WO2012017028A1

WO2012017028A1 - A novel crystalline compound comprising saxagliptin and phosphoric acid

Info

Publication number: WO2012017028A1
Application number: PCT/EP2011/063422
Authority: WO
Inventors: Fritz Blatter; Katharina REICHENBÄCHER
Original assignee: Sandoz Ag
Priority date: 2010-08-06
Filing date: 2011-08-04
Publication date: 2012-02-09
Also published as: EP2601175A1

Abstract

The present invention refers to a crystalline compound comprising a mixture of a compound of formula (I) (INN: Saxagliptin) and phosphoric acid or a hydrate thereof, wherein the molar ratio of the compound of formula I and the phosphoric acid is in the range of from 1:0,8 to :1,2, as well as a process of obtaining the same.

Description

A novel crystalline compound comprising saxagliptin and phosphoric acid

The present invention relates to a novel crystalline compound comprising saxagliptin and phosphoric acid and hydrates thereof. The present invention also relates to methods of making the novel crystalline compound.

Saxagliptin (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl)

acetyl]-2-azabicyclo[3.1 .0]hexane-3-carbonitrile and its hydrochloride salt is an orally active reversible dipepdidyl peptidase-4 (DPP4) inhibitor, which is used as a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases. It is disclosed for example in US 6,395,767, example 60.

Specific crystal forms of saxagliptin free base and specific acid addition salts including saxagliptin hydrochloride polymorphs, a fumarate (2: 1 ), a tartrate, a benzoate, a trifluoroacetate, a bromide, an iodide, an ammoniumsulfate complex and a nitrate are disclosed in WO 2008/131 149.

Some of the salts of saxagliptin disclosed in WO 2008/131 149 are pharma- ceutically not acceptable, while the free base is susceptible to intramolecular cyclysation.

Saxagliptin is marketed in a form wherein the base is formulated with an excess of hydrochloric acid. The formulation disclosed for example in US 2005/0266080 comprises a coated tablet formulation and a mix of saxagliptin hydrochloride polymorphs. As different polymorphs typically exhibit different properties with regard to solubility and dissolution kinetics, it can be expected to be difficult to produce a finished dosage form with reproducible dissolution properties based on such a mix of polymorphs. Moreover, the saxagliptin hydrochloride polymorphs, while in general showing good solubility in water, are quite prone to conversion to a number of different distinct hydrates upon exposure to environments differing in relative humidity, making it hard to control the polymorphic state during pharmaceutical processing. The above mentioned patent application US 2005/0266080 also describes the capsule formulation of the benzoate hydrate as showing insufficient stability. In addition the benzoate salt is described to have a limited solubility of less than 15 g/l in water. Thus, an improved salt form of saxagliptin with both good processability/polymorphic stability and good solubility would be desirable.

It is therefore an objective of the present invention to provide a novel pharmaceutically acceptable salt of saxagliptin with good solubility/dissolution

properties. It is also an objective of the present invention to provide saxagliptin in a form of a salt having a good chemical and/or physical stability and/or good processability, both during its preparation as an active pharmaceutical

ingredient as well as in the preparation of pharmaceutical compositions

containing saxagliptin.

The technical problem underlying the present invention is solved by a crystalline compound comprising a mixture of a compound of formula I (INN: Saxagliptin)

formula I and phosphoric acid or a hydrate thereof, wherein the molar ratio of the compound of formula I and the phosphoric acid is in the range of from 1 :0,8 to 1 : 1 ,2.

The invention also provides processes for forming the crystalline compound and pharmaceutical compositions comprising said crystalline compound. In the context of the present invention the following-abbreviations apply unless explicitly stated otherwise:

DVS: Dynamic (water) vapor sorption

XRPD: Powder X-ray diffraction

r.h.: relative humidity DSC: Differential scanning calorimetry

TG-FTIR: Thermogravimetry coupled with FT-infrared spectroscopy

The crystalline compound comprising saxagliptin (compound of formula I) and phosphoric acid may be a salt. Saxagliptin may be a protonated cation, for example saxagliptin protonated at the nitrogen atom of the primary amino group and the respective counterion may be a dihydrogenphosphate anion. However, as empirical formula the crystalline compound comprises saxagliptin and phosphoric acid in the denoted molar ratio.

