FIELD OF THE INVENTION
The present invention relates to novel crystalline polymorph of Luliconazo'le HBr salt.
The present invention further relates to commercial manufacturing process for the preparation of chirally pure Luliconazole using crystalline form-S of Luliconazole HBr salt, wherein the process is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Luliconazole is an antifungal agent developed by Nihon Nohyaku. Luliconazole is approved by FDA in 2013. Luliconazole is marketed by Medicis Pharmaceutical Corp under the brand name LUZU. Luliconazole is chemically described as (2E)-2-[(4R)-4-(2.4-dichlorophenyl)-l53-dithiolan-2-ylidene]-2-imidazol-l-ylacetonitrile. Its structural formula is
Formula 1 The molecular formula of Luliconazole is C14H9CI2N3S2 with a molecular weight of 354.28. Luliconazole is the R-enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration.
Luliconazole is disclosed in US 5,900,488, this patent also discloses the process for the preparation of Luliconazole by reacting (S^-bromo-l-^^-dichlorophenyOethyl methanesulfonate with potassium salt of 3,3-dimercapto imidazole intermediate to give Luliconazole. The process is shown in the scheme given below:
Scheme I:

US '488 discloses the use of silica gel chromatography technique for the purification of Luliconazole, which is highly disadvantageous at bulk level. Hence, the said process is not feasible at industrial level.
Glenmark's US 2017/0362212 Al generically discloses Luliconazole purification using acid additions salt of Luliconazole, this application though discloses crystalline Luliconazole HC1 but it is silent about the polymorphic nature of other salts of Luliconazole.
Zhejiang East Asia Pharmaceutical's CN 105541813 B discloses various acid salts of Luliconazole. This patent specifically discloses the preparation of Luliconazole HBr salt using aq hydrobromic acid. The melting range disclosed in this patent for Luliconazole HBr is 240.5-242.1°C. The melting range of novel crystalline form-S of Luliconazole prepared according to the present invention is quite different to the melting range of Luliconazole HBr disclosed in CN '813.
The present inventors have developed novel crystalline polymorph of Luliconazole HBr salt and its use in the commercial manufacturing process for the preparation of chirally • pure Luliconazole, wherein the process is highly cost effective, commercially feasible & industrially advantageous.
OBJECT OF THE INVENTION
The main object of the invention is to provide novel crystalline form-S of Luliconazole HBr salt.
The second object of the invention is to provide a simple, cost effective, robust an improved commercial manufacturing process for chirally pure Luliconazole using crystalline form-S of Luliconazole HBr salt.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel crystalline form-S of Luliconazole HBr salt of formula-IA

Formula-I A
which is characterized by an X-ray powder diffractionpattern which comprises 20 values in degrees of 12.1, 21.8, 23.5, 24.6, 25.7 and 29.0 or characterized by the DSC thermogram as depicted in Figure 2.
In a preferred aspect, the present invention provides a process for the preparation of chirally pure Luliconazole of formula-I
Formula-I which comprises, treating crystalline form-S of Luliconazole HBr salt with a base in the presence of a solvent.
In another preferred aspect, the present invention provides a process for the preparation of chiraliy pure Luliconazole of fomiula-I
Formula-I which comprises, a) Diluting crystalline form-S of Luliconazole HBr salt in a aqueous organic solvent,
b) Treating step-a solution with organic or inorganic base,
c) Extracting chirally pure Luliconazole of compound of formula-].
preparation of crystalline form-S of Luliconazole HBr salt of compound of formula-IA

which comprises, treating a mixture comprising Luliconazole and the stereoisomer/s thereof with a salt forming agent in the presence of a solvent to obtain crystalline form-S of Luliconazole HBr salt.
In yet another preferred aspect, the present invention provides a process for the preparation of crystalline form-S of Luliconazole HBr salt of compound of formula-IA
which comprises,
a) Dissolving a mixture comprising Luliconazole and the stereoisomer/s thereof in a solvent,
b) Treating step a) solution with HBr in acetic acid.
c) Maintaining the temperature between 50-'80cC,
d) Isolating the precipitated crystalline form-S of Luliconazole HBr salt.
BRIEF DESCRIPTION OF THE PRAWINGS
FIG. 1 is the X-ray powder diffraction pattern for the crystalline form-S of Luliconazole HBr.
FIG. 2 is the DSC curve for the crystalline form-S of Luliconazole HBr.
DETAILED DESCRIPTfON'OF THE INVENTION
Accordingly, the solvent used in the present invention is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethyisulfoxide. dimethylacetamide, dimethyl formamide. acetonitrile. propionitrile, butyroniirile,
dicxane, methyltert- butylether. ethyl terl-butyi etherj tetrahydrofuran and dimethoxyethane,

