Formulation and development of paediatric orally disintegrating carbamazepine tablets.

Carbamazepine is a medicine used to manage epilepsy and partial or tonic-clonic seizures. This study aimed at formulating and obtaining carbamazepine orodispersible tablets for paediatric use at a 50 mg dose, with a diameter not greater than 6 mm and a tablet weight of 80 mg, through a direct compression process. The SeDeM pre-formulation/formulation method was used to define the characteristics of both carbamazepine and the selected excipients for direct compression. This study succeeded in formulating and obtaining the proposed tablets. Following the application of the SeDeM method, the tablets met the mass uniformity test and showed appropriate hardness values for orodispersible tablets. The tablets also met the United States Pharmacopeia (USP) test specifications at t = 60 min. The orodispersible tablets obtained may improve compliance with paediatric treatment with carbamazepine, ensuring the safety and effectiveness of the medicine.

Study of tocopherol content and its potential antioxidant activity in commercial lipid emulsions for parenteral nutrition.

The objective of this study was to determine the content and evaluate the potential antioxidant effect of tocopherols in commercially available lipid emulsions, using a simple validated method adequate for further routine use. During the study, variability between manufacturers as well as between three non-consecutive batches of the same emulsion was observed. Furthermore, addition of α-tocopherol to lipid emulsions as excipient yields more stable emulsions and potentially a beneficial clinical effect. It was concluded that the variation of the tocopherol content between batches implies the importance of control and specification of tocopherol content by the manufacturers.

Topical Analgesia with Lidocaine Plus Diclofenac Decreases Pain in Benign Anorectal Surgery: Randomized, Double-blind, and Controlled Clinical Trial.

OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of a topical formulation containing lidocaine plus diclofenac (CLIFE1) compared to lidocaine (CLIFE2), to decrease pain in benign anorectal surgery (BARS) to date not evaluated. More than 50% of patients undergoing BARS, especially hemorrhoidectomy, suffer from moderate and severe postoperative pain. This remains an unresolved problem that could be addressed with the new CLIFE1 topical treatment. METHODS: A multicenter, randomized double-blind, active-controlled parallel-group superiority trial, was conducted in two Spanish hospitals. Patients undergoing BARS (hemorrhoids, anal fistula and anal fissure) were randomized at the end of surgery at a 1:1 ratio to receive first dose either CLIFE1 (n = 60) or CLIFE2 (n = 60) anorectal topical treatment, and after every 12 h for the first three postoperative days and once a day from the fourth to sixth. The primary outcome was average of pain decrease after topical treatment, measured with visual analogue scale (VAS) by the patients themselves, the evening in the surgery day and four times daily for the first three postoperative days. RESULTS: The results of 120 patients included out of 150 selected undergoing BARS show a decrease in pain after CLIFE1 topical treatment (7.47 ± 13.09) greater than with CLIFE2 (4.38 ± 6.75), difference -3.21 95% CI (-5.75; -0.68), p = 0.008, decreasing significantly postoperative pain ( ≥ 9 mm, VAS) in 35% of patients undergoing benign anorectal surgery, compared to 18.33 % treated with lidocaine. CONCLUSIONS: The CLIFE1 topical treatment shows better analgesic efficacy than CLIFE2 in BARS.

Improving tablet coating robustness by selecting critical process parameters from retrospective data.

CONTEXT: Although tablet coating processes are widely used in the pharmaceutical industry, they often lack adequate robustness. Up-scaling can be challenging as minor changes in parameters can lead to varying quality results. OBJECTIVE: To select critical process parameters (CPP) using retrospective data of a commercial product and to establish a design of experiments (DoE) that would improve the robustness of the coating process. MATERIALS AND METHODS: A retrospective analysis of data from 36 commercial batches. Batches were selected based on the quality results generated during batch release, some of which revealed quality deviations concerning the appearance of the coated tablets. The product is already marketed and belongs to the portfolio of a multinational pharmaceutical company. RESULTS: The Statgraphics 5.1 software was used for data processing to determine critical process parameters in order to propose new working ranges. DISCUSSION AND CONCLUSIONS: This study confirms that it is possible to determine the critical process parameters and create design spaces based on retrospective data of commercial batches. This type of analysis is thus converted into a tool to optimize the robustness of existing processes. Our results show that a design space can be established with minimum investment in experiments, since current commercial batch data are processed statistically.

