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Water for injection is used in multiple applications in the biopharmaceutical industry. Regarding this, several methods have been use to generate water with this high quality. Within them, the thermocompression distillation method has been widely employed. However, reports on the maintenance of the qualification and validation status of thermocompression systems used for water for injection generation are non-existent in the scientific literature. Therefore, this paper sought to give results of continuous process verification of a system used for water for injection generation over 2 years analyzing the level of conductivity, nitrate, total organic carbon, endotoxins, and microbiology in 1284 water samples. The main findings were that conductivity and nitrate values were always below the specification limit defined according to the United States Pharmacopeia and European Pharmacopoeia, respectively. The highest total organic carbon value measured was 156 ppb. Regarding the microbiology results, the maximum endotoxin content detected was 0.063 EU/mL and 2 cfu/100 mL. In conclusion, this study demonstrated that the analyzed water for injection system operated under a validated status for 2 years, and it was supported by an appropriate monitoring program according to current process validation guidelines.LAY ABSTRACT: There are multiple methods used to produce water for injection in the biopharmaceutical industry. The thermocompression distillation method has been one of the most used methods for the production of this high-quality water. Nevertheless, to verify maintenance of the validated state of these systems it is necessary to carry out continued process verification of different parameters such as conductivity, total organic carbon, limulus amebocyte lysate, and microbiology according to the mandatory requirements of the United States Pharmacopeia and the European Pharmacopoeia. Therefore, this article presents an example of the application of thermocompression technology to generate water for injection and evidence of continuous monitoring to allow demonstration of the efficiency and reliability of these systems used in the biotechnological industry.

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Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥ 2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.

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The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP-MAS (13)C nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry, and Fourier transform infrared spectrometry (FTIR) and near-infrared spectroscopy. The morphology of spray-dried chitosan acid salts showed tendency toward higher sphericity when higher temperatures in a spray-drying process were applied. Analysis by XRPD indicated that all chitosan acid salts studied were amorphous solids. Solid-state (13)C NMR spectra revealed the evidence of the partial conversion of chitosan acetate to chitin and also conversion to acetyl amide form which appears to be dependent on the spray-drying process. The FTIR spectra suggested that the organic acids applied in spray drying may interact with chitosan at the position of amino groups to form chitosan salts. With all three chitosan acid salts, the FTIR bands at 1,597 and 1,615 cm(-1) were diminished suggesting that -NH groups are protonated. The FTIR spectra of all chitosan acid salts exhibited ammonium and carboxylate bands at 1,630 and 1,556 cm(-1), respectively. In conclusion, spray drying is a potential method of preparing acid salts from chitosan obtained by deacetylation of chitin from lobster (P. argus) origin.

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The aim of this study was to develop and evaluate a floating multiparticulate gastroretentive system for the modified release of zidovudine (AZT). AZT was used as a model drug water-soluble at therapeutic doses. The floating gastroretentive system was obtained by co-precipitation, after solvent diffusion and evaporation. The proposed system was evaluated in vitro for particle morphology, lag time and floating time, loading rate, release profile, and the release kinetic of AZT release. AZT's physico-chemical characteristics were evaluated by differential scanning calorimetry (DSC), X-ray diffraction (XDR) and infrared spectroscopy (IR). The particles obtained were sphere-shaped, hollow, and had porous walls. The floating was immediate, and floating time was higher than 12 h. The loading rate was 34.0 ± 9.0%. The system obtained had an extended release. DSC and XDR results showed a modification in AZT's solid state. IR spectroscopy revealed that the chemical structure of the AZT was unchanged. The hollow microballoons presented gastroretentive, floating, and extended-release properties.

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The current drug research techniques, combinatorial synthesis and high throughput screening, enabled the obtaining and pre-evaluation of thousands of compounds in short time. In order to chose the best hits to become leads, observation of drug-likeness tries to optimize this selection. Probably, the most widely used filter is Lipinski's Rule-of-five, which proposes that molecules with poor permeation and oral absorption have molecular weight > 500, Clog P > 5, hydrogen-bond donor > 5 and hydrogen-bond acceptor > 10. In order to evaluate the Rule-of-five, the top pharmaceutical products in 2007 were analyzed. Among 60 drugs, 7 (atorvastatin, montelukast, docetaxel, telmisartan, tacrolimus, leuprolide and olmesartan) did not fit the rule, and 5 failed only one of the threshold values. It was possible to conclude that the rule is very useful to select better compounds in chemolibraries, but it must be used carefully and with criteria, to avoid a possible exclusion of promising compounds.

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New Product Portfolio Management is aimed at helping decision-makers better select projects for new products based on key criteria for the manufacturer. The Brazilian pharmaceutical industry has been undergoing change due to stricter sanitary requirements following the enactment of the Generic Law in 1999. This paper presents the results of a research study aimed at clarifying the rationale employed by national pharmaceutical companies in selecting and prioritizing their new product development projects. Consequently, proposals for an analytical structure that could help these companies better select their products were produced. The research was carried out using case study methodology in which four different companies were investigated. The results of the field study confirmed that these companies had a non-structured Product Development System and that the selection of new product development projects was made on a non-systematic basis. The research also identified key criteria for the selection of projects of new pharmaceutical products, which provided the basis for the preparation of a proposal for a managerial standard for application of New Product Portfolio Management.

