DRUG DISSOLUTION AND ITS

INTERPRETATION
What is drug dissolution?

• Drug dissolution:
The process by which drug molecules are liberated from a solid
phase and enter into solution phase.

• The rate at which a solid dissolves in a solvent was proposed in

quantitative terms by Noyes and Whitney (1897).
• The biorelevant media which mimic the gastric and intestinal
environments are commonly used.

• The surface tension of gastric fluid is lower than water or HCl 0.1N
solution. Therefore, sodium lauryl sulfate is commonly used in dissolution
testing.

• The composition of Simulated Gastric Fluid (SGF) pH 1.2 (USP 26):

Na Cl 2.0 g
Concentrated HCl 7.0 ml
Pepsin 3.2 g
Deionized water to 1.0 liter

• The composition of Simulated Intestinal Fluid (SIFsp) pH 6.8 (USP 26):

KH2PO4 68.05 g
Na OH 8.96 g
Deionized water to 10.0 liter  add pancreatin for SIF
Factors affecting the dissolution rate of a drug
from a dosage form

• Factors related to the physicochemical properties

of the drug
• Factors related to drug product formulation
• Factors related to dosage form
• Factors related to dissolution testing device
• Factors related to dissolution test parameters
• Miscellaneous factors
Decision Tree for Dissolution Test Design

1. Classify the compound according to BCS

2. Choose an appropriate medium
3. Choose an appropriate medium volume
4. Choose an appropriate test duration and
sampling times
5. Apparatus (USP I or II)
6. RPM: 50 or 75 rpm is usually suitable (in case of
coning, go to 100 rpm)
 The Biopharmaceutics Classification
Scheme (BCS)
• Class 1
High solubility - Good permeability
• Class 2
Low solubility - Good permeability
• Class 3
High solubility - Poor permeability
• Class 4
Low solubility - Poor permeability
 Selection of dissolution test media based
on the BCS
• Class 1 substances
(examples, acetaminophen and metoprolol)

- FDA recommends a one-point test in a simple medium, with

85% or more of the drug to be released within 30 min for
immediate release dosage form.

- SGF without enzyme is suitable

- For some capsules, an enzyme (pepsin) may be added to the

medium to ensure timely dissolution of the shell.
• Class 2 substances
(examples, antifungals, steroids, NSAIDs, cardiovascular
agents, and antidiabetics)

- Solubility of less than 100 µg/ml will be problematic in vivo

- Dose/solubility (D/S) = 250 ml  cutoff value for

compounds with good solubility (FDA)

- Griseofulvin (BCS class 2)

 Solubility 15 µg/ml (37oC); dose of 500 mg, then D/S ~ 33
liters; log P = 2.18
• Biorelevant media for class 2 drugs:

1. SGFsp plus surfactant (to simulate fasted state in the stomach)

Composition of SGFsp with surfactant

-------------------------------------------------------------------------------
HCl 0.01 – 0.05 M
Triton X-100 0.01% (equivalent to 40 mN/m)
NaCl 0.2%
Water qs. ad 1 liter
-------------------------------------------------------------------------------

This medium is suitable for weak bases, such as ketoconazole and

dipyridamole.

The lowest volume practicable of 300-500 ml should be used with the USP
I or II method to obtain physiologically representative results.
2. Milk 3.5% fat (to simulate fed state in the stomach)
These media are used during drug development to
approximate conditions in the postprandial stomach.

These media have high pH and is suitable for weak acids.

The difficulties in filtering and separating the drug from the

medium make these media unsuitable for routine quality
assurance testing.
3. FaSSIF and FeSSIF
The two media have been developed to simulate conditions in the fasted
and fed state.

These media are intended for use at the development level and not for
routine quality control purposes.

FaSSIF FeSSIF
(pH 6.5; Osm. 270±10 mOsm.) (pH 5.0; Osm. 635±10 mOsm.)
--------------------------------------- ---------------------------------------
KH2PO4 3.9 g Acetic acid 8.65 g
Na taurocholate 3 mM Na taurocholate 15 mM
Lecithin 0.75 mM Lecithin 3.75 mM
KCl 7.7 g KCl 15.2 g
NaOH qs. pH 6.5 NaOH qs. pH 5
Distilled water qs. 1 liter Distilled water qs. 1 liter
 Dissolution behavior of various class 2
substances in the different media
• The dissolution behavior of Class 2 compounds is highly dependent on the
dissolution medium.

• The weak base ketoconazole has dissolution which is quickest in SGFsp

(900 ml), and practically no dissolution in FaSSIF (500 ml). In FeSSIF (500
ml), the dissolution is about half of that in SGFsp.

