WO2014135834A1

WO2014135834A1 - Oxalic acid addition salts and/or solvates of a selective estrogen receptor modulator

Info

Publication number: WO2014135834A1
Application number: PCT/GB2014/000081
Authority: WO
Inventors: Srinivas Laxminarayan Pathi; Rajendra Ramachantra RAO; Rajendra Narayanrao Kankan; Chandrasekaran Ramasubbu
Original assignee: Cipla House; COTTRILL, Emily
Priority date: 2013-03-05
Filing date: 2014-03-05
Publication date: 2014-09-12
Also published as: ZA201401636B; WO2014135834A8; IN2013MU00665A

Abstract

The present invention provides raloxifene oxalate, including derivatives thereof. In particular, the present invention provides solvates and/or hydrates of raloxifene oxalate, and polymorphs thereof. The present invention also provides processes for preparing the novel compounds, pharmaceutical compositions including the novel compounds and medical uses of the novel compounds.

Description

OXALIC ACID ADDITION SALTS AND/OR SOLVATES OF A SELECTIVE ESTROGEN

RECEPTOR MODULATOR

Technical Field of the Invention

The present invention provides novel oxalic acid addition salts and/or solvates of raloxifene, process for their preparation and pharmaceutical compositions thereof.

Background of the Invention

Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor. A characteristic feature that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. SERMs, block the effects of estrogen in the breast tissue. SERMs work by sitting in the estrogen receptors in breast cells. As their name says, SERMs are "selective" - this means that a SERM that blocks estrogen's action in breast cells can activate estrogen's action in other cells, such as bone, liver, and uterine cells. SERMs can be used to treat women both before and after menopause.

Raloxifene is a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds and it is useful for the prevention and treatment of osteoporosis and beast cancer in postmenopausal women. Raloxifene is chemically termed as [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]- [4-[2-(1-piperidyl)ethoxy] phenyl]-methanone and has the structural formula I:

Raloxifene and its salts can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

Raloxifene base was disclosed in US4133814. Other methods of preparing raloxifene base are disclosed in patents such as W09848792 and US4380635.

US4358593 discloses a process of preparation of raloxifene and its salts. WO9609045 discloses non-solvated, crystalline raloxifene hydrochloride characterized by XRD, DSC and IR. US20020173645 discloses series of crystalline polymorphic forms of raloxifene hydrochloride namely Form I, Form II, Form III, Form IV and non-solvated crystalline form, characterized by XRD and the processes of preparation thereof.

WO2004/029046 discloses raloxifene L-laciate hemihydrate, DL-lactate hemihydrate and raloxifene sulphate 2-propanol solvate characterized by XRD and DSC. Processes of their preparation and pharmaceutical compositions containing these compounds is also disclosed in this patent for the treatment of cancer, osteoporosis or for inhibiting cartilage degradation. WO2004/029046 describes raloxifene salts such as DL- lactate, L-lactate, succinate, malonate and hydrates thereof. EP 584952 describes the use of acid addition salts of raloxifene such as hydrochloride, sulfate, lactate, succinate and malonate for the preparation of pharmaceutical formulations for inhibiting bone degradation and treating or preventing osteoporosis. WO2011/0999421 A2 describes raloxifene sulfamates in crystal and amorphous form and hydrates thereof.

One important property associated with solid state forms of drug substances is their aqueous solubility. Compounds having poor water solubility can lead to limited oral bioavailability when administered in patients.

Consequently, it would be a significant contribution to the art to provide new forms of raloxifene; having increased solubility, and methods of preparation, pharmaceutical formulations, and methods of use thereof.

Summary of the invention

The present invention is directed to inter alia oxalic acid addition salts and/or solvates of raloxifene and/or hydrates of raloxifene, methods of preparing such oxalic acid addition salts and/or solvates/hydrates of raloxifene and methods of treating or preventing osteoporosis and breast cancer in postmenopausal women and for treating cartilage degradation with such oxalic acid addition salts and/or solvates/hydrates of raloxifene.

The oxalic acid addition salts and/or solvates/hydrates of raloxifene may be in a pseudopolymorphic form. Accordingly, pseudopolymorphs provided include hydrates and/or solvates, more particularly, C1-C4 alcohol solvates, a THF (tetrahydrofuran) solvate and/or hydrated solvates.

According to one aspect of the present invention, there is provided raloxifene oxalate. The raloxifene oxalate may be in the form of a derivative thereof. The derivative may be a pharmaceutically acceptable solvate, hydrate, ester, tautomer, anhydrate, complex, polymorph, prodrug or combination thereof.

The raloxifene oxalate may be a solvate. The raloxifene oxalate solvate is optionally in hydrated form. Suitably, the raloxifene oxalate is a raloxifene oxalate solvate hydrate. The solvent that forms the solvate may be a C1-C4 alcoholate, for example methanol, ethanol, n-propanol, i-propanol, n-butanol, 2-n-butanol and i-butanol. Preferably, the solvent is ethanol and the raloxifene oxalate is raloxifene oxalate ethanolate optionally in hydrated form. Preferably the ethanolate is in hydrated form. Suitably, the hydrate of raloxifene oxalate ethanolate is a sesquihydrate. The inventors have discovered a suprisingly advantageous polymorphic form of raloxifene oxalate which is crystalline Form I raloxifene oxalate ethanolate sesquihydrate. This form is described in more detail herein.

Thus, the present invention provides crystalline raloxifene oxalate ethanolate sesquihydrate wherein the said ethanolate sesquihydrate is referred to as Form I.

The crystalline raloxifene oxalate ethanolate sesquihydrate is relatively stable towards moisture and humidity, thereby representing a crystalline form of raloxifene, thus enhancing the efficacy of the parent molecule in lower doses.

The crystalline raloxifene oxalate ethanolate sesquihydrate according to the present invention may be characterized by powder X-ray diffraction.

