Ultrasound-assisted surface engineering of pharmaceutical powders

Effective processing of powdered particles can facilitate powder handling and result in better drug product performance, which is of great importance in the pharmaceutical industry where the majority of active pharmaceutical ingredients (APIs) are delivered as solid dosage forms. The purpose of this work was to develop a new ultrasound-assisted method for particle surface modification and thin-coating of pharmaceutical powders. The ultrasound was used to produce an aqueous mist with or without a coating agent. By using the proposed technique, it was possible to decrease the interparticular interactions and improve rheological properties of poorly-flowing water-soluble powders by aqueous smoothing of the rough surfaces of irregular particles. In turn, hydrophilic polymer thin-coating of a hydrophobic substance diminished the triboelectrostatic charge transfer and improved the flowability of highly cohesive powder. To determine the coating efficiency of the technique, the bioactive molecule β-galactosidase was layered onto the surface of powdered lactose particles. Enzyme-treated materials were analysed by assaying the quantity of the reaction product generated during enzymatic cleavage of the milk sugar. A near-linear increase in the thickness of the drug layer was obtained during progressive treatment. Using the enzyme coating procedure, it was confirmed that the ultrasound-assisted technique is suitable for processing labile protein materials. In addition, this pre-treatment of milk sugar could be used to improve utilization of lactose-containing formulations for populations suffering from severe lactose intolerance. Furthermore, the applicability of the thin-coating technique for improving homogeneity of low-dose solid dosage forms was shown. The carrier particles coated with API gave rise to uniform distribution of the drug within the powder. The mixture remained homogeneous during further tabletting, whereas the reference physical powder mixture was subject to segregation. In conclusion, ultrasound-assisted surface engineering of pharmaceutical powders can be effective technology for improving formulation and performance of solid dosage forms such as dry powder inhalers (DPI) and direct compression products.

Characterization and evaluation of melibiose as novel excipient in tablet compaction

Lactose is probably the most used tablet excipient in the field of pharmacy. Although lactose is thoroughly characterized and available in many different forms there is a need to find a replacer for lactose as a filler/binder in tablet formulations because it has some downsides. Melibiose is a relatively unknown disaccharide that has not been thoroughly characterized and not previously used as an excipient in tablets. Structurally melibiose is close to lactose as it is also formed from the same two monosaccharides, glucose and galactose. Aim of this research is to characterize and to study physicochemical properties of melibiose. Also the potential of melibiose to be used as pharmaceutical tablet excipient, even as a substitute for lactose is evaluated. Current knowledge about fundamentals of tableting and methods for determinating of deformation behavior and tabletability are reviewed. In this research Raman spectroscopy, X-ray powder diffraction (XRPD), near-infrared spectroscopy (NIR) and Fourier-transform infrared spectroscopy (FT-IR) were used to study differences between two melibiose batches purchased from two suppliers. In NIR and FT-IR measurements no difference between materials could be observed. XPRD and Raman however found differences between the two melibiose batches. Also the effects of moisture content and heating to material properties were studied and moisture content of materials seems to cause some differences. Thermal analytical methods, differential scanning calorimetry (DSC) and thermogravimetry (TG) were used to study thermal behaviour of melibiose and difference between materials was found. Other melibiose batch contains residual water which evaporates at higher temperatures causing the differences in thermal behaviour. Scanning electron microscopy images were used to evaluate particle size, particle shape and morphology. Bulk, tapped and true densities and flow properties of melibiose was measured. Particle size of the melibiose batches are quite different resulting causing differences in the flowability. Instrumented tableting machine and compression simulator were used to evaluate tableting properties of melbiose compared to α-lactose monohydrate. Heckel analysis and strain-rate sensitivity index were used to determine deformation mechanism of melibiose monohydrate in relation to α–lactose monohydrate during compaction. Melibiose seems to have similar deformation behaviour than α-lactose monohydrate. Melibiose is most likely fragmenting material. Melibiose has better compactibility than α – lactose monohydrate as it produces tablets with higher tensile strength with similar compression pressures. More compression studies are however needed to confirm these results because limitations of this study.

