The Application of Resonance Light Scattering Technique for the Determination of Tinidazole in Drugs

Abstract

Abstract:The acid-base dissociation constant (pK a ) of a drug is a key physicochemical parameter infl uencing many biopharmaceutical characteristics. While this has been well established, the overall proportion of non-ionizable and ionizable compounds for drug-like substances is not well known. Even less well known is the overall distribution of acid and base pK a values. The current study has reviewed the literature with regard to both the proportion of ionizable substances and pK a distributions. Further to this a set of 582 drugs with associated pK a data was thoroughly examined to provide a representative set of observations. This was further enhanced by delineating the compounds into CNS and non-CNS drugs to investigate where differences exist. Interestingly, the distribution of pK a values for single acids differed remarkably between CNS and non-CNS substances with only one CNS compound having an acid pK a below 6.1. The distribution of basic substances in the CNS set also showed a marked cut off with no compounds having a pK a above 10.5. The pK a distributions of drugs are infl uenced by two main drivers. The fi rst is related to the nature and frequency of occurrence of the functional groups that are commonly observed in pharmaceuticals and the typical range of pK a values they span. The other factor concerns the biological targets these compounds are designed to hit. For example, many CNS targets are based on seven transmembrane G protein-coupled receptors (7TM GPCR) which have a key aspartic acid residue known to interact with most ligands. As a consequence, amines are mostly present in the ligands that target 7TM GPCR's and this infl uences the pK a profi le of drugs containing basic groups. For larger screening collections of compounds, synthetic chemistry and the working practices of the chemists themselves can infl uence the proportion of ionizable compounds and consequent pK a distributions. The fi ndings from this study expand on current wisdom in pK a research and have implications for discovery research with regard to the composition of corporate databases and collections of screening compounds. Rough guidelines have been suggested for the profi le of compound collections and will evolve as this research area is expanded.

Determining potential adverse effects in marine fish exposed to pharmaceuticals and personal care products with the fish plasma model and whole-body tissue concentrations

“…One study estimated that 63 – 95% of the commercially available drugs are ionizable (Manallack 2007). Consequently, this is an important factor for QSARs when predicting bioaccumulation and hence toxicity.…”

The impact of hypoxia on tumor-associated macrophages

“…From a therapeutic point of view, an inoperable vascular network limits the response to irradiation and reduces the efficacy of chemotherapeutics through different mechanisms such as insufficient distribution of the drug or a decrease in therapeutic cytotoxicity due to low oxygen levels, and/or the presence of a more acidic microenvironment (38)(39)(40).…”

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

“…pH and the drug pK a are crucial for determination of the ionization state and will significantly influence drug transport. As most drugs are weak acids and/ or bases, knowledge of the dissociation constant can help in understanding the ionic form a compound will take across a range of pH values (Manallack 2008). This is especially crucial in physiological systems where ionization state will influence the rate at which the molecule is able to diffuse across membranes and obstacles such as the blood-brain barrier (BBB) (Manallack 2008).…”

“…As most drugs are weak acids and/ or bases, knowledge of the dissociation constant can help in understanding the ionic form a compound will take across a range of pH values (Manallack 2008). This is especially crucial in physiological systems where ionization state will influence the rate at which the molecule is able to diffuse across membranes and obstacles such as the blood-brain barrier (BBB) (Manallack 2008). The pK a of a drug affects lipophilicity, solubility, protein binding and permeability which-as a consequence-directly influences pharmacokinetic (PK) features, like absorption, distribution, metabolism, and excretion (ADME) (Manallack 2008).…”