Ternary Solid Dispersions: A Review of the Preparation, Characterization, Mechanism of Drug Release, and Physical Stability

Abstract

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability.

Keywords: amorphization; amorphous solid dispersions; drug release; physical stability; poorly water-soluble drugs; ternary solid dispersion.

Figure 1

Classification of the TSD system.

Figure 2

Choosing the preparation method of the TSD system based on the solubility in the organic solvent and thermo-sensitivity. Adapted from data presented originally in Ref. [35]. Copyright 2023 Taylor and Francis.

Figure 3

FT−IR spectra of (a) each component and (b) the samples of the TSD system (F1−20% CBM, 80% Neusilin^® UFL2; F2−47.26% CBM, 32.74% Neusilin^® UFL2, 20% Kollidon^® VA64; F3−44.33% CBM, 39.79% Neusilin^® UFL2, 15.87% Kollidon^® VA64). Adapted from data presented originally in Ref. [87]. Copyright 2023 Elsevier.

Figure 4

Solid-state ¹³C NMR spectra of each material. The arrows in the figure should be derived from the hydrogen-bond formation of PBC with PVP adapted from data presented originally in Ref [101]. Copyright 2023 Elsevier.

Figure 5

A schematic illustration of a binary system and a ternary system, adapted from data presented originally in Ref. [81]. Copyright 2023 Elsevier. : Preventing the water contacting to amorphous drug, : Allowing the water contacting to amorphous drug.

Figure 6

Schematic illustration of a ternary solid dispersion prepared by HME, adapted from data presented originally in Ref. [101]. Copyright 2023 Elsevier.

Figure 7

A schematic illustration of the evolution from a ternary solid dispersion after dispersion in water. Adapted from data presented originally in Ref. [109]. Copyright 2023 ACS Publications.

Figure 8

Illustrates the general mechanism of the stability enhancement of TSDs compared to binary systems. Adapted from data presented originally in Ref. [35]. Copyright 2023 Taylor and Francis.