High-Temperature Workability of Thixocast A356 Aluminum Alloy

The present work highlights the role of globular microstructure on the workability of A356 aluminum alloy at elevated temperature. The hot deformation behavior was studied by isothermal hot compression tests in the temperature range 573 K to 773 K (300 A degrees C to 500 A degrees C) and strain rate range of 0.001 to 10 s(-1). The flow stress data obtained from the tests were used to estimate the strain rate sensitivity and strain rate hardening. Flow stress analysis of the alloy shows that the effect of temperature on strain hardening is more significant at lower strain levels and strain rate sensitivity is independent of strain. The results also reveal that the flowability of conventionally cast alloy increases after changing the dendritic microstructure into a globular structure through semisolid processing route. Thixocast alloy exhibits lower yield strength and higher elongation at elevated temperature in comparisons to conventionally cast values. This property has an important implication toward thixo-forming at an elevated temperature. (C) The Minerals, Metals & Materials Society and ASM International 2015

Determination of the rheological parameters of self-compacting concrete matrix using slump flow test

The classification of a concrete mixture as self-compacting (SCC) is performed by a series of empirical characterization tests that have been designed to assess not only the flowability of the mixture but also its segregation resistance and filling ability. The objective of the present work is to correlate the rheological parameters of SCC matrix, yield stress and plastic viscosity, to slump flow measurements. The focus of the slump flow test investigation was centered on the fully yielded flow regime and an empirical model relating the yield stress to material and flow parameters is proposed. Our experimental data revealed that the time for a spread of 500 mm which is used in engineering practice as reference for measurement parameters, is an arbitrary choice. Our findings indicate that the non-dimensional final spread is linearly related to the non-dimensional yield-stress. Finally, there are strong indications that the non-dimensional viscosity of the mixture is associated with the non-dimensional final spread as well as the stopping time of the slump flow; this experimental data set suggests an exponential decay of the final spread and stopping time with viscosity. © Appl. Rheol.

Preliminary study on melt-spinning, adhesion and adsorption properties of poly(lactic acid)

For the purpose of manufacturing cigarette filter tows and filter rods, the melt-spinning, adhesion and adsorption properties of poly(lactic acid) were studied. The rheological measurements were performed to examine the effects of various processing conditions on the melt flowability and spinnability, including those of residual moisture. The melt spinning and post-processings were followed by determining the molecular weight, thermal and mechanical properties of the fibers. The results obtained were useful to establishing the specification of the PLA resins for filter tows and filter rods manufacturing and to choosing proper melt-spinning and post-processing technologies.

Dry mixing of spice powders - investigation of effect of powder properties on mixture quality of binary powder mixtures

Dry mixing of binary food powders was conducted in a 2L lab-scale paddle mixer. Different types of food powders such as paprika, oregano, black pepper, onion powder and salt were used for the studies. A novel method based on a digital colour imaging system (DCI) was developed to measure the mixture quality (MQ) of binary food powder mixtures. The salt conductivity method was also used as an alternative method to measure the MQ. In the first part of the study the DCI method was developed and it showed potential for assessing MQ of binary powder mixes provided there was huge colour difference between the powders. In the second and third part of the study the effect of composition, water content, particle size and bulk density on MQ was studied. Flowability of powders at various moisture contents was also investigated. The mixing behaviour was assessed using coefficient of variation. Results showed that water content and composition influence the mixing behavior of powders. Good mixing was observed up to size ratios of 4.45 and at higher ratios MQ disimproved. The bulk density had a larger influence on the MQ. In the final study the MQ evaluation of binary and ternary powder mixtures was compared by using two methods – salt conductivity method and DCI method. Two binary food and two quaternary food powder mixtures with different coloured ingredients were studied. Overall results showed that DCI method has a potential for use by industries and it can analyse powder mixtures with components that have differences in colour and that are not segregating in nature.

Segregation of bulk particulates through multiple process handling steps

Segregation or de-blending of bulk particulates is a problem that is encountered in many industrial sectors. The magnitude of segregation can often determine whether a complete production batch can be transferred for onward processing within the plant or released to market. It is a phenomenon that impacts directly upon the profitability of a process. Segregation can occur through a coincidence of a range of variables that relate to the process and bulk particulate properties, common mechanisms for this include; percolation, surface effect (rolling) and elutriation. The importance to industry of predicting the sensitivity of bulk particulates to segregation cannot be under-estimated, and to this end various test procedures have been developed. Within many industries striving to improve product quality and reduce wastage, the determination of variability in blend consistency caused by segregation is an increasing priority. This paper considers recent work undertaken to evaluate the effects of multiple handling operations on the degree of segregation that results. The bulk properties of segregability (and resulting flowability) can not only influence the product consistency, but can have great influence over the process (production) control and performance.

