The present invention provides novel polymorphic forms of (R)-(-)-Tamsulosin, process for their preparation and pharmaceutical compositions thereof. The invention further provides a process for preparation of these polymorphic forms.
Tamsulosin hydrochloride is an antagonist of alpha1A adrenoceptors in the prostate and
chemically is (-)-(R)-5,4,2-[2-(0-ethoxyphenoxy)ethyl]amino-propyl-2-
methoxybenzenesulfonamide, monohydrochloride of Formula I. Tamsulosin hydrochloride is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) and are not indicated for the treatment of hypertension.
(Formula Removed)
US patent No. 4,703,063 discloses tamsulosin and acid addition salts thereof, which exhibit a strong α-adrenergic blocking action and are useful as an antihypertensive agent and a treating agent for congestive heart failure. It further provides a process for preparation of (R)-(-) or (S)-(+)-enantiomer of tamsulosin. Canadian Patent CA 1,282,077; European patents EP 257,787 and EP 380,144; PCT applications WO 02/068382, WO 03/035608, WO 04/016582, WO 04/022532 and WO 04/087623 provides various processes for the preparation of tamsulosin or its salts. PCT application WO 04/006829 provides process for the resolution of tamsulosin.
PCT application WO 03/037851 discloses racemic tamsulosin freebase in solid state, which exhibits polymorphism. It further provides two polymorphic forms of racemic tamsulosin, which are designated as Form I and Form II having characteristic XRD, IR and DSC pattern.
PCT application WO 04/087623 describes a process for the preparation of (R) (-) Tamsulosin hydrochloride, and also discloses a polymorphic form of (R)(-) Tamsulosin hydrochloride having typical XRD pattern.
The present inventors have surprisingly found hereto unknown two novel polymorphic forms of (R)-(-)-Tamsulosin, (hereinafter referred to as Morph I and Morph II). These morphs are suitable starting materials for preparation of (R)-(-)-tamsulosin hydrochloride. In addition these morphs are also useful in treatment of signs and symptoms of BPH.
A first aspect of the present invention provides Morph I of (R)-(-)-Tamsulosin having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1 of the accompanied drawing wherein characteristic 20 values are obtained at 10.32, 11.08, 12.66, 14.46, 15.08, 17.12, 17.88, 22.36 and 24.28. The Fourier Transform Infrared (FTIR) spectrum of Form I of (R)-(-)-Tamsulosin in potassium bromide is depicted in Figure 2 of the accompanied drawing. The Morph I of (R)-(-)-Tamsulosin has characteristic DSC thermogram as depicted in Figure 3 of the accompanied drawing. The DSC thermogram shows a characteristic endothermic peak at 110-120°C.
A second aspect of the present invention provides Morph II of (R)-(-)-Tamsulosin having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 4 of the accompanied drawing wherein characteristic 20 values are obtained at 11.32, 13.56, 15.32, 17.18, 18.62, 19.58, 21.54, 22.80 and 24.58. The Fourier Transform Infrared (FTIR) spectrum of Form I of (R)-Tamsulosin in potassium bromide is depicted in Figure 5 of the accompanied drawing. The Morph II of (R)-(-)-Tamsulosin has characteristic DSC thermogram as depicted in Figure 6 of the accompanied drawing. The DSC thermogram shows a characteristic endothermic peak at 125-135°C.
A third aspect of the present invention provides a process for the preparation of Morph I of (R)-(-)-Tamsulosin, which comprises of:
a) suspending (R)-(-)-tamsulosin hydrochloride in water optionally containing a miscible
organic solvent at a temperature above 45°C,
b) adding a solution of base, to the mixture obtained in step a) at the same
temperature,
c) cooling the mass to below 35°C,
d) isolating Morph I of (R)-(-)-Tamsulosin from the reaction mass thereof.
(R)-(-)-Tamsulosin hydrochloride prepared by any method known in the art and present in any polymorphic form known to a person of ordinary skills in the art can be used as starting material. (R)-(-)-tamsulosin hydrochloride is suspended in water optionally containing a miscible organic solvent and warmed to about 45-75°C. A solution of a base is added to the suspension and the mixture is stirred at the same temperature. The reaction mass is cooled to about 15-35°C. The product is filtered, washed and dried under vacuum to obtain Morph I of (R)-(-)-Tamsulosin.
The 'miscible organic solvent' is selected from a group comprising of but not limited to C1-4 straight or branched chain lower alkanols such as methanol, ethanol, n-propanol and isopropanol; acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane or mixtures thereof.
The 'base1 is selected from the group comprising of but not limited to hydroxide, carbonate, bicarbonate or alkoxide of ajkali metals or alkaline earth metals.
A fourth aspect of the present invention provides a process for the preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of:
a) adding a solution of tamsulosin hydrochloride in water optionally containing a
miscible organic solvent to a solution of base,
b) cooling the resultant mass to room temperature or below,
c) isolating Morph II of (R)-Tamsulosin from the reaction mass thereof.
