Ionization constant, drugs

This chapter considers ionizable drug-Uke molecules and the effect of such ionization on pharmaceutic properties. Most medicinal substances are ionizable [1]. The biological medium into which these substances distribute embraces a range of pH values. The ionization constant, pK, can teU the pharmaceutical scientist to what degree the molecule is charged in solution at a particular pH. This is important to know, since the charge state of the molecule strongly influences its other physicochemical properties. 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

The blue book compilations [154-158] are probably the most comprehensive sources of ionization constants collected from the literature (up to the end of 1970s). These are recommended for experts in the field. On the other hand, the red books contain critically selected values [159]. The six-volume set has been put into electronic form in cooperation with NIST (National Institute of Standards and Technology), and is available at a very reasonable price [160]. A two-volume set of critically determined constants is available from Sirius Analytical Instalments Ltd., and covers molecules of particular interest to the pharmaceutical community [161,162]. In Section 3.8 at the end of this chapter, a list of gold standard pKa values of mostly drug-like molecules is presented (see Table 3.1), with many of the values determined by the author since the early 1970s. 

Morgan, M. E. Liu, K. Anderson, B. D., Microscale titrimetric and spectrophotometric methods for determination of ionization constants and partition coefficients of new drug candidates, J. Pharm. Sci. 87, 238-245 (1998). 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Even for experimentally simple systems, a quantitative understanding of the dissolution of ionizable drugs is possible only if drug solubility, drug ionization constant, buffer concentration, buffer species, and buffer pH are known. 

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

The proportion of the total drug concentration that is present in either ionized or un-ionized form is dictated by the drug s dissociation or ionization constant (K) and the local pH of the solution in which the drug is dissolved. 

Table 1-3 Ionization Constants of Some Common Drugs. ...

Simultaneous Determination of the Ionization Constant and the Solubility of Sparingly Soluble Drug Substances 225... 

Knowledge ofthe aqueous ionization constant,pof an ionizable drug candidate is very important because it can be used to predict solubility, lipophilicity, and permeability at different pH therefore, it... 

The effect of various surfactants, the cationics-eetyl trimethyl ammonium bromide (CTAB), and cetyl pyridinium chloride (CPC), the anionic-sodium lauryl sulfate (SLS), and the nonionic-polysorbate 80 (Tween 80), on the solubility and ionization constants of some sparingly soluble weak acids of pharmaceutical interest was studied (Gerakis et al., 1993). Benzoic acid (and its 3-methyl-, 3-nitro-, and 4-tert-butyl-derivatives), acetylsalicylic acid, naproxen, and iopanoic acid were chosen as model drugs. The cationics, CTAB and CPC, were found to considerably increase th< ionization constant of the weak acidS Ka ranged from-0.21 to-3.57), while the anionic, SLS, showed a negligible effect and the nonionic, Tween 80, generally decreased the ionization constants Solubility of the acids increased in aqueous micellar and in acidiLed micellar solutions. 

Tab. 2.4 Partition coefficients and ionization constants of the eight ionizable drugs measured in the systems octanol-water and DPOC-water using the pH-metric technique (literature values are printed in italics). (Adapted from Table 1 of ref. 43)...

The ionization constants for selected pharmaceutical drugs and reference weak acids and weak bases are listed in Table 2.1. 

Ionization Constants for Drugs and Weak Acids and Bases... 

Recently, microconstant measurements have been validated for 25 drug molecules, based primarily on multiwavelength spectroscopy. The apphed methodologies, however, are difficult and limited up to triprotic molecules when no symmetry constraints are present.In more complex cases, the microspecies resolution is still possible by applying some in silico methods for predicting ionization constants. 

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

These are only the theoretical dependencies real behavior of actual molecule usually is significantly altered due to different types of intermolecular interactions. Molecular solvation, association, hydrogen bonding, and counterions all have a significant effect on drug ionization constant and partitioning and distribution coefficients. Detailed and comprehensive discussion of these effects could be found in the book by Avdeef [22]. 

An evaluation of the effect of pH on the aqueous solubility of a drug substance is an essential component of preformulation research, and such work is usually conducted along with determinations of ionization constants, solubilization mechanisms, and dissolution rates. ° Methods for the determination of the solubility... 

Many drugs have ionizable groups at physiological pH. Therefore ionization constants (p/fj are important properties for medicinal chemists to modulate properties they influence such as lipophilicity and solubility which in turn affect absorption and distribution. The presence of charged groups may also be essential for activity against certain targets. 

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