Crystalline Form I raloxifene oxalate ethanolate sequihydrate may be characterized by having an XRPD diffractogram comprising peaks at 8.59, 9.03,14.22, 17.16, 23.26 and 24.74 ± 0.2 °2Θ. The XRPD diffractogram may comprise further peaks at 10.05, 16.17, 19.23, 21.60, 24.08, 25.22, 26.60 and 27.32 ± 0.2 °2Θ. The XRPD diffractogram may comprise still further peaks at 1 1.37, 12.75, 15.47 and 20.13 ± 0.2 °2Θ. The XRPD diffractogram may be as depicted in Figure 1. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate may be characterized by having an intrinsic dissolution profile as shown in Figure 2.

According to another aspect of the present invention, there is provided a process for preparing crystalline raloxifene oxalate ethanolate sesquihydrate, the process comprising forming a solution of raloxifene base and oxalic acid di hydrate in ethanol at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtration and drying at elevated temperature. The raloxifene, as free base, may be in any polymorphic form or in a mixture of any polymorphic forms.

More particularly, the present invention provides a process for preparing crystalline Form I raloxifene oxalate ethanolate sesquihydrate as defined above and in the claims, the process comprising dissolving raloxifene base in ethanol at a temperature ranging from 40°C to 60°C (preferably the temperature ranges from 50°C to 55°C), adding a solution of oxalic acid dihydrate in ethanol to form a reaction mass, and isolating crystalline Form I. The oxalic acid is typically added at a temperature ranging from 40°C to 60°C, preferably at a temperature ranging from 50°C to 55°C. The oxalic acid is typically added over a period ranging from around 30 minutes to around 2 hours, preferably from around 45 minutes to around 1.5 hours, more preferably for a time of around 50 minutes to 1 hour 0 minutes, for example over a period of around 60 minutes.

The isolation may comprise isolating precipitated Form I from the reaction mass, followed by drying under reduced pressure at a temperature ranging from around 30°C to around 90°C (preferably at a temperature ranging from around 60°C to around 85°C; more preferably ranging from around 70°C to around 85°C) for at least 8 hours, preferably at a temperature ranging from 75°C to 85°C for around 8 hours. Immediately prior to the drying step, the reaction mass may be cooled to a temperature ranging from around 20°C to around 35°C; preferably ranging from around 25°C to around 35°C). The process may further comprise stirring the reaction mass for at least 5 hours prior to the isolation step and after the addition of the oxalic acid. Suitably, the stirring takes place for at least 7 hours, for example around 8 hours.

The raloxifene base may be prepared from a salt of raloxifene, other than raloxifene oxalate, the preparation of the free base from the salt being carried by any well known method, for example reaction of the salt with a base such as sodium hydroxide. For example, the other salt may be raloxifene hydrochloride.

According to another aspect of the present invention, there is provided crystalline raloxifene oxalate ethanolate sesquihydrate Form I prepared by a process according to the process described above. The process produces crystalline raloxifene oxalate ethanolate sesquihydrate in high yield and purity.

The derivate of raloxifene oxalate may be a non-solvated hydrate of raloxifene oxalate. Preferably, the hydrate is a hemihydrate. The inventors have discovered a surprisingly advantageous polymorphic form of raloxifene oxalate which is crystalline Form II raloxifene oxalate monohydrate. This form is described in more detail herein.

According to another aspect of the present invention, there is provided crystalline raloxifene oxalate monohydrate wherein the said crystal form of this embodiment is referred to as Form II. The crystalline raloxifene oxalate monohydrate Form II according to the present invention may be characterized by powder X-ray difractogram.

Crystalline raloxifene oxalate monohydrate Form II may be characterized by having an XRPD diffractogram comprising peaks at 14.94, 18.60 and 20.34 ± 0.2 °2Θ. The XRPD diffractogram may comprise further peaks at 20.04, 21.90 and 22.72 ± 0.2 "2Θ. The XRPD diffractogram may comprise still further peaks at 7.00, 10.00 and 16.12 ± 0.2 °2Θ. The XRPD diffractogram may be as depicted in Figure 3.

According to another aspect of the present invention, there is provided a process for preparing crystalline raloxifene oxalate monohydrate, the process comprising forming a solution of raloxifene base and oxalic acid dihydrate in methanol solvent at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtration and drying at elevated temperature. More particularly, the present invention provides a process for preparing crystalline raloxifene oxalate monohydrate Form II as defined herein and in the claims, the process comprising dissolving raloxifene base in methanol at a temperature ranging from 40°C to 60°C (preferably the temperature ranges from 50°C to 55°C), adding a solution of oxalic acid dihydrate in methanol to form a reaction mass, and isolating crystalline Form II. The oxalic acid is typically added at a temperature ranging from 40° C to 60°C, preferably at a temperature ranging from 50°C to 55°C. The oxalic acid is typically added over a period ranging from around 30 minutes to around 2 hours, preferably from around 45 minutes to around 1.5 hours, more preferably for a time of around 50 minutes to 1 hour 10 minutes, for example over a period of around 60 minutes.

The isolation may comprise isolating precipitated Form II from the reaction mass, followed by drying under reduced pressure at a temperature ranging from around 30^CC to around 90°C (preferably at a temperature ranging from around 60°C to around 85°C; more preferably ranging from around 70°C to around 85°C) for at least 8 hours, preferably at a temperature ranging from 75°C to 85°C for around 8 hours. Immediately prior to the drying step, the reaction mass may be cooled to a temperature ranging from around 20°C to around 35°C; preferably ranging from around 25°C to around 35°C). The process may further comprise stirring the reaction mass for at least 5 hours prior to the isolation step and after the addition of the oxalic acid. Suitably, the stirring takes place for at least 7 hours, for example around 8 hours. The raloxifene base may be prepared from a salt of raloxifene, other than raloxifene oxalate, the preparation of the free base from the salt being carried by any well known method, for example reaction of the salt with a base such as sodium hydroxide. For example, the other salt may be raloxifene hydrochloride. The raloxifene, as free base may be, in any polymorphic form or in a mixture of any polymorphic forms.

