Amorphous solid dispersions: Stability mechanism, design strategy and key production technique of hot melt extrusion

Abstract

Solid dispersion (SD) system has been used as an effective formulation strategy to increase in vitro and in vivo performances of poorly water-soluble drugs, such as solubility/dissolution, stability and bioavailability. This review provides a comprehensive SD classification and identifies the most popular amorphous solid dispersions (ASDs). Meanwhile, this review further puts forward the systematic design strategy of satisfactory ASDs in terms of drug properties, carrier selection, preparation methods and stabilization mechanisms. In addition, hot melt extrusion (HME) as the continuous manufacturing technique is described including the principle and structure of HME instrument, key process parameters and production application, in order to guide the scale-up of ASDs and develop more ASD products to the market in pharmaceutical industry.

Introduction

Approximately 75% of candidate drugs under development and 40% of commercially available drugs belong to poorly water-soluble drugs (Han et al., 2020, Shi et al., 2019b), resulting in various pharmaceutical performance issues for novel drug development (Vo et al., 2013). Such drugs exhibit poor water solubility in contact with the dissolution media in vitro or in vivo, which would not achieve the satisfactory solubility/dissolution rate and hence acceptable oral absorption. The influential factors of drug dissolution could be illustrated by the classic Noyes-Whitney equation (Eq. (1) (Thompson and Williams, 2021, van der Zwaan and Frenning, 2023). $d C / d t = k_{D} A (C_{s} - C_{t})$ where dC/dt represents the dissolution rate, k_D refers to the rate constant associated to the stirring and diffusion rates, A represents the total surface area of drug particles, C_s and C_t refer to the drug equilibrium solubility and the dissolution drug concentration in time (t), respectively.

According to the Noyes-Whitney equation, two approaches could be adopted to enhance the water solubility of poorly soluble components. The first approach is to increase the contact surface area between drug particles and dissolution medium, which could be achieved by reducing the drug particle size, such as micron technology (e.g., milling and de-novo production techniques for forming micro-sized particles) (Abdulkarim et al., 2019, Feng et al., 2018, Kou et al., 2023, Vogt et al., 2008) and nanotechnology (e.g., antisolvent precipitation and homogenization techniques for forming nano-sized particles) (Ahmed et al., 2019, Hou et al., 2019). The second method is to enhance the saturated solubility of drugs (i.e., improvement of water solubility). At present, common strategies include the change of drug crystal form through crystal engineering (such as polymorphism, co-crystal and co-amorphous techniques) (Han et al., 2023a, Han et al., 2020, Han et al., 2023b), or the formation of inclusion complex or solid dispersion systems to increase the water solubility/dissolution of such insoluble drugs (Hsu et al., 2019, Vasconcelos et al., 2016). Among them, the solid dispersion (SD) technique involves the above two design ideas for the solubilization of poorly soluble drugs simultaneously (Gronniger et al., 2023, Mondal et al., 2023, Wang et al., 2023). On the one hand, drugs are usually highly dispersed in water-soluble carriers to improve the wettability of the drugs in the dissolution media. On the other hand, crystalline drugs could be transformed into amorphous forms in most cases (i.e., formation of amorphous solid dispersion, ASD) to increase their water solubility/dissolution, thus enhancing their oral bioavailability (Fig. 1) (Chiang et al., 2023, Lee et al., 2023).

However, when the drugs show poor miscibility with polymeric carriers, the large amounts of polymers used in preparation process is unavoidable in order to meet the therapeutic dose of the drug in ASDs, resulting in the large volume/mass with a high polymer/drug ratio in the final dosage forms (Chavan et al., 2016, Shi et al., 2019c). Moreover, a mass of hydrophilic carriers might easily cause moisture absorption of ASDs, facilitating the recrystallization of the internal amorphous medicines (Fung et al., 2018, Shi et al., 2019c). Therefore, the understanding of stability mechanisms and rational design of satisfactory ASDs have become essential for pharmacy corporations, in order to provide effective medications to patients in a rational dosing schedule. In this review, we focus on the classification, stability mechanism and design strategy of SD (mainly ASD). In addition, hot melt extrusion as the key continuous manufacturing technique is also systemically reviewed from instrument, principle and key process parameters for industrial production.

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