This invention relates to a process for the manufacture of divalproex sodium
FIELD OF INVENTION:
The present invention particularly relates to the manufacture of Divalproex sodium in high yields. Another aspect of the invention is that Divalproex sodium manufactured by the new process displays improved flowability, which is an important aspect of consideration during the preparation of the final dosage forms. Further, the Divalproex sodium obtained by the process disclosed in this invention is non-hygroscopic and more stable.
BACKGROUND TO THE INVENTION:
Divalproex sodium is one of the most widely used epileptic agents presently available in the market. Both the constituents, valproic acid and sodium valproate themselves have also been used for the treatment of epileptic seizures and convulsions. But their utility has remained restricted since valproic acid is a liquid and is difficult to formulate for an oral dosage form whereas sodium valproate is a hygroscopic solid with poor stability characteristics. Divalproex sodium is an oligomer having 1:1 molar ratio of valproic acid and sodium valproate containing 4 to 6 units. The relevant prior art includes US 4,988,731 ('731) relates to a non-hygroscopic stable sodium hydrogen divalproate oligomer. Its probable structure is shown in Fig 1
(Figure Removed)
Where M is a about 2.As can be seen from the displayed structure, one mole each of the valproic acid forms coordinate bonds with the sodium of the sodium valproate molecule, and the valproate ion is ionically bonded to the sodium atom. The structure is thus consistent with the unique characteristic of the compound. However the
preferred mode of representing Divalproex sodium is by reference to single compound of the formula
(Formula Removed)
The said patent also describes two alternative processes for the preparation of the oligomer. According to one aspect, the oligomer is produced by dissolving sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around 0°C.
Alternatively Divalproex sodium can be isolated from a two component liquid medium, which includes acetone where in half equivalent of NaOH to the valproic acid present, preferable as a solution in an acetone miscible solvent eg. water. The new compound can be recovered from the liquid phase by evaporating the solvent(s) and, if desired, the new compound can be recrystallized, for instance from acetonitrile or others or the material may be spay-dried, lyophilized or purified by chromatography.
US'731 claims yield of 90% of theory.
Drawbacks of the above mentioned reported methods for the preparation of Divalproex sodium described in US 4988731 are difficult to reproduce on a large scale and provides inconsistent yields and the material obtained is not always free flowing in nature. The process involves the crystallization of a 1:1 mixture of valproic acid and sodium valproate from a chilled solution of acetone, followed by washing with chilled acetone. Divalproex sodium is as such fairly soluble in acetone at temperatures above 10°C and extreme care has to be taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. This problem actually comes to the fore while scaling up the process during commercialization since during centrifugation of the large volume the temperature of the mixture rises and acetone has to be cooled below 0°C, which require large amount of liquid nitrogen or dry ice. Moreover it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore requires longer time to dry eventually leading to longer time cycle for the otherwise simple single step process. Also the high moisture content in the recovered acetone makes it unsuitable for reuse. Alternatively, to avoid absorption
of water, the centrifugation had to be carried out under a blanket of dry nitrogen gas. These additional infrastructural loads add to input costs eventually making the otherwise single step low cost process becoming uncompetitive and economically unviable.
Similarly the other process involves the addition of half molar equivalent of sodium hydroxide dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which has to be recrystallized to get Divalprox of the desired specification. The process is operationally tedious and requires the reduction in the level of water in the reaction mass via evaporation of the solvent followed by re-crystallization from acetonitrile making the process lengthy and economically unviable. There is therefore a need for operationally making this single step process more efficient and high yielding.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. II depicts XRD PATTERN FOR BATCH NO: S-26/SV/469 Fig. III depicts XRD PATTERN FOR BATCH NO: S-45/SV/518
SUMMARY OF THE INVENTION:
The main object of the present invention is to provide a process for the Manufacture of Divalproex sodium.
Particularly the invention relates to manufacture of Divalproex sodium in high yields. Other object of the invention is to provide a process that yields a Divalproex sodium having improved flowability.
Another object of the invention is to provide a process capable of producing non-hygroscopic and more stable Divalproex sodium.
