Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

Abstract

Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.

Keywords: hot-melt extrusion; process analytical technology; quality by design; screw design; solid dispersion.

Fig. 1

Schematic of typical extruder system. API active pharmaceutical ingredient

Fig. 2

Cross-section of single- and twin-screw extruders (17)

Fig. 3

Classical intermeshing co-rotating and counter-rotating screws (20)

Fig. 4

Extrusion screw geometry

Fig. 5

Comparing a melt extruded solid dispersion, a physical mixture, and pure 17β-estradiol (17β E2). Dissolution medium 0.1 N hydrochloric acid (HCl). Reprinted with the permission from Hulsmann et al. (64)

Fig. 6

Influence of triethyl citrate (TEC) concentration and pre-plasticization on drug release rate of hot-melt extruded tablets containing 25% w/w 5-aminosalicylic acid (ASA). black triangle Formulation A2, pre-plasticized 12% w/w TEC; black diamond formulation A1, no pre-plasticization 12% w/w TEC; and black square formulation B, pre-plasticized 23% w/w TEC. Dissolution medium consisted of 0.1 N hydrochloric acid (HCl) pH 1.2, from 0 to 2 h; 50 mM phosphate buffer pH 6.8, from 2 to 6 h; and pH 7.4, from 6 to 12 h at 37°C and 100 rpm, apparatus 2 (n = 3). Reprinted with permission from Bruce et al. 2005 (72)

Fig. 7

Electronic tongue “taste map.” Comparison of global signal (principal component analysis, PCA, of the electrode responses) between pure paracetamol and extruded formulations to a VA 64 polymer and b Eudragit® E PO polymer after dissolution for 60 s. Reprinted with permission from Maniruzzaman et al. (80)

Fig. 8

Images of three screw configurations evaluated during hot-melt extrusion (HME) process optimization. a Thermo Fisher “standard configuration,” 40:1 L/D. b All conveying elements, 40:1 L/D. c From left to right, 110 mm of conveying elements, 22 mm of perpendicularly arranged mixing elements, and 165 mm of conveying elements 25:1 L/D (83)

Fig. 9

a Peak force (adhesive strength) and b work of adhesion of hydroxypropylcellulose (HPC) and HPC:hydroxypropyl methylcellulose acetate succinate (HPMC) films measured using a texture analyzer and rabbit intestinal mucosa as a substrate (n = 5); AUC area under the curve. Reprinted with permission from Repka et al. (86)

Fig. 10

Schematic representation of continuous preparation of solid lipid nanoparticles (SLNs) using hot-melt extrusion connected to a high-pressure homogenizer (99)

Fig. 11

Ishikawa diagram

Fig. 12

Components of quality by design approach

Fig. 13

Overview of a typical quality risk management process (123)

Fig. 14

In-line near-infrared (NIR) spectroscopic monitoring setup

Fig. 15

a Co-extruder equipment. b Interfacing of extruder by near-infrared (NIR) and Raman fiber optic probe (135)