Insights into Cocrystal Bioavailability Through Analysis of in Vitro Dissolution Experiments

Cocrystals are a promising strategy to improve the oral bioavailability of poorly soluble drugs by generating higher solubilities to create faster dissolution and supersaturation. Their solution behavior is complicated due to the numerous equilibria that determine the dissolution, supersaturation, and precipitation kinetics that control concentrations available for oral absorption. These variables can cause difficulties in the development of viable cocrystal products as supersaturation and precipitation can make experimental results unpredictable. A better understanding of cocrystal solution behavior, one with mechanistically based mathematical models, would take uncertainty and guess work out of cocrystal product development for promising new therapeutic agents. This dissertation links cocrystal thermodynamic solubility equations to aqueous kinetic dissolution, supersaturation, and precipitation behavior observed with in vitro dissolution experiments to gain knowledge of the variables responsible in controlling cocrystal oral absorption. Mathematical expressions were developed and applied to describe three aspects of cocrystal solution behavior: 1) dissolution, 2) supersaturation, and 3) precipitation. Thermodynamic solubility equations and expressions for kinetic processes were combined to describe dissolution (rotating disk and particle) and precipitation for in vitro dissolution scenarios (biphasic and biorelevant). Knowledge gained from these analyses identify key parameters controlling cocrystal solution concentrations responsible for in vivo absorption. Cocrystals of the basic drug Ketoconazole (KTZ) with the dicarboxylic acids adipic (ADP), fumaric (FUM), and succinic (SUC) were used as model compounds. Solubility equations and intrinsic surface saturation theory for these cocrystals were applied to simulate dissolution rates for cocrystal in biphasic (octanol:water) rotating disk dissolution experiments. Measured drug and coformer partitioning rates into the organic phase revealed a 34% decrease in coformer mass transfer coefficient, when diffusing in the presence of the drug indicating a significant solution phase interaction. Precipitation risk was assessed from bulk and interfacial supersaturation values determined for dissolution experiments in biorelevant media FeSSIF, FaSSIF, and blank equivalents. Under these conditions, KTZ cocrystals have bulk solubilities between 2- and 4500-times drug solubility (bulk solubility advantage or SAbulk = Scocrystal/Sdrug). When dissolving in FaSSIF, KTZ cocrystals exhibited interfacial solubility advantages (SAint) an order of magnitude lower than the associated SAbulk, suggesting ranges of precipitation risk across dissolution media and between interfacial and bulk. Cocrystal particle dissolution in FeSSIF and blank FeSSIF was simulated by combining established dissolution and cocrystal solubility theory. Cocrystal interfacial pH was estimated using mass transport theory and measured solubility experiment concentrations and final pH values. Nucleation and growth terms for bulk precipitation were added to particle dissolution equations to simulate in vitro experiments. The resulting equations fit observed results well and demonstrated that KTZ cocrystal bulk solution behavior is dominated by nucleation rate as nucleation rate constants varied over two orders of magnitude between the three KTZ cocrystals while growth constants varied by only 2- to 3-fold. Simulations using dissolution theory with measured precipitation constants estimated the effect of cocrystal dissolution and precipitation on drug concentrations available to partition in a biphasic system. KTZ cocrystals were calculated to generate 2-fold increases in dose absorbed. The absorption was predicted to increase with decreasing dissolution rate, decreasing nucleation rates or increasing permeability rates which reduces bulk supersaturation and precipitation. These analyses provide insight into how cocrystal dissolution and drug precipitation govern supersaturation and solution concentrations available for absorption in vivo and can serve as a guide for formulating cocrystal and related supersaturation generating therapeutics.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155309/1/nmwaltz_1.pd