WO2010131035A1

WO2010131035A1 - Novel crystalline polymorph of sitagliptin dihydrogen phosphate

Info

Publication number: WO2010131035A1
Application number: PCT/GB2010/050772
Authority: WO
Inventors: Vinayak Govind Gore; Maheshkumar Gadakar; Priyanka Bhosle; Suresh Shinde; Prashant Yadav
Original assignee: Generics [Uk] Limited; Generics Uk Limited; Mylan India Private Limited
Priority date: 2009-05-11
Filing date: 2010-05-11
Publication date: 2010-11-18
Also published as: WO2010131035A8; CA2759196A1

Abstract

The present invention relates to a novel anhydrous crystalline form of sitagliptin dihydrogenphosphate (I), to processes for its preparation and to its use in pharmaceutical compositions.

Description

NOVEL CRYSTALLINE POLYMORPH OF SITAGLIPTIN DIHYDROGEN PHOSPHATE

Field of the invention

Background of the invention

The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound, which is the active pharmaceutical ingredient (API), has handling difficulties during the manufacturing process and may impart undesirable properties to the final drug or dosage form. In addition it can be difficult to control the polymorphic form of the API throughout the manufacturing process.

For pharmaceuticals in which the API can exist in more than one polymorphic form, it is particularly important to ensure that the manufacturing process for the API affords a single, pure polymorph with a consistent level of polymorphic purity. If the manufacturing process leads to a polymorph with varying degrees of polymorphic purity and/ or where the process does not control polymorphic interconversion, serious problems in dissolution and/or bioavailability can result in the finished pharmaceutical composition comprising the API. Sitagliptin dihydrogenphosphate, represented by structural formula (I), is chemically named as (2R)-4-oxo-4-[3-(tofluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l- (2,4,5-trifluorophenyl)butan-2-amine dihydrogenphosphate.

Sitagliptin is an oral antiliyperglycemic of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of dipeptidyl peptidase-IV, an enzyme that inactivates both glucose- dependent insulino tropic peptide (GIP) and glucagon-like peptide 1 (GLP-I), represents a recent approach to the treatment and prevention of type-2 diabetes, also known as non- insulin dependent diabetes mellitus (NIDDM).

Therefore the novel crystalline form of the present invention can be used for the preparation of pharmaceutical compositions for the treatment and prevention of diseases and conditions for which an inhibitor of dipeptidyl peptidase-IV is indicated, in particular type-2 diabetes, hyperglycemia, insulin resistance, obesity, and high blood pressure. The novel crystalline form of the present invention can be used in combination with one or more other active ingredients if necessary.

Various structural analogues and salts of sitagliptin are disclosed in patent US 6,699,871, but no polymorphic data is given.

Solvate forms and three anhydrate polymorphs of sitagliptin dihydrogenphosphate (forms I, II and III) are disclosed in patent application US 2006/0287528. However, desolvated form II converts spontaneously to form I or III or a mixture thereof.

A process for the preparation of sitagliptin dihydrogenphosphate is disclosed in patent application US 2005/0032804 wherein the salt is prepared in isopropyl alcohol and water to afford sitagliptin dihydrogenphosphate monohydrate. However, this monohydrate form converts to an unstable dehydrated form at temperatures above 4O⁰C.

In addition, crystalline anhydrate form IV is disclosed in patent application US 2007/0021430, which is prepared from the sitagliptin dihydrogenphosphate monohydrate by heating at 120°C for 2 hours. However, form IV is metastable and converts into the ciystalline monohydrate slowly undeϊ ambient conditions or rapidly under high relative humidity.

An amorphous form of sitagliptin dihydrogenphosphate salt is disclosed in patent application US 2007/0281941. However amorphous forms are not ideally suited for commercial production and crystalline forms are generally preferred.

As discussed above, the six polymorphic forms of sitagliptin dihydrogenphosphate disclosed in the prior art suffer from several disadvantages which do not make them ideal forms for pharmaceutical development. In particular, the disadvantages associated with the prior art forms can include discolouration, polymorphic impurities and instability. The processes to prepare the respective prior art polymorphs suffer from the disadvantages of being inconsistent and difficult to reproduce. Consequently, the prior art processes can often produce polymorphically impure products. In addition, the prior art processes are particularly inconvenient for large scale production.

