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The crystal morphology of glucosamine hydrochloride (GAH) during antisolvent crystallization was investigated in this work. Particles of different shapes, such as plate-like crystals, leaflike clusters, fan-like dendrites, flower-like aggregates, and spherulites, were produced by tuning the type of antisolvents and crystallization operating conditions. The hierarchical structures of GAH crystals tended to be formed in a water + isopropanol mixture. The effects of operation parameters on the polycrystalline morphology were studied, including crystallization temperature, solute concentration, feeding rate of GAH aqueous solution, solvent-to-antisolvent mass ratio, and stirring rate. The evolution process of GAH spherulites was monitored using SEM, indicating a crystallographic branching mode. The crystal habit was predicted to identify the dominant faces. Molecular dynamics simulations were performed and the interaction energy of solute or solvent molecules on crystal surfaces was calculated. The experimental and simulation studies help to understand the branching mechanism and design a desired particle morphology. [ABSTRACT FROM AUTHOR]

Uric acid (UA) is the end product of purine metabolism and is widely found in nature. Excess uric acid will result in the deposition of pathological uric acid crystals in the kidney. However, few studies have focused on the effects of components in the human body on the crystallization of uric acid. Herein, we found multiple effects of alkali metals (Na+, K+) on uric acid dihydrate (UAD) crystal growth, which is one of the main components of urinary stones. Optical microscopy (OM) and scanning electron microscopy (SEM) were employed to detect the crystal morphology, and long rod-like crystals and hierarchical crystals were found in the presence of Na+ and K+, respectively. Powder X-ray diffraction (PXRD) and micro-Raman spectroscopy verified that the crystal structure remained unchanged in the presence of ions. In addition, single-crystal growth experiments revealed that Na+ inhibited growth along [010] and [100], and K+ promoted growth along [100] but suppressed growth along [010]. The step growth of the UAD crystal was measured by atomic force microscopy (AFM), which indicated the inhibition of crystal growth by Na+ due to kink blocking, yet the promotion of crystal growth by K+ resulted from rough growth. Our studies showed that ions in the human body not only can maintain electrolyte balance but also can affect the crystallization of pathological crystals, which provides a suggestion for a rational diet for patients with hyperuricemia and urinary stones. [ABSTRACT FROM AUTHOR]

In this study, curcumin 1,4-dioxane solvates (CUR–DIO) were obtained in two molecular ratios of 1 : 1.5 (CUR–DIO-1.5) and 1 : 1 (CUR–DIO-1) at different temperatures. In the two single crystal structures, the molecular conformation of curcumin is a planar structure and a curved structure, respectively. Moreover, the length of the hydrogen bond between the curcumin molecule and the 1,4-dioxane molecule indicates that with the increase in the system temperature, the difficulty of solvate formation increases, the solvent ratio decreases, and the inter-molecular hydrogen bond energy increases. In addition, with the increase in temperature, the crystal morphology changes from spherulites to rod-shaped crystals. The hollow spherulites of CUR–DIO-1 were obtained at 25 °C, and based on the ReactRaman data and microscope recording, a new formation mechanism of hollow spherulites was proposed. The formation mechanism and preparation method of organic small molecule hollow spherulites will play an important role in promoting the application of the hollow spherulite structures in the fields of drug loading, slow release and multifunctional drugs. [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]

Oiling‐out is a common phenomenon in industrial crystallization processes that not only prolongs the total operating time but also leads to undesirable crystal morphology, making it challenging to control crystallization paths. This review provides a comprehensive overview of the oiling‐out phenomenon in organic small molecule crystallization. First, the formation mechanisms of oiling‐out are summarized from both thermodynamic and dynamic perspectives, providing the theoretical foundation for understanding the phenomenon. Then, the universal characterization methods for studying the oiling‐out phenomenon of organic small molecules are introduced in detail, covering both offline and online analytical tools. Moreover, the regulation strategy for oiling‐out, including solvents, impurities, seeding, temperature, and mixing methods are discussed. This paper also focuses on the application of oiling‐out in co‐assembly and crystal shape modulation. Finally, future opportunities and challenges are presented to address the current shortcomings and application bottlenecks in the study of organic small molecule oiling‐out phenomena. This review aims to provide valuable insights and guidance for researchers working on the crystallization of organic small molecules, particularly in the pharmaceutical industry, to better understand, control, and utilize the oiling‐out phenomenon. [ABSTRACT FROM AUTHOR]

