Design, Preparation and Evaluation of Controlled Release Polymeric Formulations Investigating Patterns & Mechanisms of Drug Release

Abstract

The PhD research study was conducted in two phases i.e. Phase I and Phase II. Phase 1: The first phase of the study aims to design, formulate and evaluate Ciprofloxacin HCl and Diltiazem HCl once daily 200mg Controlled Release (CR) tablets using different polymers and polymers grades and various drug to polymer (D: P) ratios, both in vitro and in vivo. Determination of some of the physical and chemical properties is convincingly well-ordered in the development of effective, reproducible and stable drug delivery systems. Dissolution is the rate limiting step towards the bioavailability of these dosage forms. Thus, our efforts during the pre-formulation studies covered the detailed study of various parameters such as, particle size analysis, solubility and dissolution behavior of Ciprofloxacin and Diltiazem powders. Various characterization and evaluation techniques like Differential Scanning Calorimetry (DSC) and Fourier Transform Infra-Red Absorption spectroscopy (FTIR) were used. Evaluation of the drug powders and physical mixtures was carried out using several physical methods including bulk density, tapped density, angle of repose, Hausner’s ratio and compressibility index. In order to control the drug release rate and to maintain steady state plasma concentration, various bio- polymeric approaches have been used during the course of treatment. Ethyl cellulose ether derivatives, Carbopol 974 P NF and Eudragit RS 100 polymers were used for the design and formulation of oral controlled release hydrophobic matrix tablets using direct compression method. The prepared matrix tablets were exposed to various physical and quality control tests comprising of thickness, diameter, weight variation, hardness, friability and content uniformity. The in vitro drug release profiles and drug release mechanisms were investigated using dissolution tests and applying kinetic models on the dissolution data. The once daily CR tablets were planned to achieve diffusion controlled pH independent release with the desired zero-order kinetics for both Ciprofloxacin HCl and Diltiazem HCl. For both drugs, stability of the selected tablets was investigated during the short term accelerated stability studies. The optimized test tablets were then subjected to in vivo studies using rabbits and HPLC based simple, authentic and speedy methods. The in vivo drug release mechanism was determined using various pharmacokinetic parameters like, Cmax, Tmax, AUC, MRT, T1/2 and Cl total for both test and the reference standard tablets. Having both Ciprofloxacin and Diltiazem as test drugs, the best approach of particle size distribution was finely dissolved in phosphate buffer (pH 7.4) solution and maximum absorbance was achieved at 276 and 237 nm respectively. The physical evaluation of the preliminary materials were found to be in the best satisfactory ranges reported in the literature like, Hausner’s ratio from 1.11±0.13 to 1.29±0.05, angle of repose from 22 to 37 ̊and compressibility index ranged from 11±2 to 20±2%. The results showed that the drug release rate could be significantly altered by the change in polymer concentration and particle size. It was observed that the addition of HPMC as a co-excipient possibly caused slow hydration of the matrix tablets leading to erosion and sequentially drug release, while CMC and Starch based formulations exhibited burst release and were completely disintegrated within a few hours. Microencapsulation of Diltiazem HCL and its in-vitro dissolution study in phosphate buffer pH 7.4 as dissolution medium. The microcapsules were prepared by using polymers Ethocel 7P and Ethocel 7FP at two different drug to polymer (D: P) ratios i.e. 1:1 and 1:2 and the effect of concentration was observed on drug release behavior. While carrying out in vivo studies of both Ciprofloxacin HCl and Diltiazem HCl, simple and rapid HPLC methods were developed which revealed optimum serum concentration (Cmax) levels for both drugs predicting least chances of side or adverse effects. It was revealed that matrix tablets for both of the drugs were having significantly prolonged tmax values indicating smooth and extended absorption phase. A good co-relation between the in-vitro drug release and in-vivo drug absorption of the drugs was observed. It was also investigated that in case of both drugs, the area under the curves (AUC) for test and reference matrix tablets were not significantly different i.e. (p<0.05) from each other. From this study it was concluded that the polymers (Ethocel, Carbopol and Eudragit) could be used to prepare once-a-day controlled release matrix tablets having Ciprofloxacin HCl and Diltiazem HCl as active ingredients. Phase 2: The second part of the study was conducted in the Institute of Pharmaceutical Innovation, University of Bradford, Bradford UK. The aim of the study was to prepare and evaluate Chlorpheniramine Maleate (CPM) solid dispersions using HPMC-Acetate Succinate (HPMC-AS) as rate controlling agent. Nine batches of CPM solid dispersions were prepared at three different drug to polymer (D: P) ratios i.e. 1:1, 1:2 and 1:3 using labultima spray dryer and varying the inlet temperature as 40, 50 and 60 oC . The prepared solid dispersions were evaluated for various physic-chemical properties using various instruments like FEI Quanta 400 Scanning Electron Microscope (Cambridge, U.K.), Cary 50 Varian probe UV-visible spectrophotometer (Australia), Bruker D8 Diffractometer (UK), TA Instruments Q2000 differential scanning calorimeter (Crawley, UK), TA Instruments Q 5000 Thermo Gravimetric Analyzer (Crawley, UK), Renishaw Raman microscope analyzer (UK), Digilab FTS 2000 spectrometer (Randolph, USA). The in vitro drug release studies were carried out in analytical grade distilled water using Pharma-Test dissolution apparatus at 37 oC ± 0.1 as constant temperature. It was found that the release rate was retarded more by increasing the polymer concentration and a linear relationship was found. A 2X3 factorial design was applied to the dissolution data to analyze the effect of different process variables i.e. (1) the drug to polymer ratio and (2) inlet temperature. In the end a very good response surface methodology curve was constructed using the collected data.