The Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. A large variation is observed in induction times measured under equal 5 conditions in 1 ml solutions. Ruling out experimental errors, this variation originates from the nucleation process. The induction time distribution is explained by the stochastic nature of nucleation if the number of nuclei formed is approaching 1 per vial. Accurate heterogeneous crystal nucleation rates were determined from the induction time distributions on a 10 1 ml scale for racemic Diprophylline in two solvents. The difference in nucleation behaviour in the two solvents originates from the energy barrier for nucleation, which is much higher in the solvent in which induction times are much longer. In addition the pre-exponential factor for the crystal nucleation rate in both solvents is rather low compared to predictions using 15 Classical Nucleation Theory. Unfortunately, concentration and surface characteristics of the effective heterogeneous particles are not known which clouds a further molecular interpretation.

The polymorphic behavior of racemic and enantiopure diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization.