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 AMPICILLIN TRIHYDRATE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
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 Ampicillin trihydrate of Formula (I) with lecithin coated by using a Double planetary mixer.

BACKGROUND OF THE INVENTION

Ampicillin trihydrate of Formula (I) is chemically known as (2S, 5R, 6R)-6-[(R)-2-Amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate.

It is used to reduce the development of drug-resistant bacteria and maintain the effectiveness of ampicillin and other antibacterial drugs, ampicillin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. Its spectrum of activity is enhanced by co-administration of sulbactam, a drug that inhibits beta lactamase, an enzyme produced by bacteria to inactivate ampicillin and related antibiotics.

Ampicillin is bactericidal at low concentrations and is clinically effective not only against the gram positive organisms usually susceptible to penicillin G but also against a variety of gram-negative organisms. It is stable in the presence of gastric acid and is well absorbed from the gastrointestinal tract. It diffuses readily into most body tissues and fluids; however, penetration into the cerebrospinal fluid and brain occurs only with meningeal inflammation.

US 3157640 discloses Ampicillin trihydrate of Formula (I). The prior-art discloses the preparation of Ampicillin trihydrate (I) comprising reacting dane salt with pivaloyl chloride to obtain mixed carboxylic acid anhydride, simultaneously 6-APA is treated with triethylamine and then added to the mixed carboxylic acid anhydride and further treated with hydrochloric acid to obtain Ampicillin trihydrate (I). The process is shown in below scheme:

US 3634586 relates to the preparation of stable aqueous suspensions of Ampicillin wherein compositions are prepared by process comprising blending pulverized Ampicillin trihydrate (I), sodium chloride and anhydrous tri-sodium citrate with PVP-lecithin-methyl and propyl paraben methylene chloride solution followed by drying and repulverisation to obtain Ampicillin trihydrate (I) coated material.

The major disadvantage of the above prior-art process is non-uniform blending of sodium chloride, sodium citrate, non-uniform lecithin coated and usage of multiple process equipment’s with lengthy unit operations.

Besides the known procedures, there is still a need for a process, which is simple cost effective and industrially viable to provide a higher yield of product with higher purity to produce Ampicillin trihydrate (I) with uniform lecithin coated having reduced particle size.
The inventors of the present invention found a novel process to obtain Ampicillin trihydrate (I) with lecithin coated by using a double planetary mixer which contains single vessel i.e. highly useful for blending, evaporation and drying operations and provides uniform lecithin coated. Further, cycle time on a Double planetary mixer is significantly less than the traditional blending, evaporation and drying operations.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide Ampicillin trihydrate of Formula (I) with uniform lecithin coated having reduced particle size by using a Double planetary mixer.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size:

which comprises the steps of,
a. adding Ampicillin trihydrate of Formula (I) and lecithin solution into a double planetary mixer;
b. isolating Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size.
In specific embodiment, the present invention provides a process for the preparation of ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size:

which comprises the steps of,
a. blending Ampicillin trihydrate of Formula (I) with one or more mineral salt excipients in a double planetary mixer;
b. adding lecithin solution having one or more pharmaceutically acceptable excipients in a solvent into the double planetary mixer;
c. stirring the above contents;
d. isolating the Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Ampicillin trihydrate of Formula (I) with lecithin coated having uniform coated of all excipients and reduced particle size D(4,3) of about from 20 µm to 70 µm by using a Double planetary mixer.

The process of the present invention comprises, blending Ampicillin trihydrate (I) with one or more mineral salt excipients in a double planetary mixer then adding lecithin solution containing one or more pharmaceutically acceptable excipients and a solvent into the double planetary mixer and then stirring and isolating Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size.

The mineral salt excipients used in the above process comprises sodium chloride, sodium citrate, calcium carbonate, potassium citrate, sodium carbonate, sodium lactate or mixture thereof; the pharmaceutically acceptable excipients used in the above process comprises povidone, copovidone, crospovidone or mixture thereof.

