This study investigates the interrelationships among drug loading, steric hindrance (Sh), defined as the spatial constraints imposed by the crystallized polymer network that physically restrict drug crystal growth, effective glass transition temperature (Tgᴱ), and drug particle size in crystalline solid dispersion (CSD) systems. Furthermore, we examine how CSD formulations enhance dissolution rates, oral bioavailability, and anti-liver cancer efficacy through comprehensive in vitro and in vivo studies. SOR-P188-CSD with different drug loadings were synthesized via spray drying, utilizing Sorafenib (SOR) as the model drug and poloxamer 188 (P188) as the carrier. The association between Sh/TgE, drug particle size, and dissolution behavior of CSDs was investigated by probing the crystalline domain (particle size), crystallization kinetics, and interaction dynamics within the CSD matrices. Notably, the particle size of SOR within SOR-P188-CSD exhibited a significant reduction compared to the pure drug. Analysis of crystallization kinetics unveiled a two-step crystallization mechanism for SOR-P188-CSD, where P188 crystallization preceded that of SOR. Intriguingly, an intermolecular interaction between SOR and P188 was observed, exerting an inhibitory effect on the crystallization kinetics of both components. This inhibitory effect escalated concomitantly with increasing drug loading. Within the SOR-P188-CSD system, P188 within formulations featuring low drug loading orchestrated a reduction in drug particle size by modulating the transverse and longitudinal growth rates of SOR, with Sh serving as the primary influencing factor. Conversely, in formulations with high drug loading, TgE of CSD interacted with temperature to regulate crystal nucleation and growth rates, thereby reducing drug particle size, with TgE emerging as the principal influencing factor. Subsequent in vitro and in vivo dissolution studies demonstrated a marked enhancement in the dissolution rate and bioavailability of drugs encapsulated within SOR-P188-CSD formulations compared to the active pharmaceutical ingredient (API). In the nude mouse liver cancer xenograft model, SOR-P188-CSD can significantly inhibit tumor growth by suppressing the expression of angiogenesis related factors (CD31, CD34, VEGF), tumor proliferation related factors (Ki67), and iron death related protein (GPX4). Collectively, our findings underscore the pivotal role of Sh/TgE in modulating drug particle size within CSD matrices through distinct mechanisms. Furthermore, our study underscores the potential of P188-mediated CSD formulations in augmenting the dissolution rate and bioavailability of poorly soluble drugs by minimizing drug particle size and sustaining drug supersaturation, thereby enhancing the efficacy of sorafenib in treating liver cancer. Graphical Abstract SOR-P188-CSD achieves solubilization and improves bioavailability by reducing drug particle size and maintaining drug supersaturation, thereby enhancing the anti-liver cancer effect of drugs.

Novel crystalline solid dispersions to improve the oral bioavailability and anti-liver cancer effect of Sorafenib

期刊论文
发表日期：

2025年12月3日

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Yong Zhang,
Yujin Wang,
Baihui Gong,
Weiqi Liu,
Jun Wang,
Chunhui Hu

摘要

This study investigates the interrelationships among drug loading, steric hindrance (S_h), defined as the spatial constraints imposed by the crystallized polymer network that physically restrict drug crystal growth, effective glass transition temperature (T_g^ᴱ), and drug particle size in crystalline solid dispersion (CSD) systems. Furthermore, we examine how CSD formulations enhance dissolution rates, oral bioavailability, and anti-liver cancer efficacy through comprehensive in vitro and in vivo studies. SOR-P188-CSD with different drug loadings were synthesized via spray drying, utilizing Sorafenib (SOR) as the model drug and poloxamer 188 (P188) as the carrier. The association between S_h/T_g^E, drug particle size, and dissolution behavior of CSDs was investigated by probing the crystalline domain (particle size), crystallization kinetics, and interaction dynamics within the CSD matrices. Notably, the particle size of SOR within SOR-P188-CSD exhibited a significant reduction compared to the pure drug. Analysis of crystallization kinetics unveiled a two-step crystallization mechanism for SOR-P188-CSD, where P188 crystallization preceded that of SOR. Intriguingly, an intermolecular interaction between SOR and P188 was observed, exerting an inhibitory effect on the crystallization kinetics of both components. This inhibitory effect escalated concomitantly with increasing drug loading. Within the SOR-P188-CSD system, P188 within formulations featuring low drug loading orchestrated a reduction in drug particle size by modulating the transverse and longitudinal growth rates of SOR, with S_h serving as the primary influencing factor. Conversely, in formulations with high drug loading, T_g^E of CSD interacted with temperature to regulate crystal nucleation and growth rates, thereby reducing drug particle size, with T_g^E emerging as the principal influencing factor. Subsequent in vitro and in vivo dissolution studies demonstrated a marked enhancement in the dissolution rate and bioavailability of drugs encapsulated within SOR-P188-CSD formulations compared to the active pharmaceutical ingredient (API). In the nude mouse liver cancer xenograft model, SOR-P188-CSD can significantly inhibit tumor growth by suppressing the expression of angiogenesis related factors (CD31, CD34, VEGF), tumor proliferation related factors (Ki67), and iron death related protein (GPX4). Collectively, our findings underscore the pivotal role of S_h/T_g^E in modulating drug particle size within CSD matrices through distinct mechanisms. Furthermore, our study underscores the potential of P188-mediated CSD formulations in augmenting the dissolution rate and bioavailability of poorly soluble drugs by minimizing drug particle size and sustaining drug supersaturation, thereby enhancing the efficacy of sorafenib in treating liver cancer.

Graphical Abstract

SOR-P188-CSD achieves solubilization and improves bioavailability by reducing drug particle size and maintaining drug supersaturation, thereby enhancing the anti-liver cancer effect of drugs.