CZ304602B6 - Crystallization process of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine hydrochloride) - Google Patents

Abstract

The invented crystallization process of duloxetine hydrochloride of the general formula I is characterized in that a duloxetine hydrochloride suspension comprised is mixed in a mixture of an aprotic solvent, being selected from the group consisting of esters or ketones, and a protic solvent at a boil temperature of the solvent mixture for a period of 0.5 to 1 hour and subsequently it is cooled down during 1 hour to a temperature in the range of from about 30 to about 40 degC and is mixed at this temperature for a period of at least 1 hour. The crystalline duloxetine hydrochloride is characterized in that at least 65 percent of crystals have elongation parameter value within the range of 1 to 2 or at least 85 percent of crystals have the elongation parameter value within the range of 1 to 3. The duloxetine hydrochloride is further characterized in that its apparent density is greater than 0.25 g/cme3, its percentile value d(0.9) is at least 80 microns, its percentile value d(0.5) is at least 30 microns, and its percentile value d(0.1) is at least 10 microns.

Description

Technical field

The present invention relates to a novel process for the preparation of a crystalline form having defined physical parameters of (N, N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride, known by the generic name duloxetine hydrochloride of formula I.

Duloxetine is an inhibitor of serotonin and noradrenaline reuptake, has therapeutic use in the field of depression and urinary incontinence.

The preparation of duloxetine and its intermediates is described, for example, in patents EP 0 273 658, US 5 362 886, WO 2004/005239, US 2003/0225153. The basic preparation procedure used is shown in Scheme 1 below.

Scheme 1

The preparation of Compound I is described in Example 2 (Preparation 2) of U.S. Patent No. 5,362,886. The final product is formed by treating concentrated duloxetine base in ethyl acetate with concentrated hydrochloric acid. The seed crystal of compound I was added to the acidified reaction mixture, and the mixture was diluted with additional ethyl acetate. After stirring for 30 minutes, the mixture was again concentrated to the original volume, then stirred at room temperature for 1 hour and at 0 ° C for 1 hour.

The preparation of compound I is also described in Example 4 of WO 2005/108386. Treatment of duloxetine base in acetone with 20% HCl in 2-propanol yields crystalline hydrochloride, i.e. substance I.

However, in reproducing these processes, it has been shown that the duloxetine hydrochloride obtained contains impurities, in particular the 3-isomer of formula II,

- 1 GB 304602 B6

further, the opposite (R) enantiomer, and the substance thus prepared is additionally colored beige. Another disadvantage is the physical properties of the material prepared in this way, which makes its technological processing difficult. Duloxetine hydrochloride usually crystallizes in the form of small needles, causing difficulties in mixing the crystallization mixture and subsequent filtration. In the final treatment, ie sieving, a very airy material is created, which is very difficult to handle.

Thus, it is evident that the preparation of duloxetine hydrochloride with the quality required for pharmaceutical purposes requires additional adjustment of the physicochemical properties.

WO 2006/099468 describes the purification of duloxetine hydrochloride by crystallization in water and in a mixture of organic solvents and water. The preferred volume ratio of organic solvent to water is in the range 97: 3 to 98.25: 1.75. In the most preferred embodiment of the crystallization, where duloxetine hydrochloride is dissolved at reflux tenfold of acetone / water (acetic water = 49: 1 ratio, Examples 1c and 1d) and crystals precipitate upon cooling, yields of 80% and 100%, respectively. 73%. With higher water content (Examples 2a, 2b), the crystallization yield decreases to 68%, respectively. up to just 36%. In this embodiment, although it is possible to prepare duloxetine hydrochloride with a low impurity content, relatively large losses of mass occur. This patent does not disclose the physical properties of the prepared duloxetine hydrochloride.

For pharmaceutical purposes, the bulk density (see Czech Pharmacopoeia 2002, Chapter 2.9.15) is one of the important variables characterizing the physical properties of all solid materials, including the active substance. The bulk density, as with liquids, is defined as the weight of the material stored in a defined volume (g / cm ³ ). Normally the bulk density is measured by pouring the substance into a cylinder of defined volume and determining the bulk density using the formula:

Bulk density = substance weight (g) / volume (cm ³ )

For example, if a 20 g substance occupies a volume of 100 cm ³ , its bulk density is 0.20 g / cm ³ .

