WO2013128379A2

WO2013128379A2 - Crystalline polymorphic forms of linagliptin

Info

Publication number: WO2013128379A2
Application number: PCT/IB2013/051556
Authority: WO
Inventors: Srividya Ramakrishnan; Subbareddy Peddireddy; Lalita Kanwar
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2012-02-27
Filing date: 2013-02-27
Publication date: 2013-09-06
Also published as: WO2013128379A3

Abstract

The present application relates to crystalline polymorphs of linagliptin and to methods for their preparation. Further the present application relates to the use of the linagliptin novel polymorphs for the preparation of a medicament, and pharmaceutical compositions comprising an effective amount of the crystalline linagliptin polymorphs.

Description

CRYSTALLINE POLYMORPHIC FORMS OF LINAGLIPTIN

FIELD OF THE INVENTION

The present application relates to crystalline polymorphic forms of linagliptin, to processes for preparing them, to pharmaceutical compositions containing them, and to their uses.

BACKGROUND OF THE INVENTION

The drug compound having the adopted name "linagliptin" has chemical names 1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R)- aminopiperidin-1 -yl) xanthine, or 1 H-purine-2,6-dione, 8-[(3R)-3-amino-1 -piperidinyl]- 7-(2-butyn-1 -yl)-3,7-dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]-; the CAS Registry No. 668270-12-0; I.

Linagliptin is a DPP-IV inhibitor and is the active ingredient in a product sold as TRADJENTA®, in the form of 5 mg tablets.

U.S. Patent No. 7,407,955 discloses linagliptin, related compounds, and their pharmaceutical compositions. It also describes a process for the preparation of linagliptin, wherein tert-butyloxycarbonyl (Boc)-protected linagliptin is deprotected using 5-6 M isopropanolic hydrochloric acid, followed by purification using chromatography. The patent does not mention the polymorphic form obtained.

International Patent Application Publication No. WO 2007/128721 A1 describes crystalline Forms A, B, C, D, and E of linagliptin, and processes for the preparation of the polymorphic forms. The publication also describes polymorphic forms A, B, D, and E as being anhydrous, and polymorphic form C as a hydrate with a stoichiometry somewhere in the region of a hemihydrate or monohydrate.

New polymorphic forms, including solvates, of a pharmaceutical active ingredient can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.

Though known polymorphic forms may address some of the deficiencies in terms of a formulated product and its manufacturability, there remains a need for further improvement in these properties as well as improvements in other properties such as flowability, vapor impermeability and solubility. Further, the discovery of new salts and polymorphic forms of a drug enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.

Toward this end, it has been the endeavor of pharmaceutical scientists to provide novel and stable forms of drug substances, which would have the strengths of thermodynamic stability, enhanced solubility, rapid onset of action and an enhanced bioavailability. However, it is well known in the art that polymorphism is unpredictable, both as regards the uncertainty that any new forms will be found, and the lack of any standard methods for preparing a new form. This has been discussed in the literature, such as A. Goho, "Tricky Business," Science News, Vol. 166(8), August 21 , 2004, and A. M. Rouhi, "The Right Stuff," Chemical and Engineering News, February 24, 2003, pages 32-35.

Therefore, it would be desirable to provide stable polymorphs of linagliptin andprocesses for their preparation, which are commercially viable.

SUMMARY

The present application relates to novel polymorphic forms of linagliptin and processes for their preparation. In particular embodiments, it relates to crystalline Form I and Form II of linagliptin characterized by X-ray powder diffraction ("XRPD"), and processes for their preparation.

In one aspect the present application provides crystalline linagliptin Form I characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of about 8.2, 8.9, 20.1 , and 21 .8 ±0.2. It may be further characterized by XRPD peaks at about 7.1 , 9.8, 10.6, 12.3, 13.5, 14.1 , 14.7, 15.7, 16.8, 19.1 and 19.6 In another aspect the present application provides a process for preparation of crystalline linagliptin Form I, comprising:

a) providing a solution of linagliptin in an alcohol or a mixture of alcohols; b) combining water with the solution of step a); and

c) isolating crystalline Form I of linagliptin from the mixture of step b).

