FIELD OF THE INVENTION
The present invention provides process for micronizt dienogest (I). The present invention provides microniz* dienogest (I) . Micronization of Dienogest enhanced i1 dissolution, rate in multimedia compared to non micronize material.. The results suggest that micronization technique fc the preparation of rapidly dissolving formulations c Dienogest, and could potentially lead to improvement in tl bioavailability of oral Dienogest product.
PRIOR ART OF THE INVENTION
Dienogest is an orally active synthetic progesterone (< progestin), used as an oral contraceptive in combination c ethinylestradiol. It has antiandrogenic activity that Cc improve androgenic symptoms. It is a non-ethinylated progest: which is structurally related to testosterone.
Dienogest is chemically known as, (17a)-17-Hydroxy-3-oxo-l< norpregna-4,9-diene-21- nitrile or 17a-Cyanomethyl-17j hydroxy-4,9-estradien-3-one and it is represented by followii structure:
OH

Dienogest

The patent US 4248790, describe process for preparation of dienogest as in Scheme^ 1.
Scheme-I



MeO

KCN Ethanol/water

MeO

(ID

OH)

Methanol
Oxalic acid 2H20
D


►ienogest (I)

Pyridiniumperbromide Pyridine

(IV)
The publication Zhang Xiuping et al. , Pharmaceutical Industry (1985), 16(9), 399-401, describe the conversion of ketal (3,3-
dimethoxy-estra-5(10), 9(11)-diene-17-one) (V) to dienogest (I) in three steps as shown in Scheme-II, wherein ethylene
oxide intermediate (VI) is reacted with alcohol solution of
potassium cyanide to produce (VII) followed by acid
hydrolysis.



MeO
MeO
OMe

(V)

DMSO/THF Me3SI
^-^
NaH.DMF

OMe

(VI)


MeO
OMe
(VII)
The patent EP 1935898 disclose preparation of dienogest (I) in which the ketal (V) is reacted with CNCH2CeCl2, followed by treatment with acetic acid and hydrochloric acid.
The German patent application DD 296,495 describes a one-pot synthesis of dienogest from 3,3-dimethoxy-estra-5(10) , 9(1 1)-diene-17-one (V), on treatment with dilute sulfuric acid.
Prior art processes described above use toxic reagents like trimethyl sulfonium iodide or alkali cyanides. Removal of residual cyanide demands additional operations of destruction of cyanide which makes it a costly method. Several methods are known in the literature for purification of dienogest by crystallization. These are discussed below.
The patent US 4248790, discloses crystallization of dienogest from ethyl acetate and 80% acetonitrile. The publication Zhang Xiuping et al., Pharmaceutical Industry (1985), 16(9), 399-401, and patent DD 205170 disclose crystallization of dienogest from methanol. EP 1935898 and US 5955622 disclose crystallization of dienogest from acetone.

The patent US 20080287404 Al covers recrystallisation of dienogest from ethyl acetate, acetone, tert-butyl methyl ether, diisopropyl ether, acetonitrile, methanol, ethanol or aqueous mixtures of different ratio of these solvents.
The patent EP 1963354 Bl discloses purification of crude dienogest by preparative HPLC to obtain pure dienogest with total amount of impurities up to maximum 0.1 % and individual impurities up to maximum 0.02 % (by HPLC). This method, has the disadvantage that it is difficult on production levels.
The patents US 54 38134 and EP 231671 discloses compound 17a-cyanomethyl-17p- hydroxy-13P-methyl-gona-5(10) ,9(1 1)-diene-3-one, which is referred herein as diene impurity.
Referred from WO/2011/132045
OBJECTIVE OF THE INVENTION
The present invention provides process for 'micronized dienogest (I)- The present invention provides micronized dienogest (I) . Micronization of Dienogest enhanced ' its dissolution rate in multimedia compared to nonmicronized material. The results suggest that micronization technique for the preparation of rapidly dissolving formulations of Dienogest, and could potentially lead to improvement in the bioavailability of oral Dienogest product.
SUMMARY OF THE INVENTION
Dienogest is a progestin, or a synthetic progestogen, of the 19-nortestosterone group.It is available in combination with estradiol valerate or ethinylestradiol for use as an oral contraceptive, and by itself for the treatment of endometriosis in Europe, Australia, and Japan. Although

available in combination with estrogen as a contraceptive in the United States, dienogest is not available in this country by itself.In addition to its proyestogenic effects, dienogest has antiandrogenic activity, and as a result can improve androgenic symptoms such as acne-It is a non-ethynylated progestin which is structurally related to testosterone.
Micronized Dienogest is made up of an only one crystalline form.
Chirality
Dienogest, as steroids, shows specific rotation due to the presence of four asymmetric carbons (labelled with * in the figure below).

The 4 chiral centers present in the Dienogest molecule are at positions 8, 13, 14 and 17. Three of these centers, at 8,13 and 14, derive directly from the starting material DNG2 and before from its precursor 19-nor-5(10)-androstenedione: in fact the chemistry of the reaction doesn't influence the configuration of these carbon atoms thus remainig unchanged.
Moreover, from a spatial point of view, in DNG2 the carbon in 8 presents the hydrogen atom in (3; the carbon in 13 has the methyl group (C 18 ■ of the molecule) in (3 while the chiral carbon in 14 presents its only hydrogen atom under the plane in a position.

