WO2011026449A1

WO2011026449A1 - A method of crystallization of (s)-n-methyl-3-(1-naphthyloxy)-3- (2-thienyl)propylamine hydrochloride (duloxetine)

Info

Publication number: WO2011026449A1
Application number: PCT/CZ2010/000099
Authority: WO
Inventors: Ludek Ridvan; Josef Cinibulk; Veronika Grunwaldova; Hana Brusova
Original assignee: Zentiva, K.S.
Priority date: 2009-09-02
Filing date: 2010-09-02
Publication date: 2011-03-10
Also published as: CZ304602B6; IL218329A0; CZ2009584A3; ZA201201570B; KR20120047262A; JP2013503823A; MX2012002621A; EA021528B1; EA201290127A1; BR112012004862A2; CN102482254A; EP2473497A1

Abstract

(S)-N-Methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride of formula (I) is crystallized in such a way that suspension of duloxetine in a mixture of an aprotic solvent and a protic solvent is stirred at an increased temperature under simultaneous reduction of the volume proportion of the protic solvent.

Description

A METHOD OF CRYSTALLIZATION OF (S)-N-METHYL-3-(l-NAPHTHYLOXY)-3- (2-THIENYL)PROPYL AMINE HYDROCHLORIDE (DULOXETINE)

Technical Field

The invention deals with a new method of preparation of a crystalline form with defined physical parameters of (5)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine

hydrochloride, known under the generic name duloxetine, of formula I.

Background Art

Duloxetine is an inhibitor of serotonin and noradrenaline reuptake and is therapeutically used in the sphere of depression and urinary incontinence.

Preparation of duloxetine and its intermediates is described e.g. in the patents nos. EP

0,273,658, US 5,362,886, WO 2004/005239, US 2003/0225153. The principal preparation procedure used is shown in Scheme 1 below.

Scheme 1 Preparation of substance I is described in Example 2 (Preparation 2) of US patent 5,362,886. The final product is obtained by the action of concentrated hydrochloric acid on a solution of duloxetine base in ethyl acetate. To the acidified reaction mixture an inoculation crystal of substance I is added and the mixture is diluted with more ethyl acetate, after stirring for 30 minutes the mixture is concentrated to the original volume, followed by stirring for 1 hour at the laboratory temperature for 1 hour and at the temperature of 0°C for 1 hour.

Preparation of substance I is also described in Example 4 of WO 2005/108386. By the effect of 20% HC1 in 2-propanol on a solution of duloxetine base in acetone crystalline

hydrochloride, i.e. substance I, is obtained.

However, in a reproduction of these procedures it has shown that the obtained duloxetine contains impurities, especially the 3 -isomer of formula II

as well as the opposite (7?)-enantiomer, and the substance obtained this way also exhibits beige colouring. Another disadvantage consists in physical characteristics of material prepared this way that make its technological processing difficult. Duloxetine usually crystallizes in the form of small needles, which causes trouble during stirring of the crystallization mixture and subsequent filtration. During the final treatment, i.e. e.g. sieving, very airy material is produced that is very difficult to handle.

So it is obvious that preparation of duloxetine with a quality necessary for pharmaceutical purposes requires additional treatment of physical and chemical characteristics.

Authors of patent application no. WO 2006/099468 describe purification of duloxetine by crystallization in water and in a mixture of organic solvents and water. A convenient volume proportion of the organic solvent and water is declared to be in the range of from 97:3 to 98.25: 1.75. With the most preferred embodiment of crystallization, where duloxetine is dissolved under reflux in ten times the amount of the acetone/water mixture (acetone : water proportion = 49: 1, Examples lc and Id) and after cooling crystals are separated, the authors mention the yield of 80% and 73%, respectively. With a higher content of water (Examples 2a, 2b) the crystallization yield drops to 68% and to only 36%, resp.. With this embodiment duloxetine with a low content of impurities can be prepared; however, high losses of mass occur. This patent does not mention physical characteristics of the prepared duloxetine.

