Factors Affecting Dissolution Rate

in respect of Bioavailability
Methods of in-vitro and in-vivo
determination of rate of dissolution.
Contents
 INTRODUCTION TO DISSOLUTION
 Factors affecting Rate of Dissolution
 ROLES OF DISSOLUTION STUDIES AND ITS PURPOSE
 IN-VITRO DISSOLUTION TESTING AS QC TOOL
 Quality Control of Immediate-Release Dosage Forms
 QUALITY CONTROL OF MODIFIED-RELEASE DOSAGE FORM
 Limitations of Quality Control Dissolution Tests
 Biorelavant Dissolution Testing
 The Importance of BCS on Biorelavant
Dissolution Testing
 Biorelavant Dissolution Methods
 Biorelavant Dissolution Media for Gastric Conditions
 Biorelavant Dissolution Media for Intestinal Conditions
 Biorelavant Methods for Extended-Release Dosage Forms
 Conclusion
INTRODUCTION TO
DISSOLUTION
DISSOLUTION
Dissolution is generally defined as a process
by which a solid substance is dissolved into
the solvent to yield a solution.

This process is fundamentally controlled by

the affinity between the solid substance and
the solvent.
Steps of oral drug absorption

When a systemically acting drug is

administered in solid dosage forms its
absorption into the systemic circulation can be
generally described by four steps:
• delivery of the drug into its absorption site
• dissolution takes place in the stomach and/or in the small
intestine.
• permeation of the dissolved drug across the
gastrointestinal (GI) membrane
• the absorbed drug passes through the liver and reaches
the systemic circulation.
Significance of Dissolution Studies
 If the dissolution process is slow relative to the other three
processes, dissolution will be the rate limiting step.

 As a result, the dissolution rate will determine the overall rate

and extent of drug absorption into a systemic circulation, and
hence bioavailability.

 Dissolution analysis of pharmaceutical solids has become one of

the most important tests in drug product development.
Cont…
 Dissolution analysis is important in assessment of drug product
quality.

 Dissolution testing provide information regarding the effects of

drug substance biopharmaceutical properties and formulation
principles on the release properties of a drug product.

 A direct relationship between in vitro dissolution rate of many

drugs and their bioavailability has been demonstrated and is
generally referred to as in vitro-in vivo correlation, IVIVC.
Rate of dissolution
It may be defined as the amount of drug substance that is
dissolved into solution per unit time.
Noyes–Whitney equation can be used to describe the
dissolution rate as following:
dm/dt = A D/h (Cs − C)
where dm/dt is the rate of solid dissolution,
A is the solid surface area,
D is the diffusion coefficient,
h is the thickness of unstirred boundary layer,
Cs is the apparent solubility, and C is the concentration of drug
in dissolution media.
 Methods to increase dissolution rate

Selection of salt form

Particle size reduction

Use of surfactants

Preparation of solid dispersions

Formation of lipophilic formulations i.e. emulsions

Factors affecting Rate of Dissolution
Factors affecting Dissolution

1. related to the physicochemical properties of the drug

substance
2. factors related to drug product formulations

3. factors related to manufacturing processes

4. factors related to dissolution testing conditions.

Factors Related to the Physicochemical
Properties of the Drug Substance
SOLUBILITY:
A rough predictor for indicating any potential problems with oral absorption

Higher the solubility, higher the dissolution rates

The solubility of ionizable drugs, such as weak acids and bases, depends upon both
the pH of the medium and the pKa

Particle Size:
The dissolution rate is directly proportional to the surface area of the drug.

Micronization
Factors cont…
Solid Phase Characteristics:
Differences in the lattice energies among various polymorphic forms
result in differences in the solubilities
The solubility of amorphous forms can be several hundred times greater
than that of the corresponding crystalline state.

Salt Effects:
Salt formation is frequently used to increase the solubility of a weak
acid and base.
The dissolution rate of the salt will often be enhanced due to the
difference in the pH of the thin diffusion layer surrounding the drug
particles
Factors Related to Drug Product Formulation
Inactive ingredients (or excipients) may influence the dissolution of a drug product.

