Concept of dissolution: Dissolution apparatus, dissolution conditions, dissolution profile comparison and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Concept of dissolution: Dissolution apparatus, dissolution conditions, dissolution profile comparison and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Any dissolution test method involves immersing the dosage form in a suitable dissolution medium, which is kept in motion at a constant speed and requires determining the rate at which the drug substance is released from the dosage form and dissolves in the medium.

For immediate and delayed-release solid oral dosage forms, including tablets and capsules, USP Apparatus 1 (basket) or 2 (paddle) is recommended. Apparatus 2 is generally the first choice for immediate release because of the ease of use, hydrodynamics, reproducibility and general acceptance. For extended-release dosage forms designed to release the drug at a controlled rate over an extended period of time, USP Apparatus 3 and Apparatus 4 should also be considered because they allow for changes in the medium pH during dissolution testing. When a pH gradient is required, USP Apparatus 3 offers advantages such as ease of setup, operation and sampling relative to USP Apparatus 4. USP Apparatus 4 is particularly applicable to very poorly soluble drug substances because it allows for continuous introduction of fresh dissolution medium during the test. The most common types of USP dissolution testing equipment, Apparatus 1 and 2, are described here.

Basket Apparatus (USP Apparatus 1):

The basket apparatus consists of a motor, a metallic drive shaft, a cylindrical basket and a covered vessel made of glass or other inert transparent material. The vessel is cylindrical with a hemispherical bottom and flanged upper rim. The vessel has a capacity of 1000 mL with inside diameter of 98–106 mm and height 160–175 mm. A cover with sufficient openings to allow insertion of a shaft, a thermometer and a sample withdrawal tube may be used to retard evaporation. The dissolution medium (usually held at 37 ± 1°C) is kept in constant and smooth motion during the test, and there should be no significant agitation or vibration caused by anything other than the smoothly rotating shaft. The shaft is positioned so that the lower edge of the blade is 23–27 mm from the inside bottom of the vessel and its axis is within 2 mm of the axis of the vessels. The rotation speed of the shaft should be maintained within ±4% of the rate specified in the individual monograph using motor. The shaft has a vent and three clips to fit the basket into position. The basket is made of stainless steel (usually 40 mesh), type 316. For testing, a sample unit is placed in a dry basket at the beginning of each test.

Paddle Apparatus (USP Apparatus 2):

In this apparatus, a paddle replaces the basket as the source of agitation. Similar to the basket apparatus, the shaft should position no more than 2 mm at any point from the vertical axis of the vessel and rotate without significant wobble. The metallic blade and the shaft comprise a single entity that may be coated with a suitable inert coating to prevent corrosion. The dosage form is allowed to sink to the bottom of the flask before rotation of the blade commences.

DISSOLUTION CONDITIONS:

Selection of dissolution conditions depends on the following factors:

  • Drug substance properties such as solubility, permeability or solution stability.
  • The site of in vivo drug absorption.
  • Type of dosage form such as tablet, capsule, suspension or transdermal patch.
  • Desired release mechanism of drug product (immediate, delayed or extended release).
  • Establishment of sink conditions.

Dissolution medium commonly used are as follows:

  • 1 N HCl (pH 1.2)
  • Acetate buffer (pH 4.5)
  • Phosphate buffer (pH 6.8) and
  • Phosphate buffer (pH 7.5), for modified release dosage forms

DISSOLUTION PROFILE COMPARISON:

The comparison of dissolution profiles has extensive application throughout the product development process. A dissolution profile comparison can be used to:

  • Set dissolution specifications for the pharmaceutical product
  • Compare similarity of the pharmaceutical product
  • Establish in vitro–in vivo correlations

A model-independent mathematical approach described by Moore and Flanner is the simplest and the most widely applicable method for dissolution profile comparison. The method involves the use of two factors:

Difference factor (f1) –

f1 = {nt=1[Rt-Tt] / nt=1R}X100%                                                                                               (1)

where n is the number of dissolution time points and Rt and Tt are the reference and test dissolution values, respectively, at time t.

The f1 equation is the sum of the absolute values of the vertical distances between the reference and test mean values, i.e. (R Tt) at each dissolution time point, expressed as a percentage of the sum of the mean fractions released from the reference product at each time
point.
If f1 value is 0, the mean profiles are identical and increase proportionally as the difference between the mean profiles increases. If f1 value is between 0 and 15, the two dissolution profiles are same or equivalent and an average difference between mean dissolution profiles is not more than 10%.

