid with a supercritical or near supercritical fluid to remove the liquid to produce particles comprising non-crystalline donepezil.

[0033] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing a liquid containing donepezil and spray drying the liquid to produce particles comprising non-crystalline donepezil.

[0034] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing a liquid containing donepezil and a stabilizing excipinet and removing the liquid by contacting the liquid with a supercritical or near supercritical fluid to produce particles comprising noncrystalline donepezil and stabilizing excipient.

[0035] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing an aqueous liquid containing donepezil and an excipient and removing the aqueous liquid to produce particles comprising donepezil and the excipient.

[0036] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing an aqueous liquid containing donepezil and an excipient and removing the aqueous liquid to produce particles comprising non-crystalline donepezil and the excipient wherein the particles exhibit at least one of the characteristics of enhanced dissolution, enhanced solubility, enhanced stability, enhanced shelf life, enhanced bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

[0037] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing an organic solvent containing donepezil and removing the organic solvent to produce particles comprising non-crystalline donepezil.

[0038] In another aspect of the invention, a method of making a formulation comprising donepezil comprises providing an organic solvent containing donepezil and an excipient and removing the organic solvent to produce particles comprising non-crystalline donepezil and the excipient.

[0039] In another aspect of the invention, a method of making a formulation comprising donepezil comprises spray drying a liquid containing donepezil and an excipient to produce particles comprising non-crystalline donepezil and the excipient.

[0040] In another aspect of the invention a method of making a formulation comprising donepezil comprises providing a liquid and a donepezil free compound and adding an acid in a manner that produces the acid salt of the donepezil in solution. The liquid is then removed to form a non-crystalline donepezil acid salt.

[0041] In another aspect of the invention a method of making a formulation comprising donepezil comprises providing a liquid and a donepezil free compound and adding hydrochloric acid in a manner that produces a donepezil hydrochloride in solution. The liquid is then removed to form a non-crystalline donepezil hydrochloride.

[0042] In another aspect of the invention a method of making a formulation comprising donepezil comprises providing a donepezil free compound and reacting the donepezil free compound with a substantially equal mole of hydrochloric acid to produce donepezil hydrochloride, that is then added to a liquid. The liquid is then removed to form non-crystalline donepezil hydrochloride.

[0043] In another aspect of the invention, any two or more of the above aspects are combined.

DRAWINGS

[0044] 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:

[0045] Figure IA is a graph showing an X-ray powder diffraction (XRPD) profile for a prior art form of donepezil hydrochloride in its crystalline polymorphic Form I; [0046] Figure IB is a graph showing an X-ray powder diffraction (XRPD) profile for a prior art form of donepezil hydrochloride in its crystalline polymorphic Form II;

[0047] Figure 1 C a graph showing an X-ray powder diffraction (XRPD) profile for a prior art form of donepezil hydrochloride in its crystalline polymorphic Form III;

[0048] Figure ID is a graph showing an X-ray powder diffraction (XRPD) profile for a prior art form of donepezil hydrochloride in its crystalline polymorphic Form IV;

[0049] Figure IE is a graph showing an X-ray powder diffraction (XRPD) profile for a prior art form of donepezil hydrochloride in its crystalline polymorphic Form V;

[0050] 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;

[0051] 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;

[0052] 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;

[0053] Figure 5 is a graph showing an X-ray powder diffraction (XRPD) profile for pure non-crystalline donepezil hydrochloride particles produced by spray drying donepezil hydrochloride dissolved in an aqueous solution, in accordance with one or more aspects of the present invention, the graph was obtained shortly after preparation of the particles;

[0054] Figure 6 is a graph showing a differential scanning calorimetry (DSC) thermogram of the pure non-crystalline donepezil hydrochloride analyzed in Figure 5 after exposure to 75% relative humidity at 40°C for about 1 week;

[0055] Figure 7 is a graph showing an X-ray powder diffraction (XRPD) profile for a formulation comprising non-crystalline donepezil hydrochloride and a stabilizing excipient after the formulation was exposed to 75% relative humidity at 40°C for 3 weeks;

[0056] Figure 8 is a DVS Isotherm plot showing change in mass as a function of humidity for a pure non-crystalline donepezil hydrochloride powder;

[0057] Figure 9 is a DVS Isotherm plot showing change in mass as a function of humidity for particles comprising non-crystalline donepezil hydrochloride and a stabilizing excipient, made in accordance with one or more embodiments of the present invention;

[0058] Figure 10 is a graph showing an X-ray powder diffraction (XRPD) profile for a formulation in accordance with one or more embodiments of the present invention, comprising non-crystalline donepezil hydrochloride and a stabilizing excipient after the formulation was exposed to 60% relative humidity at 25°C for 1 week;

[0059] Figures 1 IA, 1 IB, and 11C are graphs showing X-ray powder diffraction (XRPD) profiles for a formulation comprising non-crystalline donepezil hydrochloride and a stabilizing excipient made by a SEDS particle precipitation process immediately after processing (1 IA), after the formulation was exposed to 75% relative humidity at 40°C for 9 months in capped vials (1 IB), and after the formulation was exposed to 75% relative humidity at 40°C for 6 months in uncapped vials (HC);

[0060] Figures 12A and 12B show the water uptake into the non-crystalline formulation analyzed in FigureS 11 immediately after processing (12A) and after the formulation was exposed to 75% relative humidity at 40°C for 9 months in capped vials (12B); and

[0061] Figure 13 is a DSC graph of specific heat as a function of temperature for the non-crystalline formulation analyzed in Figures 11 after the formulation was exposed to 75% relative humidity at 40°C for 9 months in capped vials. DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

[0062] One or more embodiments of the present invention relates to a formulation comprising donepezil, to a method of making a formulation comprising donepezil, and to a method of administering a formulation comprising donepezil. One or more embodiments of the present invention further relates to a pharmaceutical composition comprising donepezil, to a method of making a pharmaceutical composition comprising donepezil, and to a method of administering a pharmaceutical composition comprising donepezil. 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

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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

[0067] 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. Although 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, the preferred materials and methods are described herein.

[0068] Amount of ingredients, materials or substances are listed as the ranges or levels of ingredients in the descriptions, which follow hereto.

[0069] "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.

[0070] "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). Donepezil is one example of a drug.

[0071] 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.

[0072] 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 pharmaceutically-active agent, such as donepezil, 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. A formulation includes a co-formulation, unless otherwise clear from the context.

