Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors.

Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can affect their physicomechanical properties, and so this study aims to characterise the particle size and mechanical properties of HPMC K100M polymer grades from four different vendors. Eight polymers (CR and DC grades) were analysed using scanning electron microscopy (SEM) and light microscopy automated image analysis particle characterisation to examine the powder's particle morphology and particle size distribution. Bulk density, tapped density, and true density of the materials were also analysed. Flow was determined using a shear cell tester. Flat-faced polymer compacts were made at five different compression forces and the mechanical properties of the compacts were evaluated to give an indication of the powder's capacity to form a tablet with desirable strength under specific pressures. The results indicated that the CR grades of the polymers displayed a smaller particle size and better mechanical properties compared to the DC grade HPMC K100M polymers. The DC grades, however, had better flow properties than their CR counterparts. The results also suggested some similarities and differences between some of the polymers from the different vendors despite the similarity in substitution level, reminding the user that care and consideration should be given when substitution is required.

Synthesis and Corrosion Resistance of FeMnNiAlC10 Multi-Principal Element Compound.

A multi-principal element FeMnNiAlC10 bulk alloy was produced by vacuum arc melting. The same alloy was sintered as a thin film on a silicon substrate by ion beam sputter deposition. The bulk alloy has a multiphase structure the elements predominantly segregating into iron manganese carbides and nickel aluminium phases. The thin film is amorphous without detectable phase segregations. The absence of segregation is attributed to the film composition and deposition onto substrate at temperature below 400 K. The corrosion resistance of the thin film alloy was evaluated in 3.5% NaCl. The FeMnNiAlC10 thin film alloy has better corrosion resistance than 304SS. The hardness of the thin film was approximately 7.2 ± 0.3 GPa and the reduced Young's modulus was approximately 103 ± 4.6 GPa. FeMnNiAlC10 thin film could be a good candidate for coating oil and gas extraction soft iron infrastructure.

Application of Focus Variation Microscopy and Dissolution Imaging in Understanding the Behaviour of Hydrophilic Matrices.

Hydrophilic matrix systems can be found in a wide range of extended release pharmaceutical formulations. The main principle of these systems is that upon contact with water, the hydrophilic component swells to form a hydrated gel layer which controls drug release. The following work demonstrates an explorative study into the use of dissolution imaging and focus variation microscopy with hydrophilic polymers. This study investigated the surface properties of xanthan gum (XG), polyethylene oxide (PEO), and hypromellose (hydroxypropyl methylcellulose, HPMC) compacts with each of these three hydrophilic polymers from one of each classification of natural, semi-synthetic, or synthetic polymer using a focus variation instrument. The auto correlation length (Sal) showed all surface profiles from the compacts displayed a value below 0.1 mm, indicating that only high frequency components (i.e., roughness) were considered and that the analysis had been successful. The developed interfacial area ratio (Sdr) displayed values below 5% in line with ISO guidelines for all the polymers studied with their texture aspect ratio values (Str) > 0.5, indicating uniformity of the surfaces of the produced compacts. Of the various parameters studied, areal material ratio (Smr2) predicted XG to wet and hydrate quicker than PEO, with PEO also wetting and hydrating quicker than the HPMC. The dissolution imaging and initial swelling studies proved to concur with the findings from the areal material ratio (Smr2) parameter, suggesting porosity was not an indicator for the ease with which water ingress occurs. This study suggests the Smr2 surface parameter to potentially predict wetting and initial hydration of hydrophilic polymers, however care should be taken as this study consists of a selected number of hydrophilic polymers.

Imaging of the Effect of Alcohol-Containing Media on the Performance of Hypromellose Hydrophilic Matrix Tablets: Comparison of Direct Compression and Regular Grades of Polymer.