According to another aspect of the present invention, there is provided crystalline raloxifene oxalate monohydrate Form II prepared by a process according to the process described above. The process produces crystalline raloxifene oxalate Form II in high yield and purity.

According to another aspect of the present invention, there is provided crystalline raloxifene oxalate isopropanolate hemihydrate wherein the said crystal form of this embodiment is referred to as Form III.

The crystalline raloxifene oxalate isopropanolate hemihydrate Form III according to the present invention may be characterized by powder X-ray diffractogram. Crystalline raloxifene oxalate isopropanolate hemihydrate Form III may be characterized by having an XRPD diffractogram comprising a peak at 21.38 ± 0.2 °2Θ. The XRPD diffractogram may comprise further peaks at 15.64, 18.69, 19.42, 23.16, 24.18 and 26. 0 ± 0.2 °2Θ. The XRPD diffractogram may comprise still further peaks at 11.90 ± 0.2 °2Θ. The XRPD diffractogram may be as depicted in Figure 4. According to another aspect of the present invention, there is provided a process for preparing crystalline raloxifene oxalate isopropanolate hemihydrate Form III, the process comprising forming a solution of raloxifene base and oxalic acid dihydrate in isopropanol solvent at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtration and drying at elevated temperature.

The raloxifene, as free base, may be in any polymorphic form or in a mixture of any polymorphic forms. More particularly, the present invention provides a process for preparing crystalline raloxifene oxalate isopropanolate hemihydrate Form III as defined herein and in the claims, the process comprising dissolving raloxifene base in isopropanol at a temperature ranging from 40°C to 60°C (preferably the temperature ranges from 50°C to 55°C), adding a solution of oxalic acid dihydrate in isopropanol to form a reaction mass, and isolating crystalline Form III. The oxalic acid is typically added at a temperature ranging from 40°C to 60°C, preferably at a temperature ranging from 50°C to 55°C. The oxalic acid is typically added over a period ranging from around 30 minutes to around 2 hours, preferably from around 45 minutes to around 1 .5 hours, mere preferably for a time of around 50 minutes to 1 hour 10 minutes, for example over a period of around 60 minutes.

The isolation may comprise isolating precipitated Form III from the reaction mass, followed by drying under reduced pressure at a temperature ranging from around 30°C to around 90°C (preferably at a temperature ranging from around 60°C to around 85°C; more preferably ranging from around 70°C to around 85°C) for at least 8 hours, preferably at a temperature ranging from 75°C to 85°C for around 8 hours. Immediately prior to the drying step, the reaction mass may be cooled to a temperature ranging from around 20°C to around 35°C; preferably ranging from around 25°C to around 35°C). The process may further comprise stirring the reaction mass for at least 5 hours prior to the isolation step and after the addition of the oxalic acid. Suitably, the stirring takes place for at least 7 hours, for example around 8 hours. The raloxifene base may be prepared from a salt of raloxifene, other than raloxifene oxalate, the preparation of the free base from the salt being carried by any well known method, for example reaction of the salt with a base such as sodium hydroxide. For example, the other salt may be raloxifene hydrochloride. According to another aspect of the present invention, there is provided crystalline raloxifene oxalate isopropanolate hemihydrate Form III prepared by a process according to the process described above. The process produces crystalline raloxifene oxalate isopropanolate hemihydrate Form III in high yield and purity. According to another aspect of the present invention, there is provided crystalline raloxifene oxalate THF (tetrahydrofuran) hemisolvate monohydrate wherein the said crystal form of this embodiment is referred to as Form IV.

The crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV according to the present invention may be characterized by powder X-ray difractogram.

Crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV may be characterized by having an XRPD diffractogram comprising peaks at 18.48, 19.46 and 21.2 ± 0.2 °2Θ. The XRPD diffractogram may comprise further peaks at 10.79, 11.54, 12.02, 16.66, 17.43, 19.80, 24.30 and 24.58 ± 0.2 °2Θ. The XRPD diffractogram may be as depicted in Figure 5.

According to another aspect of the present invention, there is provided a process for preparing crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV, the process comprising forming a solution of raloxifene base and oxalic acid dihydrate, in THF solvent at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtration and drying at elevated temperature.

The raloxifene, as free base, may be in any polymorphic form or in a mixture of any polymorphic forms.

More particularly, the present invention provides a process for preparing crystalline raloxifene oxalate THF hemisolvate monchydrate Form IV as defined above and in the claims, the process comprising dissolving raloxifene base in THF at a temperature ranging from 40°C to 60°C (preferably the temperature ranges from 50°C to 55°C), adding a solution of oxalic acid dihydrate in THF to form a reaction mass, and isolating crystalline Form IV. The oxalic acid is typically added at a temperature ranging from 40°C to 60°C, preferably at a temperature ranging from 50°C to 55°C. The oxalic acid is typically added over a period ranging from around 30 minutes to around 2 hours, preferably from around 45 minutes to around 1.5 hours, more preferably for a time of around 50 minutes to 1 hour 10 minutes, for example over a period of around 60 minutes.

The isolation may comprise isolating precipitated Form IV from the reaction mass, followed by drying under reduced pressure at a temperature ranging from around 30°C to around 90°C (preferably at a temperature ranging from around 60°C to around 85°C; more preferably ranging from around 70°C to around 85°C) for at least 8 hours, preferably at a temperature ranging from 75°C to 85°C for around 8 hours. Immediately prior to the drying step, the reaction mass may be cooled to a temperature ranging from around 20°C to around 35°C; preferably ranging from around 25°C to around 35°C).

The process may further comprise stirring the reaction mass for at least 5 hours prior to the isolation step and after the addition of the oxalic acid. Suitably, the stirring takes place for at least 7 hours, for example around 8 hours. The raloxifene base may be prepared from a salt of raloxifene, other than raloxifene oxalate, the preparation of the free base from the salt being carried by any well known method, for example reaction of the salt with a base such as sodium hydroxide. For example, the other salt may be raloxifene hydrochloride.

