Statistical process control of manufacturing tablets for antiretroviral therapy

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.

Sustained release matrix tablet of 100 mg losartan potassium: Formulation development and in vitro characterization

Abstract Sustained release matrix tablets of 100 mg losartan potassium HCl were fabricated with two release retarding polymers namely HPMC K100 M and affinisol by direct compression method. Nine trial formulations were prepared by varying content of these polymers, each from 50 mg to 100 mg; keeping the total weight of the tablet 310 mg. The best formulation was selected based on in vitro drug release profile for 12 hours conducted in Type II dissolution apparatus at 50 rpm and water as dissolution medium. Pre-compression parameters such as bulk density, tap density, Carr's index and Hausner ratio were evaluated for the selected tablet. The tablets were subjected to thickness, weight variation test, drug content, hardness and friability. Drug release kinetics, surface morphology and accelerated stability study were investigated for that selected formulation. Formulation F4 with the composition of 75 mg HPMC K100M and 100 mg affinisol was selected as the best formulation that extended the drug release up to 12 hours. Pre-compression parameters and other tableting properties were within the Pharmacopoeia limit. Release kinetics analysis proved non-fickian zero-order drug release and that was further confirmed by surface morphology of the tablets before and after dissolution study visualized by SEM. The developed formulation was found to be stable for one month stored at 60 ○C.

Development of controlled release dexketoprofen tablets and prediction of drug release using Artificial Neural Network (ANN) modelling

Dexketoprofen trometamol (DT) is an active S (+) enantiomer of ketoprofen, and a non-steroidal anti-inflammatory agent. DT has a short biological half-life and the dosing interval is quite short when there is a need to maintain the desirable effect for longer time periods. Consequently, a controlled release DT tablet was designed for oral administration aiming to minimize the number of doses and the possible side effects. Calculations of the parameters for controlled release DT tablets were shown clearly. Controlled release matrix-type tablet formulations were prepared using hydroxypropyl methylcellulose (HPMC) (low and high viscosity), Eudragit RS and Carbopol, and the effects of different polymers on DT release from the tablet formulations were investigated. The dissolution rate profiles were compared and analyzed kinetically. An Artificial Neural Network (ANN) model was developed to predict drug release and a successful model was obtained. Subsequently, an optimum formulation was selected and evaluated in terms of its analgesic and anti-inflammatory activity. Although the developed controlled release tablets did not have an initial dose, they were found to be as effective as commercially available tablets on the market. Dissolution and in vivo studies have shown that the prepared tablets were able to release DT for longer time periods, making the tablets more effective, convenient and more tolerable.

Desenvolvimento de metodologia para avaliação do perfil de dissolução de comprimidos de atorvastatina cálcica 20 mg comercializados no Peru, Brasil e Bolívia / Development of a methodology to evaluate the dissolution profile of atorvastatin calcium tablets 20 mg marketed in Peru, Brazil and Bolivia

O presente estudo teve por finalidade desenvolver uma metodologia de dissolução discriminativa para avaliar comprimidos contendo diferentes polimorfos de atorvastatina cálcica (ATR). Este trabalho é conformado por quatro capítulos, no qual o primeiro apresenta uma breve revisão de literatura sobre as características dos polimorfos da ATR, abordando-se informações mais relevantes sobre o ATR em relação ao polimorfismo e sua influência na biodisponibilidade. No segundo capítulo, apresenta-se a importância da caracterização dos polimorfismos e suas implicações para a ATR. As amostras de ATR foram identificadas por difração raio X e análise térmica e, posteriormente, demonstrou-se as diferenças entre quatro amostras comercializadas no mercado brasileiro relacionadas ao hábito cristalino, tamanho de partícula e solubilidade. No terceiro capítulo, demonstra-se o desenvolvimento do método de dissolução discriminativo para comprimidos contendo duas formas polimórficas da ATR. Para tanto, avaliou-se a solubilidade destas pelo método do equilíbrio e determinou-se as condições experimentais mais adequadas para o ensaio de dissolução por intermédio de planejamento fatorial completo do tipo 23, sendo as variáveis independentes o meio de dissolução, a velocidade de agitação e as formas polimórficas (I e VIII). Os resultados obtidos foram tratados estatisticamente através da análise de variância, dos gráficos de Pareto e de superfície de resposta. Concluiu-se que a velocidade de agitação e o meio de dissolução impactam os resultados, afetando a dissolução das formulações com os polimorfos avaliados. Assim, as condições selecionadas foram: 750 mL de meio água a 65 rpm. Após o desenvolvimento do método, este foi comparado com o da Food and Drug Administration (FDA) para comprimidos de atorvastatina cálcica. Ao final dos ensaios, o método desenvolvido mostrou-se adequado para apontar diferenças entre os polimorfos da ATR. No quarto capítulo, o método desenvolvido foi utilizado para avaliar o perfil de dissolução de comprimidos comercializados em três países sul-americanos: Brasil, Peru e Bolívia. As porcentagens de fármaco dissolvidas e a Eficiência de Dissolução foram as variáveis estudadas e, posteriormente, tratadas estatisticamente através da análise de componentes principais, sendo possível comparar o perfil de dissolução de dessete formulações. Dessa forma, foi possível concluir que cinco formulações avaliadas (BR1, BR2 PE6, BR7 e BO3) possuíam a forma polimórfica VIII, enquanto duas formulações (BR5 e PE2) continham a forma polimórfica I. As demais, possivelmente, apresentam misturas ou outras formas polimórficas

