Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs

Abstract

Melting points for new drugs are reported in regulatory documents, e.g. investigational brochures, and frequently in published research; however, the authors do not typically consider that heat-induced degradation can affect the melting point measurement. Applying a single heating rate is not adequate, and thus many melting points in the literature and regulatory documentation are not valid. Our aim was to validate a five-stage approach for the melting point measurement of heat-sensitive drugs. These stages are; (1) observe melting; (2) record mass loss; (3) measure melting points at different heating rates; (4) characterise degradation and (5) test for potential isomerisation. Applying this approach to pilocarpine HCl illustrated the sensitivity of a melting point to thermal degradation. Due to salt disproportionation & loss of HCl gas, pilocarpine's melting point decreased by 14 °C when the heating rate was lowered from 20 to 1 °C/min. Epimerization occurred before melting was reached. Increasing the heating rate diminished disproportionation; however, this did not remove epimerization. Thus, the melting point of pilocarpine HCl of 205.5 ± 0.4 °C measured at 20 °C/min represents the melt of a racemic mixture containing inactive isopilocarpine. Heating above the melting point accelerated degradation, a rate of 5 °C/min recovered just 38 ± 1% of pilocarpine. Such data predicted a shelf-life of 6.6 years. Pilocarpine successfully validated the multistage approach by providing new knowledge concerning its thermal stability. Our 5-stage approach must be applied to all new drugs especially if their formulation requires heat. For example, thermal stability is an infrequently considered pre-requisite in the emerging field of 3D printing.