According to another aspect of the present invention, there is provided crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV prepared by a process according to the process described above. The process produces crystalline raloxifene oxalate THF solvate Form IV in high yield and purity.

In preparing Forms I, II, III and IV as defined herein and in the claims, the oxalic acid being in the form of a dihydrate provides the water for hydration.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising raloxifene oxalate as described above (including Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate, Crystalline Form II of raloxifene oxalate monohydrate, Crystalline Form III of raloxifene oxalate isopropanolate hemihydrate and Crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate; preferably Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate), together with one or more pharmaceutically acceptable excipients, including pharmaceutically acceptable carriers.

Suitably, the pharmaceutical composition is in the form of a tablet suitable for oral delivery. According to another aspect of the present invention, there is provided raloxifene oxalate as described above (including Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate, Crystalline Form II of raloxifene oxalate monohydrate, Crystalline Form III of raloxifene oxalate isopropanolate hemihydrate and Crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate; preferably Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate) for use in medicine. Suitably, the raloxifene oxalate is for use in treating osteoporosis (particularly in postmenopausal women), breast cancer (particularly in postmenopausal women) and/or cartilage degradation.

According to another aspect of the present invention, there is provided the use of raloxifene oxalate as described above (including Crystalline Form I of raloxifene oxalate ethanolate sesqui hydrate, Crystalline Form II of raloxifene oxalate mortohydrate, Crystalline Form III of raloxifene oxalate isopropanolate hemihydrate and Crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate; preferably Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate) for use in the manufacture of a medicament for treating or preventing osteoporosis (particularly in postmenopausal women), breast cancer (particularly in postmenopausal women) and/or cartilage degradation.

According to another aspect of the present invention, there is provided a method of treating or preventing osteoporosis (particularly in postmenopausal women), breast cancer (particularly in postmenopausal women) and/or cartilage degradation, comprising administering to a patient in need thereof a therapeutically effective amount of raloxifene oxalate as described above (including Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate, Crystalline Form II of raloxifene oxalate monohydrate, Crystalline Form III of raloxifene oxalate isopropanolate hemihydrate and Crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate; preferably Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate).

Brief Description of the Drawing Figure 1 is X-ray powder diffraction spectrum of crystalline raloxifene oxalate ethanolate sesquihydrate Form I.

Figure 2 is the Intrinsic Dissolution Rate for crystalline raloxifene oxalate ethanolate sesquihydrate Form I compared with raloxifene hydrochloride Figure 3 is X-ray powder diffraction spectrum of crystalline raloxifene oxalate monohydrate Form II.

Figure 4 is X-ray powder diffraction spectrum of crystalline raloxifene oxalate isopropanolate hemihydrate Form III.

Figure 5 is X-ray powder diffraction spectrum of crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV. Detailed Description Of The Invention

As used herein, the term "solvated" is understood to mean formation of a complex of variable stoichiometry comprising raloxifene of Formula (I) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Typically, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include C1-C4 alcohol solvents and tetrahydrofuran (THF), and solvates other than water at levels of more than 1%.

The solvate can be isolated either as an amorphous form or in a crystalline form, preferably in crystalline form.

The solvate can be further isolated either in anhydrous form or hydrated form.

As used herein, the term "hydrate" is understood as a substance that is formed by adding water molecules. The skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio. The notation for a hydrated compound may be .nH₂0, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on. As used herein, the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2Θ values within ± 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.

In one aspect the present invention provides the oxalic acid addition salt of raloxifene. The oxalate may be isolated in pseudopolymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.

Accordingly, pseudopolymorphs provided include solvates, more in particular, a THF solvate, or a C1-C4 alcohol solvate, optionally in hydrated form.

Because oxalic acid has two acid groups per molecule, compounds of these acids and raloxifene may be isolated as either mono- or di-acid addition salts and/or solvates thereof having either one or two raloxifene molecules per acid molecule respectively.

The ratio of raloxifene of formula I to oxalic acid may range from about 1 to about 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid. Preferably, the ratio is 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid.

As polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2Θ values are accurate to within ± 0.2 degrees. All the powder diffraction patterns were measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-Κ-α radiation source.

The invention further provides processes for the preparation of polymorphs. Thus, in one aspect, the present invention provides the crystalline raloxifene oxalate ethanolate hydrate.

In an embodiment, raloxifene oxalate ethanolate referred in this specification includes various degrees of hydrates. Preferably, the hydrate is sesquihydrate.

Thus in a preferred embodiment the acid addition salt and/or solvates thereof according to the invention is raloxifene oxalate ethanolate hydrate, and in a particular preferred embodiment the acid addition salt is crystalline raloxifene oxalate ethanolate sesquihydrate which is herein and in the claims designated as Form I which is substantially non-hygroscopic and has good flow characteristics.

In another aspect, the present invention provides a process for preparing the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate in high yield and purity. The present invention also provides pharmaceutical compositions comprising the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate.

In an embodiment, the ethanol content in raloxifene oxalate may vary in ratio depending on the conditions applied. Conveniently, the ratio of raloxifene to the ethanol may range between 2.5wt% (0.5 moles) to 5.0wt% (1.0 mole). While the raloxifene oxalate, comprising 0.5 molecules of ethanol per molecule of raloxifene and about 1 molecule of ethanol per molecule of raloxifene represent the lower and upper ranges respectively, ethanol content of the crystal form may vary within this range depending on the temperature of the crystal form. Thus, raloxifene oxalate forms a crystalline sesquihydrate with ethanol wherein the molar ratio of raloxifene to oxalic acid to water is approximately 2:1 :1.5 whereas ethanol is present in the non-stoichiometric ratio ranging from 2.5% (0.5 moles) to 5.0% (1.0 mole). Accordingly, the present invention provides crystalline Form I of raloxifene oxalate ethanolate sesquihydrate, methods of preparing the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate in high purity and high yield and pharmaceutical compositions comprising them. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use.