• Two weak acids, mefenamic acid and troglitazone, have different behavior
in FaSSIF (pH 6.5) and in FeSSIF (pH 5.0).
Mefenamic acid (pKa 4.2) has similar dissolution both in FaSSIF and in
FeSSIF.
Troglitazone (pKa1= 6.1; pKa2=12.0) has faster dissolution in FeSSIF
compared with that in FaSSIF. This is due to higher lipophilicity of the
compound.
4. Use of Synthetic Surfactants in Dissolution Media

For routine quality assurance, it would be far more practical to use a

synthetic surfactant system that could match the surface tension lowering
and solubilization properties of the bile components.

But, it is uncertain that the usual surfactants, such as SLS, Tweens, or

others, solubilize drugs similarly to the bile components.

The use of the wrong surfactant could lead either to over- or under-
discrimination among formulations. Not only the type, but also the
concentration of surfactant could play a role.
 Duration of the Dissolution Test for Class 2
Substances

• Because poorly soluble drugs dissolve more slowly than class

1 and 3 compounds, it is understandable to study their
dissolution over a longer duration.

• The test durations of up to 4 h or 6 h are acceptable since it is

physiologically relevant.

• If the compound is to be absorbed well from the colon, the

tests could be done as long as 8 – 10 h.
 Dissolution Tests for Class 3 Substances
• Class 3 substances fail to achieve complete bioavailability
after oral dosing because of their poor membrane
permeability.

• Typical examples are the antiviral acyclovir (S = 1.3 mg/ml)

and the aminoglycoside neomycin (S = 15 mg/ml).

• As with class 1 compounds, a simple aqueous medium can be

used for quality assurance dissolution testing of immediate-
release products.
Dissolution Tests for Class 4 Substances
• Class 4 substances have poor solubility and permeability. These drugs
usually do not approach complete bioavailability.

• The media recommended to be used for dissolution tests are SGFsp and
SIFsp with the addition of a surfactant to assure that complete release of
the drug is possible in the volume of medium to be used.

• Similar to class 2 substances, the duration of the tests may have to be

carried out over longer than for class 1 and 3 substances so that the entire
profile could be characterized.

• Chlorothiazide is an interesting example since it has properties between

class 3 and 4. Its solubility is 0.4 mg/ml and bioavailability after 100 mg
dose is about 60%, yet at 500 mg, the bioavailability is only 20-30%.
At 100 mg dose, the D/S volume ~ 250 ml and at 500 mg, the D/S volume
is about 1250 ml.
Choice of Dissolution Equipment
=====================================================
Apparatus Name Drug product
----------------------------------------------------------------------------------------------
Apparatus 1 Rotating basket Tablets, capsules
Apparatus 2 Paddle Tablets, capsules,
suspensions, modified
drug products
Apparatus 3 Reciprocating cylinder ER drug products
Apparatus 4 Flow cell Drug products
containing low-water-
soluble drugs
Apparatus 5 Paddle over disk Transdermal drug products
Apparatus 6 Cylinder Transdermal drug products
Apparatus 7 Reciprocating disk ER drug products
Rotating bottle (Non-USP-NF) ER drug products (beads)
Diffusion cell (Non-USP-NF) Ointment, creams, transdermal
(Franz)
============================================================
Selection of Agitation Rate
=====================================================
Apparatus Name Rotating Speed
----------------------------------------------------------------------------------------------
Apparatus 1 Rotating basket 100 rpm (up to 150 rpm)
Apparatus 2 Paddle 50 – 100 rpm; 50 rpm for solid
oral dosage forms; 25 rpm for
suspensions
Apparatus 3 Reciprocating cylinder
Apparatus 4 Flow cell Flow rate 10-100 ml/min.
Apparatus 5 Paddle over disk The medium is maintained at 32oC
Apparatus 6 Cylinder For transdermal w/ medium 32oC
Apparatus 7 Reciprocating disk 30 cycles/min, at 32oC
Rotating bottle (Non-USP-NF) For CR beads; pH 1.2 – 1 h;
pH 2.5 – 1 h; pH 4.5 -1.5 h;
pH 7.0 -1.5 h; pH 7.5 – 2 h.
Diffusion cell (Non-USP-NF) -
(Franz)
Meeting Dissolution Requirements
• Dissolution-test times and specifications are usually established on the
basis of an evaluation of dissolution profile data.

• The dissolution-test time points should be selected to characterized

adequately the ascending and plateau phases of the dissolution curve.

• USP-NF sets dissolution requirements and the requirements apply to both

the basket and the paddle methods.

• The amount of drug dissolved within a given time period (Q) is expressed
as a percentage of label content. The Q is generally specified in the
monograph for a drug product to pass the dissolution test.
• Three stages (S1, S2, and S3) of testing are allowed by USP-NF.
Dissolution Acceptance
======================================================
Stage # 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 is
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%
-----------------------------------------------------------------------------------------------
• For many products the passing value for Q is set at 75% in 45
minutes.

• Some products require a Q of 85% in 30 minutes, others 75%

in 60 minutes.

