Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds

Raina, Shweta A.; Alonzo, David E.; Zhang, Geoff G. Z.; Gao, Yi; Taylor, Lynne S.

doi:10.1007/s11095-015-1725-z

Cited by 44 publications

(35 citation statements)

References 46 publications

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“…The concentrations at where a sharp increase of UV absorption at 700 nm was observed were considered as LLPS onset concentration. 30…”

Section: Solubility and Liquid-liquid Phase Separationmentioning

confidence: 99%

“…As concluded by multiple reports on this subject, the LLPS phenomenon demonstrate the formation of noncrystalline drug-rich phase occurs under the condition that the critical supersaturation threshold is exceeded. 30,37,38 The HME tablet contains FEN in its amorphous state. In principle, this formulation may yield LLPS provided that a high degree of supersaturation of FEN is encountered.…”

Section: Profiles In Fessif-v2mentioning

confidence: 99%

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Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

Shi

Vela

et al. 2018

Journal of Pharmaceutical Sciences

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“…The concentrations at where a sharp increase of UV absorption at 700 nm was observed were considered as LLPS onset concentration. 30…”

Section: Solubility and Liquid-liquid Phase Separationmentioning

confidence: 99%

Section: Profiles In Fessif-v2mentioning

confidence: 99%

Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

Shi

Vela

et al. 2018

Journal of Pharmaceutical Sciences

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“…It was suggested that ASD dissolution was governed by a competition between the dissolution rate and the rate of phase separation. 37,38 If APS was initiated immediately when BMS-817399 ASD came in contact to the dissolution medium, the difference between an originally homogeneous ASD and a phase-separated ASD may not be distinguishable by the intrinsic dissolution rate, but this theory cannot explain the decreased polymer release rate after phase separation.…”

Section: The Impact Of Amorphous Phase Separation On the Dissolution mentioning

confidence: 99%

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

Chen

Pui

Liu

et al. 2018

Journal of Pharmaceutical Sciences

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Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.

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“…6,17–20 Colloid formation occurs via a phase-like transition that passes through a critical aggregation concentration (CAC), 2,21,22 akin to a critical micelle concentration (CMC), where liquid colloids rapidly appear. 23 Once formed, the colloids physically sequester proteins, 4 binding them with subnanomolar K d values 2,24 and partially denaturing them. 25 Key aspects of their structure and mechanism have remained elusive, however, owing to their physical properties and instability.…”

mentioning

confidence: 99%

Internal Structure and Preferential Protein Binding of Colloidal Aggregates

et al. 2016

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Colloidal aggregates of small molecules are the most common artifact in early drug discovery, sequestering and inhibiting target proteins without specificity. Understanding their structure and mechanism has been crucial to developing tools to control for, and occasionally even exploit, these particles. Unfortunately, their polydispersity and transient stability have prevented exploration of certain elementary properties, such as how they pack. Dye-stabilized colloidal aggregates exhibit enhanced homogeneity and stability when compared to conventional colloidal aggregates, enabling investigation of some of these properties. By small-angle X-ray scattering and multiangle light scattering, pair distance distribution functions suggest that the dye-stabilized colloids are filled, not hollow, spheres. Stability of the coformulated colloids enabled investigation of their preference for binding DNA, peptides, or folded proteins, and their ability to purify one from the other. The coformulated colloids showed little ability to bind DNA. Correspondingly, the colloids preferentially sequestered protein from even a 1600-fold excess of peptides that are themselves the result of a digest of the same protein. This may reflect the avidity advantage that a protein has in a surface-to-surface interaction with the colloids. For the first time, colloids could be shown to have preferences of up to 90-fold for particular proteins over others. Loaded onto the colloids, bound enzyme could be spun down, resuspended, and released back into buffer, regaining most of its activity. Implications of these observations for colloid mechanisms and utility will be considered.

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Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds

Abstract: Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds.

Cited by 44 publications

References 46 publications

Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

Developing Quantitative In Vitro–In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism, Microstructure, and Its Impact on Dissolution Performance

Internal Structure and Preferential Protein Binding of Colloidal Aggregates

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