FIELD OF THE INVENTION
The present invention relates to an improved, industrially advantageous and novel
process for preparation of pure polymorphic form gamma (γ) of silodosin. More
particularly, present invention relates to pure polymorphic form gamma (γ) of
5 silodosin, process for its preparation, wherein residual solvents are present in
specified limits as per ICH guidelines.
BACKGROUND OF THE INVENTION
Silodosin, having IUPAC name 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-
10 trifluoroethoxy)phenoxy]ethylamino)propyl]indoline-7-carboxamide, is a well
known pharmaceutically active ingredient useful for the treatment of dysuria and
similar diseases and is represented by chemical structure as shown below.
It was first disclosed in US patent 5,387,603 and is marketed under trade name
Rapaflo. In US patent 5,387,603 process for the preparation of silodosin and its
15 various derivatives are disclosed, however, the concrete detail of preparation and
purification have not been reported. Furthermore, isolated silodosin is
characterized using IR, NMR and specific rotation but the patent is silent on
product appearance and crystalline nature.
20 In a Japanese patent 3331048 (publication No.H07-330726), a process for
preparation of silodosin is disclosed wherein crude silodosin is dissolved in ethyl
acetate, dried over anhydrous magnesium sulfate, solvent is distilled off and again
dissolved in ethyl acetate at 70°C and crystallizes below room temperature. The
3
resulting product is characterized by melting point, IR, NMR and specific rotation. Here also disclosure is silent about polymorphic form of product.
It is known that many substance have ability to exist in more than one crystalline form, which are called polymorphs and this phenomenon is named as polymorphism. Polymorphism is considered as one of the most important solid-5 state property of drug substance, since different polymorph have different physiochemical and biological properties and in pharmaceutical chemistry it is often desired to obtain one particular form that is biologically active and also offers ease of handling during formulation. In silodosin also, polymorphism exist which has been explored in various literature references and the available 10 references are incorporated herein as given below.
US patent publication US2006/0142374A1 (equivalent European patent EP1541554B1) discloses polymorphic forms of silodosin including three crystalline polymorphic form of silodosin which are named as alpha (α), beta (β) 15 and gamma (γ) and one amorphous form. These polymorphic forms have been characterized by X-ray powder diffraction pattern. In the patent publication, processes for the preparation of all these three crystalline forms have been disclosed. In a given process, form alpha is prepared by dissolving crude silodosin in appropriate amount of ethyl acetate, ethyl formate, acetone, methyl ethyl 20 ketone, acetonitrile, tetrahydrofuran or mixture of acetone and acetonitrile (1:1), preferably ethyl acetate under heating, allowing to stand at room temperature to precipitate the crystal gradually. Similarly, form beta is prepared by dissolving crude silodosin in appropriate amount of methanol under heating, adding petroleum ether as a anti-solvent, crystal precipitation is ensured using vigorous 25 stirring. In a second process, to prepare the form beta, crude silodosin is dissolved in ethanol or 1-propanol and the reaction mass is cooled quickly. The crystalline form gamma is prepared by dissolving crude silodosin in appropriate amount of
4
toluene or a mixture of acetonitrile and toluene (1:4) or ethyl acetate and toluene (1:19), preferably in toluene, under heating, cooling to room temperature and allowing to precipitate gradually upon standing. In a second process to prepare form gamma, crude silodosin is dissolved in 2-propanol and the crystals are precipitated by adding an appropriate amount of toluene. In spite of disclosing 5 three crystalline polymorphic forms, the patent publication prefers preparation and use of form alpha by highlighting the problems faced for preparation and use of other forms. It is disclosed that crystal form beta has manufacturing difficulties at industrial scale since precipitation occurs only when the nonpolar antisolvent is added to warm solution which leads to inconsistency in quality of crystals. With 10 the second process for preparation of form beta, desired level of yield and purity has not been achieved. Further, according to this publication, preparation of gamma form involves use of toluene which can not be removed completely from final product, because of its high boiling point and raises the problem of residual solvent. In the case of toluene, a class 2 solvent, its limits should not be more than 15 890 ppm. In the exemplified process, toluene content has not been disclosed, which clearly reflects that product was not suitable for pharmaceutical composition having problem of high residual content of toluene. Furthermore patent publication also states that all the three crystal forms donot have any difference in hygroscopicity and stabilities. 20
Thereafter, several patents/publications disclose preparation of polymorphic forms alpha and beta. For example a PCT publication WO2012/147107 discloses a process for preparation of beta form using isopropyl acetate and methyl isobutylketone. In another PCT publication WO2012/077138, preparation of 25 alpha and beta forms are disclosed using various solvent system. Similarly, in a Chinese patent CN102010359, crystalline form beta is prepared by dissolving the
5
crude silodosin in alcoholic solvent by heating and the product is crystallized by cooling or by adding an antisolvent such as ketone or ether.
