CA2871886A1 - Amorphous dispersions of paroxetine mesylate - Google Patents

Abstract

Amorphous solid dispersions comprising paroxetine mesylate and a polymer and processes for the preparation thereof are provided.

Description

AMORPHOUS DISPERSIONS OF PAROXETINE MESYLATE
TECHNICAL FIELD
The present invention relates to compositions of paroxetine mesylate, and in particular, amorphous dispersions comprising paroxetine mesylate and a polymer.
BACKGROUND
The methanesulfonate salt of (3S, 4R)-3-[(2H-1,3-benzodioxo1-5-yloxy)methyI]-4-(4-fluorophenyl) piperidine (Formula 1), commonly known as paroxetine mesylate, is disclosed in W098/56787. PEXEVATm, a commercial form of paroxetine mesylate, is an orally administered psychotropic drug.

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ii (1) W099/00131 Al discloses solid dispersions of poorly soluble drugs which are prepared using a solvent or fusion process. Such dispersions are manufactured with the free base of the drug, specifically paroxetine free base, an oil, allowing for a low temperature for the fusion process, decreased organic solvent volumes for the solvent process, and the formation of a paroxetine salt during the solid dispersion manufacturing process.
W099/16440 Al discloses a free-flowing, amorphous paroxetine hydrochloride composition suitable as a therapeutic agent for premature

-2-ejaculation which can be prepared by dissolving paroxetine free base in a hydrochloric acid-ethanol solution followed by drying. The compositions comprise amorphous paroxetine hydrochloride and at least one hydroxyl-bearing compound. In one preferred embodiment, the hydroxyl-bearing compound is ethanol and the amount of ethanol present in the amorphous product is in the range of 1 to 4 weight percent based on paroxetine hydrochloride. The amorphous product is stable and substantially hygroscopic.
W099/56751 Al discloses a process for preparing solid, amorphous paroxetine comprising: (A) mixing paroxetine free base or a pharmaceutically acceptable paroxetine salt with water and a pharmaceutically acceptable polymer; and (B) drying to form a composition comprising amorphous paroxetine and polymer, eliminating the need for organic solvents common for the solvent process. The resultant amorphous solid paroxetine composition is free from the crystalline form, and yet has good handling properties, making it suitable for pharmaceutical use in the traditional tablet dosage form.
W000/01694 Al discloses paroxetine methanesulfonate, processes for preparing it, pharmaceutical compositions comprising it, and its use in therapy.
W000/78291 Al discloses pharmaceutical compositions comprising paroxetine methanesulfonate.
CA2374931 Al discloses solid or semi-solid preparations of paroxetine or one of the physiologically acceptable salts thereof in the form of a molecular-disperse distribution of paroxetine in a pharmaceutically acceptable matrix material.
CA2418038 Al discloses that paroxetine salt compositions having improved stability are formed by controlling the pH to 6.5 or less. The compositions can be made with the air of water without significant coloration problems. The paroxetine salts include paroxetine hydrochloride salts but preferably use paroxetine sulfonate salts such as paroxetine methanesulfonate.
US2004/0086559 Al is directed to novel and advantageous pharmaceutical compositions for oral administration of the antidepressant

-3-compound paroxetine. The composition is in the form of a tablet having a dissolution rate of at least 90% in 30 minutes measured with a paddle apparatus according to US Pharmacopoeia.
US6,720,003 B2 discloses a process for preparing amorphous paroxetine hydrochloride or sertraline hydrochloride, which comprises preparing a solution in which paroxetine hydrochloride or sertraline hydrochloride and a water-soluble polymer are dissolved in a co-solvent of a volatile organic solvent and water.

Said solution is dried to obtain a composition comprising amorphous paroxetine hydrochloride or sertraline hydrochloride and the water-soluble matrix.
In W02004/091585 Al, silicified microcrystalline cellulose is used to provide a tablet with oral disintegration. The tablet contains at least 30% of the silicified microcrystalline cellulose and an effective amount of a pharmaceutically active agent.
W02005/034954 A2 relates to stable pharmaceutical compositions of paroxetine and process for preparation thereof. The pharmaceutical composition includes paroxetine, microcrystalline cellulose, and one or more additional pharmaceutically acceptable inert excipients. The pharmaceutical composition is prepared by a wet granulation technique.
SUMMARY
This invention is based, at least in part, on stable amorphous solid dispersions comprising paroxetine mesylate and a cellulosic polymer, which solid dispersions may, for instance, exhibit improved flowability properties.
Methods for preparing such amorphous solid dispersions are also provided.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion comprising paroxetine mesylate and a polymer, the polymer selected from the group consisting of cellulosic polymers, polymethacrylate polymers, polyvinylpyrrolidone polymers and polyethylene glycol polymers.

-4-In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:10.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is about 1:1.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, Povidone, Copovidone, EudragitTm and polyethylene glycol.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is hydroxypropyl methylcellulose.

-5-In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is Hypromellose 2910 USP E5.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is Povidone.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is Copovidone.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is EudragitTm.
In illustrative embodiments of the present invention, there is provided an amorphous solid dispersion described herein wherein the polymer is polyethylene glycol.
In illustrative embodiments of the present invention, there is provided a process for the preparation of an amorphous solid dispersion comprising paroxetine mesylate and a polymer, the polymer selected from the group consisting of cellulosic polymers, polymethacrylate polymers and polyvinylpyrrolidone polymers, the process comprising: a. forming a solution comprising the paroxetine mesylate and the polymer in a solvent; and b.
removing the solvent from the solution, thereby isolating the amorphous solid dispersion.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, Povidone, Copovidone and EudragitTM.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the polymer is hydroxypropyl methylcellulose.

