Development of a Phytopharmaceutical Intermediate Product via Spray Drying

The influence of concentration and incorporation time of different drying excipients on the processing yields and physical properties of Eugenia dysenterica DC spray-dried extracts were investigated following a factorial design. Under the established conditions, the process yield ranged from 57.55 to 89.14%, and in most experiments, the recovered products presented suitable flowability and compressibility, as demonstrated by the Hausner factor, Carr index, and angle of repose. Additionally, in a general way, the parameters related to the dried products` flowability varied over a range acceptable for pharmaceutical purposes. An analysis of variance (ANOVA) proved that both factors and some of their interactions significantly affected most of the investigated responses at different levels. Mannitol proved to be an interesting alternative as an excipient for the drying of herbal extracts, even at low concentrations such as 12.5%. Furthermore, these results imply that the best condition to obtain dry extracts of E. dysenterica with high performance and adequate pharmacotechnical properties involves the lowest concentration and the highest incorporation time of mannitol.

Spray Drying of Extracts from Red Yeast Fermentation Broth

Red yeast rice is a pigmented material that is traditionally used in Asia as a food colorant. In addition to food applications, red yeast rice is known in traditional Chinese medicine for its therapeutic actions. The aim of this work was to study the quality interactions during spray drying of extracts from the Monascus ruber van Tiegham fermentation broth. The quality indicators used for the dry powder properties were the levels of monacolin K, ratio of red to yellow pigments, as well as their antioxidant activity. The experiments followed a Box-Behnken design to study the effects of the adjuvant/drug ratio, adjuvant incorporation time, and oulet drying temperature on the pharmacotechnical, chemical, and biological properties of the dry extract. The influences of these factors on the characteristics of the dry powder were evaluated by the bulk density, tapped density, Carr index, Hausner factor, residual moisture content, water activity, antioxidant activity, monacolin K, yellow-to-red pigment ratio, and antioxidant activity. The analysis of variance (ANOVA) on experimental data revealed that an increase in drying temperature significantly increased the dry powder yield and caused an improvement in powder flow properties, which may be related to lower moisture contents. The drying temperature did not affect the monacolin K content in dry powder but showed a complex influence on its antioxidant activity. The increase in drying adjuvant-to-drug ratio affected the yield and also indicated a protective effect on the monacolin K content. The duration of drying adjuvant incorporation had little or negligible effect on powder properties. The dry extracts of red yeast rice showed adequate properties and the process proposed herein can be used to prepare nutraceutical products.

Hot melt granulation of coarse pharmaceutical powders in a spouted bed

The hot melt granulation of a coarse pharmaceutical powder in a top spray spouted bed is described. The substrate was lactose-polyvinylpyrrolidone particles containing or not acetaminophen as a drug model. Polyethylene glycol (MW, 4000) used as binder was atomized onto the bed by a two-fluid spray nozzle. The granulation experiments followed a 2(3) factorial design with triplicates at the center point and were carried out by varying the spray nozzle vertical position, the atomizing air flow rate and the binder feed rate. Granules were evaluated by their pharmacotechnical properties like size distribution, bulk and tapped densities, Carr index, Hausner ratio and tableting characteristics. Analysis of variance showed that granule sizes were affected by the PEG feed rate and atomizing air pressure at the significance levels of 1.0 and 5.0%. respectively, but spray nozzle distance to the substrate bed was not significant. The spray conditions also affected granule flow and consolidation properties. measured by the Carr index and Hausner ratio. Measured densities, Carr indexes and Hausner ratios proved that granules flowability and consolidation properties are adequate for pharmaceutical processing and tableting. Tablets prepared with acetaminophen-containing granules showed good properties and adequate release profiles in in vitro dissolution tests. The results indicate the suitability of spouted beds for the hot melt granulation of pharmaceutical coarse powders. (C) 2008 Elsevier B.V. All rights reserved.

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.

Evaluating Properties of Blended Cements for Concrete Pavements, December 2003

The addition of supplementary cementitious materials (SCMs), such as fly ash (FA) and slag, generally improves concrete workability, durability, and long-term strength. New trends in sustainable development of concrete infrastructure and in environmental regulations on waste disposal are spurring use of SCMs in concrete. However, use of SCM concrete is sometimes limited due to a lack of understanding about material behaviors and lack of proper specifications for its construction practice. It is believed that SCM concrete performance varies significantly with the source and proportion of the cementitious materials. SCM concrete often displays slower hydration, accompanied by slower setting and lower early-age strength, especially under cold weather conditions. The present research was conducted to have a better understanding of SCM concrete behaviors under different weather conditions. In addition to the study of the effect of SCM content on concrete set time using cementitious materials from different sources/manufacturers, further research may be needed to investigate the effects of SCM combinations on concrete flowability, air stability, cracking resistance, and durability.

