EVALUATION OF THE PRESENCE OF POLYMORPHIC FORMS AND INFLUENCE ON THE DISSOLUTION PROFILE OF TENOXICAM IN ACTIVE PHARMACEUTICAL INGREDIENT AND FORMULATIONS

Polymorphism is a relatively common phenomenon among pharmaceutical compounds, and one of the main aspects to be considered in the production and development of medications. The investigation of polymorphism associated with oxicams, a group belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs) has increased in recent years and, in the case of tenoxicam, the existence of four polymorphic forms is reported in the literature. The objective of this study was to characterize the presence of different polymorphic forms of tenoxicam in active pharmaceutical ingredient and oral pharmaceutical formulations, as well as to evaluate the influence on in vitro dissolution. The characterization of the three samples of pharmaceutical ingredient of tenoxicam from different suppliers by X-Ray Diffraction (XRD), Infrared (IR) and dissolution profile indicated the presence of a form III crystalline structure, without presenting significant differences between the in vitro dissolution profiles analyzed, and a Dissolution Efficiency (DE%) of 60.30%, 60.70% and 72.34%, respectively. When the four pharmaceutical specialties of tenoxicam were submitted to XRD analysis, they also presented form III crystalline structures. Despite this, the formulations presented different dissolution profiles and a DE% of 75.23%, 83.69%, 78.19% and 90.63%, respectively, without compromising their quality. However, often polymorphism affects physico-chemical properties of drugs, showing the importance of studying this phenomenon, by correlating the presence of crystalline structures to alterations in the quality of active ingredients and pharmaceutical products

EVALUATION OF THE STABILITY OF VIGABATRIN IN HOSPITALAR EXTEMPORANEOUS FORMULATIONS

The aim of this study was to analyze the chemical stability of the anticonvulsant vigabatrin extemporaneous formulation from tablets in storage conditions of different temperatures and types of packaging used. The analysis of vigabatrin extemporaneous formulations were performed by high-performance liquid chromatography (HPLC). The method described in British Pharmacopoeia was co-validated for specificity, linearity, precision and accuracy. Vigabatrin extemporaneous solutions were prepared in triplicate and placed in amber glass and PET bottles, which were stored under three different conditions: at room temperature (15 to 30 °C), under refrigeration (2 to 8 °C), and oven (40 °C). Samples of solutions stored at room temperature and refrigeration were collected every 7 days along 35 days. The same was done for solutions kept at 40 °C, but for a period of 28 days. It was also analyzed the solutions pH in each sampling time. Vigabatrin extemporaneous solutions showed variations within the limits of British Pharmacopoeia 2016 up to 21 days in amber PET and glass bottles at room and refrigerated temperatures. Vigabatrin content for formulations kept in oven decreased above 10% after 7 days of study. The lowest pH change occurred in amber glass bottle stored under refrigeration. Results of this study will be applied as a reference for vigabatrin extemporaneous formulation in hospital, once it was demonstrated the reliability of storage time interval and proper conditions for the use. Thus, pediatric patients with fractionated doses or use of nasogastric probe will have adequately prepared extemporaneous formulations, reducing the risk of dilution errors and microbiological contamination, improving the efficacy and safety, and enabling more time for nursing assistance. 

CHARACTERIZATION OF LINAGLIPTIN USING ANALYTICAL TECHNIQUES

Linagliptin (LGT) is a member of the class of gliptins that inhibit the enzyme dipeptidyl-peptidase-4. They are used to reduce glucose blood levels in patients with type 2 Diabetes mellitus. Due to its recent development and launching on the market, LGT has no official compendium monograph, national or international, or available registries for the qualitative determination of this drug. The objective of this work was to characterize LGT by using thermal techniques, nuclear magnetic resonance, mass and infrared spectrometry, liquid chromatography and ultraviolet spectrophotometry to be used as a chemical reference substance. The range and melting point obtained are in accordance with that described in the literature. The main groups of LGT molecule were observed in infrared spectroscopy and the molecular ion m/z 473.25 ratio was found in mass spectroscopy analysis. In UV spectroscopy, the maximum wavelength absorption of the substance in different solvents can be observed. The chromatographic methods provide selectivity for LGT and can be used to analyze it qualitatively. The proposed conditions have been successfully applied for identification and qualitative analysis of LGT as a chemical reference substance, contributing to studies of this gliptin, and to the quality control of medicines that contain it.Linagliptin (LGT) is a member of the class of gliptins that inhibit the enzyme dipeptidyl-peptidase-4. They are used to reduce glucose blood levels in patients with type 2 Diabetes mellitus. Due to its recent development and launching on the market, LGT has no official compendium monograph, national or international, or available registries for the qualitative determination of this drug. The objective of this work was to characterize LGT by using thermal techniques, nuclear magnetic resonance, mass and infrared spectrometry, liquid chromatography and ultraviolet spectrophotometry to be used as a chemical reference substance. The range and melting point obtained are in accordance with that described in the literature. The main groups of LGT molecule were observed in infrared spectroscopy and the molecular ion m/z 473.25 ratio was found in mass spectroscopy analysis. In UV spectroscopy, the maximum wavelength absorption of the substance in different solvents can be observed. The chromatographic methods provide selectivity for LGT and can be used to analyze it qualitatively. The proposed conditions have been successfully applied for identification and qualitative analysis of LGT as a chemical reference substance, contributing to studies of this gliptin, and to the quality control of medicines that contain it

