betadex and apaziquone

For the development of a bladder instillation of the indoloquinone agent EO-9, use of the complexing agent 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) was considered. Therefore, a complexation study of EO-9 with HPbetaCD was performed. Complexation was studied in aqueous solution and in solid freeze-dried products. A phase solubility study, UV-visible spectroscopy (UV/VIS), and analysis of the effect of HPbetaD on the stability of EO-9 were performed. With the phase solubility study, a complexation constant (K1:1) of 32.9, a complexation efficiency (CE) of 0.0457, and a utility number (UCD) of 38.3 were calculated. These K1:1 and CE values indicate a weak complex, but the UCD shows that HPbetaCD can be very useful as solubilizer in the desired formulation. Furthermore, a positive effect of HPbetaCD on the chemical stability of EO-9 in solution was seen. Subsequently, complexation in the freeze-dried products was studied more thoroughly using Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) analyses. HPbetaCD was found to be an excellent pharmaceutical complexing agent for application in formulations for EO-9 bladder instillations. Reconstitution before use of the developed freeze-dried products can be simply accomplished with water for injection.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antineoplastic Agents; Aziridines; beta-Cyclodextrins; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Drug Stability; Indolequinones; Microscopy, Electron, Scanning; Solubility; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Two new bladder instillations of the investigational anticancer agent EO-9 containing 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and the alkalizers sodium bicarbonate (NaHCO3) and tri(hydroxymethyl)aminomethane (Tris) were developed. During the stability study of these freeze-dried products, formation of new degradation products was seen. We have characterized these products by high performance liquid chromatography in combination with photodiode array detection and mass spectrometry. In total, five new degradation products were identified of which three were detected in both freeze-dried products and two only in the freeze-dried product composed of EO-9/HP beta CD/NaHCO3. Furthermore, the purity profile of two lots of EO-9 drug substance was investigated. Five, probably synthetic intermediates were found. However, the amount of total impurities was very small for both lots of drug substance and below acceptable international limits for pharmaceutical use.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antineoplastic Agents; Aziridines; beta-Cyclodextrins; Chromatography, High Pressure Liquid; Drug Stability; Excipients; Freeze Drying; Hydrogen-Ion Concentration; Indolequinones; Mass Spectrometry; Spectrophotometry, Ultraviolet