[0073] By "donepezil" it is meant the compound l-benzyl-4-[(5,6-dimethoxy-l - indanone)-2-yl]methylpiperidine and includes all cyclic amine compounds having the following chemical formula:

Formula III

wherein r is an integer of 1 to 10 , R²² is hydrogen or methyl, and the R²² radicals can be the same or different when r is from 2 to 10; K is phenylalkyl or phenylalkyl having a substituent on the phenyl ring;

S is hydrogen or a substituent on the phenyl ring, and t is an integer of 1 to 4, with the proviso that (S)t can be a methylenedioxy group or an ethylenedioxy group joined to two adjacent carbon atoms of the phenyl ring; and q is an integer of 1 to 3,

and which have acetylcholinesterase inhibitory action properties and/or are useful in treating, preventing, slowing the onset of senile dementia, including Alzheimer-type senile dementia and/or treating any symptom associated with senile dementia, including Alzheimer-type senile dementia. The donepezil compound may be in its free compound form or in the form of any pharmaceutically acceptable salt, ester, or prodrug of donepezil. [0074] The term "pharmaceutically acceptable salts" comprise salts of an inorganic acid, salts of an organic acid, salts of an inorganic base, salts of an organic base, and salts of an acidic or basic amino acid. An acid or base is formed into a salt at an appropriate ratio of 0.1 to 5 molecules per 1 molecule of the compound. 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 inorganic bases are a salt of sodium, alkaline metals such as potassium, a salt of calcium, alkaline earth metals such as magnesium, a salt of aluminum, and an ammonium salt. Examples of salts of organic bases are salts of diethylamine, diethanolamine, meglumine, and N, N'-dibenzyl ethylene diamine. 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.

[0075] By "donepezil hydrochloride" it is meant the hydrochloride salt of donepezil, as shown by the structural formula below:

The term "donepezil hydrochloride" is further meant to include all forms, including stereoisomers, enantiomers, diastereomers, optically active forms, mixtures thereof, and a racemic mixture.

[0076] 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.

[0077] 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. "Noncrystalline" 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.

[0078] One or more embodiments of the present invention provides an improved formulation comprising non-crystalline donepezil. Among other improvements, the donepezil -containing formulation described herein offers improvements over prior art formulations containing crystalline donepezil in that the one or more embodiments of the present invention provides non-crystalline donepezil in a form where it has a dissolution rate and or dissolution profile which provides a therapeutically desired bioavailability, especially a commercially therapeutically desired bioavailability. Additionally or alternatively, one or more embodiments of the present invention is advantageous over known pure amorphous forms of donepezil in that the one or more embodiments of the methods and/or formulations of the present invention have improved processability and/or improved physical stability allowing the formulation to be stored over longer periods of time and/or allowing the formulation more time processing into a solid dosage form, such as a tablet. [0079] Solid donepezil is conventionally present in one or more of its stable crystalline forms. For example, as disclosed in U.S. Patent 5,985,864, donepezil may be processed to be in crystalline polymorphic Form I, II, III, IV, or V. Each of these crystalline polymorphic forms may be characterized by analyzing the X-ray powder diffraction pattern of the solid material. Figures IA through IE show the X-ray powder diffraction pattern disclosed in U.S. Patent 5,985,864 for crystalline polymorphic Forms I through V, respectively, of donepezil hydrochloride. Form I of donepezil hydrochloride may be characterized by the following peaks in the diffraction pattern:

and/or

Form II of donepezil hydrochloride may be characterized by the following peaks in the diffraction pattern:

and/or

Form III of donepezil hydrochloride may be characterized by the following peaks in the diffraction pattern:

,

and/or8

Form IV of donepezil hydrochloride may be characterized by the following peaks in the diffraction pattern:

and/or

Form V of donepezil hydrochloride may be characterized by the following peaks in the diffraction pattern:

[0080] Commercially available donepezil hydrochloride, supplied by Eisai Co., Ltd. of Teaneck, New Jersey, has been analyzed and determined to be at least partially crystalline.

[0081] As discussed above, the crystalline form of donepezil has proven to be stable and effective but with limited bioavailability. However, when in the non-crystalline form, one or more embodiments of the present invention provide donepezil that has a dissolution rate that provides a therapeutically desired bioavailability, especially a commercially, therapeutically desired bioavailability. In other embodiments, the non-crystalline donepezil has a dissolution rate that is indicative of improved bioavailability. In other embodiments, the non-crystalline donepezil has a dissolution rate that is comparable to or better than, a commercially available ARICEPT® product, on a dose per dose basis. Accordingly, in one or more versions of the present invention, a formulation comprising donepezil is provided in noncrystalline form, as are methods of making thereof. By providing non-crystalline donepezil, the efficacy of the donepezil is maintained while the dissolution rate is increased, thereby providing an improved form of the pharmaceutical agent.

[0082] In one or more versions, the non-crystalline formulation is produced by spray drying. During the spray drying process the donepezil is dissolved 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 donepezil. 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.

[0083] 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 donepezil 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 but often 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 50 μm. Smaller particle sizes, for example 10 μm or less, or larger particle sizes, for example about 500 μm or greater, may have applications in additional or alternative dosage forms.

[0084] 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.

[0085] 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.

[0086J 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 (centrifugal, sonic, pressure, two fluid) capable of producing droplets with a mass median diameter of less than about 100 microns could be used. Preferred for one or more embodiments of the present invention is the use of a rotary atomizer wherein the liquid flows over a wheel surface as a thin film, and is sheared away into discrete droplets, or a two-fluid atomizer wherein the liquid medium is delivered through a nozzle concurrently with a high pressure gas stream.

[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. Donepezil thus comprises one example of an active agent. In one or more embodiments, the active agent is present as a solution in water. Alcohol/water co-solvent systems according to this invention may also be employed. Other suitable solvents comprise alcohols such as methanol, ketones such as acetone, polar aprotic solvents, hydrogenated hydrocarbons such as metyhlene chloride, hydrocarbons such as cyclohexane, and mixtures thereof. 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 some 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 70°C, and may be at least 120°C, at least 135°C, at least 145°C, and may often be over 175°C, or even as high as 200°C, 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- 100°C. The drying gas may be moved through the system using conventional blowers or compressors.

[0090] The separation operation 30 is selected to achieve a high efficiency collection of the particles produced by the drying operation 20. 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 preferably achieves 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 an 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 one embodiment, 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 often advantageous in terms of its efficiency and reproducibility.

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

[0095] In one or more versions, the solvent extraction process using a supercritical or near critical fluid involves contacting a solution or suspension containing donepezil in a fluid (the "donepezil 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 donepezil solution/suspension and to cause particles comprising donepezil 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 donepezil 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 that 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 version, this process involves using the anti-solvent fluid substantially simultaneously both to extract the vehicle from, and to disperse, the donepezil 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 T_c 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 used is preferably supercritical, near-critical or liquid CO₂, especially supercritical CO₂. Preferred solvents include one or more of methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, ethylacetate, dimethylformamide, dichloromethane, MeCN (acetonitrile), N,N-dimethylacetamide (DMA). Hydroxylic solvents are particularly preferred. The processing conditions are preferably chosen to produce particles of desired sizes and/or to reduce residual solvent levels.

