Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations.
OBJECTIVE
The techniques available to study formulation stability in pressurized metered dose inhalers (pMDIs) are limited, due to the challenging conditions of working with high pressure propellants. Isothermal microcalorimetry is a valuable tool used to screen and aid in formulation development of solid and solution drug formulations; however there are currently no available methods to evaluate pMDIs. In this paper, we have developed a method that allows measurement of such pressurized systems.


METHODS
Samples were prepared by cold filling ampoules with propellant (HFA 134a) and drugs of interest. Ampoule caps were fitted with a specific O-ring, coated with paraffin and pre-conditioned prior to measurement. Samples were equilibrated at 25°C, placed in a Thermal Activity Monitor III (TAM III) system and measured isothermally at 25°C for a period of at least 24 h.


RESULTS
Using well-defined procedures and ampoule preparation techniques we were able to safely contain the volatile propellant and acquire a stable measurement baseline. We were able to rapidly determine, within 6 h, the physical stability of amorphous and crystalline drug forms of beclomethasone dipropionate and formoterol fumarate dihydrate when formulated with HFA 134a.


CONCLUSIONS
Isothermal microcalorimetry in pressurized HFA propellant systems was shown to be a rapid screening tool to evaluate pMDI formulation physical stability. This method can potentially be applied to study pMDI formulation factors to expedite product development.
Faculty of Pharmacy, The University of Sydney, Pharmacy and Bank Building A15, Science Road, Sydney, NSW, 2006, Australia, dexter.dsa@sydney.edu.au.
Dexter J
DJ
D'Sa
David
D
Lechuga-Ballesteros
Hak-Kim
HK
Chan
D000335:Aerosol Propellants / Q000737:chemistry*; D001507:Beclomethasone / Q000008:administration & dosage / Q000737:chemistry*; D002151:Calorimetry / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D004867:Equipment Design; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry*; D000068759:Formoterol Fumarate; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D036501:Metered Dose Inhalers / Q000592:standards*; D008855:Microscopy, Electron, Scanning; D013499:Surface Properties; D005466:Fluorocarbons
D000335:Aerosol Propellants; D001507:Beclomethasone; D004983:Ethanolamines; D000068759:Formoterol Fumarate; D006845:Hydrocarbons, Fluorinated; C094049:apaflurane; D005466:Fluorocarbons