Advances in Pharmaceutical Research:
From Lead Discovery to Drug Manufacturing- Spring 2003
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Edward Delaney, Ph.D., Bristol-Myers Squibb
Triamcinolone
A REINVESTIGATION OF THE D-HOMOANNULAR REARRANGEMENT AND SUBSEQUENT DEGRADATION PATHWAYS OF (11-BETA,16-ALPHA)-9-FLUORO-11,16,17,21-TETRAHYDROXYPREGNA-1,4-DIENE-3,20-DIONE (TRIAMCINOLONE) DELANEY EJ, SHERRILL RG, PALANISWAMY V, SEDERGRAN TC, TAYLOR SP, STEROIDS 59 (3): 196-204 MAR 1994
Abstract:
The commercial anti-inflammatory drug triamcinolone has been shown to rearrange by similar, but distinct pathways when exposed to certain trace metal ions or to dilute aqueous base. In the presence of aqueous base, the 16-hydroxy-20-keto system undergoes reverse aldol cleavage of the 16,17-bond, followed by aldol cyclization linking C-16 to C-20. This base-catalyzed rearrangement gives a 16 beta,17 alpha-dihydroxy product and a corresponding 16 alpha,17 alpha-dihydroxy product in roughly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16 alpha,17 alpha-dihydroxy product with exremely high stereoselectivity. Mechanistic models are propsed that help explain the ratio of products isolated from each route. The studies presented suggest that similar forms of rearrangement could be of preparative value in syntheses requiring specific stereochemistry of appropriately substituted bicyclic alpha,beta-dihydroxyketones. Under more vigorous conditions of aqueous base treatment these rearrangement products undergo further decomposition with loss of formaldehyde from the hydroxymethyl group, followed by beta-elimination of water. Reaction of the beta-elimination product with formaldehyde results in the formation of a dimeric species linked by a methylene group.
Tipredane
Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution. Varia, Sailesh A.; Faustino, Marilia M.; Thakur, Ajit B.; Clow, Charles S.; Serajuddin, Abu T. M. Pharm. Res. Dev. Dep., Bristol-Myers Squibb Pharm. Res. Inst., New Brunswick, NJ, USA. Journal of Pharmaceutical Sciences (1991), 80(9), 872-5.
Abstract:
Physiochem. factors involved in the development of a topical soln. of a novel corticosteroid, tipredane (I), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concn. (0.1% w.w.) of I required for the formulation. The solvent mixt. was also nonirritating to the skin. A buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concns., as well as that of PEG 400. Two formulations, one contg. K citrate and the other tromethamine as the buffering agents, were identified. Upon storage, Na metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation contg. K citrate. K citrate decreased the soly. and resulted in the pptn. of K2SO4 by exerting a common ion effect. Lowering of the concns. of K citrate, Na metabisulfite, and PEG 400 ensured the soly. of K2SO4 formed. There was no such pptn. of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.
Fluorine Compounds, Inorganic, Boron Trifluoride Kirk-Othmer Encyclopedia of Chemical Technology, 3rd edition 1980, v.10, p.685-693
Fluorine Compounds, Inorganic, Boron Trifluoride Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition
Boron Compounds. Boron Halides Ullmann's Encyclopedia of Industrial Chemistry, 6ht http://www.mrw.interscience.wiley.com/ueic/articles/a04_309/sect1-fs.html
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