DESC:Field of the invention:
The present invention relates to a novel process for the preparation of a hormone, Ethinyl estradiol. Particularly, the invention relates to the preparation of a high purity Ethinyl estradiol using a novel Ethinyl estradiol-dimethyl formamide solvate having 1:1 molecular ratio.

Background of Invention:
Estrogens such as estradiol are the essential hormones for the development of primary and secondary female sex characteristics. 17a-ethynylestradiol is a synthetic hormone, which is a derivative of the estradiol. Ethinyl estradiol is the most commonly used medication for cases of estrogen deficiency in humans as well as in livestock.

Ethinyl estradiol, chemically designated as 19-Nor-17a-pregna-1,3,5(10)-trien-20-yne-3,17-diol and having following chemical formula.

It is also having other synonyms such as 17-Ethynylestradiol, 17a-Ethinyl estradiol (EE2) and 17a-Ethynylestra-1,3,5(10)-triene-3,17ß-diol.
It was first reported in US2251939 and was prepared by reacting estrone with acetylene in ether solvent in presence of sodium amide base. Drawbacksof this process includeuse of sodium amide base which is extremely hazardous and highly corrosive. Use of sodium amide base is replaced with sodium methoxide in subsequent patent, US3646076. In this patent, estrone and sodium methoxide was reacted first in methanol. Then the methanol was distilled and added dimethylformamide solvent followed by reaction with acetylene in presence of acetylide-ethylenediamine complex to obtain Ethinyl estradiol. The process mentioned in this patent involves use of acetylide-ethylenediamine complex which is not commercially available and hence the process is industrially not feasible. Another patent, FR1453212, reported preparation of 17-ethinyl estradiol antipodal form by reacting the estrone antipodal form with acetylene in presence of anhydrous ammonia gas and potassium metal at -40°C. This process also involves operating at -40°C temperature which is not feasible commercially. Another patent, DD114807A1, reported reaction of estrone with acetylene in mixture of dioxane and dimethyl formamide solvents at 8°C. After completion of reaction, the reaction mass was worked up and extracted with chloroform to isolate crude Ethinyl estradiol. The crude product was re-crystallised from acetone solvent. However, this process found to be giving impurities with low yield. A journal, Cryst. Growth Des., 2008, 8 (3), pp 823-831, reported various solvates of Ethinyl estradiol including Ethinyl estradiol-hemihydrate and Ethinyl estradiol -dimethyl formamide solvate. As per the crystal structural data published in the paper, Ethinyl estradiol -dimethyl formamide solvate exists in the molecular ratio of 1:2 (herein after referred as Ethinyl estradiol: dimethyl formamide solvate (I)). The DMF solvate was prepared by heating saturated solution of dimethyl formamide (obtained by dissolving Ethinyl estradiol in dimethyl formamide solvent) to a temperature of about 10 °C to below their boiling points and cooled to room temperature. However, the paper didn’t mention the procedure for preparation of Ethinyl estradiol.

A thesis titled “Crystal Growth Using Low Temperature Gradient Sublimation in Vacuo” by KarpinskaJolanta, published on 27/09/2012, reported XRPD characteristic values of the Ethinylestradiol-dimethyl formamide solvate (1:2) ratio. The values are: 14.80, 15.50, 15.70, 16.45, 25.40,25.65,26.00,26.45,26.85,27.55,28.10 & 39.10.

Therefore, the object of the invention is to provide a novel process for preparation of high purity and stable Ethinyl Estradiol drug substance which is economical and industrially applicable to produce pure form with fewer impurities.
Summary of invention
In line with the above objective, there is provided a process for preparation of Ethinyl estradiol which comprises;
a) Reacting estrone with acetylene in presence of a base in dimethyl formamide solvent to obtain Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio; and
b) Desolvating (breaking) the EE-DMF solvate having 1:1 ratio using organic solvents to obtain high purityEthinyl estradiol.