In a preferred embodiment the molar ratio of the compound of formula I and phosphoric acid is of from 1 :0,85 to 1 : 1 , 15, more preferably of from 1 :0,9 to 1 : 1 , 1 and most preferred 1 : 1 . The crystalline compound preferably has an XRPD pattern with at least one characteristic peak (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5,6°, 7,3°, 17,6° and 18,0°, referred to as form A. Preferably, form A has at least one further peak at 4,6°, 10,8°, 1 1 ,3°, 15,0°, 19,3°, 19,5°, 22,8° and 23,2°

(expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)). Typically such an X-ray powder diffractogram is measured with copper K-alpha radiation. An X-ray powder diffractogram of a sample of form A of the first aspect is shown in figure 1 and the present invention, in a preferred embodiment, relates to form A of the first aspect displaying a XRPD pattern which is substantially in accordance with figure 1 .

Preferably, form A of the first aspect can be described by a FT-Raman spectrum comprising peaks at wave numbers of 3098, 2924, 2245, 1655, 1458, 1436, 1 184, 1 157, 772, and 698cm^"1 ± 1 cm^"1. An FT Raman spectrum of a sample of form A of the first aspect is shown in figure 2. In a preferred embodiment, form A of the first aspect is characterized by an FT Raman spectrum substantially in accordance with figure 2. The crystalline compound of the present invention further comprises water and the molar ratio of the compound of formula I and water is in the range of from 1 :0,3 to 1 :5 and even more preferred of from 1 :0,3 to 1 :2. The water content of the crystalline compound of the present invention may also be characterized in terms of weight percentages. Preferably, said water content can be determined by Karl Fischer Titration (KF titration). Preferably, the crystalline compound has a water content of from 2 wt-% to 4 wt-% and more preferably from 2, 1 wt-% to 3 wt-%.

Preferably, the molar ratio of the compound of formula I and water is in the range of from 1 :0,3 to 1 :0,7, being preferably form A. Preferably, form A has a water content of from 2 wt-% to 4 wt-%, more preferably from 2, 1 wt-% to

3 wt-%.

The crystalline compound form A of the first aspect is sometimes also simply referred to as the "hemihydrate".

The crystalline compound form A of the first aspect reveals a molar ratio of the compound of formula I and phosphoric acid of 1 : 1 confirmed by elemental composition analysis. Elemental analysis of the hemihydrate revealed a water content of 2,3% by calculation. According to the Karl-Fischer method a water content of 2,39% was found after drying. After storage at 76% relative humidity a water content of 2,25% was found.

DVS measurement reveals a slight mass change of form A in the range of 0% relative humidity to 90% relative humidity. The observed mass change is only 0,9% over this range. Thus form A of the first aspect is surprisingly hardly hygroscopic. This provides the advantage that the crystalline phosphate salt of saxagliptin of the first aspect of the invention does not require special precautions for the typical manufacture processes for pharmaceutical compositions. Compared with saxagliptin hydrochlorides disclosed in the art, which - dependent on the relative humidity to which they are exposed - convert to a number of different distinct hydrates, there is no need for stringent drying or controlling exposure time to high relative humidity during manufacture or storage of pharmaceutical compositions. These specific physical properties of form A are surprising to the skilled artisan.

In contrast, we have found in moisture sorption experiments (increase in relative humidity in 5% steps and equilibration at the increased rh-value for 50 min at 25°C) for the saxagliptin hydrochlorides that the hydrate H2-1 (saxagliptin hydrochloride dihydrate, as disclosed in WO 2008/131 149) converts to a form HO.75-3 (disclosed in WO 2008/131 149, stoichiometry saxagliptin hydrochloride: water is about 1 : 0,37) at a relative humidity of 10%, while HO.75-3 can take up even more water upon exposure to environmental conditions with a relative humidity of 20% and transforms to form H1 .25-2 (disclosed in WO 2008/131 149; stoichiometry saxagliptin hydrochloride : water is about 1 : 0,63). Consequently, the processability/polymorphic stability of said saxagliptin hydrochlorides is poor. One can not eliminate the possibility that the aforementioned saxagliptin hydro- chlorides comprised in a medicament convert when stored.