[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 about 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 about 1.5, preferably between about 0.9 and about 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 P_c 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 T_c of the anti-solvent, (iv) the anti-solvent is introduced into the vessel at a temperature T₂, where T₂ is greater than T), (v) T) 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] Although not wishing to be bound by theory, it is believed that in the method of the invention, a so-called "Mach disk" is generated in the anti-solvent flow downstream of the second fluid inlet means. In this region the fluid velocity will change abruptly to sub-sonic thus generating shock waves in the fluids present (in effect a continuous, low volume, supersonic boom). These shock waves are thought to aid mixing and dispersion of the target solution/suspension with the anti-solvent. Moreover they will propagate in the direction of the anti-solvent flow, rather than in a counter-current sense.

[00102] The arrangement of the first and second inlet means will preferably be such that the Mach disk is generated upstream (in the direction of anti-solvent flow) of the point of entry of the target solution/suspension into the particle formation vessel. It should occur in line with the longitudinal axis of the second inlet means, i.e., in line with the direction of anti-solvent flow.

[00103] The near-sonic, sonic or supersonic anti-solvent velocity is ideally achieved, in one or more embodiments of the method of the present invention, by the use of appropriate anti-solvent flow rates, back pressures and/or operating temperatures, and preferably without the aid of mechanical, electrical and/or magnetic input such as for example from impellers, impinging surfaces especially within the anti-solvent introducing means, electrical transducers and the like. Introducing the anti-solvent via a convergent nozzle, ideally as a single fluid stream, may also help in the achievement of appropriate fluid velocities.

[00104] The use of near-sonic, sonic or supersonic anti-solvent velocities can allow achievement of smaller particle sizes and narrower size distributions in GAS- 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 may have narrow size distributions, such as with a standard deviation of about 2.5 or less, preferably about 2.0 or less, more preferably about 1.9 or even about 1.8 or less.

[00105] 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.

[00106] 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 natures 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 0.001 to about 20 milliseconds. The contact preferably occurs within about 0.001 to about 10 milliseconds, such as within about 0.01 to about 5 milliseconds, of the anti-solvent entering the particle formation vessel.

[00107] 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 30 degrees, such as about 0 degrees.

[00108] When carrying out one or more embodiments 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 needs to be miscible or substantially miscible with the vehicle.

[00109] 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 about 0.2, more preferably from about 0.03 to about 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.

[00110] 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.

[00111] 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).

[00112] Preferably, the opening at the outlet end (tip) of the nozzle will have a diameter in the range of about 0.05 mm to about 2 mm, more preferably between about 0.1 mm and about 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.

[00113] Figure 5 shows the x-ray powder diffraction pattern of pure noncrystalline donepezil hydrochloride particles produced by spray drying donepezil dissolved in an aqueous solution in accordance with Example 1 (infra). By "pure non-crystalline donepezil hydrochloride" it is meant that a majority of the particles consist of donepezil hydrochloride. As can be seen, there are no characteristic peaks. Figure 6 is a DSC thermogram for the formulation of Figure 5, after one week exposure to 40°C and 75% RH. Thus, it can be determined that the formulated particles are non-crystalline. 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.

[00114] A pure non-crystalline donepezil hydrochloride formulation, i.e. absent a stabilizing excipient, made, for example, as described in Example 1 (infra) is initially stable, but under certain storage conditions will revert to a crystalline form. However, even pure non-crystalline forms of donepezil acid salts may be sufficiently stable when made in accordance with one or more versions of a process of the present invention.

[00115] Accordingly, in one or more versions of the present invention, a noncrystalline formulation comprising donepezil is formulated so as to improve its physical stability. For example, the improved stability may be provided by combining the non-crystalline donepezil with a stabilizing excipient. The stabilizing excipient is provided in a sufficient quantity to reduce the tendency of the noncrystalline donepezil to convert to a crystalline form. The donepezil 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 donepezil. The stabilizing excipient may be either noncrystalline or crystalline, as long as it serves to maintain the donepezil in a noncrystalline form.

[00116] In one or more versions, the formulation is made up of particles, and the particles comprise non-crystalline donepezil and an excipient, i.e. both the donepezil and the stabilizing excipient are present in the same formulated particle, as by co-formulating, for example. By providing the stabilizing excipient and the donepezil in the same particle, the excipient and the donepezil are in greater contact and the stabilizing excipient is better able to assert its stabilizing influence on the donepezil. In one or more versions, the donepezil and the excipient are formulated so that there is provided a solid dispersion of one component in another, such as an intimate mixture of donepezil dispersed in a matrix of the stabilizing excipient, or a solid solution of the components, whereby an intimate association results. In one or more versions, the particles comprising non-crystalline donepezil and excipient may be formulated by adding the excipient to the liquid in the product methods described above. For example, donepezil 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, evaporation, supercritical fluid extraction, or other solvent removal technique.

[00117] The stabilizing excipient may be any excipient that serves to reduce the conversion of non-crystalline donepezil to crystalline donepezil when compared to non-crystalline donepezil in the absence of the stabilizing excipient. For example, the excipient may comprise one or more polymeric or oligomeric excipients, such as polyvinylpyrrolidone (PVP), a 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; 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.

[00118] Additionally or alternatively, the stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline donepezil when compared to a formulation of non-crystalline donepezil substantially absent the excipient. The excipient preferably is partly or wholly miscible with the donepezil in the non-crystalline state. This increase in physical stability may be in terms of the formulation's storage life before crystallization, or may be in terms of its glass transition temperature at a particular relative humidity, or in terms of its hygroscopicity, or in terms of other physical stability determinants, or combinations thereof. In one or more versions, the stabilizing excipient is selected that has a higher glass transition temperature (T_g) than that of the non-crystalline donepezil, and the resulting formulation thus has a higher T_g than that of the non-crystalline donepezil. In other versions, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline donepezil, and the resulting formulation thus has a lower hygroscopicity than that of the non-crystalline donepezil. 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 donepezil and a lower hygroscopicity than that of the non-crystalline donepezil (such as donepezil hydrochloride).

[00119] Examples of other polymeric or oligomeric excipients for formulation with donepezil according to the invention include 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.

[00120] A preferred HPMC is marketed by the Dow Chemical Company under the trademark METHOCEL(R). The METHOCELs include E5, K, F or E types. Substitution types, include, without limitation, 2208, 2906, and 2910, i.e. having varying degrees of methoxyl group substitution.

[00121] 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 donepezil, to provide improved stability to the non-crystalline donepezil. In one or more embodiments, the improved stability comprises physical stability which is comparable to, or better than, that attained by a crystalline form of donepezil. In one or more embodiments, the improved stability comprises chemical stability which is comparable to, or better than, that attained by a crystalline form of donepezil. In some embodiments, the improved stability comprises a formulation maintains its non-crystalline form when stored at about 25°C and about 60% relative humidity for a period of at least 1 week, more preferably at least 1 month, more preferably at least three months. In some embodiments, the improved stability comprises a formulation maintains its noncrystalline form when stored at about 40°C and about 75% relative humidity for a period of at least 1 week, more preferably at least 1 month, more preferably at least three months. In some 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 1 week, more preferably at least 1 month, more preferably at least three months.

