Possible Applications of the Polli Dissolution Mechanism: A Case Study Using Molecular Dynamics Simulation of Bupivacaine

The recently proposed Polli equation [Polli JE. A simple one-parameter percent dissolved versus time dissolution equation that accommodates sink and non-sink conditions via drug solubility and dissolution volume. AAPS J 2023;25:1] has been discussed in the context of its ability to fit experimental dissolution transients obtained under either sink or non-sink conditions. In this work, we reveal that the Polli equation describes a complex dissolution mechanism that combines classical first-order (Noyes-Whitney) kinetics with a second-order mechanism. Possible origins of the second-order process are discussed within the framework of small-molecule drug dissolution, after first probing the general utility of the higher-order rate term in more precisely fitting typical dissolution transients (for ibuprofen and ketoconazole) taken from the referenced work. Lastly, molecular dynamics (MD) simulations are performed using the prototypical drug, bupivacaine, that is shown to dimerize in aqueous solution under acidic conditions. Our findings point us to conclude that the Polli mechanism best describes cases where the drug forms dimers in solution at a rate comparable to that with which it dissolves (per the N-W mechanism), given non-sink conditions. Under sink conditions, the Polli mechanism is second-order in drug concentration.