Even during over-encapsulation – a process some in the pharmaceutical industry would consider relatively trivial – smart formulation is critical to drug efficacy.
So demonstrated Dr. Brad Gold, director of pharmaceutical development and new technology at Metrics Inc., during his poster presentation Oct. 26 at the American Association of Pharmaceutical Scientists annual conference.
In his presentation, Gold described how a client’s promising prodrug tablet – over-encapsulated in gelatin and being used in clinical trials – failed to dissolve properly after stressed stability storage. The client approached Metrics, seeking understanding of the problem as well as solutions.
Gold supervises a team of scientists at Metrics responsible for pre-formulation, formulation development, process development and scale-up/transfer of solid dose products.
Over-encapsulation is a key component in double blind clinical trials where a new drug is examined for effectiveness in humans. Because it’s important to prevent trial participants from knowing which drug a patient receives, pharmaceutical companies place active and placebo tablets inside inert shells. “Hiding” the tablets through over-encapsulation ensures that every tablet looks exactly alike.
In over-encapsulation, however, pharmaceutical companies create an entirely new dosage form. And often the compatibility of ingredients in test tablets and their cloaking shells isn’t established. For this reason, companies store tablets under stable conditions for the duration of the study.
It’s well known that storing gelatin capsules in hot and humid conditions may impair dissolution performance of the capsules, and there also are known incompatibilities between gelatin shells and/or active ingredients and excipients, Gold said. In this case, the over-encapsulated prodrug liberated free formaldehyde as a degradant, slowing dissolution performance. A sharp-eyed chemist at the pharmaceutical company spotted the dissolution failures and contacted Metrics for help.
After identifying the problem, Metrics proposed two alternative capsule shells as solutions.
“What our thoughtful science demonstrates is that even with something as trivial as over-encapsulation, you really have to pay close attention to the fundamentals of good formulation,” Gold said. “Once Metrics properly formulated the over-encapsulated tablets, we were able to produce all the clinical batches the client needed to serve as reference for their comparative studies. We didn’t just identify the problem – we delivered a solution.”
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.
Headquartered in Greenville, N.C., Metrics has particular expertise in FTIM and Phase I, II, and III CTM manufacturing. The company has 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.