Use of Drug Release Testing to Evaluate the Retention of Abuse-Deterrent Properties of Polyethylene Oxide Matrix Tablets.

Abuse-deterrent formulations (ADFs) using physical/chemical barrier approaches limit abuse by providing resistance to dosage form manipulation to limit drug extraction or altered release. Standardizing in vitro testing methods to assess the resistance to manipulation presents a number of challenges, including the variation in particle sizes resulting from the use of various tools to alter the tablet matrix (e.g., grinding, chipping, crushing). A prototype, direct-compression ADF using a sintered polyethylene oxide (PEO) matrix containing dextromethorphan, an enantiomeric form of the opioid, levorphanol, was developed to evaluate testing methodologies for retention of abuse-deterrent properties following dosage form tampering. Sintered PEO tablets were manipulated by grinding, and drug content and release were evaluated for the recovered granules. Drug content analysis revealed that higher amounts of drug were contained in the smaller size granules (  250 μm, 55–75% of theoretical amount). Release testing was performed on various size granule fractions (> 850 μm, 500–850 μm, 250–500 μm, and  500 μm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500 μm) provided rapid drug release that was unhindered by the hydrated granule matrix. Since < 500-μm size particles are preferred for nasal abuse, improved direct-compression ADF formulations should minimize the formation of these smaller-sized particles following tampering to maintain the product’s abuse-deterrent features.