Dynamic kinetic stability

Knowledge of the 90 chemical elements and their properties in compounds led to the construction, by man, of a unique table of elements, the Periodic Table, of 18 Groups in six periods in a pattern fully explained by quantum theory, described in Chapter 2. There is then a huge variety of chemical combinations possible on the Earth and limitations on what is observable are related to element position in this Table. It also relates to the thermodynamic and/or kinetic stability of particular combinations of them in given physical circumstances (Table 11.3). The initial state of the surface of the Earth with which we are concerned was a dynamic water layer, the sea, covering a crust mainly of oxides and some sulfides and with an atmosphere of NH3, HCN, N2, C02(C0, CH4), H20, with some H2 but no 02. This combination of phases and their contents then produced an aqueous solution layer of particular components in which there were many concentration restrictions between it and the components of the other two layers due to thermodynamic stability, equilibria, or kinetic stability of the chemicals trapped in the phases. It is the case that equilibrium... 

Slipping. The slipping method exploits the kinetic stability of the rotaxane. Provided the end groups of the dumbbell are of appropriate size, they are able to reversibly thread through the macrocycle at higher temperatures, but by lowering the temperature the dynamic complex becomes kinetically trapped as a rotaxane. 

The application of the Hoffmann test """ " confirms configurational stability of these lithium compounds on the microscopic scale at low temperature, indicating that rather thermodynamic than dynamic kinetic resolution is operating at the reaction conditions " . 

Scheme 13.9 summarized kinetic resolution of N-urethane protected N-carboxy anhydrides rac-18 by methanolysis in the presence of the dimeric cinchona alkaloid catalyst 11, (DHQD)2AQN, as reported by Deng et al. [20]. These kinetic resolutions were typically conducted at low temperature - from —78 to —60 °C. Deng et al. later observed that if the reaction temperature was increased racemization of the starting aryl N-carboxy anhydrides rac-18 becomes sufficiently rapid to enable a dynamic kinetic resolution [21]. Configurational stability of the product esters... 

Dynamics and stability of thin foam films have been and continue to be an object of intensive research [e.g. 28-35]. Model studies with vertical large macroscopic films with linear sizes of the order of centimeters as well as with horizontal circular microscopic films with radius of the order of millimeters were performed. The kinetics of thinning of vertical macroscopic films in described in detail in [33]. Some of the results presenting an interpretation of the dynamic properties of films and foam are considered in Chapter 7. Microscopic foam films offer certain advantages with respect to treatment of stability of foams and foam films, since the systems studied behave under strictly defined conditions. 

The potentiality of hierarchical stratification of complex reactive systems, according to the characteristic times of the involved processes, makes it difficult to use direcdy thermodynamic tools as well as to apply the con cept of stability to very compHcated (in particular, biological) systems. The statistical approach to describe the behavior of a system that contains a large number of particles takes into account the instabihty of mechanical trajectories of individual particles. Indeed, any infinitesimally small distur bances in the particles motion can make it impossible to determine from the starting conditions the trajectory of even one particle s motion. As a result, a global instabihty of mechanical states of individual particles is observed, the system becomes statistical as a whole, and the trajectories of individual particles are no longer predictable. At the same time, the states that correspond to stable solutions of any dynamic (kinetic) problem can only be observed in real systems. In terms of a statistical approach, the dynamic solution of a particular initial state of an ensemble of particles is a fluctuation, while the evolution of instabihty upon destruction of this solution is a relaxation of this fluctuation. 

Panda D, DeLuca K, Williams D, Jordan MA, Wilson L. Antiproliferative mechanism of action of cryptophycin-52 kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends. Proc. Natl. Acad. Sci. U.S.A. 1998 95 9313-9318. 

Panda D, Daijo JE, Jordan MA, Wilson L. Kinetic stabilization of microtubule dynamics at steady state in vitro by substoichio-metric concentrations of tubulin-colchicine complex. Biochemistry 1995 34 9921-9929. 

Most protein stability studies have focused their interpretation on either a thermodynamic mechanism or a pure kinetic mechanism, and consequently there is some controversy and confusion over which mechanism is correct. Since the direction of a formulation development effort may depend on which theory is being followed, clarification of the roles of thermodynamic stabilization and kinetic stabilization in given stability problems would provide some practical benefit. This chapter is an attempt to provide such clarification. To this end, the major stresses, or destabilizing effects, that operate during the freeze-drying process are discussed, selected empirical observations regarding pharmaceutical stability in protein systems are presented, and the structure and dynamics in amorphous protein formulations are discussed. 

For such supramolecular systems, diffusion NMR may be extremely important for the determination of the structure and dynamics of the system. Diffusion is also extremely important in determining the association constant in systems, which on their formation induce a small change in the NMR spectra, and in systems in which chemical shift changes occur for reasons other than complexation, for example when protonation takes place. Diffusion NMR can also easily be used to probe the kinetic stability of multicomponent systems just by monitoring the effect of a small excess of one of the components on the diffusion coefficient of the supramolecular system. 

In Chapter 22 we saw resolution with racemisation applied to the synthesis of L-364,718. That could have been described as a dynamic resolution or possibly even a dynamic thermodynamic resolution but not a dynamic kinetic resolution as it did not depend on one enantiomer reacting faster than the other. Rather it depended on the thermodynamic stability of one crystalline form over the other. 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

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