title: Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling.
abstract: This study quantitatively explores the mechanisms underpinning the effects of model pharmaceutical polymeric precipitation inhibitors (PPIs) on the crystal growth and, in turn, maintenance of supersaturation of indomethacin, a model poorly water-soluble drug. A recently developed second-derivative UV spectroscopy method and a first-order empirical crystal growth model were used to determine indomethacin crystal growth rates in the presence of model PPIs. All three model PPIs including HP-β-CD, PVP, and HPMC inhibited indomethacin crystal growth at both high and low degrees of supersaturation (S). The bulk viscosity changes in the presence of model PPIs could not explain their crystal growth inhibitory effects. At 0.05% w/w, PVP (133-fold) and HPMC (28-fold) were better crystal growth inhibitors than HP-β-CD at high S. The inhibitory effect of HP-β-CD on the bulk diffusion-controlled indomethacin crystal growth at high S was successfully modeled using reactive diffusion layer theory, which assumes reversible complexation in the diffusion layer. Although HP-β-CD only modestly inhibited indomethacin crystal growth at either high S (∼15%) or low S (∼2-fold), the crystal growth inhibitory effects of PVP and HPMC were more dramatic, particularly at high S (0.05% w/w). The superior crystal growth inhibitory effects of PVP and HPMC as compared with HP-β-CD at high S were attributed to a change in the indomethacin crystal growth rate-limiting step from bulk diffusion to surface integration. Indomethacin crystal growth inhibitory effects of all three model PPIs at low S were attributed to retardation of the rate of surface integration of indomethacin, a phenomenon that may reflect the adsorption of PPIs onto the growing crystal surface. The quantitative approaches outlined in this study should be useful in future studies to develop tools to predict supersaturation maintenance effects of PPIs.
authors.affiliation: Department of Pharmaceutical Sciences College of Pharmacy Universiy of Kentucky Lexington, Kentucky 40506, United States.
authors.forename: Dhaval D
authors.initials: DD
authors.lastname: Patel
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
mesh_terms: D000327:Adsorption; D011232:Chemical Precipitation; D003460:Crystallization; D003505:Cyclodextrins / Q000737:chemistry; D007213:Indomethacin / Q000737:chemistry*; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D007213:Indomethacin