Relationships between surface free energy, surface texture parameters and controlled drug release in hydrophilic matrices.

The study of controlled release and drug release devices has been dominated by considerations of the bulk or average properties of material or devices. Yet the outermost surface atoms play a central role in their performance. The objective of this article has been to characterize the surface of hydrophilic matrix tablets using the contact angle (CA) method to ascertain the surface free energy, and atomic force microscopy (AFM) and confocal microscopy (CM) for the physical characterization of the surface of the hydrophilic matrix. The surface free energy results obtained show that hydroxypropylmethylcellulose K15M hinders the spreading of water on the surface of the tablet, such that the concentration of HPMC K15M increases the reaction rate of the hydrophobic interactions between the chains of HPMC K15M which increases with respect to the rate of penetration of water into the tablet. In this study, we developed a new method to characterize the swelling of the tablets and established a relationship between the new method based on microswelling and the swelling ratio parameter. The surface texture parameters have been determined and the morphology of the tablets of the different formulations and the evolution of the surface morphology after interacting with the water, swelling and forming a gel layer were characterized. This work represents significant progress in the characterization of matrix tablets.

Quality by Design approach to understand the physicochemical phenomena involved in controlled release of captopril SR matrix tablets.

The aim of this study is to obtain swelling controlled release matrix tablets of captopril using the Quality by Design methodology (ICH Q8) and to know the transport mechanisms involved in captopril release. To obtain the area of knowledge, the design of experiments studying the effect of two components (HPMC K15M and ethylcellulose) at different levels has been applied, with the captopril dissolution profile as the product's most important critical quality attribute (CQA). Different dissolution profiles have been obtained with the design of experiments performed, which is a key factor in the development of controlled release matrix tablets. Kinetic analysis according to the equations of Higuchi and Korsmeyer-Peppas demonstrates that the release mechanism is a mechanism of erosion when the whole percentage of the polymer is ethylcellulose, and a diffusion mechanism when the whole percentage of the polymer is HPMC K15M. The physico-chemical characteristics of the gel layer determine the release rate of captopril. The thickness of the gel layer, the porosity which is formed in the matrix upon contact with water, pore size, the swelling rate, the erosion rate of the matrix, and the physico-chemical characteristics of captopril, are factors related to the kinetic equations described and that allow us to predict the release mechanism of captopril. A new relationship of the kinetic equations governing the in vitro behavior with the physical characteristics of the gel layer of the different formulations has been established. This study shows that the size of water-filled pores and the degree of crosslinking between the chains of HPMC K15M of the matrix are related to the exponent n of the Korsmeyer-Peppas equation and the type of transport of the captopril from within the matrix to the dissolution medium, that is, if the transport is only through water-filled pores, or if a combination of diffusion occurs through water-filled pores with a transport through continuous polymeric networks.

The use of the SeDeM diagram expert system for the formulation of Captopril SR matrix tablets by direct compression.

The SeDeM diagram expert system has been used to study excipients, Captopril and designed formulations for their galenic characterization and to ascertain the critical points of the formula affecting product quality to obtain suitable formulations of Captopril direct compression SR matrix tablets. The application of the SeDeM diagram expert system enables selecting excipients with in order to optimize the formula in the preformulation and formulation studies. The methodology is based on the implementation of ICH Q8, establishing the design space of the formula with the use of experiment design, using the parameters of the SeDeM diagram expert system as system responses.

Characterization of alginate beads loaded with ibuprofen lysine salt and optimization of the preparation method.