-6-In illustrative embodiments of the present invention, there is provided a process described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:10.
In illustrative embodiments of the present invention, there is provided a process described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5.
In illustrative embodiments of the present invention, there is provided a process described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2.
In illustrative embodiments of the present invention, there is provided a process described herein wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the solvent is selected from the group consisting of water, alcohols, chlorinated hydrocarbons, and mixtures thereof.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the removing the solvent comprises spray-drying the solution.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the removing the solvent comprises evaporation or lyophilization.

-7-In illustrative embodiments of the present invention, there is provided a process described herein wherein the forming the solution of paroxetine mesylate and the polymer in the solvent comprises a salt exchange step whereby a salt of paroxetine, wherein the salt is not the mesylate salt, is treated with methanesulfonic acid thereby producing paroxetine mesylate with the proviso that the alternate salt is not the methanesulfonate salt.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the salt of paroxetine is a salt of paroxetine with an acid selected from the group consisting of hydrochloric acid, acetic acid, malic acid, tartaric acid, oxalic acid, fumaric acid, propionic acid, formic acid, glutamic acid, succinic acid, benzoic acid, citric acid, toluene sulfonic acid, lactic acid and mandelic acid.
In illustrative embodiments of the present invention, there is provided a process described herein wherein the salt is selected from the group consisting of paroxetine hydrochloride and paroxetine acetate.
In illustrative embodiments of the present invention there is provided a product prepared by a process described herein.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.
BRIEF DESCRIPTION OF THE DRAWINGS
In drawings which illustrate embodiments of the invention, Figure 1 is a powder X-ray diffractogram (PXRD) of crystalline paroxetine mesylate obtained according to Example 2.
Figure 2 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in hydroxypropyl methylcellulose (HPMC) (1:1) obtained according to Example 4.

-8-Figure 3 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in HPMC (1:0.5) obtained according to Example 5.
Figure 4 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in HPMC (1:2) obtained according to Example 6.
Figure 5 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in Povidone (PVP) (1:1) obtained according to Example 7.
Figure 6 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in HPMC (1:1) obtained according to Example 8.
Figure 7 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in Copovidone (1:1) obtained according to Example 13.
Figure 8 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in EudragitTm (1:1) obtained according to Example 14.
Figure 9 is a powder X-ray diffractogram (PXRD) of the sample obtained according to Example 16.
Figure 10 is a powder X-ray diffractogram (PXRD) of the sample obtained according to Example 17.
Figure 11 is a powder X-ray diffractogram (PXRD) of the sample obtained according to Example 18.
Figure 12 is a powder X-ray diffractogram (PXRD) of the sample obtained according to Example 19.
Figure 13 is a powder X-ray diffractogram (PXRD) of the sample obtained according to Example 20.

-9-Figure 14 is a powder X-ray diffractogram (PXRD) of amorphous paroxetine mesylate obtained according to Example 21.
Figure 15 is a powder X-ray diffractogram (PXRD) of amorphous solid dispersion of paroxetine mesylate in PEG 6000 obtained according to Example 24.
Figure 16 is a powder X-ray diffractogram (PXRD) of PEG 6000, obtained commercially.
DETAILED DESCRIPTION
As used herein, the term "amorphous solid dispersion" refers to a solid composition comprised of an amorphous active pharmaceutical ingredient (API) dispersed in a polymer matrix in a solid state. Amorphous solid dispersions have a variety of different embodiments.
In some embodiments of amorphous solid dispersions, the amorphous solid dispersion comprises an API dispersed within the polymer matrix at a molecular level and consists of a single, homogenous phase. Such an amorphous solid dispersion is termed herein as a "molecular dispersion". A
molecular dispersion may comprise an amorphous API and a crystalline polymer matrix. Such a molecular dispersion is termed herein as a "solid solution".
Alternatively, a molecular dispersion may comprise an amorphous API and an amorphous polymer matrix. Such a molecular dispersion is termed herein as a "glass solution".
In some embodiments of amorphous solid dispersions, the API is present as amorphous particles and/or clusters within the polymer matrix. Such an amorphous dispersion is termed herein as a "multiphase dispersion". A
multiphase dispersion may include an amorphous API and a crystalline polymer matrix or alternatively an amorphous API and an amorphous polymer matrix.
Multiphase dispersions are often less homogenous than a molecular dispersion.

