title: Solid-State Characterization of Novel Propylene Glycol Ester Solvates Isolated from Lipid Formulations.
abstract: The purpose of this study was to identify and characterize precipitates obtained from a liquid formulation of GNE068.HCl, a Genentech developmental compound, and lipophilic excipients, such as propylene glycol monocaprylate, and monolaurate. Precipitates were characterized using powder X-ray diffractometry (PXRD), differential scanning calorimetry, thermogravimetry, microscopy, nuclear magnetic resonance spectroscopy (NMR; solution and solid-state) and water sorption analysis. PXRD and NMR revealed the precipitates to be crystalline solvates of propylene glycol esters. The solvates (capryolate and lauroglycolate) were isomorphic and stable up to 70 °C, beyond which melting of the lattice occurred with subsequent dissolution of the active ingredient in the melt (microscopy and variable temperature PXRD). They were found to be mechanically stable (no change in PXRD pattern upon compression) and were nonhygroscopic up to ∼70% RH (25 °C). Our results highlight the outcome of inadvertent drug-excipient interactions in two separate lipid solution formulations with good solid-state properties and, thus, potential for further development.
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Paroma
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kothari
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Deese
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004952:Esters / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry; D008055:Lipids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D019946:Propylene Glycol / Q000737:chemistry*; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013696:Temperature; D013818:Thermogravimetry / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D004952:Esters; D005079:Excipients; D008055:Lipids; D012996:Solutions; D019946:Propylene Glycol
keywords: drug-excipient interaction; form screening; isomorphic; propylene glycol ester solvates