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

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

Congreso; 4ta Reunión Internacional de Ciencias Farmacéuticas ? RICIFA 2016; 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 conditions in the manufacture process of a press-coated tablet 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). The compacts had to meet compendial specifications for delayed and immediate release tablets, respectively. The steps of the manufacturing process were (A1) formulation, (A2) compression and (A3) enteric coating of INH core tablet; (B1) formulation and (B2) compression of the CMC-RIF outer layer. Critical process parameters (CPP) were identified through a risk analysis (decision-tree). Priority CPP were subjected to experimental verification through variable-response correlation.INH core formulations containing dibasic calcium phosphate and microcrystalline cellulose in different proportions met compendial specifications and were equally acceptable. In A3, the pan rotation speed and the coating dispersion flow were CPP, which determined complete and uniform coating. An outer layer with low friability and very fast dissolution rate (93% at 10?) was obtained. 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 microcrystalline cellulose was selected, which is less susceptible to compression forces. A 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.