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 AMORPHOUS EDETATE CALCIUM DISODIUM

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 the same is to be performed:
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of amorphous Edetate calcium disodium by using lyophilization technique.

BACKGROUND OF THE INVENTION

Edetate calcium disodium is chemically known as [[N, N’-1,2-ethanediyl-bis[N-(carboxymethyl)-glycinato]](4-)-N,N’O,O’ON,ON’]-, disodium, hydrate
(OC-6-21)-Calciate (2-) and has the following structural formula I:

In 1950 EDTA calcium disodium was used for the treatment of hypercalcemia and in 1952 it was reported to be used in the treatment of lead poisoning. Edetate calcium disodium mobilizes lead from bone and is widely used for the treatment of lead poisoning in all species. It enhances removal of lead from the body by forming a stable water-soluble lead complex that is readily excreted by the kidneys.

DD16392, discloses the preparation of Edetate calcium disodium solution. The process disclosed in DD ‘392 involves reaction of ethylenediamine tetraaceticacid (EDTA) with calcium carbonate in water followed by treatment with caustic soda to provide Edetate calcium disodium solution having a pH of about 6 to 7.

The Science and Practice of Pharmacy. 21st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1343 discloses the preparation of crystalline Edetate calcium disodium by the reaction of Edetate disodium with calcium carbonate.

CN 103172532 B discloses a process for Edetate calcium disodium, which involves reaction of tetrasodium EDTA with calcium hydroxide in water and then concentration of the solution followed by crystallization from ethanol.

CN 102311358 A discloses a process for the preparation of Edetate calcium disodium by dissolving disodium edetate with water for injection, adding calcium carbonate, filtering, removing pyrogen to obtain drug liquid, which is spray dried under sterile condition.

Doklady Akademii Nauk SSSR, 1965, 162(3), 593-6, discloses the conversion of crystalline Edetate calcium disodium heptahydrate to amorphous glass by dehydration.

The present invention provides an alternative process for the preparation of amorphous Edetate Calcium disodium to improve the stability of the reconstitution solution, in which pH value of the Edetate calcium disodium is adjusted prior to lyophilization.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of amorphous Edetate calcium disodium by using lyophilization technique.

SUMMARY OF THE INVENTION

In an aspect, the present invention provides a process for the preparation of amorphous Edetate calcium disodium, which comprises:
i) providing a solution of Edetate calcium disodium in water;
ii) degassing to remove carbon dioxide;
iii) adjusting pH of the solution of step ii) to 7.0-8.0; and
iv) lyophilizing the solution of step iii).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a powder X-ray power diffraction ("PXRD") pattern of amorphous Edetate calcium disodium obtained according to the present invention.

DETAILED DESCRIPTION OF THE IVENTION

In an aspect, the present invention provides a process for the preparation of amorphous Edetate calcium disodium, which comprises:
i) providing a solution of Edetate calcium disodium in water;
ii) degassing to remove carbon dioxide;
iii) adjusting pH of the solution of step ii) to 7.0-8.0; and
iv) lyophilizing the solution of step iii) to obtain amorphous Edetate calcium disodium.

The solution of Edetate calcium disodium in step (i) may be provided by dissolving edetate calcium disodium in water or it may be obtained from the earlier reaction step wherein the solution is formed. The compound of Edetate calcium disodium used in the present invention can be prepared by the process known in the art.

The process for Edetate calcium disodium of the present invention comprises:
a) reacting EDTA with calcium carbonate in water to obtain Edetate Calcium; and
b) treating Edetate calcium with aqueous sodium hydroxide to obtain the solution of Edetate calcium disodium;

The preparation of Edetate calcium is carried out by the addition of calcium carbonate in lot wise to a solution of EDTA in water for a period of 30 minutes to 1 hour or more to reduce the frothing due to evolution of carbon dioxide gas. The addition of calcium carbonate may be carried out at a temperature of above 30°C or at 40 to 50 °C. The resultant Edetate calcium is treated with aqueous sodium hydroxide at a temperature of about 20 to 30 °C over a period of 30 minutes to 1 hour to obtain the solution of Edetate calcium disodium.

The dissolved carbon dioxide may remain in the solution due to reaction conditions such as stirring, temperature, pressure, etc., that can interfere in the pH value of the product in two ways:
i) the reaction is stopped at different extents or
ii) the pH reading is interfered.