The Lecithin solution of the above process uses antimicrobial chemicals comprises methylparaben, ethylparaben, propylparaben or mixture thereof.

The solvent used in the above process is an organic solvent selected from but not limited to polar protic solvent comprises methanol, ethanol, isopropanol and non-polar solvent comprises chloroform, diethyl ether, dichloromethane (CH2Cl2) or mixture thereof.

In the present invention, the double planetary mixer consists of two identical High Viscosity (HV) blades which leads to uniform mixing of thick pasty material. During drying it breaks up the agglomerates and leads to obtaining the material with uniform coating of all excipients and uniform blending of all mineral salt excipients.

The present invention involves low quantities of antimicrobial chemicals such as methyl paraben and propyl paraben as preservatives.

The obtained Ampicillin trihydrate of Formula (I) with lecithin coated is applicable for sterile or non-sterile use.

Ampicillin trihydrate of Formula (I) used in the present invention is prepared by using the process disclosed in the prior art literature.

The temperature maintained in the double planetary mixer is from about 20°C to 40°C without affecting the quality of product.

The suitable RPM (Revolutions Per Minute) for obtaining uniform mass of Ampicillin trihydrate of Formula (I) with lecithin coated in the double planetary mixer is from about 5 to about 20 RPM.

Isolation of Ampicillin trihydrate of Formula (I) with lecithin coated is carried out by using techniques of distillation, drying 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 Ampicillin trihydrate with lecithin coated having reduced particle size
Ampicillin Trihydrate sterile material (600 grams), Sodium Chloride sterile (4.1 grams) & Sodium Citrate sterile (13.8 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.

Lecithin + Povidone solution was prepared by dissolving Lecithin (5.62 grams) and Povidone (10.31 grams) in methylene chloride (270 ml). Propylparaben (0.206 grams) and Methylparaben (1.85 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with methylene chloride (126 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.
Yield: 0.98 % w/w
Particle size: D (4, 3): 45.2 µm,
Bulk density: 0.43 g/ml, Tap density: 0.67 g/ml.

Example-2: Preparation of Ampicillin trihydrate with lecithin coated
Ampicillin Trihydrate sterile material (600 grams), Sodium Chloride sterile (4.12 grams) & Sodium Citrate sterile (13.86 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.

Lecithin + Povidone solution was prepared by dissolving Lecithin (5.62 grams) and Povidone (10.32 grams) in methylene chloride (450 ml). Propylparaben (0.206 grams) and Methylparaben (1.86 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with methylene chloride (150 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under vacuum under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.

Yield: 0.98 % w/w
Particle size: D (4, 3): 40.7 µm,
Bulk density: 0.44 g/ml, Tap density: 0.64 g/ml.

Example-3: Preparation of Ampicillin trihydrate with lecithin coated
Ampicillin Trihydrate sterile material (300 grams), Sodium Chloride sterile (2.04 grams) & Sodium Citrate sterile (6.84 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.
Lecithin + Povidone solution was prepared by dissolving Lecithin (2.78 grams) and Povidone (5.09 grams) in methylene chloride (450 ml). Propylparaben (0.10 grams) and Methylparaben (0.92 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with methylene chloride (150 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under vacuum under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.

Yield: 0.96 % w/w
Particle size: D (4, 3): 27.1 µm,
Bulk density: 0.45 g/ml, Tap density: 0.65 g/ml.

Example-4: Preparation of Ampicillin trihydrate with lecithin coated
Ampicillin Trihydrate sterile material (300 grams), Sodium Chloride sterile (2.06 grams) & Sodium Citrate sterile (6.87 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.

Lecithin + Povidone solution was prepared by dissolving Lecithin (2.79 grams) and Povidone (5.16 grams) in isopropyl alcohol (225 ml). Propylparaben (0.10 grams) and Methylparaben (0.93 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with isopropyl alcohol (75 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under vacuum under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.

