Melt extrusion with poorly soluble drugs – An integrated review

Abstract

Over the last few decades, hot melt extrusion (HME) has emerged as a successful technology for a broad spectrum of applications in the pharmaceutical industry. As indicated by multiple publications and patents, HME is mainly used for the enhancement of solubility and bioavailability of poorly soluble drugs. This review is focused on the recent reports on the solubility enhancement via HME and provides an update for the manufacturing/scaling up aspects of melt extrusion. In addition, drug characterization methods and dissolution studies are discussed. The application of process analytical technology (PAT) tools and use of HME as a continuous manufacturing process may shorten the drug development process; as a result, the latter is becoming the most widely utilized technique in the pharmaceutical industry. The advantages, disadvantages, and practical applications of various PAT tools such as near and mid-infrared, ultraviolet/visible, fluorescence, and Raman spectroscopies are summarized, and the characteristics of other techniques are briefly discussed. Overall, this review also provides an outline for the currently marketed products and analyzes the strengths, weaknesses, opportunities and threats of HME application in the pharmaceutical industry.

Introduction

Over many decades, the poor solubility of APIs has been a major obstacle for the development of more efficient drug delivery methods. To overcome this problem, various strategies were proposed in the literature (Alam et al., 2012, Goke et al., 2017, Wen et al., 2015). Among these strategies, hot-melt extrusion (HME) represents a complementary pharmaceutical manufacturing technology, which is widely used by industrial and academic researchers for mitigating the solubility issues of APIs.

HME was first introduced in 1971 as a formulation technology platform for the pharmaceutical industry (El-Egakey et al., 1971). Since that time, not only HME was adopted by the industry, but it was also modified and customized for multiple applications (Langley et al., 2013). The versatility of HME for various drug delivery strategies such as transdermal applications (Qi and Craig, 2016), bio-adhesive functions (Palem et al., 2016), implants (Cosse et al., 2017), orodispersible formulations (Pimparade et al., 2017), pellets, gastroretentive systems (Vo et al., 2016) lipid nanoparticles (Bhagurkar et al., 2017, Patil et al., 2015), and other applications (Fig. 1) has made it a technology that is poised to shift the entire paradigm of pharmaceutical industry research and manufacturing. One of the most significant uses of HME is the improvement of the solubility of poorly soluble drugs obtained via advanced combinatory and high-throughput screening. The strengths, weaknesses, opportunities, and threats (SWOTs) of HME are listed in Table 1. Regardless of gaining popularity, HME faces challenges (perceived or real) from various issues such as thermal degradation of API and/or carrier at processing temperatures, recrystallization of API over time, and reproducibility of HME products. However, the above issues can be addressed by reducing the processing temperatures by use of plasticizers, reduction of residence time of materials during the extrusion process and drug melting point depression by co-crystallization, etc.

HME can be considered an optimal technique for the processing of highly viscous materials without using any solvents and thus has been widely recognized as a green technology (Repka et al., 2008, Sarode et al., 2013). Its unique blending geometry promotes high-shear localized mixing while retaining the high throughput of the process. The HME screw configuration can be highly customized to tailor its shear level based on the formulation requirements (Haser et al., 2017, Morott et al., 2015). The continuous thinning, deformation, and elongation processes occurring in a very narrow space between the intermeshing elements facilitate the dissolution of drug molecules and/or their dispersion in a molten carrier (Haser et al., 2016). The high efficiency of distributive and dispersive mixing also allows contact between various chemical molecules at high frequencies without using any solvents that promote the formation of salt co-crystal species (Li et al., 2016, Liu et al., 2017). In addition, HME represents a high-throughput continuous process, which can be scaled up for industrial manufacture (Langley et al., 2013). The application of quality by design (QbD) and real-time monitoring techniques utilizing process analytical technology (PAT) strategies allows the development of HME as a continuous manufacturing (CM) platform (Islam et al., 2014, Tiwari et al., 2016), which can be used for more efficient and better controlled drug delivery (Chatterjee, 2012). This platform also offers many industrial benefits in the form of reduced labor, shorter operation times, lower investments, smaller facilities, and instrumentation (Bhagurkar et al., 2016). The concept of real-time release testing (RTRT) of pharmaceutical products proposed by the U.S. Food and Drug Administration (FDA) in 2004 promoted the use of process analytical tools for product development in the pharmaceutical industry. The resulting shift in the paradigm from batch testing to in-process testing (which improved the quality of product manufacturing) has been widely recognized and implemented. This article represents an integrated update of our previous review (Shah et al., 2013), which is written with an emphasis on the advances of HME for improved solubility and dissolution rates of poorly soluble drugs, thermodynamic aspects and mechanisms of drug/polymer solubilization, characterization techniques and its applicability as a CM technology for solid dispersions. This review also provides an overview of the current PAT tools employed in various pharmaceutical HME processes.