Effect of Overencapsulation on the Disintegration and Dissolution of Licensed Formulations for Blinding in Randomized Controlled Trials

Overencapsulation is a technique used to conceal tablet products for blinding in randomized controlled trials. A tablet is inserted in an opaque capsule shell with backfill excipient to prevent rattling. Regulatory authorities require evidence that such modification does not materially alter drug release to approve their use in trials. The objective of this study was to assess impact of overencapsulation on disintegration and dissolution of 4 immediate-release drug products (penicillin V, gemfibrozil, ciprofloxacin, and furosemide). Each unmodified tablet was compared to 3 overencapsulated tablets with differing backfill excipient (colloidal silica, lactose monohydrate, or microcrystalline cellulose). All 12 overencapsulated tablets met disintegration and dissolution acceptance criteria. Dissolution acceptance was dependent on apparatus as only 4/12 formulations met specifications using the rotating basket compared to 12/12 using the rotating paddle. Significant differences in release were observed at early time points (T₅-T₁₅). No correlation was observed between aqueous solubility and release, although dissolution of the lipophilic drug gemfibrozil was least impacted by overencapsulation. There was evidence that type/quantity of backfill delays release at early time points. These findings indicate that under the specified conditions, overencapsulated formulations of 4 drugs, 1 from each class of the Biopharmaceutics Classification System, met compendial requirements for release testing.