This present study was aimed at developing a discriminative dissolution methodology to evaluate tablets containing different calcium atorvastatin (ATR) polymorphs. This paper consists of four chapters. The first chapter presents a brief literature review of the characteristics of ATR polymorphs, and addresses more relevant information about ATR in relation to polymorphism and its influence on bioavailability. The second chapter presents the importance of the characterization of polymorphs and their implications for ATR. The ATR samples were identified by X-ray diffraction and thermal analysis. Subsequently, the differences among the four samples marketed in the Brazilian market with relation to crystalline habit, particle size and solubility were demonstrated. The third chapter demonstrates the development of the discriminative dissolution method for tablets containing two polymorphic forms of ATR. For this, their solubilities were evaluated by the equilibrium method and the most suitable experimental conditions for the dissolution test were determined by means of complete factorial design of type 23, and the independent variables were the dissolution medium, the stirring speed and polymorphic forms (I and VIII). The results obtained were statistically treated through analysis of variance, Pareto and response surface graphs. It was concluded that the stirring speed and the dissolution medium influenced the results, affecting the dissolution of the formulations with the evaluated polymorphs. Thus, the selected condition was 750 mL of water at 65 rpm. Following the development of the method, it was compared with that of the Food and Drug Administration (FDA) for atorvastatin calcium tablets. At the end of the tests, the developed method was adequate to point out differences between the ATR polymorphs. In the fourth chapter, the developed method was used to evaluate the dissolution profile of tablets marketed in three South American countries: Brazil, Peru and Bolivia. Dissolved drug percentages and Dissolution Efficiency were the studied variables and statistically treated by principal component analysis. Through this method, it was possible to compare the dissolution profile of seventeen formulations. Thus, it was possible to conclude that five formulations evaluated (BR1, BR2, PE6, PE7 e BO3) had the polymorphic form VIII, while two formulations (BR5 e PE2) contained the polymorphic form I. The others possibly have mixtures or other forms polymorphic

Preparation and in vitro & in vivo evaluation of cephalexin matrix tablets

The purpose of the study is to develop cephalexin controlled-release matrix tablets by using lower proportions of release retardant polymer and to establish their in vitro & in vivo correlation. Tablets were compressed by incorporating polymers in a matrix form along with drug which prolong the drug release. Twelve formulations were prepared by mixing ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) (three different viscosity grades) in various proportions. F-1 to F-4 formulations were prepared by incorporating drug, HPMC K4M and ethyl cellulose in 100 : 5 : 5, 100 : 10 : 5, 100 : 15 : 5 and 100 : 20 : 5; similarly, F-5 to F-8 were prepared with HPMC K15M; and F-9 to F-12 were prepared with HPMC K100M using a wet granulation process maintained same proportions, along with drug and EC. Tablets were evaluated for their pre-compression and post-compression characteristics and they were found to be in limits. From the dissolution testing, F-4 showed 100.34% medicament release in 12 h. In vivo studies were conducted on rabbit and pharmacokinetic parameters of the optimized formulation were evaluated using HPLC method. It was found that matrix tablets showed increased t1/2 and decreased Kel. The design signified that the drug release rate from tablets was influenced by the small proportion (around 7% of a tablet weight) of polymer mixture and it controlled 100% medicament release upto 12 h effectively with the low grade viscosity of HPMC combination, with good in vitro & in vivo correlation.

Processo de fabricação de comprimidos de lamivudina e zidovudina (150+300mg): avaliação retrospectiva da variabilidade e desenvolvimento de metodologia analítica por espectroscopia no infravermelho próximo com transformada de Fourier (FT-NIR) aplicada a avaliação da homogeneidade da mistura de pós / Lamivudine and zidovudine tablet manufacturing process (150 + 300mg): retrospective evaluation of the variability and development of analytical methodology by Fourier transform (FT-NIR) near infrared spectroscopy applied to the evaluation of homogeneity of the powder mixture

O uso de ferramentas estatísticas no ciclo de vida de um produto farmacêutico permite verificar e controlar o processo tendo como objetivo a sua melhoria contínua. No presente estudo foi avaliada a estabilidade e a capacidade estatística do processo de fabricação dos comprimidos revestidos de lamivudina 3TC e zidovudina AZT (150 + 300 mg) fabricados pela Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP). Esse medicamento, distribuido gratuitamente pelo programa DST/AIDS do Ministério da Saúde, e fabricado por compressão direta, processo rápido que permite a implementação futura da tecnologia analítica de processo (Process Analytical Technology - PAT). No Capítulo I foi realizada avaliação retrospectiva da variabilidade de atributos criticos da qualidade de 529 lotes dos comprimidos fabricados de acordo com a RDC ANVISA 17/2010 e as monografias oficiais, sendo tais atributos: peso médio, uniformidade de dose unitária e % m/v de fármaco dissolvido, antes e após o revestimento. O objetivo foi identificar eventuais causas especiais de variabilidade dos processos que permitam melhorias contínuas. No Capitulo II foi desenvolvida metodologia analítica empregando a espectroscopia no infravermelho próximo com transformada de Fourier para a avaliação da homogeneidade da mistura dos pós. Nesse estudo foram analisadas amostras de misturas dos fármacos lamivudina 3TC e zidovudina AZT e mistura excipiente, empregando como método de referência a CLAE, para a quantificação desses dois fármacos. No Capitulo I, a avaliação do processo para o peso médio revelou a necessidade de investigação das causa especiais de variabilidade, evidenciada por meio das cartas de controle. Os resultados do ano de 2015 indicaram necessidade de centralização e de consistência do processo, com redução de probabilidade de falha. As cartas de controle para uniformidade de dose unitária, no ano de 2013, revelaram menor variabilidade do processo. Porem, nesse ano, a análise estatística para a dissolução revelou processo descentralizado e sem consistência, com maior evidência para o fármaco 3TC que demonstrou menor desempenho, Cpk<1,0. A avaliação da estabilidade e da capacidade do processo de fabricação de comprimidos de lamivudina + zidovudina (150+300 mg), no período de 2012 a 2015, permitiu o maior entendimento de suas fontes de variação. Foi possível detectar e determinar o grau dessa variação e seu impacto no processo e nos atributos críticos de qualidade do produto com evidentes oportunidades de melhoria do processo, reduzindo os riscos para o paciente. No capítulo II, no desenvolvimento do método, as estatísticas de validação revelaram que os menores valores de BIAS foram observados para a 3TC, 0,000116 e 0,0021, respectivamente para validação cruzada e validação. Os valores de BIAS próximos a zero indicaram reduzida porcentagem de variabilidade do método. O presente estudo demonstrou a viabilidade do uso do modelo desenvolvido para a quantificação da 3TC e AZT por FT-NIR apos ajustes que contribuam para a elevação de R, R2 e RPD para valores aceitáveis. Valores de RPD acima de 5,0 que permitem o uso do modelo para uso em controle de qualidade

