Innovative pharmaceutical formulation for the treatment of tuberculosis. Quality by design in the development of press-coated tablets

LUCIANI GIACOBBE LC; ALLEMANDI, DA; ALARCON, LP; MANZO, RH; PAREDES, AJ; OLIVERA ME

Congreso; 4ta Reunion Internacional de Ciencias Farmacéuticas; 2016

Very fast dissolving matrices of a crystalline solid dispersion of carboximethylcellulose- rifampicin (CMC-RIF) significantly improved the acid stability and oral bioavailability of RIF associated to isoniazid (INH) sustained release matrices. The objective of this investigation was to explore the critical process parameters (CPP) in the manufacture of press-coated tablets of RIF and INH, through Quality by Design (QbD) strategies.Critical quality attributes were: a core tablet of delayed release INH (150 mg), covered by a very fast dissolution outer layer of CMC-RIF (300 mg of RIF) that had to meet compendial specifications. The steps of the manufacturing process included (A1) formulation, (A2) compression and (A3) enteric coating of INH core tablet; (B1) formulation and (B2) compression of the CMC-RIF outer layer. The CPP were identified through a risk analysis (decision-tree). Priority CPP were subjected to an experimental verification through variable-response correlation.Three INH core formulations containing Emcompress® and mycro-crystalline cellulose (MC) in different proportions were acceptable. Besides, six outer layer formulations were obtained. The formulations with 17% of MC and 5% of Explotab® or Ac-di-sol® showed low friability and very fast dissolution rate (both 93% at 10?). In C2, the compression force and cohesiveness between the outer layer and the core were priority CPP because they changed hardness and friability of the tablets and dissolution rate of INH, affecting the compliance of the specifications. Consequently, an INH core formulation with a higher proportion of MC was selected, which is less susceptible to high compression forces. An additional polyvinyl-alcohol coating enhanced the cohesiveness between the outer layer and the core.As proposed by the QbD, risk analysis associated to the experience of the product and its manufacturing process, was a sure way for knowledge management and optimization of the development of press-coated tablets of CMC-RIF and INH with segregated delivery properties.