Physicochemical Properties of Substances

Step 4 Consider the anatomical and physiological aspects of the routes of exposure, and the physicochemical properties of substance... 

Usually two or three different tests in bacteria and mammalian cells are selected to cover the endpoints of gene mutations, clastogenicity (structural chromosome aberrations), and aneuploidy (numerical chromosome aberrations), taking into account physicochemical properties of substances under consideration (see Chapter 11). 

Sergey Serafimovich Berdonosov, Dr. Sci. was born in 1939 in Moscow, Russia. He was a gold medalist at school in 1956 and received an excellence diploma from Moscow State University in 1961. His PhD thesis, defended in 1964, was dedicated to zirconium, hafnium, niobium, tantalum, and protactinium bromides, and his Dr. Sci. thesis (2002) was devoted to the radiochemical studies of desublimation and new approaches to the determination of physicochemical properties of substances and materials. 

However, changes in the type of bond can also be followed by studying the physicochemical properties of compounds. Much work has recently been carried out on this problem. There are many relationships between the physicochemical properties of substances and the types of chem-... 

This is also a very useful verification of the accuracy of the derivation and coding of each of the models. Both models are fairly complex, and the model equations are solved using different numerical techniques. The models also use different, independently validated parametrizations for the physicochemical properties of substances, in particular for the properties of the mixtures of ammonia and water in liquid phase. 

Very few data exist on the physicochemical properties of these substances. The stability of 2-azaadenine against hydrolysis with hot hydrochloric acid and on the formation of silver salts have been mentioned furthermore, their UV spectra have been published without detailed interpretation. ... 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

JI Wells. Pharmaceutical Preformulation The Physicochemical Properties of Drug Substances. Chichester, England Ellis Horwood LTD, 1988, pp 209-210. 

Kimura, Y. Hosoda, Y. Shima, M. Adachi, S. Matsuno, R., Physicochemical properties of fatty acids for assessing the threshold concentration to enhance the absorption of a hydrophilic substance, Biosci. Biotechnol. Biochem. 62, 443 447 (1998). 

Orally administered dosage forms are absorbed into the systemic circulation following dissolution in the GI tract. Because substances must be in solution for the absorption from the GI lumen, the absorption rate of poorly water-soluble drugs is limited by their rate of dissolution. The dissolution rate is affected by the unique physicochemical properties of the drug and by physiological factors the pH, composition, and hydrodynamics of the GI medium. 

J. I. Wells, Pharmaecutical Preformulation. The Physicochemical Properties of Drug Substances, Halsted Press, New York, 1988. 

The properties of substances can sometimes be assessed on a case-by-case basis using the read-across approach. The properties of a substance are predicted from data on close chemical analogues with similar physicochemical properties. Similar biological properties are anticipated, since toxicokinetics, in particular... 

The physicochemical properties of a drag substance must be known and well characterized (e.g., solubility, acidic constant (pKa), distribution coefficient in octanol water (logP value), pH-dependent distribution coefficient (logD), and its physical state, e.g., morphology or salt stochiometry — if the drag forms a pharmaceutical salt). 

Dose levels in vitro As for in vivo studies, it is necessary to establish a concentration-effect relationship. The upper limit of concentrations tested may be influenced by physicochemical properties of the test substance and other factors such as cytotoxicity. 

Part II starts with the possibilities of ACE for characterizing the relevant physicochemical properties of drugs such as lipophilicity/hydrophilicity as well as thermodynamic parameters such as enthalpy of solubilization. This part also characterizes interactions between pharmaceutical excipients such as amphiphilic substances (below CMC) and cyclodextrins, which are of interest for influencing the bioavailability of drugs from pharmaceutical formulations. The same holds for interactions of drugs with pharmaceutical vehicle systems such as micelles, microemulsions, and liposomes. 

For experimental studies of mixtmes, consideration is given to the possibility of changes in the physicochemical properties of the test substance during collection, storage, extraction, concentration and delivery. Chemical and toxicological interactions of the components of mixtmes may result in nonlinear dose-response relationships. 

The physicochemical characteristics of raw materials play an important role in content uniformity and bioavailability. Therefore, bioavailability of the drug over time must be thoroughly investigated before any significant changes are made. Once the physicochemical properties of drug substances (e.g., particle size of raw materials) can influence the availability and clinical effect of a product, the main characteristics of raw materials should be considered in a validation program. The... 

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