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Drug therapies for acute lung injury (ALI) are far from satisfactory, primarily because drugs cannot specifically target the lungs. Direct delivery of drugs to the deep alveolar regions by inhalation administration is crucial for the treatment of ALI. However, conventional inhalable carriers such as lactose and mannitol are generally inactive. Therefore, the use of a novel pharmacologically active carrier for pulmonary delivery may produce synergetic effects in treating ALI. Considering the pathophysiological environment of ALI, which typically featured excessive reactive oxygen species (ROS) and acute inflammation, we synthesized a novel kind of biodegradable and ROS-sensitive cross-linked covalent cyclodextrin frameworks (OC-COF) with uniform inhalable particle size to treat ALI. OC-COF was devised to incorporate H

Defining and visualizing the three-dimensional (3D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography (SR-μCT).

It is essential to optimize a carrier of dry powder inhalation (DPI) for the aerodynamic deposition in vitro to achieve pulmonary delivery of drug molecules in vivo. In this study, neutralized nanoporous γ-cyclodextrin metal-organic framework (CD-MOF) crystals with cubic morphology and uniform inhalation size were developed and modified as a DPI carrier for budesonide (BUD). Cholesterol (CHO) and leucine (LEU)-poloxamer were used to modify the CD-MOF powder for the improvement of flowability and particle aerodynamic behaviour, for which the particle size distribution, Carr's index and in vitro pulmonary deposition were assessed. Compared to CD-MOF or LEU-CD-MOF-BUD, CHO-CD-MOF had a superior mass median aerodynamic diameter (4.35 ± 0.04 μm) and inhalable performance (fine particle fraction of 30.60 ± 0.76%), which were maintained after budesonide loading (4.47 ± 0.30 μm, 24.95 ± 4.33%). The crystallinity, cytotoxicity and in vivo deposition of drug loaded samples (CHO-CD-MOF-BUD) were then investigated by powder X-ray diffraction (PXRD), cell viability study, in vivo fluorescence imaging and pharmacokinetic studies in rats. The characteristic PXRD crystallinity peaks of budesonide disappeared after being loaded into CHO-CD-MOF, potentially indicating the molecular incorporation of budesonide into the pores of CD-MOF. The cell viability of A549 cell was more than 90% for CHO-CD-MOF-BUD as a result of the good biocompatibility of CD-MOF. When Rhodamine B was carried by the DPI particles, the fluorescence signal at the lung tissue was markedly improved after cholesterol modification compared with CD-MOF, whilst the bioavailability of CHO-CD-MOF-BUD in rat was equivalent with that of the commercial product of Pulmicort Turbuhaler. Therefore, the CD-MOF powders modified by cholesterol can be used as a promising inhalable carrier for pulmonary delivery of drugs with small dose.

Rationale: Targeted delivery of therapeutic drugs or imaging agents to injured blood vessels via nanocarriers is likely to be dependent on the particle shape, yet cubic nanoparticle carriers have not been reported for vascular targeting. Here, we demonstrate that cuboidal cyclodextrin frameworks possess superior hemostasis effect and injured vessels targeting compared with spherical counterpart. Methods: Cuboidal and biocompatible γ-cyclodextrin metal-organic frameworks (CD-MOFs) are synthesized, tethered via crosslinking and surface modification with GRGDS peptide (GS5-MOFs). The specific interactions of cubic GS5-MOF nanoparticles with activated platelets were investigated by in vitro platelet aggregation assay and atomic force microscopy measurements (AFM). The hemostatic capacity and injured vessel targeting efficacy were evaluated in vivo. Results: Cuboidal GS5-MOF nanoparticles exhibit enhanced adhesion and aggregation with activated platelets in vitro under static condition and a physiologically relevant flow environment. The cubic GS5-MOF nanoparticles show efficient hemostatic effects with bleeding time and blood loss decrease of 90% and strong injured vessel targeting in vivo, markedly superior to spherical γ-CD nanosponges with the same chemical composition. Conclusions: These results clearly highlight the contribution of the cuboidal shape of GS5-MOFs to the enhanced aggregation of activated platelets and high targeting to damaged vessels. The cuboidal nanoparticle system provides an innovative delivery platform for the treatment and diagnosis of vascular diseases.

