Phase homogeneity in ternary amorphous solid dispersions and its impact on solubility, dissolution and supersaturation – Influence of processing and hydroxypropyl cellulose grade

IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Florian Pöstges , Jonas Lenhart , Edmont Stoyanov , Dominique J. Lunter , Karl G. Wagner
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Abstract

As performance of ternary amorphous solid dispersions (ASDs) depends on the solid-state characteristics and polymer mixing, a comprehensive understanding of synergistic interactions between the polymers in regard of dissolution enhancement of poorly soluble drugs and subsequent supersaturation stabilization is necessary. By choosing hot-melt extrusion (HME) and vacuum compression molding (VCM) as preparation techniques, we manipulated the phase behavior of ternary efavirenz (EFV) ASDs, comprising of either hydroxypropyl cellulose (HPC)-SSL or HPC-UL in combination with Eudragit® L 100–55 (EL 100–55) (50:50 polymer ratio), leading to single-phased (HME) and heterogeneous ASDs (VCM). Due to higher kinetic solid-state solubility of EFV in HPC polymers compared to EL 100–55, we visualized higher drug distribution into HPC-rich phases of the phase-separated ternary VCM ASDs via confocal Raman microscopy. Additionally, we observed differences in the extent of phase-separation in dependence on the selected HPC grade. As HPC-UL exhibited decisive lower melt viscosity than HPC-SSL, formation of partially miscible phases between HPC-UL and EL 100–55 was facilitated. Consequently, as homogeneously mixed polymer phases were required for optimal extent of solubility improvement, the manufacturing-dependent differences in dissolution performances were smaller using HPC-UL, instead of HPC-SSL, i.e. using HPC-UL was less demanding on shear stress provided by the process.

Abstract Image

三元非晶固体分散体的相均匀性及其对溶解度、溶解和过饱和的影响——加工和羟丙基纤维素等级的影响
三元非晶固体分散体(ASDs)的性能取决于固体特性和聚合物混合,因此全面了解聚合物之间在增强难溶性药物溶解和随后的过饱和稳定方面的协同相互作用是必要的。通过选择热熔挤压(HME)和真空压缩成型(VCM)作为制备技术,我们控制三元依韦伦(EFV) asd的相行为,包括羟丙基纤维素(HPC)-SSL或HPC- ul与Eudragit®L 100-55 (EL 100-55)(50:50聚合物比),导致单相(HME)和非均相asd (VCM)。由于与EL 100-55相比,EFV在HPC聚合物中的固态溶解度更高,我们通过共聚焦拉曼显微镜观察到,在相分离的三相VCM asd中,EFV在富HPC相中的药物分布更高。此外,我们观察到相分离程度的差异取决于所选择的HPC等级。由于HPC-UL的熔体粘度明显低于HPC-SSL,这有利于HPC-UL与EL 100-55之间部分混相的形成。因此,为了最大程度地提高溶解度,需要均匀混合的聚合物相,使用HPC-UL而不是HPC-SSL,溶解性能的制造依赖性差异更小,即使用HPC-UL对工艺提供的剪切应力要求更低。
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来源期刊
International Journal of Pharmaceutics: X
International Journal of Pharmaceutics: X Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
6.60
自引率
0.00%
发文量
32
审稿时长
24 days
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