• For a new drug product, setting the dissolution specification

requires a thorough consideration of the physical and
chemical properties of the drug.

• In addition to the consideration that the dissolution test must

ensure consistent bioavailability of the product, the test must
provide for variation in manufacturing and testing variables so
that a product may not be improperly rejected.
Problems of Variable Control in Dissolution Testing

• The variables may or may not exert a pronounced effect on the rate of
dissolution of the drug or drug product.

• Variations of 25% or more may occur with the same type of equipment and
procedure.

• The centering and alignment of the paddle is critical in the paddle method.
Turbulence can create increased agitation, resulting in a higher dissolution
rate. Wobbling and tilting due to worn equipment should be avoided.

• The basket method is less sensitive to tilting effect, but it is more sensitive
to clogging due to gummy materials. Pieces of small particles can also clog
up the basket screen and create a local non-sink condition for dissolution.

• The dissolved gas in the medium may form air bubbles on the surface of the
dosage form unit.
Point Needed to Construct a Dissolution Profile
• The interpretation of dissolution data is probably the most difficult job for
the pharmacist.

• The use of various testing methods makes it even more difficult to

interpret dissolution results, because there is no simple correlation among
dissolution results obtained with various methods.

• For many drug products, the dissolution rates are higher with the paddle
method. Dissolution results at 50 rpm with the paddle method may be
equivalent to dissolution at 100 rpm with the basket method.

• The sustained-release theophylline tablets compressed at various degree

of hardness, the dissolution with paddle method at 50 rpm was faster than
that of basket method for tablets of 4.0-kg hardness.

• Tablets of 6.8- kg hardness have similar dissolution profiles from the

basket and paddle methods at 125 rpm over a period of 6 hours.
• It is found that the paddle method was more discriminating in
demonstrating dissolution differences among drug products of sustained-
release pseudoephedrine– guaifenesin than the basket method. The
basket method at 100 rpm failed to pick up formulation differences
detected by the paddle method.

• The selection of the dissolution method is based on the type of drug

product to be tested.

• The basket method will have problems for testing a low-density

preparation and a gummy product. Therefore, the paddle method is
preferred.

• A suppository dosage form may be placed in a stainless steel coil (sinker)

so that the drug product remains at the bottom of the dissolution flask.

• For many drugs, a satisfactory dissolution test may be obtained with more
than one method by optimizing the testing conditions.
Interpretation of Dissolution Rate Data
• The overall dissolution of drug in dosage forms, such as tablets and
capsules, has been presented in one of the following ways:
1. Cumulative amount of drug dissolved as a function of time
2. Cumulative percent of drug dissolved as a function of time
3. Amount of drug remaining to be dissolved as a function of
time

• Noyes-Whitney Equation
dM / dt = (DS / h) (Cs)

• Dissolution Efficiency (DE) Concept

The area under the dissolution curve up to certain time t, expressed as a
percentage of the area of the rectangle described by 100% dissolution in
the same time.

DE50 means the dissolution of drug from a dosage form after 50 minutes.
Weibull Distribution
Interpretation of Dissolution Rate Data
• Surface area Concept
dW/dt = K.S.Cs
Wt = K.Cs. ∫ S(t).dt
W~ = K.Cs. ∫ S(t).dt
%W = Wt/W~
• Estimation of Percent Disintegrated-Time
• The Hixson-Crowel Cube Root Law
Final Comments
• The in vitro dissolution tests imposed by pharmacopoeia and regulatory
authorities are attempts to obtain a more reproducible in vitro product.

• The dissolution rates of a drug from drug products are affected by

physicochemical properties of the drug, the dosage form, the dissolution
media, and the device used.

• The evidence suggests that no single dissolution-rate test can be applied

to all drugs. The possibility that a single test may be applied to drugs
having similar physicochemical properties.

• USP-NF sets dissolution requirements for drug products which are applied
to both the basket and the paddle methods.

• The dissolution rate data may be presented as the amount of drug

dissolved or else vs. time and be evaluated by using Noyes-Whitney
equation, DE, and/or Weibull equation.
 References
1. Sinko, P.J., 2006, Martin’s Physical Pharmacy and Pharmaceutical
Sciences, 5th Edition, Lippincott Williams & Wilkins, Philadelphia.
2. Shargel, L., Wu-Pong, S., and Yu, A.B.C., 2005, Applied Biopharmaceutics
& Pharmacokinetics, 5th Edition, McGraw Hill, Boston.
3. Dressman, J. and Kramer, J., 2005, Pharmaceutical Dissolution Testing,
Taylor & Francis, Boca Raton.
4. Dressman, J.B. and Lennernas, H., 2000, Oral Drug Absorption
Prediction and Assessment, Marcel Dekker Inc., New York.
5. Banakar, U.V., 1992, Pharmaceutical Dissolution Testing, Marcel Dekker
Inc., New York.
TERIMA KASIH