Optimization and evaluation of modified release solid dosage forms using artificial neural network.

This study aims to optimize and evaluate drug release kinetics of Modified-Release (MR) solid dosage form of Quetiapine Fumarate MR tablets by using the Artificial Neural Networks (ANNs). In training the neural network, the drug contents of Quetiapine Fumarate MR tablet such as Sodium Citrate, Eudragit® L100 55, Eudragit® L30 D55, Lactose Monohydrate, Dicalcium Phosphate (DCP), and Glyceryl Behenate were used as variable input data and Drug Substance Quetiapine Fumarate, Triethyl Citrate, and Magnesium Stearate were used as constant input data for the formulation of the tablet. The in-vitro dissolution profiles of Quetiapine Fumarate MR tablets at ten different time points were used as a target data. Several layers together build the neural network by connecting the input data with the output data via weights, these weights show importance of input nodes. The training process optimises the weights of the drug product excipients to achieve the desired drug release through the simulation process in MATLAB software. The percentage drug release of predicted formulation matched with the manufactured formulation using the similarity factor (f2), which evaluates network efficiency. The ANNs have enormous potential for rapidly optimizing pharmaceutical formulations with desirable performance characteristics.

DoE-Based Design of a Simple but Efficient Preparation Method for a Non-Effervescent Gastro-Retentive Floating Tablet Containing Metformin HCl.

A sustained-release non-effervescent floating matrix tablet was prepared using a simple and efficient direct compression of spray-dried granules containing metformin hydrochloride and cetyl alcohol with hydroxypropyl methylcellulose K15M (HPMC K15M). The design of experiments was employed to explore the optimal composition of the tablet. The similarity factor was employed to evaluate the equivalence in dissolution profiles between the test tablets and Glucophage XR as a reference. Bootstrap analysis was used to eliminate the formulations for which the dissolution profile was potentially inequivalent to that of the reference. The optimized tablet consisting of 150 mg of cetyl alcohol and 17% HPMC K15M showed a dissolution profile comparable with that of the reference with a similarity factor of 52.41, exhibited a floating lag time of less than 3 s in buffer media, remained floating for 24 h, and reduced the tablet weight by about 20% compared to that of the reference. The current study sheds light on the potential use of non-effervescent gastro-retentive extended-release tablets for high-dose drugs using a simple and efficient direct compression method, and as a potential alternative treatment for Glucophage XR. This study also highlights the importance of a systematic approach to formulation optimization and the evaluation of the dissolution profile.

Comparison of Dissolution Profiles: A Statistician's Perspective.

Dissolution profile comparisons are used in the context of postapproval changes where the manufacturer has to demonstrate that the quality of the product is not affected by the change. Around this topic, basic statistical principles are in conflict with widely used interpretations of current guidelines, resulting in time-intensive discussions in pharmaceutical practice. From a statistician's perspective, the following suggestions could improve the situation regarding statistical analysis, inference, and interpretation: (1) A clear definition of the variability criterion for the similarity factor, such as that found in the EMA guideline, would be helpful. (2) Sample size recommendations should be interpreted as minimum, not as maximum, requirements. (3) In case of several batches per reference or test group, pooled comparisons should be performed instead of multiple batch-to-batch comparisons. (4) FDA Guideline recommendations concerning multivariate equivalence procedures for highly variable dissolution profiles are based on the state of statistical knowledge in 1997 and need to be updated. (5) The T2 test for equivalence is an appropriate method for comparing highly variable dissolution profiles. Application of the T2 test for equivalence enables reliable equivalence decisions and satisfies the intention of reaching scientific evidence in decision making. Software implementations of this test are available in R and SAS. The article is a summary of the poster of the same name presented at the DIA FDA Statistics Forum 2016. The poster took the third place in the poster award of the conference.

Comparison of dissolution time profiles: No similarity but where is the difference?

The similarity of the dissolution time profiles is routinely determined by various statistical methods, e.g. by calculating the f2 similarity factor, by calculating the multivariate statistical distance or determining the confidence interval of f2 metrics using the bootstrapping method. If the similarity of the dissolution profiles is not achieved, these methods provide no information about the possible causes of the differences in the final dosage forms. In this article it is shown that after introduction of summary parameters into the disintegration-dissolution model (DDM), such as intrinsic lifetime distribution of particles, saturation state function, drug load of the system and applying population data analysis, differences on the level of intrinsic lifetime distributions of particles of active pharmaceutical ingredient in immediately release formulations are identified. The identification of these differences provides important clues to target development of generic formulations or helps to explain possible differences in the in vivo behavior of products.

Determination of the Dissolution Curves of Albendazole Tablets / 中国药学杂志

OBJECTIVE: To establish a determination method of the dissolution curves of albendazole tablets with differentiation ability and investigate the similarity of dissolution curves in vitro between reference preparation and generic preparations.METHODS: Paddle method was adopted with rotation speed of 50 r•min-1 and the dissolution medium volume was 900 mL. The dissolution media were pH 1.2 hydrochloric acid solution and water. The similarity factor (f2) method was used to evaluate the comparability of dissolution curves.RESULTS: The three established dissolution curves had good distinguishing ability. As shown by the similarity factor (f2), the generic preparation from manufacture A was similar to the reference preparation, while those from the manufacture B and C were not similar.CONCLUSION: The study provides the experimental basis for the consistency evaluation of the dissolution curves of abendazole tablets.