According to an aspect, the invention providesa process for obtaining stable anhydrous form (Form-I) of Ethinyl Estradiol by desolvation of Ethinyl Estradiol DMF Solvate (1:1), which is referred herein afterEthinyl Estradiol DMF solvate (II). Accordingly, the anhydrous form (Form-I) of Ethinyl Estradiol is prepared by process comprising the steps of;
a) dissolving Ethinyl estradiol-dimethyl formamide solvate (1:1) wet cake in an organic solvent selected from esters or ethers, followed by washing the dissolved solution with water;
b) treating the solution with activated carbon followed by concentrating the solution to obtain concentrated mass;
c) dissolving the concentrated mass in a hydrocarbon solvent optionally under heating followed by cooling the mass to ambient temperature to isolate wet cake; and
d) drying the wet cake at a temperature range of 50 to 80°C to obtain Ethinyl estradiol in polymorphic form-I (anhydrous form).

In an alternate aspect, the invention provides a process for obtaining hemihydrate Form (Form-II) of Ethinyl Estradiol by desolvation of Ethinyl Estradiol DMF Solvate (1:1). In accordance with this aspect, the Ethinyl Estradiol hemihydrate Form (Form-II) is prepared by a process comprising the steps of;
a) treating the wet cake of Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio with water at about 50-60°C to obtain a slurry; and
b) filtering the slurry; washing the cake with water and drying to get Ethinyl Estradiol Form-II (hemihydrate form).
According to another aspect of the invention, there is provided a novel solvate,Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate (II) having 1:1 molecular ratio.The novel solvate, Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 molecular ratio, is prepared by a process comprising the steps of;
a) reacting estrone with acetylene in presence of a base in dimethyl formamide solvent at about 0°C; and
b) quenching the reaction mass with water followed by adjusting the pH of the reaction mass to about 5.5 using dilute HCl solution to obtain Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio.
According to yet another aspect, the novel solvate, Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 molecular ratio is characterized by 1H – NMR, 13C- NMR, DSC and XRPD, as depicted in Figs 1 to 9.

BRIEF DESCRIPTION OF DRAWINGS:

Figure 1: 1H - NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 2: Expansion of 1H - NMR Ethinyl estradiol solvate (1:1 ratio)
Figure 3: Expansion of 1H - NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 4: 13C- NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 5: Expansion of 13C- NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 6: Expansion of 13C- NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 7: Expansion of 13C- NMR of Ethinyl estradiol solvate (1:1 ratio)
Figure 8: DSC of Ethinyl Estradiol DMF solvate (New polymorph)
Figure 9: XRPD of Ethinyl Estradiol - Dimethyl formamide solvate (1:1)
Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.
The invention is directed to preparation of Ethinyl estradiol in pure form with less impurities. Accordingly, the present invention provides a process for preparation of Ethinyl estradiol which comprises;
a) Reacting estrone with acetylene in presence of a base in dimethyl formamide solvent to obtain Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio; and
b) Desolvating the EE-DMF solvate having 1:1 ratio using organic solvents to obtain pure Ethinyl estradiol.

