Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic–Lipophilic Balance

Yao, Xin; Benson, Emily G.; Gui, Yue; Stelzer, Torsten; Zhang, Geoff G. Z.; Yu, Lian

doi:10.1021/acs.molpharmaceut.2c00156

Cited by 19 publications

(25 citation statements)

References 30 publications

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“…Given Span 20 is usually a viscous liquid at room temperature, which could accelerate crystallization and facilitate molecular mobility in ASD formulations [ 21 ]; therefore, the T g values of milled extrudates and precipitates were measured. Since the heating and cooling ramps of cyclic DSC curves were applied under a dry nitrogen atmosphere, the effect of moisture content on T g was also excluded as much as possible.…”

Section: Resultsmentioning

confidence: 99%

“…However, Fule et al reported that although itraconazole by itself was miscible with Soluplus up to 40% w / w , the presence of Poloxamer drastically reduced its miscibility to <10% [ 20 ]. A few researches meanwhile reported that the addition of surfactants could strongly affect the inhibition of drug crystallization and the maintenance of supersaturation [ 21 ]. Although adsorption of polymers could inhibit crystal growth by blocking new growth unit incorporation sites [ 22 ], the presence of surfactants in the supersaturation solution usually reduces the adsorption of polymer molecules at the solid interface [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Ilevbare et al revealed that surfactant molecules could accelerate crystal growth by weakening the interaction between the polymer and the crystalline solute surface [ 25 ]. Yao et al suggested that the effect of surfactants on crystal growth and nucleation is attributed to their ability to enhance mobility [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

Wang

Zhao

et al. 2023

Pharmaceutics

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A ternary amorphous solid dispersion (ASD) system consisting of drug/polymer/surfactant is receiving increased attention to improve the oral bioavailability of poorly water-soluble drugs. The effect of polymers has been extensively studied, while the impact of surfactants has not yet to be studied to the same extent. Challenging questions to be answered are whether the surfactants should be added with the drug or separately and the resulting differences between the two operating processes. By adjusting the liquid feeding zone for Span 20 in the hot-melt twin screw extruder equipment, we investigated the effect of Span 20 on the properties of the polyvinylpyrrolidone/vinyl acetate (PVPVA)-based ASD formulations of ritonavir. We found that with the delayed feeding positions of Span 20 in the twin screw extruder, the ability of the ternary ASDs to maintain the supersaturation of the milled extrudates was observed to be significantly enhanced. Furthermore, adding surfactant after a thorough mixing of polymer and drug could decrease the molecular mobility of ternary ASD formulations. In addition, the effects of Span 20 on the complex viscosity and structure of PVPVA were also investigated. The delayed addition of Span 20 could improve the complex viscosity of PVPVA, thus leading to the drug precipitation inhibition. In conclusion, the delayed addition of Span 20 in the twin screw extruder and prolonging the mixing time of the drug and polymer may be critical to the maintenance of supersaturation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

Wang

Zhao

et al. 2023

Pharmaceutics

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“…Amorphous solid dispersions (ASDs) are increasingly used to improve the bioavailability of poorly water-soluble drugs. − However, crystallization must be managed in order to take full advantage of this formulation strategy. For that purpose, ASDs commonly contain polymers ,− and/or surfactants. − In the presence/absence of such excipients, the crystallization kinetics of drugs from the amorphous state has been intensely studied both on storage ,− and during dissolution. − …”

Section: Introductionmentioning

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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“…Span 80 was added to enhance mobility and thus crystal growth rate of RTV in the molten state. [25] A small amount of RTV/Span was placed on a glass coverslip and melted at 403 K. The melt droplet was then cooled to 373 K and seeded with Form III crystal. Afterwards, the droplet was heated to ~ 388 K until one crystal piece was left as the perfect seed.…”

Section: Introductionmentioning

confidence: 99%

Ritonavir Form III: A New Polymorph After 24 Years

Zhang

Yao

Henry

2022

Preprint

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Polymorphism occurs widely in pharmaceutical solids, and must be thoroughly studied during product development. Twenty-four years after ritonavir (RTV) Form II materialized, we report a new polymorph, Form III, discovered via melt crystallization. Form III has a unique PXRD pattern, Raman spectrum, lower melting point and heat of fusion, compared to the known polymorphs, Form I and Form II. It is the least stable form, monotropically, among the three polymorphs. Form III differs from Form I and Form II in conformation and hydrogen bonding motifs. Nucleation from RTV supercooled liquid is slow, and selected Form III exclusively. The discovery of RTV Form III demonstrates the importance of crystal nucleation studies. Crystallization from supercooled liquids should be incorporated as part of polymorph screening workflow.

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Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic–Lipophilic Balance

Cited by 19 publications

References 30 publications

Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

Effect of Span 20 Feeding Zone in the Twin Screw Extruder on the Properties of Amorphous Solid Dispersion of Ritonavir

Impact of Crystal Nuclei on Dissolution of Amorphous Drugs

Ritonavir Form III: A New Polymorph After 24 Years

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