Physicochemical and dissolution profile characterization of pellets containing different binders obtained by the extrusion-spheronization process

Abstract

With the purpose of evaluating the behavior of different polymers employed as binders in small-diameter pellets for oral administration, we prepared formulations containing paracetamol and one of the following polymers: PVP, PEG 1500, hydroxypropylmethylcellulose and methylcellulose, and we evaluated their different binding properties. The pellets were obtained by the extrusion/spheronization process and were subsequently subjected to fluid bed drying. In order to assess drug delivery, the United States Pharmacopeia (USP) apparatus 3 (Bio-Dis) was employed, in conjunction with the method described by the same pharmacopeia for the dissolution of paracetamol tablets (apparatus 1). The pellets were also evaluated for granulometry, friability, true density and drug content. The results indicate that the different binders used are capable of affecting production in different ways, and some of the physicochemical characteristics of the pellets, as well as the dissolution test, revealed that the formulations acted like immediate-release products. The pellets obtained presented favorable release characteristics for orally disintegrating tablets. USP apparatus 3 seems to be more adequate for discriminating among formulations than the basket method.Uniterms: Binders/evaluation. Pellets/dissolution profile. Pellets/physicochemical characteristics. Extrusion/spheronization process. Drug delivery/evaluation. Com a finalidade de se avaliar o comportamento de diferentes polímeros empregados como aglutinantes em pellets de pequeno diâmetro para uso oral foram preparadas formulações contendo paracetamol e um dos seguintes polímeros: PVP, PEG 1500, hidroxipropilmetilcelulose e metilcelulose por apresentarem diferentes propriedades aglutinantes. Os pellets foram obtidos pelo processo de extrusão/esferonização e secagem em leito fluidizado. Para avaliar a liberação do fármaco, empregou-se o método 3 da Farmacopeia Americana, também conhecido como Bio-Dis e o método preconizado pela mesma farmacopeia para comprimidos de paracetamol. Os pellets foram avaliados, ainda, com relação à granulometria, friabilidade, densidade verdadeira e teor. Os resultados indicaram que os diferentes aglutinantes empregados são capazes de afetar a produção e algumas das características físico-químicas dos pellets e o ensaio de dissolução revelou que as formulações comportam-se como produtos de liberação imediata. Os pellets obtidos apresentaram características de liberação favoráveis para a obtenção de comprimidos de liberação instantânea. O aparato 3 da Farmacopeia Americana demonstrou ser um método com melhor capacidade discriminatória entre as formulações, quando comparado com o método da cesta.Unitermos: Aglutinantes/avaliação. Pellets/perfil de dissolução. Pellets/características físico-químicas. Processo de extrusão/esferonização. Liberação do fármaco.

Gellan gum and polyvinylpyrrolidone (PVP) as binding agents in extrusion/spheronization pellet formulations

“…In the friability test, after granulometric separation, the sample was subjected to attrition with 200 spheres of glass in a Logan ® FAB-2 friability tester (Somerset, USA), and then a new granulometric separation was performed under the same preconditions (6). Then, the fraction (%) retained in each sieve was obtained, before and after attrition, and the difference modulus was calculated according to equation 3:…”

Physical characterization of multiparticulate systems

“…Obtention of immediate-release systems, with a focus on masking drug flavor (Hamedelniel, Bajdik, Pintye-Hódi, 2010;Issa et al, 2012b;Patel, Patel, Patel, 2010);  Controlled-release (Abbaspour, Sadeghi, Garekani, 2008;Bialleck, Rein, 2011;Cantor, Hoag, Augsburger, 2009a;Cantor, Hoag, Augsburger, 2009b;Franc et al, 2015;Ghanam, Kleinebudde, 2011;Ghosh, Chakraborty, 2013;Han et al, 2013;Heckötter et al, 2011;Hung et al, 2015;Ríos, Ghaly, 2015;Roblegg et al, 2011;Szkutnik-Fiedler et al, 2014;Wang et al, 2015;Xu, Liew, Heng, 2015;You et al, 2014);  Improvement in dissolution of poorly soluble drugs (Abdalla, Mader, 2007;Abdalla, Klein, Mader, 2008;Chopra, Venkatesan, Betageri, 2013;Ibrahim, El-Badry, 2014;Lu et al, 2009;Patel et al, 2016);  Gastro-retentive systems/ floating systems (Amrutkar, Chaudhari, Patil, 2012;Li et al, 2014;Pagariya, Patil, 2013;Qi et al, 2015;Zhang et al, 2012);  Enteric release/gastro-resistant systems (Andreo-Filho et al, 2009;Ghanam, Kleinebudde, 2011;Pund et al, 2010);  Improvement of plant extract or active ingredient stability (Araújo-Junior et al, 2013;Beringhs et al, 2012;Bu...…”

