The present invention relates to a novel polymorphic form of Tazarotene. The novel polymorphic form is designated as Form A of tazarotene. The invention further relates to the process for the preparation and pharmaceutical compositions useful in the treatment of patients having stable plaque psoriasis and facial acne vulgaris with Form A of tazarotene.
Tazarotene, a substituted thiochroman derivative of Formula I, is a member of topically used acetylenic class of retinoids and indicated for the topical treatment of patients with stable plaque psoriasis of up to 20% body surface area involvement and for the topical treatment of patients with facial acne vulgaris of mild to moderate severity. Tazarotene is chemically known as ethyl 6-[2-(4,4-dimetylthiochroman-6-yl)ethynyl]nicotinate and commercially available in the market as Tazorac® Gel and Avage® Cream for topical use.
(FORMULA REMOVED)

US Patent No. 5,420,295, US Patent No. 5,519,150, PCT Patent Application WO 95/19973 and European Patent No. 0,740,665 provide a synthetic methodology for preparation of substituted thiochroman derivatives. US Patent No. 5,089,509 and US Patent No. 5,717,094 provide a method for preparation of tazarotene and related compounds. The process provided in US '094 and US '509 patents provides tazarotene by flash chromatography as yellow solid.
The present inventors have now prepared tazarotene in novel polymorphic form, designated as Form A of tazarotene. The present polymorphic form of tazarotene is obtained as pure white crystals. Thus the present invention provides a simple process to prepare a pure form of tazarotene, which is free from coloring impurities.
A first aspect of the present invention provides a polymorphic Form A of tazarotene having typical XRPD pattern as depicted in Figure 1 of the accompanied drawing. The XRPD of Form A shows characteristic 29 values at 10.36, 13.71, 15.16, 15.31, 16.37, 18.47, 20.81, 21.84, 23.14, 23.97, 24.34, 25.02 and 25.12. Form A of tazarotene is further characterized by a XRPD pattern comprising 29 values at 10.36, 11.13, 12.28, 13.71, 14.56, 14.74, 15.16, 15.31, 16.37, 17.48, 18.47, 18.87, 19.20, 20.25, 20.42, 20.81, 21.37, 21.50, 21.84, 22.32, 22.86, 23.14, 23.97, 24.34, 25.02, 25.12, 26.16, 26.73, 27.00, 27.62, 28.52, 28.60, 29.37, 30.16, 30.83, 31.24, 32.01, 32.44, 32.96, 33.57, 34.10, 34.72, 35.00, 35.44, 36.35, 37.86, 38.32, 38.71 and 39.53. The novel polymorphic Form A has characteristic DSC thermogram as depicted in Figure 2 of the accompanied drawing. The DSC thermogram shows one characteristic endothermic peak at 97°-110°C. The novel polymorphic Form A has characteristic FTIR spectrum as depicted in Figure 3 of the accompanied drawing.
A second aspect of the present invention provides a process for the preparation of novel polymorphic Form A of tazarotene, which comprises of
treating tazarotene with a first organic solvent,
partially removing the solvent from the reaction mixture,
treating the resultant reaction mass with a second organic solvent,
isolating Form A of tazarotene from the reaction mass thereof.
Tazarotene prepared by any method known in the art can be used as starting material. Tazarotene is dissolved in a first organic solvent selected from a group comprising of acetone, methyl ethyl ketone, acetonitrile and C1-4 alkanol. The solution can be raised to a temperature of 40° to 50°C while dissolving. The solution is optionally filtered and the resultant solution is evaporated under vacuum to partially remove the solvent. A second organic solvent aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, C2-7 ethers and C3-10 cycloalkanes is added to the resultant reaction mixture and stirred at a temperature of about 20°C or less. The resultant solid is separated by filtration and washed with same or different organic solvent. The solid so obtained is dried to get Form A of tazarotene.
A third aspect of the present invention provides a pharmaceutical composition comprising polymorphic Form A of tazarotene optionally containing an excipient / diluent.
A fourth aspect of the present invention provides a method of treatment of patients with stable plaque psoriasis and facial acne vulgaris with Form A of tazarotene which comprises of administering a therapeutically effective amount of polymorphic Form A of tazarotene.
Figure 1 depicts XRPD of Form A of tazarotene. Figure 2 depicts DSC of Form A of tazarotene. Figure 3 depicts FTIR of Form A of tazarotene.
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
FT-IR of the samples were determined by using lnstrument: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.
DSC thermograms were recorded using DSC821 e, Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-350° C, Heating rate: 20° C/min, Nitrogen 80.0 mL/min, Number of holes in the crucible: 1
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 A OF TAZAROTENE:
Crude tazarotene (5 g) was dissolved in acetone (15 ml) at 45° to 50°C. The solution so obtained was charged with activated charcoal (0.25 g) and stirred for 30 minutes at 45° to 50°C. The solution was filtered through celite bed and washed with acetone (5 ml). The filtered solution was distilled under vacuum to obtain the volume of 10 ml of acetone followed by the addition of hexanes (20 ml). The reaction mixture was cooled to ambient temperature and stirred for 30 minutes. The reaction mixture was further cooled further to 10°C and stirred for 1 hour. The reaction mass was filtered and washed with hexanes (10 ml). The solid was dried under vacuum at ambient temperature to get 3.7 g of title compound as white crystalline powder.
Yield: 3.7 g HPLC purity: 99%

WE CLAIM:
1. Polymorphic Form A of tazarotene.
2. Polymorphic Form A of tazarotene having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1.
3. Polymorphic Form A of tazarotene having a XRPD pattern wherein characteristic 29 values are obtained at 10.36, 13.71, 15.16, 15.31, 16.37, 18.47, 20.81, 21.84, 23.14, 23.97, 24.34, 25.02 and 25.12.
4. Polymorphic Form A of tazarotene as claimed in claim 3, wherein characteristic 20 values further comprise 10.36, 11.13, 12.28, 13.71, 14.56, 14.74, 15.16, 15.31, 16.37, 17.48, 18.47, 18.87, 19.20, 20.25, 20.42, 20.81, 21.37, 21.50, 21.84, 22.32, 22.86, 23.14, 23.97, 24.34, 25.02, 25.12, 26.16, 26.73, 27.00, 27.62, 28.52, 28.60, 29.37, 30.16, 30.83, 31.24, 32.01, 32.44, 32.96, 33.57, 34.10, 34.72, 35.00, 35.44, 36.35, 37.86, 38.32, 38.71 and 39.53.
5. Polymorphic Form A of tazarotene having a DSC thermogram as depicted in Figure 2.
6. Polymorphic Form A of tazarotene having a DSC thermogram wherein a characteristic endothermic peak is obtained at 97°-110°C.
7. Polymorphic Form A of tazarotene having a FTIR spectrum as depicted in Figure 3.
8. A process for the preparation of novel polymorphic Form A of tazarotene, which
comprises of
a) treating tazarotene with a first organic solvent,
b) partially removing the solvent from the reaction mixture,
c) treating the resultant reaction mass with a second organic solvent,
d) isolating Form A of tazarotene from the reaction mass thereof.

9. A process according to claim 8, wherein the first organic solvent is selected from a group comprising of acetone, methyl ethyl ketone, acetonitrile and C1-4 alkanol.
10. A process according to claim 8, wherein the second organic solvent is selected from a group comprising of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, C2-7 ethers and C3-10 cycloalkanes.