[00122] Generally, in terms of weight percentage, the excipient is present at a concentration in the range of from about 1% to about 99% w/w, preferably from about 5% to about 70%, more preferably from about 10% to about 50% w/w of the formulation. The donepezil 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 99.9% by weight, and often is present from about 1 to 50%, typically from about 5 to 25% by weight.

[00123] The formulation according to the invention is preferably in particulate form, especially in the form of fine particles having a volume mean diameter (VMD) of about 5 μm 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 22 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.

[00124] Following formulation with at least one excipient, the donepezil will have improved physical stability with respect to reversion to crystalline form, for at least one week, more preferably at least one month, and most preferably at least 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 donepezil formulation over time. Preferably there is little or no change in degree of crystallinity of the donepezil 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 10%, or less than 5%, more preferably less than about 3% or 2% or % 1% change in degree of crystallinity of the donepezil within the formulation with respect to the initial amount. Preferably there is no detectable crystalline donepezil 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 25°C, or from about 20 to 23°C, such as about 22°C, 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 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 40°C and about 75% relative humidity. The formulation according to the invention is preferably stable, for the periods mentioned above, when stored at about 25°C and up to about 60% RH for a period of at least one week, more preferably at least one month, and most preferably at least three months. Even more preferably, the formulation is considered stable when stored at about 40°C, most preferably at about 40°C and up to about 75% RH for a period of at least one week, more preferably at least one month, and most preferably at least three 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.

[00125] 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.

[00126] 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.

[00127] 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.

[00128] Also there are provided methods of treatment using a pharmaceutical composition according to the present invention. The invention thus further comprises methods of treating senile dementia, particularly senile dementia of the Alzheimer type, in a patient by administering an effective amount of a pharmaceutical composition according to the present invention.

[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 donepezil and the excipient as part of the formulation of the invention. For example, the pharmaceutical composition may comprise the donepezil 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 donepezil by adding the additional active agent to the liquid containing the donepezil during the processing of the donepezil. 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 donepezil formulation or co-formulation of donepezil and excipient as described in any formulation, co-formulation, composition and method herein, together with additional excipients. In one or more embodiments, the additional excipients are blended with the donepezil co- formulation, in powder form, and roller compacted, then filled into capsules. In some embodiments, the pharmaceutical composition comprises a powder co- formulation of donepezil, especially crystalline donepezil, with an oligomeric or polymeric excipient, made by a spray drying or by a SEDS™ particle precipitation process. The powder co-formulation is then blended with microcrystalline cellulose and sodium starch glycolate, and may be roller compacted, and tableted or filled into capsules. The blending step may comprise blending in a "V" blender. In other embodiments, a pharmaceutical composition comprises a powder co-formulation of crystalline donepezil with PVP-VA, made by the Nektar™ SCF GAS particle precipitation process. The powder co-formulation is then blended with microcrystalline cellulose and sodium starch glycolate, compacted, and tabletted or filled into capsules.

Tablet Dosage Form

[00131] A non-crystalline form of donepezil may be made by spray-drying a solution of donepezil hydrochloride 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 appropriately-sized tablet dosage form, for example, containing about 5 mg or about 10 mg or more of donepezil per tablet. A wet or dry granulation process may be used to make the granules, which can than be compressed into tablets. In one or more embodiments, a tablet dissolution rate and/or profile is preferably comparable to (at least parity or near parity with) a commercially-available dosage form, especially 10 mg ARICEPT® . The tablet formulations made as described herein are preferably chemically and physically stable for at least one month at both room temperature and at accelerated conditions. The formulations additionally may be scaled to production-sized batches [00132] The non-crystalline form of donepezil may be formed by adding the donepezil to a liquid and removing the liquid in a manner that produces particles comprising non-crystalline donepezil, such as by using one or more of the solvent removal or solid extraction techniques discussed above. In one or more versions, a crystalline form of donepezil, such as a commercially-available crystalline form, may be used as the starting material that is added to the liquid. The crystalline donepezil hydrochloride, for example, is dissolved in the solvent and the solvent is removed by a process that produces the non-crystalline donepezil. Alternatively, the steps of producing crystalline donepezil and then using the crystalline donepezil as a starting material can be avoided. The free compound of donepezil, such as a commercially- available free-compound form, can be reacted with a substantially equal mole of hydrochloric acid to produce donepezil hydrochloride. This donepezil hydrochloride compound may then be introduced into a liquid, such as by dissolving the donepezil hydrochloride in the liquid, and the liquid may be removed in a manner which produces non-crystalline donepezil hydrochloride. Alternatively, the donepezil free compound and the hydrochloric acid can both be added to a liquid in a manner where the reaction to donepezil hydrochloride takes place in the liquid, and the liquid can then be removed to produce non-crystalline donepezil hydrochloride. In other versions, the donepezil free compound may be in solution in a liquid, such as a mother liquor from the synthesis process, and the hydrochloric acid may be added to this liquid, and the liquid may then be removed to produce non-crystalline donepezil hydrochloride. These latter processes are advantageous in that they avoid the steps of forming the crystalline donepezil hydrochloride and then dissolving the crystalline donepezil hydrochloride, thereby increasing throughput. When an excipient is to be included in the produced particles, the excipient may be added to the solution containing the donepezil hydrochloride or the donepezil free compound and the hydrochloric acid. In other versions, a pure non-crystalline donepezil may be produced using any of the techniques described herein and the pure non-crystalline donepezil may be used as the starting material for making particles comprising noncrystalline donepezil and a stabilizing excipient according to any of the techniques described herein. The free compound form may be obtained from a commercial source, or may be obtained as an intermediate in a synthetic process, or by other means known to the art.

[00133] The following examples illustrate the formation of non-crystalline and/or stable versions of a formulation comprising donepezil. These examples are not intended to limit the scope of the invention.

EXAMPLE 1

[00134] A first example according to the present invention involves the formulation of pure non-crystalline donepezil by spray drying. Donepezil hydrochloride is dissolved in water and the liquid mixture is spray dried as described, for example, in U.S. Patent 6,051,256, which is incorporated herein by reference in its entirety. Particles comprising donepezil hydrochloride are collected from the spray drier. The starting material may be one or more of the crystalline polymorphs of donepezil hydrochloride. The spray drying process is performed under conditions selected to result in the formation of a non-crystalline form of donepezil. Such conditions generally comprise setting a feed rate at about 5-10 mL/min and an inlet gas temperature at about 100-130°C. In functional terms, it is preferred that the formation of a non-crystalline form of donepezil comprise a free- flowing powder with a wet T_g above about 40°C, or a dry T_g of above about 50°C, or both. In general, the T_g may be about 10 to about 30 degrees above the temperature of the solvent removal process employed.

[00135] Specifically, the non-crystalline donepezil hydrochloride of Example

1 can be made by performing the following steps:

[00136] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in water at 1-15% solid content.

[00137] 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 100°C and an outlet temperature of about 60°C. [00138] 3. The particles are collected and are placed in a dry box.

