Development of Losartan Orally Disintegrating Tablets by Direct Compression: a Cost-Effective Approach to Improve Paediatric Patient's Compliance.

The development of suitable dosage forms is essential for an effective pharmacological treatment in children. Orally disintegrating tablets (ODTs) are attractive dosage forms that avoid swallowing problems, ensure dosage accuracy and are easy to administer as they disintegrate in the oral cavity. This study aimed to develop ODTs containing losartan potassium (LP) for the treatment of arterial hypertension in children. The ODTs, produced by the cost-effective manufacturing process of direct compression, consisted of a mixture of diluent, superdisintegrant, glidant and lubricant. Five superdisintegrants (croscarmellose sodium, two grades of crospovidone, sodium starch glycolate and pregelatinized starch) were tested (at two concentrations), and combined with three diluents (mannitol, lactose and sorbitol). Thus, thirty formulations were evaluated based on disintegration time, hardness and friability. Two formulations, exhibiting the best results concerning disintegration time (< 30 s), hardness and friability (≤ 1.0%), were selected as the most promising ones for further evaluation. These ODTs presented favourable drug-excipient compatibility, tabletability and flow properties. The in vitro dissolution studies demonstrated 'very rapid' drug release. Preliminary stability studies highlighted the requirement of a protective packaging. All quality properties retained appropriate results after 12 months of storage in airtight containers. In conclusion, the ODTs were successfully developed and characterised, suggesting a potential means to accomplish a final prototype that enables an improvement in childhood arterial hypertension treatment.

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.

Comparación de los perfiles de disolución de los comprimidos de Losartán potásico 100mg nacionales e importados vs precio, Paraguay (2019)

RESUMEN La hipertensión arterial es el principal factor de riesgo cardiovascular, y su prevalencia en Paraguay es la mayor de América Latina. El objetivo del presente trabajo fue comparar productos de losartán de 100 mg comprimidos de producción nacional e importada a través de los perfiles de disolución versus su precio. Se tomaron 8 marcas de losartán potásico comercializadas durante el 2017, realizándose los controles de calidad de acuerdo a lo establecido en la Farmacopea Americana (USP 38). Se determinó el porcentaje de principio activo liberado en el medio de disolución establecido por la USP 38, por medio de los perfiles de disolución. Las determinaciones se realizaron por HPLC y espectrofotometría UV/V. Los controles realizados cumplieron con las especificaciones establecidas por la USP 38. No se encontraron diferencias significativas en el análisis estadístico de los perfiles de disolución de las diferentes marcas analizadas. Los resultados demostraron que los precios de las marcas analizadas no afectaban la calidad de los productos, pero sí en el costo del tratamiento de la población de escasos recursos, debido al mayor costo de los productos importados con respecto a los de producción nacional.

ABSTRACT Hypertension is the main cardiovascular risk factor, and its prevalence in Paraguay is the highest in Latin America. The objective of the present work was to compare products of 100 mg losartan tablets made in Paraguay and imported products, through dissolution profiles versus price. Eight brands of potassic losartan commercialized during 2017 were subjected to quality controls in accordance with the provisions of the American Pharmacopoeia (USP 38). The percentage of active principle released in the dissolution medium established by USP 38 was determined by means of dissolution profiles. The determinations were made by HPLC and UV/V spectrophotometry. The controls carried out complied with the specifications established by USP 38. No significant differences were found in the statistical analysis of the dissolution profiles of the different brands analyzed. The results showed that the prices of the brands analyzed did not affect the quality of the products, but they affected the cost of treatment of the low-income population due to the higher cost of imported products compared to those of national production.

A clean photometric method for the determination of losartan potassium in pharmaceuticals exploiting light scattering effect and employing a multicommuted flow analysis approach.

