Article pubs.acs.org/crystal
Evaluating the Roles of Conformational Strain and Cohesive Binding in Crystalline Polymorphs of Aripiprazole Sean P. Delaney,† Duohai Pan,‡ Shawn X. Yin,‡ Tiffany M. Smith,† and Timothy M. Korter*,† †
Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, New York 13244-4100, United States ‡ Drug Product Science & Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
Crystal Growth & Design 2013.13:2943-2952. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/16/18. For personal use only.
S Supporting Information *
ABSTRACT: The relative stabilities of crystalline polymorphs are an important aspect of the manufacturing and effective utilization of pharmaceuticals. These stabilities are driven by both molecular conformational energy within the solid-state components and cohesive binding energy of the crystalline arrangement. The combined approach of experimental vibrational terahertz spectroscopy with solidstate density functional theory provides a powerful tool to study such properties and is applied here in the analysis of conformational polymorphism in crystalline aripiprazole. The low-frequency ( Form VI > Form III > Form V > Form IV > Form II > Form I
In this ranking, Form VII was clearly the most stable and Form I clearly the least stable. However, the ranking of the other forms is less definitive since the other five forms differ from each other by at most 1.0 kJ mol−1 and as little as 0.15 kJ mol−1. An experimental determination of the relative thermodynamic stabilities of five of the seven polymorphs (Forms I−V, excluding Forms VI and VII) was reported by Braun et al.6 and revealed a stability ranking (at 0 K) of Form V > Form II > Form IV > Form III > Form I 2948
dx.doi.org/10.1021/cg400358e | Cryst. Growth Des. 2013, 13, 2943−2952
Crystal Growth & Design
Article
To expand the range of measured stabilities, relative stability tests were also performed for this study on six of the polymorphs (excluding Form VI), through slurry experiments and solubility data. These tests yielded a stability ranking of (at 298 K): Form VII > Form V > Form IV > Form II > Form III > Form I
This is in agreement with the findings of Braun et al., except for the switching of Forms II and IV, and the addition of Form VII as the most stable polymorph considered. A differential scanning calorimetry (DSC) thermogram of Form VII is available in Figure S2 of the Supporting Information. Comparing these experimental rankings to the predicted ranking of polymorph energies, it can be seen that the least stable (Form I) and the most stable (Form VII) forms were properly calculated by the simulations. The forms of intermediate stability were generally well predicted, specifically Form V > Form IV > Form II, but Form III was found to be significantly more stable computationally than what was determined by either experimental study. The exact root of this single misordered polymorph is not known. This discrepancy in the Form III rank may be due to the small energy separations that are found in these polymorphs, with only 1.0 kJ mol−1 distinguishing the calculated Form III total energy from its experimental position. It is noteworthy that even though Form VII is the most stable polymorph, Form III is the commercially utilized API form. The use of Form III over Form VII is largely based on solubility, with preliminary aqueous solubility studies indicating that Form III is the significantly more soluble of the two. 3.3.2. Vibrational Analyses. The simulated terahertz spectra of five of the seven polymorphs of aripiprazole (excluding Form I and Form VI) are displayed in Figure 6. The calculated vibrational modes (frequencies and intensities for modes
