The Importance ofBCS on Biorelevant Dissolution Testing

The BCS, which was proposed by Amidon et al. (1995), emphasizes the contribution of three fundamental factors, dissolution, solubility, and intestinal permeability, to the rate and extent of drug absorption for solid oral dosage forms. The BCS identifies three dimensionless numbers as key parameters including absorption number (An), dissolution number (Dn), and dose number (Do) to represent the effects of dissolution, solubility and intestinal permeability on the absorption process. These three dimensionless numbers are defined as:

DCs 4nr2

Cs where Peff is the effective permeability, ro is the initial particle radius, tres is the mean residence time for the drug in the intestinal segment (n R2L/Qflow, where R is the radius, L is the length of the segment, and Qflow is the flow rate of fluid in the small intestine), D is the diffusion coefficient, p is the density, Vo is the initial gastric volume, and Mo is the amount of drug that is administered, and Cs is the saturated solubility.

According to the BCS, drug compounds are classified based upon their solubility and permeability described as follows:

Class I: High Permeability, High Solubility Class II: High Permeability, Low Solubility Class III: Low Permeability, High Solubility Class IV: Low Permeability, Low Solubility

In this system, a compound is considered highly soluble when the highest dose strength is soluble in >250 mL3 water over a range of pH from 1.0 to 7.5. For a highly permeable drug substance, the extent of absorption in humans is >90% of an administrated dose, based on mass-balance or in comparison to an intravenous reference dose. When >85% of the label amount of drug substance dissolves within 30 min using USP apparatus I (100 rpm) or II (50rpm) in a volume of <900 mL in each of the following media: (1) 0.1N HCl or USP simulated gastric fluid (SGF) without enzymes, (2) a pH 4.5 buffer, and (3) a pH 6.8 buffer or USP simulated intestinal fluid (SIF) without enzymes, a corresponding drug product is considered to be rapidly dissolving.

Although the BCS has been developed primarily for regulatory applicants and particularly for oral immediate-release drug products, it has important implications in governing the dissolution test design during the drug development. Most importantly, it provides a general guideline for determining the conditions under which IVIVC is expected, as summarized in Table 3.1 (Amidon et al., 1995). In other words, the BCS can provide an early insight into whether it is possible

3 This volume is derived based on typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water (about

Table 3.1. In Vitro-in vivo correlation expectations for immediate-release products (Amidon et al. 1995)

Class Solubility Permeability IVIVC expectation

Table 3.1. In Vitro-in vivo correlation expectations for immediate-release products (Amidon et al. 1995)

Class Solubility Permeability IVIVC expectation

I

High

High

IVIVC is expected if dissolution rate is slower than gastric emptying rate. Otherwise limited or no correlation is expected

II

Low

High

IVIVC is expected if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high

III

High

Low

Limited or no IVIVC is expected since absorption (permeability) is rate determining

IV

Low

Low

Limited or no IVIVC is expected

to develop a dissolution method capable of predicting in vivo drug absorption for immediate-release products, based primarily upon the solubility, permeability, and dissolution data.

BCS Class I compounds (e.g., metoprolol) have a high absorption number (An) and a high dissolution number (Dn), indicating that the rate determining step for drug absorption is likely to be dissolution or gastric emptying. This class of drugs is generally well absorbed if the drug is stable or does not undergo first pass metabolism. For immediate-release products of Class I compounds, the absorption rate is likely dominated by the gastric emptying time, and no direct correlation between in vivo data and in vitro dissolution data is expected. Thus, dissolution tests for such IR drug products should be designed mainly to confirm that the drug is released rapidly from the dosage form under the test conditions described above. A dissolution specification for which 85% of drug contained in the IR dosage form is dissolved in less than 15min maybe sufficient to ensure bioavailability, since the mean gastric half emptying time is 15-20 min (Amidon et al., 1995; CDER/FDA, 1997). For BCS Class I drugs, which are formulated in extended-release dosage forms and have permeability that is site independent, dissolution becomes more important and IVIVC (e.g., level A) may be expected.

Class II drugs (e.g., phenytoin) have a high absorption number (An) and a low dissolution number (Dn). Dissolution is the rate limiting step for drug absorption. The influence of dissolution on absorption of BCS Class II drugs can be classified into two scenarios: solubility-limited absorption or dissolution-limited absorption (Yu, 1999). These two scenarios are best illustrated by grisefulvin and digoxin. In the case of solubility-limited absorption, grisefulvin exhibits a high dose number (Do) and a low dissolution number (Dn). Although in theory, absorption of grisefulvin can be improved by taking more water with the administered dose (decreasing Do), this approach is impractical due to the limitation in the physiological and anatomical capacity of the stomach for water. Thus, the only practical way to improve the absorption of grisefulvin is to decrease Do and increase Dn by enhancing its solubility through appropriate formulation approaches such as solid dispersion. On the other hand, in the case of dissolution-limited absorption, digoxin has a low dose number (Do) and a low dissolution number (Dn). Despite the small volume (21 mL) of fluids required to dissolve a typical dose of digoxin (0.5 mg), this drug dissolves too slowly for the absorption to take place at the site(s) of uptake. However, its dissolution rate can be improved simply by increasing Dn through the reduction in particle size. Thus, for BCS Class II drugs, a strong correlation between in vitro dissolution data and in vivo performance (e.g., Level A) is likely to be established. When a BCS Class II drug is formulated as an extended-release product, an IVIVC may also be expected.

For BCS Class III drugs (e.g., cimetidine), permeability is likely to be a dominant factor in determining the rate and extent of drug absorption. Hence, developing a dissolution test that can predict the in vivo performance of products containing these compounds is generally not possible. Since BCS Class IV drugs, which are low in both solubility and permeability, present significant problems for effective oral delivery, this class of drugs is generally more difficult to develop in comparison to BCS Class I, II, and III drugs.

In spite of its usefulness in the drug product development and regulatory recommendations regarding biowaivers for in vivo bioequivalence studies, the BCS also has its limitations. Drug instability in the GI tract, first pass metabolism, and com-plexation phenomena of drugs with the GI contents may have significant influence upon bioavailability, but are not addressed by the BCS. Furthermore, the BCS is often considered to be a conservative measure with regard to highly soluble drugs, since they are required to show high solubility across the range of pH from 1.2 to 7.5. It is important to note that the solubility of a weak acid and weak base depends on pH. The solubility of weak bases is generally higher in the stomach than in the small intestine. Therefore, a low solubility at high pH may not inhibit absorption of weak bases as the absorption may already be complete prior to entering the low solubility, high pH GI region. In contrast, low solubility at low pH may not present a problem for the absorption of weak acids since high solubility and high permeability in the small intestine are sufficient for their complete absorption.

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