This paper describes an environmentally friendly procedure for the determination of losartan potassium (Los-K) in pharmaceuticals. The photometric method was based on the light scattering effect due to particles suspension, which were formed by the reaction of Los-K with Cu (II) ions. The method was automated employing a multicommuted flow analysis approach, implemented using solenoid mini-pumps for fluid propelling and a homemade LED based photometer. Under the optimized experimental conditions, the procedure showed a linear relationship in the concentration range of 23.2-417.6mgL-1 (r=0.9997, n=6), a relative standard deviation of 1.61% (n=10), a limit of detection (3.3*σ) estimated to be 12.1mgL-1, and a sampling rate of 140 determinations per hour. Each determination consumed 12µg of copper (II) acetate and generated 0.54mL of waste.

Phase quantification of antihypertensive drugs - Chlorthalidone, Hydrochlorothiazide, Losartan and combinations, Losartan/Chlorthalidone and Losartan/Hydrochlorothiazide - by the Rietveld method.

The identification and quantification of crystalline phases of antihypertensive drugs - Losartan potassium (LOS-K), Hydrochlorothiazide (HCTZ) and Chlorthalidone (CTD) were carried out by means of X-ray powder diffraction data and the Rietveld method. Quantitative phase analyses of Losartan potassium/Chlorthalidone (LOS-K/CTD) and Losartan potassium/Hydrochlorothiazide (LOS-K/HCTZ) combinations were also evaluated. The results indicated that for diuretics (HCTZ and CTD) only one crystalline phase was found in samples, and for LOS-K the crystal structure showed similarity between the Bragg peaks to the phase described as monoclinic and space group P21/c. After one year storage, the orthorhombic one was also observed in this sample.

Control of size in losartan/copper(II) coordination complex hydrophobic precipitate.

Reaction of highly soluble orally active, non-peptide antihypertensive drug losartan with copper(II) leads to the spontaneous formation of a very insoluble 2:1 covalent complex, which self assembles in a hydrophobic supramolecular structure of nanometric dimensions. Thermal analysis showed that Los/Cu(II) complex presents intermediate stability in comparison with its precursors KLos and Cu(OAc)2·H2O. Isothermal titration calorimetry indicated complexation to be a stepwise process, driven by enthalpy and entropy. Zeta potential and DLS measurements showed that it is possible to control the size and charge of nanoprecipitates by adjusting the relative concentration of Los(-) and Cu(II).

Development and evaluation of sustained release losartan potassium matrix tablet using kollidon SR as release retardant

The present study was undertaken to develop sustained release (SR) matrix tablets of losartan potassium, an angiotensin-II antagonist for the treatment of hypertension. The tablets were prepared by direct compression method, along with Kollidon SR as release retardant polymer. The amount of losartan potassium remains fixed (100 mg) for all the three formulations whereas the amounts of Kollidon SR were 250 mg, 225 mg, and 200 mg for F-1, F-2, and F-3 respectively. The evaluation involves three stages: the micromeritic properties evaluation of granules, physical property studies of tablets, and in-vitro release kinetics studies. The USP apparatus type II was selected to perform the dissolution test, and the dissolution medium was 900 mL phosphate buffer pH 6.8. The test was carried out at 75 rpm, and the temperature was maintained at 37 ºC ± 0.5 ºC. The release kinetics was analyzed using several kinetics models. Higher polymeric content in the matrix decreased the release rate of drug. At lower polymeric level, the rate and extent of drug release were enhanced. All the formulations followed Higuchi release kinetics where the Regression co-efficient (R²) values are 0.958, 0.944, and 0.920 for F-1, F-2, and F-3 respectively, and they exhibited diffusion dominated drug release. Statistically significant (P<0.05) differences were found among the drug release profile from different level of polymeric matrices. The release mechanism changed from non-fickian (n=0.489 for F-1) to fickian (n=0.439 and 0.429 for F-2, and F-3 respectively) as a function of decreasing the polymer concentration. The Mean Dissolution Time (MDT) values were increased with the increase in polymer concentration.

