Dissolution rate limiting

G. Levy, J. R. Leonards, and J. A. Procknal, Development of in vitro dissolution tests which correlate quantitatively with dissolution rate-limited drug absorption in man, J. Pharm. Sci., 54, 1719-1722 (1966). K. A. Javaid and D. E. Cadwallader, Dissolution of aspirin from tablets containing various buffering agents, J. Pharm. Sci., 61, 1370-1373 (1972). 

In such cases, the Nogami method can be applied to the early points curve (Fig. 6) and the solubility, S, of the polymorph can be assessed. One of the important aspects of metastable polymorphs in pharmacy is exactly their higher solubility, since the dissolution rate will also be higher [Eq. (7)]. Hence the bioavailability will be increased where this is dissolution rate limited [21]. 

However, in the foregoing systems, the predominant mechanism allows easy mathematical description. In practice, the dominant mechanism for release will overshadow other processes enough to allow classification as either dissolution rate-limited or diffusion-controlled. Bioerodible devices, however, constitute a group of systems for which mathematical descriptions of release characteristics can be quite complex. Characteristics of this type of system are listed in Table 7. A typical system is shown in Fig. 8. The mechanism of release from simple erodible slabs, cylinders, and spheres has been described [36], A simple expression describing release from all three of these erodible devices is... 

The intrinsic dissolution rate is the rate of mass transfer from the solid phase to the liquid phase. Information on the intrinsic dissolution rate is important in early drug product development. It has been suggested that drugs with intrinsic dissolution rates of less than 0.1 mg/(min cm2) will have dissolution rate-limited absorption, while drugs with intrinsic dissolution rates greater than 0.1 mg/ (min cm2) are unlikely to have dissolution rate problems. 

BCS Class II Low-solubility, high-permeability drugs. The bioavailability of products containing these compounds is likely to be dissolution-rate limited. For this reason, a correlation between in vivo bioavailability and in vitro dissolution rate (IVIVC) may be observed. 

The flow-through cell is especially useful for dissolution rate-limited products, where sink conditions may be hard to obtain (18,19). The operation of the flow-through cell is illustrated in Figure 12. A closer look at the tablet holders is shown in Figure 13. This particular apparatus can be utilized as either a closed or open system. In Figure 14, the closed system mode,... 

The physiologically based model developed by Willman et al. [53, 54], for the prediction of both rat and human Fibs, was shown to be predictive for the human situation if passively transported compounds were studied. In their study, they used a semiempirical formula for the prediction of human permeability trained with a set of 119 passively transported drugs that did not show solubility or dissolution rate-limited absorption. 

When a drug is more rapidly or completely absorbed from solution, it is very likely that its absorption will be dissolution rate limited. 

For formulating poor water-soluble compounds, use of cosolvent(s) is one of the simplest and common approach. The approach is also widely used in the early development phase, as limited information is available for the molecule. The approach also allows overcoming dissolution rate limited drug absorption. In addition, solubilized formulations are greatly popular with pediatric, geriatric, and patients with swallowing difculties. 

At low etchant concentrations, the polish rate is limited by step 2. In this dissolution rate limited region, the abrasion rate is higher than the dissolution rate. The abraded material that is not dissolved quickly redeposits onto the surface, lowering the net rate of removal. Therefore, the polish rate is approximately equal to the dissolution rate. In the dissolution rate limited region, the slurry cannot dissolve more material, and therefore increasing the mechanical abrasion rate, by increasing the pressure, has no effect on the polish rate. However, increasing the etchant concentration increases the dissolution rate of abraded material and thus increases the polish rate. 

The polish rate behavior deviates from the Preston equation at high velocities and pressure or if the pad is poorly conditioned. The apparent saturation in the polish rate observed at high velocities and pressures indicates that the polish rate enters a dissolution rate limited regime. In this regime, increasing the abrasion rate does not affect the polish rate because the slurry cannot dissolve any additional abraded material and the additional material simply redeposits. Thus, Preston s equation is only valid in an abrasion rate limited regime. 

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