Yet other object of the invention is to provide a process that can be industrially feasible, precise and reproducible. The present invention provides an operationally improved procedure, which overcomes the anomalies of the reported process to provide Divalproex sodium of high purity with excellent flow ability characteristics. The process o the present invention utilizes acetonitrile as solvent for the crystallization of Divalproex sodium which can be performed at 10-35°C without ever resorting to low temperature crystallization.
STATEMENT OF INVENTION:
Accordingly the invention provides a process for the manufacture of divalproex sodium which comprises:
(a) contacting, under stirring, the valproic acid with a compound of formula (Na)nX wherein X represents OH, OCH3, OC2H5, CO3, HCO3, or valproate, in solid form, and n is 1 or 2 optionally in presence of solvent such as herein described at a temperature above 0°C and below reflux temperature,
(b) optionally decolorizing by any known methods to get a clear solution,
(c) crystallizing the title product by contacting with the organic solvent such as here in described under stirring at a temperature ranging between -10°C and 50°C followed by
(d) isolating and washing using same solvent and then drying in a conventional manner to get Divalproex sodium as snow white solid.
According to one embodiment of this invention, the temperature in step (a) ranges from 0.0 to 90°C preferably 5°C to 85°C, more preferably 10-60°C and most preferable 30-40°C.
According to other embodiment of this invention the solvent used in step (a) is selected from.
(a) aliphatic nitrile such as acetonitrile or propionitrile,
(b) aliphatic ethers like diisopropyl ether, methyl tertiary butyl ether, diethyl ether, dibutyl ether,
(c) aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone,
(d) aliphatic halogentated/ non-halogenated hydrocarbons like dichloromethane, chloroform, carbon tetrachloride, C5-C8 aliphatic long chain or branched chain hydrocarbons,
(e) aromatic hydrocarbons like toluene / xylenes, benzene,
(f) C1-C5 Alkanols like methanol, ethanol, or a mixture thereof.
According to another embodiment of this invention the contacting of valproic acid and a compound of formula (Na)nX is performed by (i) adding compound of formula (Na)nX to valproic acid or (ii) adding valproic acid to the compound of formula (Na)nX where in n and X have the meanings as defined in Claim 1.
According to yet other embodiment of this invention half equivalent of solid compound of formula (Na)nX is used for the mechanism of contacting in step (a).
According to yet another embodiment of this invention the decolorization is carried out by charcoalization or any similar technique.
According to still other embodiment of this invention the organic solvent used for crystallization is selected from (i) aliphatic nitrile preferably acetonitrile or propionitrile or (ii) aliphatic ketones preferably acetone, methyl isobutyl ketone, methyl ethyl ketone.
According to still another embodiment of this invention the crystallization is effected at a temperature in the range of-5°C to 15°C.
Further, the drying is carried out at a temperature ranging from 40 to 50 °C for a period of 10 to 12 hours.
In accordance with the other aspect of this invention there is provided a process for the preparation of divalproex sodium which comprises.
(a) dissolving equimolar quantities of sodium valproate & valproic acid in single organic solvent or a mixture thereof.
(b) charcoalizing and filtering the reaction mixture.
(c) stirring the resultant filtrate at suitable temperature to get crystallized mass.
(d) filtering and drying the product, thus obtained, to get Divalproex sodium
as snow white solid.
DETAILED DESCRIPTION:
According to one aspect of this invention there is provided a process comprising addition of half equivalent of powdered sodium hydroxide to valproic acid at 10-60°C, and then adding acetone or acetonitrile to obtain a clear solution, followed by charcolization, cooling to 5-20°C and isolating the title compound by conventional methods. The solution after cooling is stirred for a reasonable amount of time, filtered, washed with chilled acetone and acetonitrile and dried under vacuum to obtain snow-white Divalproex sodium. The yields are above 92%. The same crystallization when performed in acetone in the absence of water as mentioned above, the reaction mass has to be cooled to around -5° to -10°C obtain high yields of Divalproex sodium. This helps in eliminating water through tedious evaporation as in case of process disclosed in'731.