The 'fluffy', often electrostatically readily chargeable material, which is difficult to pour, exhibits low bulk density values, i.e. less than about 0.25 g / cm ³ . Another parameter is the particle size distribution, which defines the relative amount of particles present in the sample depending on their size. The particle size distribution can be determined, for example, by laser diffraction using commercially available instruments (eg, Malvem Matersizer 2000). In this case, the particle size is expressed by the diameter of the equivalent sphere, which is a theoretical sphere of the same volume as the analyzed particle. When comparing the particle size distribution of different samples, it is preferable to follow the percentile values d (0.1), d (0.5) and d (0.9). These percentiles indicate that 10, 50, and 90% of the particles are less than the percentiles.

The crystal shape is closely related to the bulk density and particle size distribution. The material made up of tiny needles or rods, which are often bundled into bundles, exhibits inappropriate properties such as low bulk density and difficult flowability. The appearance of crystals can be observed by conventional optical microscope and their shape and size can be described by morphological parameters of image analysis. The surface crystallizes with a parameter related to both shape and particle size. In the calibrated image, this parameter expresses the actual projection area of the particle. The crystal shape is well characterized by the morphological elongation parameter, which is defined as the ratio of the maximum and minimum Feret projection. Maximum resp. the minimum Feret diameter is

-2GB 304602 B6 maximum resp. minimum distance between two parallel lines attached to the measured particle. The larger the elongation parameter value, the more elongated the particles. The cube or spherical particle has an elongation parameter close to 1. The elongation parameter has a relatively large value for needle-like particles.

These characteristics are directly related to the overall properties of the material, which are important for handling during the entire manufacturing process, such as filtration rate, drying, hourglass, formulation, etc.

The available literature does not address the preparation of duloxetine hydrochloride with advantageous physical properties for the technology of its preparation as well as for the subsequent formulation, ie preparation of the dosage form.

The present invention describes a solution for the preparation of duloxetine hydrochloride with a minimum content of impurities in high yield and at the same time with physical properties, such as bulk density and crystal size and shape, suitable for use in pharmaceutical production.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of the crystalline form of (S) - N -methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride, known by the generic name duloxetine hydrochloride of formula I,

having advantageous physicochemical properties.

EP 775879 (ZENTIVA) discloses the crystallization of duloxetine hydrochloride from ethyl methyl ketone in Example 7 without giving details. WO 2006/099468 describes the crystallization of duloxetine hydrochloride by dissolving it at boiling point and subsequently cooling it in a mixture of organic solvent and water, with a water content of at least 1.75%. A preferred solvent is acetone and water or 2-propanol.

We have encountered the following issues while reproducing these procedures. Due to the low solubility of duloxetine hydrochloride in ethyl methyl ketone, it is necessary to use a high excess of solvent, which is disadvantageous both in terms of utilization of production capacities and in economic terms. A small addition of water (on the order of a few percent) dramatically increases the solubility of duloxetine hydrochloride in organic solvents. In a conventional crystallization, the substance dissolves hot in a mixture of a less polar aprotic solvent (eg acetone) and a more polar protic solvent (eg water) at an elevated temperature (usually boiling) and the crystals precipitate upon cooling the solution (see examples) disclosed in WO 2006/099468), however, there is a significant yield loss for duloxetine hydrochloride. When cooling the crystallization mixture, duloxetine hydrochloride is also excreted in the form of thin long fibers or. needles, so that the crystallization mixture is very difficult to stir and consequently the filtration and washing times of the filter cake are also increased. After drying, the material obtained is difficult to cross-link, and the final product is then very fine with a low bulk density (typically about 0.2 g / cm ³ ).

-3GB 304602 B6

We have surprisingly found that by recrystallizing duloxetine hydrochloride at an elevated temperature in a suitable solvent or solvent, the crystallization of duloxetine hydrochloride is increased. the solvent mixture produces relatively large, well-settling and also well-filterable crystals. At the same time, chemical purity is also increasing. During this process, therefore, the physical properties of crystals isolation (filtration and sieving rate), the purity of the material obtained and, last but not least, its properties (crystal size and shape, bulk density, particle distribution, flowability, etc.) are improved. ).

