Drug substances dissociation constant

Generally, to produce a biological response, a drug molecule must first cross at least one biological membrane. The biological membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble substances by passive diffusion while lipid-insoluble substances can diffuse if at all across the barrier only with considerable difficulty. The interrelationship of the dissociation constant, lipid solubility, and pH at the absorption site and absorption characteristics of various drugs are the basis of the pH-partition theory. 

Information on chemical structure, molecular weight, nature of the drug substance (acid, base, amphoteric, or neutral), and dissociation constants (pKa(s))... 

In this dilemma of contradicting interests, COSMO-RS can be a valuable tool for the computational characterization of the solubility behavior of the drug candidate as well as of its dissociation constants. Both are of crucial interest since the small and very expensive amount of compound has to be dissolved and embedded in different solvents and environments for the various steps of purification, crystallization, analysis, and formulation. At present, empirical solubility parameter approaches are often used in order to classify and predict the solubility behavior of the new drug, but despite their poor physical foundation, they have the additional disadvantage that the experimental measurement of the solubility parameters of the new drug consumes time and compound. In contrast, the required DFT/COSMO calculations can be started before the compounds come to the development laboratory, and a COSMO-RS solubility and dissociation screening can be completed—even at optimal computational level— when the work in the development department starts. Furthermore, none of the valuable substance is wasted in this step. 

The active site structure of trypsin-like enzymes is considered to be very similar to that of bovine trypsin, yet little is known about them. Refinement of these structures is important also for the purpose of designing physiologically active substances. With a view to comparing the spatial requirements of active sites of these enzymes, dissociation constants of the acyl enzyme-ligand complex, K-, which were defined before, were successfully analyzed By taking advantage of inverse substrates which have an unlimited choice of the acyl component, development of stable acyl enzymes could be possible. These transient inhibitors for trypsin-like enzymes could be candidates for drugs. In this respect, the determination of the deacylation rate constants for the plasmin- and thrombin-catalyzed hydrolyses of various esters were undertaken 77). 

A search [10] of the World Drug Index revealed that 62.5% of marketed drugs are ionizable, which implies that these substances can exist in various charged states depending on the pH of the media. For ionizable drugs, solubility is pH dependent, and it is therefore important to understand the solubility in the context of pH. Ionization of a compound can be defined by the acid dissociation constant, p/C,. For the case of monoprotic compounds, the solubility at a given pH can be described by the following equations ... 

The acidity or basicity of a drug substance is defined by the dissociation constant K, which is the equilibrium constant, more conveniently represented by its logarithmic parameter pK, reflecting the degree of ionization of a substance at a particular pH and described by the Henderson-Hasselbalch equations (37.2) and (37.3). ... 

In the context of drug-like substances, hydrophobicity is related to absorption, bioavailability, hydrophobic drug-receptor interactions, metabolism and toxicity. Closely related to log P is the octanol-water distribution coefficient (logDpn), accounting for partition of pH-dependent mixture of ionizable species. Ionization of any compound makes it more water soluble and then less lipophilic. The log D can be calculated from log Pand acid dissociation constant pJC, by the following expression [Cronin, Aptula et al, 2002b Livingstone, 2003] ... 

Degradation rates of drug substances are generally affected by pH because most degradation pathways are catalyzed by hydronium and/or hydroxide ions. Water itself is also a critical reactant. If the critical path in a reaction involves a proton transfer or abstraction step, other acids and bases present in solution (usually buffer species) can affect the reaction rate. These reactions will also be pH-dependent because the fraction of any species present in its acid or base form will be dependent on its dissociation constant and the solution pH. Also, for ionizable drugs, the fraction of drug present in any particular form will depend on the solution pH. Therefore, if the reactivity of the drug depends on its form, its reactivity will be pH-dependent. 

The lUPAC dissociation constant compilations [9-12] are not focused on drug substances, although they do include some pharmaceuticals, such as morphine and other opiates, acetanilide, some barbiturates, vitamins, antibiotics, and alkaloids. In a sense, this is a limitation of these compilations. A set of cross-referencing indexes to these compilations would be a useful tool. 

Fig. 12. Theoretical dose-response relations for one-receptor and two-receptor substances. On left Abscissa concentrations of drug [A] with corresponding pDg values. Lower halves of one-receptor dose-response curves for substances with various dissociation constants (K ) of the drug-receptor complex. Reaction course calculated in accordance with Ariens s (1954) equation. On...

The pK value indicates the pH range in which the dissociation of the H" occurs. More specifically, the pK is the pH at which the group is 50% dissociated, or half of it is in the acid form and half in the base form. These values of pK are used in determining the net charge a substance (amino acid, protein, drug) will have in the body and which ones will act as good buffers to keep the pH constant, and to understand pathologic states of acidosis and alkalosis. 

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