The use of statistical tools in the life cycle of a pharmaceutical product allows verifying and controlling the process aiming at its continuous improvement. In the present study, the stability and statistical capacity of the lamivudine coated tablets 3TC and zidovudine AZT (150 + 300 mg) manufactured by the Chopin Tavares de Lima Foundation (FURP) were evaluated. This drug, distributed free of charge by the Ministry of Health's DST/AIDS program, is manufactured by direct compression, a rapid process that allows the future implementation of Process Analytical Technology (PAT). In Chapter I, a retrospective evaluation of the variability of critical quality attributes of 529 batches of tablets manufactured was carried out, such attributes being: mean weight, unit dose uniformity and % m/v of dissolved drug substances, before and after coating. The objective was to identify possible special causes of variability of the processes that allow continuous improvements. In Chapter II an analytical methodology was developed employing the near infrared spectroscopy with Fourier transform for the evaluation of the homogeneity of the powder mixture. In this study, samples of mixtures of the drugs lamivudine 3TC and zidovudine AZT and excipient mixture were analyzed, using as reference method the HPLC, for the quantification of these two drugs. In Chapter I, the evaluation of the process for the mean weight revealed the need to investigate the special cause of variability, as evidenced by the charts. The results of the year 2015 indicated the need for centralization and process consistency, with a reduction in the probability of failure. The control charts for unit dose uniformity, in the year 2013, revealed less process variability. However, in that year, the statistical analysis for dissolution revealed a decentralized process with no consistency, with greater evidence for the 3TC drug that showed lower performance, Cpk<1.0. The evaluation of the stability and capacity of the lamivudine + zidovudine tablet manufacturing process (150 + 300 mg) in the period from 2012 to 2015 allowed a better understanding of its sources of variation. It was possible to detect and determine the degree of this variation and its impact on the process and the critical quality attributes of the product with evident opportunities to improve the process, reducing risks for the patient. In Chapter II, in the development of the method, the validation revealed that the lowest values of BIAS were observed for 3TC, 0.000116 and 0.0021, respectively for cross validation and validation. BIAS values close to zero indicated a reduced percentage of variability of the method. The present study demonstrated the feasibility of using the model developed for the quantification of 3TC and AZT by FT-NIR after adjustments that contribute to the elevation of R, R2 and RPD to acceptable values. RPD values above 5.0 that allow the use of the model for use in quality control

Análise comparativa de perfis de dissolução in vitro e in silico de comprimidos de liberação modificada contendo metformina / Comparative analysis of dissolution profiles in vitro and in silico of modified release tablets containing metformin

A dissolução de um fármaco a partir de uma forma farmacêutica (FF) sólida oral é um pré-requisito para que o mesmo seja absorvido pelo organismo e cumpra seus efeitos terapêuticos. O ensaio de dissolução de medicamentos permite avaliar a quantidade de princípio ativo que é liberado a partir de sua FF, mimetizando in vitro o processo que ocorre no trato gastrointestinal (TGI). O DDDPlus® é o único programa de computador dedicado exclusivamente a simular ensaios de dissolução. O objetivo deste trabalho foi avaliar a capacidade do programa de computador DDDPlus® em fornecer perfis de dissolução in silico de comprimidos matriciais contendo metformina semelhantes aos perfis de dissolução in vitro e avaliar a possibilidade de substituir a comparação de perfis de dissolução in vitro de diferentes formulações de comprimidos matriciais contendo metformina pela comparação de perfis de dissolução in silico fornecidos pelo DDDPlus®.Para tanto, um planejamento estatístico foi realizado para obtenção de perfis de dissolução, variando a velocidade das pás e o uso do sinker. Os perfis de dissolução de 3 formulações teste (T1, T2 e T3) de comprimidos de liberação modificada por matriz polimérica contendo metformina foram comparadas pelos métodos de eficiência de dissolução (ED), tempo médio de dissolução (TMD), fator de diferença (f2) e fator de semelhança (f1). Os resultados indicaram o uso do sinker como fator determinante para a ED e TMD. Assim, o método que utilizava o sinker e a velocidade das pás de 50RPM foi utilizado para avaliar 4 produtos comercializados no Brasil. No DDDPlus® os ensaios de dissolução in vitro das formulações T1, T2 e T3 foram otimizadas para a obtenção das constantes de calibração (CC), as CC foram utilizadas para simular os ensaios de dissolução de T1, T2 e T3 em velocidades de 25 e 50RPM. Os perfis de dissolução simulados foram comparados aos perfis observados, resultando em valores de R2. Valores de R2 acima de 0,90 foram obtidos para todas as simulações realizadas utilizando CC de ensaios in vitro que utilizaram sinker, indicando o potencial do programa em auxiliar o desenvolvimento de novas formulações. Valores de R2 abaixo de 0,70 foram obtidos após a simulação de ensaios utilizando CC de ensaios in vitro que não utilizavam o sinker, indicando que o programa de computador não previu a adesão do comprimido ao fundo da cuba de dissolução durante o ensaio. Os perfis de dissolução simulados das formulações T1, T2 e T3 foram comparadas por f1 e f2 com os perfis de dissolução dos produtos do mercado. Tais comparações concluíram que o software não é indicado como substituto dos ensaios in vitro quando se almeja comparar perfis de dissolução

