The effect of ternary complexation of naproxen, a poorly water soluble anti-inflammatory drug, with hydroxypropyl-beta-cyclodextrin and the basic aminoacid L-arginine on the drug dissolution properties has been investigated. Equimolar binary (drug-cyclodextrin or drug-arginine) and ternary (drug-cyclodextrin-arginine) systems were prepared by blending, cogrinding, coevaporation, and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry. The dissolution behavior of naproxen from the different products was evaluated by means of a continuous flow through method. The results of solid state studies indicated the presence of strong interactions between the components in ternary coevaporated and coground systems, which were both of totally amorphous nature. In contrast, the presence of either free drug or free arginine was detected when the third component (cyclodextrin or aminoacid) was physically mixed, respectively, to the drug-arginine binary system (as physical mixture, coevaporate, or coground product) or to the drug-cyclodextrin binary system (as physical mixture, coevaporate, or coground product). All ternary combinations were significantly (P<0.001) more effective than the corresponding binary drug-cyclodextrin and drug-arginine systems in improving the naproxen dissolution rate. The best performance in this respect was given by the ternary coevaporate, with about 15 times increase in terms of both drug relative dissolution rate and dissolution efficiency. The synergistic effect of the simultaneous use of arginine and cyclodextrin on the dissolution rate of naproxen was attributed to the combined effects of inclusion in cyclodextrin and salt formation, as well as to a specific role played by arginine in this interaction.
At >200 K photolysis of
1-(2-azidophenyl)-3,5-dimethylpyrazole (5) gives
1,3-dimethylpyrazolobenzotriazole (6, by electrophilic cyclization of singlet nitrene
1
4) or, in the presence of diethylamine,
aminoazepine 8 (by
addition of the nucleophile and rearrangement). At lower
temperatures, the yield of these products decreases and
the azo derivative 9 (from the dimerization of triplet
nitrene 3
4) as well as products from
intramolecular radical
cyclization (again via 3
4) is obtained, to
become the only products at <100 K. Differential thermodynamic
parameters
for the reactions of 1
4 and 3
4
are determined by analysis of the temperature dependence of
products distribution
(ΔΔH
⧧ = −10 kJ mol-1 and
ΔΔS
⧧ = 34 J mol-1
K-1 in ethanol). Addition of the amine may require
previous ring
enlargement to give the dehydroazepine 12; there is no
indication that this is an intermediate of any stability,
however,
and if formed, this is in equilibrium with 1
4.
Triplet nitrene 3
4 is characterized in
matrix by UV spectroscopy, and
its photoreactions (to give mainly intramolecular hydrogen abstraction)
are separately studied.
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