KR20100122592A - Orlistat crystalline form and process for preparing the same - Google Patents

Abstract

PURPOSE: A method for preparing novel crystalline type III of orlistat is provided to ensure mobility and stability and to enhance formulation efficiency and productivity. CONSTITUTION: A crystalline type III of orlistat has a XRD pattern having a peak at .5, 10.1, 11.0, 15.6, 17.0, 18.4, and 22.7°2θ (± 0.2°). A method for preparing the crystalline type III of orlistat comprises: a step of dissolving orlistat in heptanes or alcohol of C1-C5 and filtering to remove crystalline nucleus; a step of adding alcohol of C1-C15 and mixture solution of the alcohol of C1-C15 and water, acetonitrile, mixture solution of acetonitrile and water, acetone, mixture solution of acetone and water, ether, water, or cyclohexane; and a step of stirring at -10 to 0 °C to precipitate.

Description

Orlistat crystalline form and process for preparing the same

The present invention relates to a novel crystalline form of orlistat, called crystalline form III, and a process for preparing the same.

Orlistat is a drug used to treat obesity and its chemical name is N-formyl-L-leucine (1S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] Methyl] dodecyl ester and has the structure of formula (1).

U.S. Patent No. 4,598,089 (and European Patent No. 129,748) discloses a process for the preparation of orlistat, in particular, fermenting Streptomyces toxytricine to obtain lipstatin and hydrogenating it to orlistat Disclosed is a method of preparing the same. The crude orlistat obtained is purified using a purification method via silica gel column chromatography. In addition, U.S. Patent No. 4,983,746 discloses a multistage orlistat production process comprising the esterification of an oxetanone derivative with an acid derivative in an alcohol.

It is generally known that drugs may exist in one or more crystalline forms (ie, polymorphs), and certain crystalline forms may have different physical properties in terms of physicochemical properties such as fluidity, solubility, stability, and the like. In addition, each of the crystalline forms may show a difference in the rate of absorption or absorption in the gastrointestinal tract, and thus may exhibit different bioavailability.

On the other hand, International Patent Publication No. WO03 / 047531 discloses crystalline forms of Orlistat (named Crystal Form I and Crystal Form II, respectively) and a preparation method thereof. Form I exhibits an XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3 ± 0.2 ° 2θ (± 0.2 °) and has a DSC melting endotherm at about 46.7 ° C. In addition, Form II exhibits an XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2, and 22.0 ± 0.2 ° 2θ (± 0.2 °) and has a DSC melting endotherm at about 46.6 ° C.

While the present inventors have studied an improved method for preparing orlistat, surprisingly, when the crystallization of orlistat is carried out in combination with specific solvents and crystallization at a specific temperature, the orlistat obtained is obtained in a different form than the known crystal form. It was also found that the flowability and stability are very good.

Therefore, an object of the present invention is to provide a novel crystalline form of orlistat, hereinafter referred to as crystalline form III.

It is another object of the present invention to provide a method for preparing orlistat crystalline Form III.

According to one aspect of the present invention, orlistat crystalline Form III is provided, having an XRD pattern having peaks at 5.5, 10.1, 11.0, 15.6, 17.0, 18.4, and 22.7 ° 2θ (± 0.2 °).

The orlistat crystalline Form III may have the XRD pattern shown in FIG. 1. In addition, the orlistat crystal form III may have a DSC melting endotherm at 42.4 ° C., more preferably, a DSC pattern shown in FIG. 2.

According to another aspect of the invention, (a) dissolving orlistat in heptane or C ₁ -C ₅ alcohol and filtering to remove nuclei; (b) To the filtrate obtained in step (a), a mixed solvent of C ₁ -C ₅ alcohol, C ₁ -C ₅ alcohol and water, acetonitrile, a mixed solvent of acetonitrile and water, acetone, acetone and water Adding a solvent selected from the group consisting of a mixed solvent, ether, water, and cyclohexane, followed by stirring at −10˜0 ° C. to form a precipitate; And (c) isolating the precipitate obtained in step (b).

