Search

Crystal agglomeration is a common phenomenon for most chemicals and pharmaceuticals. The formation of agglomerates usually lowers product purity and generates a broad particle size distribution. This review focuses on preventing agglomeration in solution crystallization, the storage of crystals, and pharmaceutical preparation processes. The agglomeration mechanisms in these stages are analyzed and the effects of operating parameters are summarized. Furthermore, effective control means related to the crystallization environment are elaborated, including solvents, ultrasound, and additives. Special attention is paid to the influence of additives in preventing the aggregation of both suspensions and dried powders. Besides additives used in solution crystallization, the roles of anti-caking agents, stabilizers of nanosuspensions, and excipients of solid dispersions are also discussed. The additive type and properties like hydrophilicity, hydrophobicity, ionic strength, viscosity, the steric hindrance effect, and intermolecular interactions between additives and crystals can greatly affect the degree of agglomeration. [ABSTRACT FROM AUTHOR]

Glucosamine hydrochloride (GAH) is a kind of natural hexose, which is used to promote the synthesis of mucopolysaccharides and improve the metabolism of articular cartilage. In this paper, the solubility of GAH in pure water and aqueous system with the presence of three kinds of additives (HCl, NaCl, KCl) at temperatures ranging from 278.15 K to 323.15 K was determined by gravimetric method. When there are additives in water, the solubility of GAH increases with the increase of temperature and decreases with the increase of concentration of the three kinds of additives. When the additives were at similar mole fractions, HCl led to the lowest solubility of GAH. The modified Apelblat model and van't Hoff model were used to correlate the solubility data. The average relative deviation (ARD) data of Apelblat and van't Hoff models were less than 5%, indicating good fitting results. Based on the thermodynamic data, the cooling crystallization process of GAH was performed. It was found that the additives could affect the crystal morphology, particle size, and yield of GAH products. This study supplemented the thermodynamic data of GAH and studied the cooling crystallization process in the presence of GAH additives, which provided important guidance for the optimization of the crystallization process. [ABSTRACT FROM AUTHOR]

Abstract: Clopidogrel hydrogen sulfate is a famous antiplatelet agent for vascular disease. Forms I and II can be used as medicine. However, both forms exhibit low density and flowability. In addition, form I shows low polymorph stability. To solve these problems, spherical crystallization technologies were developed for the two forms. For form I, the mechanism was studied and turned out to be 2D nucleation and spherulitic crystal growth. In case of form II, the spherical crystallization process was based on agglomeration. The influence of temperature, acid, and crystal seed were investigated. The optimized spherical forms I and II showed much higher density and flowability as well as high polymorph stability. [ABSTRACT FROM AUTHOR]

Abstract: The solvate and the solvent‐free form of sulfadiazine (SD) were investigated. SD was found to exist in one solvent‐free form and the N‐methylpyrrolidone (NMP) solvate form. The NMP solvate was shown to be a channel‐type compound. The intrinsic properties of the solvents were used to evaluate the effects of solubility on the phase transformation of SD and the NMP solvate. The SD phase could transform to the NMP solvate by NMP‐mediated phase transformation, which was governed by crystallization of the NMP solvate. The crystalline NMP solvate could transform to the solvent‐free solid state through solid‐solid transformation upon heating or water penetration‐mediated phase transformation. The rate of this water penetration‐mediated phase transformation of the NMP solvate to SD was unusually fast. It can be used to obtain SD aggregates of well‐defined shape and good powder properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The latest developments of industrial crystallization in China are reviewed. This includes the introduction of representative scientists and institutions promoting the progress of Chinese industrial crystallization. Additionally, primary application fields related to industrial crystallization are outlined to give an overview of the current research trends in China. National and international industrial crystallization meetings held in China are also presented. Finally, the expectations for the future research activities in the field of industrial crystallization in China are briefly described. [ABSTRACT FROM AUTHOR]

In this study, the liquid–liquid phase separation and crystallization of vanillin from 1-propanol/water solution were investigated. It was found that water could contribute to the improvement of vanillin solubility in 1-propanol/water solution, but the solubility of vanillin decreased with the increasing water/1-propanol ratios, when the water content was over 30 wt.%. High water fraction in 1-propanol/water solvents will result in the liquid–liquid phase separation in the crystallization process, and the liquid–liquid phase separation dominated the process before the nucleation of crystals during the crystallization of vanillin. A ternary phase diagram (vanillin/1-propanol/water) including the solubility curves and the liquid–liquid phase separation curves was measured and could, in certain cases, clearly illustrate the liquid–liquid phase separation and crystallization process of vanillin in 1-propanol/water solutions. As shown in the ternary phase diagram, liquid–liquid phase separation under high initial vanillin concentration results in low purity of vanillin crystals due to the inhibited crystallization process by liquid–liquid phase separation. Partial phase immiscibility was a function of temperature and the range of immiscibility decreased with increasing temperature. Moreover, nucleation and crystal growth of vanillin in the presence of liquid–liquid phase separation were investigated; process parameters such as the composition of solvent, cooling profiles and seeding were optimized to avoid liquid–liquid phase separation and thus increase the purity of crystallization products. [ABSTRACT FROM AUTHOR]