The crystalline Form I of raloxifene oxalate ethanolate sesquihydrate thereof according to the invention has dissolution properties in dilute hydrochloric acid that secure a high bioavailability of the compound. In particular the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate according to the invention has higher intrinsic dissolution rates in dilute hydrochloric acid compared with free raloxifene.

In an embodiment, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate has an XRD pattern with characteristics peaks at 8.59, 9.03 and 14.22 ± 0.2 °2Θ. The crystalline Form I of raloxifene oxalate ethanolate sesquihydrate may have an XRD pattern with characteristics peaks at 8.59, 9.03, 14.22, 17.16, 23.26 and 24.74 ± 0.2 °2Θ. The XRD pattern may have further peaks at 10.05, 16.17, 19.23, 21.60, 24.08, 25.22, 26.60 and 27.32 ± 0.2 °2Θ. The XRD pattern may have still further peaks at 1 1.37, 12.75, 15.47 and 20.13 ± 0.2 °2Θ.

In an embodiment, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate has an XRPD pattern with those peaks at °2Θ values ± 0.2 °2Θ as depicted in Table 1. In an embodiment, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Table 1. Table 1 : Table of values for the XRPD pattern depicted in Figure 1

Peak value (°2Θ) Relative Intensity [%]

8.59 76.1

9.03 100.0

10.05 68.8

11.37 27.4

12.75 20.4

13.22 14.2

14.22 99.1

15.47 22.8

16.17 55.3

16.60 12.2

17.16 82.8

18.16 15.3

18.42 17.9

19.23 58.3

20.13 28.4

21.60 38.2

22.25 9.6

23.26 95.8

24.08 44.8

24.74 78.4

25.22 51.0

26.60 36.0

27.32 44.9

29.22 19.7

30.00 10.6 In an embodiment, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate of the present invention is characterized by having an intrinsic dissolution profile as shown in Figure 2. To measure the intrinsic dissolution of the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate and raloxifene hydrochloride, samples were measured to compare the influence of the different parameter settings. At appropriate time intervals, an automated sample collector removes aliquots from dissolution medium for analysis. The time interval for sampling can vary, for example, from 2 to 30 minutes, depending on the properties of the drug and dissolution medium used. Suitable dissolution equipment for these operations includes LAB INDIA DISSO 2000.

Those skilled in the art would recognize that Form I may be further characterized by other methods including, but not limited to IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate. The process may comprise: dissolving raloxifene base in ethanol at 40-60°C, adding a solution of oxalic acid dihydrate in ethanol, stirring for at least 5 hours, isolating the precipitated crystalline Form I of raloxifene oxalate ethanolate sesquihydrate and drying under reduced pressure at 30-80°C, preferably at 60-80°C for at least 8 hrs.

Alternatively, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate may be prepared by a process comprising; converting any acid addition salt of raloxifene into the free base and subsequently converting free base into the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate.

The raloxifene acid addition salt used in the preparation of the Form I may be in any polymorphic form or in a mixture of any polymorphic forms wherein the said raloxifene in hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof. In a preferred embodiment, raloxifene is provided in the form of raloxifene hydrochloride.

The raloxifene hydrochloride, used for the above process, as well as for the following processes, describe in this application can be obtained by any method known to a skilled artisan.

The crystalline Form I of raloxifene oxalate ethanolate sesquihydrate obtained according to the present invention is substantially free from other forms of raloxifene. "Substantially free" from other forms of raloxifene shall be understood to mean that the polymorphs of raloxifene contain less than 10%, preferably less than 5%, of any other forms of raloxifene and less than 1 % of other impurities or solvates.

The process of invention may be used as a method for purifying any form of raloxifene, as well as for the preparation of the new polymorphic forms.

According to yet another aspect of the present invention, there is provided use of the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate as described above, in the preparation of a medicament useful in treating or preventing osteoporosis and breast cancer in postmenopausal women and for treating cartilage degradation.

Yet another aspect of the present invention provides a novel polymorphic form of raloxifene oxalate monohydrate which is hereinafter designated as Form II which is substantially non-hygroscopic and has good flow characteristics.

The ratio of raloxifene of formula I to oxalic acid may range from about 1 to about 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid. Preferably, the ratio is 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid. Thus, raloxifene oxalate forms a crystalline monohydrate with water wherein the molar ratio of raloxifene to oxalic acid to water is approximately 2:1:1.

In another aspect, the present invention provides a process for preparing the novel Form II of raloxifene oxalate monohydrate in high yield and purity. The present invention also provides pharmaceutical compositions comprising Form II of raloxifene oxalate monohydrate.

In an embodiment, the crystalline polymorph Form II of raloxifene oxalate monohydrate has an XRD pattern with characteristics peaks at 14.94, 18.60 and 20.34 ± 0.2 °2Θ. The XRD pattern may be further characterized by an XRD with peaks at 20.04, 21.90 and 22.72 ± 0.2 °2Θ. The XRD pattern comprises still further peaks at 7.00, 10.00 and 16.12 ± 0.2 "2Θ. In an embodiment, the crystalline polymorph Form II of raloxifene oxalate monohydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Table 2.