In another aspect the present application provides a process for preparation of crystalline linagliptin Form I, comprising:

a) providing a solution of linagliptin in an alcohol;

b) stirring the solution of step a); and

c) isolating linagliptin Form I from the solution.

In an aspect, the present application provides linagliptin crystalline Form II characterized by an XRPD pattern comprising characteristic peaks located at about 4.7, 17.2, and 31 .5, ±0.2 degrees 2-theta. It may be further characterized by XRPD peaks at about 9.7, 1 1 .7, 15.1 , 18.7, and 22.1 ±0.2 degrees 2-theta.

In another aspect, the present application provides a process for the preparation of linagliptin crystalline Form II, comprising:

a) providing a solution of linagliptin in an alcohol;

b) combining an ether with the solution of step a); and

c) isolating the formed solid.

In another aspect the present application provides micronized linagliptin Form

I.

In another aspect the present application provides crystalline linagliptin Form I having 90% of particles with particle size less than 300 μηι.

In another aspect the present application provides a pharmaceutical composition comprising the linagliptin Form I and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustrative example of an XRPD pattern of crystalline Form I of linagliptin, prepared in Example 1 .

Fig. 2 is an illustrative example of an XRPD pattern of crystalline Form I of linagliptin, prepared in Example 4.

Fig. 3 is an illustrative example of an XRPD pattern of crystalline Form II of linagliptin, prepared in Example 14. Fig. 4 is an illustrative example of microscopic image of unmicronized linagliptin crystalline Form I.

Fig. 5 is an illustrative example of microscopic image of micronized linagliptin crystalline Form I.

DETAILED DESCRIPTION

Aspects of the present application relate to crystalline forms of linagliptin designated herein as Form I and Form II and processes for preparation thereof.

Crystalline Form I and Form II of linagliptin may be characterized by any one or more analytical techniques, which may include XRPD patterns, infrared absorption spectra, differential scanning calorimetry (DSC) curves, and thermo gravimetric analysis (TGA) curves.

In an aspect, the present application provides a crystalline form of linagliptin, which is designated herein as "Form I." Form I may be characterized by using one or more analytical methods.

In an embodiment, there is provided crystalline Form I of linagliptin characterized by an XRPD pattern having peaks located substantially in accordance with the pattern shown in Figure 1 .

In an embodiment, there is provided crystalline Form I of linagliptin characterized by X-ray powder diffraction ("XRPD") pattern substantially as shown in Figure 2.

In an embodiment, the present application provides crystalline Form I of linagliptin characterized by an XRPD pattern comprising characteristic peaks located at about 8.2, 8.9, 20.1 , and 21 .8 ±0.2 degrees 2-theta. It may be further characterized by XRPD peaks at about 7.1 , 9.8, 10.6, 12.3, 13.5, 14.1 , 14.7, 15.7, 16.8, 19.1 and 19.6 ±0.2 degrees 2-theta.

In another aspect, the present application provides a process for preparation of crystalline Form I of linagliptin, embodiments comprising:

(a) providing a solution of linagliptin in an alcohol solvent;

(b) stirring the solution of step a); and

(c) isolating linagliptin Form I from the solution.

The individual steps are separately described herein below.

Step a) involves providing a solution of linagliptin in an alcohol solvent. The solution of linagliptin may be obtained by dissolving linagliptin in a suitable alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which linagliptin is formed.

Any form of linagliptin is acceptable for forming a solution, such as a crystalline form, an amorphous form, and mixtures thereof.

Suitable alcohol solvents that can be used include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, tertiary-butyl alcohol, and the like, including any mixtures thereof.

The quantities of solvent used for providing a solution may range from about 3 ml. to about 50 ml_, per gram of linagliptin.

