Bio-Equivalence : Module 2

DISSOLUTION AND BIO EQUIVALENCE STUDIES

Dissolution is important parameter for selecting final product for Bio-equivalence Studies. The question often arises that if the dissolution data is in order. What is the need of conducting a bioequivalence study? This question is answered by the biopharmaceutical classification system for class two and class four drug. The solubility of the drug and hence its liberation from the pharmaceutical product is the rate-limiting step, the bioavailability greatly depends on the dosage form for such products. It is essential to conduct bioavailability studies to establish their bioequivalence whereas for class one and class three drugs, which have high solubility, liberation of the drug from the pharmaceutical product is not the rate-limiting step by the bioavailability is limited by the permeability of the drug in case of class one and three drugs bioequivalence studies are not essential, and they can be established to be bioequivalent purely based on the dissolution data.

The Biopharmaceutical Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. Even various regulatory agencies allow bioequivalence of BCS class I and III drugs to be demonstrated by in vitro dissolution (Termed as Biowaiver). In the BCS, a drug is classified in one of four classes based solely on solubility and intestinal permeability.

Class I: High Solubility / High Permeability

Class II: Low Solubility / High Permeability,

Class III: High Solubility / Low Permeability

Class IV: Low Solubility / Low Permeability

The drugs are classified in BCS on the basis of following parameters:

1. Solubility

2. Permeability

3. Dissolution

The class boundaries for these parameters are:

1. Solubility class boundaries- It is based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250ml or less of aqueous media over the pH range of 1 to 7.5.

2. Permeability class boundaries- It is based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90 % or more of the administered dose based on a mass-balance determination or in comparison to and intravenous dose.

3. Dissolution class boundaries- An immediate release products is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolve within 30 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900ml or less in following media,) 0.1 N HCl or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

In general, a high soluble drug is characterized based on the largest dosage strength soluble in 250 ml or less of water over a pH range of 1-8. In addition, if the extent of drug absorption is greater than 90% given that the drug is stable in the gastrointestinal environment; it will be considered as a high permeable drug

The purpose of the in-vitro dissolution studies in the early stage of drug development is to select the optimum formulation, evaluate the active ingredient and excipient, and assess any minor changes for drug products. However, for the IVIVC perspective, dissolution is proposed to be a surrogate of drug bioavailability. Thus, a more rigorous dissolution standard may be necessary for the in-vivo waiver. Generally, a dissolution methodology, which is able to discriminate between the study formulations and which best, reflects the in vivo behavior would be selected.

In fact In-vitro drug dissolution then can be used as a surrogate for the in-vivo absorption. An In-vitro in-vivo correlation (IVIVC) has been defined by the Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response. A validated IVIVC is of significant benefit for pharmaceutical manufacturers due to minimizing the time and cost invested in additional bioavailability studies. 

Dr. Manoj Karwa


P.S

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