# Patent

## Title
Crystalline duloxetine hydrochloride

## Abstract

Crystalline duloxetine hydrochloride, compositions containing the same and methods for the production thereof.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from Great Britain Application Number GB 0612508.2, filed 23 Jun. 2006.
FIELD OF THE INVENTION
The present invention relates to crystalline duloxetine hydrochloride, to compositions containing the same and to methods for the formation thereof.
BACKGROUND OF THE INVENTION
Duloxetine hydrochloride is a potent dual reuptake inhibitor of serotonin and norepinephrine possessing comparable affinities in binding to serotonin and norepinephrine transport sites. Duloxetine hydrochloride has, therefore, been implicated in the treatment of various diseases related to these effects. For example, duloxetine hydrochloride is the active ingredient of the antidepressant drug Cymbalta®. It is also used to target pain related to diabetic neuropathy and stress urinary incontinence.
Preparation of duloxetine hydrochloride has been disclosed elsewhere, for example in U.S. Pat. No. 5,023,269. Crystalline forms of the free base of duloxetine and their preparation have been reported in WO2005/108386. The amorphous form of duloxetine hydrochloride salt together with its preparation has been reported in WO2005/019199.
There is no generally applicable method for preparing a crystalline form of an amorphous drug. For example, it is impossible to know without experimentation whether any crystalline form of a given compound exists. Even once it has been found that a drug can be crystallised, extensive experimentation is usually required before a repeatable and quantifiable process is identified from which the crystalline form can be isolated. In this respect, several independently variable conditions, such as the nature of solvent, concentration of solvent and temperature, must be correctly identified in order to elucidate a suitable process. Indeed, to date, there have been no reports describing isolation or production of crystalline duloxetine hydrochloride.
It is, therefore, an object of the present invention to provide crystalline forms of duloxetine hydrochloride together with methods for the production thereof.
SUMMARY OF THE INVENTION
According to a first aspect of the present invention, there is provided crystalline duloxetine hydrochloride.
According to another aspect of the present invention, there is provided crystalline duloxetine hydrochloride which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 11.99±0.2, 14.78±0.2, 21.44±0.2, 22.16±0.2, 23.12±0.2 and 24.12±0.2. The degree of error is preferably ±0.1.
According to a further aspect of the present invention, there is provided crystalline duloxetine hydrochloride which exhibits an X-ray diffraction pattern comprising peaks expressed in degrees two-theta at approximately 11.02±0.2, 11.99±0.2, 13.94±0.2, 14.78±0.2, 16.19±0.2, 16.87±0.2, 18.0±0.2, 18.8±0.2, 19.77±0.2, 20.84±0.2, 21.44±0.2, 22.16±0.2, 23.12±0.2, 24.12±0.2, 26.34±0.2, 26.76±0.2, 27.0±0.2, 27.45±0.2, 29.24±0.2, 29.58±0.2, 29.92±0.2, 30.4±0.2, 32.2±0.2, 32.82±0.2 and 34.17±0.2. The degree of error is preferably ±0.1.
There is also provided by the present invention, crystalline duloxetine hydrochloride which exhibits an X-ray diffraction pattern substantially the same as shown in FIG. 1.
Preferably, the crystalline duloxetine hydrochloride has a purity of at least 95%, more preferably at least 98%.
According to a further aspect of the present invention, there is provided a method for the preparation of crystalline duloxetine hydrochloride, the method comprising:

    
    
        (a) dissolving duloxetine in a first organic solvent to form a first solution;
        (b) adding the first solution to a second organic solvent solution comprising HCl to form a second solution;
        (c) allowing duloxetine hydrochloride to crystallize out from the solution; and
        (d) collecting the crystallized duloxetine hydrochloride.
    
    