The utilisation of nucleation seeds, coupling nucleation and growth during crystallization and realistic continuum are currently relatively robust, reliable and scalable methods for protein crystallization optimization. Here, we design a segmented crystallization method, in which combines the characteristics of the Taylor vortex enhanced lysozyme nucleation stage. Different crystallizer are used for the growth segment so that the nucleation segment and the growth segment are organically combined during lysozyme crystallization. During the crystal growth stage, the crystallization properties of the Couette-Taylor (CT) crystallizer, mixing Tank (MT) crystallizer and tubular crystallizer were evaluated. The experimental results emphasize the importance of shear rate, temperature, and fluid velocity in the design of segment crystallization methods to obtain products with complete crystal morphology and uniform size distribution. This strategy successfully expanded the lysozyme crystallization from the original 10 mL scale to 200 mL, realized the continuous process, and providing a promising strategy for the design and operation of continuous SFC to produce high value protein crystals in the future. [Display omitted] • Couette-Taylor crystallizer can produce high quality crystals with uniform crystal size. • The decoupling of nucleation and growth can avoid crystal gragmentation. • Slug flow mode can realize the continuous crystallization process. [ABSTRACT FROM AUTHOR]

• The mechanism of the influence of dextran on trehalose crystal morphology was revealed through experiments and MD simulation. • The bulk trehalose crystals have excellent powder properties. • The Bulk trehalose products have better mixing uniformity and more stable starch protection. The residual dextran impurities in the upstream process significantly impact the crystallization of starch-based functional sugar and the related food properties. This study intends to reveal the mechanism of dextran's influence on trehalose crystallization, and build a relationship among the dextran in syrup and the physicochemical and functional properties of trehalose. Instead of incorporating into the crystal lattice, dextran changes the assembly rate of trehalose molecules on crystal surface. The different sensitivity and adsorption capacity of the crystal surface to the chain length of dextran determines the growth rate of crystal surfaces, resulting in different crystal morphology. The bulk trehalose crystals, which were obtained from syrups with short chain dextran, have excellent powder properties, including best flowability (35◦), highest crystal strength (2.7 N), lowest caking rate (62.22 %), and the most uniform mixing with other sweeteners (sucrose/xylitol) in food formulations, achieving more stable starch preservation. [ABSTRACT FROM AUTHOR]

• Edible sugar additives can alter the morphology of myo-inositol crystals. • d -glucose transforms myo-inositol from elongated lamellar to diamond-shaped lamellar. • Diamond-shaped products exhibit excellent sensory quality and solubility performance. • The products have better flowability, filtration and compression performance. Myo-inositol, referred to as vitamin B8, is an essential nutrient for maintaining human physiological functions. However, the morphology of myo-inositol products is predominantly powder or needle shaped, leading to poor food properties. In this work, three edible sugar additives, i.e. d -glucose, l -arabinose and d -fructose, are adopted in the crystallization of myo-inositol to improve its food properties. The results show that these additives change the morphology of myo-inositol crystals. d -glucose and l -arabinose reduced the aspect ratio of myo-inositol crystals, and d -glucose transformed elongated lamellar myo-inositol crystals into diamond-shaped lamellar crystals. The diamond-shaped lamellar myo-inositol products exhibited outstanding functional food properties. It offered a smoother texture and more pleasant mouthfeel when the products were added to infant formulas and nutraceuticals. When they were applied to functional beverages, the dissolution rate was increased by 35 %. This work provides a theoretical guidance for improving food properties through crystallization and possesses considerable potential for industrialization. [ABSTRACT FROM AUTHOR]

• The concentration calibration model is established to correlate the solubility. • Process intensification and control strategies are used to optimize the products. • Multi objectives optimization is achieved by the combination of techniques. This study explores the process intensification techniques and process control strategies on the product properties optimization. α-PABA, a long needle-like shape, can cause problems for the downstream processing. This study proposes ultrasound technique, supercooling control (SSC), and temperature cycling (TC) technologies to optimize the morphology and crystal size distribution of α-PABA. Firstly, the solubility and metastable zone of α-PABA in ethanol solvent are measured to determine the operational range. Next, the concentration calibration model is established to correlate the solubility with the ATR-FTIR intensity and temperature qualitatively. Furthermore, the process improvement techniques and control strategies are introduced to optimize the products. The ultrasound intensification contributes to produce the uniform crystal seeds. The SSC is benefit for the crystal growth, and can reduce the L/D ratio of the crystal product. While, TC is an efficient tool to eliminate the fine crystals. Moreover, the combination of ultrasound, SSC, and TC technology can show a significant improvement on the product particle aspects. The L/D ratio, crystal size, crystal morphology can show different degree of improvement under the combination techniques. At last, the outlook and perspectives on the process analytical technology are developed. [ABSTRACT FROM AUTHOR]

