Physicochemical properties benzoic acids

The next step in the development of the extrathermodynamic approach was to find a suitable expression for the equilibrium constant in terms of physicochemical and conformational (steric) properties of the drug. Use was made of a physicochemical interpretation of the dissociation constants of substituted aromatic acids in terms of the electronic properties of the substituents. This approach had already been introduced by Hammett in 1940 [14]. The Hammett equation relates the dissociation constant of a substituted benzoic acid (e.g. meta-chlorobenzoic acid) to the so-called Hammett electronic parameter a ... 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

At the time that the basic formulation and testing of the mathematical models of quantitative structure-activity correlations were being made, another type of approach, the linear free-energy related model, was introduced (2). Using the basic Hammett equation (22, 36) for the chemical reactions of benzoic acid derivatives (Equation 12), several investigators attempted quantitative correlations between physicochemical properties... 

CoMFA and related 3D QSAR approaches have been applied to correlate various physicochemical properties. Equilibrium constants of the hydration of carbonyl groups could be explained by a combination of C=0 bond order, steric, and electrostatic fields [1005]. 3D QSAR studies that correlate a, inductive, and resonance parameters of benzoic acids [1015, 1016] as well as pKg values ofclonidine analogs [1017] show that a H " field precisely describes such electronic parameters, e.g. (Jm.p of benzoic acids (n = 49 rpir = 0.976 snr = 0.082 Spress = 0.093). Steric parameters of benzoic acids, like surface area and van der Waals volume can be described by a steric field alone, while values of acetic acid methyl esters need a combination of both steric and electrostatic fields (n = 21 rpix = 0.984 Sfit = 0.133 SpREss = 0.209) [1016]. 

Reference materials for combustion calorimetry have been recommended by the lUPAC Commission Physicochemical Measurements and Standards [130-132] and by the ICTAC Thermochemistry Working Group [133]. They are classified as primary, secondary and tertiary reference materials and when their properties are certified by a national or international organization, agency or laboratory authorized they are called certified reference materials . For combustion calorimetry, the recommended reference materials must be selected according to the atoms in the molecule and its physical state [133] benzoic acid (C,H,0, cr, primary), succinic acid (C,H,0, cr, secondary), hippuric acid (C,H,0,N, cr, tertiary), acetanilide (C,H,0,N, cr, secondary), nicotinic acid (C,H,0,N, cr, tertiary), 1,2,4-triazole (C,H,0,N, cr, secondary)[134], urea (C,H,0,N, cr, tertiary), thiantrene (C,H,0,S, cr, secodary), 4-fluorobenzoic acid (C,H,0,F, cr, secondary), pentafluorobenzoic acid (C,H,0,F1, cr, tertiary), 4-chorobenzoic acid (C,H,0,C1, cr, secondary), 4-bromobenzoic acid (C,H,0,Br, cr, tertiary), 4-iodobenzoic acid (C,H,0,I, cr, tertiary), triphenylphosphine oxide... 

Fig. 4.10. Scores plot for a set of benzoic acids described by seven physicochemical properties. Compounds are metabolized by the formation of glucuronide conjugates (squares) or glycine conjugates (circles) and two test set compounds are shown (triangles).

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