title: Cocrystal solubility product analysis - Dual concentration-pH mass action model not dependent on explicit solubility equations.
abstract: A novel general computational approach is described to address many aspects of cocrystal (CC) solubility product (Ksp) determination of drug substances. The CC analysis program, pDISOL-X, was developed and validated with published model systems of various acid-base combinations of active pharmaceutical ingredients (APIs) and coformers: (i) carbamazepine cocrystal systems with 4-aminobenzoic acid, cinnamic acid, saccharin, and salicylic acid, (ii) for indomethacin with saccharin, (iii) for nevirapine with maleic acid, saccharin, and salicylic acid, and (iv) for gabapentin with 3-hydroxybenzoic acid. In all systems but gabapentin, the coformer is much more soluble than the API. The model systems selected are those with available published dual concentration-pH data, one set for the API and one set for the coformer, generally measured at eutectic points (thermodynamically-stable three phases: solution, cocrystal, and crystalline API or coformer). The carbamazepine-cinnamic acid CC showed a substantial elevation in the API equilibrium concentration above pH5, consistent with the formation of a complex between carbamazepine and cinnamate anion. The analysis of the gabapentin:3-hydroxybenzoic acid 1:1 CC system indicated four zones of solid suspensions: coformer (pH<3.25), coformer and cocrystal eutectic (pH3.25-4.44), cocrystal (pH4.44-5.62), and API (pH>5.62). The general approach allows for testing of many possible equilibrium models, including those comprising drug-coformer complexation. The program calculates the ionic strength at each pH. From this, the equilibrium constants are adjusted for activity effects, based on the Stokes-Robinson hydration theory. The complete speciation analysis of the CC systems may provide useful insights into pH-sensitive dissolution effects that could potentially influence bioavailability.
authors.affiliation: in-ADME Research, 1732 First Avenue #102, New York, NY 10128, USA. Electronic address: alex@in-ADME.com.
authors.forename: Alex
authors.initials: A
authors.lastname: Avdeef
mesh_terms: D000588:Amines / Q000737:chemistry*; D002220:Carbamazepine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry*; D004355:Drug Stability; D000077206:Gabapentin; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D019829:Nevirapine / Q000737:chemistry*; D009994:Osmolar Concentration; D012995:Solubility; D013816:Thermodynamics; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D019829:Nevirapine; D007213:Indomethacin
keywords: Cocrystal solubility product; Mass action model; Oral absorption; Salt solubility product; Solubility-pH; Sparingly-soluble drugs