Drug dissolution is nearly impossible to study in the environment that it is intended to occur, namely, the human gastrointestinal (GI) tract. As a surrogate, in vitro dissolution testing is required to ensure that drug dissolves at a consistent rate from batch to batch of formulated drug product. Beyond the important quality control function of dissolution testing, the goal of this chapter will be to show how dissolution in the context of drug absorption from the GI tract can be modeled to gain insight into the important factors that control the rate of dissolution, and as a result, provide a mechanistic basis for predicting a correlation between in vitro dissolution and in vivo time profile of drug in the blood. The potential benefit from this insight will arise from the recognition of the critical factors that must be understood and controlled, and how to best design tests to ensure the quality of the finished drug products. A mechanistic model also provides a more proactive approach to the design of dosage forms, increasing the chances that the dosage form will have the desired release characteristics resulting in an efficacious drug plasma profile.
We start with an oversimplified view of dosage forms by assuming that all drugs are given as solutions with no need for disintegration and dissolution testing. It assumes that only drug in solution can cross the GI membrane.
Given this scenario, drug discovery scientists would expect that the amount of drug available systemically would increase with increasing dose, allowing them to establish a safe and efficacious dose.
In trying to explain why the amount of absorbed drug would increase with dose, one would recall the principles of physical chemistry that state that matter will tend to move from a point of higher concentration or chemical potential; drug in solution within the GI tract, to a point of lower concentration; the systemic blood supply where Aumen is the mass of drug dissolved in the GI lumen, Ka is a first-order absorption rate constant, and Adood is the mass of drug absorbed into the systemic blood supply. For simplicity, metabolism has been ignored. A simple absorption rate equation used in pharmacokinetics will be useful in making the point.
Integrating this equation from dosing at zero time where Aumen = Dose to some later time yields. For solution doses, the direct proportionality can be seen between the dose and Aumen- And because Aumen is the driving force for absorption, increasing dose increases absorption. Again, this is based on the assumption that all doses are in solution. In the real world, this is not the case, and drug dissolution occurs at a finite rate and may not be complete due to inadequate solubility.