Self-Consolidating Concrete—Applications for Slip-Form Paving: Phase II, May 2011

The goal of the project was to develop a new type of self-consolidating concrete (SCC) for slip-form paving to simplify construction an make smoother pavements. Developing the new SCC involved two phases: a feasibility study (Phase I sponsored by TPF-5[098] and concrete admixtures industry) and an in-depth mix proportioning and performance study and field applications (Phase II). The phase I study demonstrated that the new type of SCC needs to possess not only excellent self-consolidating ability before a pavement slab is extruded, but also sufficient “green” strength (the strength of the concrete in a plastic state) after the extrusion. To meet these performance criteria, the new type of SCC mixtures should not be as fluid as conventional SCC but just flowable enough to be self-consolidating. That is, this new type of SCC should be semi-flowable self-consolidating concrete (SFSCC). In the phase II study, effects of different materials and admixtures on rheology, especially the thixotropy, and green strength of fresh SFSCC have been further investigated. The results indicate that SFSCC can be designed to (1) be workable enough for machine placement, (2) be self-consolidating without segregation, (3) hold its shape after extrusion from a paver, and (4) have performance properties (strength and durability) comparable with current pavement concrete. Due to the combined flowability (for self-consolidation) and shape-holding ability (for slip-forming) requirements, SFSCC demands higher cementitious content than conventional pavement concrete. Generally, high cementitious content is associated with high drying shrinkage potential of the concrete. However, well-proportioned and well-constructed SFSCC in a bike path constructed at Ames, IA, has not shown any shrinkage cracks after approximately 3 years of field service. On the other hand, another SFSCC pavement with different mix proportions and construction conditions showed random cracking. The results from the field SFSCC performance monitoring implied that not only the mix proportioning method but also the construction practice is important for producing durable SFSCC pavements. A carbon footprint, energy consumption, and cost analysis conducted in this study have suggested that SFSCC is economically comparable to conventional pavement concrete in fixed-form paving construction, with the benefit of faster, quieter, and easier construction.

Self-Consolidating Concrete—Applications for Slip-Form Paving: Phase I (Feasibility Study), 2005

Over-consolidation is often visible as longitudinal vibrator trails in the surface of concrete pavements constructed using slip-form paving. Concrete research and practice have shown that concrete material selection and mix design can be tailored to provide a good compaction without the need for vibration. However, a challenge in developing self-consolidating concrete for slip-form paving (SF SCC) is that the new SF SCC needs to possess not only excellent self-compactibility and stability before extrusion, but also sufficient “green” strength after extrusion, while the concrete is still in a plastic state. The SF SCC to be developed will not be as fluid as the conventional SCC, but it will (1) be workable enough for machine placement, (2) be self-compacting with minimum segregation, (3) hold shape after extrusion from a paver, and (4) have performance properties (strength and durability) compatible to current pavement concrete. The overall objective of this project is to develop a new type of SCC for slip-form paving to produce more workable concrete and smoother pavements, better consolidation of the plastic concrete, and higher rates of production. Phase I demonstrated the feasibility of designing a new type of SF SCC that can not only self-consolidate, but also have sufficient green strength. In this phase, a good balance between flowability and shape stability was achieved by adopting and modifying the mix design of self-consolidating concrete to provide a high content of fine materials in the fresh concrete. It was shown that both the addition of fine particles and the modification of the type of plasticizer significantly improve fresh concrete flowability. The mixes used in this phase were also found to have very good shape stability in the fresh state. Phase II will focus on developing a SF SCC mix design in the lab and a performing a trial of the SF SCC in the field. Phase III will include field study, performance monitoring, and technology transfer.

Powder flow criteria for design of vertical silo walls

For design of vertical silos walls involving the storage of bulk solids to be safe and reliable, it is important knowing the largest possible number of variables such as: flow properties, silo geometry and pattern of flow desired. In order to validate the theories of flow prediction and design of conical hoppers, the flow properties of two bulk solids were determined, the theories of Jenike's flowability and Enstad and Walker for hopper design were analyzed and the results were compared with those experimentally obtained in a reduced model of a semicircular-section silo. Results show that Enstad theory for the hopper design is adequate to occur mass flow inside the silo, and for the sizing of the discharge outlet, the Walker's theory was closer to the appropriate than Jenike's theory, which was higher around 100% than the experimental hopper outlet.

