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This study investigates the use of twin-screw binder-free melt granulation (BFMG) in the development of high-dose solid dose formulations for low melting point thermally stable drugs. Both ibuprofen and guaifenesin are examined. By granulating pure API powder, it is shown that BFMG can successfully be used to produce granules that contain 100% API. A design of experiments (DoE) response surface methodology was used to establish the design space for the end-product. The effects of the most relevant process variables (barrel operating temperature, powder feed rate, screw speed and screw configuration) on granule properties (outlet temperature, size distribution, morphology, flowability, compressibility, porosity) and tablet attributes (tensile strength and in-vitro dissolution) were thoroughly studied. Barrel temperature (alone or in interactions with the other variables) represented the most significant variable for both drugs since it governs the formation of granules by partial melting and subsequent agglomeration of the fed powder. Interestingly, the shear action originated by screw speed and screw configuration resulted in various significant responses depending on the drug substance, indicating that it can also be affected by the nature of the processed molecule. Flow properties were improved (i.e., lower Hausner ratio) for both drugs after formation of granules. Tabletability was also tested by preparing 600 mg tablets for all samples. Surprisingly, the resulting granules were highly compactible, requiring only 1% lubricant to form strong tablets containing 96% API and 3% disintegrant. The results also showed that tablets become harder as the granule size increased, especially for guaifenesin. As expected, in-vitro dissolution results indicated that tablets and capsules showed slightly slower dissolution rates than the granules.

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RESUMO

Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire® 50:13. A two-level factorial design was used to verify the influence of Gelucire® 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non-granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability.

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Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs.

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RESUMO

In this work, principal component analysis and cluster analysis were applied as helping tools to extract useful information in the development of formulations and manufacturing processes of melt granulates. Two melt granulation processes that differ in the shear stress applied to the solid bed during melting step were designed. These processes employ equipment frequently used in the local pharmaceutical industry. The selected binders include both hydrophilic and hydrophobic excipients, which were used alone or in binary mixtures. Granulates were characterized regarding their physicomechanical properties, including their compaction behavior. The resulting tablets were also evaluated. The selected multivariate statistical methods proved to be useful in facilitating the interpretation of the collected data and the study of the properties of granulates and tablets, as well as the selection of more efficient production processes.

Neste trabalho, foram aplicadas as técnicas de análise de componentes principais e de análise de agrupamentos para extrair informações úteis no desenvolvimento de formulações e de processos de produção de granulados por fusão. Desenharam-se dois processos de granulação por fusão que apresentam diferenças na tensão de cisalhamento aplicada ao leito sólido durante a etapa de fusão. Esses processos empregam equipamentos frequentemente usados na indústria farmacêutica local. Os ligantes escolhidos incluíram excipientes tanto hidrofílicos quanto hidrofóbicos, utilizados de forma individual ou em misturas binárias. Os granulados foram caracterizados quanto às suas propriedades físico-mecânicas, incluindo seu desempenho no processo de compactação. Os comprimidos resultantes também foram avaliados. Os métodos de análise multivariada escolhidos provaram ser úteis para facilitar a interpretação dos dados coletados e o estudo das propriedades dos granulados e dos comprimidos, bem como a seleção de processos de produção mais eficientes.

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