In the production method of the present invention, the solvent of step (a) is heptane, the solvent of step (b) is methanol, ethanol, mixed solvent of ethanol and water, acetonitrile, mixed solvent of acetonitrile and water , Acetone, a mixed solvent of acetone with water, ether, and cyclohexane. Optionally, the solvent of step (a) is methanol and the solvent of step (b) may be water.

It has been found by the present invention that when crystallization is carried out at certain temperatures in combination with certain solvents, new forms of orlistat crystalline forms can be obtained. The orlistat crystalline form III is excellent in fluidity and stability, it can increase the efficiency and productivity in the formulation.

The present invention provides orlistat crystalline Form III, with new crystal forms of orlistat, namely XRD patterns with peaks at 5.5, 10.1, 11.0, 15.6, 17.0, 18.4, and 22.7 ° 2θ (± 0.2 °).

Form III of Orlistat may have the XRD pattern shown in FIG. 1. In addition, Form III of Orlistat may have a DSC melting endotherm at 42.4 ° C., more preferably, a DSC pattern shown in FIG. 2.

Orlistat crystalline Form III according to the invention is a crystalline form different from the crystalline forms disclosed in WO03 / 047531, ie the crystalline forms named Crystal Forms I and II. Form I of Orlistat disclosed in WO03 / 047531 exhibits an XRD pattern with peaks at 5.8, 18.5, 19.5 and 22.3 ± 0.2 ° 2θ (± 0.2 °) and has a DSC melting endotherm at about 46.7 ° C. In addition, Orlistat Form II shows an XRD pattern with peaks at 4.8, 5.6, 14.9, 17.3, 19.2, and 22.0 ± 0.2 ° 2θ (± 0.2 °), and has a DSC melting endotherm at about 46.6 ° C. .

Step of the present invention is also dissolved in the (a) orlistat heptane, or C ₁ ~C ₅ alcohol and filtered to remove a crystal nucleus; (b) To the filtrate obtained in step (a), a mixed solvent of C ₁ -C ₅ alcohol, C ₁ -C ₅ alcohol and water, acetonitrile, a mixed solvent of acetonitrile and water, acetone, acetone and water Adding a solvent selected from the group consisting of a mixed solvent, ether, water, and cyclohexane, followed by stirring at −10˜0 ° C. to form a precipitate; And (c) separating the precipitate obtained in step (b).

The starting material orlistat can be prepared according to conventional manufacturing methods, for example US Pat. No. 4,598,089 (and EP 129,748).

In the preparation method of the present invention, when the solvent of step (a) is heptane, the solvent of step (b) is methanol, ethanol, mixed solvent of ethanol and water, acetonitrile, acetonitrile and water mixing It may be selected from the group consisting of a solvent, acetone, a mixed solvent of acetone and water, ether, and cyclohexane. In addition, when the solvent of step (a) is methanol, the solvent of step (b) may be water. The mixed solvent of ethanol and water In the mixed solvent of acetone and water, their weight ratio is not particularly limited, for example, the ratio of water may be in the range of 1 to 50% by weight.

When orlistat is dissolved in heptane or C ₁ -C ₅ alcohol in step (a), it can be warmed to about 40 ° C. if necessary. However, when warmed for dissolution, the subsequent filtration process is preferably performed by cooling the warmed solution at room temperature (eg, 20-30 ° C., preferably about 25 ° C.).

The agitation of step (b) may be carried out at -10 to 0 ° C, more preferably at -6 to -3 ° C for 5 to 20 hours, more preferably for about 15 hours to form a precipitate.

The separation of step (c) can be carried out by a conventional method, for example by filtration, and the separated solid can be obtained by conventional drying method, for example by drying under reduced pressure, to obtain Orlistat Crystal Form III. Orlistat crystalline Form III obtained according to the preparation process of the present invention has a purity of at least 98%.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1

10 g of orlistat was dissolved in 200 mL of heptane and then filtered to remove crystal nuclei. 20 mL of ethanol was added to the filtrate, which was then cooled to -5 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to afford 7.0 g of orlistat crystalline Form III. The XRD pattern and DSC pattern of the obtained orlistat crystal form III are as shown in Figs.