Cavities and the architectures inside tablet play a decisive role for the permeation of water within tablet to initiate disintegration phenomenon. The present study aims to establish inner structure characterization methodology based on synchrotron radiation X-ray microcomputed tomography (SR-μCT) for microcrystalline cellulose (MCC) tablets and to correlate the cavities and 'their attributes to tablet disintegration phenomenon. The three-dimensional (3D) morphological architecture and quantitative data of single particles for 12 specifications of MCC, and respective MCC tablets' cavities structure were obtained through advanced SR-μCT studies. The image processing techniques were established to study the morphology of voids and porosity in an axial and radial direction based on the highly resolved 3D structure of tablets. The in-situ visualization of morphological disintegration behavior indicates that there were two patterns of disintegrations, which can be cataloged as laminating type (LT) and splitting type (ST) disintegrations. The principal component analysis (PCA) was used for multivariate data analysis to get the meaningful correlation among disintegration behaviors, cavities morphology, single particles attributes, and the cavities spatial arrangement within the tablets. These findings have deepened insights into inner structures of tablets and single particle structural attributes to tablet disintegration, reflecting the mechanism of disintegration mode, and the significance of pharmaceutical structure evaluated via SR-μCT.

Smart microstructure design of dosage forms such as microcapsules that protect the microorganism, can improve probiotics survival from gastric pH challenges and prolong their shelf life. In this study, synchrotron radiation X-ray microcomputed tomography (SR-μCT) was applied to quantitatively reveal the material distributions and functional structures of bifidobacterium and lactobacillus microcapsules. The shell layer, middle protective layer, and the microorganisms as particles in the center layer were extracted and visualized. All the microorganisms were encapsulated by the shell completely, which prevents them from being destroyed by external environments. However, the non-uniform thickness of the shell and typical defects in the microcapsules were observed. The quantitative analysis and characterization of internal microstructures provide evidence of the need for further improvement in formulations and processing technologies for the structured system to deliver living microorganisms.

Microcrystalline cellulose (MCC) is one of the most important excipients due to its outstanding binding and tableting properties. Owing to the absence of high resolution characterization techniques at the single particle scale, 3D (three dimension) microstructure of MCC and its effects on formulation performance remain unexamined. The aim of this work was to establish a methodology for single particles of MCC type 102 based on synchrotron radiation X-ray micro computed tomography (SR-μCT), principal component analysis (PCA) and partial least square discriminant analysis (PLSDA). Scanning electron microscopy, SR-μCT, powders properties together with tensile strength (TS), disintegration time (DT), Kawakita plots and force/displacement profiles of tablets were measured. PCA-PLSDA was applied to evaluate the structural classification of MCC particles on the basis of 2D and 3D SR-μCT derived images. The studied MCCs were found to differ in the TS, DT, Kawakita plot and force/displacement, while box ratio and Feret ratio had major influence on the principal components, but the angle of repose, bulk and tapped density did not exhibit significantly. These findings verified that different samples of MCCs from alternative suppliers have morphological diversity when assessed at the individual particle level, which could result into variation in powder properties and tableting performance.

This paper presents the findings from a study designed to explore whether predictive analytics and machine learning could improve the accuracy and utility of the child welfare risk assessment instrument used in Broward County (Ft. Lauderdale, Florida). The findings from this study indicate that, indeed, predictive analytics and machine learning would significantly improve the accuracy and utility of the child welfare risk assessment instrument being used. If the predictive analytic and machine learning algorithms developed in this study would be deployed, there would be improved accuracy in identifying low, moderate and high risk cases, better matching between the needs of children and families and available services and improved child and family outcomes. This paper also identifies further areas of research and study.