-10-ln some embodiments of amorphous solid dispersions, the amorphous solid dispersion is a mixture of one or more molecular dispersions and one or more multiphase dispersions.
Various techniques for preparing dispersions exist. For example, in J.
Pharm. Sc., 1971, 60(9), 1281-1302, Chiou and Riegelmann disclose solvent, melting, and solvent-melting processes. All of these processes are characterized by a step of disrupting the original solid state structure of the components to facilitate different mixing, commonly more intimate mixing, than would occur by simple mechanical mixing.
The amorphous nature of the API in the dispersions described herein may be characterized using well-known techniques, such as powder X-ray diffractometry. Using powder X-ray diffractometry, the lack of long range order in amorphous materials typically gives rise to a broad diffuse halo or a 'hump' in a resulting powder X-ray diffractogram (PXRD). The lack of peaks in PXRD is indicative of amorphous form. For amorphous solid dispersions comprised of crystalline polymer matrix, peaks arising from the crystal structure of the polymer may be observed while peaks attributable to the API may be absent.
As used herein, the term "free-flowing" refers to a characteristic of a solid composed of discrete particles that flow when tipped or inverted.
As used herein, the term "cellulosic polymer" refers to a water-soluble, amorphous polymeric cellulose derivative. Examples of cellulosic polymers include, without limitation, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
As used herein, the term "polymethacrylate polymer" refers to amorphous polymeric salts or esters of polymethacrylic acid. Examples of polymethacrylate polymers include, without limitation, methacrylic acid copolymers, methacrylic acid-methacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, ammonium methacrylate copolymers, aminoalkyl methacrylate copolymers, and the like. Examples of some commercially available polymethacrylate polymers include EudragitTm RL100, EudragitTm L100-55, EudragitTm L100 and EudragitTm E.
As used herein, the term "polyvinylpyrrolidone polymer" refers to polyvinylpyrrolidone and copolymers thereof. Examples include Povidone (PVP) and Copovidone.
As used herein, the term "polymer matrix" refers to both a crystalline polymer and an amorphous polymer.
As used herein, the term "about" generally means within 10%, often within 5%, and often within 1% of a given value or range and could be any increment thereof within 10% (e.g. 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc).
As used herein when referring to a spectrum and/or to data presented in a graph, the term "peak" refers a feature that one skilled in the art would recognize as not attributable to background noise.
The amorphous solid dispersions of paroxetine mesylate described herein may exhibit improved flow properties compared to amorphous paroxetine mesylate in isolation. Amorphous paroxetine mesylate when exposed to conditions of, for example, high relative humidity may change from a powder comprised of discrete particles to a semi-solid that is sticky and gummy in nature.
In contrast, the particulate nature (for example, powdery) of many embodiments of the amorphous solid dispersions of paroxetine mesylate described herein may be perceptibly unchanged when exposed to the same conditions in the same time frame.
Embodiments of the present invention may exhibit varying degrees of physical stability under various conditions. For example, for an embodiment which is more susceptible to crystallization upon exposure to humidity, the physical form may be preserved by avoiding such exposure, such as by maintaining an inert atmosphere.

The amorphous solid dispersions of paroxetine mesylate described herein may exhibit favourable solubility in aqueous solutions compared to crystalline forms of paroxetine mesylate.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of HPMC within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the HPMC within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the HPMC within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the HPMC within the amorphous solid dispersion is from about 1:0.3 to about 1:1.

In some embodiments of the present invention, low-viscosity grades of HPMC, such as Hypromellose 2910 USP E3 and Hypromellose 2910 USP E5, may be used in the dispersions described herein.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of PVP within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the PVP within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the PVP within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the PVP within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In some embodiments of the present invention, PVP having an average molecular weight of from about 2000 to about 3,000,000 may be used in the dispersions described herein.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of Copovidone within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the Copovidone within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the Copovidone within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the Copovidone within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In some embodiment, Copovidone having an average molecular weight of from about 2000 to about 3,000,000 may be used in the dispersions described herein.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of EudragitTm within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the EudragitTm within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the EudragitTm within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the EudragitTm within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In embodiments of the present invention, a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of polyethylene glycol within the amorphous solid dispersion is from about 1:0.3 to about 1:10. In some embodiments of the invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polyethylene glycol within the amorphous solid dispersion is from about 1:0.3 to about 1:5. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polyethylene glycol within the amorphous solid dispersion is from about 1:0.3 to about 1:2. In some embodiments of the present invention, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polyethylene glycol within the amorphous solid dispersion is from about 1:0.3 to about 1:1.
In some embodiments of the present invention, polyethylene glycol having an average molecular weight from about 1000 to about 35 000 may be used in the dispersions described herein.
The amorphous solid dispersions described herein may be prepared by forming a solution of paroxetine mesylate and a polymer described herein in a suitable solvent and subsequently removing the solvent, hereinafter termed the solvent method. In embodiments of the solvent method, there are two main steps. These steps may comprise, dissolving the paroxetine mesylate and the polymer in a solvent, thereby forming a solution, followed by removing the solvent from the solution, thereby isolating the amorphous solid dispersion.
Alternatively, the forming the solution of paroxetine mesylate and the polymer in the solvent comprises a salt exchange step whereby an alternate salt of paroxetine is treated with methanesulfonic acid thereby producing paroxetine mesylate in situ. Often, the alternate salt of paroxetine is a salt of paroxetine with an acid, such as, hydrochloric acid, acetic acid, malic acid, tartaric acid, oxalic acid, fumaric acid, propionic acid, formic acid, glutamic acid, succinic acid, benzoic acid, citric acid, toluene sulfonic acid, lactic acid or mandelic acid. Often, the alternate salt is paroxetine hydrochloride or paroxetine acetate.
A suitable solvent or mixture of solvents may be selected from a group of inert solvents capable of dissolving both paroxetine mesylate and the polymer and which can be removed from the dispersion thereafter. A suitable solvent may be sufficiently volatile to be removed from the solution without undue heating. In some embodiments of the present invention, the suitable solvent may be selected from the group consisting of water, alcohols (for example and without limitation, methanol, ethanol, and isopropanol), chlorinated hydrocarbons (for example and without limitation dichloromethane), and mixtures thereof.