The solution may be prepared at any temperatures upto the boiling point of the solvent. For example, the solution may be prepared at ambient temperatures, such as below 35 °C, or in the range of about 0°C to about 30 °C

The solution may optionally be treated with activated carbon and then filtered to remove the carbon. The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

Step b) involves stirring the solution obtained in step a) to facilitate precipitation. The solution is stirred at temperatures below 30°C.ln embodiments, the solution obtained in step a) is stirred for about 5 minutes to about 20 hours, or longer, at about -20 °C to about 30 °C. In an embodiment the solution of step a) is stirred for about 1 hour to about 10 hours.

Step c) involves isolating the solid obtained in step b). The solid may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

In another aspect, the present application provides a process for preparation of crystalline Form I of linagliptin, embodiments comprising: a) providing a solution of linagliptin in an alcohol solvent or a mixture of alcohol solvents;

b) combining water with the solution of step a); and

c) isolating crystalline Form I of linagliptin from the mixture of step b).

The individual steps are separately described herein below.

Step a) involves providing a solution of linagliptin in an alcohol solvent or a mixture of alcohol solvents.

The solution of linagliptin may be obtained by dissolving linagliptin in a suitable alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which linagliptin is formed.

Suitable mixtures alcohol solvents that can be used include, but are not limited to, a mixture of methanol and ethanol, a mixture of methanol and isopropanol, a mixture of methanol and n-propanol, a mixture of ethanol and isopropanol.

The mixture of alcohol solvents may range from about 0.5:9.5 to about 9.5:0.5. The quantities of solvent or a mixture of solvents used for providing a solution may range from about 2 ml. to about 50 ml_, per gram of linagliptin.

The solution may be prepared at any temperatures up to the boiling point of the solvent. For example, the solution may be prepared at ambient temperatures, such as below 35^, or in the range of about -I CC to about 35^.

The solution is stirred at about 0°C. In one embodiment, the solution obtained is stirred for about 5 minutes to about 20 hours, or longer, at about -20^ to about 30 °C. In an embodiment the solution obtained is stirred for about 30 minutes to about 5 hours.

Step b) includes combining water with the solution of a). The quantity of water used may range from about 0.1 ml to about 100 ml, per gram of linagliptin. The addition of water may be done at any temperatures, including about -30°C to about 65 °C. The obtained solution may be seeded with linagliptin Form I crystals. The obtained suspension may be stirred for about 15 minutes to about 20 hours, or longer, to enhance the extent of crystallization. Useful temperatures for maintaining a suspension may range from about -30 °C to about 35 °C.

Step c) involves isolating linagliptin Form I obtained in step b). The crystalline linagliptin Form I may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation of the solid, the solid optionally can be washed with the solvent used in step a) to wash out residual mother liquor.

The obtained solid of linagliptin may be dried. The drying of solid material may be carried out under suitable conditions to afford the desired crystalline form of linagliptin, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures such as about 0°C to about 60°C, or higher. Drying may be suitably carried out using equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof.

In an aspect, the present application provides a process for reducing residual alcohol in linagliptin Form I to pharmaceutically acceptable level.

The process involves contacting said linagliptin Form I with a suitable humidified gas or humidified air under conditions which permit residual alcohol to be entrained in the gas, and removing the solvent and/or gas mixture. Preferably, the humidified gas is passed through a fluidized bed or ANFD or humidity chamber of the linagliptin Form I.

The drying of linagliptin Form I can be carried out in a controlled humidity environment having a relative humidity ("RH"), such as below 96% RH, or between about 30 to about 96% RH, at temperatures such as about 0-60 °C. Exposure to a humid environment can reduce the residual solvent content. The humidification drying may be performed for any desired time periods that achieve the desired product purity and residual solvent content, such as times from about 1 hour to about 30 hours, or longer. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Preferably, the linagliptin Form I obtained contains about 3 % to about 10% of water by weight, and more preferably about 4% to about 8% of water by weight as determined by KF.

