title: Dissolution behavior of porcine somatotropin with simultaneous gel formation and lysine Schiff-base hydrolysis.
abstract: The primary goal of this work was to develop a reliable in vitro dissolution model to evaluate the effects of Schiff-base hydrolysis and gel formation on the dissolution kinetics of pellets of porcine somatotropin (pST) and pST conjugated with ortho-vanillin (ov-pST) via Schiff-base formation, in an effort to develop an extended-release pST implant. Experimentally, dissolution was investigated as a function of ov concentration in pH 7.4, phosphate buffered saline under sink conditions where steady-state (constant flux) dissolution is typically observed. However, the resulting dissolution profiles displayed variable release rates due to gel formation at the solid-liquid interface, which impeded pST release. Chemical modification of pST with ov reduced gel formation and also resulted in much lower release rates. A mathematical model was developed that quantitatively accounts for changes in dissolution rates due to transient gel formation via irreversible aggregation, along with the effects of reversible Schiff-base hydrolysis involving ov, and predicts dissolution rates in the presence of ov decrease due to the much lower solubility of ov-pST. Our results indicate that although ov-pST is less prone to aggregate, pST/ov-pST equilibration is rapid compared to dissolution and therefore aggregation remains the limiting factor, and ultimately precludes this approach as a viable extended-release delivery system.
authors.affiliation: Department of Pharmaceutical R&D, MS# 8156-16, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. christopher_j_roberts@groton.pfizer.com
authors.forename: C J
authors.initials: CJ
authors.lastname: Roberts
authors.forename: Q
authors.initials: Q
authors.lastname: Ji
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: R T
authors.initials: RT
authors.lastname: Darrington
mesh_terms: D000818:Animals; D005782:Gels; D019382:Human Growth Hormone / Q000737:chemistry*; D006868:Hydrolysis; D008239:Lysine; D012545:Schiff Bases; D012995:Solubility; D013552:Swine
chemical_list: D005782:Gels; D012545:Schiff Bases; D019382:Human Growth Hormone; D008239:Lysine