If crystalline and amorphous forms are made with polymorphic impurities, this causes instability and it can accelerate significant interconversion to another polymorphic form. Therefore, for commercial production, it is crucial to produce forms, particularly crystalline forms, with very high polymorphic purity to avoid or minimize this interconversion.

In view of the importance acquired by sitagliptin for the treatment of diabetes, there is a great need for developing an alternative, relatively simple, economical and commercially feasible process for the synthesis of sitagliptin crystalline forms with commercially acceptable yield, high polymorphic purity and polymorphic stability.

Object of the invention

Therefore an object of the invention is to provide a new polymorphic form of sitagliptin dihydrogenphosphate, which is convenient to manufacture and has improved properties suitable for a marketed pharmaceutical composition.

Summary of the invention - A -

The term "sitagliptin" as used herein throughout the description and claims means sitagliptin and/ or any salt, hydrate, solvate or tautomer thereof unless specified otherwise.

A first aspect of the present invention provides sitagliptin dihydrogenphosphate form M, characterised by an XRPD spectrum comprising the following degrees 2θ peaks: 5.0, 14.3,

18.6, 24.0 ± 0.2 degrees 2θ. Preferably sitagliptin dihydrogenphosphate form M is characterised by an XRPD spectrum comprising four or more (preferably five or more, preferably six or more, preferably seven or more, preferably eight or more, preferably nine or more, preferably ten or more, preferably eleven or more, preferably twelve or more, preferably thirteen or more, preferably fourteen or more, preferably fifteen) of the following degrees 2θ peaks: 5.0, 9.7, 13.7, 14.3, 15.4, 18.6, 19.5, 19.7, 20.3, 22.4, 24.0, 24.5,

25.7, 27.0, 27.3 ± 0.2 degrees 2θ.

Preferably, the first aspect of the present invention provides sitagliptin dihydrogenphosphate form M, characterised by an XRPD spectrum substantially comprising the following degrees 2θ peaks (± 0.2 degrees 2θ):

Preferably, the first aspect of the present invention provides sitagliptin dihydiOgenphosphate form M, characterised by an XRPD spectrum substantially as shown in Figure 1.

Preferably, the first aspect of the present invention provides sitagliptin dihydrogenphosphate form M, characterised by a DSC thermogram with an endothermic peak at about 216.3 + 2.0 ⁰C, preferably characterised by a DSC thermogram with an endothermic peak at about 216.3 ± 1.0 ⁰C.

Preferably, the first aspect of the present invention provides sitagliptin dihydrogenphosphate form M, characterised by a DSC thermogram substantially as shown in Figure 2.

Preferably, the first aspect of the present invention provides sitagliptin dihydrogenphosphate form M, characterised by a TGA curve substantially as shown in Figure 3.

A second aspect of the present invention provides a process for the preparation of sitagliptin dihydrogenphosphate form M, comprising contacting sitagliptin base with orthophosphoric acid at -10 to 100°C in an organic solvent and crystallisation of the resultant product.

Preferably, the organic solvent is an alcohol, more preferably the alcohol is a C₁ to C₆ alcohol which can be either straight chain, branched or cyclic. Preferably, the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, tert- butanol, 2-pentanol, 3-pentanol, 4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-l-ol, glycerol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 3-octanol or mixtures thereof. Most preferably, the alcohol is 2-propanol.

Preferably, in a process according to the second aspect of the invention, the organic solvent is mixed with water. Preferably, the amount of water is less than 30% v/v with respect to the organic solvent, more preferably less than 20% v/v with respect to the organic solvent, preferably less than 10% v/v with respect to the organic solvent, preferably less than 5% v/v with respect to the organic solvent. Most preferably, the amount of water is about 15- 20% v/v with respect to the organic solvent.

Most preferably, the solvent is a mixture of 2-propanol and water.