The solubility of the crystalline compound form A of the first aspect of the invention in water was determined to be > 138 g /I and is thus more than 9-fold higher than that of saxagliptin benzoate.

The polymorphic stability of the crystalline phosphate salt of saxagliptin of the first aspect of the invention is very high. Equilibration of form A of the first aspect in a variety of solvents or solvent mixtures gave no observable change to any other polymorph. For example, equilibration of the crystalline phosphate salt of saxagliptin (form A) of the first aspect in ethanol, isopropanol, acetonitril, ethylacetate, isopropylether, THF, heptane, methylethylketone, toluene, tert.butyl-methylether, aqueous ethanol ( 9: 1 v/v), methylethylketone/heptane (1 : 1 v/v)), ethanol/acetonitrile (1 : 1 ) v/v) gave no observation of a significant change in FT-Raman or XRPD. In addition, as described above, form A of the first aspect stays stable over the whole range of relative humidity conditions to which a solid oral composition is typically exposed. Furthermore, its chemical stability is comparable to that of known hydrochlorides with regard to the increase in the content of the cyclic amidine impurity disclosed for example in US2005/0266080 designated as cis-cyclic amidine (CA ) when kept dry and when stored in a closed vial at 60°C for 7 days.

Therefore the present invention also relates to pharmaceutical compositions comprising the crystalline compound of the present invention and preferably form A of the first aspect of the invention, wherein the crystalline salt in said composition is present as a stable polymorph, preferably in a physical phase purity of more than 80%, even more preferably in a phase purity of better than 90%, and most preferred in a phase purity of more than 95%. "Present as a stable polymorph" is to be understood as no decrease in phase purity of more than 2% during a storage period of 6 months, more preferably of 12 months, even more preferably of 18 months and in particular 24 months. Said phase purity can be determined by x-ray crystallography. The second aspect of the present invention preferably refers to a crystalline compound having an XRPD pattern with at least one characteristic peak

(expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5,3°, 5,7°, 1 1 ,4° and 17,2°, referred to as form B. Preferably form B has at least one further peak (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 6, 1 °, 16, 1 °, 16,4°, 18,0°, 19,3°, 20,3°, 20,6°, 21 ,0° and 22,8°. Typically such an X-ray powder diffractogram is measured with copper K-alpha radiation. An X-ray powder diffractogram of a sample of form B of the second aspect is shown in figure 3 and the present invention. In a preferred embodiment, form B has an XRPD pattern substantially in accordance with figure 3.

Preferably, form B can be described by a FT-Raman spectrum comprising peaks at wavenumbers of 3093, 2928, 2241 , 1655, 1436, 1 183, 1 157, 773, and 698cm^"1 ± 1 cm^"1. Preferably, an FT-Raman spectrum of a sample of form B of the second aspect is shown in figure 4 and the present invention, in a preferred embodiment, relates to form B characterized by an FT Raman spectrum substantially in accordance with figure 4. Preferably, the molar ratio of the compound of formula I and water is in the range of from 1 :0,7 to 1 :4, being preferably form B. Form B of the second aspect is sometimes also simply referred to as the "higher hydrate".

Form B of the second aspect is also useful as a new intermediate in the preparation of the crystalline compound form A of the present invention. For example, slurrying of form B in a suitable solvent leads to form A. The present invention further refers to a process for obtaining the crystalline compound of the present invention comprising the steps of:

a) providing a compound of formula I (INN: Saxagliptin)

formula I in a suitable solvent or a mixture of solvents

b) adding phosphoric acid to the mixture of step a)

c) optionally concentrating the composition of step b)

d) crystallizing

e) optionally equilibrating the obtained suspension of step d) and

f) isolating the obtained precipitate.

Preferably, the molar ratio of the compound of formula I in step a) and the phosphoric acid of step b) is in the range of from 1 :0,5 to 1 :3 and even more preferred in the range of from 1 :0,5 to 1 : 1 ,2.