Preferably, the first organic solvent is an aromatic hydrocarbon, more preferably toluene.
In preferred embodiments, the second organic solvent is an alcohol, more preferably a straight or branched C1 to C6 alcohol, further preferably ethanol.
Preferably, the duloxetine is dissolved in the first organic solvent in a ratio of about 40 ml first organic solvent for about every 3 g of duloxetine.
In preferred aspects, the second organic solvent comprises about 20% HCl.
It is also preferred that the first solution is added to the second organic solvent at around 0° C. The first solution is preferably added to the second organic solvent with stirring.
In order to maximize crystallization, the duloxetine hydrochloride may be allowed to crystallize out from the solution during a period of cooling at around 0° C. to around 10° C. Preferably, the duloxetine hydrochloride is allowed to crystallize out from the solution during a period of about 10 hours.
Preferably, the crystallized duloxetine hydrochloride is collected by filtration. The collected crystallized duloxetine hydrochloride is preferably washed and then dried.
In preferred embodiments, the collected crystallized duloxetine hydrochloride is washed with an aromatic hydrocarbon, more preferably toluene.
Preferably, the collected crystalline duloxetine hydrochloride is dried under vacuum.
Preferably, the method comprising the following additional steps for the preparation of duloxetine for use in step (a):
(i) placing duloxetine oxalate into a solution of a third organic solvent and water;
(ii) adding aqueous ammonia solution for dissolving the duloxetine oxalate;
(iii) isolating a separated organic layer;
(iv) washing the organic layer with saturated brine;
(v) drying the organic layer; and
(vi) removing the solvents from the organic layer.
Preferably, the third organic solvent is a C1 to C6 ester, more preferably ethyl acetate.
The duloxetine oxalate is preferably placed into a solution of the third organic solvent and water at a ratio of about 300 ml third organic solvent and water solution for about every 39 g of duloxetine oxalate.
Preferably, the solution of a third organic solvent and water contains about 1 ml third organic solvent for about every 1 ml water.
The aqueous ammonia is preferably added under stirring.
Preferably, an aqueous layer is isolated and then washed with the third organic solvent.
According to a further aspect of the present invention, there is provided crystalline duloxetine hydrochloride prepared by any of the methods above.
Preferably, the crystalline duloxetine hydrochloride has a purity of at least 95%, more preferably at least 98%.
Accordingly, the present invention describes a novel crystalline form of duloxetine hydrochloride and a process to prepare it.
It is anticipated that the crystalline form of duloxetine hydrochloride disclosed herein will be useful in the treatment of a variety of diseases which are prevented, ameliorated or eliminated by the administration of a serotonin and/or norepinephrine reuptake inhibitor. Examples of such diseases include depression, pain related to diabetic neuropathy and stress urinary incontinence, obesity, alcoholism, loss of memory, anxiety and smoking.
According to another aspect of the present invention, there is therefore provided a pharmaceutical composition comprising crystalline duloxetine hydrochloride as described herein.
According to a further aspect, there is provided a composition for treating a disease which is prevented, ameliorated or eliminated by the administration of a serotonin and/or norepinephrine reuptake inhibitor, the composition comprising crystalline duloxetine hydrochloride as described herein.
Preferably, the disease is selected from depression, pain related to diabetic neuropathy and stress urinary incontinence, obesity, alcoholism, loss of memory, anxiety and smoking.
There is also provided a method of treating a disease which is prevented, ameliorated or eliminated by the administration of a serotonin and/or norepinephrine reuptake inhibitor, the method comprising administering to a patient a therapeutically effective amount of crystalline duloxetine hydrochloride as described herein, or of the pharmaceutical composition as described herein.
Preferably, the disease is selected from depression, pain related to diabetic neuropathy and stress urinary incontinence, obesity, alcoholism, loss of memory, anxiety and smoking.
By a therapeutically effective amount, it is meant an amount which is capable of preventing, ameliorating or eliminating the diseases mentioned herein.
The crystalline duloxetine hydrochloride can be mixed with a carrier, diluent or excipient therefor, all of which are well known in the art. For example, suitable carriers may include pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders.
There are many advantages to providing a crystalline form of duloxetine hydrochloride compared to an amorphous form. A crystalline form of the drug can be easily purified by crystallisation and recrystallisation. Compared to other methods of purification, it is also cheaper and more convenient to perform crystallisation on a large scale. Furthermore, a crystalline form may be more stable than an amorphous form.



BRIEF DESCRIPTION OF THE DRAWINGS
An example of the present invention will now be described in detail with reference to the accompanying figures.
FIG. 1 shows the X-ray powder diffraction (XRD) spectrum for the crystalline form of the present invention.
FIG. 2 shows Thermogravimetric Analysis (TGA) and Differential Thermal Analysis (DTA) thermograms for the crystalline form of the present invention.



DETAILED DESCRIPTION OF THE INVENTION
Duloxetine oxalate salt was initially prepared following the procedure given in EP273658 (corresponding to U.S. Pat. Nos. 5,023,269 and 4,956,388, each hereby incorporated by reference). Duloxetine was then freed from the oxalic acid and converted directly to its hydrochloride salt by the introduction of hydrochloride in organic solvent.
The isolated crystalline duloxetine hydrochloride was fully characterized by Differential Scanning Calorimetry (DSC), solid carbon-13 NMR and X-ray powder diffraction.
Crystallization
EXAMPLE 1
Free Duloxetine Preparation:
Duloxetine oxalate (38.7 g) was placed into 300 ml of an ethyl acetate/water (1:1) mixture. Aqueous ammonium solution was added to dissolve the solid completely under stirring. The separated aqueous layer was washed with ethyl acetate twice. The combined organic solution was then washed with saturated brine, and dried with anhydrous sodium sulphate. The free duloxetine (26 g) was obtained as an oil by removing the solvents from the filtrate solution.
Crystallization of Duloxetine Hydrochloride:
The free oily duloxetine (3 g) was added to toluene (40 ml), then an ethanol solution (2 ml) containing 20% HCl was added at 0° C. The resultant solution was then stirred for an extra half hour and kept at 0-10° C. for 10 hours. The product crystallized out and was collected by filtration, washed with more toluene and dried (1.7 g, 53% yield, m.p. 154-158° C.). Its purity was determined to be 98.9% by HPLC, and its optical purity was 99.4% (chiral column HPLC). The DTA result shown m.p. was 169.2° C. The crystalline form, designated as Form II, was thus obtained.







