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.

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

“…In a different but related study, Wyttenbach et al . studied 54 compounds to ascertain the extent to which the Prigogine-Defay ratio could be used to predict the GFA (61). The physical stability (dry state) of amorphized compounds has also been explored (61) and Nurzyn’ska et al .…”

“…studied 54 compounds to ascertain the extent to which the Prigogine-Defay ratio could be used to predict the GFA (61). The physical stability (dry state) of amorphized compounds has also been explored (61) and Nurzyn’ska et al . recently presented data on the parameters related to the long-term stability of amorphous drugs (62).…”

“…recently presented data on the parameters related to the long-term stability of amorphous drugs (62). The findings from recent studies on GFA and crystallization behavior can be summarized thus:Characteristics indicating glass-forming compounds include: MW >300 g/mol, torsional bonds (τ) >4, and effective hydrogen bond number (HBN eff ) < 6 x 10 −3 (60,61,63). …”

“…Characteristics indicating glass-forming compounds include: MW >300 g/mol, torsional bonds (τ) >4, and effective hydrogen bond number (HBN eff ) < 6 x 10 −3 (60,61,63). …”

“…Furthermore, as shown in Fig 1,. the relationships and interplay between the different physicochemical properties of the compounds are not always proportional, and hence they should be considered collectively rather than individually through the use of, for example, multivariate data analysis (61,64,65). …”