In step b) neat phosphoric acid or phosphoric acid in a suitable solvent like water or any other polar solvent may be added to the mixture of step a).

In a preferred embodiment the process further comprises step g) of slurrying the isolated precipitate of step f) in a further suitable solvent or mixture of solvents being preferably acetonitrile and step h) of isolating the obtained precipitate. Preferably, form B can be converted into form A when form B is slurryied in acetonitrile.

Preferably, in step c) a part of the solvent is removed by for instance distillation or evaporation under reduced pressure or in a flow of a carrier gas like N₂.

Preferably, in step c) the entire solvent is removed by for instance distillation or evaporation under reduced pressure or in a flow of a carrier gas like N₂ and the residue is dissolved in a suitable solvent or mixture of solvents and water. Even more preferred, the solvent is selected from the group consisting of C2-C4 alcohols, a C3-C6 ketone, an ether or an acetic ester C1 -C4 alkylester, acetonitril, a hydrocarbon or mixtures thereof.

In step d), e) and/or g) the obtained mixture may be stirred. Step d), e) and/or g) may be carried out at a temperature of from 0°C to 70°C. Suspension equilibration in step e) and/or slurrying in step g) are preferably carried out at a

temperature from 10°C to 30°C and most preferred at ambient temperature. Step e) and/or g) are typically carried out for one day. Optionally, samples may be recovered from the suspension and analyzed by XRPD. Filtration is per- formed when the XRPD analysis indicates that the desired form is obtained in a reasonable purity.

In a preferred embodiment in step d), e) and/or g) seed crystals are added. Said seed crystals preferably are the desired form of the crystalline compound of the present invention which is to be obtained. Preferably, form B can be converted into form A when in step e) and/or g) form B is slurryied in acetonitrile.

Preferably the water activity for formation of the form A in step b) and/or c) is of from 0, 1 to 0,8.

Preferably, for obtaining form B subsequent to step f) and/or h) the obtained precipitate is kept in an environment wherein the relative humidity is above 90%. The molar ratio of phosphoric acid to saxagliptin base of formula I is not critical, e.g. 1 to 3 equivalents of phosphoric acid per mol of saxagliptin base, preferably 1 to 2 equivalents of phosphoric acid per mol of saxagliptin base can be used, and even more preferred one equivalent of phosphoric acid is used. The starting material saxagliptin may be any form of saxagliptin base, e.g. amorphous saxagliptin base or crystalline saxagliptin base or any solvate or hydrate thereof.

The molar ratio of saxagliptin of formula 1 to phosphoric acid may vary from 1 :0,9 to 1 : 1 . In a preferred embodiment the ratio of saxagliptin of formula I to phosphoric acid equals 1 : 1 .

In another embodiment the invention relates to a process for the preparation of the crystalline phosphate salt of saxagliptin (form A) of the first aspect comprising the steps of a) equilibrating amorphous or crystalline saxagliptin phosphate in a solvent selected from a C1 -C4 alcohol, a C3-C6 ketone, e.g. acetone, methylethyl- ketone, an ether e.g. THF or methyl tert. butylether, an acetic acid C₁ -C4 alkyl- ester or hydrocarbons optionally in presence of seed crystals of saxagliptin phosphate form A and/or in presence of water;

b) isolating the crystalline saxagliptin phosphate form A; and

c) optionally drying the isolated crystalline saxagliptin phosphate form A

is also subject matter of the present invention.

Preferred alcohols are 1 -propanol, 2-propanol, and ethanol, preferred ketones are acetone, methylethylketone and methylisobutylketone, selected ethers are diiospropylether, tetrahydrofurane and methyl tert. butylether, preferred hydrocarbons include hexanes, heptanes and toluene. Most preferred are solvent water mixtures exhibiting water activities in the range from about 0, 1 to 0,8, for instance ethanol - water 9: 1 (v/v).

The starting material Saxagliptin phosphate may be amorphous saxagliptin phosphate and preferably form B. ln another embodiment a process for the preparation of form A comprises slurrying form B in a suitable solvent being preferably acetonitrile.