methylene chloride, ethylene dicriloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl- ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
The term base used in the present invention is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHCO3, LiHC03, Na2C03, K2C03, Li2C03, CaC03. MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide. magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2s MgHOMe:.MgHOEt, CaH2; Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
Salt forming agent as described in the present invention is selected from Bromine gas, HBrin acetic acid, bromotrichloromevhane, carbon letrabromide, dibromo-dichloromethane. l-bromo-l,l-dichloroethane, N-bromosuccinimide, l,3-dibromo-5,5-dimethyl hydantoin and N-bromoaoetamide.
The term stereoisomer/s refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
In a preferred embodiment, the present invention provides novel crystalline form-S of Luliconazole HBr salt of formuIa-IA.
degrees of J.2.1, 21.8, 23.5, 24.6, 25.7 and 29.0 or characterized by the DSC thermogram as

depicted in Figure 2.
In a further embodiment crystalline form-S of Luliconazole HBr salt is characterized by an X-ray powder diffraction pattern obtained using copper Ka radiation, which comprises 2Q values (i.e., reflections at 20 values) in degrees of 4.1, 12.1, 15.6, 21.8, 23.5, 24.6, 25.7, 28.4, 29.0, and 29.9.
In a further embodiment crystalline form-S of Luliconazole HBr salt of originally defined or as defined in the foregoing aspect, and further characterized by a differential scanning calorimetry curve, obtained at a heating rate of 10° C./min, exhibiting a onset peak temperature of about 218° C±1°C and maximum at 224°C±1°C.
In yet another preferred embodiment, the present invention further provides the conversion of crystalline form-S of Luliconazole HBr salt to chirally pure Luliconazole wherein the content of Z or SE isomer of Luliconazole is less than 0.5% w/w with respect to Luliconazole as measured by HPLC.
In yet another preferred embodiment, the present invention provides a process for the preparation of chirally pure Luliconazole of formula-I
which comprises,
a) Diluting crystalline form-S of Luliconazole HBr salt in a aqueous organic solvent,
b) Treating step-a solution with organic or inorganic base,
c) Extracting chirally pure Luliconazole of compound of formula-I.
The conversion specifically involves diluting Luliconazole HBr salt with water, ethylacetate and adjusted pH-8.5-9.5 with liquor ammonia solution and again extracted with
activated carbon treatment. The resulting crude material after successful removal of solvent

was isolated in 1:1 solvent volume ratio cyclohexane and ethyl acetate afford chirally pure Luliconazole.
In yet another preferred embodiment, the present invention provides a process for the
preparation of crystalline form-S of Luliconazole HBr salt of compound of formula-IA
which comprises, treating Luliconazole with HBr in acetic acid in the presence of ethyl acetate to obtain crystalline form-S of Luliconazole HBr salt.
In yet another preferred embodiment, the present invention provides a process for the oreDaration of crystalline form-S of Luliconazole HBr salt of compound of formula-IA
which comprises,
a) Dissolving crude Luliconazole in ethyl acetate.
b) Treating step a) solution with HBr in acetic acid, c). Maintaining the temperature between 50-80°C,
d) Isolating the precipitated crystalline form-S of Luliconazole HBr salt.
Process for the preparation of chirally pure Luliconazole according to the present invention is briefly depicted in the scheme giver, below:

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. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example-1: Preparation of (S)-2-ChIoro-l-(2, 4-dichlorophenyl) ethylmethanesulfonate:
In a 500M1 RB flask 100.0 gms of (SVl-(2s4-Dichlorophenyl)-l;2-ethenediol and 90.0gm of Triethylamine are taken in 1000.0ml of Methylene chloride under gentle stirring and then reaction mass was cooled to -5 to 0°C. 76.0gms of Methane sulfonyl chloride was added dropwise at -5 to 0°C. After complete addition of Methane sulfonyl chloride the reaction mixture was stirred for 30minutes. Reaction mass was sent for HPLC monitoring, once HPLC complies the reaction mixture temperature was raised to room temperature and washed with water (3x600 ML ) to remove excess of Triethylamine and the organic layer was dried over anhydrous sodium sulphate. The dried organic phase was distilled off under reduced pressure. The obtained crude material was isolated in cyclohexane (500.0ml), The filtered solid was dried and reported the yield. Yield: 120 gm, HPLC purity: NLT 99% .
Example-2: (2E)-2-[(4R)-4-(2, 4-Dich!orophenyl)-l. 3-di thiolan-2-ylidcne]-2-imidazol-i-ylacetonifrilc:
30.0 gm of carbon disulfide (CS2) and 340.OmL of DMSO added drop wise to a uniform