Comparación de los perfiles de disolución de comprimidos de lamotrigina de 100mg comercializados en Paraguay / Comparison of the dissolution profiles of tablets of lamotrigine 100mg traded in Paraguay

Objetivo: evaluar los perfiles de disolución decomprimidos de Lamotrigina 100mg (Test) con laReferencia (Lamictal®) comercializados en Paraguay.Material y Métodos: Se utilizaron comprimidosde Lamotrigina de 100mg comercializados enParaguay. Se determinaron los perfiles de disoluciónde los productos Test y Referencia, en los tresmedios de disolución recomendados (pHs 1,2 ; 4,5y 6,8). El método analítico se basó en HPLC condetector PDA a 277nm, usando una PhenomenexLuna C18 a 40ºC, con fase móvil de buffer fosfatode sodio 0.05M pH4.0-acetonitrilo (80:20), flujode 1.3mL/min y tiempo de retención de 5 min.Resultados: Los perfiles de disolución del productoTest de Lamotrigina 100mg, fueron similaresen los diferentes pHs al producto de Referencia,liberando más del 85% a los 15 minutos en los 3medios de disolución, no siendo necesaria la comparacióncon el factor f2.Conclusión: Los perfiles de disolución de los comprimidosde Lamotrigina de 100mg Test muestranun comportamiento in vitro semejante al productode Referencia, lo que sugiere que su comportamientoin vivo podría ser también semejante.

Objectives: to evaluate the dissolution profiles ofLamotrigine tablets of 100 mg (Test) and Reference(Lamictal®) marketed in Paraguay.Material and Methods: Tablets of Lamotrigine100 mg marketed in Paraguay were used. Dissolutionprofiles of the Test and Reference productswere determined in the three recommended dissolutionmedia (pH 1.2; 4.5 and 6.8). The HPLCmethod used consisted of a Phenomenex Luna C18column, with mobile phase of 0.05M sodium phosphatebuffer pH4.0-acetonitrile (80:20), flow rateof 1.3mL / min and retention time of 5 min. Thecolumn compartment was kept at 40ºC, and thewavelength detection was 277 nm.Results: The dissolution profiles of the Test productof Lamotrigine 100mg, showed similar behavior tothe Reference product at the three different pHs,releasing more than 85% in 15 minutes in the threemedia dissolution. No calculation using the similarityfactor f2 was needed.Conclusion: Dissolution profiles of the two formulationsof Lamotrigine 100mg were similar in thedifferent pH dissolution media, thus a similar invivo behavior could be expected.

Comparison of novel granulated pellet-containing tablets and traditional pellet-containing tablets by artificial neural networks.

Novel granulated pellets technique was adopted to prepare granulated pellet-containing tablets (GPCT). GPCT and traditional pellet-containing tablets (PCT) were prepared according to 29 formulations devised by the Design Expert 7.0, with doxycycline hydrochloride as model drug, blends of Eudragit FS 30D and Eudragit L 30D-55 as coating materials, for the comparison study to confirm the superiority of GPCT during compaction. Eudragit FS 30D content, coating weight gain, tablet hardness and pellet size were chosen as influential factors to investigate the properties and drug release behavior of tablets. The correlation coefficients between the experimental values and the predicted values by artificial neural networks (ANNs) for PCT and GPCT were 0.9474 and 0.9843, respectively, indicating the excellent prediction of ANNs. The similarity factors (f2) for release profiles of GPCT and the corresponding original pellets were higher than those of PCT, suggesting that the excipient layer of granulated pellets absorbed the compressing force and protected the integrity of coating films during compaction.

Estudio comparativo de la calidad biofarmacéutica de marcas comerciales y multifuentes de tabletas de captopril y losartán del mercado colombiano / Comparative study of the biopharmaceutical quality of commercial and generic brands of captopril and losartan tablets in the Colombian market

La hipertensión arterial afecta a miles de personas en el mundo, y en Colombia permanece como una de las primeras causas de morbi-mortalidad. Los fármacos captopril y losartán constituyen la primera elección para su tratamiento. Con el fin de evaluar la conformidad de los productos y determinar su equivalencia biofarmacéutica, se evaluaron un total de 19 marcas comerciales disponibles en droguerías y farmacias de cuatro principales ciudades del país: Bogotá, Cartagena, Cali y Barranquilla. Para ello se evaluaron las características físicas, químicas y biofarmacéuticas de las tabletas, tales como variación de peso, dureza, desintegración, test de disolución, perfil de disolución, eficiencia de la disolución y valoración de principio activo, esta última, a partir de metodologías optimizadas y validadas. Los ensayos farmacopeicos se evaluaron segúún lo establecido en la USP 35. Los resultados permitieron establecer que todas las marcas analizadas cumplieron los criterios de aceptación establecidos en la farmacopea para cada principio y que el comportamiento biofarmacéutico de ellas era muy similar para ambos tipos de molécula. Los resultados de este trabajo permiten proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico.

