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April 2011, Issue 1 - Publication Review

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Posted: Wed, Mar 30 2011 2:44 PM

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April 2011, Issue 01 – Publication Review

Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions

Full paper written by: Matthias Eckhard Lauer & Olaf Grassmann & Monira Siam & Joseph Tardio & Laurence Jacob & Susanne Page & Johannes Heinrich Kindt & Andreas Engel & Jochem Alsenz

Pharm Res (2011) 28:572–584
DOI 10.1007/s11095-010-0306-4

The article describes a novel assay (test) for the compatibility of active pharmaceutical ingredient (API) and excipient in an amorphous formulation. Amorphous formulations are often used to make hydrophobic APIs soluble in the body (and hence bioavailable). The biggest problem with them is that it takes a long time (weeks-months) to ensure they're stable (don't separate or crystallize over time). With atomic force microscopy (AFM), the authors identified stable formulations in hours-days rather than weeks-months.

Why is that important? Economically, there is a tremendous business driver for detecting API crystallization faster. Developing a new drug costs $1.4B, where the window to re-coup the investment is tied to patent life. One day of development has an opportunity cost of $0.5M. Scientifically, in this research the AFM is being used to detect the phase separation of the formulation at higher resolution than what can be done with conventional electron or optical microscopy or spectroscopy.

Specifically, a screening assay for the rapid determination of API/excipient co-melt miscibility and stability of amorphous formulations generated by hot melt extrusion is reported. The applied concept uses AFM supported by Raman imaging, and optical microscopy to identify and select homogenous co-melt composites and to analyze their potential to restructure on molecular scales. Samples are analyzed by AFM before and after exposed to stress conditions, such as increased humidity or temperature, and potential de-mixing is analyzed and quantified by phase separation analysis. This allows the selection of appropriate excipients and API/excipient ratios for amorphous hot melt formulations within hours to a few days.

From the paper: Phase maps recorded with tapping mode AFM on miscible NK1(1):excipient combinations (a–d), and on corresponding CETP(2) combinations (e–h) after exposure to stress conditions. (RH=75%, T=40°C) for 2 h. The scale bars: 1μm.

View full article: http://www.springerlink.com/content/x7517n27445312j3/fulltext.pdf

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April 2011, Issue 1 - Publication Review

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