Preferably, in a process according to the second aspect of the invention, 1 to 10 molar equivalents of orthophosphoric acid is used. More preferably, 1.5 to 3.0 molar equivalents of orthophosphoric acid is used.

A third aspect of the present invention provides sitagliptin dihydrogenphosphate form M as prepared by a process according to the second aspect of the present invention.

Preferably, the sitagliptin dihydrogenphosphate form M of the first or third aspect of the present invention comprises less than: (i) 10% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or

(ii) 5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or (iii) 1% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (iv) 0.5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or (v) 0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (vi) 0.1% of sitagliptin dihydrogenphosphate in other polymorphic forms; as measured by XRPD.

A fourth aspect of the present invention provides sitagliptin dihydrogenphosphate form M comprising less than 10% of sitagliptin dihydrogenphosphate in other polymorphic forms (as measured by XRPD). Preferably, the sitagliptin dihydrogenphosphate form M comprises less than 5% of sitagliptin dihydrogenphosphate in other polymorphic forms, more preferably less than 1% of sitagliptin dihydrogenphosphate in other polymorphic forms, more preferably less than 0.5% of sitagliptin dihydrogenphosphate in other polymorphic forms, more preferably less than 0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms, and most preferably less than 0.1% of sitagliptin dihydrogenphosphate in other polymorphic forms (as measured by XRPD). Preferably, the sitagliptin dihydrogenphosphate form M of the first, third or fourth aspect of the present invention has a chemical purity of 99% or more, 99.5% or more, or 99.85% or more (as measured by HPLC).

Preferably, the sitagliptin dihydrogenphosphate form M of the first, third or fourth aspect of the present invention is suitable for use in medicine, preferably for treating or preventing a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective, preferably for treating or preventing diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure, preferably for treating or preventing diabetes type-2.

A fifth aspect of the present invention provides a pharmaceutical composition, comprising the sitagliptin dihydrogenphosphate form M according to the first, third or fourth aspect of the present invention or as prepared by a process according to the second aspect of the present invention.

A sixth aspect of the present invention provides a use of the sitagliptin dihydrogenphosphate form M according to the first, third or fourth aspect of the present invention or as prepared by a process according to the second aspect of the present invention or a use of the pharmaceutical composition according to the fifth aspect of the present invention, in the manufacture of a medicament for the treatment or prevention of a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective. Preferably, the medicament is for the treatment or prevention of diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure. More preferably, the medicament is for the treatment or prevention of diabetes type-2.

A seventh aspect of the present invention provides a method of treating or preventing a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of the sitagliptin dihydrogenphosphate form M according to the first, third or fourth aspect of the present invention or as prepared by a process according to the second aspect of the present invention or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to the fifth aspect of the present invention. Preferably, the method is for the treatment or prevention of diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure. More preferably, the method is for the treatment or prevention of diabetes type-2. Preferably the patient is a mammal, preferably a human.

In the use according to the sixth aspect of the present invention or in the method according to the seventh aspect of the present invention, optionally the sitagliptin dihydrogenphosphate form M is used in combination with one or more other active pharmaceutical ingredients, wherein the other active ingredient(s), which may be administered separately or in the same pharmaceutical composition, may be selected from insulin sensitizers such as glitazones (such as troglitazone, pioglitazone, englitazone and rosiglitazone); fenofibric acid derivatives (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate); biguanides (such as metformin and phenformin); sulfonylureas (such as glipizide); or mixtures thereof.

Brief description of the accompanying figures

Figure 1 shows an X-ray powder diffraction (XRPD) spectrum of sitagliptin dihydrogenphosphate form M.

Figure 2 shows a differential scanning calorimetry (DSC) thermogram of sitagliptin dihydrogenphosphate form M.

Figure 3 shows a thermo-gravimetric analysis (TGA) curve of sitagliptin dihydrogenphosphate form M.

Detailed description of the invention

As outlined above, the present invention provides a new crystalline form of sitagliptin dihydrogenphosphate, form M, which is non-hygroscopic, polymorphically pure and stable, and has beneficial properties which avoid the problems associated with prior art forms.