The temperature of the crystallization process is not critical and conveniently it is performed at ambient temperature. However lower temperatures, e.g. performing the slurrying under cooling, e.g. in an ice bath or at elevated temperatures, e.g. 30°C to 40°C or even heating to the boiling point of the solvent may effectively induce the crystallization. In another aspect the invention relates to a process for the preparation of form B comprising the steps of: a) dissolving saxagliptin phosphate in a mixture of a suitable solvent being preferably acetonitrile and water;

b) evaporating the solvent under a N₂ flow; and

c) keeping the humidity of the wet crystalline product at a relative humidity of more than 90%.

Any kind of saxagliptin phosphate may be used as starting material in the preparation of saxagliptin phosphate form B. Suitable starting materials include amorphous saxagliptin phosphate, saxagliptin phosphate hemihydrate (form A) or a mixture containing saxagliptin and phosphoric acid in a molar ratio of about 1 : 1 .

The preparation of amorphous saxagliptin phosphate is for example disclosed in example 4.

The crystalline compound of the present invention and preferably form A and/or form B may be used alone or in combination with one or more types of antidiabetic agents (employed to treat diabetes and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate dosage form or by injection.

The other types of antidiabetic agent which optionally employed in combination with the crystalline compound of the present invention and preferably form A and/or form are further antidiabetic agents or antihyperglycemic, hypolipidemic or lipid-modulating agents including insulin secretagogues or other antidiabetic agents preferably having a mechanism different from DPP4 inhibition and may include biguanidines, sulfonyl ureas, glucosidase inhibitors, PPAR γ agonists, such as thiazolidinediones, SGLT2 inhibitors, PAR α/γ dual antagonists, aP"-inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin and/or glucagons-like peptide-1 (GLP-1 ) or SIRT activators or mimics thereof. In carrying out the method of the invention, a pharmaceutical composition will be employed containing the crystalline compound of the present invention (phosphate salt of saxagliptin), with or without a further antidiabetic agent and/or other therapeutic agent, in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing con- ventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration, the administration by an oral route in the form of tablets, capsules, granules or powders. The dose for adults is preferably between 5 mg to 1000 mg per day. Preferably between 1 and 100 mg per day of the crystalline compound of the present invention, which can be administered in a single dose or in the individual doses from 1 -4 times a day.

A typical tablet contains one or more excipients such as bulking agents, optionally a binder and optionally a disintegrant. Examples of bulking agents include cellulose derivatives, such as microcrystalline cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, inorganic salts such as calcium salts, e.g. calcium carbonate, calcium phosphate, dicalcium phosphate, dextrin or dextranes, maltodextrin compressible sugars and/or other known bulking agents or fillers. Examples of binders suitable for use include hydroxypropylcellulose, PVP, starch, cellulose acetate as well as a wax binder such as carnauba wax, polyethylenes or other conventional binding agents or mixtures thereof, Examples of disintegrants include croscarmellose sodium, crospovidone, starch, low substituted hydroxypropyl cellulose as well as other conventional disintegrants. The lubricant optionally present include for example magnesium stearate, zinc stearate, calcium sterarate, talc, carnauba wax, stearic acid, palmitinic acid, sodium laurylsulfate or hydrogenated vetable oils and fats or other known lubricants or mixtures thereof. Tablets may be coated including a tablet core and a inner seal coating layer coated on the tablet core, a second coating layer containing the crystals of the present invention coated on the inner seal coated on the tablet core and optionally an outer protective coating layer coated on the second coating layer of the tablet as e.g. disclosed in US 2005/0266080.

Typical capsules for oral administration contain the novel crystalline phosphate hemihydrate of the invention contain e.g. , lactose, crosscarmelose, magnesium stearate or e.g. sodium stearyl fumarate. Experimental

DVS: Dynamic (water) vapor sorption is a method well known in the art to monitor the adsorption of water on a solid material. Therefore, DVS is a suitable method to determine the hygroscopic nature of a pharmaceutical active ingredient.

