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.

Herein, we report the chiral symmetry breaking of 2-methoxy-1-naphthamide atropisomers through temperature cycling without the use of any racemization reagent. The racemization rate (k 1 ) controls the deracemization process when the cooling of the slurry is slow enough to keep the system close to equilibrium. The productivity appears proportional to the racemization rate (k 1 ) multiplied by the solubility.

A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria.

The detailed characterization of several subambient solid state transitions occurring in the pharmaceutical ingredient Ciclopirox between −20 °C and −85 °C was performed by using a combination of DSC, cold-stage optical microscopy, vibrational spectroscopies, solid state NMR at controlled temperature, structural analyses by single crystal X-ray diffraction, and temperature-resolved X-ray powder diffraction. The global analysis of the available data reveals that the mechanisms of these reversible transitions involve a subtle compromise between phenomena related to molecular disorder, cooperative release of strains induced by cooling, and structural reorganization associated with topotactic changes in crystal lattice and symmetry. However, no major change in the main features of crystal packings is observed during the successive single crystal-to-single crystal transitions, which highlights the difficulty to classify such transitions in the frame of conventional theoretical frameworks. The successive thermal events and related structural changes or relaxations can be seen as the consequences of a deconvolution phenomenon for the global phase transition between the dynamically disordered room temperature form (C2/c, Z = 8, Z′ = 1) and the ordered low-temperature form (P2 1 /c, Z = 48, Z′ = 12). In this respect, the intermediate form(s) can be seen as transient states of kinetic origin with a questionable genuine crystallographic relevance.

A cocrystal screening of the chiral drug “proxyphylline” (PXL) and achiral coformers was performed using dry or solvent assisted grinding and evaporation methods, yielding 10 different original solid forms with a 1:1 stoichiometry. Among them, three anhydrous cocrystals and a monohydrated conglomerate forming system have been identified with salicylic acid (SA). The crystal structures of the monohydrate and one of the racemic anhydrous forms were determined by X-ray single crystal experiments. The dehydration mechanism of the hydrate has been investigated by thermal analysis, X-ray powder diffraction, and water sorption–desorption cycles. The importance of water molecules in the crystal structure and the concomitant loss of both water and SA (cocrystal former) during the dehydration suggest a destructive mechanism.

Temperature-cycle-induced deracemization (TCID) has been widely studied in the field of chiral separation, ranging from fundamental research to applications. In this study, the secondorder asymmetric transformation (SOAT) of 2-methoxy-1-naphthamide in an azeotropic mixture of ethyl acetate and cyclohexane is compared with TCID, in terms of process productivity. The results indicate that the volumetric productivity using SOAT was over 100times higher than that using TCID, such that a scale-up by a factor of 10 was easily implemented.

The crystallization behavior and morphological features of particles obtained from amorphous diprophylline (DPL) are reported. After fast cooling of the melt, progressive heating above the glass transition (T g ≈ 37 °C) induces the nucleation and growth of well-shaped crystals: PC for primary crystals. The combination of differential scanning calorimetry, hot stage optical microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that these PC are kinetically favored and can form spontaneously in the supercooled melt whatever the enantiomeric composition, although their development and relative stability are influenced by the presence of theophylline, the main impurity in DPL samples. Specific crystal surfaces of the PC act as favorable areas and support for the subsequent formation of previously known metastable crystal forms consisting of solid solutions of the two DPL enantiomers. This study demonstrates the complex multistep mechanism that can occur during the temperature-induced crystallization of chiral amorphous drugs, and their strong sensitivity to enantiomeric composition and chemical purity.