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Molecular Basis of Crystal Morphology-Dependent Adhesion Behavior of Mefenamic Acid During Tableting

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ABSTRACT

Purpose

The molecular basis of crystal surface adhesion leading to sticking was investigated by exploring the correlation of crystal adhesion to oxidized iron coated atomic force microscope (AFM) tips and bulk powder sticking behavior during tableting of two morphologically different crystals of a model drug, mefenamic acid (MA), to differences in their surface functional group orientation and energy.

Methods

MA was recrystallized into two morphologies (plates and needles) of the same crystalline form. Crystal adhesion to oxidized iron coated AFM tips and bulk powder sticking to tablet punches was assessed using a direct compression formulation. Surface functional group orientation and energies on crystal faces were modeled using Accelrys Material Studio software.

Results

Needle-shaped morphology showed higher sticking tendency than plates despite similar particle size. This correlated with higher crystal surface adhesion of needle-shaped morphology to oxidized iron coated AFM probe tips, and greater surface energy and exposure of polar functional groups.

Conclusions

Higher surface exposure of polar functional groups correlates with higher tendency to stick to metal surfaces and AFM tips, indicating involvement of specific polar interactions in the adhesion behavior. In addition, an AFM method is identified to prospectively assess the risk of sticking during the early stages of drug development.

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Abbreviations

AFM:

Atomic force microscopy

API:

Active pharmaceutical ingredient

EtOH:

Ethanol

MA:

Mefenamic acid

PoF:

Pull-off-force

PSD:

Particle size distribution

PXRD:

Powder X-ray diffraction

SEM:

Scanning electron microscopy

THF:

Tetrahydrofuran

XRD:

X-ray diffraction

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors thank David Wantuch and Anisha Patel for their help with PXRD; Michael Galella for single crystal X-ray diffraction analysis; Eric Chan for surface energy calculations; Nigora Issamidinova and Mario Hubert for PSD and SEM analyses; and Lynn DiMemmo and Sarah DeLeon for SEM.

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Authors and Affiliations

  1. Bristol-Myers Squibb, Co., One Squibb Dr., New Brunswick, New Jersey, 08901, USA

    Vrushali Waknis, Roxana Schlam, Sherif Badawy, Shawn Yin & Ajit S. Narang

  2. Department of Chemistry and Biochemistry, University of the Sciences, Philadelphia, Pennsylvania, 19104, USA

    Elza Chu & Alexander Sidorenko

Authors
  1. Vrushali Waknis
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  2. Elza Chu
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  3. Roxana Schlam
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  4. Alexander Sidorenko
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  5. Sherif Badawy
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  6. Shawn Yin
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  7. Ajit S. Narang
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Correspondence to Ajit S. Narang.

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Waknis, V., Chu, E., Schlam, R. et al. Molecular Basis of Crystal Morphology-Dependent Adhesion Behavior of Mefenamic Acid During Tableting. Pharm Res 31, 160–172 (2014). https://doi.org/10.1007/s11095-013-1149-6

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  • DOI: https://doi.org/10.1007/s11095-013-1149-6

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