According to an embodiment, the invention provides a process for obtaining stable anhydrous form(Form-I) of Ethinyl Estradiol by desolvation of Ethinyl Estradiol DMF Solvate (1:1).In an alternate embodiment, the invention provides a process for obtaining hemihydrate Form (Form-II) of Ethinyl Estradiol by desolvation of Ethinyl Estradiol DMF Solvate (1:1).
Accordingly, in one embodiment, Estrone solution is first prepared by dissolving Estrone in dimethyl formamide. About 7 to 14 mL N,N-dimethyl formamide (DMF) per gram of Estrone is taken for dissolution. After addition of estrone into DMF, the mixture is stirred well to make clear solution. Optionally, the mixture may be warmed to make clear solution. In another flask, a base is added into DMF at ambient temperature under nitrogen atmosphere. The base is selected from the group consisting of alkali metal hydroxide, alkali metal alkoxides and carbonates. Even more preferably, the base is selected from the group consisting of potassium hydroxide, potassium methoxide and tertiary butoxide. However, most preferred base is potassium tertiary butoxide.
Usually DMF is taken about 6 to 10 mL per gm of estrone. Preferably, total DMF (DMF charged along with estrone and potassium-t-butoxide) charged for the reaction is 160 to 220 mL per gm of estrone,whereas, potassium t-butoxide is charged about 1 to 4 moles per mole of estrone. Preferably, the base is charged 1.5 to 3 mole per mole of estrone. The reaction mass is cooled to less than 0°C;preferably, to -15°C to -5°C and passed acetylene gas into the reaction mass. Usually acetylene is required to be passed in molar equivalentsthatis greater than molar equivalents ofthe starting material, estrone. Preferably, acetylene is passed in a range between 2 to 6 moles per mole of estrone. Most preferably, acetylene gas is passed in a range between 3 to 4 moles per mole of estrone. To the obtained reaction mass, previously prepared estrone solution in DMFis added slowly over a period of an hour at about 0°C. After completion of addition, the reaction mass is further maintained for about an hour at the same temperature till completion of reaction. The progress of the reaction may be checked by HPLC by monitoring the content of un reacted Estrone.
After completion of reaction, the reaction mass is worked up by quenching with water to precipitate the product and then adjusted pH of the reaction mass to about 5.5 using dilute HCl solution. The obtained slurry is filtered and washed with water to obtain Ethinyl estradiol-dimethyl formamide solvate.Ethinyl estradiol to dimethyl formamide solvate ratio found to be 1:1.
The formation of Ethinyl estradiol to dimethyl formamide solvate in molecular ratio of 1:1 is further confirmed bychanging the temperature while drying the product.
The Ethinyl estradiol to dimethyl formamide solvate(II) in (1:1) ratio obtained in accordance with the present invention is then subjected to PXRD; characteristic 2 ? peaks at14.63,16.22,25.24 ± 0.2are observed. The Ethinyl estradiol to dimethyl formamide solvate in (1:1) molecular ratio is hither to unknown polymorphic form.
Contrary to the Ethinyl estradiol to dimethyl formamide solvate (1:1) ratio, the Ethinyl estradiol-dimethyl formamide solvate (1:2) ratio exhibits characteristic XRPD values at 14.80, 15.50, 15.70, 16.45, 25.40,25.65,26.00,26.45,26.85,27.55,28.10 & 39.10asreportedin a thesis titled “Crystal Growth Using Low Temperature Gradient Sublimation in Vacuo” by KarpinskaJolanta, published on 27/09/2012.
According to a preferred embodiment of the invention, the obtained Ethinyl estradiol-dimethyl formamide solvate (1:1) is subjected for de-solvation to obtain high purity Ethinyl estradiol.
Accordingly, the obtained Ethinyl estradiol-dimethyl formamide solvate (1:1) wet cake is dissolved in suitable organic solvents that include esters or ethers. The esters include ethyl acetate, Isopropyl acetate and butyl acetate and theethers include diisopropyl ether or diethyl ether. However, the preferred solvent is an ester, more preferably, the ester is ethyl acetate.
Usually the quantity of the solvent used for dissolution may be in the range of 3 to 10 mL per gram of the wet cake. However, 4 to 7 mL of the solvent is preferred for dissolution. After adding the solvent, the reaction mass may be warmed to get clear solution. The obtained solution is washed with water followed by layers separation to obtain the product in organic layer.
The organic layer/solution is further treated with activated carbon for about an hour. Then filtered the reaction mass on hyflo and the filtrate is concentrated under vacuum at about 50-60°C to obtain concentrated semi solid mass.
To the concentrated semi solid mass, added aliphatic hydrocarbon or aromatic hydrocarbon solvent. Aliphatic hydrocarbon solvent includes n-hexane, cyclohexane and n-heptane. Aromatic hydrocarbon solvent includes toluene and xylene. However, n-heptane solvent is preferred from aliphatic hydrocarbon solvents. The hydrocarbon solvents may be added in the range of 4 to 7 mL per gram of the Ethinyl estradiol-dimethyl formamide solvate (1:1). The slurry, obtained upon addition of the solvent, may be heated to below the reflux temperature of the solvent for about 2 hours. Then cooled the slurry slowly to ambient temperature, filtered and washed with the same solvent. The obtained cake is dried under vacuum at about 50-60°C for about 4 hours followed by further drying at about 65-80°C for 10-18 hours to obtain Ethinyl estradiol in polymorphic form-I(anhydrous form).
The purity of ethinyl estradiol so obtained by this method was found to be more than 95.5 % and any individual impurity was found to be less than 0.1%.
In an alternate embodiment, Ethinyl estradiol-dimethyl formamide solvate (1:1) wet cake may be treated with water at about 50-60°C to obtain a slurry. Then filtered the slurry and washed the cake with water and dried to get Ethinyl Estradiol Form-II (hemihydrate form).
The present invention is depicted in Scheme-1:
Scheme-1

