The Role of SeDeM Characterizing the Active Substance and Polyvynilpyrrolidone Eliminating Metastable Forms in an Oral Lyophilizate - A Preformulation Study.

A preformulation study of an oral lyophilisate with cetirizine dihydrochloride (CTZ) as active ingredient, mannitol and PVP K30 as bulking agents is presented. CTZ shown a humidity content of 0.150% and a spontaneous hygroscopicity of 0.200% (both determined by SeDeM diagram), demonstrating an adequate stability behavior in solid form. A design of experiments (DoE) performed with both mannitol and PVP K30, followed by a simple factorial design (32) has determined the optimum combination of excipients and CTZ, and showed that a higher proportion of PVP K30 was able to prevent metastable forms generated by mannitol

Determination of stress-induced degradation products of cetirizine dihydrochloride by a stability-indicating RP-HPLC method

A new, simple and accurate stability-indicating reverse phase high performance liquid chromatography method was developed and validated during the early stage of drug development of an oral lyophilizate dosage form of cetirizine dihydrochloride. For RP-HPLC analysis it was used an Eclipse XDB C8 column 150 mm × 4.6 mm, 5 μm (Agilent columns, Barcelona, Spain) as the stationary phase with a mobile phase consisted of a mixture of 0.2 M K2HPO4 pH 7.00 and acetonitrile (65:35, v/v) at a flow rate of 1 mL min −1. Detection was performed at 230 nm using diode array detector. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, specificity, limit of detection and quantification. The method results in excellent separation between the drug substance and its stress-induced degradation products. The peak purity factor is >950 for the drug substance after all types of stress, which confirms the complete separation of the drug substance peak from its stress induced degradation products. Regression analysis showed r2 > 0.999 for cetirizine dihydrochloride in the concentration range of 650 μg mL −1 to 350 μg mL−1 for drug substance assay and a r2 > 0.999 in the concentration range of 0.25 μg mL−1 to 5 μg mL−1 for degradation products. The method presents a limit of detection of 0.056 μg mL −1 and a limit of quantification of 0.25 μg mL−1. The obtained results for precision and accuracy for drug substance and degradation products are within the specifications established for the validation of the method. The proposed stability-indicating method developed in the early phase of drug development proved to be a simple, sensitive, accurate, precise, reproducible and therefore useful for the following stages of the cetirizine dihydrochloride oral lyophilizate dosage form development

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Desarrollo de un liofilizado oral antihistamínico de segunda generación

El liofilizado oral es una forma farmacéutica sólida que tiene como objetivo facilitar la administración de un medicamento mediante la disolución instantánea del mismo en la cavidad bucal, con la consiguiente deglución del contenido por vía oral. Dicha forma farmacéutica se obtiene mediante preparación previa de una solución, suspensión o emulsión que contenga el principio activo que se quiere administrar antes de la aplicación de la técnica de liofilización. La liofilización permite generar un producto de tamaño reducido y poroso que se disuelve en segundos cuando se pone en contacto con el agua o con la saliva. En la formulación de un liofilizado oral se utilizan excipientes que auxilian, tanto en la formación de la matriz liofilizada, como en facilitar la correcta disolución del medicamento en la cavidad bucal, añadiéndose componentes que enmascaren el sabor amargo del fármaco y dejen un sabor agradable en la boca. Para efectuar este proyecto se ha escogido como principio activo modelo un antihistamínico de segunda generación no sedante administrado generalmente en comprimidos recubiertos y soluciones orales que promueven el alivio de síntomas relacionados con la rinitis alérgica y la urticaria crónica idiopática. Para el desarrollo de la formulación, se ha puesto a punto previamente un método analítico para el principio activo, seguido de estudios de caracterización del principio activo (Resonancia Magnética Nuclear, Difracción de Rayos X, Espectrofotometría UV-Vis, SeDeM), y estudios de preformulación (con técnicas de Calorimetría Diferencial de Barrido y Microscopía de Liofilización) y formulación, con la consiguiente elaboración de la guía de fabricación y controles de proceso.Oral lyophilisates are solid oral dosage forms intended to facilitate the administration of a drug by instant dissolution in the oral cavity, thereby swallowing the content orally. The dosage form is obtained by previous preparation of a solution, suspension or emulsion containing the active ingredient that is going to be administered, prior to lyophilisation. Lyophilisation allows generating a reduced size product and at the same time porous, that dissolves in seconds when in contact with water or saliva. In formulating an oral lyophilisate it is necessary to use excipients that both help in the formation of the lyophilized matrix (providing the proper dissolution of the drug in the oral cavity), and to mask bitter taste of a drug, leaving a pleasant taste in the mouth of the patient. To carry out this project it has been chosen as model active ingredient a second-generation antihistamine, usually administered in coated tablets and oral solutions that promote relief related to allergic rhinitis and chronic idiopathic urticarial symptoms. For the formulation development, it has developed previously an analytical method for the active ingredient, followed by characterization studies of the active ingredient (Nuclear Magnetic Resonance, X-ray diffraction, UV-Vis spectrophotometry, SeDeM), and preformulation studies (applying techniques of differential scanning calorimetry and microscopy lyophilisation) and formulation, resulting in a manufacturing batch record with in process controls

