# US 8,772,512 B2 · Crystallisation process for 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,772,512 B2
- Document ID: US8772512B2
- Status: Granted
- Kind: B2
- Application number: 13/382,658
- Filed: 2010-07-08
- Published: 2012-05-03
- Granted: 2014-07-08
- Earliest claimed: 2009-07-10
- Assignees: Janssen Pharmaceutica NV
- Applicants: Thomas Joachim Landewald Rammeloo; Ruben De Keyser; Gustaaf Jozef Petrus Schildermans
- Inventors: Thomas Joachim Landewald Rammeloo; Ruben De Keyser; Gustaaf Jozef Petrus Schildermans
- Web page: https://patentgrep.com/patent/US8772512B2

## CPC

- C07D 309/10: Oxygen atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a crystallization procedure to obtain 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate crystals having a narrow particle size distribution and improved flowability, bulk and tap density properties.

## Claims

### Claim 1

A process for preparing 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate crystals comprising
subjecting a crystalline suspension of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate in a solvent system to at least one temperature oscillation episode and at least one mechanical particle size reduction episode.

### Claim 2 (depends on 1)

The process according to claim 1 wherein the temperature oscillation episode comprises a heating phase and a corresponding cooling phase.

### Claim 3 (depends on 2)

The process according to claim 2 wherein the heating phase precedes the cooling phase.

### Claim 4 (depends on 3)

The process according to claim 3 wherein the mechanical particle size reduction is performed by wet milling.

### Claim 5 (depends on 4)

The process according to claim 4 wherein the temperature oscillation episode precedes the mechanical particle size reduction episode.

### Claim 6 (depends on 4)

The process according to claim 4 wherein the temperature oscillation episode and the mechanical particle size reduction episode are repeated independently from one another.

### Claim 7 (depends on 1)

The process according to claim 1 wherein the solvent system is an organic solvent, or mixture of organic solvents, wherein 1-(β-D-gluco-pyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate has a large difference in solubility between the lowest and the highest temperature of the temperature oscillation episode.

### Claim 8 (depends on 1)

The process according to claim 1 wherein the solvent system is selected from ethyl acetate, 1-methylethyl acetate, or a mixture thereof, and said solvent system optionally comprises up to 20% water.

### Claim 9 (depends on 1)

The process of claim 1 comprising the consecutive steps of
a) preparing a solution of compound (I) in a solvent system under concentration and temperature conditions which allow the total solubility of compound (I);
b) cooling the said solution to a temperature such that the solution is in the metastable zone;
c) seeding the solution of compound (I) with crystals of compound (I);
d) cooling the solution of compound (I) to obtain a suspension of crystals of compound (I);
e) subjecting the crystalline suspension thus formed to mechanical particle size reduction using a shearing machine;
f) heating the crystalline suspension of compound (I) to dissolve the fine particles;
g) repeat steps d), e) and f) from 1 to 5 times;
h) cooling the crystalline suspension of compound (I) to room temperature or lower;
i) filtering off the crystals of compound (I) thus formed.

### Claim 10 (depends on 9)

The process according to claim 9 wherein the solvent system in step a) is a mixture of 1-methylethyl acetate and water.

### Claim 11 (depends on 10)

The process according to claim 10 wherein the temperature in step b) is 54° C.

### Claim 12 (depends on 11)

The process according to claim 11 wherein cooling of the solution of compound (I) in step d) is in accordance with a cubic temperature decrease.

### Claim 13 (depends on 12)

The process according to claim 12 wherein the crystalline suspension of compound (I) in step f) is heated to 55° C.

### Claim 14 (depends on 13)

The process according to claim 13 wherein step d), e) and f) are repeated 1 time.

### Claim 15 (depends on 14)

The process according to claim 14 wherein the crystalline suspension of compound (I) in step h) is cooled to 0° C.