An In Vitro Model for Release of Acetaminophen When an Overdose is Ingested Orally

Acetaminophen (paracetamol) is an analgesic and antipyretic drug that is widely used across the globe due to its efficacy and safety within the therapeutic dose range. When acetaminophen is ingested in amounts higher than the recommended dosage over several days, severe hepatotoxic effects can result. Next to the opioid drugs, acetaminophen is often deliberately ingested as an overdose, in which case multiple dosage units may be ingested. In this study, a novel in vitro model aiming to understand the dissolution of acetaminophen in overdose situations is described and implemented to compare four commercially available formulations of acetaminophen. Increasing quantities of immediate-release and extended-release tablets as well as hard and soft capsule formulations were tested in the in vitro model using United States Pharmacopeia apparatus 3 (reciprocating cylinder). When a single dose was tested, acetaminophen dissolved rapidly from the immediate-release formulation and from the immediate release part of the extended-release formulation. At higher doses, acetaminophen was released more slowly and less extensively as the dose was increased. The results obtained with the in vitro model are in line with the literature data obtained in acetaminophen clinical trials. Additionally, the in vitro model was able to reproduce pharmacobezoar formation at very high doses, which has been observed in cases of deliberate overdose.