As the ingestion of drug products with alcohol could have adverse effects on the release of drugs from dosage forms, it is important to understand the mechanisms underpinning the influence on drug release by evaluating the effect of alcohol-containing media on the behaviour of pharmaceutical excipients. In this work, the effect of hydroalcoholic media containing up to 40% v/v absolute ethanol was evaluated, employing both the regular (CR) and direct compression grades (DC) of hypromellose. X-ray microtomography (XµT) and magnetic resonance imaging (MRI) were used as complementary techniques in determining the influence of the media composition on the ability of the CR and DC polymers to form and evolve the gel layer that controls drug release. Particle and powder properties of the polymer were characterised to determine any relationship to performance in hydroalcoholic media. Triboelectrification results showed the CR grade formulation to charge electropositively whereas the DC grade charged electronegatively. The flow properties also showed the DC grade to have a superior flow as compared to its CR counterpart. Differences in particle morphology between the grades influenced charging and flow behaviour of the powders; however, it did not seem to impact significantly either on the mechanical strength or the drug release properties of the compacted formulation using the model drug propranolol HCl. XµT and MRI imaging were successfully used as complementary techniques in determining the gel layer/hydration layer thickness measurements as the layer developed, as well as following ingress of hydroalcoholic media and its impact on the dry core. The result showed that although differences were present in the gel layer thickness potentially due to differences in particle morphology, this also did not impact significantly on the dissolution process, especially in acidic and hydroalcoholic media.

Design and development of a novel fused filament fabrication (FFF) 3D printed diffusion cell with UV imaging capabilities to characterise permeation in pharmaceutical formulations.

The present work aimed at designing and developing a novel 3D printed diffusion cell capable of UV imaging using the fused filament fabrication (FFF) method. UV imaging has proven to be very versatile in the area of pharmaceutics giving insights into various phenomena including the dissolution behaviour of dosage forms, intrinsic dissolution rates and the drug precipitation processes. A 3D printed diffusion cell in the similitude of a Franz cell was successfully printed using polylactic acid (PLA) filaments equipped with quartz for the imaging area. A model ibuprofen (IBU) gel formulation was tested by introducing the dosage form through the 3D printed donor compartment. The drug concentration permeated through the skin mimic (silicone membrane) was determined from the 3D printed receptor compartment using UV imaging in real-time. The results showed successful UV imaging of the permeation of IBU gel in the novel diffusion cell potentially negating further analytical testing such as the HPLC process required for Franz cell tests thereby reducing costs. Potential interactions between the drug and filament used in the 3D printed process suggests although this concept can be moved towards commercialisation, care should be taken with choice of filament used in the 3D printing process.

Development of a novel method utilising dissolution imaging for the measurement of swelling behaviour in hydrophilic matrices.

A variety of imaging techniques are currently used within the field of pharmaceutics to help understand and determine a wide range of phenomena associated with drug release from hydrophilic matrix tablets. This work for the first time aims at developing an appropriate testing imaging methodology using a surface dissolution imaging instrument (SDI2) for determining the swelling of whole compacts using hypromellose as a model hydrophilic matrix former. The influence of particle morphology (CR and DC grades) and two compressional forces (5 and 15 kN) on the initial swelling behaviour of hypromellose were investigated. The results showed that a lower absorbance of 50 mAu with a wider measurement zone proved successful in determining the edge of the gel layer and growth measurements in real-time with high level of details under flow. Despite the differences in the morphology of the grades of hypromellose tested, it was however discovered that gel growth was statistically similar between them which may be attributed to their similar chemistry. This novel method also highlighted differences in the hydrated polymer's appearance which may have been as a result of differences in porosity and solid fraction. This information is of great importance to a formulator as gel growth plays a crucial role in determining drug release from polymer compacts.

A predictive integrated framework based on the radial basis function for the modelling of the flow of pharmaceutical powders.