A major advantage of this invention is the reproducible conditions of the process to obtain the novel polymorph and the polymorphic purity and stability of the form M. The polymorphic form of the present invention also allows sitagliptin dihydrogenphosphate to be easily purified and obtained in very high chemical purity.

The present inventors have surprisingly found that, if required, crystalline sitagliptin dihydrogenphosphate form M can be conveniently used to prepare other known crystalline forms of sitagliptin or salts of sitagliptin, such as sitagliptin dihydrogenphosphate, with very high chemical and/ or polymorphic purity.

Sitagliptin dihydrogenphosphate form M can be prepared by reacting sitagliptin free base and orthophosphoric acid in an organic solvent optionally in the presence of water. The orthophosphoric acid is used preferably at 1.0 to 3.0 molar equivalents and more preferably at about 1.5 molar equivalents. The orthophosphoric acid can be used in solid form or as a solution, such as an aqueous solution or a solution in an alcohol such as 2-propanol.

The organic solvent may be a protic or aprotic solvent. Preferably the organic solvent is an alcohol, a ketone, an ether, an alkane, a cycloalkane, a formamide, an acetate, a halogenated solvent, or a mixture thereof, optionally in the presence of water.

Preferably, the organic solvent is an alcohol, preferably a straight chain, branched or cyclic C₁ to C₆ alcohol. More preferably, the alcohol is selected from one or more of methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 2-pentanol, 3-pentanol, 4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-l-ol, glycerol, 1-heptanol, 2-heptanol, 1- octanol, 2-octanol, or 3-octanol, preferably in presence of water. The most preferred solvent is 2-propanol in the presence of water.

Preferred embodiments of the process according to the present invention involve dissolution of sitagliptin free base in about 5 to 50 volumes of 2-propanol and about 2 to 10 volumes of water to obtain a clear solution. Preferably, about 8 to 12 or about 8 to 10 volumes of 2-propanol and about 2 to 4 volumes of water are used to obtain a clear solution. To the clear solution, orthophosphoric acid is preferably added at about -10 to 85°C, preferably at about 15-30°C. The suspension or clear solution is preferably stirred at about 70-75°C for up to 10 hours until completion of the reaction. The precipitated product is preferably further stirred for 15 minutes to 12 hours at about 25-30°C until complete precipitation. The precipitated product is preferably maintained at 0-5°C for 1 hour and then preferably filtered at 0-5⁰C. The isolated product is preferably dried under reduced pressure at 45-50⁰C for 1-10 hours, more preferably for 1-3 hours. The product can be recrystallised if necessary.

Preferably, the mixture is heated to dissolve the sitagliptin. Preferably, the mixture is heated between 40-100⁰C, more preferably at about 70-75⁰C.

Preferably, the mixture is cooled before isolation of the sitagliptin dihydrogenphosphate form M. Preferably, the mixture is cooled to between -5 to 3O⁰C, more preferably to about 0-5⁰C.

The crystalline sitagliptin dihydrogenphosphate form M preferably comprises less than 0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms.

The crystalline sitagliptin dihydrogenphosphate form M obtained is preferably dried under vacuum until a constant weight is obtained. Preferably, the crystalline form M obtained is dried until the moisture content falls below 1%, preferably to below about 0.5%.

As discussed above, sitagliptin dihydrogenphosphate monohydrate is disclosed in patent application US 2005/0032804. However, this monohydrate form converts to an unstable dehydrated form at temperatures above 4O⁰C. The present inventors have surprisingly found that by reducing the amount of water used in the organic solvent medium, a novel, stable, anhydrous, solvent-free, crystalline form M can be reproducibly prepared. A solvent mixture comprising a ratio of 10:2 v/v 2-propanol:water (about 16% water v/v), afforded exclusively novel anhydrous form M. Even the wet cake obtained by following the process of the present invention exhibited an XRPD pattern identical to that of form M.

The XRPD d-values of the sitagliptin dihydrogenphosphate form M thus obtained are different from those of the reported forms I to IV and the reported monohydrate form and this XRPD data is summarised in Table 2. Table 2: XRPD d-values of prior art forms and form M

Typical XRPD 2θ values and intensity of form M are illustrated in Table 3.

