According to the solubility and permeability of drugs, the following Biopharmaceutics Classification System (BCS) is suggested in the literature (Amidon 1995)
- Case 1: High Solubility – High Permeability Drugs
- Case 2: Low Solubility – High Permeability Drugs
- Case 3: High Solubility – Low Permeability Drugs
- Case 4: Low Solubility – Low Permeability Drugs
This classification serves as a foundation for establishing in vitro dissolution specifications and also aids in predicting the probability of achieving a successful in vivo-in vitro correlation (IVIVC).
The solubility of a drug is assessed by dissolving the maximum unit dose of the drug in 250 mL of buffer, which is adjusted to a pH range between 1.0 and 8.0. A drug substance is deemed highly soluble when the ratio of dose to solubility volume of the solution is less than or equal to 250 mL.
High-permeability drugs are typically characterized by an absorption extent exceeding 90% in the absence of documented instability within the gastrointestinal tract, or those whose permeability has been experimentally determined.
The Biopharmaceutics Classification System (BCS) indicates that for high solubility, high permeability (case 1) drugs, and in certain cases for high solubility, low permeability (case 3) drugs, achieving 85% dissolution in 0.1N HCl within 15 minutes can confirm that the drug’s bioavailability is not constrained by dissolution. In such instances, the rate-limiting factor for drug absorption is gastric emptying.
The average T50% gastric residence (emptying) time is between 15 and 20 minutes when fasting. Based on this data, a cautious conclusion is that a drug product achieving 85% dissolution in 15 minutes under mild dissolution test conditions in 0.1N HCl acts similarly to a solution and typically should not encounter any bioavailability issues. If the dissolution rate is slower than gastric emptying, it is advisable to conduct a dissolution profile with multiple time points in various media.
In instances involving drugs characterized by low solubility and high permeability (case 2), the dissolution of the drug may serve as the rate-limiting factor for absorption, and an in vitro-in vivo correlation (IVIVC) can be anticipated. It is advisable to conduct a dissolution profile across various media for drug products within this category.
Conversely, for drugs classified as high solubility and low permeability (case 3), the permeability becomes the controlling factor for the rate, and a limited IVIVC may be achievable, contingent upon the comparative rates of dissolution and intestinal transit. Drugs categorized under case 4 (i.e., low solubility and low permeability) pose considerable challenges for oral drug delivery.