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Two Contrasting Failure Modes of Enteric Coated Beads

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Abstract

This study aimed to elucidate the mechanisms and kinetics of coating failure for enteric coated beads exposed to high-humidity conditions at different storage temperatures. Enteric coated beads were placed on high-humidity conditions (75 to 98% relative humidity (RH)) in the temperature range of 5 to 40°C. These stability samples of beads were tested for acid dissolution and water activity and also analyzed with SEM, X-ray CT, and DMA. Exposure of enteric coated beads to high humidity led to increased gastric release of drug which eventually failed the dissolution specification. SEM showed visible cracks on the surface of beads exposed to 5°C/high humidity and fusion of enteric beads into agglomerates at 40°C/high humidity. In a non-destructive time elapse study, X-ray CT demonstrated swelling of microcrystalline cellulose cores, crack initiation, and propagation through the API layer within days under 5°C/98% RH storage conditions and ultimately fracture through the enteric coating. DMA data showed a marked reduction in Tg of the enteric coating materials after exposure to humidity. At 5°C/high humidity, the hygroscopic microcrystalline cellulose core absorbed moisture leading to core swelling and consequent fracture through the brittle API and enteric layers. At 40°C (high humidity) which is above the Tg of the enteric polymer, enteric coated beads coalesced into agglomerates due to melt flow of the enteric coating. We believe it is the first report on two distinct failure models of enteric coated dosage forms.

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Abbreviations

3D:

Three-dimensional

API:

Active pharmaceutical ingredient

CLSM:

Confocal laser scanning microscopy

CT:

Computed tomography

DMA:

Dynamic mechanical analysis

DSC:

Dynamic scanning calorimetry

HPMC:

Hydroxypropyl methylcellulose

MCC:

Microcrystalline cellulose

MRI:

Magnetic resonance imaging

NIR:

Near infrared

SEM:

Scanning electron microscopy

T g :

Glass transition temperature

TDSC:

Thin-film differential scanning calorimetry

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Acknowledgements

The authors thank Dr. Eric C. Jensen for his thorough review and Eli Lilly and Company for providing the active pharmaceutical ingredient and the financial support.

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Authors and Affiliations

  1. Delivery Device and Connected Systems, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Galen H. Shi

  2. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Xia Dong, Michelle Lytle, Craig A. J. Kemp & Jeremy Hinds

  3. Eurofins Lancaster Laboratories, 2425 New Holland Pike, Lancaster, Pennsylvania, 17605, USA

    Robert J. Behme

  4. Device Development, Sanofi, Cambridge, Massachusetts, 02139, USA

    Zhicheng Xiao

Authors
  1. Galen H. Shi
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  2. Xia Dong
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  3. Michelle Lytle
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  4. Craig A. J. Kemp
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  5. Robert J. Behme
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  6. Jeremy Hinds
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  7. Zhicheng Xiao
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Correspondence to Galen H. Shi.

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Shi, G.H., Dong, X., Lytle, M. et al. Two Contrasting Failure Modes of Enteric Coated Beads. AAPS PharmSciTech 19, 1827–1836 (2018). https://doi.org/10.1208/s12249-018-1000-9

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  • DOI: https://doi.org/10.1208/s12249-018-1000-9

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