European patent EP2474529 discloses new polymorphic forms delta (δ) and eta (ε) of silodosin by using a solvent (tetrahydrofuran) and antisolvent (n-heptane, n-5 hexane, cyclohexane, tert butylmethyl ether). Further it discloses conversion of delta form to beta form by just heating the delta form at a particular temperature. The form delta can also be transformed into form eta by slurrying in aqueous methanol. One new crystalline form designated as delta has also been disclosed in a Chinese patent publication CN102229558. An Indian patent application 10 478/MUM/2010, also discloses a new polymorphic form Zy-S which is prepared by using solvent such as esters, aromatic hydrocarbons, ketones, and alcohols. All the above disclosures are silent about the preparation of gamma form of silodosin and only available disclosure reports that gamma form have problem of residual solvent, as impurity and is not suitable for pharmaceutical compositions. 15
Impurities may be formed or added during the manufacture of the API. Any component other than the API is considered an impurity. The impurities present in the API could be process-related impurities such as starting materials, intermediates, by-products, reagents, ligands, catalysts, filter aids, carbon 20 adsorbents, or salts as well as degradation products, enantiomeric impurities and residual solvents used in the manufacturing process. The International Conference on Harmonization (ICH) guidelines on residual solvent Q3C(R5) for impurities in API indicates that the impurity profile method should be able to detect impurities (limit of quantification) at levels 25 greater than the reporting threshold of 0.05% for drugs with maximum daily dose of ≤2 g/day and 0.03% for maximum daily dose >2 g/day.
6
Residual solvents have had official limits in the United States as set in USP [30<467> and by the FDA in 1997, same in revised USP 37<467> applicable from May 2014] and have been monitored by most pharmaceutical manufacturers extensively for more than two decades in both bulk and finished products
Residual solvents in pharmaceutical samples are monitored using gas 5 chromatography (GC) with either flame ionization detection (FID) or mass spectrometry. Based on good manufacturing practices, measuring residual solvents is mandatory for the release testing of all active pharmaceutical ingredients and is routinely performed.
In ICH guidelines there is chapter on Classification of Residual Solvents by Risk 10 Assessment. Solvents are evaluated for their possible risk to human health and placed into one of three classes as follows:
Class 1 solvents: Solvents to be avoided-
Known human carcinogens, strongly suspected human carcinogens, and environmental hazards. 15
Class 2 solvents: Solvents to be limited-
Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
Class 3 solvents: Solvents with low toxic potential- 20
Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDE's (permitted daily exposure) of 50 milligrams or more per day.