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.
Example 1: Preparation of Ethinyl Estradiol (Reference example using Tetrahydrofuran for ethynylation reaction)
Tetrahydrofuran (200ml) was taken and charged potassium tert. butoxide (13.3g 0.118moles) at 25-30° C under nitrogen atmosphere. Cooled the reaction mass up to 0 to-5°C. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to-5°C. Estrone (10g, 0.037moles) was charged in one lot into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress was checked by HPLC and observed unreacted EstroneNMT 1.0%. After which it the mass wasquenched by addition of water and adjusted pH to <1 by addition of HCl solution. Two layers observed wereseparated and the separated. Aqueous layer wasthen extracted by Ethyl acetate. Combined both the organic layers after separation and concentrated under vacuum at 55-60°C to provide Ethinyl Estradiol Technical (II) as a solid in almost quantitative yield.
Analytical Details
Purity by HPLC : Ethinyl Estradiol (II) : 96.40%
Estrone (I): 0.47%
Impurity-H : 1.30%
SMUI (Single maximum unknown impurity): 0.36%

Example 2 : Preparation of Ethinyl Estradiol DMF solvate (II) (Wet Cake)
N,N-Dimethyl formamide (DMF) (500ml) wastaken and charged Potassium tert. butoxide (66.4g 0.289moles) at 25-30° C under nitrogen atmosphere. Cooled the reaction mass up to 0 to-5°C. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to-5°C. Estrone (50g,0.1849moles) solution in DMF (400ml) wasadded within 30-60 minutes into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress waschecked by HPLC and observed unreacted Estrone NMT 2.0%. After which the mass was quenched by addition of water and adjusted pH to 5.5±1 by addition of HCl solution. Filtered the solid and washed with water. Ethinyl Estradiol DMF solvate (II) obtained as a solid in almost quantitative yield.

Analytical Details
Purity by HPLC : Ethinyl Estradiol DMF solvate (II) : 99.65%
(without DMF) Estrone (I) : BDL
Impurity-H : 0.06%
SMUI (Single maximum unknown impurity) : 0.07%
DMF content by HPLC: 15.68% (Qualitative)
Example 3: Preparation of Ethinyl Estradiol DMF solvate (II) (New polymorph)

N,N-Dimethyl formamide (DMF) (100ml) wastaken and charged Potassium tert. butoxide (13.28g 0.118moles) at 25-30° C under nitrogen atmosphere. Cooled the reaction mass up to 0 to -5°C. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to-5°C. Estrone (10g, 0.0369moles) solution in DMF (80ml) wasadded within 30-60 minutes into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress wasmonitored by HPLC and observed unreacted Estrone NMT 2.0%. After which the mass was quenched by addition of water and adjusted pH to 5.5±1 by addition of HCl solution. Filtered the product and washed with water. The wet cake thus obtained was dried under vacuum at 40-45°C. Ethinyl Estradiol DMF solvate (II) obtained as a solidin almost quantitative yield.
Analytical Details
Purity by HPLC : Ethinyl Estradiol DMF solvate (II) : 99.33%
DMF content :~ 19 % (by HPLC)
Estrone (I) : BDL
SMUI (Single maximum unknown impurity) : 0.06%

M/C : 0.23%
NMR :1H-NMR inDMSO-d6 (300MHz): 0.75(s,3H), 1.18-2.69 (m, 15H), 2.77 (s, 3H), 2.89 (s, 3H), 3.36 (s, 1H), 5.33 (s, 1H), 6.43 (s, 1H), 6.51 (d, 1H),7.05 (d, 1H), 7.95 (s, 1H), 8.99 (s,1H).
DSC : Peaks at 119.94,149.62,187.48°C
XRD : 2? Peaks at 14.63,16.22,25.24

Example 4: Preparation of Ethinyl Estradiol DMF solvate (II) (Confirmation of new polymorph by changing drying temperature)
N,N-Dimethyl formamide (DMF) (250ml) wastaken and charged Potassium tert. butoxide (33.4g 0.295moles) at 25-30°C under nitrogen atmosphere. Cooled the reaction mass up to 0 to-5°C. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to-5°C. Estrone (25.0g, 0.092moles) solution in DMF (200ml) wasadded within 30-60 minutes into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress was checked by HPLC and observed unreacted Estrone NMT 2.0%. After which the mass was quenched by addition of water and adjusted pH to 5.5±1 by addition of HCl solution. Filtered the solid and washed with water. The wet cake thus obtained was dried under vacuum at 50-55°C. Ethinyl Estradiol DMF solvate (II) obtained as a solidin almost quantitative yield.
Analytical Details
Purity by HPLC : Ethinyl Estradiol DMF solvate (II) : 99.66%
DMF content : ~ 19 % (by HPLC)
Estrone (I) : BDL
SMUI (Single maximum unknown impurity): 0.07%

