Non-ionic diffusion

Another strategy to improve the membrane permeant properties of a drug is based on the effect of non-ionic diffusion . An example is provided by the two ganglion-blocking agents hexamethonium and mecamylamine, which act as antagonists at certain receptors of the transmitter acetyl-... 

Non-ionic diffusion can also produce unwanted effects, as in the case of aspirin (acetylsalicylic acid figure 2.8b). In the acidic milieu of the stomach, this molecule will be protonated and thus uncharged, which promotes its diffusion into the cells of the stomach mucous membrane. Inside the cell, the pH is very close to neutral, which will lead to deprotonation of aspirin. Diffusion of the deprotonated (charged) form out of the cell will be much slower than entry, so that aspirin will accumulate inside the cells to con-... 

Figure 2.8. Non-ionic diffusion in drug distribution, a Stmc-tuies of acetylcholine and of its two antagonists hexamethoninm and mecamylamine. Diffusion is facile in the non-ionic form (bottom left), whereas receptor binding requires the positive charge of the protonated state, b Acetylsalicylicacidisprotonat-ed in the acidic milieu of the stomach (left) and then enters the ep-ithehal cells by non-ionic diffusion. Deprotonation at the higher intracellnlarpH leads to accumulation inside the cells.

The kidneys will excrete excess acid equivalents in the urine. At acidic pH, LSD will become protonated and therefore no longer slip back across the tubule epithelium into the circulation this will lead to accelerated elimination of LSD. We here have another example of the principle of non-ionic diffusion , which we have previously discussed in the context of drug absorption. 

Figure 2.21. Non-ionic diffusion in drug elimination - LSD as an example.

Figure 10.17. Depletion of dopamine from neurotransmitter vesicles, a Vesicular accumulation and retention of dopamine can be experimentally observed by bathing isolated vesicles in H-Dopamine. Upon addition of amphetamine, the H-dopamine is swiftly released, b Hypothetical mechanism. Amphetamine induces a futile cycle of transport which depletes intravesicular protons and thereby reduces vesicular uptake of dopamine and also promotes dopamine leakage by non-ionic diffusion.

We will consider the specific system of a non-ionic diffusant in an amorphous or semi-crystalline polymer (in contact with a liquid) at temperatures above the polymer glass temperature Tg. 

In mathematical terms, the adsorption being diffusion-limited means that the variation of the free energy with respect to 0o can be taken to zero at all times whereas the variation with respect to (j> x> 0) cannot. This has two consequences. The first is that the relation between 0o and (j)i is given at all times by the equilibrium adsorption isotherm [(3) in our model]. The solution of the adsorption problem in the non-ionic, diffusion-limited case amounts, therefore, to the simultaneous solution of the Ward-Tordai equation (8) and the adsorption isotherm. Exact analytical solution exists only for the simplest, linear isotherm, °c 0i [19]. For more realistic isotherms such as (3), one has to resort to numerical techniques (useful numerical schemes can be found in refs. [2, 8]). The second consequence of the vanishing of 5Ay/5 o is that the dynamic surface tension, Ay t), approximately obeys the equilibrium equation of state (4). These two consequences show that the validity of the schemes employed by previous theories is essentially restricted to diffusion-limited cases. 

For example, for alkyl (8-16) glycoside (Plantacare 818 UP) non-ionic surfactant solution of molecular weight 390 g/mol, an increase in surfactant concentration up to 300 ppm (CMC concentration) leads to a significant decrease in surface tension. In the range 300 < C < 1,200 ppm the surface tension was almost independent of concentration. In all cases an increase in liquid temperature leads to a decrease in surface tension. This surface tension relaxation is a diffusion rate-dependent process, which typically depends on the type of surfactant, its diffusion/absorption kinetics, micellar dynamics, and bulk concentration levels. As the CMC is approached the absorption becomes independent of the bulk concentration, and the surfactant... 

Noda, A., Hayamizu, K., and Watanabe, M., Pulsed-gradient spin-echo H and NMR ionic diffusion coefficient, viscosity and ionic conductivity of non-chloroaluminate room-temperature ionic liquids, /. Phys. Chem. B, 105, 4603,2001. 

Van-Hal, D.A., et al. 1996. Encapsulation of lidocaine base and hydrochloride into non-ionic surfactant vesicles (NSVs) and diffusion through human stratum corneum in vitro. Eur J Pharm Sci 4 147. 

The most important requirement for utilisation of this kind of ionic diffusion as a means to information transfer is the maintenance of the non-equilibrium ionic concentration gradient. This is a relatively unstable state - it requires energy to counteract the natural entropy-increasing flow back to equilibrium. This is best illustrated by the pump storage model. Ions are actively pumped through... 

D. van Hal, A. van Rensen, T. de Vringer, H. Junginger, and J. Bouwstra, Diffusion of estradiol from non-ionic surfactant vesicles through human stratum corneum in vitro, J. Invest. Dermatol. 6 72-78 (1996). 

Figure 3.8 shows the dynamic surface tension of a pure anionic and a non-ionic surfactant dependent on the absorption time after the creation of new surface for different concentrations [9]. For both surfactants, the time dependence of the surface tension is greatly reduced when the concentration increases and this effect is especially pronounced when the critical micelle concentration is reached. The reason for this dependence is the diffusion of surfactant molecules and micellar aggregates to the surface which influences the surface tension on newly generated surfaces. This dynamic effect of surface tension can probably be attributed to the observation that an optimum of the washing efficiency usually occurs well above the critical micelle concentration. The effect is an important factor for cleaning and institutional washing where short process times are common. 

These equations are called the phenomenological equations, which are capable of describing multiflow systems and the induced effects of the nonconjugate forces on a flow. Generally, any force Xt can produce any flow./, when the cross coefficients are nonzero. Equation (3.175) assumes that the induced flows are also a linear function of non-conjugated forces. For example, ionic diffusion in an aqueous solution may be related to concentration, temperature, and the imposed electromotive force. 

The effect of pH on the diffuse electric layer potential and the surface charge density that was found for foam films from the zwitterionic biosurfactant lyso PC provides new evidence of the mechanism of formation of electrostatic interactions in the case of non-ionic surface active agent. 

In conclusion it is worth noting that the method of equilibrium foam film proved to be very appropriate for the determination of the equilibrium diffuse electric layer potential at the solution/air interface. Though it is an indirect experimental technique, it provides reliable results about the appearance of a negative surface charge in the case of surfactant-free solutions as well as in the case of non-ionic surfactant solutions. The existence of an isoeletric point and the re-charging of the interface can be considered as a direct evidence. 

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