Similarity factor (f2) –

f2 = 50log10 {[1+1/n. nt=1Wt(Rt-Tt)2]-0.5 X 100}                                                                          (2)

where n is the number of dissolution time points, Rt and Tt are the reference and test dissolution values, respectively, at time t, and Wt is an optional weighting factor.
The f2 equation is a logarithmic transformation of the average of the squared vertical distances between the test and reference mean dissolution values at each dissolution time point multiplied by an appropriate weighing, i.e. Wt(Rt Tt)2. The transformation is such that the f2 equation takes values less than 100. If f2 value is 100, the test and reference mean profiles are identical.

If f2 value is between 50 and 100, the two dissolution profiles are same or equivalent and an average difference between mean dissolution profiles is not more than 10%.

For extended-, delayed- or modified-release dosage forms, dissolution profile data would be generated at typically five time points, or until 80% of the drug is released. In contrast to this, dissolution profile data for the immediate-release dosage form may be generated at fewer time points. The typical USP requirements for IR dosage forms are that 75% of the active ingredient from the dosage unit should be dissolved in water or acid at 37°C in 45 min in the USP I or USP II apparatus, which is operated at the appropriate speed (typically 100 rpm for USP I or 50 rpm for USP II). Further requirements for dissolution profile comparison are as follows:

  • At least 12 units should be used for each profile determination.
  • The dissolution measurements of the two products (test and reference) should be carried
    out under the same test conditions and the dissolution time points for both the profiles
    should be same.
  • Because f2 values are sensitive to the number of dissolution time points, only one
    measurement should be considered after 85% dissolution of the product.
  • For drug products dissolving 85% or greater in 15 min or less, a profile comparison is not

Both equations are endorsed by the FDA as acceptable methods for dissolution profile comparison, but the f2 equation is prefered.

Multiple choice questions:

1.For immediate and delayed-release solid oral dosage forms, including tablets and capsules which dissolution apparatus is/are used?

a)USP Apparatus 1

b)USP Apparatus 2

c)USP Apparatus 3

d)a and b

2.Apparatus 2 is generally the first choice for immediate release because of

a)ease of use

b)hydrodynamics

c)reproducibility

d)all of these

3.For extended-release dosage forms designed to release the drug at a controlled rate over an extended period of time which dissolution apparatus is/are used?

a)USP Apparatus 2

b)USP Apparatus 3

c)USP Apparatus 4

d)b and c

4.USP Apparatus 4 is particularly applicable to very poorly soluble drug substances because it allows for continuous introduction of fresh dissolution medium during the test. 

a)true

b)false

5.The basket apparatus consists of

a)motor

b)a metallic drive shaft

c)a cylindrical basket

d)all of these

6.The temperature of dissolution medium should be

a)37 ± 1°C

b)35 ± 1°C

c)32 ± 1°C

d)30 ± 1°C

7.The shaft is positioned so that the lower edge of the blade is

a)23–25 mm

b)23–27 mm

c)21–27 mm

d)20–25 mm

8.Selection of dissolution conditions depends on which of  the following factors?

a)Drug substance properties such as solubility, permeability or solution stability.

b)The site of in vivo drug absorption.

c)Type of dosage form such as tablet, capsule, suspension or transdermal patch.

d)all of these

9.Dissolution medium commonly used are

a)1 N HCl (pH 1.2)

b)Acetate buffer (pH 4.5)

c)Phosphate buffer (pH 6.8)

d)all of these

10.Which of the following requirements are for dissolution profile comparison?

a)At least 12 units should be used for each profile determination.

b)The dissolution measurements of the two products (test and reference) should be carried
out under the same test conditions and the dissolution time points for both the profiles
should be same.

c)Because f2 values are sensitive to the number of dissolution time points, only one
measurement should be considered after 85% dissolution of the product.

d)all of these

11.f1 is

a)Similarity factor

b)Difference factor

c)Similar factor

d)Dissimilar factor

12.f2 is

a)Similarity factor

b)Difference factor

c)Similar factor

d)Dissimilar factor

13.The f1 equation is a logarithmic transformation of the average of the squared vertical distances between the test and reference mean dissolution values at each dissolution time point multiplied by an appropriate weighing.

a)true

b)false

14.If f2 value is 100, the test and reference mean profiles are

a)identical

b)different

c)half idential half different

d)multiple

15.If f1 value is 0, the mean profiles are

a)identical

b)different

c)half idential half different

d)multiple

Solutions:

  1. d)a and b
  2. d)all of these
  3. d)b and c
  4. a)true
  5. d)all of these
  6. a)37 ± 1°C
  7. b)23–27 mm
  8. d)all of these
  9. d)all of these
  10. d)all of these
  11. b)Difference factor
  12. a)Similarity factor
  13. b)false
  14. a)identical
  15. a)identical

References:

  1. Gaurav K. Jain Theory and Practice of Physical Pharmacy, 1st edition 2012 Elsevier, page no. 292-297.
  2. Martins Physical Pharmacy, 6th edition 2011, page no. 580-584.

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