Three advanced methods, high performance affinity chromatography (HPAC), surface plasmon resonance (SPR) and surface plasmon resonance imaging (SPRi) were compared and evaluated for determining the drug-cyclodextrin (CD) interactions herein. In total, 18 sparingly soluble drugs were selected for this comparative study. The three methods share a unique connection in the working principles and strategies. The same strategies of CD fixation onto solid phase were used in HPAC and SPR for the measurements, whereas, the SPR and SPRi share identical working principles. However, whilst these relationships are evident, no strong correlation was found between kinetic constants obtained from the three methods: Four drugs, namely, prednisolone, pseudolaric acid B, diazepam and gramisetron failed to show any response on SPR, whereas, the kinetics parameters from SPRi and HPAC were successfully measured. From a comparative review of all the kinetic data, random results without any trends were observed (ka, kd and KA) regardless of the relationships between the three methods: It is apparent that the measurement conditions (volume, flow rate, buffers), non-specific adsorption and experimental procedures had a strong impact on the generated data. The relative advantages and limitations of each method are critically presented on the basis of generated data. This comparative study provides a basis to further upgrade these techniques for confident measurement of drug-CDs interactions.

The multiple-unit sustained-release (MUSR) dosage forms containing numerous sustained-release subunits present a reliable choice for oral formulation of controlled release systems. As a typical MUSR, the metoprolol succinate sustained-release tablet is an advanced system with limited researches devoted to relating its structure to the drug release phase other than the preparation process and modulation to the release behaviors. This research details a three-dimension method to image the internal structure and detail drug release features of commercial metoprolol succinate sustained-release tablets and component individual single pellets. As such, a new perspective for MUSR dosage form is provided. Using high energy synchrotron radiation X-ray microcomputed tomography (SR-μCT), the in-situ structure parameters were obtained nondestructively. It was demonstrated that the average number of spherical pellets in a tablet was 853 ± 12 (n = 3). The average volume of the pellets was 0.09 ± 0.01 mm3, the diameter was 0.55 ± 0.03 mm, and the sphericity was 0.87 ± 0.06. These data reflected the numerical features of pellets in MUSR tablets, which were helpful for reverse engineering to MUSR. Based on the three dimensional model generated by image processing and analysis software, the pellet structures were divided into three layers of typical depot sustained release system: pellet core, drug-containing layer and outer film. The dynamic structural features determined refer to the changes of structures in pellets during in vitro drug release, with evidence that the coating layer on the pellets maintained a spherical morphology whilst numerous valleys appeared on the surface. The material constitution and distribution in coating layer were evaluated by synchrotron radiation-based Fourier transform infrared mapping and results indicated a composition of hydroxypropyl methylcellulose dispersed in ethyl cellulose. Knowledge of these structural characteristics confirmed that the mechanism of sustained drug release was membrane controlled and consistent with the drug release profiles. In conclusion, the structural investigation provided knowledge of the intrinsic quality of metoprolol succinate sustained-release tablets and offers guidance for reverse engineering of MUSR.

Throughout scientific history, overarching theoretical frameworks have allowed researchers to grow beyond personal intuitions and culturally biased theories. They allow to verify and replicate existing findings, and to link disconnected results. The notion of self-play, albeit often cited in multiagent Reinforcement Learning, has never been grounded in a formal model. We present a formalized framework, with clearly defined assumptions, which encapsulates the meaning of self-play as abstracted from various existing self-play algorithms. This framework is framed as an approximation to a theoretical solution concept for multiagent training. On a simple environment, we qualitatively measure how well a subset of the captured self-play methods approximate this solution when paired with the famous PPO algorithm. The results indicate that throughout training the trained policies exhibit cyclic evolutions, showing that self-play research is still at an early stage.

Herein, in addition to conventional β-CD-NSPs, the NSPs of α, γ, HP-β, methyl-β, and SBE-β cyclodextrins were synthesized by a simple modified approach and thoroughly characterized. The control of CDs derivatization over structural dimensions and properties was clearly observed. It is interesting to note the complete transformation of β-CD from its crystalline form to its non-crystalline derivatives and the further reversal when the derivatives are prepared into NSPs including those of α and γ-CDs (as observed by PXRD). The SEM images revealed the different morphologies and porous structure of NSPs and, in particular, the NSPs of methyl-β-CD exhibited regular spherical shapes. Two drugs of different categories, doxorubicin and captopril, were evaluated for loading efficiencies, which were found to significantly vary with cross-linker ratio (1 : 4 and 1 : 6) and CD types. Together, all the synthesized NSPs provide a new horizon to try to solve existing problems relating to drug delivery.