Dissolution of a drug from an oral solid pharmaceutical form (FF) is a prerequisite for it to be absorbed by the body and to fulfill its therapeutic effects. in vitroDrug dissolution assay allows the amount of active principle released from a FF and mimics the in vivo the process that occurs in the gastrointestinal tract (TGI). DDDPlus® is the only computer program dedicated exclusively to simulating dissolution testing. The objective of this work was to evaluate the ability of DDDPlus® software to provide in silico dissolution profiles of matrix tablets containing metformin similar to in vitro dissolution profiles and to evaluate the possibility of replacing in vitro dissolution profiles comparison of different formulations of matrix tablets containing metformin for a comparison of in silico dissolution profiles provided by DDDPlus®. For this purpose, a statistical design was used, varying agitation speed and the use of sinker to obtain dissolution profiles for 3 test formulations (T1, T2 and T3) of polymer matrix-modified release tablets containing metformin. Dissolution profiles were compared by means of dissolution efficiency (ED), mean dissolution time (TMD), difference factor (f2) and similarity factor (f1). The results indicated the use of sinker as a determinant factor for ED and TMD. Thus, the method that used sinker and agitation speed of 50RPM was used to evaluate 4 products commercialized in Brazil. in vitro dissolution tests of the T1, T2 and T3 formulations were optimized using In DDDPlus® to obtain the calibration constants (CC), which were used to simulate dissolution profiles of T1, T2 and T3 at speeds of 25 and 50RPM. in silico dissolution profiles were compared to in vitro dissolution profiles, resulting in R2 values. R2 values above 0.90 were obtained for all simulations performed using CC from in vitro assays using sinker, indicating the potential of the program to assist the development of new formulations. R2 values below 0.70 were obtained after the simulation of assays using CC from in vitro assays that did not use the sinker, indicating that the computer program did not predict adhesion of the tablet to the bottom of the dissolution cell during the assay. The simulated dissolution profiles of the T1, T2 and T3 formulations were compared by f1 and f2 with the dissolution profiles of the market products. Such comparisons concluded that the software is not indicated as a substitute for in vitro assays when comparing dissolution profiles is desired

Development of self-nanoemulsifying tablet (SNET) for bioavailability enhancement of sertraline

The purpose of the study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form. Self-nanoemulsifying drug delivery system (SNEDDS) was prepared to enhance the solubility and thus oral bioavailability of sertraline. Aqueous titration method was used to prepare the liquid SNEDDS; ternary phase diagrams were constructed and based on smaller droplet size (24.8 nm), minimum viscosity (153.63 cP) and polydispersity index (0.182), higher percentage transmittance (95%) and in vitro drug release (97%), an optimum system was designated. Liquid SNEDDS was transformed into free-flowing powder by solid adsorption technique followed by compression into tablets. In vitro release of sertraline from liquid and solid SNEDDS was found to be highly significant compared to plain sertraline (p<0.01). Pharmacokinetic studies after oral administration of liquid and solid SNEDDS in rats showed about 6-and 5-fold increased absorption of sertraline compared to the aqueous suspension of sertraline. These studies demonstrate that the solid SNEDDS are promising strategies for successful delivery of poorly water-soluble drug like sertraline

Measurement uncertainty of dissolution test of acetaminophen immediate release tablets using Monte Carlo simulations

ABSTRACT Analytical results are widely used to assess batch-by-batch conformity, pharmaceutical equivalence, as well as in the development of drug products. Despite this, few papers describing the measurement uncertainty estimation associated with these results were found in the literature. Here, we described a simple procedure used for estimating measurement uncertainty associated with the dissolution test of acetaminophen tablets. A fractionate factorial design was used to define a mathematical model that explains the amount of acetaminophen dissolved (%) as a function of time of dissolution (from 20 to 40 minutes), volume of dissolution media (from 800 to 1000 mL), pH of dissolution media (from 2.0 to 6.8), and rotation speed (from 40 to 60 rpm). Using Monte Carlo simulations, we estimated measurement uncertainty for dissolution test of acetaminophen tablets (95.2 ± 1.0%), with a 95% confidence level. Rotation speed was the most important source of uncertainty, contributing about 96.2% of overall uncertainty. Finally, it is important to note that the uncertainty calculated in this paper reflects the expected uncertainty to the dissolution test, and does not consider variations in the content of acetaminophen.

Effects of granule particle size and lubricant concentration on tablet hardness containing large concentration of polymers

ABSTRACT The objective of this research work is to demonstrate the impact of granule size and lubricant concentration on the hardness of tablets in formulations containing higher concentration of polymers and to resolve the hardness issue during compression process. The work involves optimization of a milling process for size reduction of granules and blending process to achieve tablets of good hardness on compression. To optimize the granule size, different sized co-mill screens were used. The different concentration of lubricant were studied on different sized granules to check the effect on hardness of tablets and to obtained the desired hardness of tablets. Compression of lubricated blend in various concentration was performed using the gravity feeder and force feeder separately to check the impact on the over lubrication effect. This ultimately leads to less hardness tablets. Lubricated blends were evaluated by performing the Bulk Density, Tapped Density, Hausner ratio and compressibility index tests. Tablets were evaluated for the physical characteristics like weight variation, hardness, thickness and dissolution. It has been conclude that on using the optimum granules size and lubricant concentration in formulation, all the downstream problems can be resolved and this in turn helps in compression of tablets and also provides the good hardness to the tablets.

Preparation and physicochemical characterization of meloxicam orally fast disintegration tablet using its solid dispersion

ABSTRACT Meloxicam (MLX) is a non-steroidal, anti-inflammatory drug that is prescribed in the treatment of rheumatoid arthritis and osteoarthritis. MLX is practically insoluble in water and exhibits a slow onset of action. In this study, MLX solid dispersions (MLX SDs) were prepared to improve the water solubility of this poorly water-soluble drug. Then orally disintegrating tablets (ODT) of MLX were developed using MLX SD to decrease the onset of action of this drug. MLX, poloxamer 188, and crospovidone of different ratios were melted in molten poloxamer 188 as a hydrophilic carrier. The optimum SD with the highest saturation solubility in water (13.09±0.34 microgram/mL) consisting of MLX: poloxamer 188: crospovidone in the ratio of 1:2:0 was used for the preparation of MLX ODTs. MLX ODTs were prepared by the direct compression method and optimized by the 23 factorial design. The effect of the superdisintegrant concentration, the mannitol-avicel ratio, and the level of compression force on the disintegration time, hardness, and percent of dissolved MLX from MLX ODTs after 30 min was evaluated. DSC and XRD analysis approved an amorphous form of MLX in SDs. The optimized ODT formulation containing 10% of superdisintegrant, and mannitol and avicel in the ratio of 4:1 respectively was compressed using a high level of compression force. The optimized ODT showed hardness (34.37±2.1 N) and friability (1.26±0.04%). This formulation showed a rapid disintegration in 12.66±2.5 seconds, which 82.66±5.1% of the MLX released within 30 min. MLX ODTs, prepared from MLX SD, could be introduced as a suitable dosage form of MLX with improved solubility and the onset of action.

