A prediction system: regulating effect of small-molecule additives on properties of amorphous solid dispersions prepared by hot-melt extrusion technology

Abstract

Amorphous solid dispersions (ASDs) with solubility advantage are suffering from the recrystallization risk and subsequent reduced dissolution triggered by high hygroscopicity of hydrophilic polymers and the supersaturation of ASD solutions. To address these issues, in this study, small-molecule additives (SMAs) in the Generally Recognized as Safe (GRAS) list were introduced into drug-polymer ASD. For the first time, we systematically revealed the intrinsic correlation between SMAs and properties of ASDs at the molecular level and constructed a prediction system for the regulation of properties of ASDs. The types and dosages of SMAs were screened by Hansen solubility and Flory-Huggins interaction parameters, as well as differential scanning calorimetry. X-ray photoelectron spectroscopy and adsorption energy (E_abs) calculation showed that the surface group distribution of ASDs and E_abs between ASD system and solvent were vital factors affecting the hygroscopicity and then stability. The radial distribution function revealed that interactions between components were proposed to be the critical factor for the dissolution performance. Based on this, a prediction system for regulating the properties of ASDs was successfully constructed mainly via molecular dynamics simulations and simple solid-state characterizations, and then validated by cases, which efficiently reduces the time and economic cost of pre-screening ASDs.

Introduction

Approximately 90% of new drug candidates belonging to Biopharmaceutics Classification System class II and IV drugs exhibit poor aqueous solubility [1]. Low solubility is one of major challenges for developing effective drug delivery, as it can impede drug absorption after oral administration [2]. Amorphous solid dispersions (ASDs) that refer to a homogeneous dispersion system where drugs in amorphous state are highly dispersed within polymer carriers have been widely used to enhance solubility and dissolution of poorly soluble drugs [3], [4]. However, the high hygroscopicity caused by hydrophilic polymers commonly used (VA64, Soluplus, PVA, etc.) would decrease the glass transition temperature of ASDs and then increase the recrystallization risk [5], [6]. In addition, the supersaturation of ASD solutions will also drive the crystallization of drugs in amorphous state during dissolution [7], [8], in turn resulting in the loss of solubility advantage.

To address these issues, surfactants [9], [10], polymers [8], [11], and pH adjusters [12], [13] were added into ASDs to inhibit the phase separation and recrystallization by providing sufficient interactions with components. Among these strategies, the addition of surfactants involves the safety and miscibility concerns, polymers would increase the volume/mass of the final dosage form, and the pH adjusters are only suitable for pH-dependent drugs, which will not provide universal guidance for extensive use of ASDs. In our preliminary study, small-molecule additives (SMAs) including small molecules in the Generally Recognized as Safe (GRAS) list such as sweetening agents and nutritional supplement, or small-molecule API with synergistic pharmacological effects were introduced into drug-polymer ASD, which could significantly affect the physicochemical properties of drugs like solubility, hygroscopicity and stability. Further, a critical question “What is the internal relationship between SMAs and the properties of ASDs?” needs to be explored. The trial-and-error screening of SMAs is time-consuming and high-cost, meaning that it is necessary to construct a prediction system to obtain ternary ASD with targeted physicochemical properties.

In this study, for the first time, we systematically elucidated the influence mechanism of the types and dosages of SMAs on the formation and properties of ASDs from the molecular level and constructed a prediction system for the regulation of properties of ASDs by screening SMAs. To implement the objective of this work, acetaminophen (AC, Fig. 1A) as an antipyretic and analgesic agent was utilized as a model drug to prepare ASDs with hydrophilic polymer Soluplus (Fig. 1G) via HME technology. SMAs, including sweetening agents like mannitol (MA, Fig. 1B) and saccharin (SAC, Fig. 1C) [14]; nutritional supplements like niacinamide (NIC, Fig. 1D) and myricetin (MYR, Fig. 1F) [15], [16]; indomethacin (IMC, Fig. 1E), which synergizes with AC in clinical practices [17], were introduced into the API-polymer system. The prediction system for the regulating effect of SMAs on ASD properties, mainly via molecular dynamics simulation and simple solid-state characterizations, was detailly elucidated and further initially validated.

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Materials

Acetaminophen (purity of 99%), nicotinamide (purity of 99%), indomethacin (γform, purity of 99%), myricetin (purity of 96%), saccharin (purity of 98%), magnolol (purity of 98%) and curcumin (purity of 95%) were purchased from Shanghai Yuanye Bio-Technology Co., Ltd. (Shanghai, China). Mannitol and Soluplus were obtained from Beijing Fengli Jingqiu Pharmaceutical Co., Ltd. (Beijing, China). PVP K12 was provided by BASF SE (Ludwigshafen, Germany).

Peiya Shen, Chunfeng Zhang, Enshi Hu, Yuan Gao, Shuai Qian, Jianjun Zhang, Yuanfeng Wei, Weili Heng,
A prediction system: regulating effect of small-molecule additives on properties of amorphous solid dispersions prepared by hot-melt extrusion technology, European Journal of Pharmaceutics and Biopharmaceutics, 2023, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2023.06.001.

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