A gestão de portfólio de projetos de novos produtos visa a auxiliar os tomadores de decisão a selecionar projetos de novos produtos considerando critérios importantes para a organização. A indústria farmacêutica brasileira tem passado por transformações devido ao aumento das exigências sanitárias após a Lei de Genéricos, de 1999. O objetivo deste trabalho foi entender como as indústrias farmacêuticas brasileiras selecionam seus projetos de desenvolvimento de novos produtos e propor uma estrutura que possa auxiliar estas empresas a selecionar seus projetos de produtos. Foi utilizada a metodologia de estudo de caso e uma mostra de quatro organizações foi investigada. Os resultados indicam que essas empresas apresentam um desenvolvimento de produtos não estruturado e que a seleção de projetos de novos produtos é realizada de forma não-sistemática. Critérios importantes para a seleção de projetos de novos produtos foram identificados e utilizados para elaboração de um padrão gerencial para aplicação da gestão de portfólio de projetos de novos produtos.

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A stability-indicating reversed-phase liquid chromatography (LC) method was developed and validated for the determination of lumiracoxib in pharmaceutical formulations. The LC method was carried out on a Synergi fusion C(18) column (150 mmx4.6mm), maintained at 30 degrees C. The mobile phase was composed of phosphoric acid (25 mM; pH 3.0)/acetonitrile (40:60, v/v), run at a flow rate of 1.0mL/min, and detection at 272nm. The chromatographic separation was obtained within 10 min and it was linear in the concentration range of 10-100 microg/mL (r(2)=0.9999). Validation parameters such as the specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range. Stress studies were carried out and no interference of the degradation products was detected. Moreover, the proposed method was successfully applied for the assay of lumiracoxib in pharmaceutical formulations.

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The pentavalent antimonies, mainly the meglumine antimoniate, are recommends as first-choice medicines for leishmaniasis therapy. In this work we described the development of formulations of meglumine antimoniate injectable medication, as well as the analytical methodology used in the selective determination of Sb(III) and Sb(Total) by hydride generation - inductively coupled plasma atomic emission spectrometry (HG-ICP-AES) and ICP-AES, respectively. On that purpose the analytical methodology was developed focusing on the HG-ICP-AES technique. The formulations using propylene glycol/water as vehicles in a 20:80 proportion were more appropriate for subsequent use in industrial scale. These formulations also showed a lower variation on Sb(III) percentage, no need of buffer solution to stabilize the formulation and no influence of the autoclaving in the quality of the product. The results of the development of the analytical methodology point out the proposed method as an efficient alternative for the determination of Sb(III) in the presence of large quantities of Sb(V) in injectable solutions of meglumine antimoniate, in a selective, linear, accurate and precise manner. In addition, the method showed a low limit of quantification, less interference of the matrix, and more resilience than batch techniques proposed in the Brazilian Pharmacopeia.

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The pentavalent antimonies, mainly the meglumine antimoniate, are recommends as first-choice medicines for leishmaniasis therapy. In this work we described the development of formulations of meglumine antimoniate injectable medication, as well as the analytical methodology used in the selective determination of Sb(III) and Sb(Total) by hydride generation - inductively coupled plasma atomic emission spectrometry (HG-ICP-AES) and ICP-AES, respectively. On that purpose the analytical methodology was developed focusing on the HG-ICP-AES technique. The formulations using propylene glycol/water as vehicles in a 20:80 proportion were more appropriate for subsequent use in industrial scale. These formulations also showed a lower variation on Sb(III) percentage, no need of buffer solution to stabilize the formulation and no influence of the autoclaving in the quality of the product. The results of the development of the analytical methodology point out the proposed method as an efficient alternative for the determination of Sb(III) in the presence of large quantities of Sb(V) in injectable solutions of meglumine antimoniate, in a selective, linear, accurate and precise manner. In addition, the method showed a low limit of quantification, less interference of the matrix, and more resilience than batch techniques proposed in the Brazilian Pharmacopeia.

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PURPOSE: The stability of an extemporaneously prepared recombinant human interferon alfa-2b (rh-IFN-alpha2b) eye drop formulation was studied. METHODS: A volume of 3 x 10(6) International Units (IU) of rh-IFN-alpha2b formulated in solution was diluted with 5 mL of a 0.01% benzalkonium chloride solution. The stability of the extemporaneous formulation was evaluated for 30 days at room temperature (5 +/- 3 degrees C) and at 28 +/- 2 degrees C. Solutions were periodically subjected to bioactivity assay (antiviral titration), enzyme-linked immunosorbent assay, preservative-efficacy and sterility testing, organoleptic evaluation, and pH testing. Preservative efficacy was tested against five microorganisms. The organoleptic characteristics were verified by checking for the transparency and absence of suspended solids against light and dark backgrounds. Statistical significance was determined using analysis of variance after a comparison of the homogeneity of variance (Bartlett's test). RESULTS: Results from this evaluation indicated that the formulation was stable for 15 days at 5 +/- 3 C. During this storage period, the biological activity varied between 80 and 125% of the nominal value (0.5 x 10(6) IU/mL). The formulation was sterile and organoleptically acceptable. The pH ranged from 6.7 to 7.3, and the preservative was effective. The formulation was stable for 7 days when stored at 28 +/- 2 degrees C. The formulation remained sterile, colorless, and without suspended solids. The pH range was 6.7-7.3. CONCLUSION: An extemporaneously pre -pared rh-IFN-alpha2b eye drop formulation was stable at 5 +/- 3 degrees C for 15 days and at 28 +/- 2 degrees C for 7 days.

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