Alfaxalone: Effect of Temperature on Complexation with 2-Hydroxypropyl-β-cyclodextrin

Phase solubility analysis is used to investigate the complex formation of alfaxalone with various cyclodextrins(2-hydroxypropyl--cyclodextrine [HPBCD],-cyclodextrin [BCD] and2-hydroxypropyl--cyclodextrin [HPGCD]).The complexationwith HPBCD was studied in more detail by looking at the effect of temperature on the stability constants using phase solubility analysis. HPLC-analysis was used to measure the dissolved amount of alfaxalone.The solubility of alfaxalone increases linearly with increasing concentration of cyclodextrin, suggesting the formation of a 1 : 1 complex. For the parent BCD the complex starts precipitating out of solution when the solubilizer concentration exceeds 0.25% making the unsubstituted BCD less useful for the preparation of solutions of alfaxalone. Substituted cyclodextrins do not form insoluble complexes with alfaxalone. The complexation constant for BCD and HPBCD are comparable in magnitude, but for HPGCD, the constant is substantially lower.The effect of temperature on thecomplexation constant was also studied at elevated temperature. Increasing the temperature results in an increased S₀ (solubility without HPBCD) and a decrease in the value of the complexation constant. The net effect results in minor changes of the solubility of alfaxalone as a function of temperature. Based on regression analysis, the change in enthalpy for complex formation between alfaxalone and HPBCD is calculated as -4610 cal/mol.The results indicate that substitutedcyclodextrins are useful in the preparation of solutions of alfaxalone. Since 1 : 1 complexes are formed there is no theoretical danger for precipitation on dilution, e.g., after injection.     

A Novel Cyclodextrin-containing Glass Thermoplastic System (GTS) for Formulating Poorly Water Soluble Drug Candidates: Preclinical and Clinical Results

We present a novel solid solution/dispersion technology with glass thermoplastic properties that provide good dissolution rates and oral bioavailabilities for poorly water-soluble weak bases. In this process, a thermoplastic gum was prepared by mixing a polyhydroxy acid such as citric acid or tartaric acid with a weakly basic drug, hydroxypropyl--cyclodextrin (HP--CD) and a cellulose polymer such as hydroxypropylmethylcellulose (HPMC) in a protic solvent. Removal of the solvent gave a material which could be loaded into hard gelatin capsules. Several model compounds were processed in this manner including methylene blue and itraconazole. The resulting data indicated that dissolution properties of GTS's based on methylene blue was pH independent and rapid with 80% dissolved within 30 min. Three GTS formulations of itraconazole containing 100 mg of the drug and 500 mg of citric acid as well as various concentrations of HP--CD and HMPC were found to dissolve rapidly (100% in 45 min). One of these formulations was selected for human pharmacokinetic evaluation and demonstrated significant oral bioavailability relative to unmanipulated drug.The studies suggest that the components of the GTS provide for solubilization through complexation and reduced pH and that the cellulose polymer acts to inhibit recrystallization of the supersaturated solution formed. The rationaldevelopment of the GTS dosage form can be useful for generating acceptable formulations for poorly water-soluble drug candidates.     

On the p-Ranks of the Adjacency Matrices of Distance-Regular Graphs

Let be a distance-regular graph with adjacency matrix A. Let I be the identity matrix and J the all-1 matrix. Let p be a prime. We study the p-rank of the matrices A + bJ – cI for integral b, c and the p-rank of corresponding matrices of graphs cospectral with .Using the minimal polynomial of A and the theory of Smith normal forms we first determine which p-ranks of A follow directly from the spectrum and which, in general, do not. For the p-ranks that are not determined by the spectrum (the so-called relevant p-ranks) of A the actual structure of the graph can play a rôle, which means that these p-ranks can be used to distinguish between cospectral graphs.We study the relevant p-ranks for some classes of distance-regular graphs and try to characterize distance-regular graphs by their spectrum and some relevant p-rank.     

Finite element solution of the incompressible Navier-Stokes equations by a Helmholtz velocity decomposition

Finite element solution methods for the incompressible Navier-Stokes equations in primitive variables form are presented. To provide the necessary coupling and enhance stability, a dissipation in the form of a pressure Laplacian is introduced into the continuity equation. The recasting of the problem in terms of pressure and an auxiliary velocity demonstrates how the error introduced by the pressure dissipation can be totally eliminated while retaining its stabilizing properties. The method can also be formally interpreted as a Helmholtz decomposition of the velocity vector. The governing equations are discretized by a Galerkin weighted residual method and, because of the modification to the continuity equation, equal interpolations for all the unknowns are permitted. Newton linearization is used and at each iteration the linear algebraic system is solved by a direct solver. Convergence of the algorithm is shown to be very rapid. Results are presented for two-dimensional flows in various geometries.     

Mechanism of the catalytic oxidation of hydrocarbons by N-hydroxyphthalimide: a theoretical study

The mechanism of the recently proposed catalytic oxidation of hydrocarbons by oxygen in the presence of N-hydroxyphthalimide (NHPI) was established by quantum chemical calculations, consistent with experiments.     

Holographic dynamics of unstable branes in AdS

The gauge theory dual to the decay of an unstable D-particle in AdS is analysed in terms of coherent states. We discuss in detail how to count the number of particles in the decay product. We find, in agreement with the analysis in flat space, that the emission amplitude is suppressed as the mass of the radiated particles increases. To cite this article: M. Zamaklar, K. Peeters, C. R. Physique 5 (2004).

Résumé

La théorie de jauge duale à la désintégration de D-particules instables dans AdS est analysée en termes d'état cohérents. Nous discutons en détails le comptage du nombre de particule dans le produit de désintégration. Nous trouvons, en accord avec l'analyse en espace plat, que le taux d'émission est supprimé quand la masse de la particule augmente. Pour citer cet article : M. Zamaklar, K. Peeters, C. R. Physique 5 (2004).     

Mesoscopic field and current compensator based on a hybrid superconductor-ferromagnet structure

A rather general enhancement of superconductivity is demonstrated in a hybrid structure consisting of a submicron superconducting (SC) sample combined with an in-plane ferromagnet (FM). The superconducting state resists much higher applied magnetic fields for both perpendicular polarities, as the applied field is screened by the FM. In addition, FM induces (in the perpendicular direction to its moment) two opposite currents in the SC plane, under and aside the magnet, respectively. Because of the compensation effects, superconductivity persists up to higher applied currents. With increasing current, the sample undergoes SC-"resistive"-normal state transitions through a mixture of vortex-antivortex and phase-slip phenomena.     

Experimental study of trapped-electron-mode properties in tokamaks: threshold and stabilization by collisions

Trapped electron modes are one of the candidates to explain turbulence driven electron heat transport observed in tokamaks. This instability has two characteristics: a threshold in normalized gradient and stabilization by collisions. Experiments using modulated electron cyclotron heating in the ASDEX Upgrade tokamak demonstrate explicitly the existence of the threshold. The stabilization with increasing collisionality is evidenced by a strong decrease of the propagation of heat pulses, explained by a transition to ion temperature gradient driven transport. These results are supported by linear gyrokinetic calculations.