The BCS (13) was introduced as a method to identify situations that might allow in vitro dissolution testing to be used to ensure bioequivalence in the absence of actual clinical bioequivalence studies. On the basis of the theoretical approach taken, solubility and intestinal permeability were identified as the primary drug characteristics that control absorption. This lead to classification of drugs into four broad groups as follows.
• Case 1: High solubility—high permeability.
• Case 2: Low solubility—high permeability.
• Case 3: High solubility—low permeability.
• Case 4: Low solubility—low permeability.
Neither the theoretical basis for the BCS nor the theoretical approach to model dissolution and absorption presented in this chapter have inherent boundaries that would naturally place any particular drug in one of the four BCS classes. However, both approaches do have regions of greater and lesser sensitivity to dissolution that warrant consideration as to whether in vitro dissolution could be used as a surrogate for bioequivalence testing. As pointed out in the theoretical justification for the BCS, the in vivo environment in which dissolution and absorption takes place has a high degree of variability. Out of necessity, boundaries for the BCS classes would have to error on the conservative side due to the uncertainties involved in estimating solubility and permeability in the GI tract.
Although the names of the four BCS classes do not indicate so, dose is an essential piece of information used in the calculation to determine whether a drug can be considered as highly soluble as described by the BCS guidance. Its importance follows from the theoretical basis for the BCS and the dissolution theory presented in this chapter, as drug surface area in the Noyes -Whitney theory is dose-dependent. For a drug to be considered highly soluble, the highest dose must be soluble in 250 mL of water or less over a pH range of 1 to 7.5. The significance of dose has been pointed out by comparing digoxin and griseofulvin as drugs that have roughly similar physical properties of solubility and permeability, but vary considerably with respect to dose (15). As a result, the high dose of digoxin would dissolve in 250 mL of water, whereas the high dose of griseofulvin would not. Therefore, according to the BCS guidance, digoxin would be considered as highly soluble and griseofulvin would not. It should be noted that the BCS-based biowaiver does not apply to narrow therapeutic range drugs like digoxin (28).
Dissolution theory allows the formulator to calculate the rate of drug dissolution and compare it to actual experimental dissolution data. Discrepancies can then be investigated, which could be due to the effects of disintegration, wetting, inaccurate particle size information, or faulty theory. Dissolution of well dispersed, wetted drug particles in the absence of the formulation can also be done for comparison with the dissolution data from the solid dosage form and checked against the theoretical dissolution rate. This ensures that the formulator understands how the dosage form is behaving.
Given the assumption that the purpose of an immediate-release dosage form is to rapidly disintegrate to release well-dispersed and wetted drug particles, establishing the desirable drug particle size distribution remains as an important task under the control of the formulator. The question that needs to be addressed is what should the drug particle size be to rapidly dissolve according to the BCS Guidance? To explore this question, two hypothetical drugs can be compared. Both are high permeability drugs with absorption rate constants of 0.03 reciprocal minutes. One has a dose of 250 mg with a solubility of 1 mg/mL, and the other has a dose of 2.5 mg with a solubility of 0.01 mg/mL. As such, both drugs will just dissolve in 250 mL of water and are on the boundary of being considered Case 1 drugs: high solubility, high permeability.
Figure 6 compares the simulated percent of dose absorbed for both drugs, each simulated with a geometric mean particle size of 5 and 25 microns. A mean of 5 micron would be typical of drug that had been jet-milled, whereas 25 microns would not be an unusual particle size for drug milled by other conventional mills used in the pharmaceutical industry. The top two curves, representing the 250 mg dose at a solubility of 1 mg/mL, show little difference in the absorption profile
In Vitro Release and Biopharmaceutics Classification
Time (minutes)
Figure 6 Simulated absorption of drug. Legend for Figure 6 is shown in Table 4.
for particle sizes of 5 and 25 microns. However, in the third and fourth curves from the top, the simulated absorption profile for the 25 micron particle size representing a 2.5 mg dose with a solubility of 0.01 mg/mL (lowest curve) is very different than the 5 micron particle size for the same dose and solubility. The conclusion drawn from this theoretical set of simulations is that drugs in the same high solubility, high permeability BCS class do not have the same sensitivity to drug particle size with regard to dissolution. It should be noted that the 2.5 mg dose, 0.01 mg/mL solubility drug that was simulated to be sensitive to particle size has similar properties to digoxin whose absorption has been shown to be sensitive to drug particle size.
Table 4 Parameters for Simulations in Figure 6
| Solubility | Absorption rate | Drug particle | ||
| Dose (mg) | (mg/mL) | constant (1/min) | size
(fim) |
Line style |
| 250 | 1 | 0.03 | 5 | solid |
| 250 | 1 | 0.03 | 25 | dot |
| 2.5 | 0.01 | 0.03 | 5 | dash |
| 2.5 | 0.01 | 0.03 | 25 | dot-dash |
| 250 | 1 | 0.001 | 5 | solid |
| 250 | 1 | 0.001 | 25 | dot |
| 2.5 | 0.01 | 0.001 | 5 | dash |
| 2.5 | 0.01 | 0.001 | 25 | dot-dash |
Note: Simulations in Figure 6 correspond to the rows in Table 4 in the same order from top to bottom, respectively.
The same simulations as mentioned earlier can be repeated using an absorption rate constant of 0.001 instead of 0.03 reciprocal minutes, changing the drugs from Case 1 to Case 3: high solubility—low permeability, to give the lower set of four curves shown in Figure 6. The absolute differences between the Case 3 simulations are smaller than those for the Case 1 simulations. This brings up the question as to why Case 3 drugs are not eligible for a biowaiver with a single point dissolution specification of 85% at 30 minutes. If Case 3 dosage forms are rapidly dissolving, it is unlikely that variability in absorption is due to formulation effects. This point has also been made in the original theoretical justification for the BCS. However, only Case 1 drugs are currently eligible for a biowaiver based on the BCS Guidance.
CONCLUSION
Modeling approaches to simulate dissolution, ADME provide tools to help the pharmaceutical scientist understand these processes and to guide decisions on drug selection and development. Application of dissolution and absorption theory has led to the BCS, which holds promise in reducing the burden of demonstrating bioequivalence by using a single-point in vitro dissolution test as a surrogate for in vivo clinical studies for Case 1 drugs. Although the regulatory benefits are limited to Case 1 drugs, application of modelling tools in the pharmaceutical industry may reduce the time and expense of developing new drugs of all classes at each step of the discovery to market process. The theory highlights the importance of solubility, permeability, and pharmacokinetics, and brings these elements together in a way that allows for comprehensive decisions, from avoiding drugs that are likely to be difficult to develop, to setting drug particle size specification to ensure consistent dissolution, to pursuing solubility enhancing or controlled-release formulation.
