Feasibility of Focused Beam Reflectance Measurement (FBRM) for Analysis of Pharmaceutical Suspensions in Preclinical Development
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This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60 h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions.
KEY WORDSparticle size suspension homogeneity and uniformity process analytical technology sedimentation and redispersion preclinical dose formulation
The authors thank Kevin Shepard of Boehringer Ingelheim for collaboration on the design of the FBRM probe. Also, the authors thank BASF Chemicals for providing the ibuprofen. The authors thank Boehringer Ingelheim Pharmaceuticals, Inc., for supporting this work as a part of Kaushalkumar Dave’s summer internship. The authors thank Anjan Pandey of Mettler Toledo for helpful suggestions for this manuscript.
Compliance with Ethical Standards
Dr. Kaushalkumar Dave is currently employed at the United States Food and Drug Administration (FDA). This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
- 2.United States Code of Federal Regulations, Title 21, § 58.113. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=58.113. Accessed 24 Nov. 2016.
- 3.Smith A, Whitsel M. How to assess preclinical dose formulation homogeneity. Pharm Technol. 2012;36(7):90–1.Google Scholar
- 6.Schöll J, Kempkes M, Mazzotti M. Focused beam reflectance measurement. In: Chianese A, Kramer HJM, editors. Industrial crystallization process monitoring and control. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2012. doi: 10.1002/9783527645206.ch3
- 9.Heinrich J, Ulrich J. Application of laser-backscattering instruments for in situ monitoring of crystallization processes—a review. Chem Eng Technol. 2012;35(6):967–79.Google Scholar
- 17.Oldshue JY. Fluid mixing technology and practice. Chem Eng. 1983;90(12):82–108.Google Scholar
- 18.Sanchez AWM, Smith A. Determining potency of preclinical dose formulations. Pharm Technol. 2012;36(10):132–4.Google Scholar
- 19.Constantin P, Foias C. Navier-Stokes equations. Chicago: University of Chicago Press; 1988.Google Scholar