Preliminary prospection of phytotherapic compounds from the essential oils from barks and leaves of Umburana (Commiphora Leptophloeos)

Abstract The potential of the biome caatinga (exclusive from northeastern Brazil) has been evaluated in recent research for application in the pharmaceutical industry. Among the species of medicinal plants from caatinga, one can highlight the Commiphora leptophloeos (umburana), which has been used as infusions and syrups by the regional population for inflammatory and infectious diseases. Essential oils from umburana leaves and barks were obtained in a Clevenger apparatus and analyzed by gas chromatography/mass spectrometry, and total phenolic and flavonoids were determined by spectrophotometric analysis. It was observed that a large part of the major compounds present in the essential oil is described as having antitumor activity, enabling research in investigational oncology with umburana (C. leptophloeos). In addition, some little explored components have been identified, such as cadinene, alpha-selinene, and elemenone. Despite being easily found in several plants, there are no clinical trials involving their biological activity in a well-defined isolated form, which could make exploring new studies possible. Furthermore, the presence of phenolic compounds and flavonoids allows future studies about the potential antimicrobial and antioxidant activity.

Solid Phase Extraction and Simultaneous Chromatographic Quantification of some Non-steroidal Anti-inflammatory Drug Residues; an Application in Pharmaceutical Industrial Wastewater Effluent

Abstract Two sensitive and selective methods were developed for the simultaneous determination of four commonly used non-steroidal anti-inflammatory drugs (NSAIDs), namely; paracetamol (PCM), diclofenac sodium (DCF), ibuprofen (IBP), and indomethacin (IND) in wastewater effluents. The first method used HPLC for the determination of the studied drugs using a mobile phase consisting of phosphate buffer (pH 3.0) and acetonitrile at a flow rate of 1 mL/min. in gradient elution mode and detection at 220 nm. The separation process was performed on BDS Hypersil Cyano column (250 x 4.6 mm, 5 µm). The second method was a TLC-densitometric one which was performed using n-Hexane: ethyl acetate: acetic acid in the ratio (6:3.5:0.5) as a developing system. The proposed chromatographic methods were successfully applied for the selective determination of the four studied drugs in simulated and real pharmaceutical wastewater samples after their solid-phase extraction

Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Application of HACCP for development of quality risk management in a water purification system

Abstract The present work reports the implementation of the Hazard Analysis Critical Control Point (HACCP) methodology to analyze the water purification system of a pharmaceutical site, in order to assure the system quality and prevent failures. As a matter of fact, the use of HACCP for development and implementation of Quality Risk Management (QRM) is not usual in pharmaceutical plants and it is applied here to improve the performance of the water purification system of a polymerization pilot plant used to manufacture pharmaceutical grade polymer microparticles. Critical Control Points (CCP) were determined with the aid of a decision tree and questions were made to characterize whether identified hazards constitute actual CCPs and should be monitored. When deviations were detected, corrective actions were performed and action plans were used for following-up and implementation of corrective actions. Finally, microbiological and physicochemical parameters were analyzed and the obtained results were regarded as appropriate. Therefore, it is shown that HACCP constitutes an effective tool for identification of hazards, establishment of corrective actions and monitoring of the critical control points that impact the process and the quality of the final pharmaceutical product most significantly.

Desenvolvimento de rota sintética da Rosiglitazona em processo batelada e microrreator capilar / Rosiglitazone synthetic route development in batch process and capillary microreactor

