While the client’s request of Metrics Inc. seemed simple enough – let’s double the potency of a particular capsule – fulfilling the request proved somewhat more complicated.
The successful meeting of the client’s need not only demonstrated Metrics Inc.’s expertise in pharmaceutical formulation, it also provided case study material for Joe Cobb Jr., CPIP, to present in a poster session Nov. 17 at the American Association of Pharmaceutical Scientists annual conference.
Cobb, senior formulations scientist at Metrics, discussed how his team increased the drug load and potency of a capsule formulation by converting it from a simple powder blend to roller compaction.
The case study began when a Metrics client requested that the active ingredient in its 60-milligram capsule be increased to 120-milligram strength.
The original powder blend formulation for the 60-milligram capsule contained 25 percent by weight of the active pharmaceutical ingredient (API) that had been micronized to d90<10 micron with inactive ingredients including pre-gelatinized starch, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate.
Together, the ingredients were hand-sifted and blended in a low-shear tumble blender before being encapsulated into standard size 2 hard gelatin capsules using an H&K 400 encapsulator and weight-sorted with a Sade P2/P4 automated sorter. Because of the final blend’s density, the original formulation was limited to doses of up to 60 milligrams API.
In order to achieve 120-milligram potency in a size 1 capsule, the Metrics team increased the drug load of the 60-milligram formulation from 25 percent to 38.7 percent by weight, and adjusted excipient levels and the blend’s density using roller compaction and milling. Extragranular blending and lubrication was performed in a low-shear tumble blender. Capsules were filled on an H&K 400 encapsulator and weight-sorted with a Sade P2/P4 automated sorter.
Metrics scientists conducted blend testing comparisons of the two formulations, including flowability through minimum orifice and bulk density. Their drug product comparisons included potency determination, dissolution, uniformity of dosage units (USP <905>) by weight variation and yield following weight sorting.
What they found was that flowability was identical for both blends. The bulk density of the roller compacted material was nearly 50 percent higher than for the original blend. Capsule assays and dissolution for both manufacturing methods conformed to specifications, while uniformity of dosage units acceptance value improved from 9.3 percent to 6.7 percent after roller compacting. The product yield after weight sorting increased from 65 percent to 84 percent after converting the powder blend formulation to roller compaction.
Metrics concluded that they could successfully increase the potency formulation of a capsule using roller compaction.
“These are common technologies within our industry, so the information presented at AAPS in this case study is not completely novel,” Cobb said. “But our case study does demonstrate the formulation development experience and capabilities that Metrics offers clients, and confirms with actual data some theories that are general to our industry. It also highlights Metrics’ culture of positively collaborating with our clients for the successful completion of their project.”
Metrics, Inc. (metricsinc.com) is one of the most respected contract pharmaceutical development and manufacturing companies in the United States today. Started as an analytical laboratory in 1994, Metrics has evolved into a full-service provider of quality pharmaceutical formulation development; first-time-in-man (FTIM) formulations; clinical material manufacturing (CTM) for Phase I, II and III trials; commercial manufacturing; and analytical method development and validation services.
Metrics has particular expertise in FTIM and Phase I, II, and III CTM manufacturing, having conducted more than 120 FTIM projects for different chemical entities in the last five years alone – while developing more than 700 batches of CTM in the same period.