Field of the Invention:
The present invention relates to novel process for the purification and crystallization of
drospirenone.
Background of the Invention:
Drospirenone is chemically known as 6 ß, 7ß; 15ß, 16ß-dimethylene-3-oxo-17a-pregn-4-ene-
21,17-carbolactone and is represented by the following structure.

It has progestogenic, antimineralocorticoid and antiandrogenic activity. It's pharmaceutical
composition is used as a contraceptive.
Process for preparing drospirenone is described in publication Bittler et al, Angew Chemie
Int Edn, 21, 1982, pp 696-7. The patent EP 0918791 B1 describes isolation of drospirenone
by column chromatography in purity of 93%, however the details of column chromatography
are not disclosed.
The patent US 4129564 mentions purification of drospirenone by repeated preparative layer
chromatography.
Several documents disclose different methods for crystallization of drospirenone from
various solvents.
Summary of the Invention:
The present invention provides purification method of drospirenone by column
chromatography over basic alumina using tetrahydrofuran as solvent for elution. The present
invention also provides a process for crystallization of drospirenone from a mixture of
dimethylformamide and water.
Detailed description of the invention:
The first aspect of the present invention is to provide process for the purification of
drospirenone by column chromatography over basic alumina. The weight of the alumina used
is usually 20-50 times the sample weight, preferably 40 times of the sample weight. The
columns can be glass tube column varying in length and diameter with stop cock to control
solvent flow. Columns can have flasks kept on the top which act as solvent reservoir. Small
piece of cotton wool or glass wool is used as plug to support the alumina. Slurry of alumina
in tetrahydrofuran is poured in the column and column is packed by tapping. A thin layer of
cotton wool is placed on the top of the column.
Slurry of drospirenone in tetrahydrofuran is poured on alumina column followed by elution
with tetrahydrofuran. The elution of drospirenone is monitored by TLC. The fractions
containing drospirenone are combined and the solvent is distilled off to give drospirenone.
Another aspect of the present invention provides process for crystallization of drospirenone
comprising:
a) dissolution of drospirenone in dimethyl formamide;
b) addition of water;
c) heating to 50-90°C;
d) cooling to 0-20°C and
e) isolation of drospirenone.
The dissolution of drospirenone in dimethylformamide is carried out at temperature 50-90°C,
preferably 70-80°C.
Water is added at 70-80°C slowly in about 1-2 hours and then cooled to 20-30°C. Further
cooled to 0-20°C, preferably to 5-10°C.
The ratio of dimethyl formamide to water is in the range 1: 0.1 to 1:10, preferably 1:1 to 1: 5
(volume/volume).
The crystalline drospirenone can be isolated by different methods such as filtration,
concentration of slurry, evaporation etc.
The crystalline drospirenone obtained by crystallization from dimethylformamide-water
mixture is characterized by XRPD pattern having specific peaks at a reflection angle 20, of
about 9.84°, 9.99°, 10.11°, 12.15°, 12.23°, 13.77°, 14.51°, 15.57°, 16.02°, 17.09°, 17.28°,
17.53°, 20.17°, 21.18°, 23.04°, 23.31°, 23.97°, 25.23°, 26.67°, 29.40°, 30.06°, 31.31°, 33.19°
±0.2.
The crystalline drospirenone described herein is further identified by IR spectrum with
characteristic bands at 3025, 2971, 2943, 2861, 1766, 1656, 1591, 1451, 1423, 1343, 1271,
1247, 1223, 1188 cm-1.
The DSC of the crystalline drospirenoneis in the range of 197-200°C.
The methods of present invention have been described in the foregoing examples.
Example 1:
Step 1: Preparation of Drospirenone:
Pyridinium dichromate (180 g) was added to tetrahydrofuran (400 ml). The mixture was
heated and tetrahydrofuran was distilled to 80 ml. The reaction mass was cooled and
