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,
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 method for producing Penicillin G Benzathine with lecithin coating having reduced particle size by using a Double planetary mixer.

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 comp- ound 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 in the presence of ethanol to obtain dry powder of Penicillin G Benzathine.

FR 1519516 discloses the reaction of penicillin G potassium with N,N'-dibenzylethylenediamine in the presence of water and ethanol followed by treating with lecithin to obtain crystals of Penicillin G Benzathine with lecithin coating.

The major drawback associated with the prior-art processes is the higher particle size of Penicillin G Benzathine with lecithin coating. The crystalline particles of Penicillin G Benzathine with lecithin coating obtained directly by the following prior-art processes are having higher particle size. Hence, there is a need to develop an alternative process to obtain Penicillin G Benzathine with lecithin coating crystals having reduced particle size and required shape.
The inventors of the present invention found an improved process to obtain Penicillin G Benzathine with lecithin coating having reduced particle size and required shape.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide Penicillin G Benzathine with lecithin coating having reduced particle size by using a Double planetary mixer.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides Penicillin G Benzathine with lecithin coating having reduced particle size d (0.9) of about from 5 to 50 µm.

In another embodiment, the present invention provides an improved process for the preparation of Penicillin G Benzathine with lecithin coating of Formula (I):

which comprises the steps of
a. reacting Penicillin G Benzathine with lecithin solution in a double planetary mixer;
b. isolating Penicillin G Benzathine with lecithin coating of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Penicillin G Benzathine with lecithin coating having crystalline particles with reduced particle size d (0.9) of about from 5 to 50 µm.

The process of the present invention comprises, reacting Penicillin G Benzathine with lecithin solution in a double planetary mixer wherein lecithin solution is prepared by dissolving lecithin in a solvent and isolating Penicillin G Benzathine with lecithin coating having reduced particle size.

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

Penicillin G Benzathine is prepared by using the processes disclosed in the prior art.

The solvent of 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 (MDC) or mixture thereof.

The temperature maintained in the double planetary mixer is from about 20°C to 50°C without affecting the quality of product.

The suitable RPM (Revolutions Per Minute) for obtaining uniform mass of Penicillin G Benzathine with lecithin coating in the double planetary mixer is from about 5 to about 20 RPM.

Isolation of Penicillin G Benzathine with lecithin coating is carried out by using techniques of distillation, recrystallization, anti-solvent and the like.
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:

Example 1: Preparation of Penicillin G Benzathine with lecithin coating

Lecithin (2.0 g) was dissolved in ethanol (300.0 ml) at 20-30 °C and transferred the lecithin solution into double planetary mixer. Penicillin G Benzathine (200.0 g) was added to the double planetary mixer at 20-30 °C and maintained over a period of 90 minutes. Then, ethanol was distilled off completely at below 35 °C and dried for 90 minutes in double planetary mixer to obtain Penicillin G Benzathine with lecithin coating.

Particle size d(0.9): 29.40 µm
Morphology: Rod shaped particles
HPLC Purity: > 99.6%

Example 2: Preparation of Penicillin G Benzathine with lecithin coating

Lecithin (3.0 g) was dissolved in ethanol (450.0 ml) at 20-30 °C and transferred the lecithin solution into double planetary mixer. Penicillin G Benzathine (300.0 g) was added to the double planetary mixer at 20-30 °C and maintained over a period of 90 minutes. Then, ethanol was distilled off completely at below 35°C and dried over a period of 90 minutes in double planetary mixer to obtain Penicillin G Benzathine with lecithin coating.

Particle size d(0.9): 27.13 µm
Morphology: Rod shaped particles
HPLC Purity: > 99.5% ,CLAIMS:CLAIMS
We claim,
1. A process for the preparation of penicillin G benzathine lecithin coating of Formula (I):

which comprises the steps of:
a. reacting penicillin G benzathine with lecithin solution in a double planetary mixer;
b. isolating penicillin G benzathine with lecithin coating of Formula (I).

2. The process according to claim 1, wherein the lecithin solution is prepared by dissolving lecithin in a solvent.

3. The process according to claim 1 and claim 2, wherein the solvent is selected from polar protic solvent comprises methanol, ethanol, isopropanol, n-butanol, acetic acid and mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methyl pyrrolidone and mixture thereof; and non-polar solvent comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethylether, dichloromethane (MDC) and mixture 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 the temperature in the double planetary mixer is from about 20°C to 50°C, without affecting the quality of product.

6. The process according to claim 1, wherein the RPM of double planetary mixture is from about 5 to about 20 RPM.