This study presents a modelling framework to predict the flowability of various commonly used pharmaceutical powders and their blends. The flowability models were trained and validated on 86 samples including single components and binary mixtures. Two modelling paradigms based on artificial intelligence (AI) namely, a radial basis function (RBF) and an integrated network were employed to model the flowability represented by the flow function coefficient (FFC) and the bulk density (RHOB). Both approaches were utilized to map the input parameters (i.e. particle size, shape descriptors and material type) to the flow properties. The input parameters of the blends were determined from the particle size, shape and material type properties of the single components. The results clearly indicated that the integrated network outperformed the single RBF network in terms of the predictive performance and the generalization capabilities. For the integrated network, the coefficient of determination of the testing data set (not used for training the model) for FFC was R2=0.93, reflecting an acceptable predictive power of this model. Since the flowability of the blends can be predicted from single component size and shape descriptors, the integrated network can assist formulators in selecting excipients and their blend concentrations to improve flowability with minimal experimental effort and material resulting in the (i) minimization of the time required, (ii) exploration and examination of the design space, and (iii) minimization of material waste.

Finite element analysis to model ischemia experienced in the development of device related pressure ulcers.

Pressure ulcers are a common occurrence of damage to skin. Severity ranges from slightly discoloured skin to full thickness tissue damage which can be fatal in some cases. Engineering effort, typically developing computational models had made significant progress in the understanding and demonstration of the formation mechanism of pressure ulcers with the aetiology of excessive stress; however, relatively limited attempts had been made to develop relevant models for pressure ulcers caused by ischemia. The aim of this article is to present evidence of a computational model developed to simulate ischemic pressure ulcer formation and demonstrate the established relationship between the computational data and the acquired clinically relevant experimental data by utilising Laser Doppler Velocimetry. The application of the presented computational model and the established relationship allows the evaluation of the effect of a mechanical loading to the cutaneous blood flow velocity which is a step closer to understand and evaluate a mechanical load to the formation of pressure ulcers caused by ischemia.

Effect of preparation method on the surface properties and UV imaging of indomethacin solid dispersions.

This work explores the use of UV imaging in solid dispersion systems. Solid dispersions are one of the common strategies used in improving the dissolution of poorly soluble drugs. Three manufacturing techniques (spray drying (SD), freeze drying (FD) and homogenising (HG)) are investigated. Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD) was used in characterising the solid dispersions. Advanced imaging was implemented to give an insight into how these solid dispersions performed. The DSC and XRPD results showed that all three methods and the various ratios studied produced amorphous solid dispersions. Ultra-Violet (UV) imaging of the pseudo Intrinsic Dissolution Rate (IDR) deduced only two samples to have superior pseudo IDR values to the IDR of the parent drug indomethacin (INDO). The whole dose imaging of the capsule formulation however showed all the samples (SD, FD and HG) to have superior dissolution to that of INDO which was in contrast to the IDR results. The UV images obtained from the determination of the pseudo IDR also showed a phenomenon the authors are reporting for the first time where increased polymer (Soluplus) content produced "web-like" strands that migrated to the top of the quartz cell which may have been responsible for the low pseudo IDR values. The authors also report for the first time using this UV imaging technique, the tip of a capsule coming off for drug to go into solution. The area under the curve suggested the best five samples dissolution wise to be 1:3 SD > 1:1 HG > 1:1 SD > 1:3 FD > 1:3 HG meaning a ratio of INDO to SOL in these dispersion of up to 1:3 being sufficient to produce significant dissolution increases. The developed interfacial (surface) area ratio (Sdr) highlighted how the surface area of the IDR compacts varied between the batches, in particular highlighting larger surface area gains for the FD and HG compacts. A choice of instrumentation/techniques to use in making solid dispersions may well come down to cost or instrument availability for a formulator as all three techniques were successful in improving the dissolution of indomethacin. This work thus highlights the importance of having both complimentary IDR and whole dosage imaging techniques in giving a better understanding of solid dispersion systems.

Hot-melt extrusion process impact on polymer choice of glyburide solid dispersions: The effect of wettability and dissolution.

The aim of this study was to evaluate the choice of polymer and polymer level on the performance of the microstructure and wettability of hot-melt extruded solid dispersion of Glyburide (Gly) as a model drug. The produced solid dispersion were characterised using scanning electron microscopy (SEM), image analysis using a focus variation instrument (FVI), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), X-ray microtomography (XµT), dynamic contact angle measurement and dissolution analysis using biorelevant dissolution media (FASSIF). SEM and focus variation analysis showed that the microstructure and surface morphology was significantly different between samples produced. This was confirmed by further analysis using XµT which showed that an increase in polymer content brought about a decrease in the porosity of the hot-melt extruded dispersions. DSC suggested complete amorphorisation of Gly whereas XRPD suggested incomplete amorphorisation. The static and dynamic contact angle measurement correlated with the dissolution studies using FASSIF media indicating that the initial liquid imbibition process as captured by the dynamic contact angle directly affects the dissolution performance.