In some embodiments of the solvent method according to the present invention, it is possible to use any of the polymers described herein when preparing an amorphous solid dispersion of the present invention using the solvent method. In some embodiments of the present invention, when forming the solution, it is possible to select the polymer from the group consisting of hydroxypropyl methylcellulose, Povidone, Copovidone and EudragitTm.
An amount of the polymers to be used in the solvent method may be determined by considering a desired ratio of paroxetine mesylate to polymer intended for the final product. A ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion may be from about 1:0.3 to about 1:10, and in such cases the same ratio should be used when preparing the solution for the solvent method. Alternatively, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5, and in such cases the same ratio should be used when preparing the solution for the solvent method. Alternatively, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2, and in such cases the same ratio should be used when preparing the solution for the solvent method.
Alternatively, the ratio of the amount by weight of the paroxetine mesylate within the amorphous solid dispersion to the amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:1, and in such cases the same ratio should be used when preparing the solution for the solvent method.
In an embodiment, when the polymer has a stabilizing effect on the amorphous form of the paroxetine mesylate, it may be desirable to adjust the amount of polymer within the dispersion to optimize the stability and avoid crystallization. For example, increasing the amount of polymer with respect to the paroxetine mesylate may have the effect of stabilizing the amorphous form of the paroxetine mesylate in the dispersion.
In some embodiments of the solvent method according to the present invention, removing the solvent comprises spray-drying the solution. In some embodiments of the solvent method according to the present invention, removing the solvent comprises evaporation. In some embodiments of the solvent method according to the present invention, removing the solvent comprises lyophilization.
In some embodiments of the solvent method according to the present invention, removing the solvent comprises vacuum evaporation. In some embodiments of the solvent method according to the present invention, removing the solvent comprises freeze-drying. Dispersion at the molecular level may be favoured by conducting the solvent evaporation at a temperature below the crystallization temperature for paroxetine mesylate. It is possible to use many standard means known in the art for removing the solvent.
EXAMPLES
The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in any way.
The materials listed below were used in the examples that follow:
Paroxetine hydrochloride used was pharmaceutical grade with a purity as measured by High performance Liquid Chromatography (HPLC) of greater than 99.5%.
Hydroxypropyl methylcellulose (HPMC): Hypromellose 2910 USP E5.
Polyvinylpyrrolidone (PVP): MW 1 300 000.
Poly(1-vinylpyrrolidone-co-vinyl acetate) (Copovidone): MW 50 000.
EudragitTM: EudragitTM RL100 is a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride). The ammonium groups are present as salts and make the polymers permeable. The molar ratio of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate is approx. 1:2:0.2 =
GeluctreTm: GelucireTm 50/13 EP/NF (stearoyl polyoxy1-32 glycerides) is a non-ionic, water dispersible surfactant composed of well-characterized PEG-esters, a small glyceride fraction, and free PEG.
Powder X-Ray Diffraction Analysis:
Data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and anX-Celerator RTMS detector. The diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2-theta range of 3 to 40 degrees using CuKa radiation at a power of 40 mA and 45 kV.
CuK8 radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees was used.
Example 1:
Paroxetine hydrochloride (100.0 g) was suspended in toluene (1.0 L) at room temperature. A IN aqueous solution of NaOH (1.5 eq.) was slowly added and the mixture was stirred at room temperature. The layers were separated and the organic layer was washed with distilled water (2 x 100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo by rotary evaporation at below 55 C to yield paroxetine free base as an oil (Yield: 94%).
Example 2:
Paroxetine free base (5.0 g) was dissolved in toluene (32 mL) at room temperature. The solution was cooled to 19 C followed by slow addition of methanesulfonic acid (1.53 g). The solution was cooled to room temperature and stirred overnight whereupon a suspension was obtained. The solid was collected by filtration, washed with toluene (1 x 10 mL) and dried at 40 C under high vacuum to afford crystalline paroxetine mesylate. (Yield: 98%). A PXRD taken of this sample is shown in FIG 1.
Example 3:
Paroxetine free base (85.84 g) was dissolved in toluene (215 mL) and acetone (430 mL) at room temperature. The solution was cooled to 18 C, methanesulfonic acid (26.27 g) was added and the mixture was stirred for 1.5 hours to yield a suspension. The solid was collected by filtration, washed with acetone (2 x 50 mL) and dried under high vacuum at 40 C overnight to afford paroxetine mesylate (Yield: 86%).
Example 4:
A mixture of hydroxypropyl methylcellulose (HPMC, 20.0 g) and 10%
aqueous methanol (40 mL water/360 mL methanol) was stirred at room temperature for 70 minutes to yield a clear solution. Paroxetine mesylate (20.0 g) was charged and the mixture was stirred for an additional hour to yield a clear solution. The solution was spray-dried to yield an amorphous solid dispersion of paroxetine mesylate:HPMC (1:1 weight:weight) as a white powder. A PXRD
taken of this sample is shown in FIG 2. A sample of the powder was placed in an uncapped vial and stored under the same conditions reported for the amorphous form in Example 21. The sample remained a powder comprised of discrete particles after this storage period.
Spray drying conditions:
Equipment Model/Make: Yamato Scientific/ D-L41 Spray Dryer Gas: N2 N2 Pressure: 0.1 MPa Aspirator Gauge: 1.0 m3/hour Inlet Temperature: 140 C