It has been noticed that polymorphic gamma form of silodosin when prepared as per the process reported in the prior art is not isolated in pure form; it is found to 25 have residual solvent (toluene) in unacceptable amounts and is difficult to remove
7
even after drying at higher temperature for longer durations. As is evident from the prior art, no further attempts have been made to prepare the polymorphic form gamma of silodosin using any other alternate process or if tried the process may not overcome the residual solvent problem hence were not documented. The availability of only one disclosure to prepare the gamma form of silodosin 5 strongly necessitates the need in art to develop other improved processes to prepare the gamma form which not only passes the criteria of residual solvent limits as per ICH guidelines, Q3C, but also provides the consistency in crystal form. Therefore, the present invention aimed to solve the problems associated with the prior art and to provide an efficient and novel process for the preparation 10 of polymorphic form gamma of silodosin, wherein residual solvents are within limits, as per ICH guidelines.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, industrially 15 advantageous, efficient and novel process for preparation of polymorphic form gamma of silodosin.
Another object of the present invention is to provide a process for preparation of polymorphic form gamma of silodosin wherein residual solvents are within 20 specified limits as per ICH guidelines.
SUMMARY OF THE INVENTION Accordingly, the present invention provides an efficient and novel process for preparation of polymorphic form gamma of silodosin of following formula, 25 wherein residual solvents are present in specified limits as per ICH guidelines.
8
According to one embodiment, the present invention provides a process for
preparation of polymorphic form gamma of silodosin, which comprises the steps
of:
a) dissolving any polymorphic 5 form of silodosin in a suitable solvent by
heating,
b) cooling the resulting solution,
c) seeding with form gamma of silodosin,
d) cooling the resulting solution to ambient temperature,
10 e) adding a suitable antisolvent,
f) stirring the reaction mixture,
g) isolating pure polymorphic form gamma of silodosin, and
h) optionally micronizing polymorphic form gamma of silodosin.
15 According to one embodiment, the present invention provides a process for
preparation of polymorphic form gamma of silodosin, which comprises the steps
of:
a) dissolving any polymorphic form of silodosin in a suitable solvent by
heating,
20 b) cooling the resulting solution,
c) seeding with form gamma of silodosin,
d) cooling the resulting solution to ambient temperature, and
e) isolating pure polymorphic form gamma of silodosin.
9
According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin, wherein residual solvents are present in specified limits as per ICH guidelines, which comprises the steps of:
a) providing polymorphic form gamma of silodosin having toluene content 5 greater than 890 ppm,
b) micronizing polymorphic form gamma of silodosin as described in above step,
c) optionally refluxing the micronized compound in a suitable solvent,
d) drying the resulting compound, 10
e) isolating polymorphic form gamma of silodosin having toluene content less than 890 ppm.
According to one other embodiment, the present invention provides pure polymorphic form gamma of silodosin, having residual solvents in specified 15 limits as per ICH guidelines, specifically toluene content less than 890 ppm.
According to one other embodiment, the present invention provides a process for preparation of polymorphic form gamma of silodosin by incorporating step of seeding of gamma form of silodosin during crystallization of silodosin. 20
BRIEF DESCRIPTION OF DRAWINGS
Figure-1: represents powder X-ray diffractogram of polymorphic form gamma of silodosin.
Figure-2: represents DSC thermogram of polymorphic form gamma of silodosin. 25
10
DETAILED DESCRIPTION OF THE INVENTION
As used herein "form gamma (γ)" means a crystalline silodosin having X-ray diffraction pattern and DSC that substantially corresponds to as given in Figures 1 and 2.
As used herein "crude silodosin" means the silodosin or silodosin base or any 5 polymorphic form of silodosin prepared by prior art processes or can be procured from market. It can be used as such or can be purified.
As used herein "seed of gamma form of silodosin" means the crystal of gamma form of silodosin which can be prepared by using process disclosed in literature or process as discloses herein. 10
As used herein "pure polymorphic form gamma of silodosin" means the crystal of gamma form of silodosin which have residual solvents in specified limits as per ICH guidelines, specifically toluene content less than 890 ppm, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm. 15
As used herein "micronization" means the process of reducing the average diameter of a solid materials particles. Micronization size reduction process involves acceleration of particles so that grinding occurs by particle-to-particle impact or impact against a solid surface.
