Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs

• Published in: Molecular pharmaceutics 2020-01, Vol.17 (1), p.219-228
• Main Authors: Skrdla, Peter J, Floyd, Philip D, Dell’Orco, Philip C
• Format: Article
• Language: English
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.9b00940

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a “kinetic solubility” effect), characterizing its duration (i.e., the so-called “parachute” effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial “denucleation” (dissolution) character. On the other hand, “nucleation and growth” (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution–recrystallization transient of the drug, obtaining a fit of R 2 = 0.993. By precisely characterizing the duration of the “parachute” in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.