Understanding Conformational Polymorphism in Ganciclovir: A Holistic Approach

We present a holistic crystallographic study of the antiviral ganciclovir, including insights into its solid-state behavior, which could prove useful during drug development, making the process more sustainable. A newly developed methodology was used incorporating a combination of statistical and thermodynamic approaches, which can be applied to various crystalline materials. We demonstrate how the chemical environment and orientation of a functional group can affect its accessibility for participation in hydrogen bonding. The difference in the nature and strength of intermolecular contacts between the two anhydrous forms, exposed through full interaction maps and Hirshfeld surfaces, leads to the manifestation of conformational polymorphism. Variations in the intramolecular geometry and intermolecular interactions of both forms of ganciclovir were identified as possible predictors for their relative thermodynamic stability. It was shown through energy frameworks how the extensive supramolecular network of contacts in form I causes a higher level of compactness and lower enthalpy relative to form II. The likelihood of the material to exhibit polymorphism was assessed through a hydrogen bond propensity model, which predicted a high probability associated with the formation of other relatively stable forms. However, this model failed to classify the stability of form I appropriately, suggesting that it might not have fully captured the collective impacts which govern polymorphic stability.

The Role of A-Cations in the Polymorphic Stability and Optoelectronic Properties of Lead-free ASnI3 Perovskites

Tin-based ASnI3 perovskites have been considered an excellent candidate for lead-free perovskites solar cell applications, however, our atomistic understanding of the role of A-cations in the physical chemistry properties is...

Microstructure and performance of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) crystal clusters obtained by the solvation-desolvation process

The microstructure and performance of HMX were adjusted by a solvation-desolvation process. HMX solvates were prepared by recrystallization in N,N-dimethylformamide (DMF) and N-methylpyrrolidone (NMP), respectively. Specific microstructures of HMX with microcrystal clusters were obtained by the desolvation of HMX solvates through anti-solvent extraction and vacuum pyrolysis. With different solvents and desolvation methods, the HMX crystals show a variety of morphologies, particle size, and polymorphic stability. The microcrystalline HMX clusters can be easily broken into superfine crystals by ultrasonic dispersion system and have higher β→δ polymorphic transformation temperature than the raw β-HMX. Moreover, microcrystalline HMX clusters have reduced impact and friction sensitivity and are expected to enhance the reliability of small booster charges and improve the overall performance of the HMX-based booster.

Crystal habit modification and polymorphic stability assessment of a long-acting β2-adrenergic agonist

Crystal habit modification of a drug substance by performing a slurry test at a temperature higher than the melting point.

Polymorphic stability of progesterone under stress conditions

Progesterone (PRG) is an essential hormone in regulating the female reproductive system. It is used in gynecology, including contraception, medical abortion, and treatment of conditions related to endometrial and myometrial growth [1]. This drug exhibits two different crystal structures: forms 1 (PRG-1) and 2 (PRG-2); both with equal pharmacological effects. PRG-2 is the metastable form and it is 1.1 kcal/mol less stable than PRG-2 [2]. Polymorphic instability occurs when a metastable solid form (PRG-2) transforms into the most thermodynamically stable (PRG-1) [3]. It is well-known the therapeutic efficacy of a drug substance or drug product can be altered by its polymorphic or chemical transformation [4]. In order to study the polymorphic stability both polymorphs, PRG-1 and PRG-2, were placed under the same mechanical, thermal and high humidity stress conditions. X-ray powder diffraction (XRPD) analysis showed PRG-2 maintained its crystal structure after 3 months of exposure to dark storage condition at 400C/75% relative humidity and 1 month to light. High performance liquid chromatography (HPLC) showed no degradation of PRG-1 and PRG-2. However, mechanical stress (grinding) on PRG-2 produced seeds of PRG-1 that induced its polymorphic transformation (Figure 1A). DSC curve showed and endothermic events at 120.70C corresponding to the melting point of PRG-2 followed by the recrystallization at 123.80C of PRG as PRG-1, finally the fusion of PRG-1 at 127.90C. The Ea average value was higher in PRG-2 than in PRG-1; it suggested PRG-2 is more thermally stable than PRG-1 and, the decomposition behavior is different between these two polymorphs. Degradation products from thermal stability studies were monitored by coupled TGA-FT-IR analyses and different analyses (Table 2 inset in Figure 1). PRG-1 shows a high maximal rate of degradation (Tdmax) and initial temperature of thermal decomposition (To) compares to PRG-2.