As used herein "ambient temperature" means temperature of the surrounding. It 20 means any suitable temperature found in the laboratory or the other working quarter, and is generally not below about 15°C to and not above about 30°C.
Accordingly, present invention provides a novel process for preparation of pure polymorphic form gamma of silodosin by incorporating a step of seeding of 25 gamma form of silodosin during crystallization of silodosin. Alternatively pure polymorphic form gamma of silodosin can be prepared by using micronization of
11
polymorphic form gamma of silodosin having unacceptable limits of residual solvent.
Silodosin to be used as the starting material can be prepared by any process known in the literature. According to one aspect, the present invention provides a 5 process for the preparation of gamma form of silodosin by dissolving any polymorphic form of silodosin by heating in a suitable solvent at suitable temperature, cooling the resulting solution, seeding the reaction mixture with the polymorphic form gamma of silodosin, again lowering the temperature, adding a suitable antisolvent, stirring the reaction mass for sufficient time for complete 10 crystallization and isolating pure polymorphic form gamma of silodosin.
The suitable solvent which can be used to dissolve the silodosin is selected from alcoholic solvent such as C2-C6 alcohols, and a mixture of alcoholic solvent with hydrocarbon solvents such as toluene,1,2 and 1,4 xylene and the like. The solution 15 of silodosin can be prepared by heating at a temperature that can vary from 30-100°C depending on the solubility of silodosin in the particular solvent and volume of solvent used. Particularly, the temperature required to dissolve the silodosin can be in range of 30-70°C, preferably temperature can be 40-60°C or the temperature at which silodosin dissolve completely to give clear solution is 20 preferred. The resulting solution is then cooled to temperature ranging between 30-50°C, preferably between 35-45°C. The cooling conditions may be slow, rapid or gradual cooling over a specific time at a specific temperature. In the warm reaction mass, a seed of crystalline gamma form may be added and subsequently reaction mass can be further cooled to ambient temperature to accelerate the 25 crystallization process. Seeding a solution with a crystal of the product is a well-established technique to induce crystallization. It has also been used to encourage the formation of particular polymorph consistently. Seeding is preferably used to
12
obtain crystals of high polymorphic purity, and especially with very high perfection and desired crystal orientation in consistent and reproducible manner. Using the seeding process during crystallization to prepare gamma form of silodosin forms a inventive part of the present invention, which overcome the drawbacks for preparation of gamma form of silodosin, mentioned in prior art. 5
The antisolvent that can used during crystallization includes but not limited to alkane such as n-hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2 and 1,4 xylene; ethers such as methyl tertiary butyl ether or mixtures thereof. After addition of antisolvent, the reaction mass can be further stirred at 10 ambient temperature for sufficient time for complete crystallization. Particularly, the reaction mass can be stirred at a temperature of 5ºC to 30ºC, for few minutes to few hours and preferably from 10 minutes to 4 hour. After complete crystallization, the solid compound can be recovered by known techniques such as filtration or centrifugation, preferably, filtration is carried out at a temperature of 15 5ºC to 30ºC and more preferably at a temperature of 15ºC to 25ºC. Thereafter, the resulting crystalline gamma form of silodosin can optionally be washed with a solvent such as alkane. Washing can be performed by routine wash or can be by slurring of resulting solid in a suitable solvent. Most preferably, the washing can be done using the same antisolvent as is used during crystal formation. Thereafter 20 product can be dried, particularly, drying can be carried out under vacuum at a temperature of about 35 to about 60ºC for the time ranging from few minutes to few hours and preferably from 1 hours to 20 hours. Alternatively, the resulting crystalline gamma form of silodosin can optionally be micronized to further reduced the desired level of residual solvent depending upon the solvent used 25 during crystallization. Although process of present invention as described above, provides crystalline gamma form of silodosin which passes in the criteria of residual solvent limits, still a remarkable lowering of residual solvent can be
13
achieved, if product is micronized. The residual solvents of gamma form of silodosin so obtained, are within limits i.e. toluene content less than 890 ppm by GC, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm.
