Formulation and characterisation of a combination captopril and hydrochlorothiazide microparticulate dosage form for paediatric use

Thesis (PhD)--Rhodes University, Pharmacy Faculty, Department of Pharmaceutics, 202

Preparation and evaluation of captopril - ion exchange resin complexes

Restricted access-thesis embargoed for 2 year

Formulation and Characterisation of a Combination Captopril and Hydrochlorothiazide Microparticulate Dosage Form

Cardiovascular diseases such as hypertension and cardiac failure in South African children and adolescents are effectively managed long term, using a combination treatment of captopril and hydrochlorothiazide. The majority of commercially available pharmaceutical products are designed for adult patients and require extemporaneous manipulation, prior to administration to paediatric patients. There is a need to develop an age appropriate microparticulate dosing technology that is easy to swallow, dose and alter doses whilst overcoming the pharmacokinetic challenges of short half-life and biphasic pharmacokinetic disposition exhibited by hydrochlorothiazide and captopril. An emulsion solvent evaporation approach using different combinations of polymers was used to manufacture captopril and hydrochlorothiazide microparticles. Design of experiments was used to develop and analyse experimental data, and identifyoptimum formulation and process conditions for the preparation of the microparticles. Characterisation studies to establish encapsulation efficiency, in vitro release, shape, size and morphology of the microparticles were undertaken. The microparticles produced were in the micrometre size range, with an encapsulation efficiency >75% for both hydrochlorothiazide and captopril. The microparticulate technology is able to offer potential resolution to the half-life mediated dosing frequency of captopril as sustained release of the molecule was observed over a 12-h period. The release of hydrochlorothiazide of >80% suggests an improvement in solubility limited dissolution

Stability indicating HPLC-ECD method for the analysis of clarithromycin in pharmaceutical dosage forms: Method scaling versus re-validation.

An isocratic high-performance liquid chromatographic method using electrochemical detection (HPLC-ECD) for the quantitation of clarithromycin (CLA) was developed using Response Surface Methodology (RSM) based on a Central Composite Design (CCD). The method was validated using International Conference on Harmonization (ICH) guidelines with an analytical run time of 20 min. Method re-validation following a change in analytical column was successful in reducing the analytical run time to 13 min, decreasing solvent consumption thus facilitating environmental and financial sustainability. The applicability of using the United States Pharmacopeia (USP) method scaling approach in place of method re-validation using a column with a different L–designation to the original analytical column, was investigated. The scaled method met all USP system suitability requirements for resolution, tailing factor and % relative standard deviation (RSD). The re-validated and scaled method was successfully used to resolve CLA from manufacturing excipients in commercially available dosage forms. Although USP method scaling is only permitted for columns within the same L-designation, these data suggest that it may also be applicable to columns of different designation

Assessment of taste masking of captopril by ion-exchange resins using electronic gustatory system

The objective of the study was to mask the unpleasant taste of captopril (CPT). Taste masking was achieved by complexation of CPT with a basic ion exchange resin, Dowex® 66, using the batch method. Dowex® 66 was used for the adsorption of CPT, and physical and chemical parameters of the CPT resinates complex were evaluated. A central composite design was used to generate the experiments for the manufacture of resinates using different process and formulation variables. In vitro dissolution studies were performed for 2 h in 0.01N HCl (pH 1.6) using USP Apparatus I. The compatibility of CPT and the resin was evaluated by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). The resinates were evaluated for micromeritic properties and further characterised using FTIR, DSC, and PXRD. Response surface methodology was used to determine the significance of input variables on the CPT content and release. The CPT resin ratio was found to have a significant impact on content of the resinates and on CPT release. The formulations were also studied for taste masking ability by means of an electronic gustatory system – electronic tongue