Diacerein

The present investigation aims on the preparation and in-vitro/in-vivo examination of inclusion complex of Diacerein (DAR) an anthraquinone derivative indicated for treatment of osteoarthritis by inhibiting interlukin-1 and hydroxypropyl-β-cyclodextrin (HP-β-CD). In this study, the inclusion complexes of DAR with β-cyclodextrin (β-CD), HP-β-CD, methyl-β-cyclodextrin (M-β-CD) and γ-cyclodextrin (γ-CD) were prepared and characterized for phase solubility study and inclusion efficiency. On the basis of results obtained, HP-β-CD was selected to prepare inclusion complexes with DAR by physical mixing, kneading method and freeze drying method and subjected to solid state characterizations. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD) and Infra-red spectroscopy (IR) analysis confirmed the formation of perfect inclusion complex of DAR with HP-β-CD in solids. In-vitro dissolution and % drug content of DAR in freeze dried inclusion complex showed its superiority over plain drug and commercial formulation. . In-vitro cell cytotoxicity studies (MTT Assay) using Caco-2 cell line model confirmed the bio-tolerability of DAR-inclusion complex. . The relative oral bioavailability of DAR in Albino rabbits resulted from Freeze dried inclusion complex was found 3.32 fold and 2.03 fold greater than plain DAR and marketed formulation, respectively which ultimately demonstrated the enhancement of oral bioavailability of DAR in freeze dried inclusion complex with HP-β-CD.

A stability-indicating HPLC method was developed and validated for the quantitative determination of diacerein in capsule dosage form. An isocratic separation was achieved using a C18, 250×4.6 mm, 5 µm particle size column with a flow rate of 1 ml/min and using a UV detector to monitor the eluent at 258 nm. The mobile phase consisted of Water: acetonitrile (70:30v/v). The drug was subjected to oxidation, hydrolysis, neutral, thermal and photolytic degradation. Diacerein was found to degrade under acidic, basic, oxidative, neutral and also dry heat condition. Complete separation of degraded products was achieved from the parent compound. All degradation products were eluted in an overall analytical run time of approximately 10 min with the parent compound diacerein eluting at approximately 6.44 min. The method was linear over the concentration range of 5-15 µg/ml (R2 = 0.999) with a limit of detection and quantitation of 0.0093 and 0.028 µg/ml respectively. The method has the requisite accuracy, selectivity, sensitivity, precision and can be used to assay diacerein in tablet. Degradation products resulting from the stress studies did not interfere with the detection of diacerein and the assay is thus stability-indicating.

  The present work describes the development of stability indicating assay method for Diacerein and Aceclofenac in their combined dosage form that would provide helpful information to the manufacturers. Stress studies were conducted on the drug substance and product under the ICH prescribed stress conditions viz. hydrolysis, oxidation, humidity, photolysis, thermal stress. The separation of the drug from its degradation products, trials were made by taking acetonitrile: water, acetonitrile: phosphate buffer, acetonitrile: phosphoric acid in various blends. Separation was achieved using C-18 column and a mobile phase comprising of Acetonitrile: Phosphoric acid 0.1 M (61: 39) at a flow rate of 1.5 mL/min. The detection wavelength was 260 nm. The drug showed sufficient decomposition under alkaline hydrolysis (0.05 N NaOH), acidic hydrolysis (0.05 N HCl), neutral hydrolysis (distilled water), and oxidative hydrolysis (6% H2O2). The drug was found to be moderately sensitive to humidity studies (75 % RH), photochemical studies (UV 254 nm), and thermal studies (600C). Recovery studies were also carried out for both the drugs and the mean percent recovery were found to be 100.69 for diacerein and 99.15 for aceclofenac. Mean percent estimation in marketed formulation gave 99.63% for diacerein and 100.04% for aceclofenac. The above method was validated for accuracy, precision, ruggedness, limit of detection, limit of quantitation and was found to be satisfactory for routine analysis of diacerein and aceclofenac in their combined dosage form in the presence of their degradation products.   Key words: Aceclofenac, Diacerein, Stress Degradation, Stability Indicating, Validation