5
In one other aspect, the present invention provides a process for the preparation of gamma form of silodosin by dissolving any polymorphic form of silodosin in suitable solvent at suitable temperature, filtering the obtained solution through micron filter paper, removing the solvent, dissolving the residue in suitable solvent at suitable temperature, cooling the resulting solution, seeding the reaction 10 mixture with the polymorphic form gamma of silodosin, again lowering the temperature, adding a suitable antisolvent, stirring the reaction mass for sufficient time for complete crystallization and isolating pure polymorphic form gamma of silodosin.
15
The suitable solvent which can be used to dissolve the silodosin is selected from alcoholic solvent especially lower alcohols such as methanol. The suitable temperature for dissolution of silodosin selected from range 15-30˚C preferably room temperature. The obtained solution is filtered using a micron filter paper of suitable size preferably micron filter paper of size ranging from 10-0.22 micron 20 can be used. The solvent from the obtained clear solution can be evaporated using suitable techniques such as distillation or like and the obtained residue is further dissolved in a suitable solvent. The suitable solvent that can be used to dissolve the silodosin is selected from alcoholic solvent such as C2-C6 alcohols, and a mixture of alcoholic solvent with hydrocarbon solvents such as toluene,1,2 and 25 1,4 xylene and the like. The solution of silodosin can be prepared by heating at a temperature that can vary from 30-100oC depending on the solubility of silodosin in the particular solvent and volume of solvent used. Particularly, the temperature
14
required to dissolve the silodosin can be in range of 30-70oC, preferably temperature can be 40-60oC or the temperature at which silodosin dissolve completely to give clear solution is preferred. The resulting solution is then cooled to temperature ranging between 30-50oC, preferably between 35-45oC. The cooling conditions may be slow, rapid or gradual cooling over a specific time 5 at a specific temperature. In the warm reaction mass, a seed of crystalline gamma form may be added and subsequently reaction mass can be further cooled to ambient temperature to accelerate the crystallization process.
The antisolvent that can used during crystallization includes but not limited to 10 alkane such as n-hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2 and 1,4 xylene; ethers such as methyl tertiary butyl ether or mixtures thereof. After addition of antisolvent, the reaction mass can be further stirred at ambient temperature for sufficient time for complete crystallization. Particularly, the reaction mass can be stirred at a temperature of 5ºC to 30ºC, for few minutes 15 to few hours and preferably from 10 minutes to 4 hour. After complete crystallization, the solid compound can be recovered by known techniques such as filtration or centrifugation, preferably, filtration is carried out at a temperature of 5ºC to 30ºC and more preferably at a temperature of 15ºC to 25ºC. Thereafter, the resulting crystalline gamma form of silodosin can optionally be washed with a 20 solvent such as alkane. Washing can be performed by routine wash or can be by slurring of resulting solid in a suitable solvent. Most preferably, the washing can be done using the same antisolvent as is used during crystal formation. Thereafter product can be dried, particularly, drying can be carried out under vacuum at a temperature of about 35 to about 60ºC for the time ranging from few minutes to 25 few hours and preferably from 1 hours to 20 hours. Alternatively, the resulting crystalline gamma form of silodosin can optionally be micronized to further reduced the desired level of residual solvent depending upon the solvent used
15
during crystallization. Although process of present invention as described above, provides crystalline gamma form of silodosin which passes in the criteria of residual solvent limits, still a remarkable lowering of residual solvent can be achieved, if product is micronized. The residual solvents of gamma form of silodosin so obtained, are within limits i.e. toluene content less than 890 ppm by 5 GC, preferably less than 500 ppm, more preferably less than 200 ppm, most preferably less than 100 ppm.