The crystalline Form I of linagliptin obtained by processes of the present application may have a polymorphic purity greater than about 95%, or greater than about 98%, or greater than about 98.5%, or greater than about 99%, or greater than about 99.5%.

The crystalline Form I of linagliptin obtained by a process of the present application may be utilized for the preparation of an amorphous form, as well as other crystalline polymorphs.

In an aspect, the present application provides pharmaceutical formulations comprising crystalline Form I of linagliptin and at least one pharmaceutically acceptable excipient.

The crystalline Form I of linagliptin produced according to processes of the present application is useful for making pharmaceutical dosage forms for the treatment of type II diabetes mellitus, prediabetes, i.e., reduced glucose tolerance, and obesity.

In an aspect, the present application provides a crystalline form of linagliptin, which is designated herein as "Form II." Form II may be characterized by using one or more analytical methods.

In embodiments, there is provided crystalline Form II of linagliptin characterized by an XRPD pattern having peaks located substantially in accordance with the pattern shown in Figure 3.

In embodiments, the present application provides crystalline Form II of linagliptin characterized by an XRPD pattern comprising characteristic peaks located at about 4.7, 17.2, and 31 .5, ±0.2 degrees 2-theta. It may be further characterized by XRPD peaks at about 9.7, 1 1 .7, 15.1 , 18.7, and 22.1 ±0.2 degrees 2-theta.

d) providing a solution of linagliptin in an alcohol;

e) combining an ether with the solution of step a); and

f) isolating the formed solid.

The individual steps are separately described herein below.

Step b) includes combining an anti-solvent with the solution of a). Anti- solvents that may be used for the preparation of linagliptin Form I I include, but are not limited to, ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), and the like. The quantities of anti-solvent used may range from about 3 ml. to about 50 ml_, per gram of linagliptin. Addition of the anti-solvent may be performed at any temperatures, including about 0°C to about 35 °C. The obtained suspension may be stirred for about 15 minutes to about 20 hours, or longer, to enhance the extent of crystallization. Useful temperatures for maintaining a suspension may range from about -30 °C to about 60 °C.

Step c) includes isolating a solid from the mixture of step b). The solid may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example, the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, and the like. After isolation, the solid may optionally be washed with a suitable solvent such as diethyl ether, diisopropyl ether, MTBE, and the like to wash out residual mother liquor.

The crystalline Form II of linagliptin obtained by processes of the present application may have a polymorphic purity greater than about 95%, or greater than about 98%, or greater than about 98.5%, or greater than about 99%, or greater than about 99.5%.

The crystalline Form II of linagliptin obtained by processes of the present application may be utilized for the preparation of an amorphous form, as well as other crystalline polymorphs.

In an aspect, the present application provides pharmaceutical formulations comprising linagliptin crystalline Form I or linagliptin crystalline Form II or a mixture of linagliptin crystalline Form I and Form II together with at least one pharmaceutically acceptable excipient.

The linagliptin crystalline Form I and Form II of the present application are useful for making pharmaceutical dosage forms for the treatment of type II diabetes mellitus, prediabetes, i.e. reduced glucose tolerance, and obesity. The present application also provides micronized linagliptin Form I. Linagliptin Form I is stable upon micronization. Linagliptin is practically insoluble in water (0.01 mg/ml). Micronized linagliptin has significant pharmaceutical advantages. For example micronized linagliptin has a much higher specific surface area (SSA) than the non-micronized form. An increase in the SSA of low aqueous solubility materials may improve therapeutic activity. Micronized linagliptin Form I may be characterized by particle size or specific surface area.

In another aspect, the present application provides crystalline linagliptin Form I having particle sizes less than about 300 μηι, preferably less than about 200 μηι, more preferably less than about 100 μηι, most preferably less than about 50 μηι, and still moost preferably less than about 20 μηι.