TABLE 1







The XRD spectrum for the crystalline form obtained


according to Example 1.









2theta (degree)
I/I0
d(A)












11.021
16
8.021


11.993
54
7.373


13.936
18
6.349


14.780
73
5.988


16.192
32
5.469


16.868
15
5.251


17.997
25
4.924


18.792
30
4.718


19.765
16
4.488


20.842
31
4.258


21.444
100
4.140


22.159
58
4.008


23.120
84
3.843


24.122
71
3.686


26.341
24
3.380


26.760
19
3.328


27.000
31
3.299


27.448
12
3.246


29.240
19
3.051


29.580
19
3.017


29.920
21
2.983


30.398
12
2.938


32.200
14
2.777


32.820
10
2.726


34.165
14
2.622
















TABLE 2





TGA/DTA parameters


















Detector
DTG-60H



Sample Weight
7.698 mg



Temperature Rate
10° C.



Hold Temperature
300° C.



Hold Time
0 min

## Claims

1. A method for the preparation of crystalline duloxetine hydrochloride, the method comprising:
(a) dissolving duloxetine in a first organic solvent to form a first solution;
(b) adding the first solution to a second organic solvent comprising HCl to form a second solution;
(c) allowing duloxetine hydrochloride to crystallize out from the solution; and
(d) collecting the crystallized duloxetine hydrochloride,

wherein the first organic solvent is an aromatic hydrocarbon.

2. The method of claim 1, wherein the first organic solvent is toluene.

3. The method of claim 1, wherein the second organic solvent is an alcohol.

4. The method of claim 3, wherein the second organic solvent is ethanol.

5. The method of claim 1, wherein the duloxetine is dissolved in the first organic solvent in a ratio of about 40 ml first organic solvent for about every 3 g of duloxetine.

6. The method of claim 1, wherein the second organic solvent comprises about 20% HCl.

7. The method of claim 1, wherein the first solution is added to the second organic solvent at around 0° C.

8. The method of claim 1, wherein the first solution is added to the second organic solvent with stirring.

9. The method of claim 1, wherein the duloxetine hydrochloride is allowed to crystallize out from the solution during a period of cooling at around 0° C. to around 10° C.

10. The method of claim 1, wherein the duloxetine hydrochloride is allowed to crystallize out from the solution during a period of about 10 hours.

11. The method of claim 1, wherein the crystallized duloxetine hydrochloride is collected by filtration.

12. The method of claim 1, wherein the collected crystallized duloxetine hydrochloride is washed and then dried.

13. The method of claim 12, wherein the collected crystallized duloxetine hydrochloride is washed with an aromatic hydrocarbon.

14. The method of claim 13, wherein the collected crystallized duloxetine hydrochloride is washed with toluene.

15. The method of claim 1, comprising the following additional steps for the preparation of duloxetine for use in step (a):
(i) placing duloxetine oxalate into a solution of a third organic solvent and water;
(ii) adding aqueous ammonia solution for dissolving the duloxetine oxalate;
(iii) isolating a separated organic layer;
(iv) washing the organic layer with saturated brine;
(v) drying the organic layer; and
(vi) removing the solvents from the organic layer.

16. The method of claim 15, wherein the third organic solvent is a C1 to C6 ester.

17. The method of claim 16, wherein the third organic solvent is ethyl acetate.

18. The method of claim 15, wherein duloxetine oxalate is placed into a solution of the third organic solvent and water at a ratio of about 300ml third organic solvent and water solution for about every 39g of duloxetine oxalate.

19. The method of claim 15, wherein the solution of a third organic solvent and water contains about 1 ml third organic solvent for about every 1 ml water.

20. The method of claim 15, wherein the aqueous ammonia is added under stirring.

21. The method of claim 15, wherein an isolated aqueous layer is washed with the third organic solvent.

22. The method of claim 15, wherein the organic layer is dried with anhydrous sodium sulphate.