In an another aspect, the present invention provides a process for reducing level of residual solvent from gamma form of silodosin wherein residual solvent is present 10 in greater than specified limit. Generally gamma form of silodosin having toluene content greater than 890 ppm is prepared as per process reported in literature. Particularly gamma form of silodosin is prepared by recrystallization of silodosin in toluene and resulting gamma form have toluene content greater than 1800 ppm. Alternatively, gamma form is prepared by using isopropanol and toluene mixture 15 and resulting gamma form have toluene content greater than 1600 ppm. Reduction in residual solvent content is achieved by using micronization process. In a specific aspect, gamma form of silodosin having toluene content greater than 890 ppm can be micronized followed by drying of resulting compound. The drying can be done under vacuum at a temperature of about 35ºC to about 60ºC for few 20 minutes to few hours. Optionally micronization process can be repeated to achieve residual solvent in specified limit and to maintain the quality of product. In an alternative embodiment, micronized gamma form of silodosin can be purified using a suitable solvent or a mixture of solvent.
25
The suitable solvent that can be used to purify, form gamma of silodosin can be selected from alcoholic solvents such as C2-C6 alcohol, hydrocarbon solvents, alkane solvents, ethers solvents or mixtures thereof. The purification of gamma
16
form using a suitable solvent can be performed before micronization or after micronization to achieve the desired level of product quality and hence these can be performed at various stage of process and can be repeated any number of times, if desired. The resulting compound can be dried under vacuum at a temperature of about 35 to about 60ºC. 5
Further micronization may be performed for semidry compound or wet material, or after the completion of drying of the product. Micronization process may be repeated to get desired specific results. Employing the micronization process along with seeding or independently, either of the process, to achieve the desired 10 level of residual solvent, makes the process of present invention novel and inventive.
In a preferred aspect of the present invention, micronization process has been adopted which is a well known technique to reduce the particle size of substance. 15 In the case of silodosin, reduction of particle size ease the removal of entrapped residual solvent, and this may be achieved due to collision of material under air pressure with walls of micronizer. In a precise manner, small particles upon drying firstly loose the interparticle solvent and if these small particles further stirred in some suitable solvent then intraparticle solvent removes smoothly. As a 20 consequence, problem of residual solvent has been solved which constitutes a novel part of the present invention.
All the above processes and inherent variation of these, yield gamma form of silodosin having residual solvent content much below the recommended ICH limit 25 of residual solvents preferably below 890 ppm, more preferably below 500 ppm most preferably below 100 ppm and thus pass the criteria of ICH guidelines.. Further decrease in the levels of residual solvents also improves the quality of
17
product as entrapped solvent in silodosin makes it sticky and difficult to handle during preparation of tablets and capsules. Particularly, pure gamma form of silodosin, as obtained herein, is non-hygroscopic, solvent free, free flowing, having mean particle size less than 50μm, and thus especially suitable for the preparation of pharmaceutical drug. 5
The polymorphic form gamma of silodosin as prepared herein, is characterized by X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns were measured on PAN analytical, X'pert PRO powder diffractrometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray 10 tube was operated at 40kV and 30mA. The experiments were conducted over the 2θ range of 2.0°-40.0°. One with ordinary skills in the art understands that experimental differences may arise due to differences in the instrument, sample preparation and other factors.
15
The DSC measurements of gamma form of silodosin were carried out on TA Q1000 of TA instrument. The experiments were performed at heating rate of 5 or 10.0 °C/min over a temperature range of 40 °C to 180 °C purging with nitrogen at a flow rate of 50ml/min.
20
Crude silodosin, or any other form of silodosin, as used in the process to prepare pure gamma form of the present invention, can be prepared by any one of the method known in prior art as described in US patent US5,387,603 and EP 1541554 and other prior art available and is not a constrain for the present invention. 25
18
EXAMPLES:
Example 1: Preparation of Polymorphic Form Gamma (γ) of Silodosin using toluene
Silodosin (35.0g) was taken in toluene (350ml) and heated at 65°C to get a clear 5 solution. Thereafter reaction mass was cooled to 20-25°C, stirred for 6.0hours, filtered and washed with toluene, dried under vacuum at 55°C for 15.0hours. Toluene content was found 1872 ppm.