Table 3: XRPD 2θ values and intensity of form M

The pharmaceutical composition according to the fifth aspect of the present invention can be a solution or a suspension, but is preferably a solid oral dosage form. Preferred oral dosage forms in accordance with the invention include tablets, capsules and the like which, optionally, may be coated if desired. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry granulation. Capsules are generally formed from a gelatine material and can include a conventionally prepared granulate of excipients in accordance with the invention.

The pharmaceutical composition according to the present invention typically comprises one or more conventional pharmaceutically acceptable excipient(s) selected from the group comprising a filler, a binder, a disintegrant, a lubricant, and optionally further comprises at least one excipient selected from colouring agents, adsorbents, surfactants, film-formers and plasticizers.

If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be prepared from at least one film-former such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments and fillers.

Preferably the pharmaceutical compositions according to the present invention are in unit dosage form comprising sitagliptin in an amount of from 1 mg to 500 mg, such that the amount of sitagliptin administered is from 0.1 mg to 100 mg per kg per day.

Preferably, the pharmaceutical compositions according to the fifth aspect of the present invention are for use in the treatment and prevention of diseases and conditions for which an inhibitor of dipeptidyl peptidase-IV is effective. Preferably, the use is in the treatment of diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure. More preferably, the use is in the treatment of diabetes type-2. The novel crystalline form of the present invention can be used in combination with other active ingredients. Examples of other active ingredients that may be administered in combination with the crystalline form of the present invention and either administered separately or in the same pharmaceutical composition, include but are not limited to other dipeptidyl peptidase IV (DP-IV) inhibitors; insulin sensitizers such as glitazones (such as troglitazone, pioglitazone, englitazone and rosiglitazone); fenofibric acid derivatives (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate); biguanides (such as metformin and phenformin); sulfonylureas (such as glipizide); or mixtures thereof.

The details of the invention, its objects and advantages are illustrated below in greater detail by a non-limiting example.

Example

Sitagliptin Dihydrogenphosphate Form M

Sitagliptin free base (10.0 gm, 24.5 mmol) was charged in 2-propanol (80.0 ml, 8.0 vol) and water (20.0 ml, 2.0 vol) at 25-3O⁰C. The clear solution was stirred for 10 minutes. Meanwhile, a clear solution of orthophosphoric acid (85%) was prepared at 25-30°C [2.40 gm (1.0 eq, 24.5 mmol) in 20.0 ml (2.0 vol) of 2-propanol]. Slow addition of the solution of orthophosphoric acid to the solution of sitagliptin free base was carried out at 25-3O⁰C. The addition was completed within 15-20 minutes. The thick solution was further diluted with 2-propanol (20.0 ml, 2.0 vol) and the white suspension was further heated at 70-75⁰C and maintained for 1 hour before the reaction mixture was allowed to cool gradually at 25- 30⁰C within 1.5 hour. The white suspension was stirred at 25-30⁰C for 1 hour until a white thick solution was obtained. After 1 hour of stirring at 25-30⁰C, the mixture was cooled to 0-5⁰C and maintained at 0-5⁰C for 1 hour. The product was filtered at 0-5⁰C and washed with 2-propanol (50.0 ml, 5.0 vol). The product was suction filter dried for 30 minutes and then dried at 40-45⁰C at reduced pressure for 1-2 hours to obtain crude sitagliptin dihydrogenphosphate. XRPD, DSC and TGA analysis data confirmed that the crude sitagliptin dihydrogenphosphate obtained is form M. Molar yield: 81% (10.0 gm) Chemical purity: >99.50% (measured by HPLC) Polymorphic purity: no levels of other polymorphic forms detected (measured by XRPD) The crude sitagliptin dihydiOgenphosphate (10.0 gm) was further crystallised from a mixture of 2-propanol (100.0 ml, 10.0 vol) and water (20.0 ml, 2.0 vol) to obtain very pure sitagliptin dihydrogenphosphate. XRPD, DSC and TGA analysis data confirmed that the pure sitagliptin dihydrogenphosphate obtained is form M. Molar yield: 85% (8.5 gm)

Chemical purity: >99.85% (measured by HPLC) Polymorphic purity: no levels of other polymorphic forms detected (measured by XRPD)

XRPD and DSC analysis data for the crude and pure products obtained from the example (see Figures 1 and 2) confirmed that the products obtained were a novel polymorph of sitagliptin dihydrogenphosphate. The novel polymorph obtained, crystalline form M, was substantially pure polymorphically with no levels of other forms detected.

