Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs

Abstract

Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products.

Introduction

The poor aqueous solubility and dissolution rate of API is one of the biggest challenges in pharmaceutical development and is becoming more common among new drug candidates over the past two decades due to the use of high throughput and combinatorial screening tools during the drug discovery and selection phase [1], [2], [3]. According to the Biopharmaceutics Classification System (BCS), a drug compound is poorly soluble if the highest dose strength is not soluble in 250 ml aqueous media over the pH ranges at 37 °C [4]. These compounds mostly belong to Class II (IIa or IIb), which are poorly soluble and highly permeable according to the pH of the gastrointestinal fluid and tend to present solubility or dissolution rate-limited absorption [5]. Despite their high permeability, these drugs often have low oral bioavailability because of their slow and limited release of drug in gastrointestinal fluid [6]. Therefore, one of the major challenges of the pharmaceutical industry is to apply strategies that improve the dissolution and/or apparent solubility of poorly soluble drugs to develop such problematic compounds into orally bioavailable and therapeutic effective drugs [3], [5].

Various approaches to overcome the poor aqueous solubility of drug candidates have been investigated in drug research and development such as salt formation [7], prodrug formation [8], particle size reduction [9], complexation [10], micelles [11], microemulsions [12], nanoemulsions [13], nanosuspensions [14], solid–lipid nanoparticle [15] and solid dispersion which is considered one of the most successful strategies to improve the dissolution profile of poorly soluble drugs. The term solid dispersions has been defined as a dispersion of one or more API in an inert carrier or matrix at the solid state prepared by solvent, melting or solvent–melting method [16]. The API in solid dispersions can be dispersed as separate molecules, amorphous particles, or crystalline particles while the carrier can be in the crystalline or amorphous state. Numerous studies on solid dispersions have been published and have showed many advantageous properties of solid dispersions in improving the solubility and dissolution rate of poorly water-soluble drugs. These advantages include reducing particle size, possibly to molecular level, enhancing wettability and porosity, as well as changing drug crystalline state, preferably into amorphous state [6].

Despite such high active research interests, the number of marketed products arising from solid dispersion approaches is disappointingly low. This low number is mainly due to scale-up problems and physicochemical instability in the manufacturing process or during storage leading to phase separation and crystallization [17], [18], [19], [20]. Only a few commercial products have been marketed during the past half-century (Table 1). Therefore, in-depth knowledge that has been acquired on various aspects of solid dispersions such as carrier properties, preparation methods, physicochemical characterization techniques as well as the pharmaceutical mechanism of matrix formation and drug release are very important to ensure the preparation of a productive and marketable solid dispersion. The aim of this review is to provide new knowledge from recent advances on solid dispersion areas to overcome some problems and issues that limit the marketability of solid dispersion products. As a continued work of previous reviews in this field, this article newly suggests the four classifications of solid dispersions according to the development by generation that has been investigated so far. Finally, the future perspectives and strategies of solid dispersions are also discussed.