M/C : 0.24%
DSC : Peaks at 118.68,150.22,186.98°C
XRD : 2? Peaks at 14.61,16.25,25.25

Example 5 : Preparation of Ethinyl Estradiol API by solid phase desolvation (Hemihydrate Form)
N,N-Dimethyl formamide (DMF) (100ml) wastaken and charged Potassium tert. butoxide (13.28g 0.118moles) at 25-30° C under nitrogen atmosphere. Cooled the reaction mass up to 0 to-5°C. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to-5°C. Estrone (10g, 0.0369 moles) solution in DMF (80ml) was added within 30 minutes into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress was checked by HPLC and observed unreacted Estrone NMT 2.0%. After which the mass was quenched by addition of water and adjusted pH to 5.5±1 by addition of HCl solution. Filtered the solid and washed with water. Charged wet cake into D M water (100 ml) then heated up to 70-75°C and filtered the mass at 25-30°C, washed wet cake with D M Water (20mlX2). The wet cake was dried under vacuum at 50-55°C up to constant weight. Ethinyl Estradiol obtained as a solid in almost quantitative yield.

Analytical Details
Purity by HPLC : Ethinyl Estradiol : 99.65%
Estrone (I) : Not detected
SMUI (Single maximum unknown impurity) : 0.08%
M/C : 2.83%
DSC : Peaks at 111.51,135.4,144.49,187.19°C
XRD : 2? Peaks at 13.82,16.74,18.27,19.63, 24.95 (Form-II)

