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Isothermal Microcalorimetry of Pressurized Systems II: Effect of Excipient and Water Ingress on Formulation Stability of Amorphous Glycopyrrolate

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ABSTRACT

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.

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Abbreviations

(CaCl2):

Calcium chloride

(COPD):

Chronic obstructive pulmonary disease

(DSPC):

Distearoyl-sn-glycero-3-phosphatidylcholine

(FTIR):

Fourier transform infrared

(GP):

Glycopyrrolate

(pMDIs):

Pressurized metered dose inhalers

(TAM III):

Thermal activity monitor III

(Tg):

Glass transition temperature

(βCD):

β-Cyclodextrin

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ACKNOWLEDGEMENTS AND DISCLOSURES

The authors gratefully acknowledge [1] the financial support of the Australian Research Council (DP120102778) and [2] the facilities, and the scientific and technical assistance of the Australian Centre for Microscopy and Microanalysis at the University of Sydney. D. D’Sa is a recipient of the Australian IPRS and APA scholarships.

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Authors and Affiliations

  1. Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Camperdown, NSW, 2006, Australia

    Dexter J. D’Sa & Hak-Kim Chan

  2. Pearl Therapeutics, Redwood City, California, USA

    David Lechuga-Ballesteros

  3. Faculty of Pharmacy, Pharmacy and Bank Building A15, The University of Sydney, Science Road, Camperdown, NSW, 2006, Australia

    Hak-Kim Chan

Authors
  1. Dexter J. D’Sa
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  2. David Lechuga-Ballesteros
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  3. Hak-Kim Chan
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Correspondence to Hak-Kim Chan.

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D’Sa, D.J., Lechuga-Ballesteros, D. & Chan, HK. Isothermal Microcalorimetry of Pressurized Systems II: Effect of Excipient and Water Ingress on Formulation Stability of Amorphous Glycopyrrolate. Pharm Res 32, 714–722 (2015). https://doi.org/10.1007/s11095-014-1499-8

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  • DOI: https://doi.org/10.1007/s11095-014-1499-8

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