SI21746A - Crystal forms of olanzapine and processes for their preparation - Google Patents

Abstract

The invention relates to a novel and well defined solvate form of olanzapine which is characterized by the x-ray structure in Figure 1 and by the NMR spectra in Figure 2 and which contains 2 molecules of water and one molecule of isopropanol per 2 molecules of olanzapine. The olanzapine used as a starting material for the preparation of the described olanzapine water-isopropanol mixed solvate can be in any form, e.g. it can be used when it is contained in reaction solution, crude, in filtrate when various solvents are present, or in anhydrous or any solvated form. In the prefered embodiment the herein prepared and described olanzapine water-isopropanol mixed solvate is used for the preparation of form I of olanzapine.

Description

The present invention relates to the field of organic chemistry and relates to a new mixed solvate form of 2-methyl-4- (4-methyl-1-piperazinyl) -1077-thieno [2,3-Z>] [1,5] benzodiazepine (in hereinafter referred to as its generic name olanzapine) to a process for its preparation and a process for the preparation of polymorphic form I of olanzapine.

Olanzapine has been shown to have high activity for the central nervous system and is also useful for the treatment of schizophrenia and related disorders, acute mania, mild anxiety and psychosis.

TECHNICAL PROBLEM

In the prior art, solvents such as methylene chloride and acetonitrile are used to crystallize form I olanzapine, but these often do not lead to satisfactory total yields of form I olanzapine. In addition, these prior art procedures often do not lead to olanzapine having a purity satisfactory for the preparation of pharmaceutical formulations because impurities that are difficult to remove by prior art are present.

In addition, there is still a need for an improved process for the preparation of purified olanzapine, to avoid the above disadvantages and to obtain olanzapine with a purity that would make it very suitable for the preparation of pharmaceutical formulations.

Furthermore, there is a need for precursors that would allow the easy preparation of olanzapine polymorphic forms or conversion to other forms of olanzapine.

These problems are solved by the present invention.

BACKGROUND OF THE INVENTION

British Patent GB 1 533 235 describes antipsychotically effective thienobenzodiazepines with a generic formula also covering olanzapine.

US Patent 5,229,382 explicitly describes olanzapine. The process described for its synthesis further includes crystallization from acetonitrile, the crystallized form having a melting point at 195 ° C.

EP-B-733 635 requires protection for crystalline form II of olanzapine, and this polymorphic form is said to be more stable than material obtained in accordance with US 5,229,382, which is called form I of olanzapine. Both Form I and Form II of olanzapine are determined e.g. with X-ray data. The preparation of the more stable form II of olanzapine is carried out by dissolving olanzapine of technical quality in ethyl acetate and crystallizing from the resulting solution by any conventional method such as grafting, cooling, scraping the reaction vessels or other conventional techniques.

WO 02/18390 describes monohydrate form I and dihydrate form I of olanzapine, a process for their preparation and a process for preparing form I of olanzapine, comprising the steps of: mixing olanzapine monohydrate or crude olanzapine or form II olanzapine in methylene chloride, refluxing, cooling and drying. It is also described that repeating the process described in US 5,229,382, example 1, sub-example 4 does not lead to the formation of form I olanzapine.

WO 03/101997 relates to processes for the preparation of form I olanzapine by adjusting the pH of the solution.

WO 03/055438 describes crystallization from ethanol and then conversion of an ethanol solvate to polymorphic form I of olanzapine.

US Patent 5,637,584 describes the (mono) methylene chloride solvate form of olanzapine and the process for its conversion to polymorphic form I of olanzapine.

EP-B-733 634 relates to three specific olanzapine solvates, namely methanolic, ethanol and 1-propanol solvates, and a process for the preparation of form II olanzapine by drying the corresponding solvate.

WO 03/097650 describes two new mixed solvate forms, mixed water / methylene chloride and water / DMSO solvate, processes for preparing them and converting them to polymorph I.

WO 04/006933 A2 describes the preparation of Form I preparation, certain pseudopolymorphic forms, namely isopropanol solvate, acetonitrile / methylene chloride / aqueous mixed solvate, and acetonitrile / aqueous mixed solvate of olanzapine, polymorphic Form A, and processes for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an ORTEP view of an asymmetric unit Ci7H2oN ₄ SH ₂ 0.1 / 2 (C3H70H). It should be emphasized that in FIG. 1 population of disordered isopropanol molecule 0.50.

FIG. 2 shows the NMR spectrum of C ₇ H ₂ oN ₄ SH ₂ 0.1 / 2 (C ₃ H ₇ OH).