[00139] The resultant solution 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 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 2

[00140] A second example according to the present invention involves the formation of pure non-crystalline donepezil 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. Donepezil is dissolved in an organic solution, such as an organic solution, such as a solution comprising methanol, or dichloromethane, or a mixture thereof, and optionally acetone. The solution is then contacted, in a particle precipitation process, by supercritical carbon dioxide which extracts the donepezil to produce particles comprising donepezil. The starting material may be one or more of the crystalline polymorphs of donepezil hydrochloride. The process is performed under conditions selected to result in the formation of a non-crystalline form of donepezil. Such conditions generally comprise a reactor vessel temperature of between about 35-80°, and a reactor vessel pressure of between about 85-200 bar. In functional terms, it is preferred that the formation of a non-crystalline form of donepezil comprise a free- flowing powder with a wet T_g above about 40°C, or a dry T_g of greater than about 50°C, or both.

[00141] Specifically, the non-crystalline donepezil hydrochloride of this

Example 2 can be made by performing the following steps: [00142] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in an organic solvent comprising methanol and/or dichloromethane, at 1-20% solids content, preferably at 2.5-10% solids content.

[00143] 2. The solution is then contacted, in a particle precipitation process, with a supercritical or near supercritical fluid anti-solvent, such as supercritical CO₂, which extracts the donepezil hydrochloride from the solution.

[00144] The solution of step 1 can alternatively or additionally be made into powder as described above.

EXAMPLE 3

[00145] In a third example, a spray drying process is used to produce particles comprising non-crystalline donepezil and a stabilizing excipient. In this version, the stabilizing excipient can be any excipient that increases the physical stability of the non-crystalline donepezil hydrochloride when compared to a formulation of noncrystalline donepezil hydrochloride substantially absent the excipient.

[00146] Specifically, the non-crystalline donepezil hydrochloride and excipient of this Example 3 can be made by performing the following steps:

[00147] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in water at 1-25% solids content.

[00148] 2. A stabilizing excipient is then added to the solution in a weight ratio of from about 0.1 : 10 to 10:0.1 , preferably from about 1 : 10 to 10:1, and more preferably about 1 :1.

[00149] 3. The solution is spray dried under the conditions set forth in

Example 1 to form non-crystalline particles comprising donepezil hydrochloride and the stabilizing excipient.

[00150] The stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline donepezil when compared to a formulation of non-crystalline donepezil substantially absent the excipient. The excipient preferably is partly or wholly miscible with the donepezil in the noncrystalline state. This increase in physical stability may be in terms of the formulation's storage life before crystallization, or may be in terms of its glass transition temperature at a particular relative humidity, or in terms of its hygroscopicity, or in terms of other physical stability determinants, or combinations thereof. In one or more versions, the stabilizing excipient is selected that has a higher glass transition temperature (T_g) than that of the non-crystalline donepezil, and the resulting formulation thus has a higher T_g than that of the non-crystalline donepezil. In other versions, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline donepezil, and the resulting formulation thus has a lower hygroscopicity than that of the non-crystalline donepezil. 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 donepezil and a lower hygroscopicity than that of the non-crystalline donepezil (such as donepezil hydrochloride). In one or more embodiments, stabilizing-effective excipients comprise polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), vinylpyrrolidone/vinyl acetate (40:60) copolymer in a VA:VP 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; 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

[00151] Additional and/or alternative stabilizing excipients comprise 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 mixtures of the above, etc. More than one excipient, for example, more than one stabilizing excipient, may be formulated or co-formulated with the donepezil in accordance with one or more embodiments of the present invention.

[00152] 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 4

[00153] Example 4 represents a specific version of Example 3. In the production of Example 4, the following steps are carried out:

[00154] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in water at 1-25% solids content.

[00155] 2. Hydroxy propyl methyl cellulose (HPMC) is then added to the solution in a weight ratio of from about 0.1 : 10 to 10:0.1, preferably from about 1 :10 to 10:1, more preferably form about 1 : 1 to about 6:1 and most preferably about 1 :1.

[00156] 3. The solution is spray-dried under the conditions set forth in

Example 1 to form non-crystalline particles comprising donepezil hydrochloride and the HPMC.

EXAMPLE 5

[00157] Example 5 represents a specific version of Examples 3 and 4. In the production of Example 5, the following steps were carried out:

[00158] 1. 1O g of crystalline donepezil hydrochloride was dissolved in

70 ml of water. The solution was chilled with ice. [00159] 2. 30 ml of water was heated to 90°C.

[00160] 3. 10 g of HPMC, such as Methocel E5 from Dow Chemical Co, was added to the heated water with agitation until all particles were wet.

[00161] 4. The chilled solution containing the donepezil hydrochloride was added to the HPMC mixture and agitated for 20 minutes until clear and homogeneous. This gaves a substantially 1:1 (w/w) donepezil hydrochloride:HPMC mixture with a solids content of about 20%.

[00162] 5. The solution was then spray dried as described in Example 1.

[00163] 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.

[00164] The particles comprising non-crystalline donepezil hydrochloride and stabilizing excipient made in accordance with Example 5 were analyzed and have been found to be non-crystalline with improved physical stability. An X-ray powder diffraction pattern of the powder particles after formulation showed the powder to be non-crystalline. The powder particles were then stored for 3 weeks at about 75% relative humidity at about 40°C. Figure 7 shows the X-ray powder diffraction pattern of the powder following this storage and shows the powder to have remained noncrystalline in that no crystallinity-indicative peaks are present. In addition, the powders produced in accordance with Example 5 are less hygroscopic than the pure donepezil hydrochloride powders. Figure 8 is a DVS Isotherm plot showing change in mass as a function of humidity for the pure donepezil hydrochloride powders of Example 1. In contrast, Figure 9 shows the same plot for the powders of Example 5. As can be seen, the Example 5 powders have improved hygroscopicity. [00165] Table 1 below compares properties of the spray-dried powder of this

Example 5 immediately after preparation, and after accelerated storage for one week at the temperature/humidity conditions indicated.

Table 1

[00166] The particles formed in accordance with Example 5 have further advantages. For example, the particles remained flowable after exposed to 25°C/60% RH and 40°C/75% RH stability conditions, while the pure non-crystalline donepezil hydrochloride tends to become liquid and gel-like under the same conditions. Thus, the particles of Example 5 will have improved powder handling qualities during further processing, such as tablet forming processes.

EXAMPLE 6

[00167] Example 6 represents another specific version of Example 3. In the production of Example 5, the following steps are carried out:

[00168] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in water at about 1 -25% solids content.

[00169] 2. Polyvinyl pyrrolidone (PVP) is then added to the solution in a weight ratio of from about 0.1 : 10 to 10:0.1 , preferably from about 1 : 10 to 10:1, more preferably from about 1 : 1 to about 1.5:1 and most preferably about 1:1. [00170] 3. The solution is spray-dried under the conditions set forth in

Example 1 to form non-crystalline particles comprising donepezil hydrochloride and the PVP.

EXAMPLE 7

[00171] Example 7 represents another specific version of Example 3. In the production of Example 7, the following steps are carried out:

[00172] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in water at about 1-25% solid content.

