Claims for Patent: 7,560,445

Summary for Patent: 7,560,445

Title:	Process for preparing malathion for pharmaceutical use
Abstract:	The present invention provides a process for preparing a highly pure form of malathion having a reduced level of toxic impurities. In addition, the malathion prepared by the process of this invention is storage stable. The level of toxic impurities in the malathion, e.g., isomalathion, O,O,S-trimethyl phosphorodithioate (MeOOSPS), O,O,S-trimethyl phosphorothioate (MeOOSPO), O,S,S-trimethyl phosphorodithioate (MeOSSPO), malaoxon, isomalathion, diethyl fumarate, methyl malathion, dimethyl malathion, O,O-methyl,ethyl-S-(1,2-dicarboethoxy)ethyl-phosphorodithioate are lower than that of any other commercial preparation of malathion that may be used for pharmaceutical purposes.
Inventor(s):	Gutman; Daniella (Rishon Lezion, IL), Baidussi; Wael (Hamisholash, IL)
Assignee:	Taro Pharmaceuticals North America, Inc. (Cayman, KY)
Application Number:	11/427,863
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,560,445
Patent Claims:	1. A process for preparing malathion for a topical pharmaceutical composition comprising the steps of: (a) preparing a solution of O,O-dimethyldithiophosphoric acid in an organic solvent selected from the group consisting of toluene, xylene and benzene; (b) extracting the O,O-dimethyldithiophosphoric acid into water to generate an aqueous solution of O,O-dimethyldithiophosphoric acid; (c) reacting the aqueous solution of O,O-dimethyldithiophosphoric acid with diethyl maleate to form malathion; and, (d) treating the malathion from step (c) with a sulfur reagent, wherein the sulfur reagent has a pH less than about 7.0; wherein the malathion comprises greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid, less than 0.1% (w/w) methyl malathion, less than about 0.1% (w/w) malaoxon, and less than about 0.1% (w/w) isomalathion. 2. The process of claim 1, wherein the O,O-dimethyldithiophosphoric acid in step (a) is prepared by a process comprising the steps of: (i) adding phosphorous pentasulfide (P.sub.2S.sub.5) to toluene to form a suspension; (ii) heating the suspension to about 60.degree. C.; (iii) adding methanol to the suspension; (iv) stirring the suspension after addition of the methanol for at least about 1 hour, while maintaining the temperature of the suspension from about 55.degree. C. to about 60.degree. C.; (v) filtering the suspension from step (iv) after cooling to about 18.degree. C. to about 25.degree. C.; and, (vi) subjecting the suspension from step (v) to vacuum distillation. 3. The process of claim 1, further comprising the step of isolating the malathion from step (d) after treatment with the sulfur reagent. 4. The process of claim 1, further comprising adding a polymerization inhibitor in step (c) during the reaction of the aqueous solution of O,O-dimethyldithiophosphoric acid with the solution of diethyl maleate. 5. The process of claim 4, wherein the polymerization inhibitor is hydroquinone. 6. The process of claim 1, wherein the sulfur reagent is selected from the group consisting of alkali metal bisulfites and alkaline earth metal bisulfites. 7. The process of claim 6, wherein the sulfur reagent is sodium bisulfite. 8. The process of claim 1, further comprising the steps of: (e) washing the malathion in step (d) after treatment with the 20% sodium bisulfite solution with water; (f) washing the malathion in step (e) with a 5% NaOH solution; and, (g) washing the malathion in step (f) at least two times with water. 9. The process of claim 8, further comprising the steps of (h) assaying the malathion from step (g) for the presence of at least one impurity selected from the group consisting of MeOOSPS, malaoxon, diethyl fumarate, dimethyl malathion, methyl malathion, isomalathion and O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate, and combinations thereof; (i) assaying the malathion for purity; (j) repeating steps (e) to (i) if the malathion at step (g) contains greater than about 5.0% (w/w) diethyl fumarate; and, (k) isolating the malathion. 10. A process according to claim 8, further comprising the steps of (l) adding water to the malathion; (m) subjecting the malathion from step (k) to azeotropic distillation; (n) repeating steps (l) to (m) at least one (1) time; and, (o) isolating the malathion. 