Example 2

10 g of orlistat was dissolved in 250 mL of heptane and then filtered to remove nuclei. 20 mL of methanol was added to the filtrate, which was then cooled to -5 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 7.3 g of Orlistat crystalline Form III.

Example 3

10 g of orlistat was dissolved in 200 mL of heptane and then filtered to remove crystal nuclei. 10 mL of ethanol and 3 mL of water were added to the filtrate, which was then cooled to -6 to -3 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 7.6 g of orlistat crystalline Form III.

Example 4

5 g of orlistat was dissolved in 100 mL of heptane and then filtered to remove crystal nuclei. 10 mL of acetonitrile was added to the filtrate, which was then cooled to -5 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 2.8 g of Orlistat crystalline Form III.

Example 5

5 g of orlistat was dissolved in 100 mL of heptane and then filtered to remove crystal nuclei. 10 mL of acetone was added to the filtrate, which was then cooled to -6 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 3.1 g of orlistat crystalline Form III.

Example 6

5 g of orlistat was dissolved in 100 mL of heptane and then filtered to remove crystal nuclei. 15 mL of acetone and 3 mL of water were added to the filtrate, which was then cooled to -6 to -3 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 3.3 g of orlistat crystalline Form III.

Example 7

5 g of orlistat was dissolved in 100 mL of heptane and then filtered to remove crystal nuclei. 20 mL of ether was added to the filtrate, which was then cooled to -5 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 3.5 g of orlistat crystalline Form III.

Example 8

5 g of orlistat was dissolved in 70 mL of methanol, and then filtered to remove crystal nuclei. 14 mL of water was added to the filtrate, which was then cooled to -5 to -3 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 3.8 g of orlistat crystalline Form III.

Example 9

5 g of orlistat was dissolved in 50 mL of heptane and then filtered to remove crystal nuclei. 30 mL of cyclohexane was added to the filtrate, which was then cooled to -3 to 0 ° C and stirred at this temperature for 15 hours. The reaction mixture was filtered to give a precipitated solid which was dried under reduced pressure at about 25 ° C. for 16 hours to give 3.6 g of orlistat crystalline Form III.

1 shows the XRD pattern of orlistat crystalline Form III prepared according to the present invention.

2 shows the DSC pattern of orlistat crystalline Form III prepared according to the present invention.

Claims (7)

Orlistat Crystal Form III, having an XRD pattern with peaks at 5.5, 10.1, 11.0, 15.6, 17.0, 18.4, and 22.7 ° 2θ (± 0.2 °). The orlistat crystalline Form III of claim 1, having the XRD pattern shown in FIG. 1. The orlistat crystalline Form III according to claim 1 or 2, having a DSC melting endotherm at 42.4 ° C. Orlistat crystalline Form III according to claim 3, having the DSC pattern shown in FIG. comprising the steps of: (a) dissolving orlistat in heptane or a C ₁ ~C ₅ alcohol and filtered to remove a crystal nucleus; (b) To the filtrate obtained in step (a), a mixed solvent of C ₁ -C ₅ alcohol, C ₁ -C ₅ alcohol and water, acetonitrile, a mixed solvent of acetonitrile and water, acetone, acetone and water Adding a solvent selected from the group consisting of a mixed solvent, ether, water, and cyclohexane, followed by stirring at −10˜0 ° C. to form a precipitate; And (c) separating the precipitate obtained in step (b) Comprising, orlistat crystalline form III. The method of claim 5, wherein the solvent of step (a) is heptane, the solvent of step (b) is methanol, ethanol, mixed solvent of ethanol and water, acetonitrile, mixed solvent of acetonitrile and water, acetone , A mixed solvent of acetone and water, ether, and cyclohexane. A process according to claim 5, wherein the solvent of step (a) is methanol and the solvent of step (b) is water.

Images