DVS was performed with a Surface Measurement Systems Ltd. DVS-1 water sorption analyzer or with SPS1 1 -100η moisture sorption instrument from Projekt MeBtechnik, Ulm, Germany. Program: The relative humidity was kept at starting value of 50% for two hours, then continuously scanned from 50% to 0%, kept constant at 0% for four hours, and then scanned to 96% relative humidity, and kept constant for four hours, then r.h. was scanned back to 50% and kept there for two hours. The scanning change rate of relative humidity was 5% per hour.

In another measurement method the measurement cycle was started at 50% relative humidity (r.h.), decreased in 5% relative humidity steps to 0% r.h.

increased in 5% relative humidity steps to 90% r.h.

The temperature was 25 ± 0, 1 °C.

Solubility determination

The solubility in water was determined by suspending the corresponding salt in water. The suspensions were shaken for 24 hours at 25°C and 500 rpm. After filtration the solution was investigated by HPLC.

HPLC method

HPLC Apparatus: TSP HPLC (UV3000, AS3000, P4000, SCM1000 Soft

Version 4.1 ) or Agilent 1 100 Series (UV/Vis detector)

Column: CC06 (Penomenex Luna C18; 150 x 4,60 mm 3 pm)

Mobile phase A: 0,49 g of sulfamic acid (SAS), 1000 g of H₂0

Mobile phase B: 0,49 g of sulfamic acid (SAS), 300 g of H₂0, 587 g of acetonitrile Gradient:

Flow: 0,8 ml/min

Injection volume: 10 pm

Wavelength: 220 nm

The same HPLC method was used for stability determination.

Raman Spectroscopy:

FT- Raman spectroscopy was performed using a Bruker RFS100 ( Nd:YAG

1064 nm exitation , 300 mW laser power, Ge detector, 64 scans, range

25-3500 cm^"1 , 2 cm^"1 resolution ). DSC:

Differential scanning calorimetry is a well known method in the art that measures the heat flow through a sample upon heating at a defined rate. It is a suitable method to determine the melting temperatures, the glass transition temperature, or other thermal events such as phase conversions or thermal decomposition.

DSC was performed using a Perkin Elmer DSC 7. Measurements were performed in closed Au crucibles, at heating rates or 10 or 20°C min^"1 , range -50°C to 250°C.

XRPD:

The measurements were carried out with a Bruker D8 Advance powder X-ray diffractometer using Cu K radiation in the Bragg-Brentano reflection geometry. Generally, the 2Θ values are accurate within an error of ±0, 1 - 0,2°. The relative peak intensities can vary considerably for different samples of the same crystalline form because of different preferred orientations of the crystals. The samples were prepared without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders of either 0,5 mm or 0, 1 mm depth and 12 mm cavity diameter were used. The tube voltage and current were 40 kV and 40 mA, respectively. The X-ray diffractometer is equipped with a LynxEye detector. A variable divergence slight was used with a 3° window. The step size was 0,02 °2Θ with a step time of

37 seconds. The samples were rotated at 0,5 rps during the measurement.

NMR:

The ¹ H-NMR spectra were recorded in D₆-DMSO using a Bruker DPX300 instrument TG-FTIR:

Thermogravimetry coupled with FT-infrared spectroscopy is a well known method that allows to monitor the mass loss of a given sample upon heating while identifiying the volatile substances by infrared spectroscopy. Therefore, TG-FTIR is a suitable method to identify solvates or hydrates.

TG-FTIR was performed on a Netzsch Thermo-Microbalance TG 209, which is coupled to a Bruker FT-IR Spectrometer Vector 22. The measurements were carried out with aluminum crucibles with a micro pinhole under a nitrogen atmosphere and at a heating rate of 10 °C/min over the range 25-250 °C.