[00173] 2. Polyvinylpyrrolidone-vinyl acetate (PVP-VA) is then added to the solution in a weight ratio of from about 0.1 :10 to 10:0.1, preferably from about 1 : 10 to 10:1, more preferably form about 1 :1 to about 1.5:1 and most preferably about 1 :1.

[00174] 3. The solution is spray-dried under the conditions set forth in

Example 1 to form non-crystalline particles comprising donepezil hydrochloride and the PVP-VA.

EXAMPLE 8

[00175] Example 8 represents yet another specific version of Example 3. In the production of Example 8, the following steps were carried out:

[00176] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt was dissolved in water at about 1-25% solids content.

[00177] 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.

[00178] 4. The solution was spray-dried under the conditions set forth in

Example 1 to form non-crystalline particles comprising donepezil hydrochloride and HPC.

[00179] 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.

[00180] The particles comprising non-crystalline donepezil hydrochloride and

HPC made in accordance with Example 8 were analyzed and have been found to be non-crystalline with improved physical stability, initially, and after storage for 1 week at 60% relative humidity at 25°C.

EXAMPLE 9

[00181] 1. 0.5 g of crystalline donepezil hydrochloride and 40 mg of citric acid were dissolved in 20 ml of water.

[00182] 2. The solution of step 1 was titrated with NaOH to a pH of about

6.0.

[00183] 3. The solution of step 2 was chilled with ice.

[00184] 4. 20 ml ofwater was heated to 90°C.

[00185] 5. 3 g of HPMC, such as Methocel E5 from Dow Chemical Co, was added to the heated water with agitation until all particles were wet.

[00186] 6. The chilled solution containing the donepezil hydrochloride was added to the HPMC mixture and agitated for 20 minutes until clear and homogeneous. This gave a substantially 1 :6 (w/w) donepezil hydrochloride (plus sodium citrate):HPMC mixture.

[00187] 7. The solution was then spray dried as described in Example 1. [00188] The solvent of this example can be removed and/or other solvents employed as described above.

[00189] The particles comprising non-crystalline donepezil hydrochloride and stabilizing excipient made in accordance with Example 9 were analyzed and have been found to be non-crystalline with improved physical stability. As shown by Figure 1OA, an X-ray powder diffraction pattern of the powder particles after formulation showed the powder to be non-crystalline. The powder particles were then stored for 1 week at 75% relative humidity at 40°C and were determined to have remained non-crystalline, as seen in Figure 1OB.

[00190] Table 2 below compares properties of the spray-dried powder of this

Example 9 soon after preparation, and after accelerated storage for one week at the temperature/humidity conditions indicated.

Table 2

EXAMPLE 10

[00191] In this example, a supercritical fluid is used to remove the solvent, such as an organic solvent, from the solution to produce non-crystalline donepezil and a stabilizing excipient. In this and other embodiments and examples, the stabilizing excipient can be any excipient that increases the physical stability of the non-crystalline donepezil hydrochloride when compared to a formulation of noncrystalline donepezil hydrochloride substantially absent the excipient. [00192] Specifically, the non-crystalline donepezil hydrochloride and excipient of Example 10 can be made by performing the following steps:

[00193] 1. Starting with the commercially available crystalline donepezil hydrochloride, the salt is dissolved in an organic solvent, such as methanol and/or dichloromethane, and optionally, acetone (particularly when methanol is used) at 1- 20% solids content, preferably about 5-20% solids content.

[00194] 2. The stabilizing excipient is then added to the solution in a weight ratio of stabilizing excipient to donepezil hydrochloride of from about 0.1 :10 to 10:0.1, more preferably from about 1:10 to 10:1, more preferably from about 2:1 to 3:1, and most preferably about 7:3.

[00195] 3. The solution is contacted, in a particle precipitation process, with a supercritical fluid or near super-critical fluid anti-solvent which removes the solvent from the solution of donepezil hydrochloride and stabilizing excipient.

[00196] The solvent of this example can be removed by other organic solvent removal processed, such as freeze drying, spray freeze drying, evaporation, or vacuum drying. The solvent of this example may alternatively or additionally comprise other organic solvents. For example, for the SEDS™ process, the desired solutes are dissolved or dispersed in a solvent and or solvent mixture which is miscible with carbon dioxide. Solvent choice may include, for example, one or more of methanol, ethanol, propan-2-ol, 1-propanol, 2-methyl-l propanol, butanol, dimethylsulfoxide, dichloromethane, toluene, hexane, ethyl ether, heptane, chloroform, acetone, ethyl acetate, toluene, acetonitrile, isopropyl acetate, methyl acetate, methylethylketone, methylisobutylketone, tetrahydrofuran, cyclohexane, N,N-dimethylformamide and dimethylacetanilide.

[00197] As described herein, the stabilizing excipient may be selected to be any excipient that increases the physical stability of the non-crystalline donepezil hydrochloride when compared to a formulation of non-crystalline donepezil hydrochloride 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 donepezil. In another version, the stabilizing excipient may be selected so that it has a lower hygroscopicity than the non-crystalline donepezil, especially donepezil hydrochloride. For example, suitable excipients comprise PVPVA, ethyl cellulose, Eudragit E, hydroxypropyl cellulose and hydroxypropyl beta cyclodextrin and mixtures of the above. Additional stabilizing excipients include cellulose polymers especially enteric cellulose polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate etc. Particular excipients or excipient combinations may be 50:50 (w/w) donepezil hydrochloride and ethyle cellulose; 50:45:5 (w/w) HPMC phthalate 55, ethyl cellulose, donepezil hydrochloride; 50:50 (w/w) donepezil hydrochloride and cellulose acetate phthalate; 40:60 (w/w) donepezil hydrochloride and cellulose acetate phthalate; 33.3:66.7 (w/w) donepezil hydrochloride and cellulose acetate phthalate; and 25:75 (w/w) donepezil hydrochloride and cellulose acetate phthalate.

EXAMPLE 11

[00198] Example 11 represents a specific version of Example 10. In the production of Example 11, the following steps were carried out:

[00199] 1. 7 g of ethyl cellulose was added to 100 ml dichloromethane and the mixture was stirred and/or sonicated to dissolve the excipient.

[00200] 2. 7 g of crystalline donepezil hydrochloride was added to the solution of step 1 and dissolved by stirring and/or sonication. Steps 1 and 2 may be reversed.

[00201] 3. The solution was processed using a SEDS™ particle precipitation process using a nozzle with a 200 μm tip for the CO₂ line and a 125 μm tip for the solution line. The conditions used (at pilot plant scale) were reaction vessel pressure and temperature of 85 bar and 40°C; a solution flow rate of 1 ml min^"1; a CO₂ anti-solvent flow rate of 12-12.5 kg-hr^'1; a CO₂ inlet temperature of 85°C; and a CO₂ pump back pressure of 260-270 bar, with a stovepipe (an attachment around the anti-solvent orifice into which the solution orifice protrudes) of the type having a length of 100 mm and a diameter of 20 mm.