Micronized linagliptin Form I may be characterized by its particle size. Preferably at least about 90% micronized linagliptin particles have a particle size of less than about 100 microns, more preferably less than about 50 microns, and most preferably less than about 20 microns.

Particle size distributions of linagliptin particles may be measured by any technique known in the art. For example, particle size distributions of linagliptin Form I particles may be measured using light scattering equipment, such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, linagliptin suspended in light liquid paraffin, size range: 0.01 μηι to 3000 μηι).

The methodology and protocols for particle size distribution of linagliptin Form I by laser diffraction are described below.

Instrument: Malvern Mastersizer 2000

Sample Handling Unit (Accessory): Hydro 2000S (A)

Range: 0.02 μηι to 2000 μηι

Pump/Stirrer Speed: 2500 RPM

Dispersant: Light liquid paraffin

Backgroud: With Dispersant

Obscuration: Between 10-20%

Sample Preparation: Transferred about 200 mg of linagliptin Form I sample into a 30 mL stoppered test tube and added 20 mL of dispersant and 2-3 drops of Span 8.5. Then the mixture was kept on cyclomixture for one minute and sonicated for 15 seconds. Another aspect of the present application provides pharmaceutical compositions comprising crystalline Form I and/or Form II of linagliptin, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical composition comprising crystalline Form I and/or Form II of linagliptin with a pharmaceutically acceptable carrier may be formulated into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, modified release, and any combinations thereof. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix, reservoir, or combinations of matrix and reservoir systems. The compositions may be prepared using any of techniques such as direct blending, dry granulation or wet granulation, or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated.

Pharmaceutically acceptable excipients that are useful include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropylmethylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex-forming agents such as various grades of cyclodextrins and resins; and release rate-controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

In embodiments of compositions of the present application, linagliptin is a useful active ingredient in the range of about 1 mg to about 50 mg, per dosage unit.

Certain specific aspects and embodiments of the application will be described in further detail by the examples below, being provided only for the purpose of illustration and not intended to limit the scope of the disclosure in any manner.

The polymorphic forms, produced by the methods of the present application can be analyzed by Powder X-ray Diffraction (PXRD) was performed on an X-ray Powder Diffractometer, equipped with a Cu-anode (λ=1 .54 Angstrom), X-ray source operated at 45 kV, 40 mA, and a Ni filter is used to strip K-beta radiation. Two theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range= 2-50 ° 2Θ, step width=0.017°; and measuring time per step 22 sec.

EXAMPLES

EXAMPLE 1 : PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (6.0 g) and ethanol (120 mL) were placed into a 250 mL round bottom flask, heated to 78°C, and stirred for 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was cooled to 25 °C and rapidly cooled to -10 ° and maintained for 30 minutes at -10 *0 to 0*0. The precipitate that formed was filtered and the wet solid was suction dried, to afford linagliptin Form I.

PXRD pattern: Fig. 1

Water Content: 5.13%

Organic Volatile Impurities (OVI) (Ethanol): 34140 ppm.

EXAMPLE 2: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (2 g) and ethanol (40 mL) were placed into a 100 mL round bottom flask, heated to 78°C, and stirred for 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was cooled to 25^ and maintained for 1 hour at 25 °C. The precipitate that formed was filtered and the wet solid was suction dried, and the material was dried in a vacuum tray drier at 40 °C to afford linagliptin Form I.

PXRD pattern is same as Fig. 1

Water Content: 5.52%

OVI (Ethanol): 28757 ppm;

EXAMPLE 3: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (10 g) and ethanol (200 mL) were placed into a 500 mL round bottom flask, heated to 79°C, and stirred for 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was cooled to -5 to -10*0 and maintained for 1 .5 hours at -5 to -I CC. The precipitate that formed was filtered and the wet solid was suction dried, and the material was dried in a vacuum tray drier at 40*0 for 4hrs to afford linagliptin Form I.