(R)-(-)-Tamsulosin hydrochloride in water optionally containing a miscible organic solvent is added to a solution of a base. The resulting mass is cooled to about room
temperature and stirred. The product is filtered, washed and dried under vacuum to obtain Morph II of (R)-(-)-Tamsulosin.
The 'miscible organic solvent' is selected from a group comprising of but not limited to C1-4 straight or branched chain lower alkanols such as methanol, ethanol, n-propanol and isopropanol; acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane or mixtures thereof.
The 'base' is selected from the group comprising of but not limited to hydroxide, carbonate, bicarbonate or alkoxide of alkali metals or alkaline earth metals.
A fifth aspect of the present invention provides a process for the preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of:
a) dissolving tamsulosin in a suitable organic solvent,
b) adding an anti-solvent to the solution obtained in step a)
c) isolating Morph II of (R)-Tamsulosin from the reaction mass thereof.
(R)-(-)-Tamsulosin prepared by any method known to a person of ordinary skills in the art can be used as starting material. (R)-(-)-Tamsulosin is dissolved in an organic solvent. An anti-solvent is added to the solution. The suspension is stirred and filtered. The resultant mass was washed and dried under vacuum to obtain Morph II of (R)-(-)-Tamsulosin.
The 'organic solvent' can be selected from a group comprising of but not limited to chlorinated hydrocarbons such as chloroform or methylene chloride; lower alkanols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane; esters such as ethyl acetate, n-butyl acetate, isopropyl acetate etc or ketones such as acetone, ethyl methyl ketone or mixtures thereof.
The 'anti-solvent' can be selected from a group comprising of but not limited to C6-8 straight or branched chain alkanes, petroleum ether, C5-7 cycloalkanes, C4-12 ethers or mixtures thereof.
A sixth aspect of the invention provides a process for preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of crystallizing (R)-(-)-Tamsulosin from a C1-4 alkanol optionally containing a C2-6 ester.
(R)-(-)-Tamsulosin is added to a C1-4 alkanol optionally containing a C2-6 ester, and warmed. The solution is allowed to cooled and stirred. The suspension obtained is filtered, washed and dried under vacuum to obtain Morph II of (R)-(-)-Tamsulosin.
A seventh aspect of the present invention provides a pharmaceutical composition comprising Morph I or Morph II of (R)-Tamsulosin optionally containing an excipient / diluent.
A eighth aspect of the present invention provides a method of treating signs and symptoms of benign prostrate hyperplasia comprising administering to a mammal in need thereof a therapeutically effective amount of Morph I or Morph II of (R)- (-)-Tamsulosin.
An ninth aspect of the present invention provides a process for preparation of pharmaceutically acceptable salt of (R)-(-)-Tamsulosin which comprises of treating Morph I or Morph II of (R)-(-)-Tamsulosin with a suitable pharmaceutically acceptable acid and isolating the pharmaceutically acceptable acid addition salt of (R)-(-)-Tamsulosin from the reaction mass thereof.
Figure 1 depicts XRD of Morph I of (R)-(-)-Tamsulosin Figure 2 depicts FTIR spectrum of Morph I of (R)-(-)-Tamsulosin Figure 3 depicts DSC of Morph I of (R)-(-)-Tamsulosin Figure 4 depicts XRD of Morph II of (R)-(-)-Tamsulosin
Figure 5 depicts FTIR spectrum of Morph II of (R)-(-)-Tamsulosin Figure 6 depicts DSC of Morph II of (R)-(-)-Tamsulosin
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
FTIR of the samples were determined by using Instrument: Perkin Elmer,16 PC, SCAN: 16scans, 4.0 cm-1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1 PREPARATION OF FORM I OF (R)(-)-TAMSULOSIN
(R)-(-)-Tamsulosin hydrochloride (130 g) was suspended in water (585 ml) and warmed to 55-60°C. A solution of sodium carbonate (36 g dissolved in water (200 ml)) was added to the suspension over 10 minutes. The heterogeneous mixture was stirred for 1.5 hours at 55-60°C. The reaction mass was cooled to 30°C in 30 minutes and stirred for 30 minutes. The product was filtered and washed with water (260 ml X 2). The wet product (260 g) obtained was dried under vacuum for about 23 hours at 50°C to obtain the title compound. Yield: 119 g.
EXAMPLE 2 PREPARATION OF FORM II OF (R)(-)-TAMSULOSIN
Sodium hydroxide (1.98 g) was dissolved in water (200 ml) and cooled to 28°-30°C. (R)-(-)-Tamsulosin hydrochloride (15 g) was added to the solution in 5 minutes. The thick slurry formed was stirred for about 14 hours at 28-30°C and filtered to collect the product. The product was washed with water (100 ml X 2) to yield about 42 g of wet material. The material was dried at 40°C for 10 hours and at 30°C for 12 hours to obtain the title compound.
