Nanocrystal dispersion of DK-I-56-1, a poorly soluble pyrazoloquinolinone positive modulator of α6 GABAA receptors: Formulation approach toward improved in vivo performance.

DK-I-56-1 (7­methoxy­2-(4­methoxy­d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one), a recently developed deuterated pyrazoloquinolinone, has been recognized as a lead candidate for treatment of various neuropsychiatric disorders. During preclinical investigation of poorly water-soluble compounds such as DK-I-56-1, the application of nanotechnology could be advantageous due to improved safety and possibly increased bioavailability of nanosized formulation. DK-I-56-1 nanosuspensions stabilized by polysorbate 80, alone or in combination with poloxamers 188 i.e. 407 or d-α-tocopheryl polyethylene glycol 1000 succinate, were prepared using a small-scale media milling device. With particle size 208.7-250.6 nm and polydispersity index <0.250, selected nanodiseprsions were stable for three weeks. Pharmacokinetic and biodistribution studies following intraperitoneal administration of three types of formulation in mice indicated high plasma DK-I-56-1 levels after solution (10,228.6 ±â€¯1037.2 ngh/ml) and nanosuspension (6770.4 ±â€¯770.7 ngh/ml) but not suspension administration (966.0 ±â€¯58.1 ngh/ml). However, distribution of DK-I-56-1 after solution was heavily influenced by its composition, and brain availability of nanosuspension was superior to that of solution formulation. In spontaneous locomotor activity test, the expected hyperlocomotor effect was observed after nanosuspension administration, without compromising impact of the vehicle/excipients used. Therefore, nanonization of drug compound assembled with proper selection of stabilizers may seemingly contribute further thorough testing of DK-I-56-1 preclinical efficacy.

Influence of the organic complex concentration on adsorption of herbicide in organic modified montmorillonite.

This study was undertaken to determine the impact of the organic complex concentration on the adsorption of herbicide (acetochlor) at the surface of the organic modified montmorillonite. In this work, natural montmorillonite from Bogovina (Boljevac municipality, Serbia) was used for organic modification. Cation-exchange capacity of this montmorillonite was determined using a methylene blue method (86 mmol/100 g of clay). Montmorillonite has been modified first with NaCl and then with hexadecyltrimethylammonium bromide (HDTMA-bromide) organic complex. Saturation of cation exchange capacity (CEC) was 50%, 100%, and 150%. Changes in the properties of the inorganic and organic montmorillonite have been examined using the X-ray diffraction, Fourier transform infrared spectroscopy, and batch equilibrium method. Montmorillonite modified with HDTMA-bromide demonstrated higher uptake of the herbicide, compared to the inorganic montmorillonite. Comparing the values Freundlich coefficients in batch equilibrium method, it can be seen that the adsorption of acetochlor decreased in the series: 0.5 CEC HM > 1 CEC HM > 1.5 CEC HM > NaM.