For pharmaceutical purposes one of important quantities characterizing physical properties of all solid materials, i.e. of the active substance as well, is apparent density (see Czech

Pharmacopoeia 2002, chapter 2.9.15). Apparent density is, similarly to liquids, defined as the weight of material occupying a certain volume (g/cm³). Apparent density is commonly measured in such a way that the material is poured into a cylinder with a defined volume and apparent density is determined using the following formula:

Apparent density = material weight (g) / volume (cm³)

If e.g. a substance weighing 20 g occupies the volume of 100 cm³, its apparent density is 0.20 g/cm³.

"Fluffy", often electrostatically easily chargeable material that is difficult to pour exhibits low apparent density values, i.e. lower than roughly 0.25 g/cm³. Another parameter is the particle size distribution, which defines the relative quantity of particles present in a sample depending on their size. Particle size distribution can e.g. be determined with laser diffraction using commercially available devices (e.g. Malvern Master seizer 2000). In this case the particle size is expressed by means of the diameter of the equivalent sphere, which is a theoretical sphere of the same volume as the analyzed particle. In the comparison of the particle size distributions of various samples it is convenient to monitor the values of the percentiles d(0.1), d(0.5) and d(0.9). These percentiles express that 10, 50 and 90 % of particles are smaller than the value of the percentile.

The shape of crystals is closely related to apparent density and particle size distribution. The material consisting of tiny needles or sticks, which are often united in bundles, exhibits inconvenient characteristics as low apparent density and difficult pouring properties. The appearance of crystals can be observed with a common optical microscope and their shape and size can be described with morphological parameters of pattern analysis. The crystal area is a parameter related both to the shape and the size of the particle. This parameter expresses the actual area of the particle projection in a calibrated image. The shape of the crystal well characterizes the morpho logical parameters of elongation, which is defined as a ratio of the maximum and minimum Feret's diameters. The maximum and minimum Feret's diameters are the maximum and minimum distances, resp., between two parallels applied to the measured particle. The higher the value of the elongation parameter is, the more elongated the particles are. For particles having the shape of a cube or sphere the value of the elongation parameter approximates 1. In the case of needle-like particles the value of the elongation parameter is relatively high.

These characteristic quantities are directly related to general properties of the material, which are important for handling during the whole production process, such as the speed of filtration, drying, pouring, preparation of the dosage form, etc. Available literature does not describe preparation of duloxetine with convenient physical characteristics for the technology of preparation thereof as well as for subsequent formulation, i.e. preparation of the dosage form.

This invention describes a method of preparation of duloxetine with a minimum content of impurities in a high yield and at the same time with physical characteristics, such as apparent weight, and size and shape of crystals, advantageous for use in pharmaceutical production.

Disclosure of Invention

The essence of the invention comprises a method for the preparation of a crystalline form of (5)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride, known under the generic name duloxetine, of formula I,

with convenient physical and chemical characteristics.

EP patent 1 758 879 patent (ZENTIVA) describes, in Example 7, crystallization of duloxetine from ethyl methyl ketone without mentioning any details. WO 2006/099468 describes crystallization of duloxetine by dissolution thereof under boiling and subsequent cooling in a mixture of an organic solvent and water where the content of water is at least 1.75%. A preferred solvent is acetone and water or 2-propanol. In reproducing these procedures we encountered the following problems. Due to low solubility of duloxetine in ethyl methyl ketone a high excess of the solvent must be used, which is inconvenient both in terms of productive capacity utilization and of economy. A small addition of water (in the order of a few per cent) dramatically increases solubility of duloxetine in organic solvents. However, in the case of carrying out the crystallization in the usual way, where the substance is dissolved while hot in a mixture of a less polar aprotic solvent (e.g. acetone) and a more polar protic solvent (e.g. water) at an increased temperature (usually under boiling) and crystals precipitate after cooling of the solution (see the examples mentioned in WO 2006/099468) considerable yield losses occur in the case of duloxetine. In addition, on cooling of the crystallization mixture duloxetine precipitates in the form of long fibres or needles, so that the crystallization mixture is very difficult to stir and the time of filtration and washing of the filter cake get consequently longer. After drying, sieving of the obtained material is difficult and the final product is very fine with a low apparent density (typically about 0.2 g/cm³). We have surprisingly found out that during recrystallization of duloxetine at an increased temperature in a suitable solvent or a mixture of solvents relatively large crystals showing good sedimentation and good filtration capability are produced. At the same time, the chemical purity is improved. This means that during this process physical characteristics are improved, which is manifested during the isolation of crystals (filtration and sieving rates), in the purity of the obtained material and last, but not least, in its properties (size and shape of crystals, apparent density, distribution of particles, pouring characteristics, etc.). Apparent density of duloxetine prepared by known methods typically varies in the range of 0.18 to 0.25 g/cm³. Duloxetine prepared in accordance with the crystallization procedure described herein typically achieves values of 0.30 to 0.40 g/cm³. Apparent density of the material is related to the size and shape of particles of the particular material.