The bulk density of duloxetine hydrochloride prepared by known methods is typically in the range of 0.18 to 0.25 g / cm ³ . Duloxetine hydrochloride prepared according to the crystallization process described herein typically reaches values of 0.30 to 0.40 g / cm ³ . The bulk density of the material is related to the particle size and shape of the material.

An example of the particle size distribution (measured on a Malvem Matersizer 2000) of duloxetine hydrochloride prepared according to known procedures is shown in Figs. 1. Examples of particle size distribution according to the process of recrystallized duloxetine hydrochloride according to the invention are shown in FIG. 2 and 3. It can be seen from these figures that the recrystallization of duloxetine hydrochloride described herein significantly changes the particle size distribution percentiles d (0.5) and d (0.9). Duloxetine hydrochloride prepared according to known procedures (Fig. 1) has a d (0.5) = 19 pm and d (0.9) = 59 pm, i.e. it contains 50% of particles larger than 19 pm and 10% of particles larger than 59 pm . On the other hand, the recrystallized duloxetine hydrochloride according to the invention (Figs. 2 and 3, respectively) achieves d (0.5) = 73 pm and d (0.9) = 174 pm, i.e. 50% of the particles are greater than 72 pm and % of the particles is greater than 174 µm resp. d (0.5) - 47 µm and d (0.9) - 129 µm, i.e. 50% of the particles are larger than 47 µm and 10% of the particles are larger than 129 µm. Thus, the recrystallization described herein can produce duloxetine hydrochloride with a significantly larger proportion of relatively large particles.

When measuring the projection area of the crystals, we found that duloxetine hydrochloride prepared according to the previously described procedures reaches a value of approximately 90 pm ² , whereas duloxetine hydrochloride prepared according to the new procedure achieves a value more than double (see Fig. 4 compared to Figures 5 and 6) . In addition to the particle size, the shape of the crystallization is suitably performed by crystallization, as evidenced by photographs (Figs. 4, 5 and 6) as well as morphological elongation parameters (see Figs. 3 and 4). Duloxetine hydrochloride prepared according to known methods contains a relatively large proportion of rod-shaped particles. With such a material (Fig. 7), only 33% of the particles have an elongation parameter in the interval of 1 to 2. In contrast, the particles according to the invention recrystallized duloxetine hydrochloride are smooth and transparent platelet-shaped (Figs. 5 and 6). Their elongation parameter (Figures 8 and 9) is for 74% of the particles in the interval of 1 to 2. Thus, the particles of recrystallized duloxetine hydrochloride according to the invention are significantly less elongated than duloxetine hydrochloride particles prepared according to the prior art.

Solvents used for crystallization can generally be divided into protic, which contain an OH group in their chemical structure, and aprotic. Common protic solvents include water and alcohols such as methanol, ethanol, 2-propanol and the like. Duloxetine hydrochloride dissolves very well in aprotic solvents and mixtures thereof. Conversely, duloxetine hydrochloride is poorly soluble in aprotic solvents such as ketones (e.g. acetone, ethylmethylketone) or esters (e.g. ethyl acetate) and virtually insoluble is duloxetine hydrochloride in hydrocarbons (e.g. heptane) or ethers (e.g. diethyl ether, tert-butyl methyl ether) ).

Suitable solvents for the recrystallization of duloxetine hydrochloride are, in particular, relatively less polar ketones C3-6 and / or C3-6. C3-6 esters, such as acetone, ethylmethylketone, ethyl acetate, in admixture with protic solvents such as water, methanol, ethanol or 2-propanol. Suitably, the content of the more polar solvent in the solvent mixture is from about 50% to 0% by volume, and may preferably decrease from higher to zero during recrystallization. The water content during the crystallization is in the range of 1.70% by volume to 0% by volume.

-4GB 304602 B6

The reduction of the protic solvent content of the mixture can be achieved by the following methods:

(a) an aprotic solvent is added to the mixture, (b) a protic solvent is distilled from the mixture, (c) a protic solvent is distilled from the mixture, and an aprotic solvent is added.