Gastroretentive Extended-Release Floating Granules Prepared Using a Novel Fluidized Hot Melt Granulation (FHMG) Technique

The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid of low melting point materials, using Compritol 888 ATO and Gelucire 50/13 as meltable binders, in place of conventional liquid binders. The physicochemical properties, morphology, floating properties, and drug release of the manufactured granules were investigated. Granules prepared by this method were spherical in shape and showed good flowability. The floating granules exhibited sustained release exceeding 10 h. Granule buoyancy (floating time and strength) and drug release properties were significantly influenced by formulation variables such as excipient type and concentration, and the physical characteristics (particle size, hydrophilicity) of the excipients. Drug release rate was increased by increasing the concentration of hydroxypropyl cellulose (HPC) and Gelucire 50/13, or by decreasing the particle size of HPC. Floating strength was improved through the incorporation of sodium bicarbonate and citric acid. Furthermore, floating strength was influenced by the concentration of HPC within the formulation. Granules prepared in this way show good physical characteristics, floating ability, and drug release properties when placed in simulated gastric fluid. Moreover, the drug release and floating properties can be controlled by modification of the ratio or physical characteristics of the excipients used in the formulation.

Micromechanical analysis of cohesive granular materials using the discrete element method with an adhesive elasto-plastic contact model

An adhesive elasto-plastic contact model for the discrete element method with three dimensional non-spherical particles is proposed and investigated to achieve quantitative prediction of cohesive powder flowability. Simulations have been performed for uniaxial consolidation followed by unconfined compression to failure using this model. The model has been shown to be capable of predicting the experimental flow function (unconfined compressive strength vs. the prior consolidation stress) for a limestone powder which has been selected as a reference solid in the Europe wide PARDEM research network. Contact plasticity in the model is shown to affect the flowability significantly and is thus essential for producing satisfactory computations of the behaviour of a cohesive granular material. The model predicts a linear relationship between a normalized unconfined compressive strength and the product of coordination number and solid fraction. This linear relationship is in line with the Rumpf model for the tensile strength of particulate agglomerate. Even when the contact adhesion is forced to remain constant, the increasing unconfined strength arising from stress consolidation is still predicted, which has its origin in the contact plasticity leading to microstructural evolution of the coordination number. The filled porosity is predicted to increase as the contact adhesion increases. Under confined compression, the porosity reduces more gradually for the load-dependent adhesion compared to constant adhesion. It was found that the contribution of adhesive force to the limiting friction has a significant effect on the bulk unconfined strength. The results provide new insights and propose a micromechanical based measure for characterising the strength and flowability of cohesive granular materials. 

Improved polymeric medical devices for active substances delivery

The work presented in this thesis was developed in collaboration with a Portuguese company, BeyonDevices, devoted to pharmaceutical packaging, medical technology and device industry. Specifically, the composition impact and surface modification of two polymeric medical devices from the company were studied: inhalers and vaginal applicators. The polyethylene-based vaginal applicator was modified using supercritical fluid technology to acquire self-cleaning properties and prevent the transport of bacteria and yeasts to vaginal flora. For that, in-situ polymerization of 2-substituted oxazolines was performed within the polyethylene matrix using supercritical carbon dioxide. The cationic ring-opening polymerization process was followed by end-capping with N,N-dimethyldodecylamine. Furthermore, for the same propose, the polyethylene matrix was impregnated with lavender oil in supercritical medium. The obtained materials were characterized physical and morphologically and the antimicrobial activity against bacteria and yeasts was accessed. Materials modified using 2-substituted oxazolines showed an effective killing ability for all the tested microorganisms, while the materials modified with lavender oil did not show antimicrobial activity. Only materials modified with oligo(2-ethyl-2-oxazoline) maintain the activity during the long term stability. Furthermore, the cytotoxicity of the materials was tested, confirming their biocompatibilty. Regarding the inhaler, its surface was modified in order to improve powder flowability and consequently, to reduce powder retention in the inhaler´s nozzle. New dry powder inhalers (DPIs), with different needle’s diameters, were evaluated in terms of internal resistance and uniformity of the emitted dose. It was observed that they present a mean resistance of 0.06 cmH2O0.5/(L/min) and the maximum emitted dose obtained was 68.9% for the inhaler with higher needle´s diameter (2 mm). Thus, this inhaler was used as a test and modified by the coating with a commonly-used force control agent, magnesium stearate, dried with supercritical carbon dioxide (scCO2) and the uniformity of delivered dose tests were repeated. The modified inhaler showed an increase in emitted dose from 68.9% to 71.3% for lactose and from 30.0% to 33.7% for Foradil.