MAIN CONTENT OF THE INVENTION

The present invention relates to a new and well-defined solvate form of olanzapine, characterized by the X-ray structure of FIG. 1 and with the NMR spectrum of FIG. 2 containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine. This isopropanol / aqueous mixed olanzapine solvate is prepared from an isopropanol / water solvent mixture.

The solvent mixture comprises isopropanol and water in a ratio of 9-35 parts by volume of isopropanol per 1 volume of water. Preferably this ratio is 9: 1, more preferably 20: 1 and most preferably 35: 1.

Olanzapine used as starting material may be in any form, e.g. it may be in the reaction solution, in the raw form, in the filtrate, in the anhydrous, solvated or hydrated form or in the form of mixtures thereof.

It has been unexpectedly found that the preparation of the isopropanol / aqueous mixed solvate of olanzapine can be easily performed if olanzapine is crystallized using a solvent mixture comprising isopropanol and water. In this way, the persistent impurities are removed from the active compound and olanzapine can also be recovered from the filtrates.

The process for preparing Form I olanzapine typically involves dissolving the isopropanol / aqueous mixed solvate of olanzapine in a solvent mixture comprising methylene chloride and then crystallizing and recovering the product by conventional methods. Using the above crystallization conditions, it is possible to isolate form I olanzapine from the isopropanol / aqueous mixed solvate form olanzapine with yields, purity and quality, all of which are improved in comparison with the prior art.

Form I olanzapine is quite difficult to prepare in a substantially pure form, because the formation of thermodynamically more stable Form II is preferred. According to the process of the present invention, it can be prepared in substantially pure Form I without Form II and solvates.

The preferred embodiments of the process are described below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a new and well-defined solvate form of olanzapine, characterized by the X-ray structure of FIG. 1 and with the NMR spectrum of FIG. 2 and containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine.

X-ray diffraction data for a single crystal were collected at room temperature on a Nonius Kappa CCD diffractometer using Nonius Collect software. The structure was resolved using SIR97 (direct procedures), and purification was performed using X'tal software.

Crystallographic data for isopropanol / aqueous mixed solvate of olanzapine, especially the interplaname distances (a, b, c) and angles (α, β, γ), are shown in Table 1.

Table 1

space group C2 / c (No 15) a 2,455 nm b 1,251 nm c 1,531 nm a 90 ° β 125.3 ° γ 90 ° R 0,059

NMR data were obtained on a Varian UNITY + 300 (300 MHz) spectrometer in CDCI3 with tetramethylsilane as an internal standard.

¹ H NMR (CDCI3, 300 MHz) signal determination:

chemical shift δ_determination

1.20 (3H, d)

2.30 (3H, s)

2.34 (3H, s) 2.20-2.40 (2H, br s) 2.49 (4H, m)

3.52 (4H, m)

4.03 (0.5 H, dq) 5.02 (H, broad s) 6.29 (H, broad s) 6.29-7.05 (4H, m)

CH ₃ -isopropanol

4'-CH ₃

2- CH3 H-water 3'-CH ₂ 2'-CH ₂

CH-isopropanol

10-NH

3- CH 6,7, 8, 9-H

Olanzapine used as starting material for the preparation of the described isopropanol / aqueous mixed solvate of olanzapine may be in any form, e.g. it can be used if it is contained in the reaction solution, in the crude form, in the filtrate with various solvents present, or in anhydrous or any solvated or hydrated form or in a mixture thereof.

In a preferred embodiment, isopropanol / aqueous mixed solvate of olanzapine prepared and described in accordance with the present invention is used to prepare high-purity form I olanzapine or any other solvated, hydrated or anhydrous form of olanzapine.

When the isopropanol / aqueous mixed solvate of olanzapine described here is prepared from the reaction mixture, the mixture of 4-amino-2-methyl-10H-thieno [2,3-b] [1,5] benzodiazepine hydrochloride and 1-methylpiperazine is heated in solvents with high boiling point, such as dimethylsulfoxide and toluene or mixtures thereof, preferably at reflux, until the reaction is complete, preferably from 3 hours to 12 hours. The solution is cooled, preferably to temperatures in the range of 90 ° C to room temperature, and optionally distilled off, preferably under vacuum, at temperatures in the range of room temperature to 90 ° C, preferably at 50 ° C to 90 ° C.

Isopropanol and water, or a mixture thereof, are subsequently added later in any order to the resulting solution, which is partially partially distilled off, preferably under vacuum. In a preferred embodiment, isopropanol is added first and then water is added to initiate crystallization.

