CZ304027B6 - Process for preparing (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl[2,3-bicyclo[2.2.1]heptanedicarboxamide hydrochloride - Google Patents

Abstract

The present invention relates to a crystalline polymorphic form I of lurasidone hydrochloride of the general formula I, which exhibits the following peaks in the X-ray difractogram

Description

Technical field

The invention relates to a process for the preparation of polymorphs and the purification of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl 2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I.

(AND)

BACKGROUND OF THE INVENTION

The synthesis of the compound of formula I is described by Japanese authors (EP 0 464 846). This application describes the preparation of a compound of formula I as a free base of formula II,

which must be chromatographically purified before being converted to the hydrochloride of formula I by treatment with isopropanolic hydrogen chloride. In addition, an expensive dibenzo-18-crown-6-ether phase transfer catalyst must be used. This process is completely unsuitable from an industrial point of view, since chromatographic purification allows only small amounts of the substance to be prepared. In addition, the product obtained with the melting point of 215-217 ° C described above is in polymorphic form III (Fig. 3), which is difficult to handle and, in addition, the product does not achieve sufficient purity. In reproducing this procedure, the XRPD spectrum of this material, shown in Figure 3, was measured as polymorphic form III.

SUMMARY OF THE INVENTION

The present invention provides polymorphs I, II and III (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 -cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I with a maximum uniform impurity content of less than 0,1%. The preparation of a compound of formula I in a particular polymorphic form is important not only in terms of their physicochemical properties, but especially in terms of therapeutical, essential pharmacological and pharmacokinetic properties, in which polymorphic forms of the same substance may differ substantially and only significantly affect pharmacokinetic and clinical studies. . The physico-mechanical properties of the solid affect, for example, the flowability of the material during grinding. The ease with which the material flows during transport and grinding is very important for industrial processing. Another factor influenced by the crystallographic structure of the substance is the affinity for electrostatic charging. Again, this has a great effect on the ease of handling the material and can sometimes make it even practically impossible to grind the material. In some cases, an unsuitable polymorphic form can even cause a large volume concentration of dissipating energy released during grinding, which causes local thermal degradation of the material and thus deterioration of the drug. Solubility in aqueous solutions or storage stability are affected. Therefore, there is a need to look for suitable polymorphic forms.

These practical physical properties are due to the conformation and orientation of the molecules in the crystal lattice, which defines a certain polymorphic form of the substance. The polymorphic form has a different thermal behavior from the amorphous material or other polymorphic form. Thermal behavior is measured by various laboratory techniques such as: melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (XRPD), infrared spectroscopy 15 (IR).

The preparation process proposed by us allows the preparation of a compound of formula I in polymorphic form I (FIG. 1), which is very suitable for handling in terms of physical-mechanical properties. In addition, the process described provides a compound of formula I of high purity.

By appropriate pH adjustment to form the hydrochloride of formula I, polymorph form II was also obtained (Fig. 2).

The following data are characteristic of crystalline polymorphic form I: XRPD diffractogram (Fig. 1) with peaks 9, 11.6, 13, 17.5, 19, 20.8, 23, 25, 29.3 ± 0.2 degrees 2 theta. The DSC thermogram of FIG. 4 with an endothermic peak with a maximum at 177.9 ° C. M.p. 172-178 ° C.

The following data are characteristic of crystalline polymorphic form II: XRPD diffractogram (Fig. 2) peaks 9, 11.6, 13, 17.5, 20.8, 25, 29.3, 31.8 ± 0.2 degrees 2 theta . DSC thermogram (Fig. 5) with an endothermic peak of 183 ° C. Mp 181-183 ° C.

The crystalline polymorphic form III is characterized by the following data: XRPD diffractogram (Fig. 3) peaks 4.5, 9, 12, 14.5, 15.5, 17, 21, 24 ± 0.2 degrees 2 theta. DSC thermogram (Fig. 6) with endothermic peaks of 101.5, 216.7, 223.6 ° C. Mp 217-223 ° C.

The advantages of the method according to the invention are as follows:

Obtaining polymorphic forms of the compound of formula I;

• high crystallization yields and high purity of the substances;

· Simple insulation of fabrics.

Overview of the drawings

Giant. 1 - XRPD Diffractogram of polymorph form I FIG. 2 - XRPD Diffractogram of polymorph form II FIG. 3 - XRPD Diffractogram of polymorph form III FIG. 4 - DSC Thermogram of polymorph form I FIG. 5 - DSC Thermogram of polymorph form II

Giant. 6 - DSC Thermogram of polymorph form III

-2GB 304027 B6

DETAILED DESCRIPTION OF THE INVENTION

The essence of the process according to the invention is explained in more detail in the following examples. These examples are illustrative only and in no way limit the scope of the invention.

Example 1

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution with stirring. Then 0.9 ml of 20% hydrochloric acid was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.25 g (85%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. DSC - Fig. 4. Impurity content 0.17%.

