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 WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
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 INVENTION

The present invention relates to a method for producing crystalline Penicillin G Benzathine with reduced particle size and bulk density by using a Homogenizer.

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-carboxy-lic 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 in 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 Penicillin G Benzathine in which sodium penicillin G condensed with N,N'-dibenzylethylenediamine diacetate in the presence of water to obtain Penicillin G Benzathine as white crystalline powder. The process is shown in below scheme:

US 2745785 discloses a process for the preparation of Penicillin G Benzathine by reacting potassium penicillin G with N,N'-dibenzylethylene diamine in the presence of aqueous formamide to obtain crystals in the form of regular plates with a bulk density of 2.5 g/ml. The plates of Penicillin G Benzathine are further micronized by comminuting with an air blast under pressure which results fragmentation to obtain crystals having the particle size from about 5 to 20 µm.

CN101357926 discloses the reaction of penicillin G potassium with N,N'-dibenzylethylenediamine diacetate in the presence of ethanol to obtain dry powder of Penicillin G Benzathine with a particle size of about from 30 to 80 µm.

The major drawback associated with the prior-art processes of Penicillin G Benzathine are the higher particle size and bulk density and of crystalline particles. The crystals of Penicillin G Benzathine obtained directly by the prior-art processes are having high bulk density and particle size. Hence, there is a need to develop an alternative process to obtain Penicillin G Benzathine crystals with reduced bulk density and particle size.

The inventors of the present invention found an improved process to obtain Penicillin G Benzathine crystals with a reduced particle size and bulk density.

OBJECTIVE OF INVENTION

The objective of the present invention is to provide crystalline Penicillin G Benzathine with reduced particle size and bulk density by using a Homogenizer.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides crystalline Penicillin G Benzathine with reduced particle size d (0.9) of about from 5 to 50 µm and bulk density in range of about from 0.15 to 0.33 g/ml.

In another embodiment, the present invention provides an improved process for the preparation of Penicillin G Benzathine 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 a solvent to obtain Penicillin G Benzathine;
b. crystallizing Penicillin G Benzathine of Formula (I) using a Homogenizer.

In a preferred embodiment, the present invention provides a process for the preparation of Penicillin G Benzathine of Formula (I):
,
which comprises the steps of:
a. reacting Penicillin G potassium of Formula (IIa)

,
with N,N'-dibenzylethylenediamine diacetate of Formula (IIIa)
,
in the presence of a solvent to obtain Penicillin G Benzathine;
b. crystallizing Penicillin G Benzathine of Formula (I) using a Homogenizer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Penicillin G Benzathine crystalline particles with reduced particle size d(0.9) of about from 5 to 50 µm and bulk density in range of about from 0.15 to 0.33 g/ml by using a Homogenizer.

The process of the present invention comprises, reacting Penicillin G salt of Formula (II) wherein salt is selected from potassium or sodium with N,N'-Dibenzylethylenediamine of Formula (III) or its pharmaceutically acceptable salt thereof in the presence of solvent to obtain Penicillin G Benzathine of Formula (I) followed by transferring the reaction mixture of Formula (I) in to a Homogenizer to obtain Penicillin G Benzathine with reduced particle size and bulk density.

The obtained Penicillin G Benzathine is applicable for sterile or non-sterile use.

Penicillin G salt of Formula (II) is prepared by using the processes disclosed in the prior art.

The pharmaceutically acceptable salt of N,N'-Dibenzylethylenediamine of Formula (III) is selected from diacetate.
Solvent used in above reaction system include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction of reacting Penicillin G salt of Formula (II) with N,N'-Dibenzylethylenediamine of Formula (III) or its pharmaceutically acceptable salt thereof 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.

The temperature for circulating Penicillin G Benzathine in the homogenizer is about from 0°C to about 15°C.

The homogenizer used in the present invention is selected from MT-SHS Homogenizer (Super High Shear Homogenizer) or IKA Magic Lab Homogenizer.