The role of SeDeM for characterizing the active substance and polyvinyilpyrrolidone eliminating metastable forms in an oral lyophilizate—A preformulation study

A preformulation study of an oral lyophilisate with cetirizine dihydrochloride (CTZ) as active ingredient, mannitol and PVP K30 as bulking agents is presented. CTZ shown a humidity content of 0.150% and a spontaneous hygroscopicity of 0.200% (both determined by SeDeM diagram), demonstrating an adequate stability behavior in solid form. A design of experiments (DoE) performed with both mannitol and PVP K30, followed by a simple factorial design (32) has determined the optimum combination of excipients and CTZ, and showed that a higher proportion of PVP K30 was able to prevent metastable forms generated by mannitol. © 2018 Flórez Borges et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Reig Jofré Group has provided the active substance and the Freeze-Drying Centre of Excellence (Reig Jofré Group) for the FDM analysis.Peer reviewe

Perfil de auto-anticorpos detectados em substrato rim-estômago de rato no Hospital São Lucas da PUCRS = Autoantibody profile in rat kidney-stomach substrate in the São Lucas Hospital of PUCRS

Objetivo: O trabalho descreve o perfil de autoanticorpos utilizando-se o substrato rim-estômago de rato em um centro de saúde terciário no período de um ano. Material e métodos: O estudo foi de série de casos, com dados obtidos do banco de dados do Setor de Imunologia do Laboratório de Patologia Clínica do Hospital São Lucas da PUCRS. Resultados: Em 262 pacientes (68% do sexo feminino) previamente selecionados por triagem clínica, avaliou-se o perfil de auto-anticorpos em substrato rim-estômago de rato através de imunofluorescência indireta. Anticorpos antimúsculo liso prevaleceram (31%), seguidos por anticorpos anti-reticulina (27%), anticorpos antimitocondriais (24%), anticélulas parietais gástricas (21%), anticorpos anti-”brush border” (4%) e antiLKM (liver-kidney microsome) (0,4%). A maioria dos pacientes com teste positivo para anticorpos antimúsculo liso cursou com titulações inferiores a 1/80 (ponto de corte para hepatite auto-imune). Anticorpos anti-ribossomais não foram detectados em quaisquer pacientes. À exceção do anticorpo antiLKM (presente apenas em um caso, sexo masculino), observou-se predominância do sexo feminino nos auto-anticorpos analisados; tal predomínio, entretanto, só alcançou significância estatística para anticorpos antimitocondriais (P = 0,04). Conclusão: O achado corrobora a possível relação entre fatores genéticos e hormonais na auto-imunidad

The Role of SeDeM Characterizing the Active Substance and Polyvynilpyrrolidone Eliminating Metastable Forms in an Oral Lyophilizate - A Preformulation Study.

A preformulation study of an oral lyophilisate with cetirizine dihydrochloride (CTZ) as active ingredient, mannitol and PVP K30 as bulking agents is presented. CTZ shown a humidity content of 0.150% and a spontaneous hygroscopicity of 0.200% (both determined by SeDeM diagram), demonstrating an adequate stability behavior in solid form. A design of experiments (DoE) performed with both mannitol and PVP K30, followed by a simple factorial design (32) has determined the optimum combination of excipients and CTZ, and showed that a higher proportion of PVP K30 was able to prevent metastable forms generated by mannitol

Determination of stress-induced degradation products of cetirizine dihydrochloride by a stability-indicating RP-HPLC method

A new, simple and accurate stability-indicating reverse phase high performance liquid chromatography method was developed and validated during the early stage of drug development of an oral lyophilizate dosage form of cetirizine dihydrochloride. For RP-HPLC analysis it was used an Eclipse XDB C8 column 150 mm × 4.6 mm, 5 μm (Agilent columns, Barcelona, Spain) as the stationary phase with a mobile phase consisted of a mixture of 0.2 M K2HPO4 pH 7.00 and acetonitrile (65:35, v/v) at a flow rate of 1 mL min −1. Detection was performed at 230 nm using diode array detector. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, specificity, limit of detection and quantification. The method results in excellent separation between the drug substance and its stress-induced degradation products. The peak purity factor is >950 for the drug substance after all types of stress, which confirms the complete separation of the drug substance peak from its stress induced degradation products. Regression analysis showed r2 > 0.999 for cetirizine dihydrochloride in the concentration range of 650 μg mL −1 to 350 μg mL−1 for drug substance assay and a r2 > 0.999 in the concentration range of 0.25 μg mL−1 to 5 μg mL−1 for degradation products. The method presents a limit of detection of 0.056 μg mL −1 and a limit of quantification of 0.25 μg mL−1. The obtained results for precision and accuracy for drug substance and degradation products are within the specifications established for the validation of the method. The proposed stability-indicating method developed in the early phase of drug development proved to be a simple, sensitive, accurate, precise, reproducible and therefore useful for the following stages of the cetirizine dihydrochloride oral lyophilizate dosage form development

DSC of CTZ, mannitol and PVPK30.

<p>Fig 4A and Fig 4C without metastable forms, Fig 4B with metastable forms.</p

SeDeM diagram of CTZ.

<p>SeDeM diagram of CTZ.</p