Roller Compaction, Granulation and Capsule Product Dissolution of Drug Formulations Containing a Lactose or Mannitol Filler, Starch, and Talc

Abstract

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°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.

Dissolution of Gelatin Capsules: Evidence and Confirmation of Cross-Linking

“…The time and cost of previously required bioequivalence studies have been saved. However, various studies continue in this field, including studies to prevent capsule crosslinking by incorporating glycine and citric acid into the capsule formulation (6), studies to establish a correlation between the concentration of formaldehyde and the reduction in dissolution of gelatin capsules (30), studies to investigate the influence of excipient composition on granulation characteristics and pellicle formation inside gelatin capsules (31), studies to explore the challenges in liquid and semisolid filled gelatin capsules (32), and studies to determine the disintegration and changes in in vitro drug release from cross-linked HGCs containing water-insoluble drugs (33,34).…”

“…The most frequent observation is a significant increase in disintegration time (8,11,38,40,41). The other observations are the formation of a gellike film (11,14,31,40), swollen, rubbery elastic matrix (8,14,22), or gelling with embedded drug blend (41). The differences in the reported descriptions might be due to the different experiences of the analysts who performed the dissolution testing.…”

“…The differences in observation may be related to the different levels of cross-linking from different stressed conditions and due to the variability and inhomogeneity of cross-linking. Although the pellicle itself may be difficult to observe (46), noticeable pellicle formation has been reported in more than one study (30,31). Keeping a written record of visual observations has been a typical practice.…”

Use of Enzymes in the Dissolution Testing of Gelatin Capsules and Gelatin-Coated Tablets-Revisions to Dissolution <711> and Disintegration and Dissolution of Dietary Supplements <2040>

“…The degree of cross-linking is not usually uniform within one capsule or among different capsules. As consequence, dissolution results will have higher variability when gelatin capsules are cross-linked (5,6,8,9,11).…”

Enzymes in the Dissolution Testing of Gelatin Capsules

“…In the presence of certain compounds such as aldehydes or when exposed to high humidity and temperature, gelatin can cross-link rendering it insoluble in aqueous solvents. The presence of cross-linking will alter the in vitro dissolution behavior of the gelatin capsules; the capsule will not open and release its contents into the dissolution medium (1)(2)(3)(4)(5)(6)(7). This failure may not reflect a possible failure to dissolve in the body.…”