Concept of dissolution: In vitro In vivo correlation, Biopharmaceutical Classification system and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam
IN VITRO–IN VIVO CORRELATION:
IVIVC refers to a relationship between a physicochemical characteristic of the dosage form, as determined by in vitro dissolution and biological property and as determined by in vivo pharmacokinetics. The objectives of IVIVC are to use the rate of dissolution as a discriminating parameter with respect to minor changes including changes in equipment, manufacturing process, formulation, batch size and manufacturing site. IVIVC also helps in setting dissolution specifications. For successful IVIVC, in vitro dissolution has to be the rate-limiting step in the absorption of the drug to the systemic circulation. Levels of IVIVC generally recognized are described below:
Level A – It represents a point to-point relationship between in vitro dissolution and the in vivo pharmacokinetics. In this case, the in vitro dissolution curve can be superimposed to the in vivo pharmacokinetic curve and can serve as a surrogate for in vivo performance. A correlation of this type is the best predictor of bioavailability from the dosage form.
Level B – Based on the principle of statistical moment analysis, the mean in vitro dissolution time is compared either with the mean in vivo dissolution time or with the mean residence time.
Level C – It establishes a single-point relationship between one of the dissolution parameters (e.g. time for specific amount dissolved) and one pharmacokinetic parameter (e.g. AUC or Cmax). Level C correlation is the weakest IVIVC and does not reflect the complete shape of the plasma concentration–time curve of the dissolution profile.
Multiple level C – It relates to the amount of drug dissolved at several time points of the dissolution profile to one or several pharmacokinetic parameters.
BIOPHARMACEUTICAL CLASSIFICATION SYSTEM:
The Biopharmaceutical Classification System (BCS) is the scientific basis for classifying drugs based on the key determinants of the rate and extent of drug absorption from immediate release solid orals—aqueous solubility, intestinal permeability and dissolution. The BCS classifies the drug substance into four distinct classes.
Table no. 1 – Classification of drugs based on the biopharmaceutical classification system
| Class | Properties |
| Class 1 | High solubility High permeability Examples: diltiazem, metoprolol, propranolol, verapamil |
| Class 2 | Low solubility High permeability Examples: danazol, ketoconazole, mefenamic acid, nifedipine, phenytoin |
| Class 3 | High solubility Low permeability Examples: acyclovir, captopril, cimetidine, neomycin B |
| Class 4 | Low solubility Low permeability Examples: taxol |
Solubility – The drug is considered highly soluble when the highest dose strength is soluble in 250 mL (approximately 8 ounces) or less of aqueous media over the pH range of 1–7.5.
Permeability – The drug is considered highly permeable when the extent of drug absorption in humans is 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose.
Dissolution – The drug is considered rapidly dissolving when the immediate-release product of the drug releases 85% or greater of the labelled amount of the drug within 30 min, using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in a d900 mL of acidic media such as 0.1 N HCl or Simulated Gastric Fluid USP without enzymes, a pH 4.5 buffer and a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.
To develop immediate-release generic products, the FDA requires demonstration of bioequivalence of the potential generic version with the innovator product. In addition to routine quality control tests, in vitro dissolution tests have been used to grant biowaivers (waive bioequivalence studies) for lower strengths of a dosage form. The BCS characteristics (aqueous solubility and intestinal permeability), together with the dissolution of the drug from the dosage form, supports in vivo bioavailability and bioequivalence waivers for immediate release solid dosage form of drugs.
Conditions to obtain biowaiver for immediate-release solid oral dosage forms are as follows:
- Based on an adequate dissolution test, biowaivers are provided for lower strengths after it has been demonstrated that the highest strength is bioequivalent to the innovators.
- The drug products containing the lower dose strengths should be compositionally proportional or qualitatively the same as the higher dose strengths and have the same release mechanism.
- The drug substances should belong to BCS Class 1, with rapid in vitro dissolution and with the caveat that excipients in the dosage form must not significantly affect absorption of the drug substance.
- The drug product should meet the profile comparison criteria, and the test and reference products should have similar dissolution profile.
Multiple choice questions:
1.IVIVC refers to a relationship between a physicochemical characteristic of the dosage form, as determined by in vitro dissolution and biological property and as determined by in vivo pharmacokinetics.
a)true
b)false
2.The objectives of IVIVC are to use the rate of dissolution as a discriminating parameter with respect to minor changes including changes in
a)equipment
b)manufacturing process
c)formulation
d)all of these
3.For successful IVIVC, _____ has to be the rate-limiting step in the absorption of the drug to the systemic circulation.
a)in vivo dissolution
b)in vitro dissolution
c)intrinsic dissolution
d)intrinsic solubility
4.How many Levels of IVIVC are?
a)1
b)2
c)3
d)4
5.Which of the following represents a point to-point relationship between in vitro dissolution and the in vivo pharmacokinetics?
a)Level A
b)Level B
c)Level C
d)Multiple level C
6.Which of the following is based on the principle of statistical moment analysis, the mean in vitro dissolution time is compared either with the mean in vivo dissolution time or with the mean residence time?
a)Level A
b)Level B
c)Level C
d)Multiple level C
7.Which of the following establishes a single-point relationship between one of the dissolution parameters (e.g. time for specific amount dissolved) and one pharmacokinetic parameter (e.g. AUC or Cmax)?
a)Level A
b)Level B
c)Level C
d)Multiple level C
8.Which of the following is the weakest IVIVC and does not reflect the complete shape of the plasma concentration–time curve of the dissolution profile?
a)Level A
b)Level B
c)Level C
d)Multiple level C
9.Which of the following relates to the amount of drug dissolved at several time points of the dissolution profile to one or several pharmacokinetic parameters?
a)Level A
b)Level B
c)Level C
d)Multiple level C
10.BCS stands for
a)Biopharmaceutical Classification System
b)Biological Classification System
c)Biopharmaceutical Classification Standard
d)Biochemical Classification System
11.The BCS classifies the drug substance into _____ distinct classes.
a)1
b)2
c)3
d)4
12.According to BCS system which of the following is example of Class 1?
a)diltiazem
b)neomycin B
c)taxol
d)phenytoin
13.Class 4 is associated with
a)High solubility High permeability
b)Low solubility High permeability
c)High solubility Low permeability
d)Low solubility Low permeability
14.The drug is considered highly permeable when the extent of drug absorption in humans is _____ or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose.
a)10%
b)50%
c)90%
d)100%
15.Which of the following conditions obtain biowaiver for immediate-release solid oral dosage forms?
a)Based on an adequate dissolution test, biowaivers are provided for lower strengths after it has been demonstrated that the highest strength is bioequivalent to the innovators.
b)The drug products containing the lower dose strengths should be compositionally proportional or qualitatively the same as the higher dose strengths and have the same release mechanism.
c)The drug substances should belong to BCS Class 1, with rapid in vitro dissolution and with the caveat that excipients in the dosage form must not significantly affect absorption of the drug substance.
d)all of these
Solutions:
- a)true
- d)all of these
- b)in vitro dissolution
- d)4
- a)Level A
- b)Level B
- c)Level C
- c)Level C
- d)Multiple level C
- a)Biopharmaceutical Classification System
- d)4
- a)diltiazem
- d)Low solubility Low permeability
- c)90%
- d)all of these
References:
- Gaurav K. Jain Theory and Practise of Physical Pharmacy, 1st edition 2012 Elsevier, page no. 297-299.
- Martins Physical Pharmacy, 6th edition 2011, page no. 576-577.
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