Outlet Temperature: 80 C
Flow Rate: 12-14 mL/min The system was conditioned for 1.5 hours prior to run.
Example 5:
A mixture of hydroxypropyl methylcellulose (HPMC, 10.0 g) and 10%
aqueous methanol (300 mL) was stirred at room temperature for one hour to yield a clear solution. Paroxetine mesylate (20.0 g) was added and the mixture was stirred for an additional hour to yield a clear solution. The solution was spray-dried to yield an amorphous solid dispersion of paroxetine mesylate:HPMC
(1:0.5 weight:weight) as a white powder. A PXRD taken of this sample is shown in FIG 3.
Spray drying conditions:
Equipment Model/Make: Yamato Scientific/ D-L41 Spray Dryer Gas: N2 N2 Pressure: 0.1 MPa Aspirator Gauge: 1.0 m3/hour Inlet Temperature: 140 C
Outlet Temperature: 80 C
Flow Rate: 12-14 mL/min The system was conditioned for 1 hour prior to run.
Example 6:
A mixture of hydroxypropyl methylcellulose (HPMC, 20.0 g) and 10%
aqueous methanol (300 mL) was stirred at room temperature for 2 hours to yield a clear solution. Paroxetine mesylate (10.0 g) was added and the mixture was stirred for an additional hour to yield a clear solution. The solution was spray-dried to yield an amorphous solid dispersion of paroxetine mesylate:HPMC (1:2 weight:weight) as a white powder. A PXRD taken of this sample is shown in FIG
4.
Spray drying conditions:
Equipment Model/Make: Yamato Scientific/ D-L41 Spray Dryer Gas: N2 N2 Pressure: 0.1 MPa Aspirator Gauge: 1.0 m3/hour Inlet Temperature: 140 C
Outlet Temperature: 80 C
Flow Rate: 12-14 mL/min The system was conditioned for 1 hour prior to run.
Example 7:
Polyvinylpyrrolidone (PVP, 20.0 g) was charged to methanol (400 mL) at room temperature and stirred for 50 minutes to yield a clear solution.
Paroxetine mesylate (20.0 g) was charged and the mixture was stirred for an additional hour to yield a clear solution. The solution was spray-dried to yield an amorphous solid dispersion of paroxetine mesylate:PVP (1:1 weight:weight) as a fluffy, white powder. A PXRD taken of this sample is shown in FIG 5.
Spray drying conditions:
Equipment Model/Make: Yamato Scientific/ D-L41 Spray Dryer Gas: N2 N2 Pressure: 0.1 MPa Aspirator Gauge: 1.0 m3/hour Inlet Temperature: 130 C
Outlet Temperature: 80 C
Flow Rate: 12-14 mL/min The system was conditioned for 1 hour prior to run.

Example 8:
Hydroxypropyl methylcellulose (HPMC, 5.0 g) was charged to distilled water (30 mL) and the suspension was heated to 82 C. Ice cold water (60 mL) was added at 80 C and a clear solution was obtained. Paroxetine mesylate (5.0 g) was added and the mixture was stirred at room temperature for one hour to yield a clear solution. The solution was frozen by submersion in liquid nitrogen and subjected to freeze-drying for about 24 hours (VirTis Freezemobile) at ambient temperature to yield an amorphous solid dispersion of paroxetine mesylate:HPMC (1:1 weight:weight) as a single layer on the flask that resembled foam. The solid was broken into large, light-weight pieces that had a spongy appearance. A PXRD taken of this sample is shown in FIG 6.
Example 9:
Hydroxypropyl methylcellulose (HPMC, 5.0 g) was dissolved in dichloromethane/methanol (50 mL/30 mL) at room temperature. Paroxetine mesylate (5.0 g) was added and the mixture was stirred for 30 minutes to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator and further dried under high vacuum for 24 hours at room temperature to yield an amorphous solid dispersion of paroxetine mesylate:HPMC (1:1 weight:weight) as a shiny solid.
Example 10:
A mixture of polyvinylpyrrolidone (PVP, 5.0 g) and methanol (50 mL) was stirred at room temperature for one hour to yield a clear solution. Paroxetine mesylate (5.0 g) was added at room temperature and the mixture was stirred for a further 30 minutes to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator at a temperature below 45 C to yield an amorphous solid dispersion of paroxetine mesylate:PVP (1:1 weight:weight) as a shiny solid.

