CA1135272A - Maufacture of sodium hydrogen divalproate - Google Patents

Abstract

Abstract of the Disclosure Sodium hydrogen divalproate can be made in pure, crystalline form by adding a highly concentrated aqueous sodium hydroxide solution to twice the stoichiometric amount of valproic acid and evaporation of the water from the reaction mixture.

Description

~3S~i~;2 Detailed Description of the Invention In the last decade, 2-propylpentanoic acid and its alkali or earth alkali salts (hereinafter referred to as valproic acid and valproates or valproate salts, re-spectively) have been introduced in the arsenal of drugsuseful for treating epileptic seizures or convulsions.
Most commonly used are valprioc acid itself or its sodium salt. The former is a liquid and as such is less desir-able for preparing an oral dosage form while the latter is a solid that has poor stability characteristics partially due to pronounced hygroscopicity.
It has now been found that a highly stable, non-hygroscopic, solid entity can be prepared from valproic acid and its salts, representing a single chemical mole-cule with well-defined physical characteristics, although a definite structure has not been assigned to this entity.
The new compound represents a single crystalline entity consisting of one molecule each of valproic and and sodium valproate. While it has not been determined for sure whether the new compound represents a solution of the valprioc acid in sodium valproate or a complex between the two compound~, the new material has been tentatively assigned the following structure:

CH3CH2CH2\ ~ o .... Na~ CH2CH2CH3 f HC CCP. I
CH3CH2C~2 OH .... O `CH2CH2CH3 In previous methods, the above compound was pre-pared by dissolving one mole each of valproic acid and sodium valprcate in 1000 ml. of acetone at about 50C.
After cooling the solution to OC~ or belcw, the formed new compound was filtered, washed if desired with pre-cooled acetone, and dried under reduced pressure to re-move all traces of acetone. Another method involved a two-component liquid medium which included acetone. In this instance~ sodium valproate was formed ln situ by .~, ~3~

adding NaOH at a level of one-half of a molecular equiva-lent of the valproic acid present, preferably as a solution in an acetone-miscible solvent for said NaOH, e~g., water.
The new dimer was then recovered from the liquid phase by evaporating the solvents.
It has now been found that, against expecta-tions and documented precedents, the above compound can be prepared without use of an organic solvent; i.e., by simply admixing an aqueous solution of sodium hydroxide of at least 10% concentration and valproic acid, said sodium hydroxide being used in an amount corresponding to 48 - 52% of the stoichiometric amount of said valproic acid, and removing the water from the reaction mixture by evaporation.
Best results are obtained when the sodium hy-droxide solution is concentrated, i.e., about 50% NaOH
and is used or a molar amount of exactly one-half of the molar amount of valproic acid used. A preferred NaOH
solution contains at least 35~i of NaOH on a weight basis.
If preferred, the two reactants can be admixed at elevated temperatures, although a temperature range of 5 - 100C. is suitable for the reaction. The term "ad-mixing" is to be understood to express that the reactants should be allowed to intimately mix to a homogeneous mix-ture. This can be done by allowing a long contact time, stirring, heating, vibrating or any other means increas-ing the contact between two materials.
The new procedure leads to very fluffy crystal-line needles in a substantially theoretical yield, while older methods were associated with losses of 10% or more.
In addition, older methods required large volumes of or-ganic solvents. For instance, an acetone solution con-taining 10% of sodium hydrogen divalproate becomes so thick upon cooling that it has to be scooped out of the reaction vessel.
The present aqueous process requires the use of a sodium hydroxide solution with a concentration of above 10~ by weight At lower concentrations, intimate mixing of the two reactants becomes a more significant step be-cause sodium hydroxide tends to increase the proportion of sodium valproate in the lower sections of the reac~ion vessel ~ith valproic acid going to the top. Dispropor-tionments of this kind are known to exist and are the reason for the required use of organic solvents in the formation of sodium hydrogen fatty acid salts. However, when the sodium hydroxide is used in a concentration of at least 10%, disproportionment does not occur even with only moderate mixing and of course, removal of the water introduced with the sodium hydroxide and that which is generated by the reaction, will take less time and energy.
The above dimer represents a single chemical mole-cule as can be determined by microanalysis, nmr spectrum, mixed melting point determination, IR spectrum and/or X~ray diffraction. Compound I made in this manner does not have the aforementioned detrimental physical characteristics as-sociated with valproic acid or sodium valproate; it is a crystalline, stable solid.
The new process for making the above compound is best illustrated by reference to the following examples which, however, are not intended to limit the invention in any respect.
Examples To 2500 ml. of water was added 1.595 kg. of sodium hydroxide pellets under agitation. To avoid heat-ing above 90C., external cooling was provided. To the solution obtained in this fashion, 11.5 kg. of valproic acid was added and the mixture was stirred for 30 minutes.
The homogeneous solution was then evaporated in a flat-bottom, centrifugal spray drier using an inlet temperature of 255-60C., a feed rate of 27 ml./min. and an atomizing force of 100 psig. The outlet temperature was 80-81C. A total of 712 g. of the above material was fed of which 422 g. was recovered in the cyclone chamber and 95 g. on the chamber walls.

Using a two-fluid spray-drier, the following re-sults were obtained.
Feed Rate ml./min. 70 45 51 105 101 Total feed ml. 1900 900 200 7090 15380 Inlet temp: C~ 100 80 125 130 130 Outlet temp: C. 80~5 75 7~-80 74-5 75-6 Cyclone Collection (g) 299 130 300 963 2555 Chamber Collection (9) 0 0 180 907 3201 Chamber Wall (g) 730 270 453 2405 2795 In all runs, the atomize~ force was set at 100 psig and the chamber collections were heavy and loose, except in the case of the run using an inlet temperature of 80C. where the crystals were heavy and hard on the chamber wall.
In another experir,~ent, the outlet temperature was set at 100C. with a feed temperature of 120-150C., resulting in a melted precipitate on the chamber walls.
- Essentially identical results were obtained when the feed solution was made from 1563 g. of sodium hydroxide pellets in 2.8 liters~of water, using 11.5 kg.
of valproic acid.
Two moles of valproic acid were reacted with 0.98 moles of sodium hydroxide dissolved in 60 ml. of water at 65C. The mixture was stirred for 30 minutes and then the water was removed by stripping under vacuum to a po~ temperature of 115C. The vacuum was then re-leased and the sodium hydrogen divalproate was isolated by pouring the hot melt into a pan and cooling, allowing it to crystallize.
The above expe~imental runs were too short to focus on maximum yields. A larger run was carried out using an inlet temperature of 160C., an outlet temper-ature of 75C., direct gas heat, a centrifugal atomizer wheel of 7" diameter and 21,000 rpm, an air-sweep temper-ature of 6-8C. The 80% solution was fed at a rate of

2.4 lbs./min. and most of the dried, crystalline material ~s~

was collected in the cyclone chamber, producing a yield of ~1% of theory. Essentially 100% yields are obtained when the first cyclone leads into a second cyclone which, in turn, leads into a bag house. The above-reported losses are thus mechanical losses due to equipment shortcomings.
rrhe above examples produce a material which has equal or better physical properties than crystalline ma-terial obtained from organic solvents. Since the new dimer salt has far superior physical characteristics than either "monomer" from which it is made, it greatly facili-tates the preparation of solid pharmaceutical dosage forms, and specific amounts can be weighed out and blended with starch and/or other binders to form a flowable powder which can be forwarded to standard tableting machines after sranulation. Neither the hygroscopic sodium salt of valproic acid nor the liquid valproic acid itself can be processed in this fashion without special precautions or absorbents.
The new compounds can be tableted in accord-ance with Example XIII of U. S. 3,325,361 and analogous methods. In these procedures, one or more diluents and/or excipients are used, e.g., starch, talcum powder, lubri-cants, disintegrators, flavoring agents, coloring agents and the like. These additives, of course, are the usual pharmaceutically acceptable carriers or diluents employed in routine fashion by tablet formulators.
While the above structure I is the most likely true two-dimensional view of the sodium/hydrogen divalpro-ate and seems to be confirmed by IR and nmr spectra, by by molecular weight and microanalytic values, it is possi-ble that the two molecules bind to one another in some other fashion. Thus, the new material should be charac-terized by reference to a single compound of for~ula (C3H7)2CHCO2Na/(C3H7)2HCO2H or [(Pr2CHCO2)(Pr2C~CO2)]Na,H, or by reference to sodium/hydrogen divalproate.

Claims (10)

1. THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
   PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
   l. A process for manufacturing sodium hydrogen divalproate consisting essentially in admixing an aqueous solution of sodium hydroxide of a concentration of at least 10% by weight and valproic acid, said sodium hy-droxide being used in an amount corresponding to 48-52%
   of the stoichiometric amount of said valproic acid; and removing the water from the reaction mixture.
2. 2. The process of Claim 1 wherein said valproic acid and aqueous sodium hydroxide solution are combined at a temperature of between 5°C. and 100°C.
3. 3. The process of Claim l wherein said water is removed from the reaction mixture by spray drying.
4. 4. The process of Claim 3 wherein spray drying is carried out at an inlet temperature of 100-260°C.
5. 5. The process of Claim 1 wherein said water is removed by air drying.
6. 6. The process of preparing crystalline sodium hydrogen divalproate consisting essentially in adding an aqueous sodium hydroxide solution of at least 35% concen-tration to valproic acid at a temperature above 40%C., said sodium hydroxide being used in an amount corresponding to one-half of the stoichiometric amount of said valproic acid, and removing the water from the reaction mixture by evaporation.
7. 7. The process of Claim 6 wherein said water evaporation is carried out by spray-drying, using an inlet temperature of 100-260°C.
8. 8. Sodium hydrogen divalproate when prepared by the process of Claim l, 2 or 3.
9. 9. Sodium hydrogen divalproate when prepared by the process of Claim 4, 5 or 6.
10. 10. Sodium hydrogen divalproate when prepared by the process of Claim 7.