Predicting the solubility enhancement of amorphous drugs and related phenomena using basic thermodynamic principles and semi-empirical kinetic models

• Published in: International journal of pharmaceutics 2019-08, Vol.567, p.118465-118465, Article 118465
• Main Authors: Skrdla, Peter J., Floyd, Philip D., Dell'Orco, Philip C.
• Format: Article
• Language: English
• Subjects: Amorphous drug; ASD; Chemistry, Pharmaceutical; Crystallization; Dispersion; Glass transition; Gordon-Taylor equation; Kinetics; Models, Theoretical; Moisture; Pharmaceutical Preparations - chemistry; Solubility; Solubility advantage; Thermodynamics
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2019.118465

[Display omitted] The accurate prediction of the solubility enhancement offered by neat amorphous drugs and amorphous solid dispersions, over their crystalline (API) counterparts, has been discussed in several landmark works dating back at least two decades. Against this backdrop, an assessment of the current state-of-the-art for rigorously, yet simply (circumventing computational methods), determining the amorphous:crystalline solubility ratio based on thermo-analytical quantities is presented herein. Included in this work is a brief survey of the literature together with a discussion of the advantages and shortcomings of some of the most popular approaches, to-date. While the focus is on neat amorphous drugs, both before and after moisture sorption, the methodology presented is readily extended to more complex (e.g. ternary) systems that form a single, homogeneous phase. Six key questions are addressed in the context of how to most accurately determine the amorphous:crystalline solubility ratio: (1) How is the lattice energy of the crystalline phase assessed? (2) What is the role of heat capacity? (3) How does the pKa impact the solubility ratio prediction (for ionizable drugs)? (4) How does one incorporate the effects of moisture sorption on the amorphous phase? (5) How might one characterize (predict) the rate of drug recrystallization under various conditions (since the duration of the solubility enhancement is a kinetic phenomenon)? (6) What is the best approach for linking the (loss in) solubility enhancement to the Tg-lowering of the amorphous drug (by water) and vice-versa? In addressing these questions, this work aims to put forth a standardized methodology for determining the amorphous solubility enhancement with improved accuracy.