An example of particle size distribution (measured in the Malvern Mastersizer 2000 device) of duloxetine prepared in accordance with known methods is shown in Fig. 1. Examples of particle size distribution of recrystallized duloxetine are shown in Figs. 2 and 3. These figures illustrate that with the use of the duloxetine recrystallization method described herein the values of percentiles d(0.5) and d(0.9) of particle size distribution considerably change.

Duloxetine prepared in accordance with known procedures (Fig. 1) exhibits the values d(0.5) = 19 μιη and d(0.9) = 59 μιη, i.e. it contains 50% of particles larger than 19 μηι and 10% of particles larger than 59 μιη. On the other hand, recrystallized duloxetine (Fig. 2 or 3, respectively) achieves the values d(0.5) = 73 μιτι and d(0.9) = 174 μπι, i.e. 50% of particles are larger than 72 μπι and 10% of particles are larger than 174 μπι, and d(0.5 ) = 47 μηι and d(0.9) = 129 μιη, i.e. 50 % of particles are larger than 47 μπι and 10 % of particles are larger than 129 μιτι, respectively. This means that using the recrystallization described herein duloxetine with a considerably higher proportion of relatively large particles can be prepared. When measuring the projection area of crystals we have found out that duloxetine prepared in accordance with the formerly described procedures achieves the values of up to about 90 μιη , while duloxetine prepared in accordance with the new procedure achieves a value that is more than twice as high (see Fig. 4 as compared to Figs. 5 and 6). Besides the size of particles, suitably performed recrystallization also influences their shape, which is documented by photographs (Figs. 4, 5 and 6) as well as the morphological parameters of elongation (see Figs. 3 and 4). Duloxetine prepared in accordance with known procedures contains a relatively high proportion of stick-shaped particles. In such material (Fig. 7) 33% of particles only have the elongation parameter within the interval of 1 to 2. On the other hand, particles of recrystallized duloxetine are smooth and transparent, of a lamellar shape (Figs. 5 and 6). Their elongation parameter (Figs. 8 and 9) is within the interval of 1-2 for 74% of particles. Accordingly, the particles of recrystallized duloxetine exhibit considerably smaller elongation than duloxetine particles obtained by prior art methods. The solvents used for crystallization can be generally divided into protic solvents, which contain the OH group in their chemical structure, and aprotic solvents. Common protic solvents include water and alcohols, such as methanol, ethanol, 2-propanol, etc. Duloxetine dissolves very well in protic solvents and their mixtures. On the other hand, duloxetine is poorly soluble in aprotic solvents such as ketones (e.g. acetone, ethyl methyl ketone), or esters (e.g. ethyl acetate) and duloxetine is virtually insoluble in hydrocarbons (e.g. heptane), or ethers (e.g. diethyl ether, tert-butyl methyl ether).

Suitable solvents for recrystallization of duloxetine include, above all, relatively less polar C3- 6 ketones or C3-6 esters, such as acetone, ethyl methyl ketone, ethyl acetate, in mixtures with protic solvents, such as water, methanol, ethanol or 2-propanol. A suitable content of the more polar solvent in the mixture of solvents is roughly from 50% by vol. to 0% by vol. and may conveniently decrease during the crystallization from higher values to zero. In the course of the crystallization the water content varies in the range from 1.70% by vol. to 0% by vol. Reduction of the content of the protic solvent in the mixture can be achieved in the following ways:

(a) by adding an aprotic solvent to the mixture,

(b) by removing the protic solvent from the mixture by distillation,

(c) by removing the protic solvent by distillation and adding an aprotic solvent.

