Demography and Pakistan

Demography, along with geography, has always figured in the making of nations and in inter-state relationships. But perhaps never so critically as in the case of Pakistan. Indeed, in all the annals of its proto-history and existential career, demography and Pakistan have been interminably entwined. This may sound incredible, even inexplicable.

Preparation and Evaluation of Controlled Release Matrix Formulations Using Cellulose Acetate Ether Derivatives As Release Controlling Agents

The present research work was conducted in two phases. The research work in first phase was carried out in Drug Delivery Research Laboratories of Faculty of Pharmacy, Gomal University D.I.Khan Pakistan and the second phase was carried out in the Laboratories of Centre of Pharmaceutical Engineering Science, School of Life Sciences, University of Bradford UK. The objective of the research work in first phase was to develop controlled release matrix tablets of analgesic drugs like Nimesulide and Tramadol HCl. Cellulose acetate ether derivatives were used as rate controlling agents and their effect on the drug release kinetics and mechanism was evaluated in comparison to various polymers. In this connection first preformulation studies were carried out for identification and solubility of the selected drugs and determination of any incompatibility between drugs and polymers. FTIR and DSC studies proved that there was no incompatibility between the drugs and polymer. A set of formulations were developed using Ethocel® polymer of various grades [Ethocel® Standard 7 Premium (P), Standard 7 Fine Particle (FP) Premium, Standard 10P, Standard 10FP Premium, Standard 100P and Standard 100FP Premium], Carbopols [Cabopol 974P and 934P] and Eudragit [Eudragit RS-100] in various drug to polymer ratios. Some formulations of the drugs were prepared by partial replacement of the filler (lactose) with co.excipients like CMC, Starch and HPMC KM-100 to evaluate the effect of these co.excipients on the release of drugs from the matrix tablets. The micromeritic studies of the pure drugs and physical mixtures of the formulations were carried out following official procedures which suggested that pure drugs had a poor flow properties but when different ingredients of formulations were mixed together (physical mixtures), the flow properties were enhanced which was considered to be important in tablet preparation. Matrix tablets were prepared from all formulations by following direct compression method for Nimesulide tablets and dry granulation method for Tramadol HCl. Physicochemical characterization of prepared matrix tablets was carried out by performing hardness, weight variation, dimensional, friability and content uniformity tests according to the established procedures. All these physical and quality control parameters were well within the acceptable ranges. Matrix tablets that were prepared with the fine particle (FP) premium grades of Ethocel® were harder and thinner as compared to those with conventional granular grades. The matrix tablets were then evaluated for in vitro drug release by performing in vitro dissolution tests. Dissolution tests were performed by USP method I (rotating basket method) using Monobasic potassium phosphate buffer (pH 7.4) as dissolution medium. Tablets that contain Ethocel® 7FP premium grades extended the release of the drug more efficiently than other grades of Ethocel® polymer. Viscosity grades, particle size and drug to polymer ratio were the main factors that affect the drug release rates and kinetics from matrix tablets of Ethocel® polymers. Carbopol 974P and 934P both proved to be effective in controlling the release of Nimesulide upto 24 hours depending upon the quantity of polymer used, however in case of the water soluble drug (Tramadol HCl), these two polymers fails to extend the release upto 24 hours. An extended release of drugs was demonstrated from matrices prepared with Eudragit RS 100. Co.excipients like starch, CMC and HPMC enhanced the release of the selected drugs from matrix tablets and the all of the drug was released in just 3-5 hours from these matrix tablets. Different Kinetic models were applied on the release data of the matrix tablets. Coefficient of determination (R2) values in the kinetic models showed a linear relation with drug release from matrix tablets containing Ethocel® and Carbopols without co.excipients. The diffusional exponent (n) in the Korsmeyer Peppas Kinetics showed that the release from matrix tablets without co.excipients followed anomalous non fickain release mechanism. The dissolution profiles of matrix tablets and conventional immediate release formulations were compared by determination of similarity factor (f1) and difference factor (f2). The results of in vitro dissolution studies and data from the kinetic models concluded in selection of an optimised test formulation for both the drugs. Nimesulide matrix tablets that contain Ethocel® 7FP premium in drug to polymer ratio of 10:2 and in case of Tramadol HCl matrix tablets of Ethocel® 7FP premium in a drug to polymer ratio of 10:4 were considered as the optimised test formulation for both of the drugs. A batch of each optimised test formulations was prepared with wet granulation method to determine the effect of method of preparation of matrix tablets. In case of matrix tablets of Nimesulide, Wet granulation method proved to be more effective in retarding the release rate of drug when compared with the direct compression method but while considering the release of Tramadol HCl matrix tablets, there was no significant difference in the release of drug from matrix tablets prepared by dry granulation or wet granulation. The optimised test tablets were evaluated for stability testing in short term accelerated conditions. Both the optimised formulations demonstrated good stability in accelerated conditions of temperature and humidity. Microcapsules of both the selected drugs were developed using Ethocel® 7FP as carrier in different drug to polymer ratios, with the objective of explaining the effect of change in dosage form on the release of the drugs. All batches of microcapsules demonstrated good physicochemical characteristics. The release of the drugs from microcapsules was on the basis of non fickian anomalous mechanism and was affected by quantity of the polymer. In vivo studies were carried out on the optimised test formulations by comparing the effect of the optimised test formulation and conventional IR formulations on the in vivo absorption and pharmacokinetic parameters of the drugs in animals (rabbits). In vivo pharmacokinetic parameters of test formulations showed more extended release rates as compared to reference IR formulations of Nimesulide and Tramadol HCl. Moreover, the test formulations showed good linear relationship between In vitro drug release and In vivo drug absorption, and prolonged MRT0-t and t1/2 values as compared to reference formulations. In second phase, solid dispersions of a water insoluble model drug (Ibuprofen) and a carrier polymer hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) was prepared using spray drying technique in order to enhance the solubility and ultimately the bioavailability of the drug. In this connection different batches of Ibuprofen solid dispersions were prepared by following a 32 factorial design of experiments. Effects of variables like drug to polymer ratio and inlet temperature on the percent yield and in vitro dissolution profile was studied. The physicochemical characterisation of the batches was carried out using SEM, TGA, DSC, PXRD, FTIR and RAMAN spectroscopic analysis. The results of the characterization analysis, in vitro dissolution studies and statistical application of ANOVA and response surface methodology concluded that drug to polymer ratio was the main factor responsible for the increased solubility of the model drug (Ibuprofen).