EXAMPLE 3 PREPARATION OF FORM II OF (R)(-)-TAMSULOSIN
(R)-(-)-Tamsulosin hydrochloride (12 g) was added to water (120 ml). The suspension was warmed to 90-95°C to give a clear solution. A solution of potassium carbonate in water (4 g in 20 ml) was added slowly over 5 minutes. The reaction mass was allowed to cool in about 45 minutes to 28-30°C and stirred for one hour. The product was collected by filtration and washed with water (25 ml X 2) and then dried under vacuum at 28-30°C for 16 hours to obtain the title compound.
EXAMPLE 4
PREPARATION OF FORM II OF (R)(-)-TAMSULOSIN
(R)-(-)-Tamsulosin base (10 g) was dissolved in 120 ml of dichloromethane (120 ml). Hexane (120 ml) was added to the clear solution at 28°C. The suspension was stirred for one hour at 28-30°C and filtered to collect solids. The solids were washed with 20 ml of 1:1 hexane: dichloromethane and dried under vacuum at 28-30°C for about 14 hours to obtain the title compound. Yield: 13.6 g
EXAMPLE 5 PREPARATION OF FORM II OF (R)(-)-TAMSULOSIN
(R)-(-)-Tamsulosin base (5 g) and methanol (20 ml) were added to ethyl acetate (20 ml). The suspension was warmed to 60°C to give a clear solution. The solution was allowed to cool to 28-30°C in about one hour and stirred further for 2 hours at 28-30°C. The suspension obtained was filtered to collect solids. The solids were dried after washing with methanol: ethyl acetate (1:1, 10 ml) to obtain the title compound. Yield: 3.36 g
EXAMPLE 6 PREPARATION OF FORM II OF (R)(-)-TAMSULOSIN
(R)-(-)-Tamsulosin base (5 g) was added to methanol (50 ml). The suspension was warmed to reflux to give a clear solution. The solution was allowed to cool to at 28-30°C and stirred for 2 hours. The suspension obtained was filtered and the solids were washed with methanol (10 ml). The wet material was dried under vacuum at 28-30°C for 14 hours to obtain the title compound. Yield: 3.8 g.

WE CLAIM:
1. Morph I of (R)-(-)-Tamsulosin.
2. Morph I of (R)-(-)-Tamsulosin having a XRPD pattern wherein characteristic 28
values are obtained at 10.32, 11.08, 12.66, 14.46, 15.08, 17.12, 17.88, 22.36 and
24.28.
3. Morph I of (R)-(-)-Tamsulosin having a characteristic endothermic peak at 110-120°C
in DSC.
4. Morph II of (R)-(-)-Tamsulosin.
5. Morph II of (R)-(-)-Tamsulosin having a XRPD pattern wherein characteristic 29
values are obtained at 11.32, 13.56, 15.32, 17.18, 18.62, 19.58, 21.54, 22.80 and
24.58.
6. Morph II of (R)-(-)-Tamsulosin having a characteristic endothermic peak at 125-135°C
in DSC.
7. A process for the preparation of Morph I of (R)-(-)-Tamsulosin, which comprises of:

a) suspending (R)-(-)-Tamsulosin hydrochloride in water optionally containing a
miscible organic solvent at a temperature above 45°C,
b) adding a solution of base, to the suspension obtained in step a) at the same
temperature,
c) cooling the reaction mass to below 35°C,
d) isolating Form I of (R)-(-)-Tamsulosin from the reaction mass thereof.
8. A process for the preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of:
a) adding a solution of (R)-(-)-Tamsulosin hydrochloride in water optionally
containing a miscible organic solvent to a solution of base,
b) cooling the resultant mass to room temperature or below,
c) isolating Form II of (R)-(-)-Tamsulosin from the reaction mass thereof.
9. A process as claimed in claims 7 or 8 wherein the base used is selected from
carbonates, hydroxides, bicarbonates or alkoxides of alkali metals or alkali earth metals
or ammonia.
10. A process for the preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of:
a) dissolving tamsulosin in a suitable organic solvent,
b) adding an anti-solvent to the solution obtained in step a)
c) isolating Form II of (R)-(-)-Tamsulosin from the reaction mass thereof.

11. A process as claimed in claim 10 wherein the anti-solvent is hexane.
12. A process as claimed in claim 10 wherein suitable organic solvent is C1-4 alkanol.
13. A process for preparation of Morph II of (R)-(-)-Tamsulosin, which comprises of
crystallizing (R)-(-)-tamsulosin from a C1-4 alkanol optionally containing a C2-6 ester.
14. A pharmaceutical compositions comprising Morph I or Morph II of (R)-(-)-Tamsulosin
optionally containing a pharmaceutically acceptable diluents or excipients.
15. A method of treating signs and symptoms of benign prostrate hyperplasia
comprising administering to a mammal in need thereof a therapeutically effective
amount of Morph I or Morph II of (R)-(-)-Tamsulosin.
16. A process for preparation of pharmaceutically acceptable salt of (R)-(-)-tamsulosin which comprises of treating Morph I or Morph II of (R)-(-)-tamsulosin with a suitable pharmaceutically acceptable acid and isolating the pharmaceutically acceptable acid addition salt of (R)-(-)-tamsulosin from the reaction mass thereof.