SYNTHESIS AND EVALUATION OF OLMESARTAN MEDOXOMIL COMPLEX WITH SBE7 β-CD FOR ENHANCED DISSOLUTION AND BIOAVAILABILITY

Objective: Olmesartan is a BCS class II anti-hypertensive drug with limitations of low aqueous solubility and bioavailability. ­­Present work was designed to use complexation as an approach to explore the ability of modified cyclodextrin such as sulphobutyl ether7 β-cyclodextrin (SBE7β-CD) to develop an inclusion complex with poorly soluble olmesartan medoxomil (OLM) for improving its dissolution rate and relative bioavailability.Methods: Inclusion complexes were prepared by different techniques of physical mixing, kneading and lyophilisation. Prepared complexes were characterized by differential scanning calorimetry (DSC), powder x-ray diffractometry (X-RPD), proton nuclear magnetic spectroscopy (1H NMR) and fourier transforms infrared spectroscopy (FT-IR). Molecular interaction and encapsulation in an inclusion complex at the molecular level were considered using docking chemistry. Results: Phase solubility analysis revealed 13 fold increase in aqueous solubility with stability constant Ks=249 M−1at 1:1 stoichiometry of complexation. DSC and XPRD confirmed the reduction of crystallinity in complexes with improved solubility. 1H NMR and FT-IR studies depicted the interaction among functional groups with varied hydrogen shifts confirmed by molecular modelling. Dissolution studies of complexes have shown an improved dissolution rate when compared to plain OLM. Pharmacokinetic profile of OLM/SBE7β-CD has shown a significant enhancement in the relative bioavailability.Conclusion: SBE7β-CD may be successfully used as a carrier for the oral administration of OLM with enhanced bioavailability subjected to future scale up.Â

Validated HPLC method for quantification of copanlisib in mice plasma: application to a pharmacokinetic study

Copanlisib is a pan phosphatidylinositol 3-kinase (PI3K) inhibitor approved for follicular lymphoma. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of copanlisib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of copanlisib along with internal standard (IS, enasidenib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic resolution of copanlisib and the IS was achieved on a Hypersil Gold C18 column maintained at 40 °C using a binary gradient mobile phase [10 mM ammonium formate (pH 4.0) and acetonitrile]. The flow-rate was 0.8 mL/min. For the detection of copanlisib and the IS, the photo-diode array detector was set at λmax 310 nm. Copanlisib and the IS eluted at 6.60 and 7.80 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 50 to 5000 ng/mL for copanlisib (r2 0.998). The results of intra- and inter-day accuracy and precision studies were within the acceptable limits. Copanlisib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycle and long-term storage at -80 °C. The application of the validated method was shown in a mice pharmacokinetic study