Formulation, preparation and in vitro - in vivo evaluation of compression-coated tablets for the colonic-specific release of ketoprofen

ABSTRACT The aim of this study was to formulate and prepare compression-coated tablets for colonic release (CR-tablets), and to evaluate the bioavailability of ketoprofen following the administration of a single dose from mini-tablets with immediate release (IR-tablets) compared to CR-tablets. CR-tablets were prepared based on time-controlled hydroxypropylmethylcellulose K100M inner compression-coating and pH-sensitive Eudragit® L 30D-55 outer film-coating. The clinical bioavailability study consisted of two periods, in which two formulations were administered to 6 volunteers, according to a randomized cross-over design. The apparent cumulative absorption amount of ketoprofen was estimated by plasma profile deconvolution. CR-tablets were able to delay ketoprofen's release. Compared to IR-tablets used as reference, for the CR-tablets the maximum plasma concentration (Cmax) was lower (4920.33±1626.71 ng/mL vs. 9549.50±2156.12 ng/mL for IR-tablets) and the time needed to reach Cmax (tmax) was 5.33±1.63 h for CR-tablets vs. 1.33±0.88 h for IR-tablets. In vitro-in vivo comparison of the apparent cumulative absorption amount of ketoprofen showed similar values for the two formulations. Therefore, the obtained pharmacokinetic parameters and the in vitro-in vivo comparison demonstrated the reliability of the developed pharmaceutical system and the fact that it is able to avoid the release of ketoprofen in the first part of the digestive tract.

In vitro evaluation of sustained released matrix tablets containing ibuprofen: a model poorly water-soluble drug

ABSTRACT A matrix system was developed that releases ibuprofen (IB) over a 12-hour period and the influence of the polymer type and concentration on the release rate of the drug was evaluated. Tablets containing different concentrations of Carbopol (CP), hydroxypropyl methylcellulose (HPMC), or ethyl cellulose (EC) were prepared using direct compression and the drug content, content uniformity, hardness, friability, dissolution performance, and in vitro release kinetics were examined. Formulated tablets were found to be within acceptable limits for physical and chemical parameters. The release kinetics of the Carbopol(r)971P 8% formulation showed the best linearity (r 2 =0.977) in fitting zero-order kinetics, suggesting the release rate was time independent. The drug release from tablets containing 8% CP was extended over approximately 18 hours and the release kinetics were nearly linear, suggesting that this system has the potential to maintain constant plasma drug concentrations over 12 hours, which could reduce the frequency of administration and the occurrence of adverse effects associated with repeated administration of conventional IB tablets.

Evaluación comparativa entre los perfiles de disolución de comprimidos similares de lamotrigina de 25mg y el fármaco innovador, comercializados en Paraguay / Evaluation comparative between dissolution profiles of tablets 25mg lamotrigine similar and innovative drug, traded in Paraguay

La epilepsia es la enfermedad neurológica más frecuente en el mundo, esta situación impulsó el desarrollo de nuevos fármacos anticonvulsivantes (FAE) como lamotrigina (LMT) que presenta un elevado costo económico para la población con crisis convulsivas. El propósito del estudio fue comparar los perfiles de disolución de comprimidos de LMT de 25 mg (Test) comercializados en Paraguay y la Referencia (Lamictal®). Se tomaron productos de LMT 25mg comprimidos, con registros sanitarios vigentes y comercializados en Paraguay, realizándose los controles de calidad acorde a criterios generales de las farmacopeas oficiales. Posteriormente, se determinó la cinética de disolución de los productos Test y Referencia, en los 3 medios de disolución recomendados (pHs 1,2 ; 4,5 y 6,8). Los perfiles de disolución de los productos evaluados de LMT, presentaron comportamientos similares a los diferentes pHs, liberando más del 85% a los 15 minutos en los 3 medios de disolución, no siendo necesario la comparación con la prueba f1 y f2. Se concluye que la cinética de disolución de los comprimidos de LMT de 25mg analizados, mostraron un comportamiento in vitro semejante entre las formulaciones. Estos resultados son orientadores, permitiendo tan sólo guiar prospectivamente la puesta en marcha del ensayo de bioequivalencia entre el medicamento Test y Referencia evaluado in vitro. Se pretende que estos ensayos llevadosa cabo con LMT, constituyan el paso inicial, para estudiar el comportamiento de las cinéticas de disolución de otros medicamentos Test y sus correspondientes Referencias del mercado paraguayo.

Epilepsy is the most common neurologic disease in the world, this situation boosts the development of new anticonvulsant drugs (AEDs) as lamotrigine (LMT) having, the latter, ahigh economic cost for the population with seizures. The aim of the study was to comparethe dissolution profiles of LMT tablets of 25 mg (Test) marketed in Paraguay and the Reference or innovator (Lamictal®). LMT 25mg tablets were chosen with the current health register sold in Paraguay and performing the quality controls according to general criteria ofthe official pharmacopoeia. Subsequently, the kinetics of dissolution of the Test and Reference products were determined in the three recommended dissolution media (pH 1,2 ; 4,5 and 6,8). The dissolution profiles of LMT products evaluated presented similar behaviorat the three different pHs, releasing more than 85% within 15 minutes in the three dissolution media. No comparison with the f1 and f2 test was necessary. The kinetics of dissolution of the tablets of LMT 25 mg analyzed showed a similar in vitro behavior between the formulations. These results constitute only a guide for the implementation of bioequivalence studies between the Test and the Reference assayed in vitro. These tests carried out with LMT could emerge as an initial step in order to study the behavior of dissolution profiles of the Test product and the corresponding references in the Paraguayan market.