Table 2: Table of values for the XRPD pattern depicted in Figure 3

Peak value (°2Θ) Relative Intensity [%]

7.00 27.2

10.00 26.7

11.64 12.1

12.02 13.9

13.40 19.7

13.97 6.4

14.94 80.50

16.12 24.5

17.36 12.0

18.60 100.0 20.04 60.2

20.34 72.3

21.90 31.9

22.72 57.8

24.30 18.4

24.90 4.1

25.94 13.3

28.86 9.1

29.89 15.1

30.48 5.7

In an embodiment, the crystalline polymorph Form II of raloxifene oxalate monohydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Figure 3. Those skilled in the art would recognize that Form II may be characterized by other methods including but not limited to IR, solic^" state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of crystalline Form II of raloxifene oxalate monohydrate. The process may comprise the steps of: dissolving raloxifene base in methanol at 55-60°C, adding a solution of oxalic acid dihydrate in methanol, stirring for at least 8 hours, isolating the precipitated crystalline Form II of raloxifene oxalate monohydrate and drying under reduced pressure at 30-80°C, preferably at 60-80°C for at least 8 hrs. The present invention further provides a novel polymorph form of raloxifene oxalate isopropanolate hemihydrate which is hereinafter designated as Form III which is substantially non-hygroscopic and has good flow characteristics. The ratio of raloxifene of formula I to oxalic acid may range from about 1 to about 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid. Preferably, the ratio is 2 molecules of raloxifene of formula I per 1 molecule of oxalic acid. Thus, raloxifene oxalate forms a crystalline hemihydrate with isopropanol wherein the molar ratio of raloxifene to oxalic acid to IPA to water is approximately 2:1 :2:0.5.

In another aspect, the present invention provides a process for preparing the novel Form III of raloxifene oxalate isopropanolate hemihydrate in high yield and purity. The present invention also provides pharmaceutical compositions comprising Form III of raloxifene oxalate isopropanolate hemihydrate.

In an embodiment, the crystalline polymorph Form III of raloxifene oxalate isopropanolate hemihydrate has an XRD pattern with a characteristic peak at 2 .38 ± 0.2 "2Θ. The XRD pattern may be further characterized by an XRD with peaks at 15.64, 18.69, 19.42, 23.16, 24.18 and 26.10 ± 0.2 °2Θ. The XRD pattern comprises a still further peak at 1 1.90 ± 0.2 °2Θ.

In an embodiment, the crystalline polymorph Form III of raloxifene oxalate isopropanolate hemihydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Table 3.

Table 3: Table of values for the XRPD pattern depicted in Figure 4

In an embodiment, the crystalline polymorph Form III of raloxifene oxalate isopropanolate hemihydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Figure 4.

Those skilled in the art would recognize that Form III may be characterized by other methods including but not limited to IR, solid state NMR and Raman spectroscopy. According to another aspect of the present invention there is provided a process for the preparation of crystalline Form III of raloxifene oxalate isopropanolate hemihydrate. The process may comprise the steps of dissolving raloxifene base in isopropanol at 55-60°C, adding a solution of oxalic acid dihydrate in isopropanol, stirring for at least 8 hours, isolating the precipitated crystalline Form III of raloxifene oxalate isopropanolate hemihydrate and drying under reduced pressure at 30-80°C, preferably at 60-80°C for at least 8 hrs.

Yet another aspect of the present invention provides a novel polymorphic form of raloxifene oxalate THF hemisolvate monohydrate which is hereinafter designated as Form IV which is substantially non-hygroscopic and has good flow characteristics.

Thus, raloxifene oxalate forms a crystalline hemisolvate with THF wherein the molar ratio of raloxifene to oxalic acid to THF to water is approximately 2:1 :0.5:1. In another aspect, the present invention provides a process for preparing the novel Form IV of raloxifene oxalate THF hemisolvate monohydrate in high yield and purity. The present invention also provides pharmaceutical compositions comprising Form IV of raloxifene oxalate THF hemisolvate monohydrate. In an embodiment, the crystalline polymorph Form IV of raloxifene oxalate THF hemisolvate monohydrate has an XRD pattern with characteristics peaks at 18.48, 19.46 and 21.2 ± 0.2 °2Θ. The XRD pattern may be further characterized by an XRD with peaks at 10.79, 11.54, 12.02, 16.66, 17.43, 19.80, 24.30 and 24.58 ± 0.2 °2Θ. The XRD pattern comprises still further peaks at 20.62 and 25.64 ± 0.2 °2Θ. In an embodiment, the crystalline polymorph Form IV of raloxifene oxalate THF hemisolvate monohydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Table 4. Table 4: Table of values for the XRPD pattern depicted in Figure 5

Peak value (°2Θ) Relative Intensity

[%]

6.82 19.5

7.61 8.5

8.98 7.5

9.83 11.5

10.79 59.6

11.54 37.5

i

12.02 51.7

13.62 12.8

16.66 55.0

17.43 30.1

18.48 100.0

19.46 76.5

19.80 58.7

20.62 20.0

21.20 82.5

22.23 17.1

23.18 15.5

24.30 44.0

24.58 38.2

25.64 24.1

27.48 13.2 In an embodiment, the crystalline polymorph Form IV of raloxifene oxalate THF hemisolvate monohydrate has substantially the same XRPD pattern with peaks at 2Θ values as depicted in Figure 5. Those skilled in the art would recognize that Form IV may be characterized by other methods including but not limited to IR, solid state NMR and Raman spectroscopy.

According to another aspect of the present invention there is provided a process for the preparation of crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate. The process may comprise the steps of: dissolving raloxifene base in THF at 55-60°C, adding a solution of oxalic acid dihydrate in THF, stirring for at least 8 hours, isolating the precipitated crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate and drying under reduced pressure at 30-80°C, preferably at 60-80°C for at least 8 hours. The process of invention may be used as a method for purifying any form of raloxifene oxalate, as well as for the preparation of the new polymorphic forms.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising polymorphic forms of raloxifene oxalate as described above, together with one or more pharmaceutically acceptable excipients. The raloxifene oxalate used in the preparation of pharmaceutical compositions may substantially consist of one of forms I, II, III or IV described above, or may substantially consist of a combination of two or more of said forms. According to yet another aspect of the present invention there is provided use of polymorphic Forms of raloxifene oxalate as described above, in the preparation of a medicament useful in treating or preventing osteoporosis and breast cancer in postmenopausal women and for treating cartilage degradation. The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples 1

a) Preparation of raloxifene base:

Raloxifene HCI (200 gm) was stirred with methanol (2000 ml) at room temperature. An aqueous solution of sodium hydroxide (50 gm dissolved in 200 ml of water) was added, stirred and cooled to 15°C - 20°C.The pH of the reaction mass was adjusted to 8.0 to 8.5 using 20% aqueous HCI solution. The temperature of the reaction mass was raised to 25°C - 30°C and stirred for 12 hours. To the reaction mass was added water (4000 ml) and the pH was adjusted to 8.0 - 8.5 using 10% aqueous NaOH solution and stirred for 30 minutes. The product was isolated by filtration, washed with water (100 ml) and dried under vacuum at 85°C - 95°C for 8 hours to yield 180 gm of titled compound. b) Preparation of crystalline Form I of raloxifene oxalate ethanolate sesquihydrate:

Raloxifene Base (180 gm) was dissolved in ethanol (1800 ml) at 50°C-55^CC. A solution of oxalic acid dihydrate (23.01 gm in 460 ml of ethanol) was added slowly at 50°C-55°C over a period of 60 minutes and stirred for 8 hours. The reaction mass cooled to 25°C - 30°C, stirred for 30 minutes. The solid was isolated by filtration, washed with ethanol (100 ml) and dried under vacuum at 75°C - 85°C for 8 hours to yield 190 gm of titled compound.

Example 2

Comparative Intrinsic Dissolution Study

Preparation of tablet- General process for preparing tableting mixture comprising crystalline Form I of raloxifene oxalate ethanolate sesquihydrate:-

A tableting mixture (50 mg) comprising solely crystalline Form I of raloxifene oxalate ethanolate sesquihydrate prepared according to the example 1 (i.e. with no excipients), was prepared and compressed to a pellet using a manual hand press operating at a compression pressure of 1 ton for 1 minute.

In-vitro dissolution studies were performed on the 50 mg pellet in a LAB INDIA DISSO 2000.

The pellet was fixed in a PFTE holder, such that only the pellet surface came into contact with the dissolution medium. The PFTE loaded holder was placed in the dissolution vessel containing 900 ml of 2% SLS (sodium lauryl sulphate) in water at 35°C - 40°C. Two pellets were measured for each run of the design of the experiments. Stirring was performed with a paddle rotating at 100 rpm. The dissolution was followed up to 1440 min and the concentration of active ingredient, raloxifene, dissolved in the test medium was determined by removing samples of 10 ml at the specified time intervals.

The concentration of crystalline Form I of raloxifene oxalate ethanolate sesquihydrate was quantified by UV method at a maximum wavelength of 280 nm under the conditions as specified below:

Standard Preparation: 50 mg raloxifene hydrochloride dissolved to 50 ml with Acetonitrile

Water (1 :1).

5 ml of this solution diluted to 00 ml with dissolution medium.

2 ml of this solution further diluted to 5 ml with purified water.

Sample Aliquot: 2 ml of aliquot further diluted to 5 ml with purified water.

Blank Purified water:Dissolution medium (2:3)

Diluent Acetonitrile: water (1 :1)

Wavelength 280nm

Path length 1 cm (Covet size)

The percentage of raloxifene released from the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate as well as from the raloxifene hydrochloride physical mixture were plotted against time as shown in Figure 2. The intrinsic dissolution rate was derived from the slope of this curve. Table 2 shows the results in tabular form.

Table 2: Intrinsic Dissolution Profile of crystalline Form I of raloxifene oxalate ethanolate sesquihydrate with raloxifene hydrochloride

When compared with raloxifene hydrochloride, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate exhibited a superior rate of dissolution as shown in Table 2. The peak dissolution of 82.0 % was achieved at 1080 min for the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate; whereas, at the same time, 62.0 % was achieved for raloxifene hydrochloride. Thus, another aspect of the present invention is crystalline Form I of raloxifene oxalate ethanolate sesquihydrate characterised by a peak dissolution (typically when measured at a temperature ranging from 35°C to 40°C) of at least around 75%, preferably at least around 79%, more preferably at least around 81%, particularly when dissolution is measured in accordance with the above procedure. Typically, the crystalline Form I of raloxifene oxalate ethanolate sesquihydrate is characterised when in the form of a compressed tablet. Example 3

Preparation of crystalline Form II of raloxifene oxalate monohydrate:

Raloxifene Base (10 gm) was dissolved in methanol (100 ml) at 50°C - 55°C. A solution of oxalic acid dihydrate (1.27 gm in 25 ml of methanol) was added slowly at 50°C - 55°C over a period of 60 minutes and stirred for 8 hours. The reaction mass cooled to 25°C - 30°C, stirred for 30 minutes. The solid was isolated by filtration, washed with methanol (10 ml) and dried under vacuum at 75°C -85°C for 8 hours to yield 9.0 gm of titled compound.

Example 4

Preparation of crystalline Form III of raloxifene oxalate isopropanolate hemihydrate: Raloxifene Base (10 gm) was dissolved in isopropanol (100 ml) at 50X - 55°C. A solution of oxalic acid dihydrate (1.27 gm in 25 ml of isopropanol) was added slowly at 50°C - 55°C over a period of 60 minutes and stirred for 8 hours. The reaction mass cooled to 25°C - 30°C, stirred for 30 minutes. The solid was isolated by filtration, washed with isopropanol (10 ml) and dried under vacuum at 75°C -85°C for 8 hours to yield 9.2 gm of titled compound. Example 5

Preparation of crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate:

Raloxifene Base (10 gm) was dissolved in THF (100 ml) at 50°C - 55°C. A solution of oxalic acid dihydrate (1.27 gm in 25 ml of THF) was added slowly at 50°C - 55°C over a period of 60 minutes and stirred for 8 hours. The reaction mass cooled to 25°C - 30°C, stirred for 30 minutes. The solid was isolated by filtration, washed with THF (10 ml) and dried under vacuum at 75°C -85°C for 8 hours to yield 9.7 gm of titled compound. It will be appreciated that the invention may be modified within the scope of the appended claims.