Similarly Divalproex sodium can also be obtained in comparable yields by adding half molar equivalent of powdered sodium hydroxide to valproic acid in minimum amount of solvents like acetone, chloroform, carbon tetrachloride, dichloromethane, aliphatic ethers like diisopropyl ether, diethyl ether, methyl tertiary butylether, dibutyl ether, non polar aliphatic alkanes like n-pentane, pentanes, n-hexane, hexanes, n-heptane, heptanes, n-octane, octanes and aromatic solvents like benzene, toluene, xylenes etc at 5°C and above and then either adding the mixture to acetonitrile or adding acetonitrile to the mixture and the cooling the mixture to 0 -25°C for crystallization and filtering.
A still another option, is heating equimolar mixture of Sodium valproate and valproic acid in acetonitrile at 60-75°C to provide a clear solution, which is then optionally filtered to remove the suspended particles and then slowly cooled to 10-30°C and filtered and washed with acetonitrile and dried to obtain Divalproex sodium as a snow white powder in above 95% yield.
The material thus isolated displays IR and powder XRD pattern identical to the one obtained as per the reported procedure from chilled acetone as described in US 4988731. The XRD spectrums of both the samples are displayed in Table 1 and in Fig II and Fig III of the drawings accompanying this specification respectively. Also the prepared sample of Divalproex sodium displayed very low levels of residual acetonitrile in the head space GC analysis. Additionally, Divalproex sodium in comparable yields and quality can also be obtained from a 0.1:6 to 0.25:15 mixtures of acetone and acetonitrile at 10-30°C.
TABLE 1
XRD DATA OF DIVALPROEX SODIUM SAMPLES CRYSTALLIZED FROM ACETONITRILE AND ACETONE

(Table Removed)
Example I:
To 100g of Valproic acid with stirring at 20-30°C, powdered NaOH ( 13g; half molar)
is added & the resulting reaction mixture is stirred at 40-50°C for 1 hr. Then
acetonitrile
(600ml) is added to obtain clear solution at 40-50°C and the solution is charcoalized
at 40-50°C followed by filtration at 40-50°C through hyflo-bed. The resultant reaction
mixture was stirred at 10-20°C for 2-3 hr. The solid , thus obtained, was filtered and
product was dried at 40-45°C for 10-12 hr. (102.25g, 95%)
Example II:
To 100g of Valproic acid with stirring at 20-3 0°C, powdered NaOH (13g; half molar) is added & the resulting reaction mixture is stirred at 30-40°C for 1 hr. Then acetone (600ml) is added to obtain clear solution at 30-40°C and the material is charcoalized at 30-40°C followed by filtration through hyflo-bed. The resultant reaction solution was stirred at -5°C to -10°C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-45°C for 10-12 hr. (55g, 51.11%)
Example III:
To a solution of Valproic acid (100g) in dichloromethane (200ml) at 20-30°C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 30-40°C for 1 hr to get clear solution. Then acetonitrile (600ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5°C for 2-3 hr followed by filtration. The product was dried at 40-45°C for 10-12 hr. (lOOg; 93%)
Example IV:
To a solution of Valproic acid (100g) in diisopropyl ether(200ml) at 20-30°C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50°C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5°C for 2-3 hr followed by filtration. The product was dried at 40-45°C for 10-12 hr. (104g; 96.65%)
Example V:
To a solution of Valproic acid (100g) in methyl tertiary butyl ether(200ml) at 20-30°C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-50°C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-5°C for 2-3 hr followed by filtration. The product was dried at 40-45°C for 10-12 hr. (102g; 94.79%)
Example VI:
To a solution of Valproic acid (100g) in toluene (200ml) at 20-30°C, powdered
caustic
(13g ; half molar) is added & the reaction mixture is stirred at 40-50°C for 1 hr to get
clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the
product. The solid, thus obtained, is further stirred at 0-5°C for 2-3 hr followed by
filtration. The product was dried at 40-45°C for 10-12 hr. (101g; 93.87%)
Example VII:
A mixture of sodium valproate (60g) and valproic acid (52.04g) was taken in acetonitrile (800ml) and heated at reflux to obtain a clear solution, which was filtered through hyflo-bed to remove suspended particles. Then the solution was stirred at 10-20°C for 2-3 hr. The solid, thus obtained, was filtered and washed with acetonitrile (100ml). The product was dried at 40-45°C for 10-12 hr. (105g ; 93.75%)
Example VIII:
To a solution of valproic acid (100g) in methanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30°C for 1 hr. Then the methanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-5°C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(102g; ~ 95%) Example IX:
To a solution of valproic acid (100g) in methanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30°C for 1 hr. Then the methanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -10°C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45°C for 10-12 hr.(54g; ~ 50.11%) Example X:
To a solution of valproic acid (lOOg) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30°C for 1 hr. Then the ethanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-5°C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(101g;~ 93.87%)
Example XI:
To a solution of valproic acid (lOOg) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-30°C for 1 hr. Then the ethanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -10°C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-45°C for 10-12 hr.(55g; ~ 51%)
ADVANTAGES:
> The process is high yielding.
