Dynamic Phase Behavior of Amorphous Solid Dispersions Revealed with In Situ Stimulated Raman Scattering Microscopy

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Teemu Tomberg, Ilona Hämäläinen, Clare J. Strachan* and Bert van Veen, 
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引用次数: 0

Abstract

This study reports the application of in situ stimulated Raman scattering (SRS) microscopy for real-time chemically specific imaging of dynamic phase phenomena in amorphous solid dispersions (ASDs). Using binary ritonavir and poly(vinylpyrrolidone-vinyl acetate) films with different drug loadings (0–100% w/w) as model systems, we employed SRS microscopy with fast spectral focusing to analyze ASD behavior upon contact with a dissolution medium. Multivariate unmixing of the SRS spectra allowed changes in the distributions of the drug, polymer, and water to be (semi)quantitatively imaged in real time, both in the film and the adjacent dissolution medium. The SRS analyses were further augmented with complementary correlative sum frequency generation and confocal reflection for additional crystallinity and phase sensitivity. In the ASDs with drug loadings of 20, 40, and 60% w/w, the water penetration front within the film, followed by both surface-directed and bulk phase separation in the film, was apparent but differed quantitatively. Additionally, drug-loading and phase-dependent polymer and drug release behavior was imaged, and liquid–liquid phase separation was observed for the 20% drug loading ASD. Overall, SRS microscopy with fast spectral focusing provides quantitative insights into water-induced ASD phase phenomena, with chemical, solid-state, temporal, and spatial resolution. These insights are important for optimal ASD formulation development.

用原位受激拉曼散射显微镜研究非晶固体分散体的动态相行为
本研究报道了原位受激拉曼散射(SRS)显微镜在非晶固体分散体(ASDs)中动态相现象的实时化学特异性成像中的应用。以不同载药量(0-100% w/w)的二元利托那韦和聚(乙烯基吡咯烷酮-醋酸乙烯酯)薄膜为模型体系,采用快速光谱聚焦的SRS显微镜分析ASD与溶解介质接触后的行为。SRS光谱的多元分离允许药物、聚合物和水分布的变化(半)实时定量成像,无论是在薄膜还是邻近的溶解介质中。SRS分析进一步增强了互补的相关和频率产生和共聚焦反射,以获得额外的结晶度和相灵敏度。在药物负荷为20%、40%和60% w/w的asd中,膜内的水渗透前沿明显,随后是膜内的表面定向分离和体相分离,但在数量上有所不同。此外,对载药量为20%的ASD进行了载药、相依赖的聚合物和药物释放行为成像,并观察了液-液相分离。总的来说,快速光谱聚焦的SRS显微镜提供了对水引起的ASD相现象的定量见解,具有化学,固态,时间和空间分辨率。这些见解对于优化ASD配方开发非常重要。
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来源期刊
Molecular Pharmaceutics
Molecular Pharmaceutics 医学-药学
CiteScore
8.00
自引率
6.10%
发文量
391
审稿时长
2 months
期刊介绍: Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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