11. The process of claim 10, further comprising the steps of (p) assaying the malathion at step (o) for the presence of at least one impurity selected from the group consisting of MeOOSPO, MeOSSPO, malaoxon, MeOOSPS, diethyl fumarate, dimethyl malathion, methyl malathion, O,O-methyl, ethyl S-(1,2-dicarboethoxy)ethyl phosphorodithioate, tetraethyl dithiosuccinate, isomalathion, malathion carboxylic acid, mercaptosuccinate, tetraethyl thiodisuccinate and combinations thereof; (q) assaying the malathion for purity; and, (r) repeating steps (l) to (o) if the malathion in step (o) has greater than about 0.2% (w/w) MeOOSPS, greater than about 0.1% (w/w) malaoxon, greater than about 0.2% (w/w) diethyl fumarate, greater than about 0.2% (w/w) dimethylmalathion, greater than about 0.3% (w/w) methylmalathion, greater than about 0.1% (w/w) isomalathion, or there is less than about 98.5% (w/w) malathion. 12. A topical pharmaceutical composition comprising malathion, said malathion having a purity of greater than about 98.5% (w/w) and, containing less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid, less than 0.1% (w/w) methyl malathion, less than 0.1% (w/w) malaoxon and less than about 0.1% (w/w) isomalathion, and wherein the composition is a lotion, gel, cream or solution. 13. The topical pharmaceutical composition of claim 12, comprising from about 0.1% (w/w) to about 10% (w/w) malathion. 14. The topical pharmaceutical composition of claim 12, comprising about 0.65% (w/w) malathion. 15. The topical pharmaceutical composition of 12, further comprising terpineol, dipentene malathion pine needle oil, and isopropyl alcohol. 16. The topical pharmaceutical composition of 14, comprising about 12.67% (w/w) terpineol, about 10.49% (w/w) dipentene, and about 0.28% (w/w) pine needle oil. 17. The topical pharmaceutical composition of claim 12, wherein, after storage at 5.degree. C. for 3 months, the malathion in the composition contains less than about 0.5% (w/w) diethyl fumarate, less than about 0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less than about 0.1% (w/w) malaoxon, and/or less than about 0.5% (w/w) dimethylmalathion, and less than 0.5% (w/w) of any other detectable impurity. 18. The topical pharmaceutical composition of claim 12, wherein, after storage at 5.degree. C. for 3 months, the malathion in the composition contains less than about 0.02% (w/w) diethyl fumarate, less than about 0.2% (w/w) methylmalathion, less than about 0.05% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion. 19. The topical pharmaceutical composition of claim 12, wherein, after storage at 25.degree. C. for 3 months and 60% relative humidity, the malathion in the composition contains less than about 0.5% (w/w) diethyl fumarate, less than about 0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion, and less than 0.5% (w/w) of any other detectable impurity. 20. The topical pharmaceutical composition of claim 12, wherein, after storage at 5.degree. C. for 3 months, the malathion in the composition contains less than about 0.01% (w/w) diethyl fumarate, less than about 0.1% (w/w) methylmalathion, less than about 0.05% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion. 21. The topical pharmaceutical composition of claim 12, wherein, after storage for 3 months at 30.degree. C. and 60% relative humidity, the malathion in the composition contains less than about 0.5% (w/w) diethyl fumarate, less than about 0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion, and less than 0.5% (w/w) of any other detectable impurity. 22. The topical pharmaceutical composition of claim 12, wherein, after storage for 3 months at 30.degree. C. and 60% relative humidity, the malathion in the composition contains less than about 0.02% (w/w) diethyl fumarate, less than about 0.02% (w/w) methylmalathion, less than about 0.05% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion. 23. The topical pharmaceutical composition of claim 12, wherein, after storage for 3 months at 40.degree. C. and 75% relative humidity, the malathion in the composition contains less than about 0.5% (w/w) diethyl fumarate, less than about 0.5% (w/w) methylmalathion, less than about 0.1% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.03% (w/w) dimethylmalathion, and less than 0.5% (w/w) of any other detectable impurity. 24. The topical pharmaceutical composition of claim 12, wherein, after storage for 3 months at 40.degree. C. and 75% relative humidity, the malathion in the composition contains less than about 0.01% (w/w) diethyl fumarate, less than about 0.04% (w/w) methylmalathion, less than about 0.07% (w/w) isomalathion, less than about 0.03% (w/w) malaoxon, and/or less than about 0.22% (w/w) dimethylmalathion. 25. