title: Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.
abstract: Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. 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 concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.
authors.affiliation: Pharmaceutics R&D Department, Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, NJ 08903.
authors.forename: S A
authors.initials: SA
authors.lastname: Varia
authors.forename: M M
authors.initials: MM
authors.lastname: Faustino
authors.forename: A B
authors.initials: AB
authors.lastname: Thakur
authors.forename: C S
authors.initials: CS
authors.lastname: Clow
authors.forename: A T
authors.initials: AT
authors.lastname: Serajuddin
mesh_terms: D000287:Administration, Topical; D000730:Androstadienes / Q000008:administration & dosage*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D011232:Chemical Precipitation; D005079:Excipients; D011092:Polyethylene Glycols / Q000008:administration & dosage; D019946:Propylene Glycol; D011409:Propylene Glycols / Q000008:administration & dosage; D012997:Solvents; D013431:Sulfates / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D005079:Excipients; D011409:Propylene Glycols; D012997:Solvents; D013431:Sulfates; C051756:tipredane; C031512:potassium sulfate; D011092:Polyethylene Glycols; D019946:Propylene Glycol