Isothermal microcalorimetry of pressurized systems II: effect of excipient and water ingress on formulation stability of amorphous glycopyrrolate.

PURPOSE: Use isothermal microcalorimetry to directly evaluate the effects of excipients and water content to produce a stable amorphous glycopyrrolate pressurized metered dose inhaler (pMDI) formulation.
METHODS: Amorphous glycopyrrolate particles with and without excipients (Distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) or β-cyclodextrin (βCD)) were spray dried and cold filled along with HFA 134a into customized thermal activity monitor (TAM) measurement ampoules. When applicable, a known amount of water was also pipetted into the ampoule. Sample ampoules were hermetically sealed, equilibrated to 25°C and measured isothermally for at least 24 h using the TAM III (TA Instruments, Sollentuna, Sweden).
RESULTS: Amorphous glycopyrrolate particles were highly unstable and crystallized rapidly when suspended in HFA 134a. Co-spray drying the glycopyrrolate with DSPC failed to mitigate this instability, but co-spray drying with βCD protected the amorphous glycopyrrolate from crystallization, resulting in a stable formulation at low water contents (≤ 100 ppm).
CONCLUSIONS: This study shows that isothermal microcalorimetry can easily differentiate between physically stable and unstable pMDI formulations of glycopyrrolate within a few hours. Furthermore, it allows rapid screening of various formulation factors (drug form, excipients, water ingress), which can greatly reduce the time required to develop marketable products with acceptable shelf life.