Para que os fármacos possam ser comercializados economicamente, a sua escala de produção deve ser aumentada para atender à demanda do mercado. Atualmente, a maior parte dos fármacos são sintetizados em processos batelada que possuem limitações quanto à eficiência de mistura, temperatura e pressão. O uso de microrreatores surge como alternativa na indústria químico-farmacêutica, aumentando a eficiência dos processos de maneira segura. Ferramentas utilizadas no segmento computacional multidisciplinar teórico, como o DFT (Density Functional Theory), podem prever e compreender o comportamento das reações químicas, podendo ter grande utilidade na síntese de novos fármacos economizando tempo, investimento e reduzindo a geração de resíduos. A diabetes mellitus é uma doença de caráter epidêmico, que a cada ano vem aumentando o número de casos. O emprego de fármacos derivados das glitazonas no tratamento de diabetes mellitus tipo 2 é recomendado devido ao excelente controle glicêmico que esta classe de fármacos oferece. Neste trabalho, foi sintetizada a Rosiglitazona, um fármaco derivado das glitazonas, que auxilia no tratamento da diabetes mellitus tipo 2, sendo estudadas duas rotas de síntese distintas, que foram otimizadas com o intuito de maximizar o rendimento de seus intermediários, obtendo a Rosiglitazona com pureza de cerca de 94%. Foi realizada, para os intermediários, aqui denominados, 1R, 2R2 e 3R2 a síntese one-pot e para os intermediários 1R, 2R1 e 3R2 foi realizada a transposição do processo usual em batelada para fluxo contínuo no microrreator, com rendimentos de até 93%. Com o auxílio da química quântica computacional, a reação de síntese do intermediário 1R, foi elucidada teoricamente e determinadas as grandezas termodinâmicas (ΔH‡, ΔG‡ e ΔS‡) no estado de transição, que foram comparadas com os valores experimentais, sendo constatada uma boa concordância, com desvio máximo de 14%

In order for drugs to be commercialized economically, their production scale must be increased to meet market demand. Currently, most drugs are synthesized in batch processes that have limitations in terms of mixing efficiency, temperature and pressure. The use of microreactors appears as an alternative in the chemical-pharmaceutical industry, increasing the efficiency of the synthesis processes in a safe way. Tools used in the theoretical multidisciplinary computational segment, such as DFT (Density Functional Theory), can predict and understand the behavior of chemical reactions, and can be very useful in the synthesis of new drugs, saving time, investment and reducing waste generation. Diabetes mellitus is an epidemic disease that has been increasing the number of cases every year. The use of drugs derived from glitazones in the treatment of type 2 diabetes mellitus is recommended due to the excellent glycemic control that this class of drugs offers. In this work, Rosiglitazone, a drug derived from glitazones, which helps in the treatment of type 2 diabetes mellitus, was synthesized. Two different synthetic routes were studied and optimized in order to maximize the yield of its intermediates, obtaining Rosiglitazone with purity of about 94%. One-pot synthesis was performed to 1R, 2R2 and 3R2 intermediates, and the transposition from the usual batch process to continuous flow in microreactor was performed to 1R, 2R1 and 3R2 intermediates, with yields of up to 93%. With the aid of computational quantum chemistry, the intermediate 1R synthesis reaction was theoretically elucidated and the thermodynamic properties were determined (ΔH‡, ΔG‡ and ΔS‡) in the transition state, which were compared with the experimental results, obtaining good agreement, with a maximum deviation of 14%.

A cross-industry collaboration to assess if acute oral toxicity (Q)SAR models are fit-for-purpose for GHS classification and labelling.

This study assesses whether currently available acute oral toxicity (AOT) in silico models, provided by the widely employed Leadscope software, are fit-for-purpose for categorization and labelling of chemicals. As part of this study, a large data set of proprietary and marketed compounds from multiple companies (pharmaceutical, plant protection products, and other chemical industries) was assembled to assess the models' performance. The absolute percentage of correct or more conservative predictions, based on a comparison of experimental and predicted GHS categories, was approximately 95%, after excluding a small percentage of inconclusive (indeterminate or out of domain) predictions. Since the frequency distribution across the experimental categories is skewed towards low toxicity chemicals, a balanced assessment was also performed. Across all compounds which could be assigned to a well-defined experimental category, the average percentage of correct or more conservative predictions was around 80%. These results indicate the potential for reliable and broad application of these models across different industrial sectors. This manuscript describes the evaluation of these models, highlights the importance of an expert review, and provides guidance on the use of AOT models to fulfill testing requirements, GHS classification/labelling, and transportation needs.

Entry Into New Therapeutic Areas: The Effect of Alliance on Clinical Trials.