PXRD pattern is same as Fig. 1 .

OVI (Ethanol): 38575 ppm;

EXAMPLE 4: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (2 g) and a 1 :1 mixture of methanol and isopropanol (40 mL) were placed into a round bottom flask, heated to 56°C, and stirred for about 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was seeded with linagliptin Form I crystals (0.1 g) at room temperature, gradually cooled to C and maintained for 2 hours at 0°C. The precipitate that formed was filtered and the wet solid was suction dried, and the material was dried in a vacuum tray drier at 40 °C for 4hrs to afford linagliptin Form I. PXRD pattern: Fig. 2

TGA weight loss: 7.2%

Moisture: 4.16%

OVI (Methanol): 2400 ppm (Isopropanol): 3000 ppm.

EXAMPLE 5: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (3 g) was suspended in methanol (30 mL) at 25 °C. The mixture was heated to 55°C and stirred for 30 minutes at 55°C. The clear solution was filtered and the filtrate was cooled to 27°C, linagliptin Form I crystals (150 mg) were added, and the mixture was gradually cooled to 5°C over a period of 30 minutes and stirred for 1 hour at 5°C. The suspension was filtered and suction dried for about 10 minutes to obtain a solid. The solid was dried in a vacuum tray drier at 40 °C for about 4 hours in a vacuum tray dryer, to afford linagliptin Form I.

PXRD pattern is same as Fig. 2

Moisture: 7.71 %

OVI (Methanol): 743 ppm.

EXAMPLE 6: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (2 g) and a 1 :1 mixture of methanol and isopropanol (40 mL) were placed into a round bottom flask, heated to 50°C, and stirred for about 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was charged with water (0.3 mL) and linagliptin Form I crystals (0.1 g). The obtained solution was stirred for 1 hour at 25 °C. The mixture was gradually cooled to 0°C and maintained for 1 hour at 0°C. The precipitate that formed was filtered and the wet solid was suction dried. The solid was dried in a vacuum tray drier at 40 °C for about 4 hours in a vacuum tray dryer, to afford linagliptin Form I.

PXRD pattern is same as Fig. 2.

EXAMPLE 7: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (1 g) was suspended in mixture of isopropanol and water (29 mL of Isopropanol and 1 ml of water) at 25 *0. The mixture was heated to 60-65 °C and stirred for 30 minutes at 60-65 °C. The clear solution was filtered and the filtrate was placed into a round bottom flask and cooled to 28*0, then linagliptin Form I crystals (0.3 mg) seeded. The mixture was cooled to 0 *0 within 15 minutes and maintained for 2 hour at 0*0. The precipitate that formed was filtered and the wet solid was suction dried. The solid was dried in a vacuum tray drier at 40 °C for 3 hours in a vacuum tray dryer, to afford linagliptin Form I.

PXRD pattern is same as Fig. 2

TGA weight loss: 6.7%

OVI (Isopropanol): 7439 ppm. EXAMPLE 8: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (3 g) was suspended in mixture of isopropanol and water (58.8 mL of Isopropanol and 1 .2 mL of water) at 25^., heated to 65°C, and stirred for about 30 minutes. The clear solution was filtered and the filtrate was placed into a round bottom flask and the solution was charged with linagliptin Form I crystals (150 mg), gradually cooled to I CC over a period of 1 hour and further cooled to 0°C in 30 minutes and maintained for 1 hour at 0°C. The precipitate that formed was filtered and the wet solid was suction dried, to afford linagliptin Form I.

PXRD pattern is same as Fig. 1

Moisture: 4.77%

OVI (Isopropanol): 55186 ppm.

EXAMPLE 9: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I.