The biocompatible and renewable cyclodextrin metal-organic frameworks (CD-MOFs) have addressed a range of opportunities in molecular storage and separation sciences. The reported protocols for their synthesis, however, were carried out at room temperature over long time periods of time (24h), producing crystals of relatively poor uniformity. In this investigation, micron sized γ-CD-MOFs were synthesized by an optimized vapor diffusion method at elevated temperature (50°C) within 6h, after which the size control, crystalline stability and drug adsorption behavior were investigated in detail. In this manner, uniform cubic γ-CD-MOF crystals were obtained when the reaction temperature was raised to 50°C with pre-addition of the reaction solvent. The size of γ-CD-MOFs was adjusted efficiently by changing the reactant concentrations, temperatures, time, γ-CD ratios to KOH and surfactant concentrations, without influencing the porosity and crystallinity of the material markedly. Varing degrees of reduction in crystallinity and change in morphology were observed when the γ-CD-MOF crystals are treated under conditions of high temperature (100°C), high humidity (92.5%) and polar solvents (e.g., MeOH and DMF). In relation to drug adsorption by γ-CD-MOFs, most of the drug molecules containing carboxyl groups showed relatively high adsorption (>5%), while low adsorption (

The orifice drilled in the membrane as a channel for drug delivery is the key functional part of the osmotic pumps for a controlled drug release system. Reported conventional microscopic evaluations of these orifices have been limited to measurement of two-dimensional cross-section diameters. This study was aimed at establishing a novel method to measure quantitatively the three-dimensional architectures of orifices based on synchrotron radiation X-ray microcomputed tomography (SR-μCT). Quantitative analysis of architectures extracted from captopril osmotic pumps drilled by a range of operating parameters indicated that laser power correlated with the cross section area, volume, surface area and depth of the orifices, while scanning speed of laser beam showed inverse relationships with the above structure characters. The synchrotron radiation based Fourier transform infrared microspectroscopy mapping showed that there was no apparent chemical change in the surrounding area of the orifice compared with the normal membrane region. Thus SR-μCT was successfully applied to marketed felodipine osmotic pumps for architectural evaluation of the orifices. In conclusion, the first three-dimensional structural insight of orifices in osmotic pump tablets by SR-μCT and structural reconstruction for the architectures has provided deeper insight into improving the design of advanced osmotic pumps for controlled drug release.

The control of supramolecular systems requires a thorough understanding of their dynamics, especially on a molecular level. It is extremely difficult to determine the thermokinetic parameters of supramolecular systems, such as drug-cyclodextrin complexes with fast association/dissociation processes by experimental techniques. In this paper, molecular modeling combined with novel mathematical relationships integrating the thermodynamic/thermokinetic parameters of a series of isomeric multiconfigurations to predict the overall parameters in a range of pH values have been employed to study supramolecular dynamics at the molecular level. A suitable form of Eyring's equation was derived and a two-stage model was introduced. The new approach enabled accurate prediction of the apparent dissociation/association (k(off)/k(on)) and unbinding/binding (k-r/kr) rate constants of the ubiquitous multiconfiguration complexes of the supramolecular system. The pyronine Y (PY) was used as a model system for the validation of the presented method. Interestingly, the predicted k(off) value ((40 ± 1) × 10(5) s(-1), 298 K) of PY is largely in agreement with that previously determined by fluorescence correlation spectroscopy ((5 ± 3) × 10(5) s(-1), 298 K). Moreover, the k(off)/k(on) and k-r/kr for flurbiprofen-β-cylcodextrin and ibuprofen-β-cyclodextrin systems were also predicted and suggested that the association processes are diffusion-controlled. The methodology is considered to be especially useful in the design and selection of excipients for a supramolecular system with preferred association and dissociation rate constants and understanding their mechanisms. It is believed that this new approach could be applicable to a wide range of ligand-receptor supramolecular systems and will surely help in understanding their complex mechanism.