The parameters influencing alginate ionotropic gelation and the production of alginate beads loaded with hydrosoluble ibuprofen lysine salt (IBU-L) were studied, as well as the optimization of the method for its attainment. A three-factor and three-level factorial design (3(3)) was carried out to determine the influence of three experimental variables: polymer concentration, CaCl2 concentration, and curing time on the dependent variables drug load and encapsulation efficiency. The effect of the pH used in the preparation bath was also evaluated. Concentrations of CaCl2 and pH of gelling bath were seen to affect bead formation and stability as well as their ability to properly entrap the drug. In this work, IBU-L was used as a model of a non-steroidal anti-inflammatory drug with good solubility in alginate solutions. IBU-L was successfully encapsulated in alginate beads obtained by the ionotropic gelation method. The obtained alginate matrixes are able to modify the release of the entrapped IBU-L and this occurs in a pH-sensitive way that can be correlated with the swelling behaviour of the alginate-produced beads. Morphological characteristics were evaluated by means of scanning electron microscopy.

Impact of physical parameters on particle size and reaction yield when using the ionic gelation method to obtain cationic polymeric chitosan-tripolyphosphate nanoparticles.

Ionic gelation is the most frequently used method to obtain chitosan-tripolyphosphate nanoparticles due to its simplicity and because it does not generate waste solvents in the samples prepared. This paper presents a study of the physical factors involved in this method for obtaining nanoparticles in order to determine which of them significantly influences the particle size of polymeric nanoparticles made from low-molecular-weight chitosan, without any additional chemical treatment, with the aim of standardising and optimising the method conditions, in addition to establishing the reaction yield. The results indicate that stirring speed during ionic gelation reaction is decisive for the size of the nanoparticles obtained. Furthermore, it thus follows that the stirring speed during ionic gelation significantly affects reaction yield, and therefore, by manipulating this parameter a greater proportion of nanoparticles of a given size range can be obtained.

Contribución de la experiencia del Departamento de Farmacia y Tecnología Farmacéutica (Universidad de Barcelona) para la creación y organización del Sistema de Registro de Medicamentos en Angola / Contribution of the experience of the Department of Pharmacy and Pharmaceutical Technology (University of Barcelona) for the creation and organization of Drugs Registration System in Angola

El gobierno de Angola después de consolidar el proceso de paz y reconciliación nacional, se encuentraen un proceso de transición del estado de emergencia al estado de desarrollo económico y social sostenible, a través de iniciativas capaces de solucionar los principales problemas nacionales, de los que pueden mencionarse en lo relativo al sector farmacéutico: la inexistencia en el sistema de salud de servicios que garantice el registro, control e inspección de medicamentos. Este trabajo fue diseñado con la intención de apoyar el área de regulación y reglamentación del sector farmacéutico angoleño, contribuyendo a la mejora institucional del Ministerio de Salud de Angola mediante el desarrollo de dos importantes comisiones técnicas en relación con la evaluación técnico científica de la documentación presentada para el registro de medicamentos, a petición de la Dirección Nacional de Medicamentos y Equipamientos (DNME). La creación de estas comisiones aseguran los más elevados patrones de salud pública además de prevenir los riesgos decurrentes de la utilización de medicamentos en Angola, ya que como función primordial emitirán dictámenes sobre la evaluación de la seguridad, eficacia y calidad de los medicamentos(AU)

After consolidating the peace process and national reconciliation, the government of Angola is going through a transition process, from a state of emergency to a state of sustainable economic and social development. Through initiatives that can solve the country’s main problems which, in the pharmaceuticals sector, include the absence in the health system of services to record, audit and inspect medicines. The present project contributes to the development of Angola's health system, and more specifically the control and regulation area of the pharmaceutical sector in Angola, through the proposed of creating technical committees to ensure the proper technical and scientific evaluation of each application for drug registration which will serve as support for the political and administrative decision of the National Drug and Equipment Directorate (DNME). The creation of these committees assure the highest standards of public health in addition to preventing the risks incurred through the use of drugs in Angola, since primary function is the issuing opinions on the assessment of the safety, efficacy and quality of medicines(AU)

Total organic carbon (VCSN and VWP) and HPLC analysis for cleaning validation in a pharmaceutical pilot plant.

