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.

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.

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.

In vitro evaluation of the effectiveness and cytotoxicity of meglumine antimoniate microspheres produced by spray drying against Leishmania infantum.

The aim of the present study was to evaluate the in vitro activity and cytotoxicity of meglumine antimoniate microspheres produced by spray drying on Leishmania infantum and the effect of the excipients used in them. The parasite strain shows sensitivity to the meglumine antimoniate microspheres prepared. All the antimony IC50 values from encapsulated meglumine antimoniate (3.80 +/- 0.34 to 9.53 +/- 0.70 microg SbV/ml for promastigotes assay) are considerably lower compared to the mean value of IC50 in Glucantime solution (112 +/- 12.74 microg SbV/ml). Interesting IC50 values for the excipient chitosan (112.64 +/- 0.53 mg/ml for promastigotes and 100.81 +/- 26.45 mg/ml for amastigotes) were obtained (without cytotoxic activity), whereas the rest of the excipients did not show any activity. This new delivery system could offer a new pharmacological tool for the treatment of leishmaniosis that reduces the doses required, lowering toxic side effects because of meglumine antimoniate.

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

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

Development and validation of a new HPLC analytical method for the determination of alprazolam in tablets.

A new analytical method is developed together with its latter validation study, by means of a high resolution liquid chromatography (HPLC) of reverse phase to quantify alprazolam (8-chloro-1-methyl-6-phenyl-4H-[1,2,4] triazole [4,3,-alpha]-[1,4] benzodiazepine) in tablets. Determination is carried out by means of an ODS C18 column (200 mm x 4.6 mm i.d., 5 microm particle size); the mobile phase consisted of a mixture of 0.02 M buffer solution of phosphates (pH 6.0) and acetonitrile (45:55, v/v). It is pumped through the chromatographic system at a flow rate of 0.50 ml min(-1). The UV detector is operated at 254 nm. The validation study is carried out fulfilling the ICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics show the capacity of an analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy and sensitivity. The method is applied during the working day for the quality control of commercial alprazolam tablets in order to quantify the drug and its degradation products and to check the content uniformity test.

Study of formulation parameters by factorial design in metoprolol tartrate matrix systems.

The study of formulation parameters in hydrophilic matrices of metoprolol tartrate by 2(3) factorial design wass made. We compared the dissolution profiles of two hydrophilic polymers (hydroxypropylmethylcellulose and hydroxyethylcellulose) at high and low concentrations and in the presence or absence of an insoluble excipient (calcium hydrogen phosphate dihydrate). The results showed that the presence of an insoluble excipient influenced almost all of the dissolution parameters.

Estudio farmacotécnico comparativo de siete especialidades farmacéuticas de calcitonina en aerosol para aplicación intranasal / Pharmacotechnical comparative study of seven finish products of intranasal spray calcitonin´s

Se efectúa un estudio comparativo de siete marcas de calcitonina aerosol intranasal desde el punto de vista farmacotécnico. Para ello se procede al análisis de los siguientes ensayos. pH de la disolución de calcitonina,estudio de posibles alteraciones organolépticas de la disolución en situaciones forzadas de temperatura (40 °C y 55 °C) y acción de la luz solar, volumen de dosificación, tipo de envase y características, alteración del envase sometido a situac iones forzadas de temperatura (40 °C y 55 °C) y acción de la luz solar, en envases de plástico observación del comportamiento a la permeabilidad en condiciones de baja y alta humedad ambiental, características de la válvula de dosificación, características del pulsador, exactitud de dosificación por pulsación (control de descarga), ángulo de pulverización, diámetro de salida del pulverizador, índice del caudal de salida (lectura "Solex'), dosis totales por unidad, uniformidad de masa por dosis, hermeticidad, texto impreso en el envase primario y en el envase secundario (AU)