Example 2: Preparation of Polymorphic Form Gamma (γ) of Silodosin using 10 toluene and isopropanol
Silodosin (48 g) was taken in isopropanol (43.2 ml) and toluene (432 ml) and mixture was heated to 50-55°C to obtain clear solution. Thereafter reaction mass was cooled to 20-25°C and stirred for 6.0 hours at 20-25°C. The resulting solid was filtered and washed with toluene (43.2 ml) and dried at 50-55°C for 16 hours 15 to obtain title compound having purity of 99.83 % by HPLC, and toluene content 1672 ppm by GC.
From the above resulting product, (28.9g) was purified in a mixture of toluene (115.6 ml), and isopropanol (11.5 ml) and dried at 55°C for 16 hours to obtain title compound having purity of 99.88 %.and toluene content 1327 ppm. 20
Example 3: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin (15g) having toluene content 1872 ppm, was micronized under air pressure. The micronized product was dried under vacuum at 55°C-600C for 23.0 hours to afford pure polymorphic form gamma of silodosin having toluene 25 content 460 ppm.
Example 4: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin [having toluene content 1327 ppm] was micronized under air pressure. The micronized product was dried under vacuum at 55°C-600C for 16.0 hours to 30
19
afford pure polymorphic form gamma of silodosin having toluene content 350 ppm.
Example 5: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin crude (3.0g) was dissolved in isopropanol (12 ml) at 50˚C and reaction 5 mass was cooled to 35˚C and seed of silodosin gamma form (0.1g) was added. Thereafter reaction mass was again cooled to 15-20˚C and cyclohexane (30 ml) was added to the reaction mass and stirred for further 0.5 hour. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 34 ppm. 10
Example 6: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin crude(3.0g) was dissolved in a mixture of isopropanol (12 ml) and toluene (0.45 ml) at 50˚C. Thereafter reaction mass was cooled to 40˚C and seed of silodosin gamma form (0.1g) was added and further cooled to 30˚C. To the 15 resulting reaction mass, cyclohexane (30 ml) was added, cooled further and stirred for 2.0 hours at 10-15˚C. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 41 ppm.
20
Example 7: Preparation of pure polymorphic form gamma (γ) of silodosin
Silodosin crude(3.0g) was dissolved in isopropanol (12 ml) at 50˚C and reaction mass was cooled to 35˚C and seed of silodosin gamma form (0.1g) was added. Thereafter reaction mass was again cooled to 15-20˚C, cyclohexane(30 ml) was added and stirred for further 0.5 hour at 15-20˚C. The resulting solid, thus 25 obtained was filtered, washed with cyclohexane and dried to afford silodosin polymorphic form gamma. Toluene content was found 62 ppm.
20
Example 8: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin crude (50.0g) was dissolved in methanol and stirred for 10 minutes at room temperature. The obtained clear solution is filtered through micron filter paper of size 0.22 micron and solvent was distilled out under vacuum at 40-45°C.
The residue was dissolved in isopropanol (200 ml) at 50°C and stirred for10 5 minutes. Thereafter reaction mass was cooled to 40-43°C and seed of silodosin gamma form (1.0g) was added and further cooled to 25-30°C. To the resulting reaction mass, cyclohexane (500 ml) was added, cooled further and stirred for 1.0 hours at 15-20°C. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin 10 having toluene content 12 ppm.
Example 9: Preparation of pure Polymorphic Form Gamma (γ) of Silodosin
Silodosin crude (60.0g) was dissolved in methanol and stirred for 10 minutes at room temperature. The obtained clear solution is filtered through micron filter 15 paper of size 0.22 micron and solvent was distilled out under vacuum at 40-45°C.