This paper presents a useful method using total organic carbon analyzers employing both combustion and wet oxidation for validating equipment cleaning procedures and verifying cleaning in a pharmaceutical pilot plant. The results are compared with those obtained using high-performance liquid chromatography. The study summarizes the initial steps that should be taken into account and focuses particularly on the solutions to some of the most critical considerations (e.g., glass material, detection and quantification limits, recovery). Also described are the calculation of control limits and the good results obtained.

Method for the development of topical medicinal aerosols using liquified hydrocarbon gas.

Low chain liquid hydrocarbons (LH) at room temperature and atmospheric pressure can be used to simulate the effect of gas hydrocarbons (GH) in aerosol systems without the need of using pressured flasks. Samples of different tetracycline formulations were tested with LH and GH in order to study their behaviour and physicochemical stability in the system. The results showed a similar behaviour between samples when LH or GH were used, suggesting the use of LH to simulate the effect of GH introduction in the system, as a useful predictive method for the development of pressured aerosol formulations without using pressured containers in early steps of the process, such as pre-formulation studies.

Aplicación del diseño experimental a la optimización farmacéutica de procesos de fabricación de medicamentos / Application of the experimental design to the pharmaceutical optimization on the production process of drugs

A partir de una fórmula famacotécnicamente correcta y tras concluir las pruebas de cualificación individuales de los equipos se plantea el último paso del desarrollo galénico, entendiéndose como tal la optimización del proceso de elaboración. Para la optimización se aplica la técnica del diseño de experimentos a fin de determinar la combinación óptima y conjunta de los parámetros críticos del proceso de elaboración que dan un valor de respuesta óptima. Las respuestas del proceso de compresnión a optimizar (fórmula para realizar en las prácticas de pregrado de la licenciatura de farmacia) pueden ser varias, en este caso se escogieron la riqueza media de los comprimidos (de una muestra de 10 comprimidos), el % de disolución a los 30 minutos (de una muestra de 6 comprimidos) y la dureza (de una muestra de 10 comprimidos), cuyos resultados se presentan resumidos, los cuales demuestran la validez y utildad de esta herramienta para la validación farmacéutica rutinaria, herramienta que será muy útil para el desarrollo pleno de las normativas ICH Q8, ICH q9 y ICH Q10, dentro del desarrollo galénico y la validación

From a formula tecnologically correct and after concluding the individual tests of qualification of the equipments the last step of the phamaceutical development starts, understanding itself as that of the optimization of teh process of production. For the optimization the technology of the experimental design is applied in order to determine the ideal combination of the critical parameters of the process of compression to optimizing can be different, in this case was chosen the average content of the tablets (of a sample of 10 tablets), the % of dissolution to 30 minutes (of a sample of 10 tablets). Results demonstrate the validity and usefulness of this tool for the pharmaceutical routine validation, tool that also will be very useful for the full, development of the next regulations ICH Q8, ICH Q9 and ICH Q10

Stability evaluation of amoxicillin in a solid premix veterinary formulation by monitoring the degradation products through a new HPLC analytical method.

A methodology (by VICH guidelines) for the stability evaluation of amoxicillin in granular premixes is described. This method is based on the monitoring of the degradation products formed during the stability study by a new HPLC-RP method, which has been developed and validated for the simultaneous determination of amoxicillin and its degradation products. The method uses a Nucleosil 120 C18 column and gradient elution. The mobile phase consisted of a mixture of methanol and buffer solution pH 3+/-0.05 at different proportion according to a time-schedule programme, pumped at a flow rate of 1.750 ml min(-1). The DAD detector was set at 230 nm. The validation study was carried out fulfilling the VICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics showed the capacity of analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy, sensitivity (LOD, LOQ) and robustness. The method was applied during the stability study of an amoxicillin premix in order to quantify the drug (amoxicillin) and all its degradation products to evaluate the shelf life of the new veterinary dosage form. The method also proved to be suitable as a rapid and reliable quality control method.