Crystallization can be carried out either by heating the suspension of duloxetine hydrochloride in the solvent mixture, adjusting the ratio thereof and then cooling, or preparing the solution of duloxetine hydrochloride hot in the solvent mixture, adjusting their ratio and then cooling. The size and shape of the duloxetine hydrochloride crystals depend on the mixing time as well as the temperature. A suitable stirring time of the suspension is in the range of about 0.5 hour to 24 hours, preferably 1 hour to 6 hours. When the duloxetine hydrochloride solution is cooled to below 35 ° C, the substance tends to crystallize in relatively small crystals, respectively. clusters of smaller crystals. Thus, a suitable crystallization temperature is in the range of about 30 ° C to 120 ° C, most preferably from 40 ° C to the boiling point of the solvent or the solvent. solvent mixtures. A preferred embodiment of the recrystallization of the duloxetine hydrochloride suspension consists in stirring the mixture at the boiling point of the solvent or the solvent. boiling the solvent mixture for 0.5 hour to 1 hour, then cooling to 30 to 40 ° C and stirring the mixture.

Thus, suitably performed crystallization can significantly change the size and shape of the duloxetine hydrochloride crystals, resulting in a change in the physical properties of the material obtained. These physical properties can be characterized by various methods, eg determination of bulk density, particle distribution, elongation parameter, etc. Physical properties have a fundamental influence on processes used both in the preparation of duloxetine hydrochloride (eg filtration or drying rate) and in drug preparation. forms (e.g., overfilling, granulating, direct tabletting, homogenizing or mixing with excipients).

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives to the preparation of duloxetine hydrochloride according to the invention, are illustrative only and do not limit the scope of the invention in any way.

Overview of the drawings

Giant. 1: Particle size distribution of crystalline duloxetine hydrochloride prepared according to Example 2 (previously known procedure).

Giant. 2: Particle size distribution of crystalline duloxetine hydrochloride prepared according to Example 3.

Giant. 3: Particle size distribution of crystalline duloxetine hydrochloride prepared according to Example 6.

Giant. 4: Crystalline duloxetine hydrochloride prepared according to Example 2 (previously known procedure).

Giant. 5: Crystalline duloxetine hydrochloride prepared according to Example 3.

Giant. 6: Crystalline duloxetine hydrochloride prepared according to Example 6.

Giant. 7: Elongation of crystalline duloxetine hydrochloride particles prepared according to Example 2 (previously known procedure).

Giant. 8: Elongation of crystalline duloxetine hydrochloride particles prepared according to Example 3. FIG. 9: Elongation of crystalline duloxetine hydrochloride particles prepared according to Example 6.

-5GB 304602 B6

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (previously described procedure)

Preparation of (S) -N-methyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (duloxetine) hydrochloride

To a solution of (N, N -methyl-3- (naphthyloxy) -3- (2-thienyl) propanamine (311 g) in toluene (1200 mL) was added diisopropylethylamine (210 mL) followed by phenylchloroformate (150 mL) at 60 ° C. After stirring at 80 ° C for two hours, the mixture is cooled, shaken with dilute hydrochloric acid solution, water and 2% sodium bicarbonate solution, the organic phase is dried over sodium sulphate and evaporated and the residue is dissolved in dimethylsulfoxide (300 ml) and refluxed. After 5 hours at 60 ° C, the mixture was diluted with water (1000 mL) and the duloxetine base was extracted into tert-butyl methyl ether (300 mL), diluted with ethyl methyl ketone (butanone) and cooled to 0 ° C. The pH was adjusted by dropwise addition of conc. Hydrochloric acid to a value of about 5. The precipitated, slightly brownish crystals were then aspirated to yield crude duloxetine hydrochloride 183 g (55%), mp 167-169 ° C.

Bulk density 0.18 g / cm ³ .

d (0.5) = 22 pm and d (0.9) = 65 pm.

Particle content with elongation parameter in the interval 1 to 2: 29%.

Example 2 (previously described procedure)

Recrystallization of (S) - N, N -dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (duloxetine hydrochloride)

A suspension of duloxetine hydrochloride (183 g) in ethyl methyl ketone (1100 mL) was refluxed for 1 hour. The mixture was then cooled to 10 ° C and filtered. Yield 178 g (97%), m.p. Mp 169-171 ° C.

Bulk density 0.20 g / cm ³ .

d (0.5) = 19 pm and d (0.9) = 59 pm.

Particle content with elongation parameter in the interval 1 to 2: 33%.