Linagliptin (30 g) was suspended in methanol (150 mL) at 25*0. The mixture was heated to 55 °C and the clear solution that formed was filtered and the filtrate was cooled to 25*0, water (7.5 mL) was added and seeded with linagliptin Form I crystals (150 mg), and the mixture was stirred for 1 hour at 27°C. The suspension was cooled to 0 *0 and stirred for 1 hour at 0*0. The suspension was filtered and suction dried for about 10 minutes to afford linagliptin Form I.

PXRD pattern is same as Fig. 2

Moisture: 5.58%:

OVI (Methanol): 14389 ppm.

EXAMPLE 10: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I

Linagliptin (100 g) was suspended in methanol (500 mL) at 25 °C. The mixture was heated to 54 °C and the clear solution that formed was filtered and the filtrate was cooled to 35^, water (25 mL) was added and seeded with linagliptin Form I crystals (5 g), and the mixture was stirred for 1 hour at 30 'C. The suspension was cooled to 0°C and stirred for 1 hour at 0°C. The suspension was filtered and suction dried for about 10 minutes and the wet material was dried in a vacuum tray drier at 40°C mmHg for 8 hours to afford Linagliptin Form I. OVI (Methanol): 10253 ppm. The dry material was humidified at 40 °C and 75%RH for 6 hours. Then the humidified material was dried in a vacuum tray drier at 40°C and 690 mmHg for 8 hours and checked for methanol content. OVI (Methanol): 4300 ppm.

The material was again humidified at 40 °C and 75%RH for 4 hours. Then the humidified material was dried in a vacuum tray drier at 40°C and 690 mmHg for 3 hours to afford Linagliptin Form I. OVI (Methanol): 1521 ppm; Moisture content: 7.27%.

EXAMPLE 1 1 : PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I

Linagliptin (80 g) was suspended in methanol (200 mL) at 25°C. The mixture was heated to 60 °C and the clear solution that formed was filtered and the filtrate was cooled to 35°C, water (200 mL) was added and seeded with linagliptin Form I crystals (4 g), and the mixture was stirred for 1 hour at 30 'C. The suspension was cooled to 0°C and stirred for 1 hour at 0°C. The suspension was filtered and suction dried for about 10 minutes and the wet material was dried in a vacuum tray drier at 40 °C and 650 mmHg for 3 hours and checked for methanol content. OVI (Methanol): 6000 ppm.

The material was humidified at 40*0 and 75%RH for 4 hours. Then the humidified material was dried in a vacuum tray drier at 40°C and 690 mmHg for 4 hours to afford Linagliptin Form I. OVI (Methanol): 1500 ppm; Moisture content: 7.32%.

EXAMPLE 12: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM I

Linagliptin (40 g) was suspended in methanol (200 mL) at 25*0. The mixture was heated to 58 °C and the clear solution that formed was filtered and the filtrate was cooled to 35*0, water (10 mL) was added and seeded with linagliptin Form I crystals (2 g), and the mixture was stirred for 1 hour at 30 *0. The suspension was cooled to 0°C and stirred for 1 hour at 0*0. The suspension was filtered and suction dried for about 10 minutes to yield 40 g of wet linagliptin Form I. OVI (Methanol): 27876 ppm.

20 g of the wet material was subjected to humidification in fluidized bed drying at 40 °C and ambient relative humidity (56% RH) for 6 hours. The results are tabulated below.

(hours) ppm

0 27876

2 9876

4 3461

6 2076

EXAMPLE 13: MICRONIZATION OF LINAGLIPTIN CTYSTALLINE FORM I

10 g of the wet linagliptin crystalline Form I obtained in example 12 was milled by micronizer The feed nitrogen rate was 4kg/cm² and the grinding nitrogen was 3- 6 bar to get 8 g of micronized linagliptin Form I. The results are tabulated below.

5 g of the micronized linagliptin crystalline Form I was subjected to humidification in fluidized bed drying at 40°C and 90% relative humidity for 6 hours. The results are tabulated below.

EXAMPLE 14: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM II.