Selection of operational parameters for the production of instant soy protein isolate by pulsed fluid bed agglomeration

The objective of this study was to select the optimal operational conditions for the production of instant soy protein isolate (SPI) by pulsed fluid bed agglomeration. The spray-dried SPI was characterized as being a cohesive powder, presenting cracks and channeling formation during its fluidization (Geldart type A). The process was carried out in a pulsed fluid bed, and aqueous maltodextrin solution was used as liquid binder. Air pulsation, at a frequency of 600 rpm, was used to fluidize the cohesive SPI particles and to allow agglomeration to occur. Seventeen tests were performed according to a central composite design. Independent variables were (i) feed flow rate (0.5-3.5 g/min), (ii) atomizing air pressure (0.5-1.5 bar) and (iii) binder concentration (10-50%). Mean particle diameter, process yield and product moisture were analyzed as responses. Surface response analysis led to the selection of optimal operational parameters, following which larger granules with low moisture content and high process yield were produced. Product transformations were also evaluated by the analysis of size distribution, flowability, cohesiveness and wettability. When compared to raw material, agglomerated particles were more porous and had a more irregular shape, presenting a wetting time decrease, free-flow improvement and cohesiveness reduction. (C) 2010 Elsevier B.V. All rights reserved.

Relationship between processing, surface energy and bulk properties of ultrafine silk particles

Silk particles of different sizes and shapes were produced by milling and interactions with a series of polar and non-polar gaseous probes were investigated using an inverse gas chromatography technique. The surface energy of all silk materials is mostly determined by long range dispersive interactions such as van der Waals forces. The surface energy increases and surface energy heterogeneity widens after milling. All samples have amphoteric surfaces and the concentration of acidic groups increases after milling while the surfaces remain predominantly basic. We also examined powder compression and flow behaviours using a rheometer. Increase in surface energy, surface area, and static charges in sub-micron air jet milled particles contributed to their aggregation and therefore improved flowability. However they collapse under large pressures and form highly cohesive powder. Alkaline hydrolysis resulted in more crystalline fibres which on milling produced particles with higher density, lower surface energy and improved flowability. The compressibility, bulk density and cohesion of the powders depend on the surface energy as well as on particle size, surface area, aggregation state and the testing conditions, notably the consolidated and unconsolidated states. The study has helped in understanding how surface energy and flowability of particles can be changed via different fabrication approaches.

Estudo de pré-formulação para dose fixa combinada dos tuberculostáticos rifampicina, isoniazida, pirazinamida e etambutol (4 em 1)

According to the global framework regarding new cases of tuberculosis, Brazil appears at the 18th place. Thus, the Ministry of Health has defined this disease as a priority in the governmental policies. As a consequence, studies concerning treatment and prevention have increased. Fixed-dose combination formulations (FDC) are recognized as beneficial and are recommended by WHO, but they present instability and loss on rifampicin bioavailability. The main purpose of this work was to carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs: rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients (lactose, cellulose, magnesium stearate and talc), in order to develop an FDC product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250 mg of ethambutol). The studies consisted of the determination of particle size and distribution (Ferret s diameter) and shape through optical microscopy, as well as rheological and technological properties (bulk and tapped densities, Hausner Factor, Carr s Index, repose angle and flux rate) and interactions among drugs and drug excipient through thermal analysis (DSC, DTA, TG and your derivate). The results showed that, except isoniazid, the other drugs presented poor rheological properties, determined by the physical characteristics of the particles: small size and rod like particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol, beyond its low density. The 4 drug mixture also not presented flowability, particularly that one containing drug quantity indicated for the formulation of FDC products. In this mixture, isoniazid, that has the best flowability, was added in a lower concentration. The addition of microcrystalline cellulose, magnesium stearate and talc to the drug mixtures improved flowability properties. In DSC analysis probable interactions among drugs were found, supporting the hypothesis of ethambutol and pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3- formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the mixtures containing lactose Supertab® DSC curves evidenced incompatibility among drugs and excipient. In the DSC curves of mixtures containing cellulose MC101®, magnesium stearate and talc, no alterations were observed comparing to the drug profiles. The TG/DTG of the binary and ternary mixtures curves showed different thermogravimetrics profiles relating that observed to the drug isolated, with the thermal decomposition early supporting the evidences of incompatibilities showed in the DSC and DTA curves