O presente estudo foi realizado para desenvolver (SR) matriz de comprimidos de liberação sustentada de losartana, um antagonista da angiotensina II, para o tratamento da hipertensão arterial. Os comprimidos foram preparados pelo método de compressão direta com Kollidon SR como polímero de liberação lenta. A quantidade de losartana potássica permanece fixa (100 mg) para todas as três formulações enquanto que as quantidades de Kollidon SR foram de 250 mg, 225 mg e 200 mg para F-1, F-2 e F-3, respectivamente. A avaliação envolve três etapas- propriedades micromeríticas dos grânulos, estudo das propriedades físicas dos comprimidos e estudos de cinética de liberação in vitro.. Selecionoou-se o aparelho USP tipo II para realizar o teste de dissolução em meio com 900 mL de tampão fosfato pH 6,8 . O teste foi realizado em 75 rpm e a temperatura foi mantida a 37 ºC ± 0.5 ºC. Analisou-se a cinética de liberação utilizando-se vários modelos cinéticos. Conteúdo mais alto de polímero na matriz reduziu a taxa de liberação do fármaco. Em níveis mais baixos de polímero, a taxa e a extensão de liberação do fármaco foram aumentados. Todas as formulações seguiram a cinética de liberação de Higuchi, em que os valores do coeficiente de regressão (R2) foram 0,958 , 0,944 e 0,920 para F-1, F-2 e F-3, respectivamente, e elas apresentaram liberação do fármaco dominada pela difusão. Encontraram-se diferenças estatisticamente significativas (P<0,05) entre os perfis de liberação do fármaco com diferentes níveis de matrizes poliméricas. O mecanismo de liberação mudou de não-fickiano(n=0,489 para F-1) para fickiano(n=0,439 e 0,429 para F-2 e F-3, respectivamente) em função da diminuição da concentração de polímero. Os valores do Tempo de Dissolução Média (TDM) aumentaram com o aumento da concentração polímero.

Comparative study of analytical methods by direct and first-derivative UV spectrophotometry for evaluation of losartan potassium in capsules / Estudo comparativo de métodos analíticos por espectrometria de UV directa e derivada de primeira ordem para a avaliação de losartano potássico em cápsulas

Losartan potassium is an antihypertensive non-peptide agent, which exerts its action by specific blockade of angiotensin II receptors. The aim of the present study was the validation and application of analytical methods for the quality control of losartan potassium 50 mg in pharmaceutical capsules, using direct and first-derivative UV spectrophotometry. Based on losartan potassium spectrophotometric characteristics, a signal at 205 nm of the zero-order spectrum and a signal at 234 nm of the first-derivative spectrum, were found adequate for quantification. The results were used to compare these instrumental techniques. The linearity between the signals and concentrations of losartan potassium in the ranges of 3.0-7.0 mg L-1 and 6.0-14.0 mg L-1 for direct and first-derivative spectrophotometry in aqueous solutions, respectively, presented a correlation coefficient (r) of 0.9999 in both cases. The methods were applied for losartan potassium in capsule dosage obtained from local pharmacies, and were shown to be efficient, easy to apply and low cost. These methods do not use polluting reagents and require relatively inexpensive equipment.

O losartano potássico é um agente anti-hipertensivo não peptídico, que exerce sua ação por bloqueio específico dos receptores da angiotensina II. Este trabalho propôs a validação e aplicação de métodos analíticos orientados ao controle de qualidade de losartano potássico 50 mg na forma farmacêutica cápsula, utilizando a espectrofotometria direta e derivada de primeira ordem na região do UV. Baseado nas características espectrofotométricas de losartano potássico, um sinal a 205 nm do espectro de ordem zero e um sinal a 234 nm do espectro de primeira derivada foram adequados para a quantificação. Os resultados foram usados para comparar essas duas técnicas instrumentais. O coeficiente de correlação entre as respostas e as concentrações de losartano potássico na faixa de 3,0-7,0 mg L-1 e 6,0-14,0 mg L-1 para espectrofotometria direta e derivada de primeira ordem em solução aquosa, respectivamente, foi de (r) of 0,9999 para ambos os casos. Os métodos foram aplicados para quantificação de losartano potássico em cápsulas obtidas de farmácias de manipulação locais e demonstraram ser eficientes, fáceis de aplicar e de baixo custo. Além disso, não necesitam de reagentes poluentes e requerem equipamentos economicamente viáveis.