Investigation into the internal structure of coated microparticles to support formulation and coating process development

Valentyn Mohylyuk, Kavil Patel, Darragh Murnane, Craig Richardson, Fang Liu

Research output: Contribution to conferencePosterpeer-review


Purpose Fluid-bed coating of microparticles using aqueous polymer dispersions is a challenge due to particle agglomeration. Agglomeration is an undesirable phenomenon especially for modified release products resulting in inconsistent and unreliable coating thickness and drug release profile. Due to the small particle size and relatively high coating level, the determination of agglomerated particles is complicated and cannot be performed by common methods such as sieve analysis and observation under light microscope. The objective of this study was to investigate appropriate methods to determine the internal structure of coated microparticles to support decision making in formulation and coating process development. Methods Metoprolol succinate drug loaded and sustained release film-coated microparticles were prepared in a fluid-bed coater (Mini-Glatt, Glatt AG, Germany) using MCC-cores (Cellets 90) with 86.5 µm particle size (D50, LD-method), HPMC, aqueous Eudragit NM 30D (Evonik AG, Germany) based coating with admixture of talc and magnesium stearate. Three batches were prepared using the same coating composition but different coating processing parameters. Laser diffraction (LD; ASPIROS dosing, RODOS dispersing, and HELOS / KF LD-detector) and dynamic imagine analysis (DIA; VIBRI dosing, RODOS, and QICPIC/R06 digital camera with capturing 500 frames/s) were performed for particles size analysis of coated microparticles. Light microscopy investigation of the cross-section of the coated microparticles was performed with and without colour contrast liquid penetrant (methylene blue solution). For sample preparation, the microparticles were embedded into a molten polymer mixture (at ≈70⁰C) on the surface of the microtome-compatible plastic holder. The polymer mixture contained polyethylene-vinyl acetate (40%), vinyl acetate (10 %), terpene-phenol resin (30%) and paraffin (20%). The embedded microparticles were cut cross-sectionally using microtome (AS 325 Retraction, Shandon Southern Products Ltd., England). Non-destructive cone-beam X-ray computed tomography (CT; ImagiX 50 CT system, North Star Imaging Inc., Minnesota, USA) was performed by applying X-ray tube with a tungsten target, 70 kV tube voltage, and 140 μA tube current. A total of 1 440 images have been acquired (1 image every 0.25 degree) at 2 frames per second (500 ms integration time) and 3.3 µm resolution (voxel size). 3-D reconstruction and visualization of CT-images were performed using specialised software (myVGL, software version 3.0.3, Volume Graphics GmbH, Germany; and efX-CT, ver., North Star Imaging Inc., Minnesota, USA). Advanced segmentation was applied to reconstructed and visualized CT-scans using special software (Simpleware, ver. N-2018.03; Synopsys Inc., CA, USA). Results Different particle size distribution profiles were obtained for the three batches investigated using LD (fig. 1) and DIA. Despite the possibility to filter and visually inspect particle images using the DIA method, no agglomerates were detected for all three batches. In order to investigate internal microstructure of coated microparticles, the destructive method of sample preparation was developed. The investigation of prepared cross-sections under the light microscope with the assistance of colour contrast liquid penetrant allowed determination of hidden internal agglomerates (fig. 2 A) in one of the batches (Batch 1). Non-destructive CT method was applied to clarify internal structure of the obtained batches. The visual analysis of 3-D reconstructed CT-scans allowed determination of the differences in internal structure between the analysed batches and detecting of hidden agglomerates in Batch 1 (fig. 2 B-D). Using additional software and advanced segmentation the internal porosity of the microparticles were determined and compared (Batch 1 > Batch 2 ≈ Batch 3). However, due to the limitation of the CT-method, the resolution of porosity determination was limited (3-5 voxels across is 9.9-16.5 µm) and did not reflect real internal porosity. Conclusion Computed tomography with 3-D reconstruction and visualization was found as an effective non-destructive method for comprehensive sample analysis and determination of hidden agglomerates. Additionally, the advanced segmentation of 3-D reconstructed CT-scans allowed, to some extent, to quantify and compare differences in the internal porosity of coated microparticles.
Original languageEnglish
Number of pages1
Publication statusPublished - 06 Nov 2018
Externally publishedYes
EventAAPS PharmSci360 - Walter E. Washington Convention Center, Washington, DC, United States
Duration: 04 Nov 201807 Nov 2018


ConferenceAAPS PharmSci360
CountryUnited States
CityWashington, DC
Internet address


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