Surface Enhancement of Crystal Nucleation in Amorphous Acetaminophen

Wu, Hao; Yao, Xin; Gui, Yue; Hao, Hongxun; Yu, Lian

doi:10.1021/acs.cgd.2c00695

Cited by 12 publications

(28 citation statements)

References 53 publications

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“…This strong surface-accelerating effect on nucleation was attributed to the anisotropic molecular packing at the surface and its structural similarity to the surface-nucleating polymorph. , In another study on APAP, the same metastable polymorph, Form III, favored nucleation both in the bulk and at the surface . The authors also reported that the molecular packing at the surface was mainly attributed to surface nucleation enhancement . In this work, the results are similar to those of the study on APAP .…”

Section: Resultssupporting

confidence: 85%

“…They found surface nucleation to be vastly enhanced by 12 orders of magnitude for D-arabitol and by approximately 9 orders of magnitude for posaconazole . This strong surface-accelerating effect on nucleation was attributed to the anisotropic molecular packing at the surface and its structural similarity to the surface-nucleating polymorph. , In another study on APAP, the same metastable polymorph, Form III, favored nucleation both in the bulk and at the surface . The authors also reported that the molecular packing at the surface was mainly attributed to surface nucleation enhancement .…”

Section: Resultsmentioning

confidence: 94%

“…The nucleation rates were vastly increased at the surface, and a different polymorph was selected . However, in another study of the surface effect on nucleation of acetaminophen (APAP), the same metastable polymorph nucleated in the bulk and at the surface, which was different from the studies on D-arabitol and posaconazole. , …”

Section: Introductionmentioning

confidence: 94%

“…Nucleation is also influenced by the liquid/vapor interface. ,− A drug molecule at the free surface is in a special environment compared with those in the interior. ,, Compared to bulk molecules, surface molecules have higher degrees of freedom due to having fewer or different neighbors, thus exhibiting a higher mobility . It has been reported that surface molecules exhibit different molecular orientations compared to bulk molecules .…”

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: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Additionally, the film geometry allows easy characterization of crystallinity in the amorphous phase and solution separately through a microscope, but it is hard for powders to distinguish the two crystallization processes. Finally, milling amorphous drugs into powders may induce nucleation to an unknown extent, , likely due to the pressure, , heat, and large surface area ,−− created. However, nuclei density in an amorphous film can be measured and controlled using the developed method …”

Section: Resultsmentioning

confidence: 99%

Impact of Crystal Nuclei on Dissolution of Amorphous Drugs

Yao

Zhang

2023

Mol. Pharmaceutics

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Amorphous drugs are used to improve bioavailability of poorly water-soluble drugs. Crystallization must be managed to take full advantage of this formulation strategy. Crystallization of amorphous drugs proceeds in a sequence of crystal nucleation and growth, with different kinetics. At low temperatures, crystal nucleation is fast, but crystal growth is slow. Therefore, amorphous drugs may generate dense but nanoscale crystal nuclei. Such tiny nuclei cannot be detected using routine powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). However, they may negate the dissolution advantage of amorphous drugs. In this work, for the first time, the impact of crystal nuclei on dissolution of amorphous drugs was studied by monitoring the real-time dissolution from amorphous drug films, with and without crystal nuclei, and the evolving crystallinity in the films. Three model drugs (ritonavir/RTV, posaconazole/POS, and nifedipine/NIF) were chosen to represent different crystallization tendencies in the supercooled liquid state, namely, slow-nucleation-and-slow-growth (SN-SG), fast-nucleation-and-slow-growth (FN-SG), and fast-nucleation-and-fast-growth (FN-FG), respectively. We find that although the amorphous films containing nuclei do not show obvious differences from the nuclei-free films under PLM and PXRD before dissolution, they have inferior dissolution performance relative to the nuclei-free amorphous films. For SN-SG drug RTV, crystal nuclei have negligible impact on the crystallization of amorphous films, dissolution rate, and supersaturation achieved. However, they cause earlier de-supersaturation by inducing crystallization in solution as heterogeneous seeds. For FN-SG drug POS and FN-FG drug NIF, crystal nuclei accelerate crystallization in the amorphous films leading to lower supersaturation achieved with POS, and elimination of any supersaturation with NIF. Dissolution profiles of amorphous films can be further analyzed using a derivative function of the apparent dissolution rate, which yields amorphous solubility, initial intrinsic dissolution rate, and onset of crystallization in the amorphous films. This study highlights that although crystal nuclei are undetectable with routine analytical methods, they can significantly negate, or even eliminate, the dissolution advantage of amorphous drugs. Hence, understanding crystal nucleation process and developing approaches to prevent it are necessary to fully realize the benefits of amorphous solids.

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