Example 6: Preparation of Ethinyl Estradiol API by solid phase desolvation (Anhydrous Form)
Ethinyl Estradiol DMF solvate wet solid (II) (71.5g) was charged into D M Water (250 ml) then heated up to 50-55°C and maintained at the same temperaturefor 60 minutes. Filtered the suspended mass and washed with D M water (25mlx2). Wet cake (30.8gm) was charged into Ethyl acetate (125ml), stirred to obtain clear solution. Activated carbon slurry charged into solution and agitated for 30 min. Filtered the charcoalized mass on filter aid (Hyflo) and washed the bed with Ethyl acetate (25ml). The clear filtrate was concentrated under vacuum at 50-55°C then stripped out the mass with n-Heptane(50ml) under vacuum at 65-70°C to give oil/solid mass. Charged n-Heptane (200ml) into Oil/Solid mass and temperature of the suspended mass was raised upto 70-75°C. The obtained slurry wasthen stirred for 2 hours at 70-75°C. Then cooled the slurry mass up to 30±5°C and maintained for 30 minutes at same temperature. The mass wasfiltered and washed with n-Heptane (25ml x 2) and dried under vacuum at 50-55°C for 4 hours and then at 70-75°C for about 10-15 hours to provide Ethinyl Estradiol (III) as a solid in almost quantitative yield.
Analytical Details
Purity by HPLC : Ethinyl Estradiol (III) : 99.57%
Estrone (I) : 0.03%
SMUI (Single maximum unknown impurity) : 0.08%
M/C : 0.24%
LOD : 0.22%
DSC : Peak at 188.18°C
XRD : 2? Peaks at 13.17,13.94,15.72,17.18,18.37,19.60, 22.53 (Form-I)
The obtained FORM-I is subjected for accelerated storage stability study for 6 months at 40±2°C/75±5% RH and found that it is stable.
Example 7: Preparation of Ethinyl Estradiol API by solution phase desolvation (Anhydrous Form)
N,N-Dimethyl formamide (DMF) (750ml) wastaken and charged Potassium tert. butoxide (66.4g 0.289moles) at 0 to -5° C under nitrogen atmosphere. To the obtained reaction mass purged Acetylene gas for 2hrs at 0 to -5°C. Estrone (75g,0.2773moles) solution in DMF (600ml) wasadded within 30-60 minutes into the reaction mass. The reaction mass wasthen stirred for 1 hour at 0 to -5°C. Reaction progress waschecked by HPLC and observed unreacted Estrone NMT 2.0%. After which the mass was quenched by addition of water (600 ml) and adjusted pH between 5.5-6.5 by addition of HCl solution. Filtered and washed the solid with water (150ml). Wet solid of Ethinyl Estradiol DMF solvate (II) about 113.2g obtained.
Ethinyl Estradiol DMF solvate wet solid (II) (113.2 g) wasdissolved in Ethyl acetate (750ml). Then the Ethyl acetate layer waswashed with D M water (375 mlX3) and then the Ethyl acetate layer was separated, charged activated carbon into solution and agitatedfor 30 min. Filtered the charcoalized mass on filter aid (Hyflo) and washed the bed with Ethyl acetate (75ml). The clear filtrate was distilled under vacuum at 50-55°C. Charged n-Heptane (750ml) into the mass and temperature of the suspended mass was raised upto 70-75°C. The obtained slurry wasthen stirred for 2 hours at 70-75°C. Then cooled the slurry mass up to 30±5°C and maintained for 30 minutes at same temperature.The mass wasfiltered and washed with n-Heptane (75ml x 2) and dried under vacuum at 50-55°C for 4 hours and then at 65-75°C for about 18 hours to provide Ethinyl Estradiol (III) (66.5g) as a solid in almost quantitative yield.
Analytical Details
Purity by HPLC : Ethinyl Estradiol (III) : 99.79%
Moisture Content : 0.02%
LOD : 0.30%
DSC Analysis :Peak at 186.21°C
XRD : 2? Peaks at 13.15,13.91,15.72,17.17,18.42,19.62, 22.56 (Form-I).
,CLAIMS:1. A process for preparation of Ethinyl estradiol comprising the steps of;
a) Reacting estrone with acetylene in presence of a base in dimethyl formamide solvent to obtain Ethinylestradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio; and
b) Desolvating (breaking) the EE-DMF solvate having 1:1 ratio using organic solvents to obtain Ethinyl estradiol.
2. The process as claimed in claim 1, wherein, the EthinylEstradiol is obtained in anhydrous form (Form-I), prepared by process comprising the steps of;
a) dissolving Ethinylestradiol-dimethyl formamide solvate (1:1) wet cake in an organic solvent selected from esters or ethers, followed by washing the dissolved solution with water;
b) treating the solution with activated carbon followed by concentrating the solution to obtain concentrated mass;
c) dissolving the concentrated mass in a hydrocarbon solvent optionally under heating followed by cooling the mass to ambient temperature to isolate wet cake; and
d) drying the wet cake at a temperature range of 50 to 80°C to obtain Ethinyl estradiol in polymorphic form-I (anhydrous form).
3. The process as claimed in claim 2, wherein, the esters include ethyl acetate, Isopropyl acetate and butyl acetate and the ethers include diisopropyl ether or diethyl ether.
4. The process as claimed in claim 3, wherein, the solvent is ethyl acetate.
5. The process as claimed in claim 4, wherein, the hydrocarbon solvent is selected from an aliphatic hydrocarbon solvent selected from n-hexane, cyclohexane and n-heptane or an aromatic hydrocarbon solvent selected from toluene and xylene.
6. The process as claimed in claim 1, wherein, the Ethinyl estradiol is obtained in hemihydrate Form (Form-II), prepared by a process comprising the steps of;
a) treating the wet cake of Ethinylestradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio with water at about 50-60°C to obtain a slurry; and
b) filtering the slurry; washing the cake with water and drying to get Ethinyl Estradiol Form-II (hemihydrate form).
7. Ethinyl estradiol-dimethyl formamide (EE-DMF) solvate having Ethinyl estradiol to dimethyl formamide (1:1) molar ratio characterised by PXRD having 2 ? peaks at 14.63, 16.22, 25.24 ± 0.2.
8) A process for preparation of Ethinylestradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio of claim 7, comprising;
a) reacting estrone with acetylene in presence of a base in dimethyl formamide solvent at about 0°C; and
b) quenching the reaction mass with water followed by adjusting the pH of the reaction mass to about 5.5 using dilute HCl solution to obtain Ethinylestradiol-dimethyl formamide (EE-DMF) solvate having 1:1 ratio.
9. The process as claimed in claim 8, wherein, the base is selected from the group consisting of alkali metal hydroxide, alkali metal alkoxides and carbonates.