Influence of spray drying operating conditions on microencapsulated rosemary essential oil properties

Spray drying is an important method used by the food industry in the production of microencapsulated flavors to improve handling and dispersion properties. The objective of this study was to evaluate the influence of the process conditions on the properties of rosemary essential oil microencapsulated by spray drying using gum Arabic as encapsulant. The effects of the wall material concentration (10-30%), inlet air temperature (135-195 ºC), and feed flow rate (0.5-1.0 L.h-1) on the moisture content, hygroscopicity, wettability, solubility, bulk and tapped densities, particle density, flowability, and cohesiveness were evaluated using a 2³ central composite rotational experimental design. Moisture content, hygroscopicity and wettability were significantly affected by the three factors analyzed. Bulk density was positively influenced by the wall material concentration and negatively by the inlet air temperature. Particle density was influenced by the wall material concentration and the inlet air temperature variables, both in a negative manner. As for the solubility, tapped density, flowability, and cohesiveness, the models did not fit the data well. The results indicated that moderate wall material concentration (24%), low inlet air temperature (135 ºC), and moderate feed flow rate (0.7 L.h-1) are the best spray drying conditions.

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.

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

Variability of physicochemical properties of an epoxy resin sealer taken from different parts of the same tube

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of the propylene glycol association on some physical and chemical properties of mineral trioxide aggregate

Duarte MAH, Alves de Aguiar K, Zeferino MA, Vivan RR, Ordinola-Zapata R, Tanomaru-Filho M, Weckwerth PH, Kuga MC. Evaluation of the propylene glycol association on some physical and chemical properties of mineral trioxide aggregate. International Endodontic Journal, 45, 565570, 2012. Abstract Aim To evaluate the influence of propylene glycol (PG) on the flowability, setting time, pH and calcium ion release of mineral trioxide aggregate (MTA). Methodology Mineral trioxide aggregate was mixed with different proportions of PG, as follows: group 1: MTA + 100% distilled water (DW); group 2: MTA + 80% DW and 20% PG; group 3: MTA + 50% DW and 50% PG; group 4: MTA + 20% DW and 80% PG; group 5: MTA + 100% PG. The ANSI/ADA No. 57 was followed for evaluating the flowability and the setting time was measured by using ASTM C266-08. For pH and calcium release analyses, 50 acrylic teeth with root-end cavities were filled with the materials (n = 10) and individually immersed in flasks containing 10 mL deionized water. After 3 h, 24 h, 72 h and 168 h, teeth were placed in new flasks and the water in which each specimen was immersed had its pH determined by a pH metre and the calcium release measured by an atomic absorption spectrophotometer with a calcium-specific hollow cathode lamp. Data were analysed by using one-way anova test for global comparison and by using Tukeys test for individual comparisons. Results The highest value of flowability was observed with MTA + 20% DW and 80% PG and the lowest values were found with MTA + 100% DW. They were significantly different compared to the other groups (P < 0.05). The presence of PG did not affect the pH and calcium release. The MTA + 100% PG favoured the highest (P < 0.05) pH and calcium release after 3 h. Increasing the PG proportion interfered (P < 0.05) with the setting time; when used at the volume of 100% setting did not occur. Conclusion The addition of PG to MTA-Angelus increased its setting time, improved flowability and increased the pH and calcium ion release during the initial post-mixing periods. The ratio of 80% DW 20% PG is recommended.

Estudos de pré-formulação de cápsulas gelatinosas duras contendo formulação de extrato de Gymnema sylvestre em pó

Gymnema sylvestre extract (GSE) is a plant product widely used as an adjuvant in the treatment of diabetes mellitus and commercially available as a powder. Owing to its low flowability, the manufacturing of hard gelatin capsules containing GSE faces specific problems. The purpose of this study was to investigate the best excipient (starch, lactose or microcrystalline cellulose) for hard gelatin capsules containing GSE. The technological properties such us bulk density (ρβ); tapped density (ρt); inter-particle porosity (Ie); Carr index (CI); Hausner ratio (HR); loss on drying (%LOD) and particle size distribution (%Pf) of the various GSE mixtures were investigated with the aim of identifying the best excipient. The need for lubricants (talc/magnesium stearate) was also assessed. GSE was characterized as a fine powder with more than 50% of its particles between 0.149mm to 0.250mm; furthermore, CI=25.6%; RH=1.3 and Ie = 25.6% and, as expected with such properties, it showed poor flowability. All the excipients investigated were able to change the technological properties of GSE and the powder mixture containing microcrystalline cellulose gave the best results.

Construção e desenvolvimento de um secador de leito pulso-fluidizado para secagem de pastas e polpas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)