Purpose of the study The objective of current research work was to develop and evaluate microspheres for controlled drug delivery. These pH dependent polymeric microspheres were designed to deliver drug in a controlled release fashion, to minimize dosing frequency, to increase bioavailability and minimize drug toxicity. Methodologies In this study various polymeric microsphere formulations were prepared using methacrylate derivatives and ethyl cellulose (EC) by oil-in-oil (O/O) solvent evaporation method. Span 80 was used as an emulsifier. Ivabradine HCl (IBH), anti-anginal was used as a model drug. IBH was encapsulated into microspheres by in-situ method in all formulations. A series of formulations with three different polymeric combinations i.e., eudragit L100-55-EC (Formulation code FA1-FA7), eudragit FS30D-EC (formulation codes FB1-FB7) and Kollicoat MAE 100P-EC (formulations codes FC1-FC7) were developed. Prepared microspheres of all formulations were characterized by recovery of microspheres, percentage yield, percentage drug loading, encapsulation efficiency and swelling studies. Optical and scanning electron microscopy (SEM) was used to examine the morphology and size of microspheres. Particle size distribution analysis was performed by Zetasizer. Rheological properties were conducted to measure the flow properties of resultant microspheres. Chemical stability of IBH loaded microspheres was confirmed by fourier transform infrared spectroscopy (FTIR), x-ray diffractometry (X-RD), differential scanning calorimetery (DSC) and thermal gravimetric analysis (TGA). In-vitro drug release studies were performed in phosphate buffer solution of pH 1.2, 5.5, 6.0 and 7.4. On the basis of results of in-vitro dissolution studies optimized formulations (FA7, FB7 and FC7) were selected for in-vivo studies on rabbits. Results and Discussion All formulations were synthesized and characterized successfully. Rheological studies showed that the formed microspheres were free flowing in nature. SEM images confirmed that resultant microspheres were spherical and smooth surfaces. SEM images showed that microspheres were in the size range of 20-80 μm with spherical shape. Zeta size analysis showed all formulation were in micromeritic range with narrow size distribution. FTIR spectra confirmed the presence of drug in pure form and reflected no interaction between drug and polymers. DSC and X-RD xx determined that the nature of drug in drug-loaded microspheres was in amorphous form. X-RD clearly indicated that drug particles were uniformly distributed in the polymeric matrix. TGA indicated that prepared microspheres showed much better thermal stability than pure drug. The microspheres executed pH dependent swelling behavior. The Maximum percentage entrapment efficiency of IBH was found upto 81 ± 2.15, 45.1% and 82 ± 2.11 for developed microspheres of eudragit L100-55-EC, eudragit FS30D-EC and Kollicoat MAE100P-EC respectively. Maximum percentage yield of eudragit L100-55-EC, eudragit FS30D-EC and Kollicoat MAE100P-EC microspheres was found 88± 2.65, 71.66 ± 2.12 % and 89 ± 3.31 respectively. In-vitro studies revealed that all formulations (FA1-FA7, FB1-FB7 and FCI-FC7) showed pH responsive drug release. All polymeric carrier presented negligible cumulative drug release in buffer solution of pH 1.2. The Maximum drug release 94.5%, 95.9% and 90% of optimised formulation (FA7, FB7 and FC7) was observed at pH 7.4 which demonstrated that all formulations had a pH-dependent drug release. Maximum controlled release effect was observed in formulations (FA7, FB7 and FC7) containing 50:50 of eudragit and EC due to reduction in swelling of microspheres. Results showed that high concentration of EC results in a longer diffusional path length, so drug release is extended and drug release mechanism gradually transfer from diffusion to erosion. Cumulative drug release data of all formulations were analyzed by using different kinetic models. The result showed that first order was best fit to the data and followed by drug release. By applying Korsmeyer-peppas model the value of (n) for release of drug was calculated. The value of (n) was found between 0.435- 0.830 which indicates that diffusion mechanism was non-fickian. High-performance liquid chromatographic (HPLC) method was developed and validated for analysis of IBH in mobile phase and rabbit plasma as per ICH-guidelines. The separation was performed on HSC18 (25 cm x 4.6 mm, 5μm) column with Acetonitrile: Buffer pH 6.0), 40:60 v/v) as mobile phase and a flow rate of 1.0 ml/min in the isocratic mode. A well-defined chromatographic peak of IBH was exhibited with a retention time of 4.062 minutes and tailing factor of 1.658.The linear regression analysis data for calibration plots showed good linear relationship with R=0.9998 in the concentration range of 1.56-100 μg/ml both in mobile phase and in plasma. The method was validated for precision, recovery and robustness. Intra and inter-day precision were less than 2%. The method showed the mean recovery of 96% to 102% and relative standard deviation (RSD) < 1% in Mobile phase and rabbit plasma. HPLC method was found to be highly precise, sensitive and accurate for determination of IBH in xxi pharmaceutical dosage form successfully applied to the commercial tablets without any interference of excipients. Optimized polymeric formulations were selected on the basis of in-vitro results and further studied for biological evaluation in rabbits in order to validate their effectiveness up to a considerable extent. After administration of single oral dose of drug solution and selected microspheres were subjected to in-vivo studies to calculate pharmacokinetics parameters. Pharmacokinetic parameters (pk) were calculated by Phoenix WinNonLin® Version 6.3 software the linear trapezoidal method was used to calculate AUC from time versus plasma concentration. All the polymeric microspheres (FA7, FB7 and F7C) had significantly prolonged Tmax, mean residence time (MRT), lower maximum plasma drug concentration (Cmax) had higher area under curve (AUC) in comparison to oral drug solution. Statistical analysis was performed by using one-way analysis of variance (ANOVA) in order to determine statistical significant and non-significant interpretation. The P value was < 0.05 which indicates a significant difference in results. Conclusion In short, pH dependent polymeric carriers; eudragit L100-55-EC, eudragit FS30D-EC and Kollicoat MAE100P-EC microspheres having potential to release drug in a controlled fashion, have been developed successfully. The results of in-vitro and in-vivo studies confirmed that microspheres entrapped IBH and prolonged its pharmacological effects due to increase of biological half-life. Collectively, these in-vivo results manifested that pH-dependent microspheres had a reasonable controlled release. This polymeric microspheres system can be further explored for the drug targeted delivery with maximum therapeutic efficacy and minimum adverse effects.