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AAPS PharmSciTech

, Volume 19, Issue 4, pp 1647–1651 | Cite as

Application of Ultra-Centrifugation and Bench-Top 19F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products

  • Xinyi Wang
  • Sharadrao M. Patil
  • David A. Keire
  • Xiaoming Xu
  • Kang ChenEmail author
Brief/Technical Note

Abstract

Generic drug products are expected to have the same active pharmaceutical ingredient (API) (Q1) with the same content (Q2) and microstructure arrangement (Q3) as the innovator product. In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field 19F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation. The average water phase content of different Durezol® lots was 32 ± 3% with 1% variation from method reproducibility test. The partition results were 52 ± 2% for the in-house control products prepared in Q1/Q2 equivalence to Durezol® but by a different process. The significant difference in DFPN-phase partition between Durezol® and the in-house formulation demonstrated manufacture difference readily changed the API partition. The newly developed ultra-centrifugation and 19F NMR by benchtop instrument is a simple, robust, and sensitive analytical method for ophthalmic emulsion drug product development and control.

KEY WORDS

durezol API distribution phase NMR 

Notes

Acknowledgements

We thank Haiou Qu from CDER/OPQ/OTR for providing the in-house formulations. We thank CDER colleagues Bing Cai, Vincent Li, Jin Xu from OPQ/OLDP, Darby Kozak from OGD/ORS and Jiangnan Peng from OPQ/OTR for the helpful discussions.

Compliance with Ethical Standards

Disclaimer

This article reflects the views of the author and should not be construed to represent U.S. FDA’s views or policies.

Supplementary material

12249_2018_973_MOESM1_ESM.docx (413 kb)
ESM 1 (DOCX 412 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Xinyi Wang
    • 1
    • 2
  • Sharadrao M. Patil
    • 1
  • David A. Keire
    • 3
  • Xiaoming Xu
    • 4
  • Kang Chen
    • 1
    Email author
  1. 1.Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  2. 2.Center for Intelligent Chemical Instrumentation, Clippinger Laboratories, Department of Chemistry and BiochemistryOhio UniversityAthensUSA
  3. 3.Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSt. LouisUSA
  4. 4.Division of Product Quality and Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA

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