The residue was dissolved in isopropanol (240 ml) at 50°C and stirred for10 minutes. Thereafter reaction mass was cooled to 40-43°C and seed of silodosin gamma form (1.0g) was added and further cooled to 25-30°C. To the resulting reaction mass, cyclohexane (600 ml) was added, cooled further and stirred for 1.0 20 hours at 15-20°C. The resulting solid, thus obtained, was filtered, washed with cyclohexane and dried to afford pure polymorphic form gamma of silodosin having toluene content 14 ppm.

We Claim
1. A process for the preparation of polymorphic form gamma of silodosin comprises the steps of;
a) dissolving any polymorphic form of silodosin in a suitable solvent by heating at 30-100oC; 5
b) cooling the resulting solution at temperature 30-50oC;
c) seeding with form gamma of silodosin;
d) cooling the resulting solution to ambient temperature;
e) adding a suitable antisolvent;
f) stirring the reaction mixture; 10
g) isolating pure polymorphic form gamma of silodosin; and
h) optionally micronizing polymorphic form gamma of silodosin.
2. The process as claimed in claim 1, wherein in step a) solvent is selected from C2-C6 alcohols and mixtures of C2-C6 alcohols and hydrocarbons 15 such as toluene, 1,2-xylene and 1,4-xylene.
3. The process as claimed in claim 1, wherein in step e) antisolvent is selected from alkanes such as n-hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene; ethers such as 20 methyl tertiary butyl ether or mixtures thereof.
4. A process for the preparation of polymorphic form gamma of silodosin comprises the steps of;
a) dissolving any polymorphic form of silodosin in a suitable solvent by 25 heating;
b) cooling the resulting solution at temperature 30-50oC;
c) seeding with form gamma of silodosin;
22
d) cooling the resulting solution to ambient temperature; and
e) isolating pure polymorphic form gamma of silodosin.
5. The process as claimed in claim 4, wherein in step a) solvent is selected from C2-C6 alcohols and mixtures of C2-C6 alcohols and hydrocarbons. 5
6. A process for the preparation of polymorphic form gamma of silodosin, wherein residual solvents are present in specified limits as per ICH guidelines comprises the steps of;
a) providing polymorphic form gamma of silodosin having toluene content 10 greater than 890 ppm;
b) micronizing polymorphic form gamma of silodosin;
c) optionally refluxing the micronized compound in a suitable solvent;
d) drying the resulting compound;and
e) isolating polymorphic form gamma of silodosin having toluene content 15 less than 890 ppm.
7. The process as claimed in claim 6, wherein in step c) suitable solvent is selected from C2-C6 alcohols; hydrocarbons; alkanes; ethers such as methyl tertiary butyl ether or mixtures thereof. 20
8. A process for the preparation of polymorphic form gamma of silodosin, comprises the steps of;
a) dissolving any polymorphic form of silodosin in a suitable solvent by heating at 15-30oC; 25
b) filtering the obtained solution through micron filter paper;
c) removing the solvent;
23
d) dissolving the residue in suitable solvent at suitable temperature at 30-
100oC;
e) cooling the resulting solution at 30-50oC;
f) seeding with form gamma of silodosin;
5 g) cooling the resulting solution to ambient temperature;
h) adding a suitable antisolvent;
i) stirring the reaction mixture;
j) isolating pure polymorphic form gamma of silodosin; and
k) optionally micronizing polymorphic form gamma of silodosin.
10
9. The process as claimed in claim 8, wherein in step a) solvent is selected
from C2-C6 alcohols; in step d) solvent is selected from C2-C6 alcohols and
mixtures of C2-C6 alcohols and hydrocarbons such as toluene, 1,2-xylene
and 1,4-xylene; in step h) antisolvent is selected from alkanes such as n15
hexane, cyclohexane, cycloheptane; hydrocarbons such as toluene, 1,2-
xylene, 1,4-xylene; ethers such as methyl tertiary butyl ether or mixtures
thereof.
10. A pure polymorphic form gamma of silodosin wherein residual solvent
20 i.e., toluene present in less than 890 ppm as specified in ICH guidelines.