BACKGROUND: Entry into a new therapeutic area, that is, one in which a pharmaceutical firm lacks experience, is a considerable challenge for firms that need to overcome scientific and technological barriers. To address this issue, the present study aims to explore the potentiality of alliances in an empirical manner. METHODS: From the clinical trials sponsored by 20 major pharmaceutical firms during 2008-2016 listed at ClinicalTrials.gov (n = 14,941 clinical trials), cases of entering a new therapeutic area for a pharmaceutical firm were extracted (n = 73), followed by statistical analyses to evaluate the effect of alliances in this regard. RESULTS: We found that the average number of participating organizations in the cases of entering a new therapeutic area was significantly larger than that in the cases of entering an area in which firms had experience (P < .01), suggesting that alliance has a positive effect on new therapeutic entry for these pharmaceutical firms. Second, we found that the cases of partnering with nonindustrial or nongovernmental organizations (ie, universities, research institutes, hospitals, funding agencies, and others; n = 32 of the 73) were significantly associated with these new entry trials (adjusted odds ratio = 1.1, P < .05). Furthermore, we identified that 10 of the 32 clinical trials were associated with rare diseases, which is an overrepresentation compared to the occurrence in the universe (1015 of the 14,941; P < 10-5). CONCLUSIONS: These findings strongly suggest the importance of alliances with diversified partners in new therapeutic entry and also provide a basis for further detailed investigation of key success factors for pharmaceutical firms.

Moulds associated with contaminated ocular and injectable drugs: FDA recalls, epidemiology considerations, drug shortages, and aseptic processing.

Recent (2012) grave but rare outbreaks of fungal meningitis and endophthalmitis associated with drugs contaminated with select environmental moulds (Exserohilum and Fusarium, respectively) have exacerbated mycology concerns for formulation, good laboratory practices (GLP), and use of the final drug product. Intensified investigations (2013-2015) by the Food and Drug Administration (FDA) that included added responsibilities for specialty compounding laboratories have prompted at least nine voluntary mould-related drug recalls during 2014-2015. Both primary manufactures (five recalls, two companies) and secondary-processing compound laboratories (at least eight recalls, six companies) and near 0.8 million units were involved. These constituted minor fractions of recalled drug products in an estimated 2500 recalls among other causes during this time period. Recalls of similar drugs in 2016 were indirectly related to fungi. None of the mould-related- drug-recall episodes during 2014-2016 have been identified with fungal disease outbreaks. The recalls included drugs in short supply worldwide such as injectable sodium chloride- and related saline solutions as well as ocular formulations. Insufficient environmental monitoring and GLP compliance, particularly for aseptic processing of non-preserved formulations, appeared to be underlying factors in the fungal contaminations. Observations of mould growth in drugs during their processing should be accurately recorded and investigated; cryptic listings under "particulate" designations should be avoided. Confirmed identifications for chronic contaminants are recommended. Heat-tolerant moulds with resistant morphotypes are prime concerns.

Application of statistical process control for spotting compliance to good pharmaceutical practice

ABSTRACT For the release of pharmaceutical products into the drug market; most of the pharmaceutical companies depend on acceptance criteria - that are set internally, regulatory and/or pharmacopeially. However, statistical process control monitoring is underestimated in most quality control in cases; although it is important not only for process stability and efficiency assessment but also for compliance with all appropriate pharmaceutical practices such as good manufacturing practice and good laboratory practice, known collectively as GXP. The current work aims to investigate two tablet inspection characteristics monitored during in-process control viz. tablet average weight and hardness. Both properties were assessed during the compression phase of the tablet and before the coating stage. Data gathering was performed by the Quality Assurance Team and processed by Commercial Statistical Software packages. Screening of collected results of 31 batches of an antibacterial tablet - based on Fluoroquinolone -showed that all the tested lots met the release specifications, although the process mean has been unstable which could be strongly evident in the variable control chart. Accordingly, the two inspected processes were not in the state of control and require strong actions to correct for the non-compliance to GXP. What is not controlled cannot be predicted in the future and thus the capability analysis would be of no value except to show the process capability retrospectively only. Setting the rules for the application of Statistical Process Control (SPC) should be mandated by Regulatory Agencies.

Antiulcer, wound healing and hepatoprotective activities of the seaweeds Gracilaria crassa, Turbinaria ornata and Laurencia papillosa from the southeast coast of India

Seaweeds have bioactive compounds of interest in the pharmaceutical industry. In India, seaweeds are used exclusively for phycocolloids production and have not yet received consideration as a dietary supplement. So, it has become imperative to explore the biomedical potential of seaweeds and promote their utilization as a functional food. The seaweeds Turbinaria ornata, Gracillaria crassa and Laurencia papillosa, collected from the Tuticorin coast of the Southeast coast of India and selected based on preliminary screening, were extracted with acetone and evaluated for antiulcer, wound healing and hepatoprotective activities. L. papillosa showed the highest level of gastric protection activity (81%) at 200 mg/kg, comparable to the standard drug ranitidine (90%). G. crassa followed with 76%. G. crassa and L. papillosa, showed marked wound-healing activity. G. crassa at 200 mg/kg, showed a marked effect on the serum marker enzymes indicating prominent hepatoprotective activity. The noteworthy wound-healing and hepato-protective properties of G. crassa besides anti-ulcer activity next to L. papillosa were indicative of its potential for further consideration.