solution of,40.0g of potassium hydroxide and 340.0ml of DMSO and the reaction mixture was maintained for 120-140 minutes under gentle stirring at room temperature to afford SK. salt of 1-cynomethylimidazole.The obtained in-situ SK salt reaction mixture was cooled to 10-15°. To above cooled solution added a solution of 100.0 gm of (S)-2-chloro-l-(234-dichlorophenyl) ethylmethanesulfonate 340.0mL of DMSO dropwise at 10-15°.The reaction mixture was stirred for 60 minutes, Once starting material HPLC is complies. The reaction mixture was quenched into another Round bottom flask which contains 3300.0 mL of Water at 10-15° and then extracted with ethyl acetate (2x1500.0ml). The combined organic layers were washed with water (2000.0mL), with saturated Brine solution.
ExampIe-3:
Preparation of Luliconazole HBr salt in Acetic acid:
The crude Luliconazole material obtained after removal of solvent under reduced pressure was isolated as HBr salt by dissolving it in ethyl acetate (1000.0ml) completed further raised the temperature to 60-65° and maintained it for 180-240 minutes. The precipitated HBr salt in acetic acid and ethyl acetate was cooled to 10-15°. The resulting pure Luliconazole HBr salt was filtered and washed with ethyl acetate to obtain crystalline form-S of Luliconazole characterized by PXRD pattern as depicted in Fig-1.
ExampIc-4: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, . 500.00 mL of ethylacetale and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with. Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in 1:1 solvent volume ratio vyclohexane and ethyl acetate at 25-35° afford 65 gms of chirally pure Luliconazole.
Exnmplc-5: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of ethylacetate and Adjusted pH - 8.5-9.5 with aqueous sodium carbonate solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers
material after successful removal of solvent was isolated in 1:1 solvent volume ratio cyclohexane and ethyl acetate at 25-35° afford 65 ems of chirally pure Luliconazole.

Example-6: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of Ethylacetate and adjusted pH - 8.5-9.5 with TEA and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in 1:1 solvent volume ratio Cyclohexane and Ethyl acetate at 25-35° afford 65 gms of chirally pure Luliconazole.
Example-7: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of ethylacetate and adjusted pH ~ 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in 1:1 solvent volume ratio n-hexane and ethyl acetate at 25-35° afford 65 gms of chirally pure Luliconazole.
Example-8: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of ethylacetate and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in 1:1 solvent volume ratio n-heptane and ethyl acetate at 25-35° afford 65 gms of chirally pure Luliconazole.
Example-9: Preparation of Chirally Pure Luliconazole:
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of ethylacetate and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in n-heptane at 25-35° afford 75 gms of chirally pure Luliconazole.

Example-tO: Preparation of Chirally Pure Luliconazole
. Luliconazole HBr salt obtained from example 3 was diluted with 600.0'*mL of water; 500.00 mL of ethylacetate and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 2-00.00mL of ethyl acetate and the combined organic layers were finally washed with water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in cyclohexane at-25-35° afford 70 "gms of chirally pure Miconazole.
Example-11: Preparation of Chirally Pure Luliconazole
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water, 500.00 mL of ethylacetate and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in ethyl acetate at 25-35° afford 60 gms of chirally pure Luliconazole.
'Examplc-12: Preparation of Chirally Pure Luliconazole
Luliconazole HBr salt obtained from example 3 was diluted with 600.0 mL of water. 500.00 mL of ethylacetate and adjusted pH - 8.5-9.5 with liquor ammonia solution and again extracted with 200.00mL of ethyl acetate and the combined organic layers were finally washed with Water followed by activated carbon treatment. The resulting crude material after successful removal of solvent was isolated in 1:1 solvent volume ratio hexanes and ethyl acetate at 25-35° afford 65 gms of chirally pure Luliconazole.

We claim,
1. A novel crystalline form-S of Luliconazole HBr salt of formula-IA
rormuia-lA which is characterized by an X-ray powder diffraction pattern which comprises 20 values in degrees of 12.1, 21.8, 23.5, 24.6, 25.7 and 29.0 or characterized by the DSC thermogram as depicted in Figure 2.
2. Crystalline form-S of Luliconazole HBr as claimed in claim 1, further characterized by X-ray powder diffraction pattern obtained using copper KQ radiation, which comprises 28 values (i.e., reflections at 29 values) in degrees of 4.1, 12.1, 15.6, 21.8, 23.5, 24.6, 25.7, 28.4, 29.0, and 29.9.
3. A process for the preparation of chirally pure Luliconazole of formula-I
which comprises, treating crystalline form-S of Luliconazole HBr salt with a base in the presence of a solvent.
4. A process as claimed in claim 3, wherein the solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether. dielhylether, diisopropyl ether. 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofurari and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone,

- butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
S A nrnppcc fnr thp nrpnarntinn nf rhirnllv r\nrf» T nlinnnn^nlp nFfrtrmiiln-T
which comprises,
a) Diluting crystalline form-S of Luliconazole HBr salt in a aqueous organic solvent,
b) Treating step-a solution with organic or inorganic base,
c) Extracting chiraliy pure Luliconazole of compound of formula-I.

6. A process as claimed in claims 3 & 4, wherein the chiraliy pure Luliconazole comprises Z or SE isomer of Luliconazole less than 0.5% w/w with respect to Luliconazole as measured by HPLC.
7. A process for the preparation of crystalline form-S of Luliconazole HBr salt of compound offormula-IA
which comprises, treating a mixture comprising Luliconazole and the stereoisomer/s thereof with salt forming agent in the presence of a solvent to obtain crystalline form-S of Luliconazole HBr salt.
8. A process for the preparation of crystalline form-S of Luliconazole HBr salt of compound offormula-IA

which comprises,
a) Dissolving a mixture comprising Luliconazole and the stereoisomer/s thereof in a solvent,
b) Treating step a) solution with HBr in acetic acid,
c) Maintaining the temperature between 50-80°C,
d) Isolating the precipitated crystalline form-S of Luliconazole HBr salt.