Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation

Tang, Weiwei; Li, Tonglei

doi:10.1021/acs.molpharmaceut.2c00125

Cited by 6 publications

(5 citation statements)

References 16 publications

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“…The difference in free energy ΔG v between the crystalline and amorphous phases is calculated from the Hoffman equation (3) where T m is the melting point, and ΔH m is the heat of fusion.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Crystallization consists of nucleation and growth processes, and each process influences the overall crystallization. − Considerable attention has been given to nucleation processes due to their indispensable role in drug polymorph selection. − In recent years, polymorphic selectivity of drugs has been observed in the process of melt crystallization, and new polymorphs can be discovered via melt crystallization. − Yu and co-workers found that polymorphs with a low density and high energy tend to nucleate first, while this correlation is by no means perfect . The influencing factors and mechanism of polymorph nucleation from melts are not well understood …”

Section: Introductionmentioning

confidence: 99%

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Investigation into Surface Effects on the Crystal Nucleation and Growth of Clotrimazole Polymorphs

Zhang

Xu²,

et al. 2023

Crystal Growth & Design

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Molecules at the surface are spatially different compared to those in the bulk and potentially influence crystallization. In this study, surface effects on crystallization behaviors of two clotrimazole (CMZ) polymorphs were investigated. Form 2 of CMZ is favored to nucleate both at the surface and in the bulk. The nucleation rates of CMZ polymorphs at the surface are vastly accelerated by 5−6.5 orders of magnitude compared to their bulk nucleation rates. The surface-accelerating effect on the nucleation rates for Form 2 is relatively stronger than that for Form 1. The surface molecular structure and surface dynamics exhibit a combined effect on the enhancement of surface nucleation. The surface also enhances growth rates of the two polymorphs while exhibiting a greater accelerating effect on Form 1. The growth rates of Form 2 are higher in the bulk, while they show the opposite order at the surface, with Form 1 growing faster. The classical nucleation theory holds true in the present system both at the surface and in the bulk, and the thermodynamic barriers of the two nucleation processes are similar. This study is relevant for understanding the nucleation and growth kinetics of drug polymorphs at the surface.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigation into Surface Effects on the Crystal Nucleation and Growth of Clotrimazole Polymorphs

Zhang

Xu²,

et al. 2023

Crystal Growth & Design

View full text Add to dashboard Cite

show abstract

“…However, when the nucleation rates are comparable, the effect of the growth process is particularly significant, and the construction of detailed nonlinear growth kinetics will significantly improve the accuracy of polymorph computation. Admittedly, the disadvantage of the Ostwald ratio is that it is not possible to separate nucleation from growth and study the effect of one process on the results separately. , However, the polymorph prediction potential of the Ostwald ratio is unlimited. In particular, the introduction of nonlinear dynamics in the growth term will allow for greater applicability of the model in dimorphic systems.…”

Section: Discussionmentioning

confidence: 99%

“…Admittedly, the disadvantage of the Ostwald ratio is that it is not possible to separate nucleation from growth and study the effect of one process on the results separately. 54,55 However, the polymorph prediction potential of the Ostwald ratio is unlimited. In particular, the introduction of nonlinear dynamics in the growth term will allow for greater applicability of the model in dimorphic systems.…”

Section: Discussionmentioning

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

Ind. Eng. Chem. Res.

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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.

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“…Therefore, it is particularly crucial to develop highly efficient screening and production methods for solid-state forms of drugs with the least possible amount of sample. Generally speaking, conventional solution-based crystallization, Figure a, is the most common method for obtaining polymorphs, salts, and co-crystals. − However, the process is time-consuming, trial and error intensive, and inevitably involves a variety of hazardous organic solvents. It is also not conducive to the principle of drug savings in the early stages of new drug development.…”

mentioning

confidence: 99%

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

Zhao

Liu

et al. 2023

ACS Sustainable Chem. Eng.

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The pharmaceutical industry is required to constantly broaden its development areas and accelerate technical transformation because of the continued global rise in medicine consumption. However, the usage of organic solvents in pharmaceutical production results in up to 20 million tons annually of chemical waste, causing a serious environmental problem. Here, we proposed a solvent-free sustainable chemical technology, sublimation crystallization, for highly efficient screening and preparation of pharmaceutical solid forms (i.e., polymorphs), which eliminates the wastes associated with solvent use from the source. By adjusting the parameters of sublimation crystallization, we have obtained multiple polymorphs of several important drugs, including the antituberculosis drug pyrazinamide (PZA) and nonsteroidal anti-inflammatory drugs (NSAIDs), flufenamic acid (FFA) and mefenamic acid, particularly γ form of PZA and polymorphs IV and VII of FFA, which are difficult to produce from conventional solution crystallization methods. Mechanical property measurements from both powder and single crystal tests reveal that the γ form of PZA readily prepared by sublimation crystallization has the most excellent tabletability properties. In situ crystal growth observations indicate a direct vapor-to-crystal growth mechanism for the sublimation crystallization process consistent with conventional vapor phase deposition. Furthermore, the governing factors and growth mechanisms of sublimation and solution crystallization processes were analyzed and discussed, and it was found that the rate-limiting step of crystal growth is the surface-integration process in solution crystallization, whereas it becomes the surface diffusion process in sublimation crystallization. Overall, our developed sublimation crystallization provides a promising green technology for the development and production of (new) drugs, broadening the thinking behind the development of sustainable chemicals.

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Kinetic Retraction at the Onset of Concomitant Crystallization and Implication on Polymorphic Formation

Cited by 6 publications

References 16 publications

Investigation into Surface Effects on the Crystal Nucleation and Growth of Clotrimazole Polymorphs

Investigation into Surface Effects on the Crystal Nucleation and Growth of Clotrimazole Polymorphs

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

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

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