The clear solution was cooled to temperatures from boiling point to 10 ° C and water was added to initiate crystallization. The product was then filtered off, washed with isopropanol, dried at room temperature under vacuum to constant weight, to give isopropanol / aqueous mixed olanzapine solvate.

When the isopropanol / aqueous mixed olanzapine solvate described herein is prepared from olanzapine in mother liquors containing e.g. methylene chloride, or when prepared from methylene chloride solvate form, the solvent is optionally distilled off, and isopropanol and water, or a mixture thereof, subsequently optionally distilled into the resulting solution, which is partially distilled off, preferably under vacuum, subsequently and in any order. In a preferred embodiment, isopropanol and then water are added first to initiate crystallization as above. When the crystallization is complete, the precipitate is filtered off and dried.

Olanzapine, used as a starting material for the preparation of the described isopropanol / aqueous mixed solvate of olanzapine, may also be crude olanzapine or olanzapine in anhydrous or any solvated or hydrated form or in the form of mixtures thereof. Olanzapine is dissolved by heating in isopropanol and water, which are added subsequently and in any order, or in a mixture thereof. If olanzapine is dissolved in water, isopropanol is added later, and if olanzapine is dissolved in isopropanol first, water is added later. Both solvents can also be added at a later time and in any order.

The clear solution was cooled to temperatures from boiling point to 10 ° C and water was added to initiate crystallization. The product was then filtered off, washed with isopropanol, dried at room temperature under vacuum to constant weight to give isopropanol / aqueous mixed olanzapine solvate.

The described isopropanol / aqueous mixed olanzapine solvate, prepared by any of the foregoing methods, is of high quality and substantially free of impurities and can thus be used to prepare various other solvates, hydrates or mixtures thereof.

After crystallization is complete, the precipitate is filtered off and dried. The isopropanol / aqueous mixed olanzapine solvate obtained can be optionally recrystallized.

During the process of crystallization or precipitation in any embodiment of the invention, the disodium salt of ethylenediaminotetraacetic acid is optionally added and, after stirring, the dissolved material is filtered hot.

To prepare Form I, the isopropanol / aqueous mixed solvate of olanzapine, prepared by any of the above methods, is then suspended in methylene chloride and heated until a clear solution is obtained. After obtaining a clear solution, the solvent portion is evaporated in vacuo or optionally at atmospheric pressure or in combination with the fly at temperatures ranging from the boiling point of the solution to -20 ° C to isolate the olanzapine methylene chloride solvate.

In another preferred embodiment, the isopropanol / aqueous mixed solvate of olanzapine is suspended in methylene chloride and heated to 35 ° C to a clear solution, and a drying agent, preferably drierite (anhydrous CaSO3, is added).

Vaccination with higher amounts of crystalline methylene chloride solvate is optional.

To the olanzapine methylene chloride solvate, isopropanol in w / v was added. a ratio of 2 to 5, preferably 2 to 3, and the suspension is stirred at a temperature of 15 ° C to 35 ° C, especially at room temperature from 15 minutes to 90 minutes, preferably from 30 minutes to 60 minutes. Optional polymorphic form I vaccination is used. The methylene chloride solvate is optionally suspended in olanzapine-supersaturated isopropanol with w / v. with a ratio of from 2 to 30, preferably from 3 to 15, and the suspension is stirred at a temperature of 5 ° C to 50 ° C, especially at room temperature from 15 min to 90 min, preferably from 30 min to 60 min. The product was filtered off and dried under vacuum at room temperature to constant weight, then at 50 ° C to constant weight. Form I olanzapine is isolated.

Methods known in the art can also be used to prepare the Form I isopropanol / aqueous mixed solvate of olanzapine described herein.

The present invention is illustrated by the following Examples without being limited thereto.

Preparation of isopropanol / aqueous mixed solvate of olanzapine

Example 1

A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (120 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 200 ml of the distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 25 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 22.84 g. Loss on drying (140 ° C): 13.6%. Water content (KF): 5.12%.

Example 2

A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (36 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 80 ml of distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 35 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 21.98 g. Loss on drying (140 ° C): 13.2%. Water content (KF): 5.09%. Isopropanol (GC) test: 8.55%.

Example 3

A mixture of 4-amino-2-methyl-10 N -thieno [2,3-b] [1,5] benzodiazepine hydrochloride (26.6 g), 1methylpiperazine (92 ml), dimethyl sulfoxide (36 ml) and toluene (120 ml) is heated at reflux for 4 hours. The solution was cooled to 95 ° C and distilled 120 ml of the distillate under vacuum. The residue was cooled to room temperature, isopropanol (180 ml) was added, the solution was further cooled to 0 ° C and water (36 ml) was added to initiate crystallization. After crystallization was complete, the precipitate was filtered off and washed with isopropanol (20 ml). The wet product was suspended in isopropanol (200 ml) and heated to reflux to give a clear solution. The disodium salt of ethylene diaminotetraacetic acid (3 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 35 ° C and water (6 ml) was added to initiate crystallization. The suspension was cooled to 0 ° C, and after crystallization was complete, it was filtered off and washed with isopropanol (10 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 24.35 g. Loss on drying (140 ° C): 13.5%. Water content (KF): 5.05%.

