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Preparation of Crystalline Linagliptin Polymorphic Form A, Form B and a Mixture of Form A and Form B

IP.com Disclosure Number: IPCOM000246131D
Publication Date: 2016-May-11
Document File: 5 page(s) / 426K

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The IP.com Prior Art Database

Abstract

Provided are processes for preparation of linagliptin crystalline Form A, Form B and a mixture of Form A and Form B.

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Preparation of Crystalline Linagliptin Polymorphic Form A, Form B and a Mixture of Form A and Form B

    Linagliptin, 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-
(R)-aminopiperidin-1-yl) xanthine, is a DPP-IV inhibitor and has the following structure.

    Provided are processes for preparation of linagliptin crystalline Form A, Form B and a mixture of Form A and Form B.

    Linagliptin crystalline Form A, characterized by an X-ray powder diffraction pattern having peaks at about 8.4, 9.8, 10.3, 11.1, 11.6 and 12.3 ± 0.2 degrees two theta, is prepared by the following steps:

a) suspending linagliptin in an organic solvent;

b) heating the suspension of step (a) to a temperature of 50 °C to 100 °C;

c) cooling the solution of step (c) to a temperature of 20 °C to 50 °C; and

d) isolating linagliptin crystalline Form A.

    Linagliptin crystalline Form B, characterized by an X-ray powder diffraction pattern having peaks at about 8.8, 9.4, 10.6, 10.7, 11.8 and 12.6 ± 0.2 degrees two theta, is prepared by the following steps:

a) heating linagliptin to a temperature of 70 °C to 150 °C,

b) cooling the linagliptin of step (a) to a temperature of 10 °C to 30 °C;

c) suspending the linagliptin of step (b) in an organic solven;, and

d) isolating linagliptin crystalline Form B.

    A mixture of linagliptin crystalline Form A and Form B, characterized by an X-ray powder diffraction pattern having peaks at about 8.4, 8.8, 9.4, 9.8, 10.3, 10.6, 10.7,
11.1, 11.6, 11.8, 12.3 and 12.6 ± 0.2 degrees two theta, is prepared by mixing or blending the crystalline Form A and Form B.

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1. Preparation of linagliptin crystalline form A

Linagliptin and isopropyl alcohol were charged into a round bottom flask and stirred at 30 °C, and the suspension was heated to 80 °C. The clear solution was filtered through a Celite® bed and the organic layer was cooled to 60 °C. Linagliptin Form A crystals (1 gm) was added and stirred for 30 minutes. Cooled to 22.5 °C and stirred for 3 hours. The suspension was filtered and the wet cake was washed with ethylacetate (50 mL ͯ 2). The compound was dried under vacuum at below 25 °C to yield 40.8 gm of crystalline Form A of linagliptin. Main XRD peaks of Linagliptin Form A are 8.4, 9.8, 10.3, 11.1,
11.6 and 12.3 ± 0.2 degrees two theta.

The obtained crystalline Form A was characterized by Powder X-Ray diffractogram pattern is shown in Figure 1.


2. Slurrying linagliptin crystalline Form A at -10 °C

Ethylacetate (75 mL) was charged into a 100 mL EasyMax reactor and cooled to -20 °C. Linagliptin (3 gm) was charged into the solvent and the suspension was stirred for 20 hours at -20 °C. The suspension was filtered and suck dried for 30 minutes. PXRD matches with crystalline form A. Direct cooling of Linagliptin Form A did not yield Linagliptin Form B.

Powder X-Ray diffractogram is shown in Figure 1.


3. Preparation of linagliptin crystalline Form B

Linagliptin (7 gm) was into a vacuum tray drier at 3...