STUDY OF FLAVONOIDS PRESENT IN POMELO (Citrus Maxima) BY DSC, UV-VIS, IR, 1H AND 13C NMR AND MS

Flavonoids are among the most important plant metabolites. Due to their potential benefits, there is a considerable interest in this natural product. In genus Citrus, some plants have not yet been much exploited in Brazil, as in the case of grapefruit (Citrus maxima), whose main flavonoids are naringin and their aglycone naringenin. The physico-chemical characteristics are important pre-requisites of reference chemical in future studies. In this context, the objective of this study was to determine the characterization of naringin and naringenin by melting point, DSC, UV-VIS, 1H and 13C NMR, IR and MS. Results revealed that, naringin and naringenin after characterization, can be used as a chemical of reference in future studies and contribute to seeking possible technological applications

Study of flavonoids presente in Pomelo (Citrus máxima) by DSC, UV-VIS, IR, 1H and 13C NMR and MS

Flavonoids are among the most important plant metabolites. Due to their potential benefits, there is a considerable interest in this natural product. In genus Citrus, some plants have not yet been much exploited in Brazil, as in the case of grapefruit (Citrus maxima), whose main flavonoids are naringin and their aglycone naringenin. The physico-chemical characteristics are important pre-requisites of reference chemical in future studies. In this context, the objective of this study was to determine the characterization of naringin and naringenin by melting point, DSC, UV-VIS, 1H and 13C NMR, IR and MS. Results revealed that, naringin and naringenin after characterization, can be used in future studies and contribute to seeking possible technological applications

In vitro toxic evaluation of two gliptins and their main impurities of synthesis

Background: The presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). Methods: MTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated. Results: Cytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 μM of sitagliptin and 10 μM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations. Conclusions: This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied

Development of an analytical method using modified QuEChERS and DLLME for the determination of erythromycin residues in fish by LC-MS/MS

Ainda que as ferramentas analíticas venham evoluindo significativamente ao longo dos anos, a determinação de concentrações de compostos orgânicos a níveis residuais (por exemplo, 0,99, homocedástico), alta detectabilidade (LQ 1,0 &mu;g kg-1), precisão (CV0,99, homocedástico; precisão com CV 0.99, homoscedastic), high detectability (LOQ 1.0 &mu;g kg-1), precision (CV 0.99, homoscedastic; accuracy with CV <2.1%; veracity with CV <2.2%). The efficiency of incorporation of ERI into feed was 72% and the method was able to produce feed with adequate homogeneity (CV <2.0%) of the ERI concentration and low leaching (<1.1%) of the compound when in contact with the water for up to 15 minutes. The depletion study was carried out on pacu fish and involved a treatment with the medicated feed at a daily oral dose of 100 mg (kgPV)-1, during 7 consecutive days. The average water temperature was 30°C, and the minimum withdrawal period estimated was 8 days (or 240 degree-day) for elimination of ERI at levels below the concentration considered safe for this substance (MRL 100 &mu;g kg-1), with 95% confidence and considering the tolerance limit of 99%

Impurezas farmacêuticas : análise do contexto nacional e internacional

É crescente a preocupação das agências regulatórias com a determinação de impurezas nos produtos farmacêuticos. Estas podem ser originadas por diferentes processos, como durante a síntese ou extração do princípio ativo e durante o armazenamento, sendo inevitável a sua presença em medicamentos. A qualificação e a avaliação de impurezas são imprescindíveis para garantir que a segurança e a eficácia dos medicamentos não sejam afetadas. Órgãos como o ICH, o FDA e a ANVISA definiram limites e requisitos de pureza, reforçando a necessidade de identificação e qualificação. Metodologias analíticas seletivas e sensíveis, como a cromatografia e a espectroscopia, são amplamente utilizadas na determinação de impurezas, permitindo a separação e a elucidação estrutural dessas substâncias. Após a confirmação da substância, ensaios toxicológicos devem ser realizados para verificar qualquer atividade biológica indesejada. Devido à importância da segurança e eficácia no tratamento medicamentoso, este trabalho apresenta uma revisão de aspectos relacionados às impurezas, sua determinação e avaliação. Para tanto, realizou-se uma revisão da literatura utilizando as bases de dados Scopus, ScienceDirect, Pubmed, Springer e Web of Science. É evidente o crescimento das pesquisas na área, principalmente em países como os Estados Unidos, a China e a Índia. Os estudos realizados sobre impurezas farmacêuticas são essenciais para o controle de qualidade dos produtos farmacêuticos e para a segurança do paciente em tratamento.There is a growing concern of regulatory agencies with the determination of impurities in pharmaceuticals. These can be caused by different processes, such as the synthesis or extraction of the active ingredient and during storage, and their presence in medicines is inevitable. The qualification and evaluation of impurities are essential to ensure that the safety and efficacy of medicinal products are not affected. Entities such as ICH, FDA and ANVISA defined limits and purity requirements, reinforcing the need for identification and qualification. Selective and sensitive analytical methods, such as chromatography and spectroscopy, are widely used in determination of impurities, allowing the separation and structural elucidation of these substances. After confirming the substance, toxicological tests should be performed to check for any unwanted biological activity. Owing to the importance of safety and efficacy of drug treatment, this work presents a review of aspects related to impurities, their determination and evaluation. For this, we carried out a literature review using Scopus, ScienceDirect, Pubmed, Web of Science and Springer databases. Cleary there is a growth of research in the area, specially in countries as United States, China and India. Studies of pharmaceutical impurities are essential for the quality control of pharmaceuticals and to patient safety in treatment