Stability Studies of Microparticulate System with Piroxicam as Model Drug

Abstract

Non-steroidal anti-inflammatory agent, piroxicam (PIR), is particularly employed in treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain in musculoskeletal disorders, and acute gout (1). This drug has also been in clinical practice as an analgesic in dental, postoperative and postpartum pain (2). According to the biopharmaceutical classification system, PIR is included in class 2, having characteristics of low solubility and high permeability characteristics. The pharmacokinetic data reveal that this molecule undergoes slow and gradual absorption pattern when given orally. This leads to a delayed onset of anti-inflammatory and analgesic effect. Poly(lactide-co-glycolide) (PLGA) has been the polymer of choice for injectable microparticulate systems due to its biocompatible nature (3). Release behavior from PLGA polymers are either by diffusion, erosion, or a combination of both (4). The dissolution kinetics can be affected by a number of significant factors like polymer molecular weight, copolymer ratio and crystallinity (5–8), properties related to the molecule (9–11), dissolution conditions employed in the study (12,13), and formulation factors like preparative conditions, particle size, and encapsulation efficiency (14–18). Depending upon the type of PLGA, the drug release profiles from PLGA microspheres can range from days to months. Hence, accelerated release testing of such systems especially for in vitro drug release kinetics becomes imperative. However, it should be noted that in ideal situation, the drug release from accelerated test and “real-time” study should follow the same release mechanism and a 1:1 correlation is expected. Exaggerated conditions like temperature, pH of media, etc. are generally employed in the test to achieve rapid release. It is possible that the release mechanism may alter due to these exaggerated conditions. Literature study shows that an increase in drug release from PLGA has been achieved either by increase in temperature (due to increased mobility of polymer and hence drug diffusion), by acid or alkali catalyzed hydrolysis, by addition of a surfactant that would enhance the dissolution, by addition of a cosolvent, or by radiation (19–24). Degradation of polylactic acid and PLGA polymers of different copolymer ratios and molecular weights at 37°C and 60°C with change in mass loss, molecular weight, and formation of respective acid components has been reported (25). Stability of a pharmaceutical dosage form is very significant as it reflects the quality of the dosage form during its shelf life. The stability studies give proof on how the quality of a drug substance or product varies with time under the influence of environmental factors like temperature, humidity, and light. Regulatory bodies lay emphasis on performing stability studies and is a part of the product submission requirements. International conference on harmonization (ICH) has laid guidelines for stability studies. The ICH Q1A(R2) is for stability testing of new drug substances and products. ICH Q3A, Q3B, and Q3C are based on the impurities in drug substance, drug product, and residual solvents, respectively. The specifications, test procedures, and acceptance criteria for new drug substances and products are dealt in ICH Q6A. The stability studies should be an integral part of the development cycle for new dosage forms. Often it is observed that the stability aspect is often neglected during the development of a new pharmaceutical product. To get more insight on how the product fairs during shelf life, we performed stability studies on the final system. Extensive literature search indicates that not much attention has been given to evaluate the quality of microsphere based products on storage for prolonged time period along with real-time release profiling for long-term release products. In the above context, a strong need was felt to conduct real-time stability studies for the developed PIR–PLGA microparticulate formulation. A sensitive stability indicating high-performance thin-layer chromatographic (HPTLC) method developed and validated in our lab was employed for estimation of drug. An attempt was made in the present investigation to focus on the stability aspects of PIR–PLGA microsphere system.