Limited dissolution

From Eq. (12), the dependence of Fa on both An and Do is apparent. The relationship suggests that a lower fraction of dose will be absorbed at a higher dose. However, for compounds with low solubility and/or high dose, the concentration in the intestinal lumen may not be the same as the solubility, owing to slow dissolution. Dissolution-limited absorption is discussed in Section III.B. 

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

Class II drugs, i.e., low-solubility/high-permeability compounds, are expected to have a dissolution-limited absorption. Thus, for these types of drugs an IVIVC... 

Hydrodynamics in the upper GI tract contribute to in vivo dissolution. Our ability to forecast dissolution of poorly soluble drugs in vitro depends on our knowledge of and ability to control hydrodynamics as well as other factors influencing dissolution. Provided suitable conditions (apparatus, hydrodynamics, media) are chosen for the dissolution test, it seems possible to predict dissolution limitations to the oral absorption of drugs and to reflect variations in hydrodynamic conditions in the upper GI tract. The fluid volume available for dissolution in the gut lumen, the contact time of the dissolved compound with the absorptive sites, and particle size have been identified as the main hydrodynamic determinants for the absorption of poorly soluble drugs in vivo. The influence of these factors is usually more pronounced than that of the motility pattern or the GI flow rates per se. 

If not in an ER product, a drug is likely to exhibit dissolution-limited absorption if it is poorly soluble in the GI lumen. Usually, identification of a compound with dissolution-limited GI absorption is based on D S ratio (4) when D S is about < 250 mL over the pH range of 1-7.5, the compound is usually considered to have less than ideal lumenal dissolution characteristics (3,5), with 250 mL being a conservative estimate of the total volume of fluids that will be in contact with the dose in the upper GI tract under fasting conditions. However, this approach has several weaknesses ... 

Key operating parameters that may change (or be optimized) throughout a product s development and approval cycle are dissolution sampling time points and dissolution limits or specifications by which the dissolution results should be evaluated. The results generated from the dissolution test need to be evaluated and interpreted based on the intended purpose of the test. If the test is used for batch-to-batch control, the results should be evaluated in regard to the established limits or specification value. If the test is being utilized as a characterization test (i.e., biopharmaceutical evaluations, formulation development studies, etc.) the results are usually evaluated by profile comparisons. 

Optimally, specifications should be established such that all lots that have dissolution profiles within the upper and lower limits of the specifications are bioequivalent. Less optimally but still possible, lots exhibiting dissolution profiles at the upper and lower dissolution limits should be bioequivalent to the clinical/bioavailability lots or to an appropriate reference standard. 

Sometimes, absorption can be described by sequential zero-order and Lrst-order absorption processes. Conceptually, if the Lrst-order rate constant is linked to the zero-order input, the model can be postulated as the consequence of dissolution-limited absorption (Garrigues et al., 1991 Holford et al., 1992). 

Table 17.2 illustrates the absolute oral bioavailability of several Danazol formulations nanoparticle dispersion, solubilized cyclodextrin oral formulation, and conventional suspension. Danazol represents a poorly water-soluble compound (H /mL) whose oral bioavailability is dissolution limited. 

Pharmacopoeial applications include assays for single drugs and mixtures of drugs, analyses involving colour reactions (colorimetric methods), tests for tablet dissolution, limit tests for impurities, and assays of bulk drugs or an extract thereof. Further applications are for physicochemical measurements, such as pK or velocity constants in enzymatic reactions. The scope of such applications has been significantly extended by methods which can confer additional specificity, namely difference spectrophotometry and derivative spectrophotometry. 

Nevertheless, the problem of pellicle formation and eventual fall in dissolution rate is still of concern, as the drug bioavailability may be influenced if there is a severe challenge. There is a report where exposure of phenytoin capsules to high humidities resulted in poor dissolution as well as destruction of clinical efficacy. Moreover, the enzyme test is not official in pharmacopoeias other than USP and the products stand a chance of being recalled, if the normal pharmacopoeial dissolution limits are not met. 

This study indicates that dissolution-limited absorption is a prerequisite for rVrVC using dissolution, but one should also realize that modihcation of the biorelevant media, in terms of composition, but also dissolution conditions, might result in development of a model that does provide for an IVIVC. 

Fig. 5. Generalized cross-section through Elm Fork study area in southwest Oklahoma, showing dissolution limits of Flowerpot salt beneath principal river.

Sometimes, two first-order absorption processes do not adequately describe the data and the absorption profiles are better described by a combination of first-order and zero-order processes (40, 56-59). Lag time may be added for each type of absorption, which then will determine whether the two processes are simultaneous or sequential. Moreover, if the first-order rate constant is finked to the zero-order input parameters, the model can be interpreted as the consequence of dissolution-limited absorption. The ordering of the processes (first-order absorption first, or zero-order absorption first) is usually empirical or data driven. Pathophysiology and/or physicochemical characteristics of the compound may help in deciding the order. 

Nanosizing and amorphous formulation approaches were examined with some success, providing approximately five- and nine-fold enhancements in exposure in dogs, respectively, compared to the formulation used in the clinical capsule [57], These data, along with the data from solution dosing, provided evidence that addressing dissolution-limited absorption had the potential to improve plasma exposure of BMS-488043 (9) following oral administration. 

Cell permeability Ability to traverse an intact cell monolayer unchanged in an in vitro system For compounds stable to first pass effect and with no solubility or dissolution limitations, often correlates with oral bioavailabiUty Caco-2, MDCK, etc. 

---