Formulation, evaluation and characterization of an oral modified realease naproxen sodium preparation.

Abstract

The motivation for the present study is systematically presented and the aims and objectives

of the study are clearly defined. A comprehensive review on modified release drug delivery

has been presented to provide the basis for the meltable aqueous dispersion technique as an

approach to the formulation of a multiple-unit oral modified release drug delivery system.

In addition, a brief discussion on the theory of dissolution testing and the mechanisms and

interpretation of the dissolution process has been presented. Naproxen sodium, a potent

non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic activity

employed in the study, has been briefly discussed.

In the present study, the coacervation phase separation technique utilizing ethylcellulose

was initially investigated but proved unsuccessful in producing a formulation displaying

suitable drug release characteristics. Subsequently, the meltable aqueous dispersion

technique utilizing cetostearyl alcohol was successfully employed to formulate a multipleunit

modified release naproxen sodium preparation containing 550 mg of naproxen sodium.

The use of cetosteary!alcohol, as·a·retarding material, generated modified ·drug release

characteristics as a function of its content. Magnesium stearate (anti-tackiness agent) and

Span 20 and Tween 60· (surfactants) were incorporated in the formulation to optimize

particle size and sphericity. The influence. of various formulation variables on drug release

characteristics were investigated:

An optimized formulation displaying a desirable modified release profile of naproxen

sodium was achieved employing a 1:1 ratio of naproxen sodium:cetostearyl alcohol, 2% m/m .. ..

magnesium stearate, and 1%m/m Span 20 dispersed in a liquid manufacturing vehicle of pH

0.6 containing 2% m/m Tween 60. In vitro dissolution studies on the selected formulation

showed drug release to be predictable and reproducible, dependent on the dissolution

method, agitation rate, and the pH of the dissolution media (i.e. pH-dependent drug

release). The density of the microspheres was shown to decrease as the concentration of

cetostearyl alcohol increased whilst the mean specific surface area increased with

increasing concentrations of cetostearyl alcohol.

Differential scanning calorimetric studies reveals a change in the thermograms which is

suggestive of eutectic formation. Scanning electron microscopy proved useful in evaluating

the integrity and surface morphology of the microspheres as well as in elucidating the drug

release characteristics of the formulation. Energy dispersive x-ray microprobe analysis

revealed the elemental composition of the microspheres to be a composite of the pure

ingredients. X-ray mapping and the line scan depicted the homogenous distribution of drug

within the microspheres and confirmed that the formulation is a matrix-type modified release I'

preparation.

Stability studies were performed on the selected formulation at room temperature

(21 :t 1°C), 40°C, 37°C with 80% relative humidity, and at low temperature (5 :t 1°C). The

shelf-life of the selected formulation was determined to be 1.29 years. Applying the data to

five different kinetic models to investigate the drug release mechanisms showed that first order

and cube-root release characteristics were exhibited by the microspheres.