title: Drug-excipient complexation in lipid based delivery systems: an investigation of the Tipranavir-1,3-dioctanolyglycerol complex.
abstract: This report describes the solubility properties of a poorly soluble drug-excipient complex in a lipid based formulation. Tipranavir (TPV) was used as the model drug and 1,3-dioctanoylglycerol (DOG) as the excipient. The TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60 degrees C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-to-DOG molar ratio was confirmed by XRPD, DSC, and NMR. At 25 degrees C, total solubility of TPV decreased with increasing DOG concentration. The solubility properties of the TPV-DOG complex can be described by two simultaneous equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium among the various species in the liquid phase. A model equation was derived accordingly with two parameters, the intrinsic solubility of the complex (S(o)), and the solution complex constant (K(41)). The model was in good agreement with experimental results. The values of S(o) and K(41) are 0.0186 +/- 0.0025 (M) and 21.97 +/- 7.19 (1/M(4)), respectively. The equation can successfully predict the concentrations of total and free TPV as a function of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid based formulations.
authors.affiliation: Department of Pharmaceutics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. shirlynn.chen@boehringer-ingelheim.com
authors.forename: Shirlynn
authors.initials: S
authors.lastname: Chen
authors.forename: Mayur S
authors.initials: MS
authors.lastname: Dudhedia
authors.forename: Zeren
authors.initials: Z
authors.lastname: Wang
authors.forename: Richard T
authors.initials: RT
authors.lastname: Darrington
authors.forename: Toby
authors.initials: T
authors.lastname: Tamblyn
authors.forename: John A
authors.initials: JA
authors.lastname: Smoliga
authors.forename: Paul-James
authors.initials: PJ
authors.lastname: Jones
authors.forename: Steven L
authors.initials: SL
authors.lastname: Krill
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D004075:Diglycerides / Q000737:chemistry*; D016503:Drug Delivery Systems; D008055:Lipids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D017711:Nonlinear Dynamics; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry*; D011753:Pyrones / Q000008:administration & dosage* / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D013449:Sulfonamides; D013501:Surface-Active Agents; D014961:X-Ray Diffraction
chemical_list: D019380:Anti-HIV Agents; D004075:Diglycerides; D008055:Lipids; D011725:Pyridines; D011753:Pyrones; D012997:Solvents; D013449:Sulfonamides; D013501:Surface-Active Agents; C058807:1,3-dicapryloylglycerol; C107201:tipranavir