[00202] The particles comprising non-crystalline donepezil hydrochloride and stabilizing excipient made in accordance with Example 11 were analyzed and have been found to be non-crystalline with improved physical stability. An X-ray powder diffraction pattern, taken immediately after preparation of the powder particles, is shown in Figure 11 A. 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 40°C with closed vials. After this storage, the particles were X-rayed again and the X-ray powder diffraction pattern is shown in Figure 1 IB. The powder particles were then stored for 1 week at 75% relative humidity at 40°C with open vials. After this storage, the particles were X- rayed again and the X-ray powder diffraction pattern is shown in Figure 11C. As can be seen, there is no indication of the conversion of the non-crystalline form to a crystalline form in either of the spectrograms of Figures 1 IB or 11C.

[00203] A scanning electron micrograph of the formulation of Example 11 after storage for 9 months at 75% relative humidity at 40°C in closed vials indicated that the donepezil was in its non-crystalline form of the formulation. Figure 12A shows the water uptake of the powder formulated in accordance with Example 11 before storage and Figure 12B shows the water uptake following storage for 9 months at 75% relative humidity at 40°C in closed vials. Figure 13 shows the glass transition temperature of the powder of Example 11. These figures show the powder to be non-crystalline.

EXAMPLE 12

[00204] Example 12 represents a specific version of Example 10. In the production of Example 12, the following steps are carried out:

[00205] 1. 0.5 g of ethyl cellulose and 4.5 g of hydroxpropylmethyl cellulose phthalate 55 are added a solution containing 50 ml methanol and 50 ml acetone and the mixture is stirred and/or sonicated to dissolve the excipient.

[00206] 2. 5 g of crystalline donepezil hydrochloride is added to the solution of step 1 and dissolved by stirring and/or sonication. The order of steps 1 and 2 may be reversed.

[00207] 3. The solution is processed using a SEDS™ particle precipitation process using a nozzle with a 200μm tip for the CO₂ line and a 125μm tip for the solution line. The conditions used (at pilot plant scale) were reaction vessel pressure and temperature of 85 bar and 40°C; a solution flow rate of 4 ml min^" '; a CO₂ anti-solvent flow rate of 12-12.5 kg-hr^'1; a CO₂ inlet temperature of 85°C; and a CO₂ pump back pressure of 260-270 bar, with a stovepipe of the type having a length of 100 mm and a diameter of 20 mm.

EXAMPLE 13

[00208] Example 13 represents a specific version of Example 10. In the production of Example 13, the following steps are carried out:

[00209] 1. 5 g of cellulose acetate phthalate (CAP) excipient is added slowly to a solution containing 120 ml methanol and 30 ml acetone and the mixture is stirred and/or sonicated to dissolve the excipient.

[00210] 2. 5 g of crystalline donepezil hydrochloride is added to the solution of step 1 and dissolved by stirring and/or sonication. The order of steps 1 and 2 may be reversed.

[00211] 3. The solution is processed using a SEDS™ process using a nozzle with a 200μm tip for the CO₂ line and a 125μm tip for the solution line. The conditions used (at pilot plant scale) were reaction vessel pressure and temperature of 85 bar and 40°C; a solution flow rate of 4 ml- min^-1; a CO₂ anti-solvent flow rate of 12-12.5 kg-hr^-1; a CO₂ inlet temperature of 85°C; and a CO₂ pump back pressure of 260-270 bar, with a stovepipe of the type having a length of 100 mm and a diameter of 20 mm.

EXAMPLE 14

[00212] To any of the above examples, an additional active agent may be added to the solution to allow for the production of particles comprising noncrystalline donepezil, the additional active agent, and optionally a stabilizing excipient. The relative weight proportion of donepezil to the additional active agent will vary depending on the active agent and the desired therapeutic profile.

EXAMPLE 15

[00213] In any of the above examples, the free compound of donepezil may be used as the starting material instead of the crystalline donepezil hydrochloride. For each of the examples, instead of adding the crystalline donepezil hydrochloride, equal molar amounts of donepezil free compound and hydrochloric acid are added. The donepezil and the hydrochloric acid react to form donepezil hydrochloride that may then be processed into non-crystalline donepezil hydrochloride. Alternatively, the starting material may be a liquid that contains donepezil 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 donepezil hydrochloride. This example allows for the crystallization step and the dissolution step to be avoided.

EXAMPLE 16

[00214] 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 17

[00215] 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 senile dementia, and particularly to treat a patient having senile dementia, particularly senile dementia of the Alzheimer type. For example, the formulations described herein may be formulated into a tablet containing 2 mg, 5 mg, 10 mg, or more of non-crystalline donepezil hydrochloride. These amounts may be altered in order to achieve a desired therapeutic profile.

Analytical Methods

[00216] The analytical techniques employed in some of the examples are more fully described below.

X-ray powder diffraction (XRD/XRPD)

[00217] 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.

Scanning electron microscopy (SEM)

[00218] Particle size and morphology are investigated using a FEI XL30 TMP

Scanning Electron Microscope. SEM is used to observe the morphology of the particles before and after exposure to moisture. Samples are mounted on silicon wafers that were then mounted on top of double-sided carbon tape on an aluminum SEM stub. The mounted powders are then sputter-coated with gold: palladium in a Denton sputter-coater for 60 to 90 seconds at 75mTorr and 42mA. This produces a coating thickness of approximately 15θA. Images are taken with a Philips XL30 ESEM operated in high vacuum mode using an Everhart-Thornley detector to capture secondary electrons for the image composition. The accelerating voltage is set at 2OkV using a LaB6 source. The working distance is between 5 and 6 mm.

Differential scanning calorimetry (DSC)

[00219] 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. The DSC pan is hermetically sealed using a sample encapsulation press. 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.

Thermogravimetric Analysis (TGA)

[00220] This method is used to assess changes in water content of the product during storage by measuring the loss of mass on heating. The sample weight loss at elevated temperatures is measured using TGA-2950 instrument made by TA Instruments. The sample is immediately heated, in order to minimize the initial dehydration by the dry nitrogen gas, from room temperature to 250°C at a rate of 2°C/min and/or 0.2°C/min. The % weight loss is calculated using the TA software. Dynamic Vapor Sorption

[00221] 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 are 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.

Materials

[00222] Crystalline donepezil was obtained, for example from Eisai Co., Ltd of Teaneck, New Jersey.

[00223] PVPVA is commercially available from BASF, for example, under the trademark Kollidone®

[00224] HPC/HPMC is commercially available from Dow Chemical for example, under the trademark METHOCEL®.

[00225] Other chemicals, reagents and materials were obtained from Sigma, or from other commercial suppliers.

[00226] 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 composition comprising non-crystalline donepezil, wherein the composition is physically and chemically stable for at least one month at about 25° C and about 60% RH.

2. The composition of claim 1 wherein the composition is physically and chemically stable for at least three months at 25° C and 65% RH.