dimethyl formamide (60 ml) was added. The reaction mixture was distilled till complete
removal of tetrahydrofuran. Triethylamine (60 ml) was added dropwise to the mixture. In
another flask, 17-alpha-(3-hydroxypropyl)-6-beta,7-beta; 15-beta, 16-beta-dimethylene-5-
beta-androstane-3-beta,5,17-beta triol (40 gm) was dissolved in tetrahydrofuran (400 ml
tetrahydrofuran and distilled to 40 ml). Dimethyl formamide (60ml) was added to the
solution and distilled till tetrahydrofuran was completely removed. This solution was added
to the pyridinium dichromate solution. The reaction is heated to 60-65°C and stirred for 4
hours. Tetrahydrofuran (200 ml) was slowly added and distilled. The reaction mixture was
further heated for 2 hours. Tetrahydrofuran (200 ml) was added and distilled till complete
removal of tetrahydrofuran. Dimethylformamide (80 ml) was added to the reaction mixture
followed by addition of tetrahydrofuran (1200 ml). The mixture is stirred, filtered and
washed with tetrahydrofuran. The filtrate was as such used in step 2.
Step 2: Column Chromatography using tetrahydrofuran:
The filtrate (obtained in step 1) was loaded on basic alumina (800 gm) column (diameter 3.5
cm). The column was eluted with tetrahydrofuran and monitored by TLC. The fractions
containing drospirenone were combined and distilled under reduced pressure for complete
removal of THF. Activated carbon (8 g) was added and stirred and the residue was degassed.
The reaction mass was filtered and washed with dimethylformamide (40 ml). The solution
was used as such used in step 3.
Step 3: Crystallization of drospirenone from dimethylformamide-water:
To the concentrated solution of drospirenone in tetrahydrofuran was added dimethyl
formamide (to make up the volume upto 280 ml) and heated to 75-80°C. To the solution,
water (560 ml) was slowly added in about 1 hour (at 70-80°C). The reaction mixture was
cooled to 20-30°C, stirred for two hours and chilled to 5-10°C. The solid was filtered,
washed with water and dried under reduced pressure and used as such in step 4.
Step 4: Crystallization of Drospirenone from methanol:
Crude drospirenone(10g) was dissolved in methanol (100 ml) at 45-50°C and was stirred to
get a clear solution. The methanol was distilled to about 30 ml under reduced pressure. The
mixture was cooled to ambient temperature and stirred for 40-60 minutes at 0-5°C. The
mixture wasfurther chilled to 0-5°C, stirred and filtered. The solid was washed with water
and was dried under reduced pressure.
Yield: 8.1 grams; HPLC Assays 97.3%
We Claim:
1) The process for preparation of crystalline drospirenone comprising the steps:
a) dissolution of drospirenone in dimethyl formamide;
b) addition of water;
c) heating to 50-90°C;
d) cooling to 0-20°C and
e) isolation of drospirenone.
2) The process of claim 1 wherein the dissolution of drospirenone in dimethylformamide
is carried out at temperature 50-90°C.
3) The process of claim 2 wherein the dissolution of drospirenone in dimethylformamide
is carried out at 70-80°C.
4) The process of claim lwherein water is added at 70-80°C.
5) The process of claim 1 wherein cooling is carried at 0-20°C.
6) The process of claim 5 wherein cooling is carried at 5-10°C.
7) The process of claim 1 wherein ratio of dimethyl formamide to water is in the range
1:0.1 to 1:10 (vol/vol).
8) The process of claim 6 wherein preferable ratio of dimethyl formamide to water is in
the range 1: 1 to 1:5 (volume / volume).
9) The process for the purification of drospirenone by column chromatography over
basic alumina wherein elution is carried out with tetrahydrofuran.
10) The process for the preparation of drospirenone as described in the foregoing
examples.

ABSTRACT

The present invention provides purification of drospirenone by column chromatography over
basic alumina and elution with tetrahydrofuran. The present invention further relates to a
process for crystallization of drospirenone from dimethylformamide-water mixture.