The crystallization can be carried out either by heating a suspension of duloxetine in a mixture of solvents, adjusting their proportions and subsequent cooling, or by preparing a duloxetine solution in a hot mixture of solvents, adjusting their proportions and subsequent cooling. The size and shape of duloxetine crystals depends on the stirring time as well as on the

temperature. A suitable stirring time of the suspension is in the range of from about 0.5 hour to 24 hours, most preferably from 1 hour to 6 hours. When the duloxetine solution is cooled below 35 °C the substance tends to crystallize in relatively small crystals or clusters of smaller crystals. Accordingly, a suitable temperature for crystallization is in the range of about 30 °C to 120 °C, most preferably from 40 °C to the boiling point of the solvent or mixture of solvents. A preferable embodiment of recrystallization of duloxetine suspension consists in stirring of the mixture at the boiling temperature of the solvent or the boiling temperature of the mixture of solvents for 0.5 to 1 hour, followed by cooling to 30 to 40 °C and stirring of the mixture. It is therefore possible to significantly change the size and shape of duloxetine crystals by means of suitably performed crystallization, which results in a change of physical properties of the obtained material. These physical properties can be characterized by various methods, e.g. by determining the apparent density, distribution of particles, the elongation parameter, etc. Physical properties have a principal influence both on processes used within the preparation of duloxetine (e.g. filtration or drying speeds) and on processes used in the preparation of the dosage form (e.g. pouring of the material, granulation, direct compression, homogenization, or mixing with auxiliary substances).

The invention is explained in a more detailed way with the use of the examples below. These examples, which illustrate preferred alternatives of the preparation of duloxetine according to the invention, have an exclusively illustrative character and do not limit the range of the invention in any respect.

Brief Description of Drawings:

Fig. 1 : Particle size distribution of crystalline duloxetine prepared according to Example 2 (prior method)

Fig. 2: Particle size distribution of crystalline duloxetine prepared according to Example 3 Fig. 3: Particle size distribution of crystalline duloxetine prepared according to Example 6 Fig. 4: Crystalline duloxetine prepared according to Example 2 (prior method)

Fig. 5: Crystalline duloxetine prepared according to Example 3

Fig. 6: Crystalline duloxetine prepared according to Example 6

Fig. 7: Elongation of particles of crystalline duloxetine prepared according to Example 2 (prior method)

Fig. 8: Elongation of particles of crystalline duloxetine prepared according to Example 3 Fig. 9: Elongation of particles of crystalline duloxetine prepared according to Example 6 Examples

Example 1 (prior method)

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

(duloxetine)

To a solution of (S)-NN-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)-propanamine (31 1 g) in toluene (1200 ml) diisopropylethylamine (210 ml) is added, folloed by addition of phenyl chloroformate (150 ml) at 60°C. After two hours of stirring at 80 °C the mixture is cooled, shaken with a diluted solution of hydrochloric acid, water and 2% solution of sodium hydrogen carbonate. The organic phase is dried with sodium sulphate and evaporated. The evaporation residue is dissolved in dimethyl sulfoxide (300 ml) and a 5M solution of potassium hydroxide (400 ml) is added dropwise under reflux. After two hours at 60°C the mixture is diluted with water (1000 ml) and duloxetine base is extracted with tert-butyl methyl ether (300 ml). The solution is diluted with ethyl methyl ketone (butanone) and cooled to 0 °C. Then, pH is adjusted to the value of about 5 by dropwise addition of concentrated hydrochloric acid. Then the precipitated lightly brownish crystals are aspirated. The yield of crude duloxetine is 183 g (55%), m.p. 167-169 °C.

Apparent density 0.18 g/cm³.

d(0.5) = 22 μπι and d(0.9) = 65 μπι.

Content of particles having the elongation parameter in the interval 1-2: 29%.

Example 2 (prior method)

Recrystallization of (5)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine

hydrochloride (duloxetine)

A suspension of duloxetine (183 g) in ethyl methyl ketone (1 100 ml) is refluxed for 1 hour.

