title: Theoretical Considerations of the Prigogine-Defay Ratio with Regard to the Glass-Forming Ability of Drugs from Undercooled Melts.
abstract: Drug behavior in undercooled melts is highly important for pharmaceutics with regard to amorphous solid dispersions, and therefore, categories were recently introduced that differentiate glass formers (GFs) from other drugs that are nonglass formers (nGFs). The present study is based on the assumption that molecular properties relevant for the so-called Prigogine-Defay (PD) ratio would be indicative of a drug's glass-forming ability. The PD ratio depends in theory on the entropy of fusion and molar volume. Experimental data were gathered from a broad set of pharmaceutical compounds (n = 54) using differential scanning calorimetry. The obtained entropy of fusion and molar volume were indeed found to significantly discriminate GFs from nGFs. In a next step, the entropy of fusion was predicted by different in silico methods. A first group contribution method provided rather unreliable estimates for the entropy of fusion, while an alternative in silico approach seemed more promising for drug categorization. Thus, a significant discrimination model employed molar volume, a so-called effective hydrogen bond number, and effective number of torsional bonds (or torsional units) to categorize GFs and nGFs (p ≤ 0.0000). The results led to new insights into drug vitrification and to practical rules of thumb. The latter may serve as guidance in pharmaceutical profiling and early formulation development with respect to amorphous drug formulations.
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wyttenbach
authors.affiliation: Institute of Pharmaceutical Technology, University of Applied Sciences and Arts Northwestern Switzerland , Gründenstrasse 40, 4132 Muttenz, Switzerland.|Institute of Pharmaceutical Technology, University of Basel , Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Kirchmeyer
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.affiliation: Institute of Pharmaceutical Technology, University of Applied Sciences and Arts Northwestern Switzerland , Gründenstrasse 40, 4132 Muttenz, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D003460:Crystallization; D004355:Drug Stability; D005898:Glass / Q000737:chemistry*; D006860:Hydrogen Bonding; D044366:Transition Temperature
keywords: amorphous drug; crystallization tendency; glass-forming ability; in silico prediction; undercooled melt