Example 3

Recrystallization of (iHH / N-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine hydrochloride (duloxetine hydrochloride)

Duloxetine hydrochloride (160 g) was stirred in 500 mL of ethyl methyl ketone and poured into 8.5 mL of water. The mixture is heated to boiling and the suspension is refluxed for 30 minutes. Then, 300 ml of MEK (butanone) was added dropwise at reflux for 30 minutes. After the dropwise addition, the suspension was cooled to 35 ° C over 1 hour and stirred for 1 hour. The crystals are filtered off with suction, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield 144 g (90%), m.p. 170.5-171.5 ° C.

Bulk density 0,31 g / cm ³ .

d (0.5) = 72 pm and d (0.9) = 174 pm.

Particle content with elongation parameter between 1 and 2: 74%.

-6GB 304602 B6

Example 4

Recrystallization of (S) - N, N -dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (duloxetine hydrochloride)

Duloxetine hydrochloride (160 g) was stirred in 750 ml of ethyl methyl ketone and 75 ml of methanol, and the mixture was heated to boiling. 150 ml (methanol / ethyl methylketone azeotropic mixture) is then distilled off over 30 minutes and then 150 ml of ethyl methyl ketone is added dropwise. The suspension was cooled to 30 ° C over 1 hour and stirred at 30 ° C for 1 hour. The crystals are filtered off with suction, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield 146 g (90%), m.p. 170.5-171.5 ° C.

Bulk density 0,32 g / cm ³ .

d (0.5) = 38 pm and d (0.9) = 94 pm.

Particle content with elongation parameter in the interval 1 to 2: 71%.

Example 5

Recrystallization of (S) - N, N -dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (duloxetine hydrochloride)

Duloxetine hydrochloride (160 g) was stirred in 1200 ml of ethyl methyl ketone and poured into 19 ml of water. Then 300 ml (azeotropic water / ethyl methyl ketone mixture) was distilled off over 1 hour. The suspension is cooled to 30 ° C over 1 hour and stirred for 1 hour. The crystals are filtered off with suction, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield 144 g (90%), m.p. 170.5-171.5 ° C.

Bulk density 0,31 g / cm ³ .

d (0.5) = 51 pm and d (0.9) = 112 pm.

Particle content with elongation parameter in the interval 1 to 2: 72%.

Example 6

Recrystallization of (N) - N, N -dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (duloxetine hydrochloride) hydrochloride

Duloxetine hydrochloride (160 g) was stirred in 750 ml of ethyl methyl ketone and 75 ml of methanol, and the mixture was heated to boiling. 150 ml (methanol / ethyl methyl ketone azeotropic mixture) are then distilled off over 60 minutes while 150 ml of ethyl methyl ketone is added dropwise. The suspension was cooled to 30 ° C over 1 hour and stirred at 30 ° C for 1 hour. The crystals are filtered off with suction, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield 146 g (90%), m.p. 170.5-171.5 ° C.

Bulk density 0,38 g / cm ³ .

d (0.5) = 47 pm and d (0.9) = 129 pm.

Particle content with elongation parameter in the interval 1 to 2: 75%.

The bulk density was determined by pouring the substance freely (without shaking) into a 100 cm ³ volumetric cylinder and determining its weight.

-7EN 304602 B6

The particle size distribution was determined by wet laser diffraction under the following conditions:

Apparatus

Measurement parameters:

Sample preparation unit Indirect fracture Absorption Dispersant

Refractive index of dispersant

Model

Sensitivity

Time of sample and background measurement

Zástin

Mixing

Ultrasound

Delay before measurement

Malvern Mastersizer 2000

Hydro 2000S

1.63

0.01

0.1% lecithin in hexane solution 1.38

General purpose Enhanced p

5-15%

2100 RPM (rpm) before measurement, 30 s at 100% min

The average of 20 measurements is considered as the result of the analysis.

The area and crystal elongation parameters were obtained from micrographs of samples using NIS - Elements image analysis software.