The mixture is then cooled to 10 °C and filtered. Yield: 178 g (97%), m.p. 169-171 °C.

Apparent density 0.20 g/cm³.

d(0.5) = 19 μτη and d(0.9) = 59 μπι.

Content of particles having the elongation parameter in the interval 1-2: 33%. Example 3

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

hydrochloride (duloxetine)

Duloxetine (160 g) is stirred up in 500 ml of ethyl methyl ketone and 8.5 ml of water are added. The mixture is heated to boil and the suspension is refluxed for 30 minutes. Then, 300 ml of MEK (butanone) are added dropwise under reflux during 30 minutes. After the addition the suspension is cooled to 35 °C during 1 hour and stirred for 1 hour. The crystals are aspirated, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield: 144 g (90%), m.p. 170.5-171.5 °C.

Apparent density 0.31 g/cm³.

d(0.5) = 72 μιη and d(0,9) = 174 μτη.

Content of particles having the elongation parameter in the interval 1-2: 74%.

Example 4

Recrystallization of (5)-N_^V-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine

hydrochloride (duloxetine)

Duloxetine (160 g) is stirred up in 750 ml of ethyl methyl ketone and 75 ml of methanol and the mixture is heated to boil. Then, 150 ml (azeotropic mixture of methanol / ethyl methyl ketone) are removed by distillation during 30 minutes and subsequently 150 ml of ethyl methyl ketone are added dropwise. The suspension is cooled to 30 °C during 1 hour and stirred at this temperature for 1 hour. The crystals are aspirated, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield: 146 g (90%), m.p. 170.5-171.5 "C.

Apparent density 0.32 g/cm³.

d(0.5) = 38 μιη and d(0.9) = 94 μπι.

Content of particles having the elongation parameter in the interval 1-2: 71 %.

Example 5

Recrystallization of (5)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine

hydrochloride (duloxetine)

Duloxetine (160 g) is stirred up in 1200 ml of ethyl methyl ketone and 19 ml of water are added. Then, 300 ml (azeotropic mixture of water / ethyl methyl ketone) are removed by distillation during one hour. The suspension is cooled to 30 °C during one hour and stirred for 1 hour. The crystals are aspirated, washed with ethyl methyl ketone and tert-butyl methyl ether. Yield: 144 g (90%), m.p. 170.5-171.5 °C.

Apparent density 0.31 g/cm³.

d(0.5) = 51 μπι and d(0,9) = 112 μιη.

Content of particles having the elongation parameter in the interval 1-2: 72%.

Example 6

Recrystallization of (5)-N,N-dimethyl-3 -(naphthyloxy)-3 -(2-thienyl)propylamine

hydrochloride (duloxetine)

Duloxetine (160 g) is stirred up in 750 ml of ethyl methyl ketone and 75 ml of ethanol and the mixture is heated to boil. Then, 150 ml (azeotropic mixture of methanol / ethyl methyl ketone) are removed by distillation during 60 minutes and at the same time 150 ml of ethyl methyl ketone are added dropwise. The suspension is cooled to 30 °C during 1 hour and stirred at this temperature for 1 hour. The crystals are aspirated, washed with ethyl methyl ketone and tert- butyl methyl ether. Yield: 146 g (90%), m.p.: 170.5-171.5 °C.

Apparent density 0.38 g/cm³.

d(0.5) = 47 /xm and d(0,9) = 129 /an.

Content of particles having the elongation parameter in the interval 1-2: 75%.

The apparent density was determined in such a way that the substance was freely poured (without shaking) into a graduated cylinder with the volume of 100 cm³ and its weight was determined.

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

Device Malvern Master seizer 2000

Measurement parameters:

Sample preparation unit Hydro 2000S

Refraction index of particles 1.63

Absorption 0.01

0.1 % solution of lecithin in

Dispersant hexane

Refraction index of the dispersant Model General purpose

Sensitivity Enhanced

Measurement time of the sample

and background 15 s

Dark field 5 - 15 %

Mixing 2100 RPM

before measurement, 30 s at

Ultrasound 100 %

Delay before measurement 3 min

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

The parameters of area and elongation of crystals were obtained from photomicrographs of the samples by means of the NIS - Elements pattern analysis software.