Example 4

Anhydrous olanzapine (10 g) was suspended in isopropanol (108 ml) and heated to reflux to give a clear solution. Cool the solution slowly. Water (6 ml) was added at 57 ° C to initiate crystallization. The suspension was cooled to 0 ° C and, after crystallization, was filtered off and washed with isopropanol (5 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 10.97 g. Loss on drying (140 ° C): 13.3%. Water content (KF): 5.13%.

Example 5

Olanzapine obtained from mother liquors (60 g) was suspended in isopropanol (650 ml) and heated to reflux to give a clear solution. Ethylenediaminotetraacetic acid disodium salt (7.9 g) was added and the suspension stirred for 1 hour. The undissolved material is hot filtered. The clear solution was cooled to 25 ° C and water (16 ml) was added to initiate crystallization.

The suspension was cooled to 0 ° C, after crystallization was complete, filtered off and washed with isopropanol (50 ml). The product was dried at room temperature under vacuum to constant weight. Yield: 57.64 g. Loss on drying (140 ° C): 13.5%. Water content (KF): 5.26%.

Preparation of the methylene chloride solvate of olanzapine

Example 6

The isopropanol / aqueous mixed solvate of olanzapine (lig) was suspended in methylene chloride (132 ml) and heated to give a clear solution. Distill off with 66 ml of solvent. A further 16 ml of methylene chloride was added and distilled off. The mixture was filtered hot and concentrated under vacuum to a volume of 36 ml. During vacuum distillation, the solution is cooled and the product precipitated. The product was filtered off and dried under vacuum at room temperature to constant weight. Yield: 8.47 g. Loss on drying (140 ° C): 12.7%. Water content (KF): 0.40%.

Example 7

The isopropanol / aqueous mixed solvate of olanzapine (30 g) was suspended in methylene chloride (330 ml) and heated to 35 ° C to give a clear solution. Add drierite (anhydrous CaSO ₄ , 45 g) and stir for 1 hour. The suspension was hot filtered and concentrated under vacuum to a volume of 100 ml. During vacuum distillation, the solution is cooled and the product precipitated. The product was filtered off and dried under vacuum at room temperature to constant weight. Yield: 21.31 g. Loss on drying (140 ° C): 11.3%. Water content (KF): 0.51%.

Preparation of form I olanzapine

Example 8

The olanzapine methylene chloride solvate (10 g) was suspended in isopropanol (20 ml). The suspension was stirred at room temperature for 1 hour. The product was filtered off and dried under vacuum at room temperature to constant mass and then at 50 ° C to constant mass. Yield: 7.8 g.

Example 9

The olanzapine methylene chloride solvate (10 g) was suspended in isopropanol (150 ml, pre-saturated solution with olanzapine). The suspension was stirred at room temperature for 1 hour. The product was filtered off and dried under vacuum at room temperature to constant mass and then at 50 ° C to constant mass. Yield: 14.3 g.

Claims (8)

Patent claims An isopropanol / aqueous mixed solvate of olanzapine containing 2 molecules of water and 1 molecule of isopropanol per 2 molecules of olanzapine. 2. The isopropanol / aqueous mixed olanzapine solvate determined by the X-ray structure of FIG. 1. 3. The isopropanol / aqueous mixed solvate of olanzapine, determined by the NMR spectrum of FIG. 2. 4. Isopropanol / aqueous mixed solvate of olanzapine, determined by the NMR spectrum in CDCI3 and containing signals at about 1.20 ppm, 2.20-2.40 ppm and 4.03 ppm. 5. A process for the preparation of an isopropanol / aqueous mixed solvate of olanzapine according to claim 1, characterized in that the solvent mixture contains isopropanol and water in a ratio of 9 to 35 parts by volume of isopropanol per 1 volume of water, preferably a ratio of 9: 1, more preferably 20 : 1 and most preferably 35: 1. Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of form I olanzapine. Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of any other solvate, hydrated forms of olanzapine or mixtures thereof. Use of the isopropanol / aqueous mixed solvate of olanzapine according to claim 1 for the preparation of anhydrous forms of olanzapine.