Contrasting the crospovidones functionality as excipients for direct compression

Specific values of technological properties of excipients allow the establishment of numerical parameters to define and compare their functionality. This study investigates the functionality of Polyplasdones XL and XL10. Parameters studied included tablet disintegration profiles, compactibility profiles and powder flow. The results allowed the establishment of quantitative surrogate functionalities of technological performance, such as absolute number, and as a value relative to the known microcrystalline cellulose type 102. Moreover, the establishment of an explicit functionality to improve the technological performance of two diluents and a model drug was investigated, as was setting up of these functionalities, as quantitative values, to determine the input variables of each material and its probable functionality in a drug product. Disintegration times of pure Polyplasdone XL and its admixtures were around half that of Polyplasdone XL10. The improvement in tablet compactibility was 25-50% greater for Polyplasdone XL10 than Polyplasdone XL. Crospovidones proportions of up to 10% have little effect on the flow properties of other powders, although pure Polyplasdone XL10 and its admixtures display compressibility indexes about 20% greater than Polyplasdone XL. The observed results are in line with a smaller particle size of Polyplasdone XL10 compared to Polyplasdone XL.

Os valores específicos de propriedades tecnológicas de excipientes permitem o estabelecimento de parâmetros numéricos para definir e comparar a sua funcionalidade. Este estudo investiga a funcionalidade dos excipientes. Os parâmetros estudados foram perfis de desintegração dos comprimidos, perfis de compactação e fluxo de pó. Os resultados permitiram expressar o desempenho tecnológico através de valores absolutos e valores relativos à conhecida celulose microcristalina tipo 102. Do mesmo modo, permitiram estabelecer uma funcionalidade explícita para melhorar o desempenho tecnológico de dois diluentes e um fármaco modelo. A criação destas funcionalidades, como valores quantitativos, permite conhecer as variáveis de entrada de cada material e sua provável funcionalidade em um medicamento. Os tempos de desintegração do Poliplasdone XL e das suas misturas são cerca da metade do observado para as misturas com o Poliplasdone XL10. Melhoria da compressão de comprimidos que contêm Polyplasdone XL10 é 25-50% maior do que o Polyplasdone XL. Crospovidonas em proporções de até 10% têm pouco efeito sobre as propriedades de fluxo dos outros pós embora o Poliplasdone XL10 e suas misturas exibam índices de compressibilidade cerca de 20% maior do que o Poliplasdone XL. Os resultados observados estão em sintonia com o menor tamanho de partícula do Poliplasdone XL10, em comparação com o Poliplasdone XL.

Evaluation of Prunus domestica gum as a novel tablet binder

To evaluate binding potential of Prunus domestica gum in tablets formulations. Six tablet batches (F-1B to F-6B) were prepared by wet granulation method, containing Avicel pH 101 as diluent, sodium diclofenac as model drug using 10, 15 and 20 mg of Prunus domestica gum as binder and PVP K30 was used as standard binder. Magnesium stearate was used as lubricant. Flow properties of granules like bulk density, tapped density, Carr index, Hausner’s ratio, angle of repose as well as physical parameters of the compressed tablets including hardness, friability, thickness and disintegration time were determined and found to be satisfactory. The FTIR spectroscopic analysis showed that the formulation containing plant gum is compatible with the drug and other excipients used in tablets formulation. Hence the plant gum has role as a potential binder in tablets formulations. The dissolution profile showed that tablets formulations containing Prunus domestica gum 15 mg/200 mg of total weight of tablet as binder showed better results as compared to PVP K30.

Para avaliar a propriedade aglutinante da goma Prunus domestica em formulações de comprimidos, seis lotes (F-1B para F-6B) foram preparados pelo método de granulação úmida, contendo Avicel pH 101 como diluente e diclofenaco de sódio como fármaco modelo, usando 10, 15 e 20 mg de goma de Prunus domestica como agente aglutinante e PVP K30 como aglutinante padrão. O estearato de magnésio foi utilizado como lubrificante. Propriedades de fluxo dos grânulos, como a densidade, índice de Carr, razão de Hausner, ângulo de repouso, bem como parâmetros físicos dos comprimidos, incluindo o tempo de dureza, friabilidade, espessura e desintegração foram determinados e se mostraram satisfatórios. A análise espectroscópica no FTIR mostrou que a formulação contendo goma vegetal é compatível com o fármaco e outros excipientes utilizados na formulação dos comprimidos. Assim, a goma vegetal tem papel potencial como aglutinante em formulações de comprimidos. O perfil de dissolução das formulações que contêm 15 mg/200 mg do peso total do comprimido em goma de Prunus domestica como aglutinante mostrou melhores resultados comparativamente ao PVP K30.

Correlação in vitro - in vivo de comprimidos matriciais de furosemida complexada à hidroxipropil-ß-ciclodextrina: métodos in vitro, in vivo e in silico / In vitro - in vivo correlation of matrix tablets of furosemide complexed with hidroxypropyl-ß-cyclodextrin: in vitro, in vivo and in silico methods