Hypertension affects thousands of people around the world and in Colombia remains one of the leading causes of morbidity and mortality. The captopril and losartan drugs are the first choice for treatment. In order to assess the conformity of products and determine their biopharmaceutical equivalence, a total of 19 commercial brands available in drug stores and pharmacies in four major cities of the country (Bogotá, Cartagena, Cali and Barranquilla) were evaluated. To this end the physical, chemical and biopharmaceutical characteristics of the tablets, such as weight variation, hardness, disintegration, dissolution, dissolution profile, the dissolution efficiency and value of the active substance were evaluated. This latter from optimized and validated methodologies. Pharmacopeial assays were evaluated as provided in USP 35 NF 30. The results obtained allowed to establish that all models tested met the acceptance criteria in the Pharmacopoeia for each principle, and the biopharmaceutical behavior of brands is very similar for both types of molecule. The results of this work allows to propose the scientific community the determination of the biopharmaceutical equivalence as support in making purchasing decisions in the pharmaceutical service.

Formulation and Evaluation of Cephalexin Extended-release Matrix Tablets Using Hydroxy Propyl Methyl Cellulose as Rate-controlling Polymer.

The present investigation reports the design and evaluation of six-hour extended release film-coated matrix tablets of cephalexin using different grades of hydrophilic polymer hydroxypropylmethylcellulose (HPMC) employing direct compression method. The preformulation studies performed included the physical compatibility studies, Differential Scanning Calorimetry analysis, drug characterization using Fourier Transform Infra Red spectroscopic analysis and particle size analysis using sieve method. The tablets were evaluated for weight variation, hardness, thickness and friability. Results of the studies indicate that the polymers used have significant release-retarding effect on the formulation. The dissolution profile comparison of the prepared batches P1 to P8 and market preparation (Sporidex AF 375) was done by using Food and Drug Administration-recommended similarity factor (f(2)) determination. The formulation P8 (10% HPMC K4M, 15% HPMC 15cps) with a similarity factor (f(2)) of 77.75 was selected as the optimized formulae for scale-up batches. The dissolution data of the best formulation P8 was fitted into zero order, first order, Higuchi and Korsemeyer-Peppas models to identify the pharmacokinetics and mechanism of drug release. The results of the accelerated stability study of best formulation P8 for three months revealed that storage conditions were not found to have made any significant changes in final formulation F3. The release of cephalexin was prolonged for 6 h by using polymer combinations of HPMC and a twice daily matrix tablet was formulated.

Development and validation of new discriminative dissolution method for carvedilol tablets.

The objective of the present study was to develop and validate a discriminative dissolution method for evaluation of carvedilol tablets. Different conditions such as type of dissolution medium, volume of dissolution medium and rotation speed of paddle were evaluated. The best in vitro dissolution profile was obtained using Apparatus II (paddle), 50 rpm, 900 ml of pH 6.8 phosphate buffer as dissolution medium. The drug release was evaluated by high-performance liquid chromatographic method. The dissolution method was validated according to current ICH and FDA guidelines using parameters such as the specificity, accuracy, precision and stability were evaluated and obtained results were within the acceptable range. The comparison of the obtained dissolution profiles of three different products were investigated using ANOVA-based, model-dependent and model-independent methods, results showed that there is significant difference between the products. The dissolution test developed and validated was adequate for its higher discriminative capacity in differentiating the release characteristics of the products tested and could be applied for development and quality control of carvedilol tablets.

Formulation and evaluation of cephalexin extended release matrix tablets using 3 factorial design.

The aim of the present investigation was to prepare extended release film coated matrix tablets of cephalexin using binary mixture of two grades of hydrophilic polymer, hydroxypropyl methyl cellulose (HPMC), by direct compression method. Results of the preliminary trials indicated that the polymers used have significant release retarding effect on the formulation. To study the effect of concentration of polymers on drug release from matrix tablets, 3(2) full factorial design was applied. The concentration of HPMC K15M and HPMC 15cps were used as independent variables, while percentage drug release was selected as dependent variable. The dissolution data were fitted into zero-order, first-order, Higuchi and Korsemeyer-Peppas models to identify the pharmacokinetics and mechanism of drug release. Comparative study of dissolution profile of final batch F3 with market preparation (Sporidex AF 375) was done by similarity factor (f(2)) determination and it was concluded that final formulation F3 (10% HPMC K15M, 17.5% HPMC 15cps) shows good similarity with the market product. The results of the accelerated stability study of final formulation F3 for 1 month revealed that storage conditions were not found to have made any significant changes in final formulation F3. The release of cephalexin was prolonged for 6 h by using polymer combinations of HPMC and a twice daily matrix tablet was formulated.