The important intermediate thiothiamine for Vitamin B1 production is often challenged by issues related to mixed polymorphs and needle-shaped crystal morphology in industrial production. These challenges can be effectively addressed through crystal engineering strategies. In this study, the key factors affecting the crystal form were investigated in reactive crystallization. Subsequently, the reactive crystallization process was monitored online using in-situ ATR-FTIR and FBRM techniques. It was determined that crystallization process is the rate-limiting step throughout the reactive crystallization process. Various factors affecting the crystal morphology were identified. Through process control and optimization, a product was achieved with a filtration time reduced by over 60% and a moisture content reduction of >20%. Overall, this study provides valuable insights from a crystal engineering perspective to address the poor powder properties. [Display omitted] • Identified the thiothiamine crystal form I and II as enantiotropic polymorph. • The key factors affecting the crystal form were determined. • The high reaction temperature helps to optimize the crystal morphology. • The co-optimization of crystal morphology and crystal form was realized. [ABSTRACT FROM AUTHOR]

[Display omitted] • Changing the crystal morphology of API by means of crystal engineering. • Continuous pressing was used to simulate sticking in pharmaceutical manufacturing. • Sticking was explored by investigating crystal habits, excipients and structure. • Computer-aided methods explore the understanding of sticking at molecular level. Punch sticking during tablet manufacturing is a prevalent issue for many active pharmaceutical ingredients (APIs) encountered by the pharmaceutical industry. Tenofovir amibufenamide fumarate (TMF), a heavyweight drug for the treatment of hepatitis B, was selected as a model drug due to its tendency to punch sticking during tablet compression. In this study, the cause of sticking was explored by investigating crystal habits, excipients and structure characteristics. The difference in sticking of three crystal habits can be visually represented through direct compression experiments on powdered samples and analysis of crystal surfaces. The excipients play a direct role in decreasing the probability of sticking, and the extent of sticking can be assessed by measuring the tensile strength of the tablet. Additionally, the plasticity index was utilized to theoretically analyze the potential enhancements of four excipients. These experimental results indicate that the block-shaped crystals have superior ability of anti-sticking and that suitable excipients can significantly improve the sticking situation of TMF. Ultimately, the phenomenon of punch sticking was additionally examined through computational calculations, focusing on the mechanical characteristics of TMF molecules and intermolecular interactions. The strategy of combining experiments and simulation calculations has broader significance for the study of drug production. [ABSTRACT FROM AUTHOR]

Clopidogrel hydrogen sulfate occupies a large market share of antithrombotic drugs. Its metastable form I has the advantages of high solubility and bioavailability. However, the poor powder properties and stability limit its application. This work solved the issue by building spherulitic growth operating space in "isopropyl acetate + lower alcohol" binary solvent systems. The systems were selected by the indicators of solubility and isosteric adsorption heats. By investigating crystal morphologies, polymorph transformation, and gelation with supersaturation gradient experiment, ATR-FTIR spectroscopy, and inverted tube method, these binary solvent systems follow the supersaturation-dependent spherulitic growth mechanism providing operating spaces significantly larger than the reported single solvent system. Hence, an optimal crystallization process was designed to prepare high-quality spherulites of form I avoiding polymorph transformation and gelation. Compared with the reported single solvent system, the optimized product presents better powder properties with residual solvent decreased by 59% and operating time decreased by 75%–90%. [Display omitted] • The spherical CHS (form I) is designed by spherulitic growth operating space. • Solvent systems are selected by solubility and isosteric adsorption heats. • The optimized product presents good powder properties and high stability. • The residual solvent decreases by 59% and the operating time decreases by 75%–90%. • The mechanism of polymorph transformation and gelation are investigated. [ABSTRACT FROM AUTHOR]

