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Related Experiment Videos

Excipient quantitation and drug distribution during formulation optimization.

Robert Forget1, Suzanne Spagnoli

  • 1Merck Frosst Canada & Co., Pharmaceutical R&D, P.O. Box 1005, Pte Claire-Dorval, Quebec, Canada H9R 4P8. robert_forget@merck.com

Journal of Pharmaceutical and Biomedical Analysis
|February 21, 2006
PubMed
Summary

Scale-up of oral granules caused drug variability due to mannitol loss. HPLC with refractive index (RID) or evaporative light scattering (ELSD) detectors identified mannitol losses, enabling process optimization.

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Area of Science:

  • Pharmaceutical Sciences
  • Process Chemistry
  • Analytical Chemistry

Background:

  • Oral granules formulation scale-up led to increased drug content variability.
  • Mannitol's physical properties (small particle size, low density) suggested preferential loss during top spray granulation.
  • A rapid analytical method was needed to troubleshoot and optimize the process, as conventional HPLC/UV was unsuitable due to mannitol's lack of UV absorbance.

Purpose of the Study:

  • To develop and evaluate rapid, reproducible analytical techniques for quantifying mannitol in oral granules.
  • To identify the root cause of active drug content variability during manufacturing scale-up.
  • To optimize the oral granules formulation and manufacturing process.

Main Methods:

  • Evaluation of three alternative analytical techniques: HPLC/RID, HPLC/ELSD, and LC/MS.

Related Experiment Videos

  • Assessment of techniques based on ease of use, reproducibility, linear dynamic range, and rapidity.
  • Analysis of sieve samples from granulations using the selected HPLC methods.

    • Main Results:

    • HPLC/RID and HPLC/ELSD proved to be rapid and reproducible alternatives to HPLC/UV.
    • LC/MS exhibited poor reproducibility for this application.
    • Analysis confirmed mannitol loss in filter bags and an increase in low-sized granules with low active drug content.
    • Process modification, including reduced initial airflow, minimized mannitol losses.

    Conclusions:

    • HPLC/RID and HPLC/ELSD are suitable for analyzing mannitol in oral granules, facilitating process troubleshooting.
    • Mannitol losses during granulation were identified as the cause of drug content variability.
    • Optimized granulation process parameters successfully reduced material loss and improved content uniformity.