SOLID DISPERSION AS AN APPROACH FOR SOLUBILITY AND DISSOLUTION ENHANCEMENT OF IBUPROFEN AND PIROXICAM

ABSTRACT

The aim of this study was to enhance the solubility and hence dissolution rate of two poorly soluble drugs: ibuprofen and piroxicam using Eudragit RS 100 and hydroxymethyl propyl cellulose (HPMC) as carriers, by solid dispersion technique and to evaluate the effect of trona (sodium sesquicarbonate) on the dispersions . Solid dispersions of ibuprofen and piroxicam were prepared using HPMC or Eudragit RS 100 and their combinations by the solvent evaporation method. The prepared dispersions were characterized with respect to drug content, production yield, moisture sorption and desorption, Fourier Transform Infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC). The solubilities of the pure drug, solid dispersions and their physical mixtures were studied using standard method. In vitro drug release of ibuprofen and piroxicam from the solid dispersions was evaluated in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes in a sequential fashion. Anti-inflammatory effects of the solid dispersions were investigated in comparison to the pure drug using the egg albumin induced paw odema in rats. Stability studies at 75% relative humidity and room temperature (28oC) was carried out on the prepared solid dispersions. Results indicate that the solid dispersions with HPMC entrapped greater amount of drug in comparison to those with Eudragit RS 100. Moisture sorption studies indicate the amorphous state of drugs in the solid dispersions. Solubility studies revealed marked increase in solubility of drugs from solid dispersions when compared to pure drugs and physical mixtures. Solid dispersions of ibuprofen with HPMC containing 1:2 drug : polymer ratio had 8 fold increase in solubility when compared to pure drug . Solid dispersions of piroxicam with Eudragit and HPMC (ratio 0.1:1:1) gave a 3 fold increase in solubility when compared to the pure drug. Solid dispersion of the drugs with HPMC gave a faster drug release in simulated gastric fluid while Eudragit RS 100 based solid dispersions exhibited a delayed release of ibuprofen in the fluid. Solid dispersions of piroxicam incorporating trona showed enhanced solubility and dissolution when compared to dispersions without it, but trona was seen to decrease solubility and dissolution of ibuprofen. The FT-IR spectroscopic studies revealed that there was no chemical interaction between the drug and the polymers, while the DSC scans showed changes from crystalline to amorphous form of the drug. Solid dispersions were seen to have enhanced anti-inflammatory effect relative to the pure drug. Stability studies of these solid dispersions revealed that the formulations were stable.

CHAPTER ONE

1.0 INTRODUCTION

The oral route of drug administration is the most common and preferred method of delivery owing to convenience and ease of ingestion (Kumar et al., 2012). From a patient‘s perspective, swallowing a dosage form is a comfortable and a familiar means of taking medication. As a result, patient compliance and hence drug treatment is typically more effective with orally administered medications when compared with other routes of administration, for example, parenteral (Dhirendra et al., 2009).

Although the oral route of administration is preferred, for many drugs it can be a problematic and inefficient mode of delivery for a number of reasons. Limited drug absorption resulting in poor bioavailability is paramount amongst the potential problems that can be encountered when delivering an active agent via the oral route. Drug absorption from the gastrointestinal (GI) tract can be limited by a variety of factors with the most significant contributors being poor aqueous solubility and/or poor membrane permeability of the drug molecule. When delivering an active agent orally, it must first dissolve in the gastric and/or intestinal fluids before it can then permeate the membranes of the GI tract to reach systemic circulation. The poor dissolution of water insoluble drugs is a substantial problem confronting the pharmaceutical industry.

A poorly water soluble drug, more recently, has been defined in general terms as a drug which requires more time to dissolve in the gastrointestinal fluid than it may take to get absorbed in the gastrointestinal tract (Reena and Vandana, 2012). The absorption rate of a poorly water –soluble drug formulated as an orally administered solid dosage form, is controlled by its dissolution rate in the fluid at the absorption site. The dissolution rate is often the rate determining step in drug absorption. Therefore, the solubility and dissolution behavior of a drug are the key determinants of the oral bioavailability (Kumar et al., 2012). A drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate-limited absorption.

With recent advances in molecular screening methods for identifying potential drug candidates, an increasing number of poorly water-soluble drugs are being identified as potential therapeutic agents. In fact, it has been estimated that 40% of new chemical entities currently being discovered are poorly water-soluble (Lipinski, 2001). Unfortunately, many of these potential drugs are abandoned in the early stages of development owing to solubility concerns.

One of the major current challenges of the pharmaceutical industry is related to strategies that improve the water solubility of drugs (Ueda et al., 2006). It is therefore becoming increasingly more important that methods for overcoming solubility limitations be identified and applied commercially such that the potential therapeutic benefits of these active molecules can be realized.

Various approaches available to improve drug solubility as well as drug dissolution of poorly aqueous soluble drugs include micronisation, formation of inclusion complexes with cyclodextrins, formation of amorphous drugs, and formulation of solid dispersions of drugs using various hydrophilic carriers. Among them, formulation of solid dispersions is one of the most successful strategies to improve drug release of poorly water- soluble drugs (Hasnain and Nayak, 2012). In the Biopharmaceutics Classification System (BCS), drugs with low aqueous solubility and high membrane permeability are categorized as class II drugs. Solid dispersions technologies are particularly promising for improving the oral absorption and bioavailability of BCS class II drugs (Dhirendra et al., 2009).