Optimising process conditions to improve drug delivery characteristics: part I

Hot melt extrusion (HME) is a versatile, continuous and solvent-free process technology that has gained significant popularity in the pharmaceutical industry in recent years. The high number of poorly soluble drugs in both development pipelines and commercial products has directed formulators to utilise HME to manufacture amorphous solid dispersions (ASDs); the high energy state of the amorphous active and stabilising properties of the polymeric excipients provide significant increases in apparent solubility without sacrificing permeability — potentially resulting in great improvements in bioavailability.^1–3

Hydroxypropyl methylcellulose (HPMC) is an amorphous, water-soluble polymer used in both immediate-release and controlled-release applications. Although HPMC has been shown to be highly successful at inhibiting recrystallisation and increasing bioavailability when used as the polymeric stabiliser in ASDs, it has been disadvantaged in hot melt extrusion owing to a high glass transition temperature (Tg), high melt viscosity and a significant colour change at elevated temperatures, requiring unique formulation work to overcome processing difficulties.^4–6 Recently, The Dow Chemical Company introduced a new grade of HPMC, AFFINISOL HPMC HME, designed for hot melt extrusion with a notably lower Tg, reduced melt viscosity and reduced colour change at elevated temperatures.⁷

AFFINISOL HPMC HME can be successfully processed at a wide range of conditions into binary solid dispersions, with the resulting formulations providing increased solubility of the model compounds.⁸ Ritonavir (RTV) is a poorly soluble drug used in the treatment of HIV-infection (Figure 1). Previous studies have confirmed that RTV, when formulated into an ASD, can greatly improve the drug’s solubility and a commercial ASD is currently available.^6,9 However, RTV displays thermal instability above its melt temperature, making formulation by extrusion challenging. In HME formulation, it may be necessary to include additives that enable process temperature reductions to ensure the stability of each component during extrusion. However, this can create undesirable formulation complexity and such additives may not be required if the operating design space is adequately explored. Thus, it is important to understand the impact of key process variables on drug degradation and product performance to fully optimise a system and ensure robust production.

The primary variables controlled by the operator include barrel temperature, which will dominate the extent of thermal exposure the active experiences, screw speed, which changes the residence time distribution and can generate viscous/frictional heating, and feed rate, which will dictate the residence time of the material within a twin screw extruder. In the present study, solid dispersions of RTV and AFFINISOL HPMC HME 15LV (AFF) were prepared by HME. The impact of the process variables (screw speed, feed rate and temperature) on drug degradation — as well as drug release rate — were explored using a factor screening Design of Experiments (DoE).