Example 11:
A mixture of polyvinylpyrrolidone (PVP, 5.0 g) and distilled water (50 mL) was stirred at room temperature for 30 minutes to yield a clear solution.
Paroxetine mesylate (5.0 g) was added and the mixture was stirred at room temperature for one hour to yield a clear solution. The solution was frozen by submersion in liquid nitrogen and subjected to freeze-drying for about 24 hours (VirTis Freezemobile) at ambient temperature to yield an amorphous solid dispersion of paroxetine mesylate:PVP (1:1 weight:weight) as a single layer on the flask that resembled foam. The solid was ground into a solid.
Example 12:
A mixture of polyvinylpyrrolidone (PVP, 2.0 g) and ethanol (20 mL) was stirred at room temperature for one hour to yield a clear solution. Paroxetine mesylate (2.0 g) was charged and the mixture was stirred for a further 40 minutes. Two further portions of ethanol (2x10 mL) were charged followed by 20 minute stirring periods after each addition to facilitate dissolution.
Following dissolution, the solvent was evaporated in vacuo on a rotary evaporator at a temperature below 45 C to yield an amorphous solid dispersion of paroxetine mesylate: PVP (1:1 weight:weight) as a shiny solid.
Example 13:
A mixture of poly(1-vinylpyrrolidone-covinyl acetate) (Copovidone, 2.0 g) in methanol (20 mL) was stirred at room temperature for 45 minutes to yield a clear solution. Paroxetine mesylate (2.0 g) was added at room temperature and the mixture was stirred for 45 minutes to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator at a temperature below 15 C to yield an amorphous solid dispersion of paroxetine mesylate: Copovidone (1:1 weight:weight) as a shiny solid. A PXRD taken of this sample is shown in FIG
7.

Example 14:
A mixture of EudragitTm RL100 (2.0 g) in methanol (10 mL) was stirred at room temperature for 30 minutes to yield a clear solution. Paroxetine mesylate (2.0 g) was added at room temperature and the mixture was stirred for one hour to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator at a temperature below 45 C to yield an amorphous solid dispersion of paroxetine mesylate:EudragitTm (1:1 weight:weight) as a shiny solid. A PXRD

taken of this sample is shown in FIG 8.
Example 15:
A mixture of hydroxypropyl methylcellulose (HPMC, 2.0 g) in 10%
aqueous methanol (20 mL) was stirred at room temperature for one hour to yield a clear solution. Paroxetine mesylate (2.0 g) was charged and the mixture was further stirred for 30 minutes to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator at a temperature below 45 C to yield an amorphous solid dispersion of paroxetine mesylate:HPMC (1:1 weight:weight) as a shiny solid.
Example 16:
Polyethylene glycol 6000 (PEG 6000, 2.0 g) was charged to dichloromethane (10 mL) at room temperature. The suspension was stirred for minutes to yield a clear solution. Paroxetine mesylate (2.0 g) was added at room temperature and the mixture was stirred for 30 minutes to yield a clear solution. The solvent was removed in vacuo on a rotary evaporator resulting in a 25 white solid. This protocol failed to yield an amorphous dispersion. A
PXRD
taken of this sample is shown in FIG 9.

Example 17:
Polyethylene glycol 8000 (PEG 8000, 1.0 g) was charged to methanol (10 mL) at room temperature. The suspension was stirred for 30 minutes to yield a clear solution. Paroxetine mesylate (1.0 g) was added at room temperature and the mixture was stirred for a further 40 minutes to yield a clear solution.
The solvent was removed in vacuo on a rotary evaporator to yield a white solid.
This protocol failed to yield an amorphous dispersion. A PXRD taken of this sample is shown in FIG 10.
Example 18:
Polyethylene glycol 20 000 (PEG 20 000, 2.0 g) was charged to dichloromethane (10 mL) at room temperature. The suspension was stirred 30 minutes to yield a clear solution. Paroxetine mesylate (2.0 g) was added at room temperature and the mixture was stirred for a further 30 minutes to yield a clear solution. The solvent was removed by evaporation on a rotary evaporator resulting in a white solid. This protocol failed to yield an amorphous dispersion.
A PXRD taken of this sample is shown in FIG 11.
Example 19:
Polyethylene glycol 35 000 (PEG 35 000, 2.0 g) was charged to dichloromethane (10 mL) at room temperature. The suspension was stirred for minutes to yield a clear solution. Paroxetine mesylate (2.0 g) was added at room temperature and the mixture was stirred for a further 30 minutes to yield a clear solution. The solvent was removed by evaporation on a rotary evaporator 25 resulting in a white solid. This protocol failed to yield an amorphous dispersion.
A PXRD taken of this sample is shown in FIG 12.

