Diazepam solubilization

Diazepam As mentioned earlier, because of shortcomings of rectal administration, the nasal delivery of diazepam has gained interest. The nasal bioavailability of diazepam in sheep was estimated and further compared with results obtained earlier in humans and rabbits [106] in this study, human and rabbit nasal bioavailability for the first 30min was reported to be 37 and 54%, respectively [113]. Diazepam solubilized in PEG 300 was used for nasal administration via a modified nasal device, a Pfeiffer unit dose (Princeton, NJ). The sheep received the nasal formulations in a fixed standing position such that the head was slightly tilted back. It was found that the serum concentration after administration of a 7-mg solution of diazepam was... 

Kraus, C. Mehnert, W. Eroemming, K.H. Interactions of P-cyclodextrin with solutol HS 15 and their influence on diazepam solubilization. PZ Wiss. 1991, 4 (1), 11-15. 

Rubino, J.T., Blanchard, J., and Yalkowsky, S.H. Solubilization by cosolvents IV benzocaine, diazepam and phenytoin in aprotic cosolvamiter mixturesj. Parent. Sci. Technpl41, 172-176,... 

Rosoff, M., and A. T. M. Serajuddin. 1980. Solubilization of diazepam in bile salts and in sodium cholate-lecithin-water phaseint. J. Pharm.6 137-146. 

Solubilizing Capacities and Partition Coefficients of Diazepam as a Function of Temperature... 

Lin and Yang (1987) also calculated the thermodynamic parameters of diazepam for micellar solubilization in Pluronic surfactant solutions at different temperatures (Table 13.4). For all systems, AG was negative, indicating micellar solubilization was spontaneous. The sign of entropy has been associated with the location of solubilized molecules within the micelles. Positive values have been observed for molecules embedded in the micelle center and negative values for adsorption of the molecules on the micelle surface. The results in this paper indicate that in the F-108 and F-88 Pluronics, diazepam molecules can penetrate into the micelle interior, whereas for F-68 and lower concentrations of F-88, diazepam is adsorbed on the micelle surface without penetration into the micellar core. 

Thermodynamic Parameters for the Solubilization of Diazepam by Pluronic Surfactants... 

Various drugs, for example, diazepam and indomethacin, doxorubicin, anthracy-cline antibiotics, and polynucleotides, were effectively solubilized in polymeric micelles. Also polymeric micelles can carry various reporter (contrast) groups and... 

Although diazepam has a high bioavailability after oral administration (approaching 100%), it is administered in equine practice primarily by the i.v. route. Because of its low water solubility, diazepam is solubilized in propylene glycol for injection. The bioavailability of this formulation is poor after i.m. administration and diazepam is not recommended for i.m. use. When i.m. administration of a benzodiazepine is desired, the more water-soluble agent midazolam is recommended. In contrast to diazepam, midazolam has a poor oral bioavailability (42%) because of its high hepatic clearance and first-pass metabolism. Zolazepam, in combination with tiletamine, can also be administered i.m. 

In the search for water-soluble derivatives of the tranquillizer and anticonvulsant diazepam, scientists from Roche imagined an original solubilization approach, based on the attachment of a basic side chain to the ring-opened diazepam molecule (Figure 38.17). 

Rubino JT, Yalkowsky SH. Solubilization by cosolvents. Part 3. Diazepam and benzocaine in binary solvents. Bull Parenteral Drug Assoc 1985 39 106-111. 

Bile salts such as sodium cholate, taurocholate and glycocholate form micelles in solution. Long chain phosphotidyl choline may be added and the phospholipid molecules, although for geometric reasons they do not form micelles on their own, can be incorporated into the bile acid micelles. These so-called mixed micelles are relatively well tolerated when injected intravenously. They have been used to solubilize water-insoluble vitamins and other slightly soluble pharmaceuticals, such as diazepam. 

Propylene glycol and 20 % Cremophor EL have been compared as vehicles for diazepam [170] in view of the number of reports of thrombophlebitis associated with intravenous diazepam. The Cremophor vehicle caused significantly less postinjection thrombophlebitis possibly because it prevents the precipitation of the drug substance at the site of injection by its solubilizing effect. Ease of injection... 

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