Xianzhen Yin

Microstructural investigation to the controlled release kinetics of monolith osmotic pump tablets via synchrotron radiation X-ray microtomography

Tomographic imaging techniques are attractive tools for the visualization of the internal structural characteristics of pharmaceutical solid dosage forms. In this paper, the internal structure of the tablet core for a monolith osmotic drug delivery system, felodipine sustained-release tablet, was visualized via synchrotron radiation X-ray computed microtomography during the drug release process. The surface areas and three dimensional parameters of the tablet core were calculated based on the three dimensional reconstruction of the images. At different stages of the drug release process, the surface morphology, the hydration, the swelling, and the structure changing of the tablet, were visualized from the two dimensional monochrome X-ray images. The three dimensional volumes of the remaining tablet core correlated well with the percentages of felodipine (R=0.9988). Also, the three dimensional surface area almost unchanged during the drug release process, which clearly demonstrated the intrinsic drug release mechanism of the osmotic drug delivery system. In conclusion, the synchrotron radiation X-ray computed microtomography, with rapid acquisition, high intensity and micro-scale spatial resolution, was found to be a useful tool for the quantitative elucidation of the intrinsic drug release kinetics and the three dimensional parameters such as surface areas of the remained core obtained by the synchrotron radiation. Thus, X-ray computed microtomography can be considered as a new and complimentary analytical tool to standard compendial pharmaceutical tests for quality control of osmotic drug delivery systems.

Visualization and quantitative profiling of mixing and segregation of granules using synchrotron radiation X-ray microtomography and three dimensional reconstruction.

Tomographic imaging techniques have great potential for improving understanding of the dynamics of granular materials during manufacturing, handling, and storage. In this study, the synchrotron radiation X-ray computed microtomography (SR-μCT) was used non-invasively to monitor blend homogeneity of binary mixtures. Granular samples of microcrystalline cellulose and starch were characterized using the SR-μCT individually. Simultaneously, particle distribution was investigated by calculating the frequency distribution of a statistic for testing sphericity. Then, the microcrystalline cellulose and starch granules were blended in a cylindrical container. Influences of the time of rotations TR and the time of vibration TV on the mixture homogeneity were studied with the SR-μCT and statistical evaluation. The mixing index is also adopted to evaluate the mixture homogeneity of the particle system. The results showed that mixture homogeneity is improved with increasing TR. Furthermore, segregation increased with longer TV when particles are different in size and shape. The larger starch granules of non-spherical shape have a tendency to rise to the top, while the smaller microcrystalline cellulose granules which are spherical tend to migrate to the bottom of the mixture. Therefore, we demonstrate that SR-μCT can investigate the mixing and segregation of granular materials in three-dimensions combined with statistic method.

Quantification of Swelling and Erosion in the Controlled Release of a Poorly Water-Soluble Drug Using Synchrotron X-ray Computed Microtomography

The hydration layer plays a key role in the controlled drug release of gel-forming matrix tablets. For poorly water-soluble drugs, matrix erosion is considered as the rate limiting step for drug release. However, few investigations have reported on the quantification of the relative importance of swelling and erosion in the release of poorly soluble drugs, and three-dimensional (3D) structures of the hydration layer are poorly understood. Here, we employed synchrotron radiation X-ray computed microtomography with 9-μm resolution to investigate the hydration dynamics and to quantify the relative importance of swelling and erosion on felodipine release by a statistical model. The 3D structures of the hydration layer were revealed by the reconstructed 3D rendering of tablets. Twenty-three structural parameters related to the volume, the surface area (SA), and the specific surface area (SSA) for the hydration layer and the tablet core were calculated. Three dominating parameters, including SA and SSA of the hydration layer (SAhydration layer and SSAhydration layer) and SA of the glassy core (SAglassy core), were identified to establish the statistical model. The significance order of independent variables was SAhydration layer > SSAhydration layer > SAglassy core, which quantitatively indicated that the release of felodipine was dominated by a combination of erosion and swelling. The 3D reconstruction and structural parameter calculation methods in our study, which are not available from conventional methods, are efficient tools to quantify the relative importance of swelling and erosion in the controlled release of poorly soluble drugs from a structural point of view.

Ultra-high-resolution 3D digitalized imaging of the cerebral angioarchitecture in rats using synchrotron radiation

The angioarchitecture is a fundamental aspect of brain development and physiology. However, available imaging tools are unsuited for non-destructive cerebral mapping of the functionally important three-dimensional (3D) vascular microstructures. To address this issue, we developed an ultra-high resolution 3D digitalized angioarchitectural map for rat brain, based on synchrotron radiation phase contrast imaging (SR-PCI) with pixel size of 5.92 μm. This approach provides a systematic and detailed view of the cerebrovascular anatomy at the micrometer level without any need for contrast agents. From qualitative and quantitative perspectives, the present 3D data provide a considerable insight into the spatial vascular network for whole rodent brain, particularly for functionally important regions of interest, such as the hippocampus, pre-frontal cerebral cortex and the corpus striatum. We extended these results to synchrotron-based virtual micro-endoscopy, thus revealing the trajectory of targeted vessels in 3D. The SR-PCI method for systematic visualization of cerebral microvasculature holds considerable promise for wider application in life sciences, including 3D micro-imaging in experimental models of neurodevelopmental and vascular disorders.