Claims (22)

PATENT CLAIMS Crystalline duloxetine hydrochloride, characterized in that at least 65% of the crystals have an elongation parameter value in the interval of 1 to 2 or at least 85% of the crystals have an elongation parameter value in the interval of 1 to 3, NIS Elements. Crystalline duloxetine hydrochloride according to claim 1, characterized in that its bulk density is greater than 0.25 g / cm ³ . Crystalline duloxetine hydrochloride according to claim 1 or 2, characterized in that its bulk density is in the range of 0.30 to 0.40 g / cm ³ . Crystalline duloxetine hydrochloride according to claims 1 to 3, characterized in that it has a percentile value of d (0.9), obtained by measuring by laser laser diffraction in a 0.1% solution of lecithin in hexane at 2100 rpm after 30 s sonication to 100% delayed measurement start time of 3 min using Malvern MasterSizer 2000, at least 80 µm. Crystalline duloxetine hydrochloride according to claim 4, characterized in that it has a percentile value d (0.9), obtained by laser diffraction measurement, in the range of 90 to 190 µm. -8EN 304602 B6 Crystalline duloxetine hydrochloride according to claims 1 to 3, characterized in that it has a percentile value d (0.5), obtained by measuring by laser laser diffraction on a wet path in a 0.1% lecithin in hexane solution at a speed of 2100 rpm for 3 axis sonication. to 100% with a 3-minute delay on the start of measurement using a Malvem MasterSizer 2000, at least 30 pm. Crystalline duloxetine hydrochloride according to claim 6, characterized in that it has a percentile value d (0.5), obtained by laser diffraction measurement, in the range of 35 to 80 µm. Crystalline duloxetine hydrochloride according to claims 1 to 3, characterized in that it reaches the percentile d (0,1) obtained by measuring by laser laser diffraction on a wet path in a 0.1% lecithin / hexane solution at 2100 rpm after 3 axis sonication. to 100% with a 3 min delay on the start of measurement using a Malvem MasterSizer 2000, at least 10 pm. The crystalline duloxetine hydrochloride of claim 8, characterized in that it has a percentile value d (0.1), obtained by laser diffraction measurement, in the range of 10 to 30 µm. Crystalline duloxetine hydrochloride according to claims at least 10% of crystals larger than 90 µm. Crystalline duloxetine hydrochloride according to claims at least 33% of crystals larger than 50 µm. Crystalline duloxetine hydrochloride according to claims at least 90% of crystals larger than 10 µm. up to 3 characterized by containing up to 3 characterized by containing up to 3 characterized by containing up to 3 characterized by containing The crystalline duloxetine hydrochloride of claim 1 crystals with an average surface area greater than 150 µm ² . Crystalline duloxetine hydrochloride according to claims 1 to 13, characterized in that it comprises smooth transparent crystals. Process for the production of crystalline (3O) -N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine hydrochloride, i.e. duloxetine hydrochloride of the formula I according to claims 1 to 14, characterized in that duloxetine the hydrochloride crystallizes from a mixture of an aprotic solvent selected from the group consisting of a ketone and a C 3 -C 6 ester, an aprotic solvent, wherein the crystallization consists in stirring the mixture at boiling point for 0.5 to 1 hour and subsequently cooling the mixture to a temperature of 30 to 40 ° C and stirring at this temperature for at least 1 hour. 16. The process of claim 15 wherein the aprotic solvent is ethyl acetate, acetone or ethyl methyl ketone (2-butanone) and the protic solvent is water, methanol, ethanol or 2-propanol. -9EN 304602 B6 A process according to any one of claims 15 and 16, characterized in that the protic solvent is water and has a content of from 1.70% to 0% by volume during crystallization. Process according to any one of claims 15 and 16, characterized in that the protic solvent is methanol, ethanol or 2-propanol and the content of the protic solvent during the crystallization is in the range from 50% to 0% by volume. The process according to claims 15 to 18, characterized in that the volume ratio of the aprotic and protic solvent is adjusted during the crystallization by successive addition of the aprotic solvent. Process according to Claims 15 to 19, characterized in that the content of the protic solvent during the crystallization is reduced by gradually distilling off the protic solvent or by distilling off the protic solvent. azeotropic solvent mixtures. Process according to Claims 15 to 20, characterized in that the content of the protic solvent during the crystallization is reduced by gradually distilling off the protic solvent or by distilling off the protic solvent. an azeotropic solvent mixture, and at the same time adding an aprotic solvent. 22. A pharmaceutical composition comprising the crystalline duloxetine hydrochloride of claims 1 to 14 and other pharmaceutically acceptable excipients.