This work combines the crystallization experiments and constant chemical potential molecular dynamics simulations to investigate the solvent-mediated crystal morphology selection of an anti-tuberculosis drug, isoniazid. Experiments show that the aspect ratio of isoniazid crystals decreases with the decrease in the relative solvent polarity. Simulations provide a rationale for the experimentally observations and reveal the solvents role in controlling growth of important surfaces that modulate the crystal morphology, a rough growth mechanism for the fast growing (1 1 0) surface and stepwise growth for the slow growing (0 0 2) surface are also discovered. • Experiments and constant chemical potential molecular dynamics simulations are combined to investigate the solvent effects on isoniazid crystal morphology. • Experiments show that the aspect ratio of isoniazid crystals grown from solution decreases with the decrease in the relative solvent polarity. • Simulations reveal a rough growth mechanism for the fast growing (1 1 0) surface and stepwise growth for the slow growing (0 0 2) surface. In solution crystallization, solvent has a profound effect on controlling crystal morphology. However, the role played by solvents in affecting crystal morphology remains elusive. Here, we accompany experiments with molecular dynamics simulations to investigate crystallization of an anti-tuberculosis drug, isoniazid, in different solvents. Experiments show that isoniazid grows as needle-like crystals in water, while in alcohols such as methanol, ethanol and isopropanol, it exhibits a rod-like crystal habit. The aspect ratio of isoniazid crystals decreases with the decrease in the relative solvent polarity. We modeled these experiments by performing molecular dynamics simulations of isoniazid crystallization in different solvents at constant chemical potential thus keeping the solution concentration constant. The simulation results reveal a rough growth mechanism for the fast growing (1 1 0) surface, and bulk transport of the solute from solution to the growing surface is the limiting-step. In accordance with experiments, the relative growth rate of this surface decreases from methanol, ethanol to isopropanol. On the other hand, the slow growing (0 0 2) surface appears to follow a stepwise growth mechanism, with a surface integration step chiefly controlling the growth. The relative growth rate of this surface increases from methanol to ethanol and isopropanol. [ABSTRACT FROM AUTHOR]

[Display omitted] • Solution crystallization was used to prepare high-quality vitamin products. • Crystallization temperature influenced product purity and particle agglomeration. • Crystallization and temperature cycling optimized product quality. This study employed solution crystallization in food engineering to prepare a high-purity vitamin intermediate, optimize its crystal morphology and regulate its particle size distribution. Model analysis was performed to investigate the quantitative correlations between the process variables and target parameters, indicating the substantial effect of temperature on separation performance. Under optimal conditions, the product purity exceeded 99.5%, which meets the requirement of the subsequent synthesis process. A high crystallization temperature reduced the agglomeration phenomenon and increased particle liquidity. Herein, we also proposed a temperature cycling strategy and a gassing crystallization routine to optimize the particle size. The results illustrated that the synergistic control of temperature and gassing crystallization could substantially improve the separation process. Overall, based on a high separation efficiency, this study combined model analysis and process intensification pathways to explore the process parameters on product properties such as purity, crystal morphology, and particle size distribution. [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]

Thiamine hydrochloride (THCL) was produced in methanol accompanied with agglomeration in industry, the plate like morphology of THCL in methanol was not deserve to have a good quality. Selecting a suitable solvent should be considered because solvent could be one of the essential factors to impact morphology. Methanol and methanol/ethyl acetate solvent (0.2 vol fraction of methanol) was selected as the solvent system in reactive crystallization of THCL. The experiment results show the THCL crystal morphology in methanol/ethyl acetate solvent system was granular and more regular than that in methanol. In order to explicate the different crystal morphology in different solvents, molecular dynamics (MD) simulation was introduced to simulate crystal morphology in different solvents. The attachment energy (AE) model was employed to investigate the morphology of THCL under vacuum conditions, methanol and methanol/ethyl acetate solvent conditions, respectively. The simulation crystal morphology was in a good agreement with that of experimented. The particle of THCL in methanol/ethyl acetate solvent has less tendency to agglomeration, and then it is favorable to the downstream process, such as filtration, storage and transportation. [ABSTRACT FROM AUTHOR]