> The process produces Divalproex sodium with improved flowability.
> The process produces Divalproex sodium that is non-hygroscopic and more stable.
> The process is industrially feasible, precise, reproducible and does not require sophisticated infrastructure.

WE CLAIM:
1. A Process for the Manufacture of Divalproex sodium which comprises:
(e) contacting, under stirring, the valproic acid with a compound of formula (Na)n-X wherein X represents OH, OCH3, OC2H5, CO3, HCO3, or valproate, in solid form, and n is 1 or 2, optionally in presence of solvent at a temperature above 0°C and below reflux temperature,
(f) optionally decolorizing to get a clear solution,
(g) crystallizing the title product by contacting with the organic solvent under stirring at a temperature ranging between -10°C and 50°C followed by
(h) isolating and washing using same solvent and then drying in a conventional manner to get Divalproex sodium as snow white solid.
2. A process as claimed in claim 1 wherein temperature in step (a) ranges from 0.0 to
90°C preferably 5°C to 85°C, more preferably 10-60°C and most preferable 30-40°C.
3. A process as claimed in claim 1 wherein the solvent used in step (a) is selected
from.
(g) aliphatic nitrile such as acetonitrile or propionitrile,
(h) aliphatic ethers like diisopropyl ether, methyl tertiary butyl ether, diethyl
ether, dibutyl ether, (i) aliphatic ketones like acetone, methyl isobutyl ketone, methyl ethyl ketone, (j) aliphatic halogentated/ non-halogenated hydrocarbons like dichloromethane,
chloroform, carbon tetrachloride, C5-C8 aliphatic long chain or branched chain
hydrocarbons, (k) aromatic hydrocarbons like toluene / xylenes, benzene, (1) C1-C5 Alkanols like methanol, ethanol etc.
or a mixture thereof.
4. A process as claimed in claim 1 wherein the contacting of valproic acid and a
compound of formula (Na)nX is performed by (i) adding compound of formula
(Na)nX to valproic acid or (ii) adding valproic acid to the compound of formula (Na)nX wherein n and X have the meanings as defined in Claim 1.
5. A process as claimed in claim 1 wherein half equivalent of solid compound of formula (Na)n-X is used for the mechanism of contacting in step (a).
6. A process as claimed in claim 1 wherein the decolorization is carried out by charcoalization or any similar technique.
7. A process as claimed in claim 1 wherein the organic solvent used for crystallization is selected from (i) aliphatic nitrile preferably acetonitrile or propionitrile or (ii) aliphatic ketones preferably acetone, methyl isobutyl ketone, methyl ethyl ketone.
8. A process as claimed in claim 1 wherein the crystallization is effected at a temperature in the range of-5°C to 15°C.
9. A process as claimed in claim 1 wherein the drying is carried out at a temperature ranging from 40 to 50 °C for a period of 10 to 12 hours.
10. A process for the manufacture of Divalproex sodium which comprises.

(e) dissolving equimolar quantities of sodium valproate & valproic acid in single organic solvent or a mixture thereof.
(f) charcoalizing and filtering the reaction mixture.
(g) stirring the resultant filtrate at suitable temperature to get crystallized mass,
(h) filtering and drying the product, thus obtained, to get Divalproex sodium
as snow white solid.
11. A Process for the Manufacture of Divalproex sodium substantially as herein
described.