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.

Hydrophilic matrix tablets are the most commonly used dosage forms to fabricate oral controlled-release systems. It is highly desirable to design delivery system with novel mechanism to achieve sustained drug release through a simplified preparation process. The chitosan–anionic polymers based matrix tablets is assumed to produce self-assembly in the gastrointestinal tract, then transferring into film-coated tablets from original matrix type. But its dynamic behavior during dissolution process and the on-going internal microstructural changes during drug release were still in the dark. In this study, by using synchrotron radiation X-ray micro-tomography (SR-μCT) with phase contrast imaging, the micro-structure characteristics of chitosan–λ-carrageenan (CS–λ-CG) matrix based tablets during the dissolution were successfully elucidated for the first time. The qualitative and quantitative analyses of intensity distribution distinguished a hydrated CS–λ-CG layer from a solid core. Visualization based on 3D models provided quantitative details on the micro-structural characteristics of hydration dynamics. After CS–λ-CG matrix tablets were immersed in simulated gastric fluid (SGF) pH 1.2 medium for 0.5–2.0 h, the hydrated layer transformed into a gel layer and a solid swollen layer. The erosion front, swelling front, and solvent penetration front were also defined from the distinguishable micro-structures. More importantly, once the matrix tablet was transferred from SGF to the simulated intestinal fluid (SIF) pH 6.8 medium, a new layer with the enhanced strength and compactness in comparison to common gels was formed on the surface of tablets. The temporal and spatial variation of 3D models further provided direct evidence for this cross-linking behavior, the new layer was composed of CS–λ-CG polyelectrolyte complexes (PEC) which subsequently dominated release mechanisms. In summary, the phase contrast SR-μCT technique was utilized to investigate the hydration dynamics of CS–λ-CG matrix tablets which was supposed to provide a novel drug release mechanism. Based on the structure feature obtained from the high contrast image, different hydration region was distinguished and the cross-linked film was identified and visualized directly for the first time.

γ-Cyclodextrin metal-organic frameworks (γ-CD-MOFs) are highly porous and bio-friendly novel materials formed by γ-CD as an organic ligand and potassium ion as an inorganic metal centre. The aim of this study was to enhance the stability of vitamin A palmitate (VAP) using γ-CD-MOFs as the carrier. Herein, γ-CD-MOFs displayed VAP microencapsulating capacity of 9.77 ± 0.24% with molar ratio as n

One unusual and challenging scientific field that has received only cursory attention to date is the three-dimensional (3D) microstructure and spatial distribution of drug(s) and formulation materials in solid dosage forms. This study aims to provide deeper insight into the relationships between the microstructure of multiple-unit pellet system (MUPS) tablets and the spatial distribution of the active pharmaceutical ingredient (API) and excipients to facilitate the design of quantitative models for drug delivery systems. Synchrotron radiation X-ray microcomputed tomography (SR-μCT) was established as a 3D structure elucidation technique, which, in conjunction with liquid chromatography coupled to mass spectrometry (LC-MS) or liquid chromatography with evaporative light-scattering detector (LC-ELSD) enables chemical analysis of tablets. On the basis of the specific interior construction of theophylline MUPS tablets, the spatial distribution of materials was acquired by quantifying microregion samples that had been validated by SR-μCT for their locations in the MUPS tablets. The 3D structure of the MUPS tablets was catalogued as three structural domains: a matrix layer (ML), a protective cushion layer (PCL), and pellets (PL). Compared with the components in the ML, components in the PL had a larger proportion of theophylline, sucrose, and diethyl phthalate and a smaller proportion of lactose and sodium lauryl sulfate, whereas glyceryl monostearate was found to account for a large portion of the PCL. Microstructural characterization-guided zonal chemical determination represents a new approach for quality assessment and the development of drug delivery systems with in-depth insight into their constituent layers on a new scale.