Algas marinhas possuem compostos bioativos de interesse para a indústria farmacêutica. Na Índia, as algas marinhas são usadas exclusivamente para a produção de ficocolóides e ainda não receberam a consideração como um suplemento dietético. Assim, tornou-se imperativo explorar o potencial biomédico de algas e promover a sua utilização como alimento funcional. As algas marinhas Turbinaria ornata, Gracillaria crassa e Laurencia papillosa, coletadas de Tuticorin, na costa sudeste da Índia, e selecionadas com base em triagem preliminar, foram extraídas com acetona e avaliadas quanto à atividade antiúlcera, de cicatrização de feridas e de hepatoproteção. L. papillosa mostrou o mais alto nível da atividade de proteção gástrica (81%) na dose de 200 mg/kg, comparável ao fármaco padrão, ranitidina (90%). G. crassa mostrou atividade de 76%. G. crassa e L. papillosa mostrou atividade martcante na cicatrização de feridas. G. Crassa, a 200 mg/kg, mostrou efeito alto sobre o marcador sérico das enzimas, indicando atividade hepatoprotetora proeminente. A notável cura de feridas e as propriedades hepatoprotetoras de G. Crassa, além da atividade antiúlcera, próxima da L. Papillosa, foram indicativos do seu potencial para uma análise mais aprofundada.

Assay and physicochemical characterization of the antiparasitic albendazole

The aim of this study was to characterize three batches of albendazole by pharmacopeial and complementary analytical techniques in order to establish more detailed specifications for the development of pharmaceutical forms. The ABZ01, ABZ02, and ABZ03 batches had melting points of 208 ºC, 208 ºC, and 209 ºC, respectively. X-ray diffraction revealed that all three batches showed crystalline behavior and the absence of polymorphism. Scanning electron microscopy showed that all the samples were crystals of different sizes with a strong tendency to aggregate. The samples were insoluble in water (5.07, 4.27, and 4.52 mg mL-1, respectively) and very slightly soluble in 0.1 M HCl (55.10, 56.90, and 61.70 mg mL-1, respectively) and additionally showed purities within the range specified by the Brazilian Pharmacopoeia 5th edition (F. Bras. V; 98% to 102%). The pharmacopeial assay method was not reproducible and some changes were necessary. The method was validated and showed to be selective, specific, linear, robust, precise, and accurate. From this characterization, we concluded that pharmacopeial techniques alone are not able to detect subtle differences in active pharmaceutical ingredients; therefore, the use of other complementary techniques is required to ensure strict quality control in the pharmaceutical industry.

O objetivo do trabalho foi caracterizar três lotes de albendazol com técnicas analíticas farmacopéicas e complementares a fim de estabelecer especificações mais detalhadas para o desenvolvimento de formas farmacêuticas. Os lotes ABZ01, ABZ02 e ABZ03 apresentaram fusão em 208 ºC, 208 ºC e 209 ºC. Foi possível evidenciar, por difração de raios X, que os três lotes apresentaram comportamento cristalino e ausência de polimorfismo. Através da microscopia eletrônica de varredura verificou-se que todas as amostras apresentaram cristais com diferentes tamanhos e forte tendência de agregação. As amostras foram insolúveis em água (5,07; 4,27 e 4,52 µg mL-1) e muito pouco solúveis em HCl 0,1M (55,10; 56,90 e 61,70 µg mL-1) e, ainda, apresentaram pureza dentro da faixa especificada pela F.Bras.V (98% a 102%). O método farmacopéico de doseamento não foi reprodutível, e algumas mudanças foram necessárias. O método foi validado e demonstrou ser seletivo, específico, linear, robusto, preciso e exato. A partir dessa caracterização, pode-se concluir que apenas técnicas farmacopéicas não são capazes de detectar diferenças sutis entre os ingredientes farmacêuticos ativos, necessitando, portanto, de uso de outras técnicas complementares para garantir um rígido controle de qualidade na indústria farmacêutica.