“…For this purpose, a strain chart can be obtained by using a texture analyzer device, in which the material is exposed to a given load against time (Santos et al, 2006;Šibanc et al, 2013;Yeung, Rein, 2015). Equation 4δ = tensile strength; F = intensity of the force required to break; r 2 = radius of the particle obtained by Feret´s diameter For friability, different adjustments are performed (Table IX), typically using glass or steel balls, in order to increase the material´s abrasion and improve the sensitivity of the method (Chopra, Venkatesan, Betageri, 2013;Issa et al, 2012b;Santos et al, 2006). A friabilometer is the equipment used in most cases, where sometimes a stirring system is used instead (Chevalier et al, 2010;Stoltenberg, Breitkreutz, 2011).…”

“…The result is obtained by determination of the percentage mass of the material lost when exposed to abrasion, requiring the use of a sieve to separate the fraction formed as powder which is weighed during the assay. The study of Issa et al (2012b) reported an alternative in which the mass loss is measured by comparing the amounts retained in the sieves, where the particle size distribution is carried out before and after the assay. Bialleck, Rein, 2011;Podczeck, Newton, 2014;Santos et al, 2005 Pellets Hardness, tensile strength and relaxation module Cespi et al, 2007Pellets Hardness Costa, Pais, Sousa, 2004Ghanam, Hassan, Kleinebudde, 2010;Hamedelniel, Bajdik, Pintye-Hódi, 2010;Rabišková et al, 2012;Rahmaniam, Naji, Ghadiri, 2011 Pellets Tensile strength and elastic modulus Šibanc et al, 2013Minitablets Hardness Aleksovski et al, 2015Lopes et al, 2006;Stoltenberg, Breitkreutz, 2011;Tomuta, Leucuta, 2007;Weyenberg et al, 2006 Minitablets Tensile strength Tissen et al, 2011 *Hot melt extrusion…”

“…Controlled-release (Almeida et al, 2011;Grassi et al, 2003;Phaechamud, Thongpin, Choncheewa, 2012;Sharma, Amin, 2013;Tran et al, 2011;Verhoeven, Vervaet, Remon, 2006);  Gastro-retentive/floating systems (Malode, Paradkar, Devarajan, 2015);  High drug loading in immediate-release systems (Cai et al, 2013);  Combination of different delivery systems (Dierickx et al, 2012;Dierickx, Remon, Vervaet, 2013);  Obtention of immediate-release systems, with a focus on masking drug flavor (Gryczke et al, 2011;Issa et al, 2012b);  Improvement in dissolution of poorly soluble drugs (Deng et al, 2012;Kalidova, Fischbach, Kleinebudde, 2012 Controlled-release (Aleksovski et al, 2015;Lopes et al, 2006;Tomuta, Leucuta, 2007);  Combination of different delivery systems (Souza, Goebel, Andreazza, 2013);  Colonic release (Vemula, 2015);  Ocular bio-adhesives (Bozdag et al, 2010;Weyenberg et al, 2003;Weyenberg et al, 2006);  Gastro-retentive/floating systems (Goole et al, 2008;Hauptstein et al, 2013;Katakam et al, 2014);  Obtention of immediate-release systems, with a focus on masking drug flavor (Eckert, Pein, Breitkreutz, 2014);…”