Gastrointestinal tract drug dissolution

Orai Administration The oral route is the most common way of administering a drug. For a drug to be absorbed into the bloodstream, it has to be soluble in the fluids of our gastrointestinal tract. Drugs are often formulated with excipients (components other than the active drug) to improve manufacturing and dissolution processes (see Section 5.6). 

Hotter, D., Dressman, J. B. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv. Drug Deliv. 

Returning to Fig. 6, it can be seen that the oral administration of two 15-mg tablets of propantheline 1.5 hours before atenolol delayed the rate of availability of this p-blocker, while increasing its extent of availability [11]. This increased extent might be due to more complete dissolution of the drug, resulting from its increased time in the gastrointestinal tract. 

S Chakrabarti, MZ Southard. Control of poorly soluble drug dissolution in conditions simulating the gastrointestinal tract flow. 1. Effect of tablet geometry in buffered medium. J Pharm Sci 85 313-319, 1996. 

A summary of how physiological factors affect the dissolution rate is given in Table 21.2. The effective surface area will be affected by the wetting properties of the bile acids and other surface-active agents in the gastrointestinal tract. The dif-fusivity of a drug molecule in the intestinal juice will be altered by changes in viscosity that are induced, for instance, by meal components. An increased dissolution rate could be obtained at more intense intestinal motility patterns or increased... 

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

In vitro dissolution testing is an important tool in the development of solid drug products, as well as in batch quality controls. The aim of the test is to see that the drug is appropriately dissolved in the gastrointestinal tract and made available for absorption. It is therefore highly desirable that the in vitro tests provide data that correlate to the in vivo situation. However, attainment of IVIVC has often failed-and the concept of IVIVC has been challenged. 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

Since the rate of absorption of many drugs from the gastrointestinal tract is controlled by their dissolution rate, this becomes the rate-limiting step. Accurate and reliable measurements of dissolution rate are therefore required in the pharmaceutical sciences. The measurement and interpretation of the dissolution rates of solid drugs in the pure state or from formulations, such as tablets, capsules, and suppositories, has an extensive pharmaceutical literature [95-100]. Moreover, the design, operation, and interpretation of dissolution rate measurements on pharmaceutical solids have been the subject of considerable scientific study, technical development, and debate. 

The basis for all CAT models is the fundamental understanding of the transit flow of drugs in the gastrointestinal tract. Yu et al. [61] compiled published human intestinal transit flow data from more than 400 subjects, and their work showed the human mean small intestinal transit time to be 199 min. and that seven compartments were optimal in describing the small intestinal transit process using a compartmental approach. In a later work, Yu et al. [58] showed that between 1 and 14 compartments were needed to optimally describe the individual small intestine transit times in six subjects but in agreement with the earlier study, the mean number of compartments was found to be seven. This compartmental transit model was further developed into a compartmental absorption and transit (CAT) model ([60], [63]). The assumptions made for this CAT model was that no absorption occurs in the stomach or in the colon and that dissolution is instantaneous. Yu et al. [59] extended the CAT model... 

The medium selected for the dissolution test must consider the drug solubility. Aqueous media with a typical plT range between 1 and 7 to mimic the human gastrointestinal tract are preferred over organic solvents. The operating parameters of the dissolution setting should be optimized to ensure complete dissolution. ... 

The rate of dissolution is effected by solubility as is the actual concentration of drug in the bulk of the solution (aqueous contents of gastrointestinal tract). The concentration of drug in solution is the driving force of the membrane transfer of drug... 

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