Roller compaction, granulation and capsule product dissolution of drug formulations containing a lactose or mannitol filler, starch, and talc

Abstract

This study investigated the influence of excipient composition to the roller compaction and granulation characteristics of pharmaceutical formulations that were comprised of a spray-dried filler (lactose monohydrate or mannitol), pregelatinized starch, talc, magnesium stearate (1% w/w) and a ductile active pharmaceutical ingredient (25% w/w) using a mixed-level factorial design. The main and interaction effects of formulation variables (i.e., filler type, starch content, and talc content) to the response factors (i.e., solid fraction and tensile strength of ribbons, particle size, compressibility and flow of granules) were analyzed using multi-linear stepwise regression analysis. Experimental results indicated that roller compacted ribbons of both lactose and mannitol formulations had similar tensile strength. However, resulting lactose-based granules were finer than the mannitol-based granules because of the brittleness of lactose compared to mannitol. Due to the poor compressiblility of starch, increasing starch content in the formulation from 0% to 20% w/w led to reduction in ribbon solid fraction by 10%, ribbon tensile strength by 60%, and granule size by 30%. Granules containing lactose or more starch showed less cohesive flow than granules containing mannitol and less starch. Increasing talc content from 0% to 5% w/w had little effect to most physical properties of ribbons and granules while the flow of mannitol-based granules was found improved. Finally, it was observed that stored at 40 degrees C/75% RH over 12 weeks, gelatin capsules containing lactose-based granules had reduced dissolution rates due to pellicle formation inside capsule shells, while capsules containing mannitol-based granules remained immediate dissolution without noticeable pellicle formation.

Fig. 1

Ribbon solid fraction with respect to the starch content

Fig. 2

Ribbon tensile strength with respect to the starch content

Fig. 3

Ribbon tensile strength with respect to solid fraction

Fig. 4

Particle size distribution of API and excipients

Fig. 5

Particle size distribution of selected dry granulation samples and a dry blend (as reference)

Fig. 6

Volume averaged mean diameter of dry granules with respect to the starch content

Fig. 7

Mean value (MTA) and coefficient of variation (COV) of avalanche time of dry granules with respect to the starch content

Fig. 8

Percent dissolved (arithmetic averages, n = 6) for the tested formulations at 12 weeks 40 °C/75% (upper plot) and 24 weeks refrigerated (lower plot)