Crystal nucleation from solution is a key process for the rational design and precise production of the desired structure and properties of crystalline materials. Understanding of crystal nucleation mechanism and hence the precise control is of fundamental importance. Crystal nucleation was studied for several centuries, and two main schools of thought, classic nucleation theory and non-classic nucleation mechanism, were proposed. The review summarized the research progress in recent years on molecular mechanism of crystal nucleation from solution. It was briefly introduced the development and problem of classic nucleation theory. Recent studies on solution chemistry, polymorphic formation and crystal nucleation mechanism were reviewed in detail. Two-step mechanism and pre-nucleation cluster pathway were then introduced, and the application of understanding and control of crystal nucleation was summarized. Finally, the future study on crystal nucleation mechanism was discussed and outlooked.
The study on pharmaceutical polymorphs is a hot topic in the field of drug. Meanwhile, the molecular assembly rules and the controlling methods of pharmaceutical polymorphs are the key contents in the research of polymorphs. In this paper, the nucleation theories, including the classical nucleation theory and two-step nucleation theory, as well as the methods about how to control pharmaceutical polymorph are introduced. In particular, some new strategies for polymorph regulation are highlighted, such as ionic liquid, template agent and microchannel technology. In addition, two practical examples are used to illustrate the important role of phase transformation in improving the quality of pharmaceutical products.
The paper summarizes the research methods of solid solution equilibrium, and analyzes the factors which influence the dissolution balance. The commonly used methods such as balance method and dynamic method are introduced, and the application of these methods with other analytical techniques are compared. It provides some references for the determination of solubility of new drugs and the determination of solubility of substances in crystallization separation.
Pharmaceutical polymorphism is a critical factor that affects the stability and efficacy of the drug. In recent years, a growing number of pharmaceutical cocrystals have been found to be polymorphic and different polymorphs do show different properties. Accordingly, the research of polymorphism in cocrystals is attracting greater attention. In this contribution, the studies which focus on polymorphic cocrystals are reviewed. The concept of polymorphic cocrystals is explained and its different types are identified, including synthon polymorph, packing polymorph, conformational polymorph as well as tautomeric polymorph. The screening methods of polymorphic cocrystals are introduced in detail. Furthermore, the difference in the properties of pharmaceutical cocrystals due to different crystal forms is emphasized.
In this work, four solid forms of ibrutinib (form A, form B, form C and pseudo-polymorph anisole solvate) were prepared. The solid forms were characterized by X-ray diffraction, infrared spectroscopy and thermal analysis, and the stable form was selected by suspension experiments. The results show that the chemical and physical properties of the four forms of ibrutinib have obvious differences. The stability relationship of anhydrous forms is:form A>form C>form B, and form A is the thermodynamic stable crystalline form.
The dual feed crystallization was used to control the crystallization environment within the crystallization metastable zone, successfully avoid the spontaneous nucleation, the operation was simple and easy to control. The influences of initial concentration, feeding speed, stirring speed, pH scope, quantity of seed crystal and crystal growing time on the yield, crystal habits and crystal size distribution of products were studied using single factor way. The products were obtained with whole crystal habits and homogeneous size distribution at 0.43 g/g initial concentration, 2 mL/min feeding speed, 2.5~2.7 pH scope, 60 min crystal growing time and the quantity of seed crystal was calculated by equation. In addition, with the stirring speed of 70 or 140 r/min, the cluster crystal or clubbed crystal were obtained, respectively. The yield can reached 92%.
The solubilities of meso-Erythritol in water were experimentally measured from 283.15 K to 363.15 K at atmospheric pressure by employing the synthetic method. The experimental data were correlated by using the modified Apelblat equation and λh equation, the accuracy of which could meet the need of their industrial use. The dissolution enthalpy, dissolution entropy and molar Gibbs energy of the dissolution of meso-Erythritol in water were then calculated. The cooling crystallization of meso-Erythritol had been studied by using FBRM-PVM on the basis of the measured crystallization thermodynamics data. The experimental data and the correlation equations in this work can be used as essential data and models in the industrial manufacture process optimization and crystallizer design of meso-Erythritol.
The crystal habit can affect the crystal mobility, bulk density and other properties. At present, sodium chloride exists mainly in the way of cubic crystal, which results in its caking easily in its packaging, transportation and other processes. In order to solve the caking problem of cubic sodium chloride and develop the multi-species edible salt, we studied the effects of multiple operating conditions in the evaporation crystallization experiment on the crystal habit of sodium chloride. In addition, the changes of crystal habit of cubic sodium chloride dissolved in methanol-water mixed solvent were studied and the effects of small-scale liquid evaporation on the crystal growth of sodium chloride were also studied. It can be concluded that the spherical sodium chloride crystals could be obtained by using the optimized operating conditions in the evaporation crystallization experiment. Moreover, sodium chloride can dissolve into a spherical crystal when the cubic sodium chloride is dissolved in a methanol-water mixed solvent,which having a mass fraction of methanol about 0.5. Finally, it can be found that the plate-like crystal with large particle size can be obtained by using the method of small-scale liquid evaporation.
In this paper, the structural basis of polymorph stability was investigated using the conformational polymorphic drug ritonavir as a model drug. For Form I and Form Ⅱ, the molecular conformations were analyzed, the intermolecular hydrogen bonds were analyzed by PLATON software and the intermolecular interaction potential and packing energy were calculated by UNI method. In addition, the relative contributions of various intermolecular contacts were calculated by Hirshfeld surface method. The results showed that compared with Form I, the ritonavir molecules of Form Ⅱ have lower intermolecular interaction potential, lower packing energy and higher packing index, so they can arrange in a more stable packing structure.
The drop-microfluidic method was used to investigate the effect of temperature, droplet size and solvents composition on L-glutamic acid polymorphism. Microscope and powder X-ray diffraction (PXRD) were used to analyze the forms of crystals. The results show that the higher temperature favors the nucleation of metastable crystal form, while lower temperature favors the nucleation of stable crystal form under the same degree of supersaturation. When the degree of supersaturation and the crystallization temperature are same, droplet size has no effect on L-glutamic acid polymorphs. The higher the mole fraction of ethanol in ethanol aqueous solution is, the higher the percentage of metastable crystals is.
High quality single crystals of cyclohexanecarboxylic acid (CCA) were obtained by melt crystallization. The crystal structure of CCA crystal determined by single-crystal X-ray diffraction is first reported here. It crystalizes in the monoclinic system, space group P21/c with cell parameters a=1.19113 nm, b=1.07421 nm, c=1.10733 nm, and β=94.72°. The crystal habit of CCA crystal was predicted based on the crystal structure using Material Studio. The nucleation temperatures and induction period under various cooling rates were measured by DSC. Furthermore, the crystal growth of CCA crystal was determined online using hot-stage microscopy. The growth rates of main appeared crystal faces were measured under different temperature, indicating exponential dependency of growth kinetics on supercooling degree.