TGA analysis data (see Figure 3) showed that the novel crystalline anhydrous form of sitagliptin dihydrogenphosphate form M displays no weight loss in the temperature range of 5O⁰C to 225⁰C.

The XRPD was recorded on a Bruker D8 Advance Instrument, using copper radiation as the X-ray source and LynxEye as the detector, with a 2θ range of from 3° to 50°, a step- size of 0.05° and a time/step of 1 sec.

The DSC was recorded on a Perkin Elmer Pyris 6, with a temperature range of from 25°C to 250⁰C and a rate of heating of 10°C/min.

The TGA was recorded on a Perkin Elmer Pyris 1, with a temperature range of from 25⁰C to 25O⁰C and a rate of heating of 10°C/min.

The crude and pure products were also subjected to two months accelerated stability studies, monitoring chemical and polymorphic purities, and it was found that the sitagliptin dihydrogenphosphate form M is stable. The accelerated stability studies were performed as follows. Sitagliptin dihydrogenphosphate form M was kept in a single polyethylene bag in a triple laminated aluminium pouch. This pouch was kept in a HDPE container. This container was kept in a stability chamber at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for two months. The sitagliptin dihydrogenphosphate form M was found to be very stable chemically and very stable polymorphically with no conversion over time to other polymorphs.

It will be understood that the present invention has been described above by way of example only. The example is not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

1. Sitagliptin dihydtogenphosphate form M, characterised by an XRPD spectrum comprising the following degrees 2θ peaks: 5.0, 14.3, 18.6, 24.0 ± 0.2 degrees 2θ.

2. Sitagliptin dihydrogenphosphate form M according to claim 1, characterised by an

XRPD spectrum substantially comprising the following degrees 2θ peaks (+ 0.2 degrees 2θ):

3. Sitagliptin dihydrogenphosphate form M according to claim 1 or 2, characterised by an XRPD spectrum substantially as shown in Figure 1.

4. Sitagliptin dihydrogenphosphate form M according to any preceding claim, characterised by a DSC thermogram with an endothermic peak at about 216.3 + 2.0 °C.

5. Sitagliptin dihydrogenphosphate form M according to any preceding claim, characterised by a DSC thermogram substantially as shown in Figure 2.

6. Sitagliptin dihydrogenphosphate form M according to any preceding claim, characterised by a TGA curve substantially as shown in Figure 3.

7. A process for the preparation of sitagliptin dihydrogenphosphate form M according to any preceding claim, comprising contacting sitagliptin base with orthophosphoric acid at

-10 to 100⁰C in an organic solvent optionally in the presence of water and crystallisation of the resultant product.

8. A process according to claim 7, wherein the solvent is an alcohol.

9. A process according to claim 8, wherein the alcohol is a C₁ to C₆ alcohol which can be either straight chain, branched or cyclic.

10. A process according to claim 9, wherein the alcohol is selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol, tert-butanol, 2-pentanol, 3-pentanol,

4-penten-2-ol, 1,6-hexanediol, 1-hexanol, 5-hexen-l-ol, glycerol, 1-heptanol, 2-heptanol, 1- octanol, 2-octanol, 3-octanol or mixtures thereof.

11. A process according to claim 10, wherein the alcohol is 2-propanol.

12. A process according to any one of claims 7 to 11, wherein the organic solvent is mixed with water.

13. A process according to claim 12, wherein the amount of water is: (i) less than 30% v/v with respect to the organic solvent; and/or

(ii) less than 20% v/v with respect to the organic solvent; and/ or

(iii) less than 10% v/v with respect to the organic solvent; and/ or

(iv) less than 5% v/v with respect to the organic solvent; and/or

(v) about 15-20% v/v with respect to the organic solvent.