According to the USP monograph for Edetate calcium disodium, the pH value should be in between 6.5 to 8.0. The inventors of the present invention found that if the carbon dioxide is evolved or present in the solution, the pH of the solution is inconsistent and is difficult to achieve desired pH as required by the USP monograph.

Therefore, to control the content of carbon dioxide, the reaction solution from step b) is degassed by purging of ultra-pure nitrogen gas for a period of about 1 hour or more or of about 6 hours to remove carbon dioxide.

The resultant solution is subjected to pH adjustment of value between to 7.0-8.0 by the addition of EDTA at 20-30 °C for a period of 30 minutes or more. The solution may be filtered through 0.22 µ filter to remove the particulate matter and then lyophilized to obtain amorphous Edetate calcium disodium.

Degassing and pH adjustment of the solution of Edetate Calcium disodium prior to lyophilization are very required in order to avoid inconsistent pH of the solution and particulate formation or precipitation after reconstitution of the lyophilized product.

Examples of amorphous Edetate Calcium disodium obtained using the above process is characterized by powder X-ray diffraction (“PXRD”) pattern substantially as illustrated by Fig. 1.

The resultant Edetate calcium disodium of the present invention has assay by titrimetry greater than 100.0% w/w and content of disodium edetate impurity is less than about 0.5% w/w.

Having described the invention with reference to certain aspects embodiments, embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing the preparation of amorphous Edetate calcium disodium. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

EXAMPLE 1: PREPARATION OF AMORPHOUS EDETATE CALCIUM DISODIUM.

Hydrochloric acid (56 g of 35% w/w) was added to a solution of Edetate disodium dihydrate (100 g) in water (1000 ml) at 20-30 °C slowly over a period of 30 minutes. The pH of the reaction mixture was adjusted to 2-3, filtered the product and washed with water. The obtained solid was suspended into water (1500 ml), heated to 40-50°C and stirred for about 1 hour. The suspension was filtered, washed with water and dried at 50-60 °C. The obtained ethylenediamine tetraaceticacid (EDTA) (70.22 gm) has an assay of about 99.70% w/w by titrimetry.

Calcium carbonate (17.12 g) was added to a solution of EDTA (50 g) in water (175 ml), at 40-50 °C over a period of 45 minutes. The reaction mixture was cooled to 20-30 °C to precipitate edetate calcium. Aqueous sodium hydroxide solution (13.8gm of NaOH in 75ml of water) was added to the above formed edetate calcium suspension over a period of 45 minutes (pH of the solution: 5.0 observed). The ultra-high pure nitrogen was purged into the reaction solution at 20-30 °C for 6 hours (pH: 10.0 observed). pH of the reaction mixture was adjusted to 7.2-7.5 by using EDTA, continued stirring of the reaction mixture for 30 minutes at 20-30 °C and filtered through 0.22 micron filter. The obtained clear filtrate was subjected for lyophilization to obtain amorphous Edetate Calcium disodium having water content in the range of 5-10% w/w.
Yield: 57.82 g.
Disodium Edetate content: 0.30 % w/w by titrimetry.
Assay: 100.73% w/w/ by titrimetry. ,CLAIMS:WE CLAIM:

1. A process for the preparation of amorphous Edetate calcium disodium, comprising the steps of:

i. providing a solution of Edetate calcium disodium in water;
ii. degassing to remove carbon dioxide;
iii. adjusting pH of the solution of step ii); and
iv. lyophilizing the solution of step iii)

2. The process as claimed in claim 1, wherein the degassing is carried out prior to the lyophilization.

3. The process as claimed in claim 1, wherein the degassing is performed by purging ultra-pure N2 gas.

4. The process as claimed in claim 1, wherein the pH is adjusted in the range of 7-8.

5. The process as claimed in claim 1, wherein the pH is adjusted by EDTA.

6. The process as claimed in claim 1, wherein the pH adjustment is carried out at 20-30 °C.

7. The process as claimed in claim 1, wherein the solution of step (iii) is filtered through 0.22 µ filter.

8. The process as claimed in claim 1, wherein the Edetate calcium disodium has impurity content of disodium edetate less than about 0.5% w/w.