The Role of Solvent Composition and Polymorph Surface Chemistry in the Solution-Mediated Phase Transformation Process of Cefaclor

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The investigation of polymorphism thermodynamic stability and nucleation process of spironolactone was performed to control the final solid forms. Spironolactone–water–acetone ternary phase diagrams were determined in the temperature range of 5.0–45.0 °C. Meanwhile, the nucleation processes were investigated at different supersaturations and different water contents via in situ PVM and PXRD. Results show that the stable form transforms from form II to the hydrate with increasing water content, and the transition point moves toward higher water contents as the temperature increases. Besides, the nucleation of stable form appears away from the eutectic point or at low supersaturation near the eutectic point. Concomitant nucleation occurs at the eutectic point or at high supersaturation near the eutectic point, because of thermodynamic effects or combined effects of thermodynamic and kinetic factors. Molecular dynamics simulation explains the formation of different solid forms in terms of molecular interactions. The results manifest the role of kinetic influences on solid forms control while considering thermodynamic stability.

Section: Experiments and Simulationmentioning

confidence: 99%

Solid Forms Selection of Spironolactone: Ternary Phase Diagram and Nucleation Process

Dai

Yang

Zhu

et al. 2019

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“…Compared with the nucleation from a clear solution, epitaxy or chemical matching can reduce the supersaturation and shorten the time required for stable phase nucleation on the specific face of the metastable form. ,, Furthermore, for carbamazepine, although there is no epitaxy between the two forms, FIII was still observed to nucleate on the side faces of FI crystal. In addition, the nucleation of the stable polymorph on the side faces of a metastable polymorph were also observed in the SMPT process of cefaclor and 2,6-dihydroxybenzoic acid without studying the epitaxy. This indicates that the nucleation on a face of a metastable form is a common phenomenon in the SMPT process, whether the epitaxy between two forms exists or not.…”

Section: Introductionmentioning

confidence: 99%

“…In their research, the rate-determining steps of the SMPTs process were determined by monitoring both solution and solid phase data at the same time. They rationalized the SMTP into four principal scenarios: dissolution controlled polymorphic transformation, growth controlled polymorphic transformation, nucleation–dissolution controlled polymorphic transformation, and nucleation–growth controlled polymorphic transformation. − The process modeling and simulation of SMPTs have also been extensively investigated. Zong et al studied the SMPT of lansoprazole through the thermodynamic and population balance models.…”

Section: Introductionmentioning

confidence: 99%

“…In this work, the mechanism of SMPT among more than two forms was studied. Since the stable form often nucleates on the specific face of the metastable form, ,,,, the different exposed crystal surfaces per unit mass can provide different nucleation sites for stable forms. Thus, the exposed crystal surface per unit mass (crystal size) of the metastable form was investigated in this work.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism and Regulation Strategy of Solution-Mediated Polymorphic Transformation: A Case of 5-Nitrofurazone

Wang

et al. 2021

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Solution-mediated polymorphic transformation (SMPT) exists extensively in crystallization from solution in many polymorphic systems. To obtain the desired products, it is crucial to understand the mechanism of the SMPT process and then to develop a regulation strategy for it. However, the mechanism of SMPT of different polymorphs is still not well understood. In this work, the mechanism and control strategy of SMPT were studied in detail by using 5nitrofurazone as a model compound. A series of SMPT experiments were carried out. Different 5-nitrofurazones form β (different sizes or with different amounts of impurities/additive) can (1) transform to form α directly, or (2) transform to form γ directly, or (3) initially transform to mixture of form α and form γ and then finally transform to form γ. Then, the mechanism of the SMPT process of 5-nitrofurazone was explored by using quantum chemical calculation, solubility determination, lattice energy calculation, single crystal indexing, and lattice matching calculation. Finally, the regulation strategy of the SMPT process of 5-nitrofurazone was proposed: form α can be obtained through decreasing size of form β. Form γ can be directly obtained through the addition of a certain amount of 5-nitrofurfural.

“…Polymorphism is a common phenomenon in crystallization, especially in pharmaceuticals. − The significant differences in performance between different polymorphs were brought to light by a number of drug withdrawals in the 20th century, and this is why the polymorphism in chemicals, especially in organic small molecule drugs, has gradually gained widespread recognition and attention in the last 30 years. − Concomitant polymorphism is a special type, which refers to the phenomenon of simultaneous nucleation and growth of two or more polymorphs in the same environment under the combined influence of thermodynamic and kinetic factors. − The occurrence of concomitant crystallization can significantly affect the consistency of the drug, leading to the reduction of bioavailability, dissolution performance, subsequent processing performance, and so on. , Therefore, the study of solution chemistry, molecular assembly, and its intrinsic connection with concomitant polymorphism are crucial in improving the quality of polymorphic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Control of Nonlinear Growth Kinetics and Nucleation Kinetics in the Concomitant Crystallization of Aripiprazole as Reflected by the Ostwald Ratio

Gao

Cen

Lin

et al. 2022

Some polycrystalline drugs are subject to concomitant polymorphism during the manufacturing process, resulting in large batch-to-batch variation and reduced drug bioavailability. Most existing studies on concomitant polymorphism have focused only on differences in nucleation kinetics and lacked analysis of the role of growth processes in polymorph control. Herein, we conducted a systematic study on the concomitant crystallization of aripiprazole Form III and Form V under the influence of thermodynamic and kinetic factors employing thermal analysis with the Ostwald ratio as a medium. It shows that the nucleation and growth rates of both forms cross over with increasing supersaturation. The comparison between the polymorph composition computed by the Ostwald ratio and the experiments highlights the considerable influence of crystal growth on the formation of concomitant polymorphism. The effect of crystal growth at lower supersaturation is indeed minimal due to the large difference in nucleation rates, but as the supersaturation increases, the difference in nucleation rates becomes smaller and the growth rate ratio gradually becomes a key factor. The images plotted with initial concentration and crystallization temperature further demonstrate that the introduction of actual nonlinear growth kinetics can lead to improved computation accuracy of the Ostwald ratio. This work provides evidence for the application of the Ostwald ratio in the design of batch crystallization for a concomitant system.