Abstract
This work reports the use of X-ray microscopy (XRM) imaging to characterize the microstructure of semisolid formulations containing multiple immiscible phases. For emulsion-based semisolid formulations, the disperse phase globule size and its distribution can be critical quality attributes of the product. Optical microscopy and light diffraction techniques are traditionally used to characterize globule size distribution. These techniques are subjected to sample preparation bias and present challenges from matrix interference and data processing. XRM imaging is an emergent technique that when combined with intelligent data processing has been used to characterize microstructures of pharmaceutical dosage forms including oral solid formulations, controlled release microspheres, and lyophilized products. This work described our first attempt to use XRM imaging to characterize two complex emulsion-based semisolid formulations, a petrolatum-based ointment with a dispersed phase comprising a hydrophilic liquid, and an oil-in-water cream. This initial assessment of technology showed that microstructure details such as globule size distribution, volume fraction, spatial distribution uniformity, inter-globule spacing, and globule sphericity could be obtained and parameterized. It was concluded that XRM imaging, combined with artificial intelligence–based image processing is feasible to generate advanced characterization of semisolid formulation microstructure through 3D visualization and parameterization of globule attributes. This technique holds promise to provide significantly richer microstructure details of semisolid formulations. When fully developed and validated, it is potentially useful for quantitative comparison of microstructure equivalence of semisolid formulations.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Langley N, Michniak-Kohn B, Osborne D. AAPS advances in the pharmaceutical sciences series volume 36: the role of microstructure in topical drug product development: Springer International Publishing; 2019.
Fatima M, Sheraz MA, Ahmed S, Kazi SH, Ahmad I. Emulsion separation, classification and stability assessment. J Pharm Pharm Sci. 2014;2:56–62.
Wu K, Yeoh T, Hsieh YL, Osborne D. Quality assessment of API in semisolid topical drug products. In: Langley N, Michniak-Kohn B, Osborne D, editors. AAPS advances in the pharmaceutical sciences series volume 36: the role of microstructure in topical drug product Development. Springer International Publishing; 2019. p. 89-106
Chang RK, Raw A, Lionberger R, Yu L. Erratum to: Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products. AAPS J. 2015;17:1522. https://doi.org/10.1208/s12248-015-9823-8.
Draft guidance on acyclovir. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Acyclovir_topical%20cream_RLD%2021478_RV12-16.pdf
Fujii MY, Yamamoto Y, Koide T, Hamaguchi M, Onuki Y, Suzuki N, Suzuki T, Fukami T. Imaging analysis enables differentiation of the distribution of pharmaceutical ingredients in Tacrolimus ointments. Appl Spectrosc. 2019;73:1183–92. https://doi.org/10.1177/0003702819863441.
Fahier J, Muschert S, Fayard B, Velghe C, Byrne G, Doucet J, Siepmann F, Siepmann J. Importance of air bubbles in the core of coated pellets: synchrotron X-ray microtomography allows for new insights. J Control Release. 2016;237:125–37. https://doi.org/10.1016/j.jconrel.2016.06.041.
Zhang S, Stroud PA, Zhu A, Johnson MJ, Lomeo J, Burcham CL, Hinds J, Allen-Francis Blakely K, Walworth MJ. Characterizing the impact of spray dried particle morphology on tablet dissolution using quantitative X-Ray microscopy. Eur J Pharm Sci. 2021;165:105921. https://doi.org/10.1016/j.ejps.2021.105921.
Zhang S, Byrne G. Characterization of transport mechanisms for controlled release polymer membranes using focused ion beam scanning electron microscopy image-based modelling. J Drug Deliv Sci Technol. 2021;61:102136. https://doi.org/10.1016/j.jddst.2020.102136.
Zhang S, Goldman J, Chen X, Rowe J, Lin S, Zhou L. Non-Invasive, quantitative characterization of lyophilized drug product using three-dimensional X-Ray microscopy analytics. Drug Dev Deliv. 2020;20:32–40.
Nagapudi K, Zhu A, Chang D, Lomeo J, Rajagopal K, Hannoush R, Zhang S. Microstructure, quality, and release performance characterization of long-acting polymer implant formulations with X-ray microscopy and quantitative AI analytics. J Pharm Sci. 2021;110:3418–30. https://doi.org/10.1016/j.xphs.2021.05.016.
Riddick J, Bunger W, Sakano T. Techniques of chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons.; 1985. p. 275.
Spectrum. Safety Data Sheet: White Petrolatum, White, USP. Accessed 4 February 2022.
Speight JG. Chapter 7 - Wax deposition and fouling. In: Fouling in refineries, Gulf Professional Publishing 2015. p155-173.
Specific gravity of solid form, communication from the manufacturer, Gettefosse.
Chemical Book. https://www.chemicalbook.com/ProductChemicalPropertiesCB4111739_EN.htm. Accessed 30 September 2021.
National Institute of Health National Library of Medicine, PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/Oleyl-alcohol. Accessed 30 September 2021.
National Institute of Health National Library of Medicine, PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/8146#section=Density. Accessed 30 September 2021.
National Institute of Health National Library of Medicine, PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/174#section=Density. Accessed 30 September 2021.
National Institute of Health National Library of Medicine, PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/31236#section=Density. Accessed 30 September 2021.
Zhang S, Byrnes AP, Jankovic J, Neilly J. Management, analysis, and simulation of micrographs with cloud computing. Microscopy Today. 2019;27:26–33.
Taylor D. Time-series analysis: use of autocorrelation as an analytic strategy for describing pattern and change. West J Nurs Res. 1990;12:254–61. https://doi.org/10.1177/019394599001200210.
Funding
This work was funded by Pfizer Inc.
Author information
Authors and Affiliations
Contributions
Thean Yeoh, Abu Zayed Badruddoza, Jaymin Shah, and Shawn Zhang contributed to the conception and design of the work. Lisa Ma, Abu Zayed Badruddoza, and Shawn Zhang contributed to the acquisition and analysis of the work. All authors contributed to the data interpretation, drafting, and critical review of the manuscript for intellectual content; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Corresponding authors
Ethics declarations
Conflict of Interest
Thean Yeoh, Abu Zayed Badruddoza, and Jaymin Shah are employees and shareholders of Pfizer Inc. Shawn Zhang and Lisa Ma are employees of DigiM Solution.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yeoh, T., Ma, L., Badruddoza, A.Z. et al. Semisolid Pharmaceutical Product Characterization Using Non-invasive X-ray Microscopy and AI-Based Image Analytics. AAPS J 24, 46 (2022). https://doi.org/10.1208/s12248-022-00696-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12248-022-00696-z