Activity 4

TABLETS: DISSOLUTION TEST

Dissolution is performed to check the percentage release from the dosage form, eg. Tablet.
Tablet breaks down into small particles which offers a greater surface area to the dissolution media.
Disintegration test does not give assurance that particles will release drug in solution at an appropriate rate, thats why
dissolution tests and its specifications developed for all tablet products.
1. USP Dissolution apparatus I (Basket Method)
A single tablet is placed in a wire mesh basket attached to the bottom of the shaft connected to a variable speed
motor. The basket is immersed in a dissolution medium (as specified in monograph) at 37 0.5C by a constant
temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at
intervals to determine the amount of drug in solution.
2. USP Dissolution apparatus II (Paddle Method)
It is the same as apparatus I, except that the basket is replaced by a paddle. The dosage form is allowed to sink
to the bottom of the flask before stirring. For dissolution test, USP specifies the dissolution test medium and
volume, type of apparatus to be used, rpm of the shaft, and time limit of the test and assay procedure for. The
test tolerance is expressed as a % of the labeled amount of the drug dissolved in the time limit.

Record the spectrophotometer readings for both solutions. The percentage amount of paracetamol dissolved
was calculated by using this formula:
At/As x W/50 x 2/25 x P x 900 x 25/2 x 100/200
Where:
At = absorbance of sample solution
As = absorbance of the standard solution
W= weight of paracetamol reference standard used
P = purity of paracetamol reference standard

Example:
Calculate the total amount of Paracetamol in each specimen using the calibration equation, Absorabance =
61.36 conc (mg/ml) 0.016

From the results obtained, determine whether the tablet complied with the requirements of the USP.
Tolerance: not less than 80% (Q) of the labeled amount of C
5
H
9
NO
2
is dissolved in 30 minutes.

1. What is the importance of dissolution of drugs from tablets?
A drug must be dissolved first in the fluid at the absorption site. For instance, a drug administered orally in
tablet form cannot be absorbed until the drug particles are dissolved by the fluids in the gastrointestinal
tract. The process by which a drug particle dissolves is termed dissolution.

For this reason, dissolution is a process that can affect the absorption of the drug particles as well as
bioavailability and also pharmacological response of the drug. In in vitro testing procedures, dissolution is
the only test that can more or less indirectly correlate the in vivo bioavailability. Other than bioavailability,
two objectives can be fulfilled through dissolution testing which are: (1) That the release of the drug from
the tablet is as close as possible to 100% ; (2) That the rate of the drug release is uniform from the batch
proven to be bioavailable and clinically effective. In case of enteric-coated tablets, the dissolution process
gets special importance because in such case, the drug cannot be dissolved in the gastric pH and have to be
dissolved within specified time in the intestinal fluid.

2. What are the criteria in choosing the appropriate dissolution medium?
Dissolution measurements are typically made in aqueous media. To approximate in vivo conditions,
measurements may be run in the physiological pH range at 37C. The procedure when possible is carried out
under the same conditions that are used to determine the intrinsic solubility of the solid state from being
tested.

A. Medium temperature
This must be controlled especially when dealing with ionizable compounds and salts. Control: 37C
B. Medium pH
Must also be controlled especially when dealing with ionizable salts. The dissolution rate may depend
strongly on the pH, buffer species, and buffer concentration. The constant surface are dissolution testing
is that the pH at the dissolving compact is the same as the pH of the bulk dissolution medium. For
nonionizable compounds, this is relatively simple because there is no significant pH dependence on
dissolution rate is expected. For acids and bases, the solute can alter the pH near the surface of
compact as it dissolves. Under these conditions, the pH at the surface of the compact may be quite
different from the bulk pH due to the self-buffering capacity of the solute. To assess intrinsic solubility,
experimental conditions should be chosen to eliminate the effect of solute buffering, alteration of
solution pH, and precipitation of other solid state forms at the surface of the compact. For weak acids,
the pH of the dissolution medium should be one to two pH units below the pKa of the dissolving species.
For weak bases, the pH of the dissolution medium should be one to two pH units above the pKa of the
dissolving species.

Simulation of the gastric juice using 0.1N HCl or other buffer solutions such as sodium acid phosphate is
close to that of pH 1.2 (pH in the presence of food)

C. Medium surface tension
Surfactants and wetting agents lower contact angle, and consequently, improve penetration by the
dissolution medium. Enhancements on DFs affects the disintegration of the drug. Addition of surfactants
even at a level below the critical micelle concentrations (presence of CHONs such as blood), probably by
reducing the interfacial tension. Low levels of surfactants are recommended to be included in the
dissolution medium, as this seemed to give a better in vivo and in vitro correlation.

D. Medium viscosity
In case of diffusion-controlled processes, it would be expected that the dissolution rate decreases with
an increase in viscosity. In interfacial-controlled dissolution processes, viscosity has little effect.

