**6. References**

62 Toxicity and Drug Testing

1990). However many researchers have criticized this equation for its thermodynamic analysis (Johnson and Dettre, 1989; Lee, 1993). Another approach is the geometrical methods for measuring surface tension of solids including Owen Wendt and van Oss theory. These methods decompose the surface tension into different components (Owens and Wendt, 1969; van Oss et al., 1986). Ahadian and colleagues compared the surface tension of 41 artificial solid surfaces as predicted by the equation of state and compared it to the values obtained by van Oss theory and Owen Wendt equation. Results indicate that equation of state was capable of good predictability, whereas the geometric methods are

Measurements of surface rheological characteristics are of great importance for the pharmaceutical industry. Many of pharmaceutical processes depend on the cohesive and adhesive interactions between the materials used during the preparation of the product. Understanding and determination of surface free energies of both liquid and solid surfaces plays a key role in characterization of materials during their development, formulation and manufacturing of pharmaceutical applications. The chemical activity, adsorption,

There are several experimental approaches that one can employ to evaluate interfacial tension and large differences can exist among measurement methods. While one method may be proven useful for a number of applications, there are several restrictions that detract from its applicability in a specific system. The choice of the method depends on the nature of the interface, the rheology of the liquid(s), the range of temperature and pressure, ease of analysis, accuracy, precision, surface age, cost and convenience of the probing instrument. Most equilibrium methods may be used to measure dynamic tension, and there are certain methods by which one can measure solely dynamic tension. Most methods involve measurement of forces, interface shapes, pressure differences, or flow rates. Commonly used methods for measuring interfacial tension of various solutions as well as solid systems

To facilitate an in-depth process understanding, a combination of experimental and computational design may be integrated in interfacial tension of compounds. Providing a simple method of correlating and predicting the interfacial properties of materials would be of great interest for pharmaceutical technology. There are various computational techniques in which the surface tension is evaluated through its thermodynamic definition or empirical equations. These methods require input data and several adjustable parameters obtained from multicomponent system and the pure component. Some of these equations on a thermodynamic basis are the two-parameter model for liquid mixtures. With these methods calculation of the free-energy between the two systems is a challenge to be accurately determined and these methods are difficult to implement at relatively high temperature due to stability problems. Empirical equations may be used to correlate and predict surface tension using one or two parameters. Some of these models may have limited range of applicability and may require a lot of experimental data. For practical use it is very important that the surface tension of multicomponent system can be predicted from the composition of the conjugate phases and some predictable physical parameters without any

limited to higher range surface tension value of solid surfaces (Ahadian et al.,2007).

dissolution, and bioavailability of a drug may depend on the surface of the molecule.

**4. Conclusion** 

are mentioned in this chapter.

adjustable parameters.


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**4** 

*Germany* 

**Multi-Well Engineered Heart Tissue for Drug** 

Drug development is time- and cost-intensive and, overall, inefficient. Only one out of an estimated 10.000 new chemical entities (NCEs) finally enters the market. The later the failure occurs, the higher are the costs. It is for this reason that preclinical development aims at identifying the potential for failure as early as possible and with high sensitivity. On the other hand, high sensitivity generally also means low specificity, suggesting that many potentially successful NCEs are currently excluded from further development. Common reasons for exclusion are adverse drug reactions (ADR). Among the various ADRs, cardiac toxicities and arrhythmias play an important role, because they represent about 21% of all ADRs (Lasser et al., 2002) and are frequently lethal. The single most important mechanism in this context is the prolongation of cardiac repolarization bearing a proarrhythmic potential. These interferences can be visualized by standard ECGs as a prolongation of the QT-interval. Such a prolongation is called "long QT-syndrome" (LQT-syndrome) and is associated with *Torsade-de-Pointes* (TdP) arrhythmias and sudden cardiac death. In the past, several prominent drugs had to be withdrawn from the market due to TdP in humans, e.g. astemizole, terfenadine, cisapride, sparfloxacin, grepafloxacin and recently clobutinol (Silomat). Moreover, numerous drugs are still on the market that are associated with the potential to cause LQT and TdP, including widely prescribed drugs such as the antibiotic

Given the fatal consequences of LQT and TdP in healthy patients without any cardiac disposition, the regulatory bodies (FDA, EMEA and others) have decided some years ago to require testing for LQT to be an obligatory part of preclinical development of any NCE. Several tests have been developed and some of them are routinely used. The three major (but by far not exclusive) tests in the field are the HERG test, rabbit Purkinje fibers and telemetry in dogs. These tests have different advantages and disadvantages and are generally employed subsequently. The HERG test can be considered an obligatory test for all NCEs and it is unlikely that any company further develops a compound that showed major inhibitory activity in this test (of a single ion channel activity). However, examples exist of successful drugs on the market that are potent inhibitors of the HERG current without ever giving rise to TdP arrhythmia (e.g. verapamil, azithromycin). Thus, the predictive value of the HERG test is limited. Reasons lie, among others, in its inability to

**1. Introduction** 

erythromycin.

**Screening and Predictive Toxicology** 

Alexandra Eder, Arne Hansen and Thomas Eschenhagen

*Department of Experimental Pharmacology and Toxicology,* 

*University Medical Centre Hamburg-Eppendorf,* 