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.
EXAMPLES:
Reference Example 1: Preparation of Penicillin G Benzathine

Potassium Penicillin G (100.0 g ; 0.26 moles) was dissolved in water (2000 ml) at 25-30°C and simultaneously added a solution of N,N’-dibenzylethylenediamine di-acetate (46.6 g ; 0.13 moles) in water (1000 ml) over a period of 2 hours, then stirred slurry mixture at 25-30°C for 2 hours, filtered the solid and washed with water (2 x 200 ml) followed by acetone (2 x 200 ml) then dried solid at 30-35°C till the moisture content attained in the range of 5 to 8% to obtain Penicillin G Benzathine salt (123.0 g) with HPLC purity- Penicillin G (83.4%) and Benzathine (16.32%).

Particle size d (0.9): 121.74 µm
Bulk density: 0.33 g/ml

Reference Example 2: Crystallisation of Penicillin G Benzathine from Aq. Methanol
Penicillin G Benzathine (50.0 g) was dissolved in methanol (650 ml) at 60-65°C and stirred for 10 min, then added water (650 ml) over a period of 1 hour at the same temperature, then gradually cooled to room temperature and stirred for 2 hours, filtered the solid and washed with water (2 x 100 ml) followed by drying at 30-35°C till the moisture content attained in the range of range of 5 to 8% to obtain Penicillin G Benzathine salt (40.2 g) with HPLC results Penicillin G 85.79% and Benzathine 14.16%.

Particle size d(0.9): 78.18 µm
Bulk density: 0.2 g/ml
Example 1: Crystallization of Penicillin G Benzathine using MT-SHS Homogenizer
Penicillin G Benzathine was dissolved (90.0 g) in methanol (1170 ml) at 60-65°C and stirred for 10 minutes. Water (1170 ml) was added over a period of 1 hour, and then gradually cooled to room temperature. The above slurry mass was transferred to MT-SHS Homogenizer at 0-10°C and the mass was circulated for three times at 2500 RPM for 1 minute. The solid was filtered and washed with water (3 x 90 ml) and dried at 30-35°C till the moisture content attained in the range of 5 to 8% to obtain Penicillin G Benzathine salt (72.0 g) with HPLC results- Penicillin G 84.8% and Benzathine 14.92%.

Particle size d(0.9): 22.98 µm
Bulk density: 0.21 g/ml

Example 2: Crystallization of Penicillin G Benzathine using IKA Magic Lab Homogenizer
Potassium Penicillin G (25.0 g) was dissolved in water (500 ml) at 25-30°C and simultaneously a solution of N,N’-dibenzylethylenediamine di-acetate (11.9 g) in water (250 ml) was added over a period of 2 hours, then slurry mixture was stirred at 25-30°C for 2 hours. The solid was filtered and washed with water (2 x 50 ml) followed by acetone (2 x 50 ml). Suck dried the solid, suspended into the water (250 ml) and transferred the above slurry mass to IKA Magic Lab Homogenizer (6F tool) and cooled to 2-10°C at 15000 RPM for 7 min. The solid was filtered and washed with water (3 x 50 ml) and dried at 30-35°C to obtain Penicillin G Benzathine salt (27.0 g) with HPLC results- Penicillin G 85.26% and 14.03 Benzathine.

Bulk density: 0.27 g/ml ,CLAIMS:CLAIMS
We claim,
1. A process for the preparation of penicillin G benzathine of formula (I) with reduced particle size and bulk density:

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 a solvent to obtain penicillin G benzathine of formula (I);
b. crystallizing penicillin G benzathine of formula (I) using a homogenizer.

2. The process according to claim 1, wherein the N,N'-dibenzylethylenediamine pharmaceutically acceptable salt is selected from diacetate.

3. The process according to claim 1, wherein the solvent used in step (a) is selected from water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof.

4. The process according to claim 1, wherein particle size d (0.9) of penicillin G benzathine is about from 5 to 50 µm.

5. The process according to claim 1, wherein bulk density of penicillin G benzathine is about from 0.15 to 0.33 g/ml.