FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
17 TITLE OF THE INVENTION:
Process for preparing sustained release pharmaceutical composition comprising Sodium Valproate and valproic acid.
2. APPLICANT (S)
(a) NAME: Micro Labs Limited.
(b) NATIONALITY: Indian
(c) ADDRESS: CTS No. 73, Saki Estate, Off Chandivali Road, Chandivali,
Kurla (W), Mumbai - 400 072.
3. PREAMBLE TO THE DESCRIPTION
There is provided a process for preparing sustained release pharmaceutical composition comprising Sodium Valproate and valproic acid.
4. DESCRIPTION (Description shall start from the next page.)
The following specification particularly describes the invention and the manner in which it is to be performed.

Description
There is provided a process for preparing sustained release pharmaceutical composition comprising Sodium Valproate and valproic acid.
Sodium valproate and valproic acid are anticonvulsants. These are commercially available as a combination in granule or tablet form.
Sodium valproate is the sodium salt of valproic acid. It is chemically sodium 2-propylpentanoate. It is highly hygroscopic and readily absorbs water from the atmosphere, which leads to problems of poor stability in the compositions made from sodium valproate.

Valproic acid is chemically 2-propylpentanoic acid. It is disclosed in US patent number 3325361. Valproic acid is liquid at room temperature and thus not suitable for manufacturing of solid dosage forms e.g. tablets for oral administration. Valproic acid has shorter half-life and to maintain the reasonably stable plasma concentrations of the drug, sustained release formulations have been developed.

EP0956010B1 discloses pharmaceutical microspheres, characterized in that they contain, as active principle, a mixture of valproic acid and one of the pharmaceutically acceptable salts thereof, combined with a matrix carrier

selected from among the glycerol esters, hydrogenated oils, esterified polyethylene glycol or waxes.
EP0385846B1 discloses tablet for sustained release for more than 8 hours, wherein the active principle is the complex formed between one mole of valproic acid and one mole of sodium valproate, characterized in that it comprises from 8 to 10% by weight, based on the weight of the complex, of hydroxypropyl methylcellulose having a viscosity of from 8000 to 12000 mPa.s and 8 to 10% by weight of hydrated silica.
EP0133110B1 discloses pharmaceutical composition which can be administered by oral route presented in the form of tablets, characterized in that it contains, as non-combined active principles 25 to 35 % in weight of valproic acid and 75 to 65 % of sodium valproate.
FR2549371B1 discloses novel pharmaceutical composition containing Valproic acid or pharmaceutically acceptable salt thereof and a natural wax in a controlled release form.
EP1353650A2 discloses non-hygroscopic oral pharmaceutical composition comprising a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive.
EP1233758B1 discloses granular sodium valproate material having a reduced hygroscopicity.
EP0808161B1 discloses process of making a solid substance comprising valproic acid and sodium valproate which process comprises the steps of heating the valproic acid, dissolving sodium valproate therein, and cooling the resultant solution to below the melting point.

EP1815850B1 discloses controlled release tablet formulation comprising, a) a valproic acid compound in an amount of about 40% to about 80% by weight of the dosage form, and b) at least two hydrophilic polymers each in an amount of from 10% to 16% of the tablet weight.
EP0571973B1 discloses slow-release sodium valproate tablet with a coating layer, obtainable by coating a core containing sodium valproate with a coating agent comprising ethyl cellulose having dispersed therein silicic acid anhydride.
EP1948140A1 discloses enteric valproic acid soft gelatin capsule.
EP0300111B1 discloses moisture stable solid valproic acid formulation comprising:
a) 55 to 65 weight percent of valproic acid,
b) 10 to 25 weight percent of at least one filler selected from alkaline earth metal oxides, earth metal oxides, zinc oxide, clays and amorphous silicon dioxide.
EP1513503A1 discloses extended release pharmaceutical composition comprising: a) a drug capable of dissociating to produce a valproate ion; and b) at least one extended release polymer; wherein the pharmaceutical composition is manufactured under controlled atmospheric conditions.
PCT publication WO 07/081341 discloses controlled release dosage formulation comprising, a) a valproic acid compound in an amount of about 40% to about 80% by weight of the dosage form, and b) at least two polymers each in an amount of less than about 20% of the tablet weight.
Sodium valproate is solid, but an extremely hygroscopic, deliquescent substance. It absorbs water from the atmosphere already during tabletting, resulting in problems of tablet production like sticking to the punches.

The processes available to prepare the compositions sometimes utilize organic solvents during granulation which are expensive and also give rise to concerns about toxic effects on production personnel and environmental concerns relating to disposal of the solvent. Further, these solvents pose stability issues when used during granulation process.
There remains, however, the need for a process for preparing sustained release formulation of valproic acid which will avoid the above-mentioned problems. Accordingly a process for preparing a sustained release pharmaceutical composition has been provided. The essential feature of the process is granulating sodium valproate using valproic acid. Thus, the process avoids the use of other organic solvents, thus results into a final formulation without any toxic solvent impurity. Further, the process uses anhydrous silica, which is non-hygroscopic excipient. Silica is used as a desiccant to control local humidity in order to equate the hygroscopic nature of Sodium Valproate. The process involves the coating of the formulation. The process does not suffer from the processing limitations and poor stability associated with traditional processes.
In one aspect, there is provided a process for preparing sustained release pharmaceutical composition comprising Sodium Valproate and valproic acid comprising the steps of:
(a) Mixing sodium valproate with anhydrous silica and pharmaceutically acceptable release modifying agents optionally with other pharmaceutically acceptable inert excipients to form a mixture;
(b) Granulating the mixture with valproic acid to form the granules;
(c) Optionally compressing the granules to form tablets using suitable toolings.
(d) Coating the granules in step (b) or the tablets in step (c).
The sustained release pharmaceutical composition may be a solid dosage form. The sustained release pharmaceutical composition may be one or more of tablet,

capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like. The solid dosage form also includes multilayer tablets.
The sustained release pharmaceutical composition contains sodium valproate and valproic acid as active ingredients.
The release of the drug may be controlled by matrix system or reservoir system. The sustained release pharmaceutical composition comprises one or more pharmaceutically acceptable release modifying agents.
The pharmaceutically acceptable release modifying agents may be one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers and mixtures thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose and hydroxypropyl ethylcellulose.
Anhydrous silica may be present in the sustained release pharmaceutical composition in an amount ranging from 1 to 15 % by weight of the composition. The commercially available grades of anhydrous silica may also be used.
The pharmaceutical composition comprises one or more pharmaceutically acceptable inert excipients. The pharmaceutically acceptable inert excipients may be one or more of diluents, binders, lubricants, glidants and the like.

Suitable diluents may include one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like.
Suitable binder may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable lubricant may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like.
Suitable glidant may be one or more of anhydrous silica, talc or cornstarch and the like.
The pharmaceutical composition form is coated. The coating maybe one or more of seal coating and film coating. The coating may comprise one or more of film formers, solvents, plasticizers and the like. Further, commercially available coating systems like Opadry® may be used. One such system is Opadry® AMB which is an aqueous moisture barrier film coating system. It provides protection of the core tablet from moisture.
Suitable film formers may be one or more of hydroxypropyl methyl cellulose, methyl hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, polyethylene glycol, acrylates and the like.
Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methylethyl ketone, methylene chloride and the like.
Suitable plasticizers may be one or more of dibutyl phthalate, propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbates, and the like.

While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example -I
Table-1: Pharmaceutical composition of the invention

SN Ingredients
Intragranular
1. Sodium Valproate
2. Microcrystalline Cellulose
3. Hypromellose
4. Colloidal Anhydrous Silica
5. Valproic Acid Extragranular
6. Colloidal Anhydrous Silica
7. Magnesium Stearate Sea coating
8. Hypromellose
9. Dibutyl Phthalate
10. Isopropyl Alcohol
11. Methylene Chloride Film coating
12. I OpadryAMB
13. Purified water

Quantity/unit

133.20 199.80 333.00
8.20 12.30 20.50
30.00 45.00 75.00
20.00 30.00 50.00
58.00 87.00 145.00

12.00 18.00 30.00
4.60 6.90 11.50

7.12 10.68 17.80
0.88 1.32 2.20
q. s. q. s. q.s.
q. s. q. s. q.s.

12.00 18.00 30.000
q.s. q.s. q.s.

Procedure:
1. Sodium valproate was milled.
2. Microcellulose cellulose, Hypromellose, Colloidal anhydrous silica were sifted with milled sodium valproate to form a dry mixture.
3. The mixture in step 2 was granulated using Valproic acid.
4. The wet mass was dried and sifted to form granules.

5. The granules formed in step 4 were mixed with colloidal anhydrous silica to form a mixture.
6. The mixture formed in step 5 was lubricated using magnesium stearate to form a blend.
7. The blend in step 6 was compressed using suitable toolings to form tablets.
8. The tablets formed in step 7 were seal coated using seal coating solution of hypromellose, dibutyl phthalate, isopropyl alcohol and methylene chloride.
9. The seal coated tablets were film coated using film coating suspension of Opadry and purified water.

We claim:
1. A process for preparing sustained release pharmaceutical composition
comprising Sodium Valproate and valproic acid comprising the steps of:
a. Mixing sodium valproate with anhydrous silica and
pharmaceutically acceptable release modifying agents optionally with
other pharmaceutically acceptable inert excipients to form a mixture;
b. Granulating the mixture with valproic acid to form the granules;
c. Optionally compressing the granules to form tablets using suitable
toolings.
d. Coating the granules in step (b) or the tablets in step (c).
2. The process according to claim 1, wherein the composition is in the form of solid dosage form.
3. The process according to claim 2, wherein the composition is in the form of tablet.
4. The process according to claim 1, wherein the pharmaceutically acceptable release modifying agents are one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers and mixtures thereof.
5. The process according to claim 1, wherein the pharmaceutically acceptable inert excipients are one or more of diluents, binders, lubricants, and glidants.
6. The process according to claim 1, wherein the coating is one or more of seal coating and film coating.
7. The process according to claim 6, wherein the coating comprises one or more of film formers, solvents, plasticizers.

8. The process according to claim 6, wherein the film coating comprises Opadry AMB.
9. The process according to claim 1, wherein the anhydrous silica is present within the range of 1 to 15 % by weight of the composition.
10. A process for preparing sustained release pharmaceutical composition comprising Sodium Valproate and valproic acid as herein above described in the specification.