Qun Shao

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.

Multipronged evaluation of genotoxicity in Indian petrol‐pump workers

Petrol (gasoline) contains a number of toxicants. This study used human biomonitoring to evaluate the genotoxic effects of exposure to benzene in petrol fumes in 100 Indian petrol‐pump workers (PPWs) and an equal number of controls. The study was corroborated with in silico assessments of the Comet assay results from the human biomonitoring study. An in vitro study in human lymphocytes was also conducted to understand the genotoxicity of benzene and its metabolites. In a subset of the population studied, higher blood benzene levels were detected in the PPWs (n = 39; P < 0.01) than the controls (n = 18), and 100–250 ppb benzene was also detected in air samples from the petrol pumps. PPWs had higher levels of DNA damage than the controls (P < 0.01). In addition, the micronucleus assay was performed on lymphocytes from a subset of the subjects, and the micronucleus frequency for PPWs was significantly higher (n = 39; 14.79 ± 3.92‰) than the controls (n = 18; 7.54 ± 3.00‰). Human lymphocytes were treated in vitro with benzene and several of its metabolites and assayed for DNA damage with the Comet assay. Benzene and its metabolites produced significant (P < 0.05) levels of DNA damage at and above concentrations of 10 μM. The metabolite, p‐benzoquinone, produced the greatest amount of DNA damage, followed by hydroquinone > benzene > catechol > 1,2,4,‐benzenetriol > muconic acid. This study demonstrates that, using sensitive techniques, it is possible to detect human health risks at an early stage when intervention is possible. possible. Environ. Mol. Mutagen., 2008.

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.

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.

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.

Predicting the clinical effect of a short acting bronchodilator in individual patients using artificial neural networks

Artificial neural networks were used in this study to model the relationships between in vitro data, subject characteristics and in vivo outcomes from N=18 mild-moderate asthmatics receiving monodisperse salbutamol sulphate aerosols of 1.5, 3 and 6 μm mass median aerodynamic diameter in a cumulative dosing schedule of 10, 20, 40 and 100 μg. Input variables to the model were aerodynamic particle size (APS), body surface area (BSA), age, pre-treatment forced expiratory volume in one-second (FEV(1)), forced vital capacity, cumulative emitted drug dose and bronchodilator reversibility to a standard salbutamol sulphate 200 μg dose MDI (REV(%)). These factors were used by the model to predict the bronchodilator response at 10 (T10) and 20 (T20) min after receiving each of the 4 doses for each of the 3 different particle sizes. Predictability was assessed using data from selected patients in this study, which were set aside and not used in model generation. Models reliably predicted ΔFEV(1)(%) in individual subjects with non-linear determinants (R(2)) of ≥ 0.8. The average error between predicted and observed ΔFEV(1)(%) for individual subjects was <4% across the cumulative dosing regimen. Increases in APS and drug dose gave improved ΔFEV(1)(%). Models also showed trends towards improved responses in younger patients and those having greater REV(%), whilst BSA was also shown to influence clinical effect. These data show that APS can be used to discriminate predictably between aerosols giving different bronchodilator responses across a cumulative dosing schedule, whilst patient characteristics can be used to reliably estimate clinical response in individual subjects.

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.

Application of Chemomic Release Kinetics to Evaluation of the Release Characteristics of Yinqiaojiedu Tablets

ABSTRACT AIM To verify the applicability of a new theory for chemomic release kinetics of traditional Chinese medicines using the release characteristics of Yinqiaojiedu tablets. METHODS The methodological studies of the preparation of chemomic standard spectrum, linearity, precision and stability tests of the chemomes of Yinqiaojiedu tablets were processed by UV spectrophotometry and Kalman filter methods. The chemomic release profiles of Yinqiaojiedu tablets and powders were determined. RESULT The methodology studies indicated that there was a good linearity of chemomic concentration of Yinqiaojiedu tablets within the range 0.112 to 1.120 mg total herbs / mL ( r = 0.999 7). The values of RSD tested at three chemomic levels were 0.05 %, 0.07 % and 0.31 % respectively. The chemomic solutions were stable for 24 h at concentrations of 0.278, 0.556, and 1.120 mg total herb / mL. CONCLUSION The chemomic release profiles demonstrated multi-component release kinetics illustrated using a simple visualization approach. The new theory of chemomic release kinetics may advantageously provide a quantitative description for the release of the active agents from traditional Chinese medicines from a conventional dosage form or drug delivery system.

In situ 3D topographic and shape analysis by synchrotron radiation X-ray microtomography for crystal form identification in polymorphic mixtures

Polymorphism denotes the existence of more than one crystal structure of a substance, and great practical and theoretical interest for the chemical and pharmaceutical industries. In many cases, it is challenging to produce a pure crystal form and establish a sensitive detection method for the identification of crystal form in a mixture of polymorphs. In this study, an accurate and sensitive method based on synchrotron radiation X-ray computed microtomography (SR-μCT) was devised to identify the polymorphs of clopidogrel bisulphate (CLP). After 3D reconstruction, crystal particles were extracted and dozens of structural parameters were calculated. Whilst, the particle shapes of the two crystal forms were all irregular, the surface of CLP II was found to be rougher than CLP I. In order to classify the crystal form based on the quantitative morphological property of particles, Volume Bias Percentage based on Surface Smoothing (VBP) was defined and a new method based on VBP was successfully developed, with a total matching rate of 99.91% for 4544 particles and a lowest detectable limit of 1%. More important for the mixtures in solid pharmaceutical formulations, the interference of excipients can be avoided, a feature cannot achieved by other available analytical methods.