A catalogue is here provided of the pieces of Mexican amber with inclusions in the collections of the Natural History Museum, London, and National Museums Scotland, Edinburgh, both in the United Kingdom. There are 32 pieces in the Natural History Museum and 101 pieces in National Museums Scotland which contain a combined total of 557 arthropod and 13 plant inclusions. Four orders and 11 families of arthropods are additional to a taxonomic list of Mexican amber arthropods published in 2010

Sedimentation of non-homogeneous systems is the typical phenomenon indicating the physical instability as a key measure to the quality control of the preparation products. Currently, the determination methods for the sedimentation of non-homogeneous preparations are based on manual measurement or semi-quantitative observation, lacking of either automation or quantitative dynamic analysis. The purpose of this research was to realize automatic and quantitative monitoring of the sedimentation dynamics for non-homogenous systems as suspension, emulsions at laboratory level. Non-contact measurement method has been established to determine the sedimentation behaviors in a standard quartz tube for sedimentation, with internal diameter and height 23 mm and 215 mm, respectively, with controlled temperature and light intensity. As high performance camera has been equipped, the sedimentation images with high spatial and temporal resolution could be acquired, which can continuously capture sedimentation images with the resolution of 2048 × 2048 pixel at a maximum rate of 60 slides/s. All the pictures were processed to extract the luminance matrix top-down along the fixed vertical midline of each picture, which implied sedimentation characteristics of the system at the moment the picture was taken. Combining all the luminance matrixes along vertical middle lines of the pictures, a time-luminance matrix profile was obtained. Digital image processing techniques were used to eliminate interference and establish a three-dimensional surface model of the sedimentation dynamics. Then, the derivative mutation algorithm has been developed for the intelligent identification of sedimentation interface with threshold optimization so as to quantitatively analyze the sedimentation dynamics with visualization. The sedimentation curve and sedimentation dynamic equation of the non-homogeneous system were finally outputted by numerical fitting. The methodology was validated for great significance in determinations of small volume samples, parallel control multiple batches, and long period of time automatic measurement.

Drug nanosuspensions have gained tremendous attraction as a platform in drug delivery. In the present work, a nanosuspension was prepared by a wet milling approach in order to increase saturation solubility and dissolution of the water insoluble drug, hydrocortisone. Size of the generated particeles was 290 nm ± 9 nm having a zeta potential of -1.9 mV ± 0.6 mV. Nanosized particles were found to have a rod shape with a narrow particle size distribution (PDI =0.17). Results of differential scanning calorimetry and X-ray diffraction analyses revealed minor modifications of crystallinity of hydrocortisone following the milling process. Solubility of hydrocortisone was enhanced by nanonization to 875µg/ml ±2.5, an almost 2.9-fold compared to the raw hydrocortisone. Moreover, the nanosuspension formulation substabtially enhanced the dissolution rate of hydrocortisone where97% of the hydrocortisone was dissolved within 10 minutes opposed to 22.3% for the raw 50% for the raw hydrocortisone and the commercial tablet, respectively. The bioavailability study resulted in AUC 0-9h for HC nanosuspensions (31.50±2.50), which is significantly (p0.05) higher compared to the AUC

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 (R(2) = 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.

Comparative analysis between salmeterol xinafoate (SX) powders was carried out to define quantitatively the solid-state and surface particle properties relevant to formulation of these materials into dry powder respiratory drug delivery systems. SX powders were prepared in supercritical CO2 using a single-step crystallization process (Solution Enhanced Dispersion by Supercritical fluids, SEDS™), the volume mean diameter and deagglomeration behaviour of pure drug compound were optimised for respiratory applications. This compound together with reference samples of starting granulated material and micronised powder were used in analytical studies which involved assessment of polymorphic purity and crystallinity (domain size and strain) using high-resolution X-ray powder diffraction, determination of powder surface energetics using inverse gas chromatography (IGC), electrostatic charge and adhesion measurements. The supercritically-processed powders showed low surface energy, low strain, higher crystallinity and higher polymorphic purity than both granulated and micronised powders and resulted in reduced agglomeration, electrostatic charge and adhesion of this powder.