Examples

Example 1

Preparation of saxagliptin phosphate hemihydrate seeds

925 μΙ of H3PO4 ( 0,5 M) was added to a solution of 150 mg of (1 S,3S,5S)-2- [(2S)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2-azabicyclo [3.1 .0] hexane-3- carbonitrile in 4 ml of ethanol. The clear solution was evaporated under gentle N₂-flow yielding a white solid which was suspended in 2 ml of ethyl acetate. The suspension was stirred for one day at ambient temperature and filtered to yield the crystalline saxagliptin phosphate hemihydrate (form A). Example 2

Preparation of saxagliptin phosphate hemihydrate (form A)

303 mg of (1 S, 3S, 5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2- azabicyclo [3.1 .0] hexane-3-carbonitrile hemihydrate were dissolved in 4 ml of ethanol. 62,5 μΙ of H3PO4 (85%) was added. The clear solution was concentrated under a gentle N₂ flow. 5 ml of H₂0 was added and the turbid solution was evaporated. The wet residue was suspended in 3 ml of ethylacetate yielding a gel like suspension which was evaporated. The residue was dried in vacuo for 3 hours at 3 mbar. 3 ml of ethylacetate was added and the suspension was sonicated and stirred for one day at ambient temperature. After filtration a mixture of amorphous and crystalline material was obtained. The solid was suspended a second time in 5 ml of ethylacetate and after heating to approximately 50°C to 70°C was stirred for 3 days at ambient temperature. The suspension was filtered and the solid was dried in vacuo.

The XRPD pattern revealed a mixture of amorphous and crystalline material. 3 ml of ethylacetate and seed crystals were added to the solid and the suspension was heated to 50°C to 70°C and was stirred then at ambient temperature for approximately 24 hours.

The suspension was filtered and 4 ml of 2-propanol/water mixture ( 9: 1 , v:v) was added to the solid yielding a clear solution. After evaporation under a gentle N₂ stream the solid was dissolved in 0,6 ml of H₂0. 8 ml of 2-propanol was slowly added yielding a clear solution with a few particles. The sample was stirred for 30 min at ambient temperature resulting in the formation of a gel. The sample was heated to 60°C and was stirred for 2 hours at this temperature. The obtained suspension was cooled to 30°C , filtered and the crystals were dried in vacuo (~3 mbar, for approximately 16 hours ).

XRPD corresponds to figure 1 .

FT-Raman of example 2 is shown in figure 2.

Example 3

Preparation of saxagliptin phosphate hemihydrate (form A)

2 g (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2- azabicyclo [3.1 .0] hexane-3-carbonitrile was dissolved in 25 ml_ ethanol.

416,5 ml phosphoric acid (85%) was added and the solution was evaporated under gently N₂-flow. The obtained solid was vacuum dried three hours in vacuo and afterwards suspended in 10 ml_ of water and 70 mL of 2-propanol. The suspension was sonicated and then heated to 60 °C. After cooling to ambient temperature, the suspension was stirred three days at ambient temperature. The sample was filtered and the solid was vacuum dried for 14 hours at approximately 3 mbar.

Yield: 1 ,28 g Table 1 : angles 2-theta, d values (Angstrom ) and intensities of saxagliptin phosphate hemihydrate (form A)

Where it is meant that: Vs is very strong, S is strong, M is medium, W is weak, and Vw is very weak intensity.

Example 4

Preparation of Saxagliptin phosphate hemihydrate (form A) via amorphous saxagliptin phosphate

20,8 μΙ of H3PO4 (85%) was added to a solution of 100 mg of (1 S,3S,5S)-2-[(2S)- 2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2-azabicyclo [3.1 .0] hexane-3- carbonitril in 1 ml of ethanol. 1 ml of heptane was added to the clear solution yielding a suspension which was heated to the boiling point of the mixture. After cooling to ambient temperature 1 ml of heptane was added and 2 ml acetonitrile was added to the amorphous solid and the suspension was stirred one day at ambient temperature. The suspension was filtered to yield amorphous product. The amorphous product was suspended in 3 ml of acetonitril and the

suspension was stirred for 4 hours at 60°C. 0,35 ml of H₂0 was added and a clear solution was obtained.

2,5 ml of acetonitrile was added and the suspension was stirred at 60°C for 3 hours and was allowed to cool to ambient temperature. The suspension was then filtered and the crystals were dried in vacuo for approximately 30 min (3 mbar).

