Development and Evaluation of Controlled- Release Formulations of Tramadol HCl

Abstract

For the preparation of controlled-released microparticles through non-solvent addition technique ethyl cellulose (EC) was employed. Dichloromethane (DCM) was utilized as solvent for polymer; and paraffin oil as non-solvent that induced phase separation. Microparticles of different polymer concentration M1 (1:1), M2 (1:2) and M3 (1:3) were prepared. Among all these formulations, M3 presented superior and desirable characteristics i.e. 79% entrapment efficiency, good micromeritic properties, smooth morphology and more sustained effect on cumulative release. Zero order, First order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas kinetic models were applied to assess the mechanism and pattern of drug release from microparticles. Release of TmH was best fitted to Higuchi model because it presented highest values of correlation coefficient (R2=0.981) followed by zero-order kinetic model (R2=0.899). FTIR, XRD and DSC ensured the chemical stability and integrity of TmH and EC in M3; as no new bands were detected in FTIR spectra. Moreover, crystallinity of TmH was reduced in XRD, and endothermic peak was observed at the glass transition temperature of EC in DSC spectra. M3 were kept at 40°C/75% RH for three months and evaluated for stability by determining in-vitro release profile and drug assay. The effect of exaggerated environment on the stability was insignificant. The controlled-released microspheres were prepared through solvent evaporation method using ethyl cellulose as polymer. These microspheres were evaluated primarily for kinetics and stability. Microspheres of different polymer concentration M1 (1:1), M2 (1:2) and M3 (1:3) were developed and compressed into tablets i.e., T1, T2 and T3, respectively. Zero order, First order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas kinetic models were applied to assess the mechanism and pattern of drug release. Higuchi model was found to be the best among all models. The chemical and physical stability of TmH formulation was studied using FTIR, Thermal analysis, X-ray diffraction and dissolution tests. In-vitro analysis showed that tablets of ratio T2 released the drug over 12hrs and the release profile was comparable with that of reference tablet, Tramal® SR. The effect of different storage temperatures on the physicochemical stability of T2 was insignificant (p > 0.05). A controlled-release combination of Tizanidine (TZD) and Tramadol (TmH) microparticles was developed and evaluated. Microparticles of both drugs were prepared separately via temperature change method. To extend the release of formulations EC polymer was employed. Higuchi, Zero order, First order, and Korsmeyer-Peppas kinetic models were applied to appraise mechanism and mode of drugs release. Higuichi model was found to be best for all release profiles. Stability of microparticles at 40oC/75%RH over three-month duration was determined by FTIR, XRD and drugs assay. Microparticles were compatible and stable as no significant differences were observed when subjected to drug assay, FTIR and XDR during accelerated stability studies. For combination of Tramadol HCl (TmH) and Acetaminophen (AAP) microparticles coacervation via temperature change method was used. Ethyl cellulose (EC) of moderate viscosity was employed to extend the release of formulations. Microparticles of both drugs were prepared separately and then compressed into bilayer tablets. Physicochemical stability of bilayer tablets was determined using FTIR, XRD, DSC and TDA. The mechanism and pattern of drugs release was assessed by the application of Higuchi, Zero order, First order and Korsmeyer-Peppas kinetic models. Higuchi model was found best for release profiles of both drugs. FTIR, XRD, DSC and TDA result findings ensured the compatibility and stability of the new formulation. Similarly, insignificant differences were observed, when subjected to accelerated stability studies. Microencapsulated TmH and AAP can be developed into bilayer tablets. This SR combination is stable and releases the drugs over 12 hours. Floating microcapsules (FMs) using combination of ethyl cellulose (EC) and hydroxy propyl methyl cellulose (HPMC) were prepared and characterized. An easy and novel phase separation method was adopted to prepare FMs. Chloroform and paraffin oil were employed as solvent and non-solvent, respectively. Five kinetic models were applied to assess and describe the mechanism and pattern of TmH release from FMs. FMs were subjected to FTIR and XRD to evaluate TmH-HPMC-EC interaction. As EC concentration was increased, retardation in the release of TmH, improvement in flow characteristics and decrease in floating time, were observed. Kinetics of drug release was followed by Korsmeyer-Peppas kinetic model. Floating microcapsules of TMH can be produced using phase separation method. Microcapsules were stable with no drug-polymer interaction. The accelerated stability studies also ensured the physicochemical integrity of FMs. Biodegradable microspheres of Tramadol Hydrochloride (TmH) were developed using simple phase separation technique. Poly lactide-co-glycolide (PLGA) was used as release controlling polymer. Simple phase separation method was adopted to prepare microspheres; Dichloromethane (DCM) and Liquid Paraffin (LP) were employed as solvent and non-solvent, respectively. Five kinetic models were applied to assess and describe the mechanism and pattern of TmH release from biodegradable microspheres. Biodegradable microspheres were subjected to FTIR, DSC and XRD to evaluate TmH-PLGA interaction. Retardation in the release of TmH was observed as PLGA concentration was increased. Kinetics of drug release followed higuchi model. The microspheres exhibited no interaction between TmH and PLGA. Biodegradable microspheres of TmH can be produced using phase separation method. Microspheres were stable with no drug-polymer interaction. The accelerated stability studies also ensured the physicochemical integrity as differences of release profile over the period of three months were insignificant. IVIVC for microparticles of tramadol hydrochloride was also established. Four formulations of controlled-release microparticles with different polymer concentration were developed and optimized in respect of encapsulation efficiency, dissolution study, release kinetics and FTIR spectroscopy. The optimized formulations were taken for in vivo studies. For in vivo analysis, a new HPLC analytical method was developed and validated. The mobile phase, comprises of phosphate buffer (50 mM), methanol and acetonitrile (75:20:05) was run at the flow rate of 0.75 mL/minutes. In vivo study was performed on twenty four healthy human volunteers and various pharmacokinetic parameters i.e., Cmax, tmax, AUC 0-∞ and MRT were calculated. The in vitro and in vivo drug data was compared to establish relationship with the help of Wagner-Nelson method. The F-4 exhibited good IVIV correlation (R2= 0.9957) compared to F-3 (R2=0.9722).