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Abstract. The solubilization efficiency of N-methyl pyrrolidone (NMP) has been determined and compared to that of ethanol and propylene glycol for 13 poorly soluble drugs. NMP is found to be a more efficient solubilizer for all the drugs studied. The solubility enhancement as high as about 800-fold is obtained in 20% v/v NMP solution as compared to water. The mechanism of drug solubilization by NMP has also been investigated. It is proposed that NMP enhances drug solubility by simultaneously acting as a cosolvent and a complexing agent. A mathematical model is used to estimate the drug solubility in NMP-water mixture, according to which the total solubility enhancement is a sum of the two effects. This model describes the experimental data well and is more accurate than other models. A large and uniform reduction in the surface tension of water as a function of NMP concentration demonstrates its cosolvent effect. The complexation is supported by the fact that it's strength is affected by the temperature and the polarity of the medium. A strong correlation exists between log K ow of the drugs and the cosolvency coefficients. The correlation between log K ow and the complexation coefficients is weak suggesting that factors such as molecular shape and aromaticity of the drug molecule are significant in determining the complexation strength. This has been confirmed by the absence of a significant complexation between NMP and linear drug-like solutes.

Bone alkaline (AlP) and acid phosphatase (AcP) activities were simultaneously demonstrated in tissue sections obtained from mice, rats, and humans. The method involved tissue fixation in ethanol, embedding in glycol methacrylate (GMA), and demonstration of AlP and AcP activities employing a simultaneous coupling azo dye technique using substituted naphthol phosphate as a substrate. AlP activity was demonstrated first followed by AcP activity. Both enzyme activities were demonstrated in tissue sections from bones fixed and/or stored in acetone or 70% ethanol for up to 14 days or stored in GMA for 2 months. AlP activity in tissue sections from bones fixed in 10% formalin, 2% glutaraldehyde, or formal-calcium, however, was markedly inhibited after 3-7 days and was no longer detectable after 14 days of fixation. Moreover, AlP activity was diminished in tissue sections from bones fixed in 70% ethanol or 10% formalin and subsequently demineralized in 10% EDTA (pH 7) for 2 days, and the activity was completely abolished in tissue sections from bones subsequently demineralized in 5% formic acid: 20% sodium citrate (1:1, pH 4.2) for 2 days. Methyl methacrylate (MMA) embedding at concentrations above 66% completely inhibited AlP activity. AcP activity, however, was only partially inhibited by formalin, glutaraldehyde, or formal-calcium after 7 or 14 days of fixation or by MMA embedding and was unaffected by the demineralizing agent formic acid-citrate for 2 days. While AcP activity was preserved in bones fixed in formalin and subsequently demineralized in EDTA, the activity was completely abolished when EDTA demineralization was carried out on bones previously fixed in 70% ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

A semiempirical model has been developed for the estimation of the normal boiling points of organic compounds. The normal boiling point is calculated as the ratio of the enthalpy of boiling to the entropy of boiling. Both these values are estimated independently using a combination of additive group contribution and nonadditive molecular descriptors. A group contribution model is proposed for the estimation of the enthalpy of boiling, based on the experimental data for 1322 structurally diverse organic compounds. The average absolute error associated with this estimation is 0.83 kJ/mol. A semiempirical model has been developed for the estimation of the entropy of boiling using experimental entropy data for the entire set. This model is a modification of Trouton's rule and takes into account the effect of hydrogen bonding and molecular flexibility. The average absolute error associated with this estimation is 4.7 J/(K mol). The average absolute error associated with the estimation of the normal boiling point, calculated as a ratio of the enthalpy of boiling to the entropy of boiling, for the entire data set is 9.3 K (2.3%). A good correlation is observed between the estimated and the experimental boiling points with an r 2 of 0.98. This model is easy to use, accurate, and applicable to a wide variety of organic compounds.

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An equation is developed for estimating the precipitation that may occur upon diluting or injecting a (pH-)solubilized drug formulation. Since it is based on equilibrium, it is the worst case scenario for precipitation. This equation can be programmed in any commercially available spread sheet program such as Excel. According to the proposed equation, the type and the strength of the buffer species are the most significant factors that affect the pH and solubility of a drug in its microenvironment during dilution. To demonstrate the utility and robustness of the proposed equation, experimental measurements were performed using phenytoin as the model drug. The result suggests that the proposed equation can be used to indicate the possibility and the degree of precipitation that would occur upon injection. This provides a useful tool for the design of a successful pH-controlled solution formulation.