Shichao Du

Progress of Pharmaceutical Continuous Crystallization

Abstract Crystallization is an important unit operation in the pharmaceutical industry. At present, most pharmaceutical crystallization processes are performed in batches. However, due to product variability from batch to batch and to the low productivity of batch crystallization, continuous crystallization is gaining increasing attention. In the past few years, progress has been made to allow the products of continuous crystallization to meet different requirements. This review summarizes the progress in pharmaceutical continuous crystallization from a product engineering perspective. The advantages and disadvantages of different types of continuous crystallization are compared, with the main difference between the two main types of crystallizers being their difference in residence time distribution. Approaches that use continuous crystallization to meet different quality requirements are summarized. Continuous crystallization has advantages in terms of size and morphology control. However, it also has the problem of a process yield that may be lower than that of a batch process, especially in the production of chirality crystals. Finally, different control strategies are compared.

Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization

Abstract Crystal engineering strategy was applied to develop new solid forms of lamotrigine. Two novel cocrystals of lamotrigine forming with 4,4′‐bipyridine (2:1) and 2,2′‐bipyridine cocrystal (1:1.5) were successfully obtained by neat grinding and liquid assisted grinding. The novel cocrystals were fully characterized and confirmed by X‐ray diffraction, thermal and spectroscopic analysis. DXRxi Raman microscope was also used to identify the cocrystals. The factors such as solvent and the structure of coformers which influenced the cocrystal formation were discussed. Furthermore, the novel cocrystals were both obtained by slurry crystallization. Process analytical technologies including focused beam reflectance measurement and attenuated total reflectance Fourier Transform Infrared were applied to investigate the cocrystallization process and the mechanism. HPLC analysis showed that the dissolution rate and the solubility of the two novel cocrystals were both improved. Graphical abstract Figure. No Caption available.

Solvates and polymorphs of clindamycin phosphate: Structural, thermal stability and moisture stability studies

Clindamycin phosphate (CP), an antibacterial agent, has been reported to form several solid-state forms. The crystal structures of two CP solvates, a dimethyl sulfoxide (DMSO) solvate and a methanol/water solvate (solvate V), have been determined by single crystal X-ray diffraction. The properties and transformations of these forms were characterized by powder X-ray diffraction, Single-crystal X-ray diffraction, differential scanning calorimetry, thermo gravimetric analysis, hot-stage microscopy, and dynamic vapor sorption. Very different hydrogen bonding networks exist among the host-host and host-solvent molecules in the two crystal structures, resulting in different moisture stabilities. The thermal stabilities of the two solvates upon heating and desolvation were also studied. When the temperature was above the boiling point of methanol, solvate V converted to a polymorphic phase after a one step desolvation process, whereas the desolvation temperature of the DMSO solvate was below the boiling point of DMSO. At the relative humidity above 43%, the DMSO solvate transformed to a hydrate at 25 °C. In contrast, solvate V did not transform at any of the humidities studied.

Polymorphs of daidzein and intermolecular interaction effect on solution crystallization

Daidzein (DAID), known as a phytoestrogen, is an important bioactive flavonoid isolated from soybean and pueraria. However, its poor solubility and low dissolution rate limit its clinical application. With the aim of finding a form with fit-for-purpose physicochemical properties, a comprehensive solid-state screening experiment was performed. As a result, three polymorphs were discovered and the single crystal structure of stable form II was revealed for the first time. Form II was obtained in solvents with high β and π* values, while form III was produced under opposite conditions. To clarify this phenomenon, intermolecular interactions were investigated through single crystal structure analysis, solvent property analysis and computational methods. The results demonstrated that the compact arrangement of DAID and the solvents used played a critical role in solution crystallization. Moreover, the physicochemical properties of these three polymorphs were fully characterized, and the powder dissolution behavior was determined in pure water and pH 1.2 and pH 6.8 buffer solutions. The newly discovered form II exhibited better thermal stability, lower moisture sorption and faster dissolution rate compared with the other forms.