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.08% (w/w) methyl malathion. 26. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.06% (w/w) methyl malathion. 27. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.04% (w/w) methyl malathion. 28. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.07% (w/w) isomalathion. 29. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.04% (w/w) isomalathion. 30. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains no more than 0.02% (w/w) isomalathion. 31. The topical pharmaceutical composition of claim 12, wherein the malathion in the composition contains less than about 0.2% (w/w) diethyl fumarate and less than about 0.2% (w/w) dimethylmalathion. 32. The topical pharmaceutical composition of claim 12 comprising greater than about 98.5% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO, less than about 0.2% (w/w) MeOOSPS, less than about 0.3% (w/w) malathion carboxylic acid and less than about 0.02% (w/w) isomalathion. 33. The topical pharmaceutical composition of claim 12 comprising greater than about 99.0% (w/w) malathion, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02% (w/w) isomalathion. 34. The topical pharmaceutical composition of claim 12 comprising greater than about 99.0% (w/w) malathion, less than about 0.04% (w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS, 0.03% (w/w) malathion carboxylic acids and less than about 0.02% (w/w) isomalathion. 35. The topical pharmaceutical composition of claim 12 wherein, the composition is stable after storage. 36. The topical pharmaceutical composition of claim 12 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage at 5.degree. C. for 3 months. 37. The topical pharmaceutical composition of claim 12 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage for 3 months at 25.degree. C. and 60% relative humidity. 38. The topical pharmaceutical composition of claim 12 wherein the amount of isomalathion is not more than about 0.1% (w/w), after storage for 3 months at 30.degree. C. and 60% relative humidity. 39. A method for treating an ectoparasite in a mammal, comprising the step of topically applying to a mammal a therapeutically effective amount of the composition of claim 12. 40. The process of claim 1, wherein the organic solvent is toluene. 41. The process of claim 1, wherein the ratio of water to O,O-dimethyldithiophosphoric acid in step (b) is about 1:1 to about 10:1 (w/w). 42. The process of claim 41, wherein the ratio of water to O,O-dimethyldithiophosphoric acid is about 3:1 (w/w). 43. The process of claim 1, wherein the solution of O,O-dimethyldithiophosphoric acid in step (a) is filtered before extraction into water in step (b). 44. The process of claim 1, wherein the solution of O,O-dimethyldithiophosphoric acid in step (a) is distilled before extraction into water in step (b). 45. The process of claim 1, wherein the molar ratio of diethyl maleate to O,O-dimethyldithiophosphoric acid in step (c) is about 1:1 to about 2:1. 46. The process of claim 45, wherein the molar ratio of diethyl maleate to O,O-dimethyldithiophosphoric acid in step (c) is about 1:1. 47. The process of claim 45, wherein the molar ratio of diethyl maleate to the polymerization inhibitor is about 50:1 to about 500:1. 48. The process of claim 47, wherein the molar ratio of diethyl maleate to polymerization inhibitor is about 300:1. 49. The process of claim 7, wherein the sulfur reagent comprises a 20% sodium bisulfite solution having a pH from about 6.1 to about 6.3. 50. The process of claim 49, wherein the malathion in step (d) is treated with the 20% sodium bisulfite solution for about 2 hours. 51. The process of claim 10, wherein the ratio of water to malathion in step (l) is from about 2:1 (w/w) to about 10:1 (w/w). 52. The process of claim 51, wherein the ratio of water to malathion in step (l) is about 3:1 (w/w). 53. Malathion prepared by the process of claim 11, comprising greater than about 98.5% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.2% (w/w) MeOSSPS. 54. The malathion of claim 53, comprising greater than about 99.0% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.1% (w/w) MeOOSPO, less than about 0.1% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS. 55. The malathion of claim 54, comprising greater than about 99.0% (w/w) malathion, less than about 0.02% (w/w) isomalathion, less than about 0.03% (w/w) malathion carboxylic acids, less than about 0.04% (w/w) MeOOSPO, less than about 0.02% (w/w) MeOSSPO and less than about 0.1% (w/w) MeOSSPS.