Objective: This study is to formulate bi-layer tablet as a multidrug regimen against each reference listed drugs of Brand SUSTIVA® (efavirenz tablets 600 mg), EPIVER®(lamivudine tablets 300 mg), and VIREAD®(tenofovir disoproxil tablets 300 mg) to treat human immunodeficiency virus (HIV) infections. Which provides highly active antiretroviral therapy to provide effective treatment. Methods: Bilayer formulation was developed with each blend of layer-I (efavirenz) and layer-II (lamivudine and tenofovir disoproxil fumarate) through wet granulation process and roller compaction process, respectively. Further, both layers were compressed by using bi-layer compression followed by film coating. Layer-I and II formulations were developed by using various concentrations of diluents, surfactants, and disintegrants to improve the solubility of efavirenz and improve the flowability and uniformity of layer-II. Finally, the optimum formulation was developed to compare the in vitro dissolution with each branded formulation. Results: Drug-excipients interaction results revealed that the mixtures of three drug substances in 50 °C/75 % relative humidity (RH) resulted in an increase in tenofovir IMP-E and the highest unknown impurity was significantly increased and additionally decreased tenofovir assay in the presence of efavirenz. Sodium lauryl sulfate is very critical and it acts as a wetting agent and increases the solubility of efavirenz, and directly influences the dissolution of a drug product. Microcrystalline and croscarmellose sodium have a chance to affect the dissolution and friability of tenofovir. Powdered cellulose was acting as a diluent and flow property of the lamivudine part and it also affects the uniformity and dissolution. So, these ranges were optimized. X-ray diffraction (XRD) indicates there are no polymorphic changes for the optimized formulation and there is no interaction between the three active substances, and finally, in vitro dissolution results for the optimized formulation against the reference drugs. Conclusion: Optimum formulation yielded consistent drug release against each branded drug to treat human immunodeficiency virus (HIV1) infections. This formulation is robust and easily scale up for the next stage.

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.

Objective: Formulation and development of Ranolazine extended-release Tablets 500 mg and 1000 mg by using QBD with Fractional factorial design to match the similarity with Branded formulation (RANEXA®). Methods: Ranolazine extended-release tablets were developed by using various polymers, Polyquid PA100 and ETHOCEL TMstandard 7 premium and Hypromellose with a wet granulation process. QBD (Quality by Design) approach was used to identify the formulation and process variables that may affect the CQAs (critical quality attributes). Excipient compatibility studies were conducted to identify the interaction between API (active pharmaceutical ingredient) and selected excipients. Additionally, using a two-level, fractional factorial (22+3) design, the DOE (design of experiments) was employed to confirm the impacts of key process factors (fluid uptake and kneading time) on the formulation's ability to match the dissolution (f2) compared to RLD (reference listed drug) and establish a stable formulation. Results: Initial risk assessment was carried out to identify the various attributes such as API flow properties, solubility, PSD, Hygroscopicity, formulation, and process variables to impact the quality of the drug product. Flow properties of API indicate poor flow. Drug and excipients compatible study results indicate that excipients used in the compatibility study are considered compatible with the active ingredient. As per the saturation solubility studies and sink conditions, dissolution media was selected. Significant differences were found among the drug release profile by examining the various levels of polymers and binders. Using a two-level, fractional factorial (22+3) design, optimum process parameters were identified with selected formulation to match the dissolution (f2) similarity with the reference listed drug (RLD); finally, XRD (X-ray diffraction) studies confirm that the crystalline polymorphic forms (Form 1) peaks in optimum formulation (F07) comparable to the reference listed drug. Conclusion: Optimized formulation and process were established with QbD (quality by design) that provides the consistent drug release to match the f2 similarities with the extended-release tablets of RANEXA®(Ranolazine) 500 mg and 1000 mg.