Compounds which are lipophilic in nature having high partition coefficient are poorly aqueous soluble and retained in the lipophilic tissue for a longer time. In case of compounds with very low partition coefficient, it is very difficult for them to penetrate the membrane, resulting in poor bioavailability. Furthermore, partitioning effects apply equally to diffusion through polymer membranes. The choice of diffusion limiting membranes must largely depend on the partitioning characteristics of the drug .
c. Drug stability: The stability of the drugs at the site of its release and exposure bio -milieu is one more drug property that can influence the design of oral controlled drug delivery. Drugs that are unstable in gastric pH can be developed as slow release dosage form and drug release can be delayed till the dosage form reaches the intestine. Drugs that undergo gut-wall metabolism and show instability in small intestine are not suitable for controlled drug delivery systems.
Orally administered drugs can be subject to both acid -base hydrolysis and enzymatic degradation. Degradation will proceed at a reduced rate for drugs in solid state; therefore, this is the preferred composition of delivery for problem cases. For the dosage form that are unstable in stomach, systems that prolong delivery over entire course of transit in the GI tract are beneficial; this is also true for systems that delay release until the dosage form reaches the small intestine. Compounds that are unstable in small intestine may demonstrate decreased bioavailability when administered from a sustaining dosage form. This is because more drugs are delivered in the small intestine and hence, is subject to degradation. Propentheline and probanthine are representative examples of such drugs.
d. Absorption: The rate, extent and uniformity of absorption of a drug are important factors when considering its formulation into a controlled – release system. Since the rate limiting step in drug delivery from a controlled – release system is its release from a dosage form, rather than absorption, a rapid rate of absorption of drug relative to its release i s essential if the ‘system is to be successful. Since the purpose of forming a sustained release product is to place control on the delivery system, it is necessary that the rate of release is much slower than the rate of absorption. If we assume that the transit time of most drugs in the absorptive areas of the GI tract is about 8 – 12 hours, the maximum half-life for absorption should be approximately 3 – 4 hours; otherwise, the device will pass out of the potential absorptive regions before drug release is complete thus corresponds to a minimum apparent absorption rate constant of 0.17 – 0.23 hr-1 to give 80 – 95 % over this time period.
Hence, it assumes that the absorption of the drug should occur at a relatively uniform rate over the entire length of small intestine. For many compounds this is not true. If a drug is absorbed by active transport or transport is limited to a specific region of intestine, a sustained release preparation may be disadvantageous to absorption. One method to provide sustaining mechanisms of delivery for compounds is trying to maintain them within the stomach. This allows slow release of the drug, which then travels to the absorptive site. These methods have been developed as a consequence of the observation that co-administration results in sustaining effect. One such attempt is to formulate low density pellet or capsule. Another approach is that of bioadhesive materials.
e. Distribution: The distribution of a drug into vascular and extra vascular spaces in the body is an important factor in its overall elimination kinetics. Two parameters that are used to describe the distribution characteristics of a drug are its apparent volume of distribution and the ratio of drug concentration in the tissue to that in plasma at the steady state called T/P ratio. The magnitude of the apparent volume of distribution can be used as a guide for additional studies and as a predictor for a drug dosing regimen and hence the need to employ a controlled – system.
f. Metabolism: Drugs that are significantly metabolized before absorption either in the lumen or tissue of the intestine can show decreased bioavailability from slower – releasing dosage forms. Formulation of these enzymatically susceptible compounds as prodrugs is another viable solution. Drugs which are significantly metabolized before absorption, either in the lumen or the tissue of the intestine, can show decreased bioavailability from slower-releasing dosage form. Hence criteria for the drug to be used for formulating a sustained – release dosage form is,
i. Drug should have low half-life (