Yield: 0.99 % w/w
Particle size: D (4, 3): 45.1 µm,
Bulk density: 0.50 g/ml, Tap density: 0.64 g/ml.

Example-5: Preparation of Ampicillin trihydrate with lecithin coated
Ampicillin Trihydrate sterile material (600 grams), Sodium Chloride sterile (4.09 grams) & Sodium Citrate sterile (13.84 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.

Lecithin + Povidone solution was prepared by dissolving Lecithin (5.58 grams) and Povidone (10.23 grams) in 3%v/v aqueous isopropyl alcohol (225 ml). Propylparaben (0.205 grams) and Methylparaben (1.84 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with 3% aqueous isopropyl alcohol (75 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under vacuum under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.

Yield: 0.98 % w/w
Particle size: D (4, 3): 43.8 µm,
Bulk density: 0.52 g/ml, Tap density: 0.74 g/ml.

Example-6: Preparation of Ampicillin trihydrate with lecithin coated
Ampicillin Trihydrate sterile material (300 grams), Sodium Chloride sterile (2.08 grams) & Sodium Citrate sterile (7.03 grams) were blended in Double planetary mixer at 20-30°C for 60-70 minutes.

Lecithin + Povidone solution was prepared by dissolving Lecithin (2.08 grams) and Povidone (5.2 grams) in 15%v/v aqueous isopropyl alcohol (225 ml). Propylparaben (0.104 grams) and Methylparaben (0.936 grams) were charged into above Lecithin solution and stirred for 15-20 minutes. Filter the above prepared Lecithin (Lecithin+Povidone+Methylparaben+Propylparaben) solution through 0.22 micron filter and wash the filter bed with 15%v/v aqueous isopropyl alcohol (75 ml) and collect the filtrate in receiver.

The above filtered Lecithin solution was transferred into Double planetary mixer and stirred the contents over a period of 60-70 minutes under agitation. Methylene chloride was distilled off completely at below 35°C under vacuum under agitation and then dried the compound in double planetary mixer. Unload the dried material and co-milled to obtain the title compound.

Yield: 1.0 % w/w
Particle size: D (4, 3): 43.6 µm,
Bulk density: 0.39 g/ml, Tap density: 0.56 g/ml. ,CLAIMS:CLAIMS
We claim,

1. A process for the preparation of for the preparation of Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size:

which comprises the steps of
a. adding Ampicillin trihydrate of Formula (I) and lecithin solution into a double planetary mixer;
b. isolating Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size.

2. The process as claimed in claim 1, wherein the lecithin solution is prepared by using pharmaceutically acceptable excipients and antimicrobial chemicals in a solvent.

3. The process as claimed in claim 1 and claim 2, wherein the pharmaceutically acceptable excipient comprises povidone, copovidone, crospovidone or mixtures thereof.

4. The process as claimed in claim 1 and claim 2, wherein the antimicrobial chemical comprises methylparaben, ethylparaben, propylparaben or mixtures thereof.

5. The process as claimed in claim 1 and claim 2, wherein the solvent comprises methanol, ethanol, isopropanol, chloroform, diethyl ether, dichloromethane or mixture thereof.

6. A process for the preparation of for the preparation of Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size:

which comprises the steps of,
a. blending Ampicillin trihydrate of Formula (I) with one or more mineral salt excipients in a double planetary mixer;
b. adding lecithin solution having one or more pharmaceutically acceptable excipients in a solvent into the double planetary mixer;
c. stirring the above contents;
d. isolating the Ampicillin trihydrate of Formula (I) with lecithin coated having reduced particle size.

7. The process as claimed in claim 1, wherein the mineral salt excipient used in step (a) comprises sodium chloride, sodium citrate, calcium carbonate, potassium citrate, sodium carbonate, sodium lactate or mixture thereof.