The use of amorphous solid dispersions (ASDs), in which the active(s) is dispersed in a hydrophilic, water soluble excipient or matrix, is a widely recognised strategy for enhancing the bioavailability of poorly soluble drugs. However, the resulting materials are often associated with poor manufacturing efficiency. More specifically, flow properties and compressibility can be less than optimal for high throughput tableting. ASDs can be made by different processing routes including spray drying (SD) and hot melt extrusion (HME) to produce compositionally identical dispersions with substantially different physical characteristics. There is therefore scope to control processability, within the constraints of increasing bioavailability and ensuring adequate stability.
This note summarises work by researchers at the Bernal Institute, University of Limerick, Ireland to address the issue of characterising ASDs to rationalise and predict differences in downstream processing performance1. In a detailed study the morphology and flow properties of ASDs produced by SD and HME were measured and compared to identify differences with the potential to impact processing behaviour. The results highlight the value of dynamic, shear and bulk powder testing for comprehensive, process relevant ASD characterisation.
Experimental Method: Preparing ASD’s
Ternary ASDs of itraconazole (ITZ - Xi’an Liphar Biotech Ltd, Xi’an City, China), Soluplus® (BASF, Ludwigshafen, Germany) and HPMCP HP-55 (hypromellose phthalate - Shin Etsu, Chiyoda, Japan) were produced by SD and HME.
SD was carried out using a 30-40-30 w/w ITZ-Soluplus-HPMCP in dichloromethane-methanol solution, with a lab-scale spray dryer (Büchi B290, Essen, Germany). A 10% w/v concentration solution was used with a 0.7mm spray nozzle. All processing conditions were derived with reference to previous trials and the resulting powder was immediately transferred to a stainless-steel pan and then stored overnight in a vacuum oven to ensure the complete removal of residual solvent. Subsequent powder storage was in a sealed glass bottle, in a desiccator, over anhydrous molecular sieves.
To produce the ASD by HME, HPMCP was initially passed through a 435µm sieve to remove larger particles. A manually premixed 30-40-30 w/w ITZ-Soluplus-HPMCP blend was then fed into a twin-screw extruder (Three-Tec GmbH, Seon, Switzerland). The extruder heating zones, from feed to die, were controlled at 80, 110, 120, 140, 150 and 150°C; screw speed was 15 rpm. Again, these and all other processing conditions were set on the basis of previous trials. The resulting extrudate was milled for 1 min (Retsch Mixer Mill MM 400, Haan, Germany) and then sieved to produce a 90 – 435µm and <90µm fraction each of which was stored separately, under conditions identical to those used for the SD samples.
Samples of the as received ITZ, Soluplus, HPMCP, pre-extrusion raw material mix (physical mix), and prepared ASDs were subject to scanning electron microscopy (SEM – Jeol CarryScope JCM 5700, Tokyo, Japan) and powder testing (FT4 Powder Rheometer®, Freeman Technology, Tewksbury, UK) – dynamic, shear and bulk property measurement - using the standard test protocols for the instrument2. Compaction simulation, true density measurements, formulation/tableting and in vitro dissolution testing were also conducted. However, this note is limited to a discussion of the differences in morphology and powder properties between the samples, and their potential impact on in-process behaviour. Please see reference 1 for full details of the complete study.
The Impact of ASD Preparation Method: (1) Particle Morphology
SEM images show the very different particle morphologies of the three starting materials (Figure 1 A – D). The itraconazole has a relatively flat, wedge-like morphology, with crystal dimensions in the region of around 40 µm by 10µm. Soluplus, on the other hand, has more regularly shaped, almost spherical granules with a diameter of around 250µm. The HPMCP particles have an elongated, cocoon or pod-like structure with a smooth but broken surface; particle dimensions are in the region of 350 µm by 70µm. Images of the physical ...
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