Example 20:
GelucireTm (1.0 g) was charged to methanol (10 mL) at room temperature.
The suspension was stirred at room temperature for one hour to yield a clear solution. Paroxetine mesylate (1.0 g) was added and the mixture was stirred for 50 minutes to yield a clear solution. The solvent was removed by evaporation on a rotary evaporator resulting in a waxy solid. This protocol failed to yield an amorphous dispersion. A PXRD taken of this sample is shown in FIG 13.
Example 21:
Paroxetine mesylate (5.0 g) was dissolved in methanol (50 mL) at room temperature. The solvent was removed in vacuo by rotary evaporation to yield amorphous paroxetine mesylate (5.0 g) as a white solid. The solid was maintained in a capped vial until acquisition of the PXRD as shown in FIG 14.
A
sample of the solid was placed in an uncapped vial at ambient temperature and high relative humidity for 60 hours. The sample became sticky and gummy after brief exposure to these conditions.
Example 22:
Samples were placed in capped vials in a stability chamber maintained at 40 C/75% RH. The results are shown in Table 1.
Table 1: Amorphous Solid Dispersions in Accelerated Conditions Example Composition Results after capped exposure at No. 40 C/75% RH
4 Paroxetine Powder after storage for 3 weeks Mesylate:HPMC (1:1) 5 Paroxetine Powder after storage for 3 weeks Mesylate:HPMC (1:0.5) 6 Paroxetine Powder after storage for 3 weeks Mesylate:HPMC (1:2) Example Composition Results after capped exposure at No. 40 C/75% RH
7 Paroxetine Mesylate: Powder after storage for 3 weeks PVP (1:1) 13 Paroxetine Mesylate: Powder after storage for 3 weeks Copovidone (1:1) 14 Paroxetine Mesylate: Powder after storage for 3 weeks EudragitTm (1:1) Example 23:
Paroxetine hydrochloride (25.0 g) was suspended in toluene (250 mL) at room temperature. A 1N aqueous NaOH solution (1.5 eq.) was slowly added at room temperature. The layers were separated and the organic layer was washed with distilled water (2 x 25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo by rotary evaporation at below 55 C to yield paroxetine free base as an oil (21.36 g). Toluene (50 mL) was charged to the oil, the solution was cooled to 18 C, and a solution of methanesulfonic acid (5.92 g) in toluene (32 mL) was slowly added. Distilled water (76 mL) was charged to the reaction mixture and the layers were separated. The aqueous layer was treated with 10 wt% activated charcoal, filtered, and concentrated to 55 mL in vacuo at below 60 'C. Methanol (495 mL) was added at room temperature followed by hydroxypropyl methylcellulose (27.0 g) at room temperature. The suspension was allowed to stir for two hours to afford a clear solution. The solution was spray-dried to afford an amorphous solid dispersion of paroxetine mesylate in HPMC (1:1 weight:weight).
Spray drying conditions:
Equipment Model/Make: Yamato Scientific/ D-L41 Spray Dryer Gas: N2 N2 Pressure: 0.1 MPa Aspirator Gauge: 1.0 m3/hour Inlet Temperature: 140 C
Outlet Temperature: 80 C
Flow Rate: 12-14 mL/min The system was conditioned for 1.5 hours prior to run.
Example 24:
A solution of paroxetine mesylate (5.0 g) and methanol (50 mL) was concentrated in vacuo at below 45 C by rotary evaporation to afford 5.0 g of a frothy, white solid. A portion (1.0 g) of the solid was charged to PEG 6000 (1.0 g) at room temperature. The powder mixture was heated to melt. A suspension was obtained at 70 C. The mass melted to yield a clear solution at 140 C. At this point, heating was discontinued and the mass was allowed to cool slowly while stirring to room temperature. Stirring was not possible once the temperature reached 40 C. A hard solid was obtained (2.0 g). A PXRD taken of this sample is shown in FIG 15.
Example 25:
To a suspension of paroxetine hydrochloride (25.0 g) in toluene (250 mL) was slowly charged a IN aqueous NaOH solution (1.5 eq.) at room temperature.
The layers were separated and the organic layer was washed with distilled water (2 x 25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo by rotary evaporation below 55 C to yield paroxetine free base (21.97 g). Acetic acid (1.15 eq.) was charged to a cooled (15 C) solution of the free base (21.97 g) in MTBE
(220 mL). The temperature was allowed to increase to room temperature. The resulting suspension was stirred at room temperature for 50 minutes. The solid was collected by filtration and washed with MTBE (1 x 30 mL) to afford paroxetine acetate (26.0 g). The solid was suspended in ethyl acetate (52 mL), stirred at room temperature for 30 minutes, filtered and washed with ethyl acetate (1 x 20 mL) to yield paroxetine acetate (22.0 g).
Example 26:
Paroxetine hydrochloride (10.0 g) was charged to methanol (50 mL) at room temperature. A clear solution was obtained 15 minutes of stirring. To this solution was slowly charged methanesulfonic acid (2.63 g) at room temperature.

