Уважаемые коллеги! Занимаюсь контролем качества лекарств. Обнаружен брак в хлоргексидине. Скажите пожалуйста, никто случайно не владеет технологической схемой производства этого препарата? Как его делают?
А вот эти схемы не смотрели?:
CHLORHEXIDINE
Chemical Name: N,N''-Bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide
Common Name: 1,6-di(4'-Chlorophenyldiguanido)hexane
Raw Materials
- Hexamethylene bis-dicyandiamide
- p-Chloroaniline hydrochloride
Manufacturing Process
25 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of beta-ethoxyethanol are stirred together at 130°C to 140°C for 2 hours under reflux. The mixture is then cooled and filtered and the solid is washed with water and crystallized from 50% aqueous acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanido-N5,N5')hexane dihydrochloride is obtained as colorless plates of MP 258°C to 260°C.
The following is an alternative route: 19.4 parts of pchlorophenyldicyandiamide, 9.4 parts of hexamethylene diaminedihydrochloride and 100 parts of nitrobenzene are stirred together and heated at 150 C to 160°C for 6 hours. The mixture is cooled, diluted with 200 parts of benzene and filtered. The solid residue is washed with benzene and crystallized from 50% acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanido-N5,N5')hexane dihydrochloride is obtained.References
- Merck Index 2057
- Kleeman and Engel p. 189
- PDR p. 1781
- I.N. p. 212
- REM p. 1159
- Rose, F.L. and Swain, G.; US Patent 2,684,924; July 27, 1954; assigned to Imperial Chemical Industries, Ltd.
CHLORHEXIDINE DIGLUCONATE
Chemical Name: D-Gluconic acid, compd. with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecane diimidamide (2:1)
Common Name: Chlorhexidine gluconate; Clorexidina gluconato
Raw Materials
- Hexamethylene bis-dicyandiamide
- p-Chloroaniline hydrochloride
Manufacturing Process
35 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline hydrochloride and 250 parts of ?-etoxyethanol are stirred together at 130-140°C for 2 hours under reflux. The mixture is then cooled and filtered. The solid is washed with water and crystallised from 50% aqueous acetic acid.
1,1'-Hexamethylene bis(5-(p-chlorophenyl)biguanide) is obtained as colorless plates, melting point 258-260°C. By addition of D-gluconic acid to aqueous solution of chlorhexidine base is prepared 1,1'-hexamethylenebis(5-(pchlorophenyl) biguanide)digluconate (1:2).References
- Leslie F. et al.; US Patent No. 2,684,924; July 27, 1954; Assigneed to Imperial Chemical Industries Limited
- Werie P. et al.; US Patent No. 6,500,466; Dec.31, 2002; Assigneed to Degussa AG, Dusseldorf (DE)
