Impact of Processing Methods on the Physico-chemical Properties of Posaconazole Amorphous Solid Dispersions.
加工方法对泊沙康唑无定形固体分散体理化性质的影响
📄 英文摘要 English Abstract
Different methods have been exploited to generate amorphous solid dispersions (ASDs) of poorly water-soluble drugs. However, the impact of processing methods on drug stability and dissolution hasn't been studied extensively. The purpose of the current study is to investigate the impact of the two common ASD processing methods, hot-melt extrusion (HME) and spray drying, on the chemical/physical stability and supersaturation of Posaconazole (Posa) based ASDs. ASDs with 25% drug loading in hydroxypropylmethylcellulose acetate succinate were prepared using HME, and two types of spray dryers, a Procept Sprayer (ASD-Procept) and a Nano Sprayer (ASD-Nano). The relative physical stability of these ASDs upon exposure to heat and crystalline API seeding followed the order: ASD-Nano > ASD-Procept ≈HME. ASD-Procept and ASD-Nano showed similar chemical stability, slightly less stable than HME under 40°C/75%RH. All three ASDs demonstrated similar supersaturation induction times, and de-supersaturation kinetics with or without crystalline seeds. Posa ASDs prepared via spray drying were chemically less stable compared with HME, which can be attributed to their smaller particle size and hollow structure allowing oxygen penetration. For ASD-Procept and HME, the detailed phase changes involving recrystallization of amorphous Posa and a solid-solid phase transition from Posa Form I to Form Ia during the seed-induced studies were proposed. Similar dissolution and supersaturation-precipitation kinetics of three Posa ASDs indicated that any residual nanocrystals in the bulk ASDs were not enough to induce crystallization to differentiate ASDs made by three processing methods.
📄 中文摘要 Chinese Abstract
📋 英文结构化总结 English Structured Summary
摘要整理
Background:
Different methods have been exploited to generate amorphous solid dispersions (ASDs) of poorly water-soluble drugs. However, the impact of processing methods on drug stability and dissolution hasn't been studied extensively. The purpose of the current study is to investigate the impact of the two common ASD processing methods, hot-melt extrusion (HME) and spray drying, on the chemical/physical stability and supersaturation of Posaconazole (Posa) based ASDs.
Methods:
ASDs with 25% drug loading in hydroxypropylmethylcellulose acetate succinate were prepared using HME, and two types of spray dryers, a Procept Sprayer (ASD-Procept) and a Nano Sprayer (ASD-Nano). The relative physical stability of these ASDs upon exposure to heat and crystalline API seeding was studied.
Results:
The order of physical stability followed: ASD‑Nano > ASD‑Procept ≈ HME. ASD‑Procept and ASD‑Nano showed similar chemical stability, slightly less stable than HME under 40 °C/75 %RH. All three ASDs demonstrated similar supersaturation induction times, and de‑supersaturation kinetics with or without crystalline seeds. Posa ASDs prepared via spray drying were chemically less stable compared with HME, which can be attributed to their smaller particle size and hollow structure allowing oxygen penetration. For ASD‑Procept and HME, the detailed phase changes involving recrystallization of amorphous Posa and a solid‑solid phase transition from Posa Form I to Form Ia during the seed‑induced studies were proposed.
Data Summary:
Key quantitative and qualitative data include: 25% drug loading; test conditions of 40 °C/75 %RH; physical stability order ASD‑Nano > ASD‑Procept ≈ HME; similar supersaturation induction times and de‑supersaturation kinetics for all three ASDs; and a solid‑solid phase transition from Posa Form I to Form Ia observed for ASD‑Procept and HME.
Conclusions:
Similar dissolution and supersaturation‑precipitation kinetics of three Posa ASDs indicated that any residual nanocrystals in the bulk ASDs were not enough to induce crystallization to differentiate ASDs made by three processing methods. Spray‑dried ASDs were chemically less stable than HME ASDs due to particle size and structural differences.
Practical Significance:
The findings highlight that while hot‑melt extrusion and spray drying can both produce ASDs with comparable dissolution and supersaturation behaviour, the chemical stability disadvantage of spray‑dried ASDs – owing to their smaller particle size and hollow structure – should be considered in the manufacture of amorphous solid dispersions for poorly water‑soluble drugs.
📋 中文结构化总结 Chinese Structured Summary
背景:
目前已采用多种方法制备难溶性药物的无定形固体分散体（ASD），但加工方法对药物稳定性和溶出行为的影响尚未得到广泛研究。本研究旨在考察两种常用的ASD加工方法——热熔挤出（HME）和喷雾干燥——对泊沙康唑（Posa）基ASD的化学/物理稳定性及过饱和度的影响。
方法:
采用HME以及两种类型的喷雾干燥器（Procept喷雾干燥器（ASD-Procept）和Nano喷雾干燥器（ASD-Nano））制备了含药量为25%的羟丙基甲基纤维素醋酸琥珀酸酯基ASD。研究了这些ASD在受热和晶种诱导条件下的相对物理稳定性。
结果:
物理稳定性顺序为：ASD-Nano > ASD-Procept ≈ HME。ASD-Procept和ASD-Nano的化学稳定性相近，在40°C/75%RH条件下略低于HME。三种ASD的过饱和度诱导时间以及有/无晶种条件下的去饱和动力学均相似。喷雾干燥制备的Posa ASD化学稳定性低于HME，这可归因于其较小的粒径和中空结构有利于氧渗透。对于ASD-Procept和HME，在晶种诱导研究中提出了涉及无定形Posa重结晶以及Posa晶型I向晶型Ia固-固相变的详细相变过程。
数据摘要:
关键定量和定性数据包括：含药量25%；测试条件40°C/75%RH；物理稳定性顺序为ASD-Nano > ASD-Procept ≈ HME；三种ASD的过饱和度诱导时间和去饱和动力学相似；ASD-Procept和HME中观察到Posa晶型I向晶型Ia的固-固相变。
结论:
三种Posa ASD的溶出和过饱和-沉淀动力学相似，表明块状ASD中残留的纳米晶不足以诱导结晶以区分三种加工方法制备的ASD。喷雾干燥ASD由于粒径和结构差异，化学稳定性低于HME制备的ASD。
实际意义:
研究结果表明，尽管热熔挤出和喷雾干燥均可制备具有相当溶出和过饱和行为的ASD，但喷雾干燥ASD因粒径较小和结构中空导致的化学稳定性劣势，在难溶性药物无定形固体分散体的生产中应予以考虑。