Example 2

To 23 ml of acetone was added 2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1- piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride (containing 0.1-0.3% impurity), 3.6 mL of water and heated to reflux until complete dissolution. Subsequently, 0.041 g of activated carbon was added to the resulting solution and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of acetone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred at 0-5 ° C for 1 h and then filtered. The product on the filter was washed with 2 x 5 ml acetone and dried at 65-70 ° C in a hot air oven. 1.75 g (76% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1] were obtained. -piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. DSC - Fig. 4. Impurity content 0.04%.

Example 3

2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are added to 23 ml of diethyl ketone with stirring. 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride (containing 0.1-0.3% impurity), 3.6 mL of water and heated to reflux. 0.041 g of activated carbon are then added and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of diethyl ketone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred at 0-5 ° C for 1 h and then filtered. The product on the filter was washed with 2 x 5 ml diethyl ketone and dried at 65-70 ° C in a hot air oven. 1.6 g (69% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) 2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. Mp 175-178 ° C. DSC - Fig. 4. Impurity content 0.07%.

Example 4

To 23 ml of 2-butanone was added 2.3 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) - 1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride (with an impurity content of 0.1 to 0.3%), 3.6 ml of water and heated to reflux.

-3GB 304027 B6

0.041 g of activated carbon are then added and refluxed for a further 5 minutes. It is then filtered while hot, the filter cake is washed with 3.5 ml of 2-butanone and the filtrate is added to the original filtrate. The combined filtrates were cooled to 0-5 ° C with stirring. The resulting suspension was stirred at 0-5 ° C for 1 h and then filtered. The product on the filter was washed with 2 x 5 ml 2-butanone and dried at 65-70 ° C in a hot air oven. 1.55 g (67% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4 (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. Mp 175-178 ° C. DSC - Fig. 4. Impurity content 0.08%.

Example 5

To 1 ml of methanol was added with stirring 0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1- piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboxiimide hydrochloride, 2.1 ml water and the mixture was heated to reflux until complete dissolution. Then, the resulting solution is cooled to 20-25 ° C with stirring. The suspension was stirred at 20-25 ° C for 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. There was obtained 0.182 g (73% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] - 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] 20 heptanedicarboximide hydrochloride form I (Figure 1) as a white crystalline powder. DSC - Fig. 4.

Example 6

To 1 ml of ethanol was added with stirring 0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1- piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, water (2.1 ml) was added and cooled to 20-25 ° C with stirring. The suspension was stirred at 20-25 ° C for 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.2 g (80% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) 2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. T.T = 176-177 ° C, DSC - Fig. 4.

Example 7

To 1 ml of n-propanol is added 0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) - 1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarbox40 hydrochloride imide and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, water (2.1 ml) was added and cooled to 20-25 ° C with stirring. The suspension was stirred at 20-25 ° C for 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.21 g (84% crystallization) of (1R, 2S, 3R, 4S) -N [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. 1-Cyclohexylmethyl] -2,345 bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. T.T = 174-177 ° C, DSC - Fig. 4.

Example 8

To 1 ml of 2-propanol was added with stirring 0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) - 1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride and heated to reflux with stirring. The resulting solution was cooled to 30-35 ° C, water (2.1 ml) was added and cooled to 20-25 ° C with stirring. The suspension was stirred at 20-25 ° C for 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65

-4GB 304027 B6 to 70 ° C in a hot air oven. 0.21 g (84% crystallization) of (1R, 2S, 3R, 4S) -N [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] was obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. T.T = 174-177 ° C, DSC - Fig. 4.

Example 9

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution with stirring. Then 0.8 ml of 20% hydrochloric acid was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. There was obtained 2.28 g (86% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] - 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. DSC - Fig. 4. Impurity content 0.22%.

Example 10

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution with stirring. Thereafter, 1.5 ml of 20% hydrochloric acid was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.18 g (82% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] - 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. T.T = 172-174 ° C, DSC - Fig. 4. Impurity content 0.18%.

Example 11

0.25 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] is added to 1 ml of acetic acid with stirring. 1-Cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride and heated to reflux with stirring. To the solution was added 10 ml of water and cooled to 20-25 ° C with stirring. The resulting suspension was stirred at 20-25 ° C for 5 minutes and then filtered. The product on the filter is washed with 2 ml of water and dried at 65-70 ° C in a hot air oven. 0.165 g (66% crystallization) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] - was obtained. 1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. M.p. = 173-174 ° C, DSC - Figure 4.

Example 12

K 0.53 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide was added 6.6 ml of 2-butanone and the mixture was heated to reflux until complete dissolution. 1 ml of 20% hydrochloric acid is then added to the solution and refluxed for 20 minutes. The resulting emulsion was cooled to 0-5 ° C with stirring and stirred at 0-5 ° C for 1 hour. It is then filtered, the product on the filter is washed twice with 1 ml of 2-butanone and dried at 65-70 ° C in a hot-air oven. 0.2 g (32%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1] - was obtained. piperazinylmethyl] -1,5C 304027 B6 cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride form I (Figure 1) as a white crystalline powder. T.T = 173.5-179 ° C, DSC - Fig. 4. Impurity content 0.02%.

