Recebido em 16/10/10; aceito em 11/2/11; publicado na web em 15/4/11 THERMAL ANALYSIS APPLIED TO DRUGS AND PHARMACEUTICAL FORMULATIONS IN PHARMACEUTICAL INDUSTRY. Several matters of the pharmaceutical demonstrate the great importance of thermal analysis application, especially TG and DSC for the pharmaceutical industry future, namely: characterization of the drugs with the thermal events definition, in studies of drug purity, in the polymorphs identification, in compatibility studies of solid dosage pharmaceutical formulations, in drugs and pharmaceutical formulations thermal stability, and in determination of shelf life for isothermal degradation kinetics by extrapolation using the Arrhenius equation. Thus, the test results obtained from thermal analysis are directly related to the quality of a pharmaceutical product, whether the stability or bioavailability of the pharmaceutical product.Keywords: thermal analysis; pharmaceutical industry; characterization. INTRODUÇÃOVários estudos relacionados à aplicação da termogravimetria (TG) e calorimetria exploratória diferencial (DSC) na caracterização, avaliação de pureza, compatibilidade de formulação farmacêutica, identificação de polimorfismo, estabilidade e decomposição térmica de fármacos e medicamentos encontram-se descritos na literatura. A TG é utilizada para medir a variação de massa em função da temperatura em uma atmosfera controlada sob um programa de aquecimento. Para fins farmacêuticos, seu uso é descrito na caracterização, determinação de pureza e de umidade, identificação de pseudopolimorfismo, na avaliação da estabilidade de fármacos e medicamentos e em estudos de cinética de degradação. A DSC é utilizada para medir a diferença de fluxo de calor entre uma substância e um material de referência em função de um programa de aquecimento ou resfriamento. Na área farmacêutica é utilizada na caracterização térmica e determinação da pureza de fármacos, estudos de compatibilidade entre os constituintes da formulação e identificação de polimorfismo com determinação das entalpias de cada forma cristalina.Recentemente, muitos trabalhos em análise térmica têm sido publicados na área aplicada à indústria farmacêutica. Desta forma, as indústrias brasileiras estão, cada vez mais, demonstrando o interesse neste âmbito. Os artigos publicados demonstram que os dados obtidos por análise térmica estão diretamente relacionados com a qualidade final de um produto farmacêutico, seja quanto à eficácia terapêutica do medicamento ou à estabilidade do mesmo ao longo do prazo de validade. Além disso, muitos órgãos regulamentadores de insumos e produtos farmacêuticos já descrevem a importância da análise térmica e dos parâmetros de qualidade dela provenientes. 1-7 APLICAÇÕESA Farmacopeia Japonesa, JP XIV, foi a primeira a descrever os métodos de análise térmica, mas sem nenhuma exigência em monografias. 6 A TG foi descrita apenas como um método alternativo para o teste de perda por dessecação em matérias-primas e ainda foi citada como suporte para aplicações do tipo estudo de purez...

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor used worldwide to treat AIDS. The aim of this study was to investigate the structural and dynamic properties of the polymorphic form I of the drug by thermal analysis, Fourier transform infrared spectroscopy, solid-state NMR, and powder X-ray diffraction. A full assignment of 13 C NMR resonances was achieved for the first time. Variable-temperature studies were conducted, and the results were related to changes in the TDF structure and dynamics of specific molecular fragments, especially of the fumarate portion of the molecule. It was found that, under heating, the 13 C NMR signals related to the carbon atoms of the disoproxil fumarate moiety split into two resonances. The region of the phosphonate vicinity also changes. This can reflect the lack of symmetry of the two molecules in the asymmetric unit after heating. This solid−solid transformation was related to DSC and XRD observations.