A correlação in vitro - in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre uma propriedade in vitro de uma forma farmacêutica (FF) e uma característica biológica, ou parâmetros derivados destas, produzidas a partir da absorção do fármaco, liberado por uma FF. Para o desenvolvimento de uma CIVIV, são necessárias três ou mais formulações, as quais são avaliadas em relação ao comportamento de dissolução e à biodisponibilidade (BD), e por meio do cálculo de deconvolução, estimam-se as frações absorvidas. A furosemida, fármaco modelo, é um diurético usado no tratamento de hipertensão. Este fármaco é classificado como classe IV do sistema de classificação biofarmacêutico (SCB) (Amidon et al., 1995). O objetivo do presente trabalho foi estabelecer uma CIVIV para formas farmacêuticas (FFs) de liberação modificada contendo complexo de furosemida e hidroxipropil-ß-ciclodextrina (HP-ß-CD), a partir de ensaios de dissolução e estudos de BD. O complexo de furosemida e HP-ß-CD foi obtido por liofilização e caracterizado por análise térmica, solubilidade e permeabilidade. A partir do complexo, foram produzidas cinco formulações de comprimidos de liberação modificada, com diferentes concentrações de hidroxipropilmetilcelulose (HPMC) (10-30%). Estas foram submetidas aos estudos de dissolução com o aparato II. Destas, foram selecionadas três formulações com perfis distintos e submetidas ao estudo com o aparato IV e posteriormente ao estudo de BD. A partir destes resultados foi estabelecida uma CIVIV e esta foi avaliada por meio da validação interna. Foi realizado o estudo in silico de previsão das curvas de decaimento plasmático com emprego dos programas, STELLA® e Simcyp®, a partir dos dados: solubilidade da furosemida; dissolução a partir das formulações e dados farmacocinéticos obtidos a partir da injeção intravenosa do medicamento referência. Quanto à caracterização do complexo, os ensaios termoanalíticos sugerem que a furosemida forme complexo de inclusão com a HP-ß-CD pela técnica da liofilização. Observou-se o aumento da solubilidade em relação ao fármaco puro. Entretanto, quanto à permeabilidade, avaliada por meio do PAMPA (permeabilidade em membrana artificial paralela), os resultados foram semelhantes entre o fármaco puro e o complexo. Quanto ao comportamento de dissolução, avaliado com emprego dos aparatos II e IV, observou-se que as formulações apresentaram perfis de dissolução distintos. Os resultados do estudo de BD indicaram que a concentração do HPMC tem impacto relevante na absorção da furosemida. Foram obtidas correlações lineares a partir dos dados de fração absorvida e de dissolução, com coeficiente de determinação de 0,7662 para o aparato II e de 0,96017 para o IV. A validação interna da CIVIV empregando o aparato IV indicou que a correlação foi satisfatória. O estudo in silico de previsão das curvas de decaimento plasmático demonstrou que, nas condições empregadas, o modelo desenvolvido com o STELLA® foi mais preditivo do que o obtido pelo Simcyp®

The in vitro - in vivo correlation (IVIVC) refers to the establishment of a rational relationship between a in vitro property of a pharmaceutical form (PF) and a biological characteristic or parameters derived from those, produced from the absorption of a drug released from a PF. For the development of an IVIVC, it is necessary three or more formulations, which are evaluated in relation to the dissolution behavior and for bioavailability (BA), calculating by deconvolution, an estimated absorbed fractions. Furosemide, a model drug, is a diuretic used in the treatment of hypertension. This drug is classified as class IV from biopharmaceutical classification system (BCS) (Amidon et al., 1995). The objective of this study was to establish an IVIVC for pharmaceutical forms (PFs) with modified release containing furosemide complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD), from dissolution tests and BA studies. The complex of furosemide and HP-ß-CD was obtained by freeze-drying and characterized by thermal analysis, the solubility and the permeability. From the complex were produced five modified release tablet formulations, with different concentrations of hydroxypropylmethylcellulose (HPMC) (10-30%). These formulations were subjected to dissolution studies with the apparatus II. From these, three formulations with distinct profiles were selected and subjected to dissolution study with apparatus IV and subsequently to the BA study. From these results, an IVIVC was established and this was evaluated by internal validation. The in silico study was conducted to predict plasma decay curves with employment programs, STELLA® and Simcyp®, from the following data: furosemide solubility, dissolution from the formulations evaluated and pharmacokinetic data obtained from intravenous drug reference. From characterization of the complex, the thermoanalytical tests suggest that furosemide form inclusion complex with HP-ß-CD by freeze-drying technique. It was observed an increased solubility compared to the pure drug. However, permeability results, as assessed by the PAMPA (Parallel artificial membrane permeability), were similar for both furosemide and the complex. As for the dissolution behavior, evaluated with apparatus II and IV, so it was observed that the formulations showed an distintict profile. it was observed that the formulations produced showed different dissolution profiles. The results form BA assays indicated that the HPMC concentration has an important impact on the furosemide absorption. It was obtained a linear correlation from absorption fraction and dissolution data, with the determination coefficient of 0.7662 to apparatus II and 0.96017 from apparatus IV. Internal validation, with the IVIVC obtainted from apparatus IV, indicated that the correlation obtained was satisfactory. The in silico study predicted plasma decay curves, showed that under the conditions used, the model developed with STELLA® was more predictive than the model obtained by Simcyp®

Preparation and scale up of extended-release tablets of bromopride

Reproducibility of the tablet manufacturing process and control of its pharmaceutics properties depends on the optimization of formulation aspects and process parameters. Computer simulation such as Design of Experiments (DOE) can be used to scale up the production of this formulation, in particular for obtaining sustained-release tablets. Bromopride formulations are marketed in the form of extended-release pellets, which makes the product more expensive and difficult to manufacture. The aim of this study was to formulate new bromopride sustained release formulations as tablets, and to develop mathematical models to standardize the scale up of this formulation, controlling weight and hardness of the tablets during manufacture according to the USP 34th edition. DOE studies were conducted using Minitab(tm) software. Different excipient combinations were evaluated in order to produce bromopride sustained-release matrix tablets. In the scale-up study, data were collected and variations in tableting machine parameters were measured. Data were processed by Minitab(tm) software, generating mathematical equations used for prediction of powder compaction behavior, according to the settings of the tableting machine suitable for scale-up purposes. Bromopride matrix tablets with appropriate characteristics for sustained release were developed. The scale-up of the formulation with the most suitable sustained release profile was established by using mathematical models, indicating that the formulation can be a substitute for the pellets currently marketed.

A reprodutibilidade do processo de fabricação de comprimidos e o controle das suas propriedades farmacotécnicas depende da otimização dos aspectos de formulação e dos parâmetros de processo. O planejamento de experimentos como o Desenho de Experimentos (DOE) pode ser utilizado para acelerar a produção desta formulação, em particular, para a obtenção de comprimidos de liberação prolongada. Formulações de bromoprida são comercializadas sob a forma de péletes de liberação prolongada, o que torna o produto caro e de difícil fabricação. O objetivo deste estudo foi preparar novas formulações de bromoprida de liberação prolongada na forma de comprimidos e desenvolver modelos matemáticos visando ao escalonamento destas formulações, controlando o peso e a dureza dos comprimidos durante a fabricação, de acordo com a 34ª Edição da USP. Estudos de DOE foram realizados utilizando o software Minitab(tm). Diferentes combinações de excipientes foram avaliadas visando à obtenção dos comprimidos de liberação prolongada de bromoprida. No estudo de scale-up, coletaram-se e mediu-se a influência das variações nos parâmetros da máquina de compressão. Processaram-se os dados obtidos pelo software Minitab (tm), gerando equações matemáticas aptas para a previsão do comportamento de compactação do pó em escala industrial. Os comprimidos obtidos apresentavam características adequadas em termos de liberação sustentada, sendo a cinética de liberação estabelecida utilizando modelos matemáticos, indicando que esta formulação pode ser uma substituta aos péletes de bromoprida atualmente comercializados.

