The BCS categorizes drug substances into four BCS classes as follows:
- Class I: high solubility, high permeability
- Class II: low solubility, high permeability
- Class III: high solubility, low permeability
- Class IV: low solubility, low permeability
What is High Solubility?
The highest dose strength of the drug can be dissolved in ≤ 250 mL of aqueous media at a pH from 1 to 6.8 (including pH = pKa, pH = pKa + 1 and pH = pKa-1) and a temperature of 37 °C ± 1 °C.
- For a drug dose larger than the highest drug strength, additional data are required.
- Chemical stability of the substance must be guaranteed for a period that includes the last dissolution time point plus the time required for the slowest analysis method.
What is High Permeability?
The fraction absorbed reaches 85% or more, of the dose administered, based on a mass balance determination (along with evidence showing stability of the drug in the GI tract) or compared to a referred I.V. dose.
- When it comes to prodrugs, permeability is influenced by the anatomical site and the mechanism of the prodrug to drug reaction. If the reaction happens after the intestinal permeation, then permeability must be measured for the prodrug. For a prior to intestinal permeation reaction, permeability must be determined for the drug itself.
Requirements:
- The mode of administration of finished product should be with water.
- The excipients selected for test products should be the same as reference product. Any difference in the excipients should be assessed and justified that the proposed excipient differences will not affect the absorption profile of the drug substance under consideration, i.e., rate and extent of absorption, using a mechanistic and risk-based approach.
- For BCS Class-I drug substances, both the test product and reference product should have either very rapid (≥85% for the mean percent dissolved in ≤ 15 minutes) in vitro dissolution characteristics, or rapid (≥85% for the mean percent dissolved in ≤ 30 minutes) and similar in-vitro dissolution characteristics (i.e., based on f2 comparison) throughout the multimedia dissolution conditions.
- For BCS Class-III drug substances, both the test product and reference product should display very rapid (≥85% for the mean percent dissolved in ≤15 minutes) in vitro dissolution characteristics throughout the multimedia dissolution conditions.
Dissolution of test and reference product to be carried out as mentioned below:
a) pH 1.2 (0.1 N HCl), Paddle with 50 RPM or Basket with 100 RPM, 900 mL or less, 37 ± 1°C, n= 12 units.
b) pH 4.5 acetate buffer, Paddle with 50 RPM or Basket with 100 RPM, 900 mL or less, 37 ± 1°C, n= 12 units.
c) pH 6.8 phosphate buffer, Paddle with 50 RPM or Basket with 100 RPM, 900 mL or less, 37 ± 1°C, n= 12 units.
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