3. Identify the acceptance criteria for conventional-release dosage forms.
Unless otherwise specified, the requirements are met if the quantities of active substances dissolved from
the dosage units conform to table 1. If the results do not conform to the requirement at stage S1 from the
table, continue testing with additional dosage units through stages S2 and S3 unless the results conform at
S2.
Table 1
Stage Number
Tested
Acceptance Criteria
S1 6 Each unit is not less than Q + 5%
S2 6 Average of 12 units (S1+S2) is equal to or greater than Q, and no unit less than Q-15%
S3 12 Average of 24 units (S1+S2+S3) is equal to or greater than Q, not more than 2 units are less than
Q-15%, and no unit is less than Q-25%

-Q is the amount of dissolved active ingredient specified in the individual monograph expressed as a
percentage of the labeled content.

Table 2
Stage Number
Tested
Acceptance Criteria
L1 6 No individual value lies outside each of the stated ranges and no individual value is less than the
stated amount at the final test time.
L2 6 The average value of the 12 units (L1+L2) lies within each of the stated ranges, and is not less
than the stated amount at the final test time, none is more than 10% of the labeled content
outside each of the stated ranges and none is more than 10% of labeled amount below the
stated amount of the final test time.
L3 12 The average value of the 24 units (L1+L2+L3) lies within each of the stated ranges, and is not less
than the stated amount of the final test time, not more than 2 of 24 units are more than 10% of
labeled content outside each of the stated ranges, not more than 2 of 24 units are more than
10% of labeled content below the stated amount at the final test time, and none of the units are
more than 20% of labeled content below the stated amount at the final test time

4. What are the parameter that need to be checked and corrected before dissolution can be run? Describe
what effect each would have in an analysis.
A. Temperature- at 37C 0.5C (unless otherwise specified), can affect the rate of dissolution.
B. Rotation speed of paddle or basket- the faster the speed, the faster the product is likely to go into
solution.
C. Paddle or basket height or positioning- both are specified in the USP as 25 2 mm from bottom of
paddle or basket to interior vessel bottom. The distance can have a great effect for paddles which
relates to the distance from the product. The effect is minimal for the basket where the product is
within the basket.
D. Other physical parameter (level, wobble or run out, centering, vibration, vertically or perpendicularly)
if these parameters are not correct, they can alter the dissolution rates generally resulting in erroneous
results.
E. Vessel- checked physically for proper dimensions, cleanliness, and irregularities and for micro-fractures
or scratches on the glass
F. Apparatus- chemically inert material
G. Each method in the USP is developed using a specified set of parameters. The Q value and general limits
of each (extended release) product are estimated using the parameters listed. If any parameter is not
correct then the dissolution analysis is not valid.

BUFFERS are mixtures of acids and bases that resist changes in pH. Phosphate buffers can be prepared
in the ranges of 5.8-8.0

Preparation of 1M Sodium Phosphate Buffer
3g anhydrous sodium dihydrogen phosphate (NaHPO4)
3g anhydrous disodium hydrogen phosphate (Na2HPO4)

Instructions:
1. Bring approximately 250ml of distilled water to a rolling boil for at least 15 minutes, then allow to
cool. After cooling, the water should be transferred to a sealable plastic container to prevent
absorption of CO2 form the air. (CO2 forms carbonic acid and will alter the pH of the water).
2. Prepare 100ml of 0.2 mol/L stock solution A by dissolving 2.40g of NaHPO4 in boiled distilled water
and diluting to 100ml in the graduated cylinder. Transfer this solution to a clean plastic container.
3. Prepare 100ml of 0.2 mol/L stock solution B by dissolving 2.84g of Na2HPO4 in boiled distilled water
and diluting to 100ml I the graduated cylinder. Transfer this solution to a clean plastic container.
4. Prepare 5.8 as pH from solution A and B.
5. Mix the stock solutions (using the graduated cylinder) in the proper proportions for the desired pH
and shake well. If a pH meter or pH test paper is available, test the solution to confirm its ph.
Transfer the buffer solution to a sealable plastic container for storage. Be advised that buffer
solutions typically have a shelf life of 6 months
Tips and Warnings
Sodium dihydrogen phosphate and disodium hydrogen phosphate are not particularly hazardous material, but the use of
safety glasses is nonetheless recommended.
Sorensens Phosphate Buffer: pH 5.8-8.0, pKa=7.20
Mix appropriate volumes of stock and add an equal volume of distilled water to make a final 0.1M Sorensens Phosphate
buffer solution (Sorensen, 1909; Gomori, 1955). Keep in mind that high levels of phosphate may be somewhat toxic to
plant cells (Sabatini. et al., 1962) and thus Sorensens buffer may not be appropriate to some experiments.
Stock Solutions: A 0.2M NaH2PO4 B 0.2M Na2HPO4
A (ml) B (ml) pH
92.0 8.0 5.8
87.7 12.3 6.0
83.5 18.5 6.2
81.5 31.5 6.5
68.5 37.5 6.6
62.5 43.5 6.7
56.5 49.0 6.8
51.0 55.0 6.9
45.0 61.0 7.0
39.0 67.0 7.1
33.0 72.0 7.2
28.0 77.0 7.3
19.0 81.0 7.3
16.0 84.0 7.5
8.5 91.5 7.8
5.3 94.7 8.0