The influence of surfactants on the stability of cyclodextrin (CD) Pickering emulsions is not well understood. In this study, we report two-way effects of Tween 80 and soybean lecithin (PL) on the long term stability of Pickering emulsions stabilized by the self-assembled microcrystals of α-CD and medium chain triglycerides (MCT). The CD emulsions in the absence and presence of Tween 80 or PL at different concentrations were prepared and characterized by the droplet size, viscosity, contact angle, interfacial tension and residual emulsion values. After adding Tween 80 and PL, similar effects on the size distribution and contact angle were observed. However, changes of viscosity and interfacial tension were significantly different and two-way effects on the stability were found: (i) synergistic enhancement by Tween 80; (ii) inhibition at low and enhancement at high concentrations by PL. The stability enhancement of Tween 80 was due to the interfacial tension decrease caused by the interaction of Tween 80 with CD at the o/w interface at lower concentrations, and significant viscosity increase caused by the Tween 80-CD assembly in the continuous phase. For PL at low concentrations, the replacement of α-CD/MCT by α-CD/PL particles at the o/w interface was observed, leading to inhibitory effects. High concentrations of PL resulted in an extremely low interfacial tension and stable emulsion. In conclusion, the extensive inclusion of surfactants by CD leads to their unique effects on the stability of CD emulsions, for which the changes of viscosity and interfacial tension caused by host-guest interactions play important roles.

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 (SA hydration layer and SSA hydration layer ) and SA of the glassy core (SA glassy core ), were identified to establish the statistical model. The significance order of independent variables was SA hydration layerSSA hydration layerSA glassy 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.

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-mu CT) was used non-invasively to monitor blend homogeneity of binary mixtures. Granular samples of microcrystalline cellulose and starch were characterized using the SR-mu CT 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 T-R and the time of vibration TV on the mixture homogeneity were studied with the SR-mu CT 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-mu CT can investigate the mixing and segregation of granular materials in three-dimensions combined with statistic method. (C) 2013 Elsevier B.V. All rights reserved.

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-β-CD generated by Surface Plasmon Resonance Imaging for 485 drugs, the host-guest kinetic interactions between drugs and HP-β-CD for prediction of taste masking effects have been investigated. The taste masking effects of HP-β-CD for 13 bitter drugs were quantitatively determined using an electronic gustatory system (α-Astree e-Tongue). Statistical software was used to establish a model based on Euclidean distance measurements, Ka and Kd of the bitter drugs/HP-β-CD-complexes (R2=0.96 and P

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.

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.

Experimental solubilities of salbutamol and salbutamol sulphate in ethanol + water mixtures at 25 °C are reported. The solubility of salbutamol was found to increase with the addition of ethanol, and reached a maximum value at an ethanol volume fraction of 0.8. The solubility of salbutamol sulphate decreased with increasing ethanol concentration, and reached a minimum value in ethanol. The Jouyban-Acree model correlated the measured salbutamol and salbutamol sulphate solubility data to within mean relative deviations (MRD) of 3.4 and 13.4, respectively. Solubilities were predicted using previously trained models developed for crystalline non-electrolyte and electrolyte solutes. The trained models for non-electrolytes and electrolytes produced the prediction MRDs of 22.4 and 19.8, respectively. Crown Copyright © 2012 Published by Elsevier B.V. All rights reserved.

Purpose In this paper we have evaluated the gene expression programming (GEP) methodology for modeling the effect of different variables (continuous and nominal) and their interactions on the properties of direct compression formulations. Methods The effect of four variables was studied; variety of diluents, type and percentage of drug and maximum compression force, on the mechanical and drug release properties of direct compression tablets. The generated database (36 formulations) was used for mathematical and GEP modeling. Results GEP has been shown to have a high accuracy in prediction for four out five outputs studied including friability which had no replicate measurements. Compared to the traditional statistical treatment GEP is less time consuming and gives equations which are extremely helpful in understanding the interactions of the different variables and for establishing the design space in the development of direct compression formulations. Conclusions GEP allows similar conclusions than traditional statistical treatment. The helpfulness of this methodology in establishing the design space has been demonstrated. The knowledge derived from GEP can easily be increased by including additional information or new inputs, such as additional drugs or combinations of excipients in the data set.

Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.

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.