Nitroguanidine (NQ) is a commonly used explosive, which has been widely used for both civilian and military explosive applications. However, the weak flowability and mechanical performance limit its application. In this work, mechanical performance and thermodynamic stability of NQ crystals were improved by controlling crystal morphologies in the crystallization process. Typical NQ crystals with multiple morphologies and single crystal form were obtained in the presence of additives during the cooling crystallization. The morphology controlled NQ crystals showed higher density, unimodal crystal size distribution and enhanced flowability. The additives showed the inhibitory effect on the nucleation of NQ crystals by in-situ FBRM and PVM determination, and the mechanism was analyzed by means of morphological prediction and molecular simulation. Furthermore, the morphology controlled NQ crystals suggested higher thermodynamic stability according to the calculation of entropy, enthalpy, Gibbs free energy and apparent activation energy on the basis of DSC results. [ABSTRACT FROM AUTHOR]

• Cellulose polymers modify the crystal habit of DL-methionine in aqueous solution. • 2D growth rates of DL-methionine were both inhibited by polymeric additives. • Hirshfeld surface analysis, MEPs and MD simulations were performed. • Surface adsorption and steric hindrance of polymers are key for growth inhibition. Cellulose derivatives such as hydroxyethyl cellulose (HEC), methylcellulose (MC) and hydroxypropyl methycellulose (HPMC) were employed to modify the morphology and growth of DL-methionine crystals. The methodology involved a systematic study through batch cooling crystallization, slow solvent evaporation, seeded single crystal growth, solid-state characterization, and molecular simulation. The presence of the polymeric additive, at very low concentrations (1–100 ppm), has modified the crystal shape from elongated leaf-like crystals to hexagonal plates or blocks with smaller aspect ratio. All three polymers exhibited strong retardation on crystal growth along the b -axis (length) and c -axis (width) direction. The growth inhibition degree depends on the types and concentrations of the additives, which can be ranked as HPMC > MC > HEC at same concentration. To further explore the mechanism of polymeric additives on morphology modulation and growth inhibition, Hirshfeld surface analysis, molecular electrostatic potential surface calculations, and molecular dynamic simulations of additive-crystal surface system as well as aqueous solution-crystal surface system were carried out. The molecular modeling revealed surface adsorption of additives on crystal faces via electrostatic interactions, van der Waals interactions, and hydrogen bonds. Other factors like hydrophobic interactions and steric hindrance effect of polymers also have significant impact on crystal growth inhibition. [ABSTRACT FROM AUTHOR]

Abstract: The crystal growth morphology of ginsenoside compound K solvates was predicted by molecular modeling, and the solvent effect on crystal habits was considered to obtain a more accurate predicted result. The single crystal structures of two solvates of ginsenoside compound K (acetone–water solvate, monohydrate) were obtained by single crystal X-ray diffraction. On the basis of single crystal data, the crystal habits of the solvates were predicted by Bravais–Friedel–Donnay–Harker (BFDH) model and Attachment Energy (AE) model. From the image of scanning electron microscopy (SEM), it was shown that the AE model fits much better than the BFDH model. In addition, considering the interaction energy between solvent molecules and crystal faces (E int), the AE model was modified. With the modification of AE model, the predicted crystal habits were in good agreement with our experimental results. [Copyright &y& Elsevier]

[Display omitted] • Pulsed ultrasound was used to facilitate continuous reactive crystallization. • Experimental analyses of the stirred tank MSMPR cascade were performed. • A population balance model was developed and applied. • A three-stage MSMPR continuous reactive crystallization was successfully designed. In this work, pulsed ultrasound was used to facilitate steady-state reactive crystallization and increase the final yield and productivity of lithium carbonate in continuously operated single and multistage mixed suspension mixed product removal (MSMPR) crystallizers. Experimental analyses of the stirred tank MSMPR cascade were performed to investigate the effects of ultrasound field, residence time and temperature which contributed to the steady-state yield, crystal size distribution and crystal morphology. The results show that pulsed ultrasound can not only significantly enhance the reaction rate, but also help to improve the particle size distribution and the crystal habit. Subsequently, a population balance model was developed and applied to estimate the final yield of the continuous process of the lithium bicarbonate thermal decomposition reaction coupling lithium carbonate crystallization. The consistency of the final yield between the experiments and the simulations proved the reliability of the established model. Through the experimental and simulation analyses, it is demonstrated that the use of pulsed ultrasound, higher final stage temperature, MSMPR cascade design and appropriate residence time help to achieve higher yield and productivity. Furtherly, based on the conclusion drawn, pulsed ultrasound enhanced three-stage MSMPR cascaded lithium carbonate continuous crystallization processes were designed, and the maximum productivity of 44.0 g/h was obtained experimentally. [ABSTRACT FROM AUTHOR]