Theoretical and Experimental Investigation of Surface Topography Generation in Slow Tool Servo Ultra-Precision Machining of Freeform Surfaces.

Freeform surfaces are featured with superior optical and physical properties and are widely adopted in advanced optical systems. Slow tool servo (STS) ultra-precision machining is an enabling manufacturing technology for fabrication of non-rotationally symmetric surfaces. This work presents a theoretical and experimental study of surface topography generation in STS machining of freeform surfaces. To achieve the nanometric surface topography, a systematic approach for tool path generation was investigated, including tool path planning, tool geometry selection, and tool radius compensation. The tool radius compensation is performed only in one direction to ensure no high frequency motion is imposed on the non-dynamic axis. The development of the surface generation simulation allows the prediction of the surface topography under various tool and machining variables. Furthermore, it provides an important means for better understanding the surface generation mechanism without the need for costly trial and error tests. Machining and measurement experiments of a sinusoidal grid and microlens array sample validated the proposed tool path generation and demonstrated the effectiveness of the STS machining process to fabricate freeform surfaces with nanometric topography. The measurement results also show a uniform topography distribution over the entire surface and agree well with the simulated results.

Direct imaging of the dissolution of salt forms of a carboxylic acid drug.

The optimisation of the pharmaceutical properties of carboxylic acid drugs is often conducted by salt formation. Often, the salt with the best solubility is not chosen due to other factors such as stability, solubility, dissolution and bioavailability that are taken into consideration during the preformulation stage. This work uses advanced imaging techniques to give insights into the preformulation properties that can aid in the empirical approach often used in industry for the selection of salts. Gemfibrozil (GEM) was used as a model poorly soluble drug. Four salts of GEM were made using cyclopropylamine (CPROP), cyclobutylamine (CBUT), cyclopentylamine (CPENT) and cyclohexylamine (CHEX) as counterions. DSC, XRD and SEM were used to confirm and characterise salt formation. IDR obtained using UV-imaging up to 10 min for all the salts showed that an increase in the chain length of the counterion caused a decrease in the IDR. Past the 10 min mark, there was an increase in the IDR value for the CPROP salt, which was visualised using UV-imaging. The developed interfacial (surface) area ratio (Sdr) showed significant surface gains for the compacts. Full dosage form (capsule) imaging showed an improvement over the GEM for all the salts with an increase in chain length of the counterion bringing about a decrease in dissolution which correlated with the obtained UV-imaging IDR data.

Variable-focus microscopy and UV surface dissolution imaging as complementary techniques in intrinsic dissolution rate determination.

This work reports a novel approach to the assessment of the surface properties of compacts used in Surface Dissolution Imaging (SDI). SDI is useful for determining intrinsic dissolution rate (IDR), an important parameter in early stage drug development. Surface topography, post-compaction and post-SDI run, have been measured using a non-contact, optical, three-dimensional microscope based on focus variation, the Alicona Infinite Focus Microscope, with the aim of correlating the IDRs to the surface properties. Ibuprofen (IBU) was used as a model poorly-soluble drug. DSC and XRD were used to monitor possible polymorphic changes that may have occurred post-compaction and post-SDI run. IBUs IDR decreased from 0.033mg/min/cm2 to 0.022mg/min/cm2 from 10 to 20min, respectively, during the experiment. XRD and DSC showed no form changes during the SDI run. The surface topography images showed that a distinct imprint was embossed on the surfaces of some compacts which could affect IDRs. Surface parameter values were associated with the SDI experiments which showed strong correlations with the IDR values. The variable-focus microscope can be used as a complimentary tool in the determination of IDR values from the SDI.