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Quantification of Crystallinity in Substantially Amorphous Materials by Synchrotron X-ray Powder Diffractometry

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Purpose

The aim of this study was to develop a highly sensitive powder X-ray diffraction (XRD) technique for quantification of crystallinity in substantially amorphous pharmaceuticals, utilizing synchrotron radiation and a 2-D area detector.

Methods

Diffraction data were acquired at the European Synchrotron Radiation Facility (France) using a 2-D charge-coupled device detector. The crystallization of amorphous sucrose was monitored in situ, isothermally at several temperatures in the range of 90 to 160°C. An algorithm was developed for separation of the crystalline and amorphous intensities from the total diffraction pattern.

Results

The synchrotron XRD technique allowed powder diffraction patterns to be recorded with a time resolution of 40 ms. The gradual crystallization of sucrose is analogous to a series of physical mixtures with increasing content of the crystalline component. The in situ crystallization approach circumvented the problem of inhomogeneity in mixing—a potentially serious issue at extreme mixture compositions. The estimated limit of detection of crystalline sucrose in an amorphous matrix was 0.2% w/w, a considerable improvement over the reported value of ∼1% w/w with a conventional XRD.

Conclusion

High-intensity XRD can discern subtle changes in the lattice order of materials. The first evidence of crystallization can serve as an indicator of the potential physical instability of the product.

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Acknowledgments

This work was made possible by the allocation of beam time at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. We thank Dr. Theyencheri Narayanan, Scientist in Charge, ID2 High Brilliance Beamline, ESRF for his assistance and support. The scientific and technical support provided by Dr. Ramprakash Govindarajan is gratefully acknowledged.

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Author notes

  1. Cletus Nunes

    Present address: Mylan Pharmaceuticals, Morgantown, West Virginia, 26505, USA

Authors and Affiliations

  1. Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, 55455, USA

    Cletus Nunes & Raj Suryanarayanan

  2. Department of Physics, Keele University, Staffordshire, ST5 5BG, UK

    Arumugam Mahendrasingam

  3. 308 Harvard Street SE, 9-125 WDH, Minneapolis, Minnesota, 55455, USA

    Raj Suryanarayanan

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  1. Cletus Nunes
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  2. Arumugam Mahendrasingam
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  3. Raj Suryanarayanan
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Correspondence to Raj Suryanarayanan.

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Nunes, C., Mahendrasingam, A. & Suryanarayanan, R. Quantification of Crystallinity in Substantially Amorphous Materials by Synchrotron X-ray Powder Diffractometry. Pharm Res 22, 1942–1953 (2005). https://doi.org/10.1007/s11095-005-7626-9

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