Purpose: Vascular endothelial growth factor (VEGF) may contribute to the scarring process resulting from glaucoma filtration surgery, since this cytokine may stimulate fibroblast proliferation. The aim of this study was to describe a new bevacizumab-loaded polyurethane implant (BPUI) and to evaluate its effectiveness as a new drug delivery system of anti-VEGF antibody in a rabbit model of glaucoma filtration surgery. Methods: An aqueous dispersion of polyurethane was obtained via the conventional process. Bevacizumab (1.5 mg) was then incorporated into the dispersion and was subsequently dried to form the polymeric films. Films with dimensions of 3 · 3 · 1 mm that either did (group BPUI, n = 10) or did not contain bevacizumab (group PUI, n = 10) were implanted in the subconjunctival space, at the surgical site in 1 eye of each rabbit. The in vitro bevacizumab release was evaluated using size-exclusion high-performance liquid chromatography (HPLC), and the in vivo effects of the drug were investigated in a rabbit experimental trabeculectomy model by examining the bleb characteristics and collagen accumulation, and by performing immunohistological analyses of VEGF expression. Results: HPLC showed that only 10% of the bevacizumab in the implants had been released by postoperative day 5. In vivo studies demonstrated that the drug had no adverse effects; however, no significant differences in either the bleb area score or the collagen deposit intensity between the group PUI and the group that BPUI were observed. Moreover, the group BPUI presented a significantly lower proportion of VEGF-expressing fibroblasts than group PUI (0.17 -0.03 vs. 0.35 -0.05 cells/field, P = 0.005). Conclusions: This study demonstrated that bevacizumab release from the BPUIs only occurred for a short time probably from the surface of the films. Nevertheless, they were well tolerated in rabbit eyes and reduced the number of VEGF-expressing fibroblasts.

THERMAL ANALYSIS APPLIED TO SIMVASTATIN CHARACTERIZATION IN PHARMACEUTICAL FORMULATIONS. Thermogravimetry (TG) and differential scanning calorimetry (DSC) are used in pharmaceutical studies for drugs characterization, purity, formulations compatibility, polymorphism identification, stability evaluation, and thermal decomposition of drugs and pharmaceutical formulations. Simvastatin showed fusion at 138.5 ºC and thermal stability up to 248 ºC. Simvastatin was incompatible with preservative excipient butylhydroxyanisole (BHA) performing a process of crystal amorphization. The drug showed morphological polymorphism, where it has the same unit cell but with different crystal habits according to the recrystallization solvent.

An HPLC method was developed and validated aiming to quantify the cyclosporine-A incorporated into intraocular implants, released from them; and in direct contact with the degradation products of PLGA. The separation was carried out in isocratic mode using acetonitrile/water (70:30) as mobile phase, a C18 column at 80 ºC and UV detection at 210 nm. The method provided selectivity based on resolution among peaks. It was linear over the range of 2.5-40.0 µg/mL. The quantitation and detection limits were 0.8 and 1.2 µg/mL, respectively. The recovery was 101.8% and intra-day and inter-day precision was close to 2%

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Intraocular delivery systems have been developed to treat many eye diseases, especially those affecting the posterior segment of the eye. However, ocular toxoplasmosis, the leading cause of infectious posterior uveitis in the world, still lacks an effective treatment. Therefore, our group developed an intravitreal polymeric implant to release clindamycin, a potent anti-Toxoplasma antibiotic. In this work, we used different techniques such as differential scanning calorimetry, thermogravimetry, X-ray diffraction, scanning electron microscopy, and fourier-transform infrared spectroscopy to investigate drug/polymer properties while manufacturing the delivery system. We showed that the lyophilization, hot molding process, and sterilization by gamma irradiation did not change drug/polymer physical-chemistry properties. The drug was found to be homogeneously dispersed into the poly lactic-co-glycolic acid (PLGA) chains and the profile release was characterized by an initial burst followed by prolonged release. The drug profile release was not modified after gamma irradiation and non-covalent interaction was found between the drug and the PLGA. We also observed the preservation of the drug activity by showing the potent anti-Toxoplasma effect of the implant, after 24-72 h in contact with cells infected by the parasite, which highlights this system as an alternative to treat toxoplasmic retinochoroiditis.

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