14. A process according to claim 12 or 13, wherein the solvent is a mixture of 2- propanol and water.

15. A process according to any one of claims 7 to 14, wherein 1 to 10 molar equivalents of orthophosphoric acid is used.

16. A process according to claim 15, wherein 1.5 to 3.0 molar equivalents of orthophosphoric acid is used.

17. Sitagliptin dihydrogetiphosphate form M, as prepared by a process according to any one of claims 7 to 16.

18. Sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or 17, comprising less than:

(i) 10% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or

(ϋ) 5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (iii) 1% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (iv) 0.5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (v) 0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or (vi) 0.1% of sitagliptin dihydrogenphosphate in other polymorphic forms; as measured by XRPD.

19. Sitagliptin dihydrogenphosphate form M comprising less than:

(i) 10% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or

(it) 5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or

(iii) 1% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or

(iv) 0.5% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/ or (v) 0.2% of sitagliptin dihydrogenphosphate in other polymorphic forms; and/or

(vi) 0.1% of sitagliptin dihydrogenphosphate in other polymorphic forms; as measured by XRPD.

20. Sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or any one of claims 17 to 19, having a chemical purity of 99.85% or more (as measured by HPLC).

21. Sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or any one of claims 17 to 20, for treating or preventing a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective.

22. Sitagliptin dihydrogenphosphate form M according claim 21, for treating or preventing diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure.

23. Sitagliptin dihydrogenphosphate form M according claim 22, for treating or preventing diabetes type-2.

24. A pharmaceutical composition, comprising the sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or any one of claims 17 to 23.

25. Use of the sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or any one of claims 17 to 23, or use of the pharmaceutical composition according to claim 24, in the manufacture of a medicament for the treatment or prevention of a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective.

26. The use according to claim 25, wherein the medicament is for the treatment or prevention of diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure.

27. The use according to claim 26, wherein the medicament is for the treatment or prevention of diabetes type-2.

28. The use according to any one of claims 25 to 27, wherein the sitagliptin dihydrogenphosphate form M is used in combination with one or more other active pharmaceutical ingredients.

29. The use according to claim 28, wherein the other active ingredient(s) may be administered separately or in the same pharmaceutical composition.

30. The use according to claim 28 or 29, wherein the other active ingredient(s) is selected from insulin sensitizers such as glitazones (such as troglitazone, pioglitazone, englitazone and rosiglitazone); fenofibϊic acid derivatives (such as gemfibrozil, clofibrate, fenofibfate and bezafibrate); biguanides (such as metformin and phenformin); sulfonylureas (such as glipizide); or mixtures thereof.

31. A method of treating or preventing a disease or condition for which an inhibitor of dipeptidyl peptidase-IV is effective, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of the sitagliptin dihydrogenphosphate form M according to any one of claims 1 to 6 or any one of claims 17 to 23, or a therapeutically or prophylactically effective amount of the pharmaceutical composition according to claim 24.

32. The method according to claim 31, wherein the medicament is for the treatment or prevention of diabetes, hyperglycemia, insulin resistance, obesity, or high blood pressure.

33. The method according to claim 32, wherein the medicament is for the treatment or prevention of diabetes type-2.

34. The method according to any one of claims 31 to 33, wherein the sitagliptin dihydrogenphosphate form M is used in combination with one or more other active pharmaceutical ingredients.

35. The method according to claim 34, wherein the other active ingredient(s) may be administered separately or in the same pharmaceutical composition.

36. The method according to claim 34 or 35, wherein the other active ingredient(s) is selected from insulin sensitizers such as glitazones (such as troglitazone, pioglitazone, englitazone and rosiglitazone); fenofibric acid derivatives (such as gemfibrozil, clofibrate, fenofibrate and bezafibrate); biguanides (such as metformin and phenformin); sulfonylureas (such as glipizide); or mixtures thereof.