Effects of polymeric additive and ultrasound on the morphology of ropivacaine crystals. [Display omitted] • The needle-like ropivacaine was modified as block-like crystals by adding little PVP in the crystallization system. • In ultrasound-assisted crystallization, the particles of ropivacaine precipitated at extended ultrasonic time exhibited plate-like crystals with shorter aspect ratio. • Combined using of polymeric additive and ultrasound led to rice-shaped crystals, which the average particle size was further decreased. • The mechanism for the morphological evolution of ropivacaine crystals assisted by PVP and ultrasound was proposed based on the experiments and molecular dynamics simulation. The objective of this research was to modify the crystal shape and size of poorly water-soluble drug ropivacaine, and to reveal the effects of polymeric additive and ultrasound on crystal nucleation and growth. Ropivacaine often grow as needle-like crystals extended along the a -axis and the shape was hardly controllable by altering solvent types and operating conditions for the crystallization process. We found that ropivacaine crystallized as block-like crystals when polyvinylpyrrolidone (PVP) was used. The control over crystal morphology by the additive was related to crystallization temperature, solute concentration, additive concentration, and molecular weight. SEM and AFM analyses were performed providing insights into crystal growth pattern and cavities on the surface induced by the polymeric additive. In ultrasound-assisted crystallization, the impacts of ultrasonic time, ultrasonic power, and additive concentration were investigated. The particles precipitated at extended ultrasonic time exhibited plate-like crystals with shorter aspect ratio. Combined use of polymeric additive and ultrasound led to rice-shaped crystals, which the average particle size was further decreased. The induction time measurement and single crystal growth experiments were carried out. The results suggested that PVP worked as strong nucleation and growth inhibitor. Molecular dynamics simulation was performed to explore the action mechanism of the polymer. The interaction energies between PVP and crystal faces were calculated, and mobility of the additive with different chain length in crystal-solution system was evaluated by mean square displacement. Based on the study, a possible mechanism for the morphological evolution of ropivacaine crystals assisted by PVP and ultrasound was proposed. [ABSTRACT FROM AUTHOR]

Potassium chloride crystals are cubic, which often leads to caking and greatly limits their applications. This caking can be overcome by modifying the crystal shape toward sphericity. Spherical particles have a high anti-caking ability and flowability. In this work, spherical KCl particles were prepared using a simple cooling crystallization process designed to function without additives. Among the four main processes in the crystallization of spherical particles, i.e., nucleation, growth, agglomeration, and attrition, agglomeration is the greatest contributor to the formation of spherical KCl particles, which were prepared following the principle that the adhesion force must be larger than the dispersion force. The adhesion free energy between KCl particles and solvents (i.e., water, n -hexane, formamide, diazomethane, methanol, ethanol, ethyl acetate, ethylene glycol, and dimethyl sulfoxide) was calculated using the Lifshitz–van der Waals acid–base approach, and water was found to be the most appropriate solvent because of its attractive interaction with the crystals. According to the relationship between the adhesion force and dispersion forces, we found that the stirring rate should be lower than 1300 rpm. Additionally, the effects of stirring rate and cooling rate on the KCl products were investigated and optimized, and the optimal conditions were found to be 400–500 rpm and 10–15 min/ ° C, respectively. All of the spherical KCl products prepared under the optimal conditions show a better morphology, flowability, and anti-caking performance than the original crystals. [ABSTRACT FROM AUTHOR]

A method is presented for optimizing the cooling strategy and seed loading simultaneously. Focused beam reflectance measurement (FBRM) was used to determine the approximating optimal cooling profile. Using these results in conjunction with constant growth rate assumption, modified Mullin-Nyvlt trajectory could be calculated. This trajectory could suppress secondary nucleation and has the potential to control product’s polymorph distribution. Comparing with linear and two step cooling, modified Mullin-Nyvlt trajectory have a larger size distribution and a better morphology. Based on the calculating results, the optimized seed loading policy was also developed. This policy could be useful for guiding the batch crystallization process. [ABSTRACT FROM AUTHOR]