Formulation and in vitro evaluation of mucoadhesive controlled release matrix tablets of flurbiprofen using response surface methodology

The objective of the current study was to formulate mucoadhesive controlled release matrix tablets of flurbiprofen and to optimize its drug release profile and bioadhesion using response surface methodology. Tablets were prepared via a direct compression technique and evaluated for in vitro dissolution parameters and bioadhesive strength. A central composite design for two factors at five levels each was employed for the study. Carbopol 934 and sodium carboxymethylcellulose were taken as independent variables. Fourier transform infrared (FTIR) spectroscopy studies were performed to observe the stability of the drug during direct compression and to check for a drug-polymer interaction. Various kinetic models were applied to evaluate drug release from the polymers. Contour and response surface plots were also drawn to portray the relationship between the independent and response variables. Mucoadhesive tablets of flurbiprofen exhibited non-Fickian drug release kinetics extending towards zero-order, with some formulations (F3, F8, and F9) reaching super case II transport, as the value of the release rate exponent (n) varied between 0.584 and 1.104. Polynomial mathematical models, generated for various response variables, were found to be statistically significant (P<0.05). The study also helped to find the drug's optimum formulation with excellent bioadhesive strength. Suitable combinations of two polymers provided adequate release profile, while carbopol 934 produced more bioadhesion.

O objetivo do presente estudo foi formular comprimidos mucoadesivos de flurbiprofeno, de liberação controlada, e otimizar o perfil da liberação do fármaco e a bioadesão, utilizando a metodologia de superfície de resposta. Prepararam-se os comprimidos via técnica de compressão direta, que foram avaliados in vitro quanto aos parâmetros de dissolução e da força bioadesiva. Planejamento com componente central para dois fatores em cinco níveis cada foi empregado para esse estudo. Carbopol 934 e carboximetilcelulose sódica foram tomados como variáveis independentes. Efetuaram-se estudos de espectroscopia por transformada de Fourier (FTIR) para observar a estabilidade do fármaco durante a compressão direta e para avaliar a interação a fármaco-polímero. Aplicaram-se vários métodos cinéticos para avaliar a liberação do fármaco dos polímeros. Gráficos de superfície de contorno e de resposta foram efetuados para retratar a relação entre as variáveis dependentes e a resposta. Os comprimidos mucoadesivos de flurbiprofeno apresentaram cinética de liberação não-fickiana, estendendo para ordem zero, para algumas formulações (F3, F8 e F9), alcançando transporte super caso II, à medida que o valor do expoente (n) de taxa de liberação variou entre 0,584 e 1,104. Modelos matemáticos polinomiais, gerados por diversas variáveis de resposta, foram estatisticamente, significativos (P<0,05). O estudo também auxiliou a encontrar a formulação ótima do fármaco, com excelente força de bioadesão. Combinações adequadas dos dois polímeros resultaram em perfis de liberação adequado, sendo que o Carbopol 934 produziu mais adesão.

Development of fast dispersing tablets of nebivolol: experimental and computational approaches to study formulation characteristics

Formulation of FDT (fast dispersing tablets) of nebivolol was optimized and evaluated using simplex lattice design (SLD). The influence of type and concentration of three disintegrants viz., Ac-Di-Sol, Primojel and Polyplasdone XL on hardness, friability and disintegration time of tablet was studied. Response surface plot and the polynomial equations were used to evaluate influence of polymer on the tablet properties. Results were statistically analyzed using ANOVA, and a p < 0.05 was considered statistically significant. Results reveal that fibrous integrity and optimal degree of substitution in Primojel and Ac-Di-Sol are mainly responsible for the hardness of the tablet. Use of Polyplasdone in higher percentage in tablet formulation may result in high friability. Increase in concentration of Ac-Di-Sol increases the disintegration time but increased concentration of Primojel in the tablet formulation decreases the disintegration time. This is also evident from model terms for disintegration time with a high 'F' value of 14.69 and 'p' value of 0.0031 (<0.05). The reason could be that Primojel has higher swelling properties and an optimum hydration capacity, which favors fast disintegration of a tablet. In conclusion, careful selection of disintegrant for FDT could improve their properties. Use of Simplex Lattice Design for formulation development could simplify the formulation process and reduce the production cost.

Otimizou-se e avaliou-se formulação de comprimidos de dispersão rápida (CDR) de nebivolol, usando planejamento de grade simplex (PGS). Estudou-se a influência do tipo e da concentração de três desintegrantes viz, Ac-Di-Sol, Primojel e Poliplasdona XL, na dureza, friabilidade e tempo de desintegração do comprimido. O gráfico de superfície de resposta e as equações polinomiais foram utilizados para avaliar a influência do polímero nas propriedades do comprimido. Os resultados foram analisados estatisticamente por ANOVA, considerando-se p < 0,05 como estatisticamente significativo. Os resultados revelam que a integridade das fibras e o grau de substituição ótimo no Primojel e Ac-Di-Sol são os principais responsáveis pela dureza do comprimido. O uso de Poliplasdona em maior porcentagem na formulação pode produzir friabilidade elevada. O aumento de Ac-Di-Sol aumenta o tempo de desintegração, mas o aumento da concentração de Primojel na formulação diminui o tempo de desintegração. Isto é, também, evidente no modelo de tempo de desintegração com alto valor de "F" de 14,69 e "p" de 0,0031 (< 0,05). A razão poderia ser que o Primojel tem maiores propriedades de intumescimento e ótima capacidade de hidratação, favorecendo a desintegração rápida do comprimido. Em conclusão, a cuidadosa seleção de um desintegrante para CDR poderia aprimorar suas propriedades. O uso do PGS para o desenvolvimento da formulação poderia simplificar o processo de formulação e reduzir o custo de produção.