The solution was stirred at room temperature for 2.5 hours followed by evaporation of the solvent in vacuo by rotary evaporation below 45 C to yield a crude oil. Toluene (50 mL) was charged to the oil and the solvent was evaporated in vacuo by rotary evaporation to afford a white powder (5.5 g).
The powder was suspended in ethyl acetate (25 mL) at room temperature and stirred for 30 minutes. The solid was collected by filtration and washed with ethyl acetate (2 x 10 mL) to yield paroxetine mesylate (4.4 g).
Example 27:
Paroxetine acetate (2.0 g) was charged to methanol (20 mL) at room temperature to yield a clear solution after 15 minutes. Methanesulfonic acid (0.49 g) was charged at room temperature and the mixture was stirred for 42 hours. The solvent was evaporated in vacuo by rotary evaporation below 45 C
to afford a crude oil (2.2 g). Toluene (20 mL) was added to the crude oil and the solution was concentrated to dryness in vacuo by rotary evaporation below 55 C.
Another portion of toluene (20 mL) was charged and the solution was concentrated to dryness as before to yield solid paroxetine mesylate (2.1 g) Example 28:
Methanesulfonic acid (0.29 g) was charged to a suspension of paroxetine hydrochloride (1.0 g) in ethyl acetate (5 mL) at room temperature. The resulting clear solution was stirred for a further 50 minutes. The solution was cooled to 0 C and stirred for 1 hour. The solution was seeded with crystalline paroxetine mesylate (5 mg). The solution was then concentrated to dryness in vacuo by rotary evaporation below 30 C. Ethyl acetate (20 mL) was charged and the suspension was concentrated to about 10 mL in vacuo by rotary evaporation below 30 C. A further portion (30 mL) of ethyl acetate was charged and the suspension was stirred at room temperature for 30 minutes. The solid was collected by filtration and washed with ethyl acetate (1 x 5 mL) to yield paroxetine mesylate (1.0 g).
Example 29:
Methanesulfonic acid (1.44 g) was slowly charged to a solution of paroxetine hydrochloride (5.0 g) in methanol (50 mL) at room temperature. The solution was stirred for 45 minutes followed by concentration in vacuo by rotary evaporation below 45 C to yield a crude oil. Toluene (50 mL) was charged to the crude oil and the solvent was evaporated by rotary evaporation below 55 C. A
further portion of toluene (50 mL) was charged and the evaporation was repeated to yield an oily mass. Distilled water (50 mL) was charged to the oil and about 5 mL of the water was evaporated to remove traces of toluene. The aqueous mixture was washed with ethyl acetate (1 x 30 mL), dichloromethane (1 x 30 mL) and MTBE (1 x 30 mL) and concentrated in vacuo by rotary evaporation below 55 C to about 40 mL. Polyvinylpyrrolidone (PVP, 4.0 g) was charged and the mixture was stirred at room temperature for 30 minutes to yield a clear solution.
The solution was frozen by submersion in a liquid nitrogen bath and subjected to freeze-drying (VirTis Freezemobile) to yield an amorphous solid dispersion of paroxetine mesylate in PVP (1:1 weight:weight) as a white powder (7.5 g).
Example 30:
Methanesulfonic acid (1.3 g) was slowly charged to a solution of paroxetine hydrochloride (5.0 g) in distilled water (50 mL) at room temperature.
The solution was stirred for 1 hour. The water was removed in vacuo by rotary evaporation below 55 C to yield a crude oil. Distilled water (50 mL) was charged to the oily mass and the solvent was again removed in vacuo by rotary evaporation below 55 C to yield a crude oil. This procedure of charging and evaporating distilled water was repeated four further times to yield an oily mass to which distilled water (50 mL) and polyvinylpyrrolidone (PVP, 5.0 g) were charged. The mixture was stirred for 30 minutes to yield a clear solution which was subjected to freeze-drying to afford an amorphous solid dispersion of paroxetine mesylate in PVP (1:1 weight:weight) as a white powder (7.5 g).

Claims (26)

What is claimed is:

1. An amorphous solid dispersion comprising paroxetine mesylate and a polymer, the polymer selected from the group consisting of cellulosic polymers, polymethacrylate polymers, polyvinylpyrrolidone polymers and polyethylene glycol polymers.

2. The amorphous solid dispersion of claim 1 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:10.

3. The amorphous solid dispersion of claim 1 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5.

4. The amorphous solid dispersion of claim 1 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2.

5. The amorphous solid dispersion of claim 1 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is about 1:1.

6. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, Povidone, Copovidone, Eudragit.TM. and polyethylene glycol.

7. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is hydroxypropyl methylcellulose.

8. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is Hypromellose 2910 USP E5.

9. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is Povidone.

10. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is Copovidone.

11. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is Eudragit.TM..

12. The amorphous solid dispersion of any one of claims 1 to 5 wherein the polymer is polyethylene glycol.

13. A process for the preparation of an amorphous solid dispersion comprising paroxetine mesylate and a polymer, the polymer selected from the group consisting of cellulosic polymers, polymethacrylate polymers and polyvinylpyrrolidone polymers, the process comprising:
a. forming a solution comprising the paroxetine mesylate and the polymer in a solvent; and b. removing the solvent from the solution, thereby isolating the amorphous solid dispersion.

14. The process of claim 13 wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, Povidone, Copovidone and Eudragit.TM..

15. The process of claim 13 wherein the polymer is hydroxypropyl methylcellulose.

16. The process of any one of claims 13 to 15 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:10.

17. The process of any one of claims 13 to 15 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:5.

18. The process of any one of claims 13 to 15 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:2.

19. The process of any one of claims 13 to 15 wherein a ratio of an amount by weight of the paroxetine mesylate within the amorphous solid dispersion to an amount by weight of the polymer within the amorphous solid dispersion is from about 1:0.3 to about 1:1.

20. The process of any one of claims 13 to 19 wherein the solvent is selected from the group consisting of water, alcohols, chlorinated hydrocarbons, and mixtures thereof.

21. The process of any one of claims 13 to 20 wherein the removing the solvent comprises spray-drying the solution.

22. The process of any one of claims 13 to 20 wherein the removing the solvent comprises evaporation or lyophilization.

23. The process of any one of claims 13 to 22 wherein the forming the solution of paroxetine mesylate and the polymer in the solvent comprises a salt exchange step whereby a salt of paroxetine, wherein the salt is not the mesylate salt, is treated with methanesulfonic acid thereby producing paroxetine mesylate.

24. The process of claim 23 wherein the salt of paroxetine is a salt of paroxetine with an acid selected from the group consisting of hydrochloric acid, acetic acid, malic acid, tartaric acid, oxalic acid, fumaric acid, propionic acid, formic acid, glutamic acid, succinic acid, benzoic acid, citric acid, toluene sulfonic acid, lactic acid and mandelic acid.

25. The process of claim 23 wherein the salt of paroxetine is selected from the group consisting of paroxetine hydrochloride and paroxetine acetate.

26. A product prepared by the process of any one of claims 13 to 25.