Estudio farmacotécnico comparativo de cinco especialidades farmacéuticas de comprimidos de paracetamol 650 mg / comparative pharmacotechnical study of five aminophen 650 mg comercial tablets

Se efectúa el estudio farmacotécnico comparativo de cinco especialidades farmacéuticas de comprimidos de paracetamol con un contenido declarado de principio activo de 650 mg, en base a los siguientes ensayos: humedad, características organolépticas, geométricas (dimensiones), de resistencia mecánica (resistencia a la rotura y friabilidad), posológicas (uniformidad de masa, riqueza y sustancias relacionadas) y de disponibilidad (disgregación y disolución)

A comparative physical test study on five commercial acetaminophen tablets 650 mg from Spanish market is carried out. The tests applied are: moisture, appearance characteristics, dimensions (diameter, thickness), hardness, weight variation, friability, disintegration, dissolution, identification, assay and related compounds

Contribución a la aplicación en la industria farmacéutica del ensayo de disolución para formas farmacéuticas sólidas / No disponible

Se efectúa una revisión del ensayo de disoluciónde formas farmacéuticas sólidas y suaplicación como control de calidad en la industriafarmacéutica. Se revisan los aspectos técnicosdel ensayo de disolución: condiciones enque debe llevarse a cabo (condiciones “sink”),equipos utilizados, aspectos analíticos y fundamentoteórico. Finalmente, se comentan losfactores que influyen en la velocidad de disolucióndel fármaco cuando se efectúa el ensayode disolución de la forma farmacéutica

The present work performs a revision of thedissolution test for solid pharmaceutical formsand its application like quality control in thepharmaceutical industry. The technical aspectsof the dissolution test are reviewed: conditionsin which it must be carried out (“sink” conditions),used equipment, analytical aspects andtheoretical foundation. Finally, the factors commentthat influence in the speed of dissolutionof the drug when the dissolution test of thepharmaceutical form takes place

Microencapsulación: aplicaciones, métodos y caracterización / Microencapsulation: applications, methods and characterization

Se hace una revisión general de la microencapsulacióncomo recurso tecnológico en farmaciapara el desarrollo de medicamentos. Lamicroencapsulación es un campo interdisciplinarioque requiere tecnología de la emulsión,en la mayoría de los casos y de la estabilizaciónde principios activos y proteínas. Se empleanmuchas técnicas con gran variedad demateriales formadores de cubierta para la obtenciónde microcápsulas a nivel comercial, enespecial el recubrimiento en lecho fluido, laatomización y la atomización con congelación.En esta revisión también se consideran aspectossobre la caracterización de dichas microcápsulas

A revision of the microencapsulation as apharmaceutical technology for the drug developmentis made. Microencapsulation is an interdisciplinaryfield that requires knowledge ofpolymer science, emulsion technology in mostcases and an understanding of drug and proteinstabilization. Many techniques using a largevariety of coating materials are employed tomanufacture such microcapsules, in particularairsuspension coating and spray-drying orspray-congealing on a commercial scale. Aspectsof the characterization of drug-containingmicrocapsules will be considered in this review

Nueva metodología de preformulación galénica para la caracterización de sustancias en relación a su viabilidad para la compresión: Diagrama SeDeM / An original methodology of galenic preformulation for characterization solid substances for compression: SDM Method

Se propone una nueva y original metodología (Método SeDeM) para la caracterización de sustancia sólidas con el fin de facilitar los estudios de formulación para la obtención de comprimidos por vía directa. Esta nueva metodología es de aplicación en los estudios de preformulación de comprimidos y consiste en la determinación de una serie de parámetros que convenientemente analizados proporcionan la información necesaria para conocer si la sustancia sólida estudiada, sea principio activo o excipiente, es apta para la compresión directa. Los parámetros propuestos se pueden tratar matemáticamente y expresar gráficamente mediante el diagrama SeDeM. Se aporta un ejemplo de aplicación sobre un principio activo del cual se determinan aquellas características que son correctas para su posterior compresión y aquellas características deficitarias que deben ser corregidas. Se concluye que el método SeDeM es eficaz y válido, por lo que puede adoptarse como una nueva herramienta a aplicar en los estudios de preformulación de medicamentos, cuyo objetivo es aportar la información farmacotécnica necesaria para facilitar la formulación del medicamento en forma de comprimido y para definir la tecnología de fabricación más adecuada