Example 13

K 0.85 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-Bicyclo [2.2.1] heptanedicarboximide was added under stirring with 15 ml of toluene and 1 ml of a solution of hydrogen chloride in 2-propanol was added at 20-25 ° C. The resulting mixture was heated to 65-70 ° C and stirred at this temperature for 10 minutes. The resulting suspension was cooled to 20-25 ° C with stirring and stirred at 20-25 ° C for 1 hour. It is then filtered, the product on the filter is washed with 2 x 1 ml of toluene and dried at 65-70 ° C in a hot-air oven. 0.71 g (77%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride form III (Figure 3), as a white crystalline powder. M.p. = 217-223 ° C, DSC - Figure 6.

Example 14

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-Bicyclo [2.2.1] heptanedicarboximide is added with 10 ml of ethanol and the mixture is heated under reflux until complete dissolution. 0.5 ml of 36% hydrochloric acid is then added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 30-40 ° C with stirring and a total of 25 mL of water was slowly added. The resulting suspension was cooled to 20-25 ° C, 10 mL water was added and stirred at 20-25 ° C for 30 minutes. It is then filtered, the product on the filter is washed twice with 1 ml of water and dried at 65-70 ° C in a hot-air oven. 2.33 g (88%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1) as a white crystalline powder. T.T = 174-177 ° C, DSC - Fig. 4. Impurity content 0.38%.

Example 15

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution with stirring. Thereafter, 0.8 ml of 20% hydrochloric acid was added to the resulting solution to obtain a pH of 1-2. The reaction mixture was neutralized with 10% aqueous sodium hydroxide to pH 6-7 and refluxed for a further 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed twice with 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 1.92 g (73%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] are obtained. -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form II (Figure 2) as a white crystalline powder TT = 181-183 ° C, DSC - Figure 5. Impurity content 0.12 %.

Example 16

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution. Thereafter, 0.9 ml of an 8-14% aqueous hydrochloric acid solution was added to the solution and refluxed for 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed twice with 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. There was obtained 2.25 g (85%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1- 6EN 304027 B6 piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride Form I (Figure 1), as a white crystalline powder, impurity 0.15%.

Example 17

2.6 g of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide is added with 20 ml of acetone and the mixture is heated to reflux until complete dissolution with stirring. Thereafter, 0.9 ml of a 15 to 35% aqueous hydrochloric acid solution was added to the solution and refluxed for a further 20 minutes. The resulting suspension was cooled to 18-20 ° C with stirring and stirred at 18-20 ° C for 1 hour. It is then filtered, the product on the filter is washed twice with 5 ml of acetone and dried at 65-70 ° C in a hot-air oven. 2.29 g (87%) of (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1 was obtained. -cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride form I (Figure 1), as a white crystalline powder. Impurity content 0.25%.

Claims (13)

PATENT CLAIMS Crystalline polymorph I (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2 3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I, characterized in that its XRPD X-ray diffraction pattern has peaks of 9, 11.6, 13, 17.5, 19.20, 8, 23, 25, 29.3 ± 0 , 2 degrees 2Theta. (') 2. Crystalline polymorph I (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2 3-Bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I according to claim 1, characterized in that its DSC thermogram shows an endothermic peak with a maximum at 177.9 ° C. A process for preparing crystalline polymorph I (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of the formula I according to claims 1 and 2, characterized in that it is performed by crystallization of crude (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2 - [4- (1,2-Benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I from polar organic solvents mixed with water. A process for preparing crystalline polymorph I (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of the formula I according to claim 3, characterized in that the maximum uniform impurity content is less than 0.1%. -7EN 304027 B6 5. Method according to claim 3 or 4, characterized in that the polar solvent used are aliphatic ketones, C ₃ - C _5. The method according to claim 5, characterized in that aliphatic ketones are used 5 acetone, diethylketone or butanone. Method according to claim 6, characterized in that acetone is preferably used. Process according to claims 3 and 4, characterized in that C 1 -C ₃ aliphatic alcohols are used as the polar solvent. Process according to claim 8, characterized in that methanol, ethanol, propan-1-ol or propan-2-ol are used as C 1 -C ₃ aliphatic alcohols. 15 Dec Process according to claim 9, characterized in that methanol is preferably used. Process according to Claim 9, characterized in that ethanol is preferably used. Process according to Claims 3 and 4, characterized in that the polar solvent is: 20 will use acetic acid. A process for preparing crystalline polymorph I (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1- cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide hydrochloride of formula I according to claim 3, characterized in that the crude 25 (1R, 2S, 3R, 4S) -N - [(1R, 2R) -2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3- bicyclo [2.2.1] heptanedicarboximide hydrochloride is obtained by treatment of a solution of hydrogen chloride in propan-2-ol with a toluene solution of the crude base (1R, 2S, 3R, 4S) -N [(1R, 2R) -2- [4- {1,2] -benzisothiazol-3-yl) -1-piperazinylmethyl] -1-cyclohexylmethyl] -2,3-bicyclo [2.2.1] heptanedicarboximide of formula II.