Claims

C L A I M S

1. A method for the preparation of crystalline (<S)-N-methyl-3-(l-naphthyloxy)-3-(2- thienyl)propylamine hydroxide, i.e. duloxetine of formula I,

characterized in that duloxetine is crystallized from a mixture of an aprotic solvent and a protic solvent.

2. The method according to claim 1, characterized in that ethyl acetate, acetone or ethyl methyl ketone (2-butanone) is used as the aprotic solvent and water, methanol, ethanol or 2-propanol is used as the protic solvent.

3. The method according to any one of claims 1 to 2, characterized in that the

crystallization is carried out at a temperature in the range from 30 °C to the boiling point of the mixture of solvents.

4. The method according to any one of claims 1 to 3, characterized in that the content of water during the crystallization ranges from 1.70% by vol. to 0% by vol.

5. The method according to any one of claims 1 to 3, characterized in that the content of methanol, ethanol or 2-propanol in the course of crystallization ranges from 50% by vol. to 0% by vol.

6. The method according to any one of claims 1 to 5, characterized in that the volume ratio of the aprotic and protic solvents is adjusted by gradual addition of the aprotic solvent during the crystallization.

7. The method according to any one of claims 1 to 5, characterized in that the content of the protic solvent, i.e. of water, methanol, ethanol or 2-propanol, is reduced during crystallization by gradual removal of the protic solvent or of an azeotropic mixture of the solvents containing water, methanol, ethanol or 2-propanol by distillation.

8. The method according to any one of claims 1 to 5, characterized in that the content of the protic solvent, i.e. of water, methanol, ethanol or 2-propanol, is reduced during crystallization by gradual removal of the protic solvent or of an azeotropic mixture of the solvents containing water, methanol, ethanol or 2-propanol by distillation and simultaneous addition of the aprotic solvent.

9. The method according to any of claims 1 to 8, characterized in that the suspension after crystallization of duloxetine is cooled to 20 to 40°C and duloxetine is removed by filtration.

10. Crystalline duloxetine, characterized in that its apparent density is higher than 0.25 g/cm³.

11. Crystalline duloxetine, characterized in that its apparent density is in the range of 0.30 to 0.40 g/cm³.

12. Crystalline duloxetine, characterized in that it contains smooth transparent crystals.

13. Crystalline duloxetine, characterized in that it has the value of d(0.9) percentile,

measured by laser diffraction, of at least 80 μιη.

14. Crystalline duloxetine, characterized in that it has the value of d(0.9) percentile,

measured by laser diffraction, in the range of 90 to 190 μτη.

15. Crystalline duloxetine, characterized in that it has the value of d(0.5) percentile,

measured by laser diffraction, of at least 30 μιη.

16. Crystalline duloxetine, characterized in that it has the value of d(0.5) percentile,

measured by laser diffraction, in the range of 35 to 80 μιη.

17. Crystalline duloxetine, characterized in that it achieves value of d(0.1) percentile, measured by laser diffraction, of at least 10 μτη.

18. Crystalline duloxetine, characterized in that it has the value of d(0.1) percentile,

measured by laser diffraction, in the range of 10 to 30 μηι.

19. Crystalline duloxetine, characterized in that it contains at least 10% of crystals larger than 90 μηι.

20. Crystalline duloxetine, characterized in that it contains at least 33% of crystals larger than 50 μιη.

21. Crystalline duloxetine, characterized in that it contains at least 90% of crystals larger than 10 μηι.

22. Crystalline duloxetine, characterized in that at least 65% of crystals have the elongation parameter value in the range of 1 to 2.

23. Crystalline duloxetine, characterized in that at least 85% of crystals have the elongation parameter value in the range of 1 to 3.

24. Crystalline duloxetine, characterized in that it contains crystals with the average area value higher than 150 μπι ².

25. A pharmaceutical composition, characterized in that it contains duloxetine as defined in claims 10 to 24 and further pharmaceutically acceptable excipients.