Claims

1. Raloxifene oxalate.

2. Raloxifene oxalate according to claim 1 , wherein the raloxifene oxalate is in the form of a pharmaceutically acceptable derivative, which optionally comprises a pharmaceutically acceptable solvate, hydrate, ester, tautomer, anhydrate, complex, polymorph, prodrug or combination thereof.

3. Raloxifene oxalate as claimed in claim 1 or 2, wherein the raloxifene oxalate is a raloxifene oxalate solvate optionally in hydrated form.

4. Raloxifene oxalate as claimed in claim 3, which is a raloxifene oxalate solvate hydrate.

5. Raloxifene oxalate as claimed in claim 3 or 4, wherein the solvate is a C1-C4 alcoholate.

6. Raloxifene oxalate as claimed in claim 5, which is an ethanolate.

7. Raloxifene oxalate as claimed in any one of claims 2 to 6, which is a hydrate.

8. Raloxifene oxalate as claimed in claim 7, which is raloxifene oxalate ethanolate sesqui hydrate.

9. Raloxifene oxalate as claimed in claim 8, which is crystalline Form I raloxifene oxalate ethanolate sesquihydrate.

10. Crystalline Form I raloxifene oxalate ethanolate sequihydrate as claimed in claim 9, characterized by having an XRPD diffractogram comprising peaks at 8.59, 9.03,14.22, 17.16, 23.26 and 24.74 ± 0.2 °2Θ.

11. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate as claimed in claim 10, having an XRPD diffractogram comprising further peaks at 10.05, 16.17, 19.23, 21.60, 24.08, 25.22, 26.60 and 27.32 ± 0.2 °2Θ.

12. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate as claimed in claim 11 , having an XRPD diffractogram comprising further peaks at 11.37, 12.75, 15.47 and

20.13 ± 0.2 °2Θ.

13. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate as claimed in any one of claims 9 to 12, characterized by having art XRPD diffractogram as depicted in Figure 1.

14. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate as claimed in any one of claims 9 to 13 characterized by having an intrinsic dissolution profile as shown in Figure 2.

15. Raloxifene oxalate as claimed in claim 1 , which is raloxifene oxalate monohydrate.

16. Raloxifene oxalate as claimed in claim 15, which is crystalline raloxifene oxalate monohydrate Form II.

17. Crystalline raloxifene oxalate monohydrate Form II as claimed in claim 16, characterized by having an XRPD diffractogram comprising peaks at 14.94, 18.60 and 20.34 ± 0.2 °2Θ.

18. Raloxifene oxalate as claimed in claim 1 , which is raloxifene oxalate isopropanolate hemihydrate.

19. Raloxifene oxalate as claimed in claim 18, which is crystalline raloxifene oxalate isopropanolate hemihydrate Form III.

20. Crystalline raloxifene oxalate isopropanolate hemihydrate Form III as claimed in claim 19, characterized by having an XRPD diffractogram comprising a peak at 21.38 ± 0.2 °2Θ.

21. Raloxifene oxalate as claimed in claim 1 , which is raloxifene oxalate THF hemisolvate monohydrate.

22. Raloxifene oxalate as claimed in claim 21 , which is crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV.

23. Crystalline raloxifene oxalate THF hemisolvate monohydrate Form IV as claimed in claim 22, characterized by having an XRPD diffractogram comprising peaks at 18.48, 19.46 and 21.2 ± 0.2 °2Θ.

24. A process for preparing crystalline Form I raloxifene oxalate ethanolate sesquihydrate as claimed in any one of claims 9 to 14, the process comprising dissolving raloxifene base in ethanol at a temperature ranging from 40°C to 60°C, adding a solution of oxalic acid dihydrate in ethanol to form a reaction mass, and isolating crystalline Form I.

25. A process as claimed in claim 24, wherein the isolation comprises isolating precipitated Form I from the reaction mass, followed by drying under reduced pressure at a temperature ranging from 30°C to 90°C for at least 8 hours, preferably at a temperature ranging from 60°C to 80°C for at least 8 hours.

26. A process as claimed in claim 24 or 25, further comprising stirring the reaction mass for at least 5 hours prior to isolation.

27. A process as claimed in any one of claims 24 to 26, wherein the raloxifene base is in any polymorphic form or in a mixture of any polymorphic forms.

28. A process as claimed in any one of claims 24 to 27, wherein the raloxifene base is prepared from a salt of raloxifene, other than raloxifene oxalate.

29. A process as claimed in claim 28, wherein the salt used to prepare raloxifene base is raloxifene hydrochloride.

30. Crystalline Form I raloxifene oxalate ethanolate sesquihydrate prepared by a process according to any one of claims 24 to 29.

31. A pharmaceutical composition comprising raloxifene oxalate according to any one of claims 1 to 23 or 30, together with one or more pharmaceutically acceptable excipients.

32. A pharmaceutical composition according to claim 31 , which is in the form of a tablet suitable for oral delivery.

33. Raloxifene oxalate as claimed in any one of claims 1 to 23 or 30 or a pharmaceutical composition as claimed in claim 31 or 32, for use in treating or preventing osteoporosis, breast cancer and/or cartilage degradation.

34. A method of treating or preventing osteoporosis, breast cancer and/or cartilage degradation comprising administering to a patient in need thereof raloxifene oxalate as claimed in any one of claims 1 to 23 or 30 or a pharmaceutical composition as claimed in claim 31 or 32.

35. Crystalline Form I of raloxifene oxalate ethanolate sesquihydrate substantially as herein described with reference to Example 1 (b).

36. Crystalline Form II of raloxifene oxalate monohydrate substantially as herein described with reference to Example 3.

37 Crystalline Form III of raloxifene oxalate isopropanolate hemihydrate substantially as herein described with reference to Example 4. 38. Crystalline Form IV of raloxifene oxalate THF hemisolvate monohydrate substantially as herein described with reference to Example 5.