Linagliptin (4 g) was suspended in methanol (20 mL) at 25 °C. The mixture was heated to 65 °C and stirred for 1 hour at 65 °C. The clear solution that formed was filtered through a Celite® bed, and the filtrate was placed into a round bottom flask and was cooled to 30°C. Methyl tertiary-butyl ether (40 mL) was added over 10 minutes, and the mixture was stirred for about 1 hour at 28 °C. The suspension was filtered and suction dried for about 10 minutes to obtain a solid. The solid was dried at 40 °C for about 4 hours in a vacuum tray dryer (VTD), to afford linagliptin Form II. PXRD pattern: Fig. 3; TGA weight loss: 9.1 %; Moisture: 8.9%; Methanol: 410 ppm; methyl tertiary-butyl ether: 1805 ppm.

EXAMPLE 15: PREPARATION OF LINAGLIPTIN CRYSTALLINE FORM II.

Linagliptin (2 g) was suspended in methanol (10 mL) at 25 °C. The mixture was heated to 65 °C and stirred for 1 hour at 45°C. The clear solution that formed was filtered through a Celite® bed, and the filtrate was placed into a round bottom flask and was cooled to 28 °C. Methyl tertiary-butyl ether (20 mL) was added over 10 minutes, and the mixture was stirred for about 1 hour at 28*0. The suspension was filtered and suction dried for about 10 minutes to obtain a solid. The solid was dried at 40°C for about 4 hours in a vacuum tray dryer, to afford linagliptin Form II. PXRD pattern: Fig. 3; TGA weight loss: 7.1 %; Moisture: 6.1 %: Methanol: 452 ppm; methyl tertiary-butyl ether: 4138 ppm.

Claims

1 . Crystalline linagliptin Form I characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta angles of about 8.2, 8.9, 20.1 , and 21 .8 ±0.2.

2. The crystalline linagliptin Form I according to claim 1 , is further characterized by additional X-ray powder diffraction peaks at 2-theta angles of about 7.1 , 9.8, 10.6, 12.3, 13.5, 14.1 , 14.7, 15.7, 16.8, 19.1 and 19.6 ±0.2.

3. The crystalline linagliptin Form I according to claim 1 , contains about 3% to about 10% water by weight as determined by KF analysis.

4. The crystalline linagliptin Form I according to claim 3, contains about 4% to about 8% water by weight as determined by KF analysis.

5. A process for preparation of crystalline linagliptin Form I, comprising:

c) isolating crystalline Form I of linagliptin from the mixture of step b).

6. The process according to claim 5, wherein the alcohol is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or a mixture thereof.

7. The process according to claim 5, further comprises removal of residual alcohol from linagliptin Form I, having higher alcohol content, by humidification.

8. A process for preparation of crystalline linagliptin Form I, comprising:

d) providing a solution of linagliptin in an alcohol;

e) stirring the solution of step a); and

f) isolating linagliptin Form I from the solution.

9. The process according to claim 8, wherein the alcohol is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or a mixture thereof.

10. The process according to claim 8, wherein the solution is stirred at a temperature of about -10 ^<C to about 30 ^<C.

1 1 . Crystalline linagliptin Form I having 90% of particles with particle size less than 300 μηι.

12. Crystalline linagliptin Form I according to claim 14, having 90% of particles with particle size less than 100 μηι.

13. Crystalline linagliptin Form I according to claim 14, having 90% of particles with particle size less than 50 μηι.

14. Crystalline linagliptin Form I according to claim 14, having 90% of particles with particle size less than 20 μηι.

15. A pharmaceutical composition comprising crystalline linagliptin Form I and at least one pharmaceutically acceptable excipient.

16. Use of crystalline linagliptin Form I in the manufacture of a pharmaceutical composition for treating a patient suffering from type I I diabetes mellitus or reduced glucose tolerance or obesity.

17. A method of treating or preventing type II diabetes mellitus or reduced glucose tolerance or obesity comprising administering a pharmaceutical composition according to claim 16.