P. N. Murthy

Dissolution Enhancement and Physicochemical Characterization of Valsartan in Solid Dispersions with β-CD, HP β-CD, and PVP K-30

Solid dispersions (SDs) and physical mixtures (PMs) of valsartan in β-cyclodextrin (β-CD), hydroxypropyl β-cyclodextrin (HP β-CD), and polyvinyl pyrollidone (PVP K-30) were prepared to increase its solubility characteristics. The drug formulations were characterized in the solid state by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). By these physical determinations, drug–polymer interactions were found. Both the solubility and the dissolution rate of the drug in these formulations were increased. Drug contents were determined by UV spectrophotometry at a λmax of 249.5 nm. The phase solubility behavior of valsartan in various concentrations of β-CD, HP β-CD, and PVP K-30 (0.25–1.0% w/v) in distilled water was obtained at 37 ± 2 °C. The dissolution of valsartan is increased with increasing amounts of the hydrophilic carriers (i.e., β-CD, HP β-CD, and PVP K-30). Gibbs free energy (ΔGtr) values were all negative, indicating the spontaneous nature of valsartan solubilization. The SDs of valsartan with β-CD and HP β-CD were prepared at 1:1, 1:3, and 1:5 drug/carrier ratios by a kneading method, and PVP K-30 SDs were prepared at the same ratios (i.e., 1:1, 1:3 and 1:5 drug/carrier) by a lyophilization technique. The FTIR spectroscopic studies show the stability of valsartan and the absence of well-defined drug–polymer interaction. Compared with β-CD, HP β-CD showed better enhancement of dissolution rate; compared with HP β-CD, PVP K-30 showed better solubility and dissolution enhancement. INTRODUCTION From an economic point of view, low oral bioavailability results in the wasting of a large portion of an oral dose and adds to the cost of drug therapy, especially for expensive drugs (1). No matter how active or potentially active a new molecular entity (NME) is against a particular molecular target, if the NME is not available in solution at the site of action, it is not a viable candidate. As a result, the development of many exciting NMEs is stopped before their potentials are realized or confirmed because pharmaceutical companies cannot afford to conduct rigorous preclinical or clinical studies on molecules that do not have sufficient pharmacokinetic profiles due to poor water solubility (2). The rate of oral absorption of poorly soluble or BCS Class II drugs is often controlled by the dissolution rate in the gastrointestinal tract. Thus solubility and dissolution rate are the key determinants of oral bioavailability, which is the concluding point drawn for fate of oral bioavailability (3). Solubility is defined in quantitative terms as the concentration of solute in a saturated solution at a certain temperature, and in a qualitative way, it can be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion (4). McBain (5) has stated, “Any material can be solubilized in any solvent by proper choice of solubilizing agent.” Final selection of solubilizing agent should be based on phase solubility studies. Among the various approaches to improve solubility, the solid dispersion technique has often proved to be the most successful in improving the dissolution and bioavailability of poorly soluble active pharmaceutical ingredients because it is simple, economic, and advantageous (6). The solid dispersion technique provides a means of reducing particle size to a nearly molecular level. As the soluble carrier dissolves, the insoluble drug is exposed to the dissolution medium as very fine particles for quick dissolution and absorption. In particular, polymers such as polyethylene glycols and polyvinylpyrrolidone have been used extensively as carriers for dispersions because of their low melting points and their hydrophilic environments (7). Cyclodextrins (CDs), with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form noncovalent inclusion complexes (8). CDs can have both stabilizing and destabilizing effects on chemically labile compounds, they *Corresponding author. diss-18-01-06.indd 39 2/24/2011 9:46:54 AM dx.doi.org/10.14227/DT180111P39

Development and validation of a stability-indicating RP–HPLC method for estimation of atazanavir sulfate in bulk

A stability-indicating reverse phase–high performance liquid chromatography (RP–HPLC) method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C18 column Phenomenix (250 mm×4.6 mm, 5 μm) with a mobile phase consisting of 900 mL of HPLC grade methanol and 100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45 μm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90 μg/mL (coefficient of determination R2 was 0.999) with equation, y=23.427x+37.732. Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines.

Comparison of Sedimentation Stability of Azithromycin Dihydrate Suspensions using near Infrared Extinction Profiles with Different Suspending Agents

The aim of the study is to formulate and evaluate the sedimentation stability of the prepared azithromycin suspensions in a rapid way by employing near infrared transmission measurements. The mucilage extracted from Plantago ovata seeds was used as one of the suspending agents along with the traditional suspending agents like MC, HPMC and SCMC. Stability studies of suspensions are very important to enable the patient to receive the intended amount of the drug(s) in the dose administered. Physical stability of azithromycin suspensions was studied in terms of sedimentation stability in a rapid way employing infrared extinction profiles by using the instrument separation analyzer (LUMiReader®) in the present work. The LUMiReader® instantaneously measures the extinction profiles of the transmitted light across the entire length of a suspension sample employing STEP-Technology (Space-and Time-resolved Extinction Profiles Technology). Instability indices determined on different suspension formulations indicated that POM and MC are preferable suspending agents for the preparation of stable suspensions of azithromycin.

Development of Modified-Release Tablets of Zolpidem Tartrate by Biphasic Quick/Slow Delivery System

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.