DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF PENICILLIN G BENZATHINE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARKBUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of penicillin G benzathine with lecithin of formula (I) with high purity.

BACKGROUND OF THE INVENTION

Penicillin G benzathine is chemically known as (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid compound with N,N'-dibenzylethylenediamine (2:1) tetrahydrate and is marketed under the brand name Bicillin®L-A which is an intramuscular injection indicated for the treatment of infections due to penicillin-G-sensitive microorganisms that are susceptible to the low and very prolonged serum levels common to this particular dosage form.

Streptococcal infections (Group A - without bacteraemia), mild-to-moderate infections of the upper respiratory tract (e.g. pharyngitis), Venereal infections - Syphilis, yaws, bejel and pinta will usually respond to adequate dosage of intramuscular penicillin G benzathine. Bicillin®L-A therapy is indicated as prophylaxis for Rheumatic fever and/or chorea and also has been used as a follow-up prophylactic therapy for preventing rheumatic heart disease and acute glomerulonephritis. In Canada, Bicillin®L-A is the main drug used in adults for the treatment of syphilis caused by the bacterium treponema pallidum.

US 2627491 discloses a process for the preparation of penicillin G benzathine in which sodium penicillin G condensed with N,N'-dibenzyl ethylenediamine diacetate in the presence of water to obtain penicillin G benzathine as white crystalline powder. The process is depicted in below scheme:

FR 1519516 discloses the reaction of penicillin G potassium with dibenzylethylene diamine diacetate dissolved in sterile water in the presence of ethanol solvent to obtain penicillin G benzathine. The obtained penicillin G benzathine is then treated with lecithin dissolved in dichloroethane in the presence of ethanol solvent followed by drying at 55oC to obtain penicillin G benzathine with lecithin.

The major drawbacks associated with the above mentioned processes are the formation of unwanted thermal degradation or process related impurities like benzylpenicilloic acids benzathide, penicillin G methyl ester or penicillin G ethyl ester during distillation of penicillin G benzathine which are not easy to remove by conventional purification or crystallization methods and also the prior-art processes are time consuming and not commercially viable.

Hence, there is a need of an improved process for the preparation of penicillin G benzathine with lecithin of formula (I) which devoid the disadvantage of the prior art processes as mentioned herein above and gives penicillin G benzathine with lecithin of formula (I) with high purity.

The process of the present invention describes the isolation of penicillin G benzathine with lecithin of formula (I) using specific solvent system by avoiding distillation and results in uniformly coated penicillin G benzathine with lecithin having crystalline nature with rod shaped particles and rough surface without any fractured edges.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide simple and industrially viable process for the preparation of penicillin G benzathine with lecithin of formula (I) thereof with high purity and good yield.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of penicillin G benzathine with lecithin of formula (I):

comprising the steps of:
a. treating penicillin G benzathine with lecithin dissolved in a solvent;
b. adding water to crystallize penicillin G benzathine with lecithin of Formula (I).

In another embodiment, the present invention provides a process for the preparation of penicillin G benzathine with lecithin of formula (I) which comprises the steps of:
a. reacting penicillin G salt of formula (II):

,
wherein, X is sodium or potassium,
with N,N'-dibenzylethylenediamine of formula (III) or its pharmaceutically acceptable salt thereof:
,
in the presence of solvent to obtain penicillin G benzathine;
b. treating penicillin G benzathine with lecithin dissolved in a solvent;
c. adding water to crystallize penicillin G benzathine with lecithin of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of penicillin G benzathine with lecithin of formula (I) by treating penicillin G benzathine with lecithin dissolved in a solvent and adding water to crystallize penicillin G benzathine with lecithin of formula (I).

The present invention also relates to a process for the penicillin G benzathine by reacting penicillin G salt of formula (II) wherein salt is selected from potassium or sodium salt with N,N'-dibenzylethylenediamine of formula (III), wherein salt is preferably diacetate salt in the presence of solvent to obtain penicillin G benzathine.

The above reaction is conducted at a temperature of about from 20°C to 100°C without affecting the quality of product for a period of about 30 minutes to about 3 hours or more to complete the reaction.

Penicillin G salt of formula (II) may be a potassium or sodium salt and may prepared by using the process disclosed in the prior art.

The obtained penicillin G benzathine with lecithin of formula (I) may be applicable for sterile or non-sterile use.

Solvent used in the present invention is selected from but not limited to polar protic solvent comprises methanol, ethanol, isopropanol, n-butanol, acetic acid and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methyl pyrrolidone and/or mixture thereof; and non-polar solvent comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane (CH2Cl2) or mixture thereof.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1
Preparation of penicillin G benzathine tetrahydrate:
Penicillin G potassium (4 Kg, 10.738 moles) was dissolved in water (40 liters) at 20-30°C and ethanol (72 liters) was added in to the penicillin G potassium aqueous solution at 20-30°C. N,N'-dibenzylethylenediamine diacetate (1.974 kg, 5.476 moles) was dissolved in water (56 liters) at 20-30°C and added to penicillin G potassium aqueous ethanol solution slowly for about 30 minutes and continued stirring at 20-30°C for 30 minutes. Product was filtered at 20-30°C and washed with water (3 x 16 liters) and ethanol (2 x 8 liters). Product was dried at 35-40°C under reduced pressure (~20 mm Hg) to obtain white crystalline powder of penicillin G benzathine tetrahydrate - Sterile.

Yield: 4.80 Kg
Chromatographic purity (by HPLC, %w/w): 99.54% w/w.

Example-2
Preparation of penicillin G benzathine with lecithin:
Lecithin (0.05 Kg) was dissolved in ethanol (2500 ml) at 20-30°C and penicillin G benzathine tetrahydrate (1 Kg) was added at 20-30°C and then stirred for about 2 hours to get uniform slurry. Water (10 liters) was added to the slurry at 20-30°C and stirred for about 30 minutes. Product was filtered at 20-30°C and washed with water (1 liter). Product was dried at 35-40°C under reduced pressure (~20 mm Hg) to obtain white crystalline powder of penicillin G benzathine tetrahydrate with lecithin – sterile.

Yield: 0.96 Kg;
Chromatographic purity (by HPLC): 99.54% w/w.
Lecithin content (by HPLC, on anhydrous basis): 0.59% w/w ,CLAIMS:We CLAIM

1. A process for the preparation of penicillin G benzathine with lecithin of formula (I):

comprising the steps of:
a. treating penicillin G benzathine with lecithin dissolved in a solvent;
b. adding water to crystallize penicillin G benzathine with lecithin of Formula (I).

2. The process according to claim 1, wherein the solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetic acid, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, acetone, ethyl acetate, N-methyl pyrrolidine, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane or mixtures thereof.