Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

Marouene Bejaoui,Hanen Oueslati,Haykel Galai

doi:10.5772/intechopen.95518

Abstract

Amorphous ternary solid dispersion has become one of the strategies commonly used for improving the solubility and bioavailability of poorly water soluble drugs. Such multicomponent solid dispersion can be obtained by different techniques, this chapter provides an overview of ternary solid dispersion by co-milling method from the perspectives of physico-chemical characteristics in vitro and in vivo performance. A considerable improvement of solubility was obtained for many active pharmaceutical ingredients (e.g., Ibuprofen, Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen) and this was correlated to the synergy of multiple factors (hydrophilicity enhancement, particle size reduction, drug-carrier interactions, anti-plasticizing effect and complexation efficiency). This enhanced pharmacokinetic properties and bioavailability of these drug molecules (1.49 to 15-folds increase in plasma drug concentration). A particular focus was accorded to compare the ternary and binary system including Ibuprofen and highlighting the contribution of thermal and spectral characterization techniques. The addition of polyvinylpyrrolidone (PVP K30), a low molecular weight molecule, into the binary solid dispersion (Ibuprofen/β-cyclodextrin), leads to a 1.5–2 folds increase in the drug intrinsic dissolution rate only after 10 min. This resulted from physical stabilization of amorphous Ibuprofen by reducing its molecular mobility and inhibiting its recristallization even under stress conditions (75% RH and T = 40°C for six months).

Highlights

In recent years, solid dispersion technology by milling technique was largely utilized by researchers in order to enhance dissolution rate, bioavailability and therapeutic efficiency of several poorly water-soluble drugs (Table 1), as it represents a simple, economic and environmental process without using solvents [1–9]
Lauretta et al (2015) have shown that amorphous ternary solid dispersion of Gliclazid with crosslinked polyvinylpyrrolidone and SLS (Sodium Lauryl Sulfate) by co-milling method exhibited higher dissolution rate compared to the commercial product “Diabrezide” (Drug release of Gliclazid reached 90% in 2 h) [15]
The formation of physically stable ternary amorphous system by solid dispersion method using optimized ball milling technique, represents a promising alternative for drug solubility and stability enhancement. This succeeded for improving the dissolution rate of several active pharmaceutical ingredients (e.g., Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen)

Summary

Introduction

Solid dispersion technology by milling technique was largely utilized by researchers in order to enhance dissolution rate, bioavailability and therapeutic efficiency of several poorly water-soluble drugs (Table 1), as it represents a simple, economic and environmental process without using solvents [1–9]. Millings enable particle size reduction and promote the formation of drug nanoparticles, which enhance solubility, flow properties and content uniformities of pharmaceutical dosage forms [10]. Drug transition from crystalline to amorphous state which is more soluble in water but physically unstable in some cases [11] Physical stabilization of such unstable amorphous material required an optimization strategy using additives (milling time and rate, compatible carriers with optimized proportion) in order to preserve its chemical integrity (absence of degradation) and inhibiting phase transformations or polymorphic conversion towards unstable forms [11]. The challenges and strategies in developing robust ternary solid dispersion of high stability and performance are briefly discussed

Ternary solid dispersion: a new alternative to promote drug dissolution rate

Milling method

Conclusion

Perspectives