We propose a new and original methodology (the SeDeM Method) for characterizing solid substances with the aim of facilitating formulation studies for direct compression of tablets. This new methodology is useful in preformulation studies for tablets and involves measuring and analysing a series of parameters that provide necessary information as to whether the solid substance under study (an active ingredient or an excipient) is suitable for direct compression. The parameters proposed can be mathematically processed and graphically expressed as a SeDeM diagram. An example is provided of the application using an active ingredient. The characteristics that make the ingredient suitable for subsequent compression and those that must be corrected are identified. SeDeM is an effective and valid method, which means it can be adopted as a new tool to be applied in drug-preformulation studies designed to provide the pharmacotechnical information required to facilitate the formulation of drugs in tablet form and define the most suitable manufacturing technology

A new validated method for the simultaneous determination of benzocaine, propylparaben and benzyl alcohol in a bioadhesive gel by HPLC.

A new HPLC-RP method has been developed and validated for the simultaneous determination of benzocaine, two preservatives (propylparaben (nipasol) and benzyl alcohol) and degradation products of benzocaine in a semisolid pharmaceutical dosage form (benzocaine gel). The method uses a Nucleosil 120 C18 column and gradient elution. The mobile phase consisted of a mixture of methanol and glacial acetic acid (10%, v/v) at different proportion according to a time-schedule programme, pumped at a flow rate of 2.0 ml min(-1). The DAD detector was set at 258 nm. The validation study was carried out fulfilling the ICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics showed the capacity of analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy and sensitivity. The method was applied during the quality control of benzocaine gel in order to quantify the drug (benzocaine), preservatives and degraded products and proved to be suitable for rapid and reliable quality control method.

Formas farmacéuticas de retención gástrica / Gastroretentive dosage form

Durante las tres últimas décadas parte de la investigación galénica de las formas farmacéuticas de retención gástrica ha tenido como objetivo principal mejorar la absorción de algunos fármacos y mejorar, en consecuencia, la biodisponibilidad de dichos fármacos. Para conseguir este objetivo, se ha tratado de prolongar el tiempo de permanencia en el estómago de dichas formas farmacéuticas, si bien este hecho resulta a su vez un factor limitante debido al propio proceso fisiológico del vaciado gástrico y por tanto a la variabilidad existente tanto inter como intraindividuo. En este trabajo se presenta un breve resumen de algunos aspectos fisiológicos y dinámicos del tracto gastrointestinal que ayudarán a una mejor compresión de las formas farmacéuticas de retención gástrica, además de mostrar los diferentes sistemas propuestos hasta el momento para conseguir que las formas farmacéuticas queden retenidas más tiempo a nivel del estómago: sistemas bioadhesivos, sistemas flotantes, sistemas de alta densidad, sistemas a base de chitosán y sistemas que incorporan en su formulación principios activos o sustancias retardantes del vaciado gástrico

The aim of the galenic research about the gastroretentive dosage form development, since the last three decades, has been the absorption and bioavailavility enhancement of drug substances. In order to achieve this objective the residence time of the formulation in the stomach has been prolonged, although this is a limiting factor due to the physiological gastric release, and consequently the existing inter and intra-individual variability. In this work, a brief review of some of the physiological and dynamic factors of the gastrointestinal tract is presented in order to help for a better understanding of the gastroretentive dosage forms. Also, a description of the different proposed systems up to now to achieve a longer residence time of the formulation in the stomach is made: bioadhesive systems, floating systems, high density systems, chitosan based systems, and systems that have in its formulation actives or agents that delay the gastric emptying