3. The composition of claim 1 wherein the composition is physically and chemically stable for at least one month after storage at 40° C and 75% RH.

4. The composition of claim 1 wherein the composition exhibits significantly no reversion to crystalline form after least one month of storage at 25° C and 65% RH.

5. The composition of claim 1 wherein the composition comprises at least about 90% non-crystalline donepezil.

6. The composition of claim 1 wherein the composition is particulate.

7. The composition of claim 1 and further characterized by at least one of enhanced dissolution, enhanced solubility, enhanced stability, enhanced shelf life, enhanced bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

8. The composition of claim 7 and further characterized by at least two of enhanced dissolution, enhanced solubility, enhanced stability, enhanced shelf life, enhanced bioavailability, or manufacturing ease or manufacturing cost-effectiveness.

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

10. The composition of claim 1 wherein the non-crystalline donepezil is produced by the steps of (a) preparing a solution comprising donepezil and solvent;

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

(c) spray-drying the donepezil and solvent solution; wherein a plurality of particles result.

11. The composition of claim 10 in the form of a free-flowing powder.

12. The composition of claim 10 wherein the solvent is non-aqueous, and the donepezil comprises the hydrochloride salt, in an amount of between about 1 to 25% by weight.

13. The composition of claim 10 wherein the solution of donepezil and solvent further comprises an excipient, and wherein the resulting particles comprise donepezil and excipient.

14. The composition of claim 1 wherein the non-crystalline donepezil is produced by the steps of (a) preparing a solution comprising donepezil and solvent;

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

(c) removing the solvent, under supercritical conditions, to produce noncrystalline donepezil; wherein a plurality of particles result.

15. The composition of claim 14 wherein the solution of donepezil and solvent further comprises an excipient, and wherein the resulting particles comprise donepezil and excipient.

16. The composition of claim 1 wherein the amorphous donepezil is produced by the steps of (a) providing a free-compound form of donepezil;

(b) combining the free-compound form of donepezil with a substantially equimolar amount of an acid and adding thereto to a solvent; and

(c) removing the solvent to form a non-crystalline donepezil acid salt.

17. A composition comprising non-crystalline donepezil and an excipient.

18. The composition of claim 17 wherein the excipient is oligomeric or polymeric.

19. The composition of claim 18 wherein the excipient has a higher T_g, a lower hygroscopicity, or both, compared to the donepezil alone.

20. The composition of claim 19 wherein the excipient comprises PVP, PVPVA, HMPC, HPC, alkyl cellulose, derivatives thereof and mixtures thereof.

21. The composition of claim 20 wherein the composition comprising amorphous donepezil and excipient is produced by atomizing and spray-drying a solution comprising donepezil, excipient and solvent, and wherein a free-flowing powder results.

22. The composition of claim 20 wherein the composition comprising non-crystalline donepezil and excipient is produced by a supercritical particle extraction process from a target solution/suspension comprising donepezil, an excipient and a solvent, and wherein a free-flowing powder results.

23. The composition of claim 22 which has been made by co-precipitating the donepezil and the excipient from a common solvent or solvent mixture using a compressed fluid anti-solvent, and wherein the anti-solvent comprises CO₂, and the solvent comprises a hydroxylic solvent.

24. The composition of claim 22, wherein the process further comprises contacting the target solution with a compressed fluid anti-solvent under conditions which allow the anti-solvent simultaneously both to disperse the target solution and to extract the vehicle from it so as to cause particles of donepezil and excipient to precipitate as a co-formulation.

25. The formulation according to claim 22 wherein the excipient is a polymer or copolymer comprising vinyl pyrrolidone.

26. A pharmaceutical or nutraceutical composition comprising a formulation according to claim 17.

27. A formulation comprising an non-crystalline l-benzyl-4-[(5,6-dimethoxy-l- indanone)-2-yl]methylpiperidine acetylcholinesterase inhibitor compound and an excipient, the formulation prepared by a method comprising providing a target solution comprising solution or suspension of 1 -benzyl-4- [(5,6-dimethoxy- 1 -indanone)-2-yl]methylpiperidine; and contacting the target solution with a compressed fluid anti-solvent under conditions which allow the anti-solvent to extract fluid from the target solution so as to cause particles of the formulated l-benzyl-4-[(5,6-dimethoxy-l-indanone)-2- yl]methylpiperidine and excipient to precipitate as a free-flowing powder.

28. The formulation of claim 27 wherein the excipient comprises an oligomer or polymer.

29. The formulation of claim 28 wherein a ratio of l-benzyl-4-[(5,6-dimethoxy-l- indanone)-2-yl]methylpiperidine to excipient ranges from about 0.1 :10 to 10:0.1, inclusive.

30. The formulation of claim 28 wherein the l-benzyl-4-[(5,6-dimethoxy-l- indanone)-2-yl]methylpiperidine comprises donepezil, and the excipient comprises a hydrophobic polymer.

31. The formulation of claim 30, wherein a ratio of donepezil to excipient is about 1 :1.

32. The formulation of claim 31 wherein, the excipient comprises a polymer or copolymer of vinyl pyrrolidone, cellulose, alkyl cellulose, derivatives thereof, or a combination thereof.

33. A particulate co-formulation comprising an donepezil and excipient, the co- formulation prepared by a gas anti-solvent precipitation method comprising providing a target solution comprising solution or suspension of donepezil and excipient in at least one fluid; and contacting the target solution with a compressed fluid anti-solvent under conditions which allow the anti-solvent to simultaneously both to extract the target solution from the fluid, and to disperse the target solution it so as to cause particles of the coformulated non-crystalline donepezil and excipient to precipitate from the fluid.

34. The co-formulation of claim 33 wherein the excipient is a hydrophobic polymer.

35. The co-formulation of claim 33 wherein, the polymer comprises a hydroxyalkylcellulose, a vinylpyrrolidone, or a combination thereof.

36. The co-formulation of claim 35, wherein a ratio of donepezil to polymer is about 1 :1.

37. A method of preparing a particulate co-formulation comprising donepezil and a stabilizing excipient, the method comprising (a) providing a solution or suspension of donepezil and a stabilizing excipient in a solvent; and

(b) removing the liquid from the solution or suspension so as to cause particles of the formulated donepezil 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.

38. The method of claim 37 wherein the excipient comprises a PVP-VA coploymer.

39. A solid, non-crystalline formulation comprising particles of donepezil and a stabilizing excipient, wherein the formulation is more physically stable than a formulation without the stabilizing excipient.

40. A solid, non-crystalline formulation comprising donepezil and a stabilizing excipient, wherein the formulation when stored at 40°C and 75% relative humidity converts to a crystalline form more slowly than a formulation without the stabilizing excipient.

41. A solid, non-crystalline formulation comprising particles of donepezil and a stabilizing excipient, wherein the formulation has a higher glass transition temperature than a formulation without the stabilizing excipient.

42. A solid, non-crystalline formulation comprising particles of donepezil and a stabilizing excipient, wherein the formulation has a lower hygroscopicity than a formulation without the stabilizing excipient.