Milnacipran HCl is a potential candidate to treat fibromyalgia associated with or without depression like comorbid conditions. The requirements of multiple dosing, absorption in first part of small intestine and fluctuating steady state plasma concentrations of drug have made it a suitable candidate for gastro-retentive sustained release drug delivery system. The utility of chitosan as mucoadhesive and polycaprolactone as hydrophobic polymer was aimed for creation of this matrix delivery system. Modified hot melt granulation with addition of second polymeric solution was opted for preparing optimized blends of acetaminophen. Modified wet granulation technique was utilized to prepare blends of milnacipran with different ratios of polymers. The optimized solutions for formulations containing blends of three polymers and drug with two solvents, i.e., dichloromethane and chloroform was optimized using design of experiment. A simple and sensitive colorimetric method for estimation of milnacipran was developed with ninhydrin to properly estimate drug from dissolution samples at 570 nm wavelength. The optimized blends were characterized for mucoadhesive time and strength using tensiometer, drug release analysis opting HCl buffer pH 1.2 for 12 h, kinetics of drug release and drug excipient compatibility analysis by utilizing FTIR and DSC. The optimized formulations M21-M24 were compared against reference formulation specifications for similarity index (f1 and f2). The optimized formulations were also scaled down containing 30 mg of drug according to weight of animals and were characterized for release parameters, i.e., the time to release certain percentage of drug (T10%-T90%). Different pharmacokinetic parameters were evaluated for M44 formulation using both non-compartment and two compartment model approaches. The best correlation (R2) values of 1 were observed with non-compartment model so parameters calculated were used to establish in-vitro in-vivo II correlation after estimating fractions of milnacipran absorbed/unabsorbed and time to absorb specific concentration of milnacipran using Wagner-Nelson method. The developed analytical method proved sensitive and precise with LOD and LOQ values of 0.55 and 1.667 μg/ml, respectively. Mucoadhesive strength was found as 201.06±16.8 dynes for different formulations with more than 12 h of adhesion time. Drug release studies showed release independent of concentration and was best described by Korsmeyer-Peppas model representing swelling controlled system. The n values of 0.5-0.7 showed dependency of release on both dissolution and diffusion mechanism. There were only physical interactions observed at various positions of IR spectrum with functional groups of polymers and drug were found intact. Thermal studies revealed that milnacipran has sharp melting point of 179.85℃ which was lowered to round about 154.30℃ due to covalent and ionic interactions required to form true blend with polymers. M24 formulation proved best on similarity parameters, i.e., f1=6.09, and f2=72.46, representing true similarity. Cmax, Tmax, and AUC0-∞ calculated for M54 were markedly found different from oral solution (P˂0.05) proving sustained delivery of milnacipran from the formulation blends. Bioavailability of M54 formulation was three fold improved as compared to solution. Level A correlation was established by comparing the above parameters and found R2 were 0.992, 0.9831 and 0.9998. The above results proved that milnacipran might be formulated as mucoadhesive DDS using three polymers opting design of experiment approach and evidenced best on IVIVC. III