Example 5

Preparation of saxagliptin phosphate higher hydrate (form B)

49,5 mg of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2- azabicycio [3.1 .0] hexane-3-carbonitril phosphate hemihydrate was dissolved in 0,5ml acetonitrile / H20 ( 3: 1 v/v) at 50 °C. The solution was allowed to cool slowly to ambient temperature and the solvent was evaporated under a gentle N2 stream to yield a crystalline residue. TG-FTIR showed a release of water of about 34,9%

Example 6

Preparation of saxagliptin phosphate higher hydrate (form B)

100 mg of (1 S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2- azabicycio [3.1 .0] hexane-3-carbonitril phosphate was dissolved in a mixture of 0,75 ml of acetonitrile and 0,5 ml of H₂0. The solution was filtered and diluted with 0,5 ml of H₂0. The clear solution was evaporated under gentle N₂ stream to yield a crystalline residue. The wet crystalline residue was analysed by XRPD and showed peaks as indicated in table 2. Table 2: Angles 2-theta, d values (Angstrom ) and intensities of the higher hydrate (form B)

Example 7

Preparation of saxagliptin phosphate hemihydrate (Form A)

The product from example 6 (saxagliptin phosphate higher hydrate ) was suspended in 4 ml of acetonitrile and the mixture was stirred for 1 day at ambient temperature.

The suspension was filtered and the obtained solid showed the pattern of the hemihydrate (form A) by XRPD.

Claims

A crystalline compound comprising a mixture of a compound of formula I

(INN: Saxagliptin)

and phosphoric acid or a hydrate thereof, wherein the molar ratio of the compound of formula I and the phosphoric acid is in the range of from 1 :0,8 to 1 : 1 ,2.

The crystalline compound according to claim 1 , characterized in that the molar ratio of the compound of formula I and phosphoric acid is 1 : 1 .

The crystalline compound according to claim 1 or 2, characterized in that it has an XRPD pattern with at least one characteristic peak (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5,6°, 7,3°, 17,6° and 18,0°.

4. The crystalline compound according to at least one of the claims 1 to 3, characterized in that it further comprises water and the molar ratio of the compound of formula I and water is in the range of from 1 :0,3 to 1 :5, preferably having a water content of from 2 wt-% to 4 wt-%, more preferably from 2, 1 wt-% to 3 wt-%. 5. The crystalline compound according to claim 1 or 2, characterized in that it has an XRPD pattern with at least one characteristic peak (expressed in 2Θ ± 0,2° 2Θ (CuKa radiation)) at 5,3°, 5,7°, 1 1 ,4° and 17,2°. Use of the crystalline compound according to claim 5 for the preparation of the crystalline compound according to claim 3 or 4.

A process for obtaining the crystalline compound according to at least

one of the claims 1 to 5 comprising the steps of: a) providing a compound of formula I (INN: Saxagliptin)

in a suitable solvent or a mixture of solvents

b) adding phosphoric acid to the mixture of step a);

c) optionally concentrating the composition of step b);

d) crystallizing;

e) optionally equilibrating the obtained suspension of step d); and f) isolating the obtained precipitate.

The process according to claim 7, characterized in that the molar ratio of the compound of formula I in step a) and the phosphoric acid of step b) is in the range of from 1 :0,5 to 1 :3.

The process according to claim 7 or 8, further comprising step g) of slurrying the isolated precipitate of step f) in a further suitable solvent or mixture of solvents being preferably acetonitril and h) isolating the obtained precipitate.

10. The process according to at least one of the claims 7 to 9, characterized in that in step c) the entire solvent is removed and the residue is dissolved in a suitable solvent or mixture of solvents and water. The process according to at least one of the claims 7 to 10, characterized in that the solvent is selected from the group consisting of C2-C4 alcohols, a C3-C6 ketone, an ether or an acetic ester C₁ -C4 alkylester, acetonitril, a hydrocarbon or mixtures thereof.

The process according to at least one of the claims 7 to 1 1 , characterized in that in step d), e) and/or g) seed crystals are added.

13. A pharmaceutical composition comprising the crystalline compound

according to at least one of the claims 1 to 5 and optionally one or more pharmaceutically acceptable excipients.