Fractal structure determines controlled release kinetics of monolithic osmotic pump tablets

To calculate the fractal dimension values of felodipine osmotic pump tablets during drug dissolution and to characterize the mechanism of the controlled drug release kinetics through three‐dimensional fractal data.

Release behaviour of single pellets and internal fine 3D structural features co-define the in vitro drug release profile.

Multi-pellet formulations are advantageous for the controlled release of drugs over single-unit dosage forms. To understand the diffusion controlled drug release mechanism, the pellet structure and drug release from a single pellet (not at dose level) were studied using synchrotron radiation X-ray computed microtomography (SR-μCT) and a sensitive LC/MS/MS method. The purpose of this article is to introduce a powerful, non-invasive and quantitative technique for studying individual pellet microstructures and to investigate the relationship between the microstructure and drug release from single pellets. The data from the single pellet dissolution measurements demonstrated that the release profile of capsules containing approximately 1,000 pellets per unit dose was the summation of the release profiles of the individual pellets. The release profiles of single tamsulosin hydrochloride (TSH) pellets formed three groups when a cluster analysis was performed, and the dissolution rate of the individual pellets correlated well with the combined effects of the drug loading, volume and surface area of the pellets (R2 = 0.9429). In addition, the void microstructures within the pellet were critical during drug release. Therefore, SR-μCT is a powerful tool for quantitatively elucidating the three-dimensional microstructure of the individual pellets; because the microstructure controls drug release, it is an important parameter in the quality control of multi-pellet formulations.

Microstructural investigation using synchrotron radiation X-ray microtomography reveals taste-masking mechanism of acetaminophen microspheres

The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-μCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-μCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking.

Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres.

The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation–based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres.

Host-guest kinetic interactions between HP-β-cyclodextrin and drugs for prediction of bitter taste masking

&NA; Cyclodextrins (CD) are widely used bitter taste masking agents, for which the binding equilibrium constant (K) for the drug‐CD complex is a conventional parameter for quantitating the taste masking effects. However, some exceptions have been reported to the expected relationship between K and bitterness reduction and the relationship between kinetic parameters of a drug‐CD interaction, including association rate constant (Ka) and disassociation rate constant (Kd), and taste masking remains unexplored. In this study, based upon a database of kinetic parameters of drugs‐HP‐&bgr;‐CD generated by Surface Plasmon Resonance Imaging for 485 drugs, the host‐guest kinetic interactions between drugs and HP‐&bgr;‐CD for prediction of taste masking effects have been investigated. The taste masking effects of HP‐&bgr;‐CD for 13 bitter drugs were quantitatively determined using an electronic gustatory system (&agr;‐Astree e‐Tongue). Statistical software was used to establish a model based on Euclidean distance measurements, Ka and Kd of the bitter drugs/HP‐&bgr;‐CD‐complexes (R2 = 0.96 and P < 0.05). Optimized parameters, Ka3, Kd, KaKd, Kd3, Ka2 and Ka/Kd with notable influence, were obtained by stepwise regression from 12 parameters derived from Ka, Kd and K (Ka/Kd). 10‐fold cross‐validation was used to verify the reliability of the model (correlation coefficient of 0.84, P < 0.05). The established model indicated a relationship between Ka, Kd, K and taste masking by HP‐&bgr;‐CD and was successful in predicting the extent of taste masking by HP‐&bgr;‐CD of 44 bitter drugs, which was in accordance with the literature reported. In conclusion, the relationship between kinetics of drug‐CD interactions and taste masking was established and providing a new strategy for predicting the cyclodextrin mediated bitter taste masking. Graphical abstract Figure. No caption available. HighlightsThe relationship between kinetic parameter (Ka and Kd) of drug‐cyclodextrin inclusion and taste masking is revealed.A 3D model is successfully established to predict taste masking effect of drug‐cyclodextrin inclusion.A novel and high‐throughput method based on SPRi is developed to investigate taste masking.It offers a rapid way to surrogate conventional methods for taste evaluation of new drug candidates at early stage.

Visualization and quantification of deformation behavior of clopidogrel bisulfate polymorphs during tableting.

The deformation behavior of particles under pressure dominates the mechanical properties of solid dosage forms. In this study, the in situ 3D deformation of two polymorphs (I and II) of clopidogrel bisulfate (CLP) was determined to illustrate pressure distribution profiles within the tablet by the deformation of the crystalline particles for the first time. Synchrotron radiation X-ray computed microtomography (SR-μCT) was utilized to visualize and quantify the morphology of thousands crystalline particles of CLP I and CLP II before and after compression. As a result, the deformation was examined across scale dimensions from microns to the size of the final dosage form. Three dimensional parameters such as volume, sphericity, oblate and prolate of individual particle and distributions were computed and analyzed for quantitative comparison to CLP I and CLP II. The different degrees of deformation under the same compression conditions of CLP I and CLP II were observed and characterized quantitatively. The map of deformation degrees within the tablet illustrated the heterogeneous pressure distribution in various regions of the compacted tablet. In conclusion, the polymorph deformation behaviors demonstrated by SR-μCT quantitative structure analysis deepen understanding of tableting across dimensions from microns to millimeters for the macrostrcuture of tablet.