A fourth chiral center is introduced with the alkylation at position 17 performed with CH3CN during the first step of the synthesis. The mechanism of reaction and the definition of the exact configuration obtained from this aIkylie addition are explained hereafter.
DETAILED DESCRIPTION
Manufacturing route
Production of Dienogest is carried out starting from "Cyclic-3-(1, 2-ethanediyl acetal)-estra-5(10),9(11)-dien-3,17-dione" (from now on called DNG2) according to the synthesis scheme reported in the-following page.
DNG2 has been chosen as starting material since it is a commercially available substance that contains the framework of the molecule of the final product.
Below the chemical name and common name of the starting material and intermediates used in the manufacturing of Dienogest are reported.

Chemical name Use Common name / in house name
Cyclic-3-(l.2-ethanediyl acetal)-estia-5(10)?9(l 1)-dien-3.17-dione Starting material DNG2
Cyclic-3-(l,2-ethanediyl acetal)-(l7a)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21 -nitrile Unisolated intermediate DNG5
(17a)-17-Hydroxy-3 -oxo-19-norpregna-4?9-diene-21-nitrile Intermediate DNG8
(17a)-l 7-Hydioxy-3-oxo-19-noipregna-4,9-diene-21-nitrile Final product Micronized Dienosest
Scheme of Synthesis FIRST STEP


DNG2

THF, hexyllithium CH3CN

Purified water Sulphuric acid 96% Ethyl acetate. Sodium chloride

OH CN
,/

DNG5
(untsolated intermediate)

MeOH —
Dichloromethane
HCI (aq)
Sodium carbonate an.


DNG8

SECOND STEP

OH CN

DNG8

MeOH, H20
CH3CN
MeOH

Activated charcoal

DIENOGEST

Third Step


DIENOGEST

micronization
DIENOGEST MICRONIZED
Step 1 : Manufacturing of DNG8
The 17-carbonyl group of the starting material DNG2 -reacts with cyanomethyllithium according to a nucleophilic addition reaction. Then the 3-ketal function of the unisolated intermediate is cleaved by means of aqueous acid obtaining crude Dienogest called DNG8.
Step 2 : Manufacturing of Dienogest
DNG8 is purified by three different crystallizations using Methanol, Purified water and Acetonitrile.
Step 3 : Manufacturing of Dienogest micronized
Micronization of Dienogest is carried in properly.

MICRONIZATION
Milling of Dienogest was done by using Air Jet Mill.Milling performed at primary pressure 4.8 kg/cm2, secondary pressure 4.2 kg/cm2 and Screw feeder speed 5 rpm.
PARTICLE SIZE ANALYSIS
Particle size analysis of micronised and unmicronised Dienogest was done using Malvern Mastersizer 2000 (Scirocco 2000) that is based on laser diffraction technique - a non¬destructive, non-intrusive method, which can be used for size determination of either dry or wet samples. Dienogest of two different particle size distributions was used in two batches Fl ' (with nonmicronized Dienogest) and F2 (with micronized Dienogest) - prepared using Lactose monohydrate, Microcrystalline cellulose, Maize starch as diluent, Povidone as binder, Crospovidone as disintegrant, Talc as glidant and Magnesium stearate as lubricant in the pre-optimized quantities to make a 150 mg tablet containing 2.0 mg Dienogest. Dienogest, Lactose Monohydrate and Microcrystalline cellulose were passed through sieve #40. Dry mixing was done in rapid mixer granulator for 10 minutes keeping impeller at slow speed. Povidone binder solution was added over a time of 2 minutes at impeller slow speed. Kneading (Wet mixing) was done at impeller fast and chopper slow speed for 2 minutes. Drying of granules was done using a table top fluidized bed dryer at 500C inlet temperature for 4 5 minutes. Dried granules were milled in Multimill at Slow Speed Knife Forward using 1.5 mm screen and blending was done in Octagonal blender for 10 minutes with addition of Talc, then after add magnesium stearate into Octagonal blender again blend for 5 minutes. The granules of formulations (Fl and F2) were tested for flow properties such as bulk density, tap density, Hausner ratio,
compressibility index vand ,angle of repose. Compression of blend was done on 12- station single rotary compression machine using 7.00 mm Round flat beveled edged punches. Compressed tablets of formulations Fl and F2 were subjected to evaluation viz. average weight, thickness, hardness, friability and disintegration time .

We claims,
1.The present invention involve use of process for preparation of micronized dienogest :
a) It involve development of dienogest molecule and
b) Milling of Dienogest to obtain its micronized form.

2. Micronized Dienogest in claims 1 is made up of an only one crystalline form.
3. Micronization technique in claims 1 for the preparation of rapidly dissolving formulations of Dienogest.
4. Micronization in claims 1 for improve bioavailability of dienogest formulation.