Abordagem sobre os diferentes processos de secagem empregados na obtenção de extratos secos de plantas medicinais / Approach on different drying processes employed for obtaining dry extracts from medicinal plants

Na indústria farmacêutica de fitoterápicos, o extrato seco é considerado tecnologicamente viável para fins de produção em larga escala, devido à estabilidade física, química e microbiológica, além da facilidade de padronização dos princípios ativos. Entre as técnicas de secagem empregadas na preparação de extratos secos, encontra-se a nebulização ou spray-dryer, o leito de jorro, a liofilização e a evaporação rotativa. A escolha do processo de secagem é motivada pela potencialidade dos diferentes equipamentos secadores, na secagem de materiais presentes na forma líquida, no caso, soluções extrativas de plantas medicinais, fornecendo um produto de alta qualidade e com investimento relativamente baixo.

In the pharmaceutical industry of herbal medicines, the dried extract is considered technologically feasible for large-scale production, due to its physical stability, possibility of chemical and microbiological analyses and the ease of standardization of the active ingredients. Among the drying techniques used in the preparation of dry extracts are a mist or spray-dryer, the spouted bed, freeze-drying and rotary evaporation. The choice of the drying process is motivated by the potential of different drying equipments and materials present in liquid form, in this case, solutions of herbal extracts provide a high quality product and a relatively modest investment.

Management of effluents and waste from pharmaceutical industry in Minas Gerais, Brazil

Today the management of solid waste and wastewater is a major concern for humanity. In the last decade, traces of pharmaceuticals have been reported in the water cycle and have raised concerns among regulators, water suppliers and the public regarding the potential risks to human health. This study evaluated solid waste management in the state of Minas Gerais and concluded that the main fate of hazardous waste has been incineration, while the non-hazardous waste has been recycled or sent to landfills. However, complaints to the Environmental Agency - FEAM have indicated that a significant number of companies just send their hazardous wastes to landfills or even to garbage dumps, thus highlighting the urgent need for adequate waste management in Minas Gerais. Most of the pharmaceutical companies in Minas Gerais use conventional wastewater treatment. Mass spectrometry with electrospray ionization (ESI-MS) showed that the treatment routes adopted by the two 2 selected pharmaceutical industries were not effective enough since residues and degradation products of antibiotics were detected. The physicochemical analysis of the effluents showed variability in their characteristics, which may influence their treatability. The degradation assay with Fenton's reagent stood out as a promising route in achieving a higher removal capacity compared to the conventional treatment. This study contributes to enhancing our knowledge of the management of wastewater as well as of solid waste from the pharmaceutical industry in Minas Gerais and points out the need for further research.

Atualmente, a gestão de resíduos sólidos e águas residuais é uma grande preocupação para a humanidade. Na ultima década, a detecção de traços de medicamentos no ciclo da água tem sido reportada e tem gerado preocupação entre os agentes reguladores, fornecedores de água e público devido os riscos potenciais para a saúde humana. As empresas farmacêuticas, em Minas Gerais, aplicam tratamentos convencionais para as águas residuais e não há praticamente avaliação sobre a eficiência de remoção de resíduos de antibióticos. Este estudo avaliou a gestão de resíduos sólidos e concluiu que o destino principal foi, para o caso de resíduos perigosos, a incineração e, para os não perigosos, a reciclagem e o aterro sanitário. No entanto, denúncias apresentadas à Agência Ambiental - FEAM indicam que número significativo de empresas envia seus resíduos perigosos para aterros sanitários e até mesmo para lixões, ressaltando, assim, a necessidade urgente de adequada gestão dos resíduos gerados. A espectrometria de massas com ionização electrospray (ESI-MS) mostrou que a rota de tratamento convencional adotada por duas empresas do setor selecionadas não foi suficientemente eficaz, uma vez que resíduos e fragmentos de antibióticos foram detectados. Os resultados da caracterização físico-química de efluentes evidenciaram suas características variáveis, que podem influenciar a sua tratabilidade. O ensaio de degradação com o reagente Fenton destaca-se como caminho promissor para alcançar maior remoção. Este estudo contribuiu para elevar o nível de conhecimento no gerenciamento de águas residuais e resíduos sólidos da indústria farmacêutica no estado de Minas Gerais e evidenciou a necessidade de estudos mais detalhados.