• The crystallization process was investigated to improve downstream performance. • The crystalline product habit was modified by using ultrasound. • The rod-like crystal were preferred in the desolvation process of the solvate. • The ultrasound-assisted crystallization process could increase the yield. The ultrasound-assisted crystallization process has promising potentials for improving process efficiency and modifying crystalline product properties. In this work, the crystallization process of fotagliptin benzoate methanol solvate (FBMS) was investigated to improve powder properties and downstream desolvation/drying performance. The direct cooling/antisolvent crystallization process was conducted and then optimized with the assistance of ultrasonic irradiation and seeding strategy. Direct cooling/antisolvent crystallization and seeding crystallization processes resulted in needle-like crystals which are undesirable for downstream processing. In contrast, the ultrasound-assisted crystallization process produced rod-like crystals and reduced the crystal size to facilitate the desolvation of FBMS. The metastable zone width (MSZW), induction time, crystal size, morphology, and process yield were studied comprehensively. The results showed that both the seeding and ultrasound-assisted crystallization process (without seeds) can improve the process yield and the ultrasound could effectively reduce the crystal size, narrow the MSZW, and shorten the induction time. Through comparing the drying dynamics of the FBMS, the small rod-shaped crystals with a mean size of 9.6 μ m produced by ultrasonic irradiation can be completely desolvated within 20 h, while the desolvation time of long needle crystals with an average size of about 157 μ m obtained by direct cooling/antisolvent crystallization and seeding crystallization processes is more than 80 h. Thus the crystal size and morphology were found to be the key factors affecting the desolvation kinetics and the smaller size produced by using ultrasound can benefit the intensification of the drying process. Overall, the ultrasound-assisted crystallization showed a full improvement including crystal properties and process efficiency during the preparation of fotagliptin benzoate desolvated crystals. [ABSTRACT FROM AUTHOR]

• The crystal structures of two novel solvates of sulfadiazine were determined and analyzed. • The processes of the rapid solvent-mediated phase transformations in water were investigated. • The products obtained by phase transformation are aggregated crystals with well-defined morphology. • The product has high bulk density. Two new solvates of the widely used antibiotic sulfadiazine were found and fully characterized. The crystal structures of these two solvates were determined. Differences between various sulfadiazine forms were elucidated by analyzing intermolecular interactions, crystal packing modes and molecule conformations. In addition, the phase transformations between solvates and solvent-free form were investigated. The sulfadiazine solvates quickly transformed into solvent-free form in water. The obtained particles were aggregates but with well-defined shape. They maintained the morphology and size of the solvate crystals. The results indicated that solvates can be used as intermediates to regulate the morphology of solvent-free form product through rapid solvent-mediated phase transformation. [ABSTRACT FROM AUTHOR]

• Influence of the solvent on the crystal habit of nifedipine was investigated. • Indexing of the crystal facets was performed. • The crystal packing and intermolecular interactions were examined. • Hydrogen bonding interactions turn the crystal morphology of nifedipine. The modification of the crystal habits by the solvent selection approach has been widely applied. However, the underlying regulation mechanism by solvents, specifically solute recognition and assembly process at crystal-solution interface is not yet well-understood. Herein, the effects of solvents on crystal habit and interface assembly of nifedipine (NFD) were investigated by growth experiments in five selected organic solvents of distinct hydrogen bond affinity properties. It was found that the crystal habits of NFD can be tuned by the hydrogen bond acceptor (HBA) ability of solvents, which elevates the aspect ratio of the crystals. The X-ray diffraction (XRD) and differential scanning calorimeter (DSC) further confirmed that no polymorphs were involved and related with the morphology changes. The face indexing calculated by single crystal XRD of experimental morphologies, Hirshfeld surface analysis, and the surface chemistry of the different crystal facets revealed a directionality of solvent interactions with crystal faces, induced by the solute-solvent hydrogen bonding interactions. Further, the strength of the solute-solvent interactions quantified by the adsorption energy calculations and the RDF analyses correlates well with the HBA ability of the solvents and the experimental morphology. In all, it was unveiled that the directionality of solute-solvent hydrogen bonding interactions interrupts anisotropically the recognition and assembly of solutes at the crystal-solution interface, resulting in the modification of the crystal morphology. [ABSTRACT FROM AUTHOR]