FORMULATION AND EVALUATION OF FIXED-DOSE COMBINATION OF BILAYER TABLETS OF ATAZANAVIR SULFATE AND RITONAVIR 300 MG/100 MG
Keywords:Fixed-dose combination formulation, Human immunodeficiency virus (HIV) infections, Bilayer technology, Quality by design (QbD), Design of experiments (DOE), 23 3 and 22 3full factorial and fractional factorial design
Objective: The objective of this study is to formulation and development of fixed-dose combination as a single dosage regimen by using the design of experiments (DOE) approach against the single dose of reference listed drugs of brand reyataz capsule 300 mg (atazanavir sulfate) and norvir tablets 100 mg (ritonavir tablets) to treat human immunodeficiency virus (HIV) Infections.
Methods: Formulation was developed with each blend of ritonavir by using hot-melt extrusion and atazanavir sulfate by wet granulation process and compressed by bilayer technology followed by film coating. Formulation and process optimization by design of experiments (DOE) to evaluate dissolution and related substances of the finished product. Fractional factorial (22+3) and full factorial design (33+3) by using a design expert (version 11.0) were used to evaluate the formulation and process variables to prepare a robust formulation.
Results: Results indicate that the sorbitan monolaurate range has played a key role to achieve the dissolution for ritonavir formulation. The studied temperature range and interaction of temperature and feed rate, temperature and screw speed during the hot-melt extrusion process impact on the related substances of the bi-layer tablet. Analysis of variance (ANOVA) also finding the P-value less than 0.0500 and the studied range was significant. Design space was established for the significant factors to control the results within the acceptable limits. The studied formulation and wet granulation process for atazanavir sulfate have no significant impact on dissolution and related substances of the finished product. Further, the studied hardness range of 16-28kp for bi-layer tablets has no critical impact on the dissolution. Optimum formulation and process of bi-layer tablets in F37 yielded similar drug release and related substances against the reference drug product.
Conclusion: The present invention of fixed-dose combination can be recommended as a single dosage regimen with the consistent drug release and control of the unknown impurities in the prototype formulation against the individual reference drug product.
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