 For immediate-release dosage forms, excipients improve the drug

release or solubilization of a drug substance.
Disintegrants such as starch

For poorly soluble drugs, incorporation of surfactants (e.g., polysorbate)

Improve solubility by promoting drug wetting and by decreasing the surface tension
of hydrophobic drug particles with the dissolution
For modified-release drug products, specific excipients to control
the rate and extent of drug release or to target the delivery to selective sites in the
GI tract.
 For instance, in matrix-based formulations, the active ingredient is embedded in a
polymer matrix, which controls drug release through using mechanisms such as
swelling, diffusion, erosion.
Factors Related to Manufacturing Processes
 Wet granulation improve the wettability of poorly soluble
drugs by incorporating hydrophilic properties into the surface
of granules, hence resulting in a greater dissolution rate
 Direct compression
For instance, high compression may reduce the wettability
Formation of firmer and effective sealing layer by the
lubricant is likely to occur under the high pressure that is
usually accompanied by high temperature.
Factors Related to Dissolution Testing Conditions
External factors, such as temperature and viscosity of the dissolution
medium
effect on the diffusivity of a drug molecule.
According to the Stokes–Einstein equation, the diffusion coefficient of a
spherical molecule in solution is given by
D = kT
6πηr
where T is the temperature, r is the radius of a molecule in solution, η is
the viscosity of the solution, and k is the Boltzmann constant. This
equation indicates that
diffusion is enhanced with increasing temperature but is reduced with
increasing viscosity.
ROLES OF DISSOLUTION STUDIES AND ITS
PURPOSE
 ROLES OF DISSOLUTION STUDIES
 In the development and production of solid dosage forms
mainly for API.
 to develop and evaluate the performance of new formulations
by examining drug release from dosage forms.
monitoring and assessing the formulation consistency and
changes. In formulation optimization, process development
and scale up during Phases II and III
Roles cont…
It is also employed to evaluate the quality of the product
during its shelf life.
to obtain an in vitro–in vivo correlation (IVIVC) information
that will guide bioavailability and/or bioequivalence
assessment of drug products
predict in vivo performance.
PURPOSE OF DISSOLUTION & DRUG RELEASE TESTS
Formulation development and selection
Confirmation of batch-to-batch reproducibility
Establish drug product stability
Evaluate biopharmaceutical implications of a product
change
consistent performance of a drug throughout its use
IN-VITRO DISSOLUTION TESTING AS QC
TOOL
IN-VITRO DISSOLUTION TESTING AS QC TOOL
The purpose of the dissolution test indicates the choice of dissolution
media.
In principle, dissolution testing should be carried out under physiological
conditions if possible, allowing interpretation of dissolution data with
respect to the in vivo performance of a drug product.
Particularly, as a QC and testing tool, it is critical to develop a dissolution
method, which can consistently deliver a reliable test result and also
assess drug product quality attributes (e.g., particle size, polymorphic
form, or excipients) that are sensitive to formulation and manufacturing
changes.
 The design of a dissolution test used for QC is therefore often dictated
by the physicochemical properties (particularly solubility) of a drug
substance and its formulation
Dissolution Method for Quality Control of Immediate-
Release Dosage Forms
 Dissolution Media :
According to FDA the pH of these media should be within the
physiologic pH range of 1.2-6.8,where pH1.2 and pH6.8 represent the pH
values under the gastric and intestinal conditions, respectively.
Hydrochloric acid, acetate, or phosphate buffer in the physiological pH
range are commonly used and accepted as a dissolution medium for QC.
The use of pure water in dis- solution testing is usually not
recommended primarily due to its limited buffering capacity.
 For some poorly soluble drugs that cannot dissolve adequately in
aqueous solutions within the physiologic pH range, surfactants may be
required to provide sink conditions and achieve a complete drug
dissolution within reasonable time.
Apparatus and Test Conditions
The most commonly used dissolution apparatus for solid
oral dosage forms are :
The basket method (USP Apparatus I).
 The paddle method (USP Apparatus II).
 The reciprocating cylinder (USP Apparatus III).
The flow-through cell system(USP Apparatus IV).
The first two apparatus are commonly used for dissolution
testing of immediate-release dosage forms.
Due to the potential need for the large volume of medium,
the flow-through cell system is not suitable for a dissolution
test that is used routinely for the QC purpose.
For QC or drug product release testing, mild agitation
conditions should be maintained during dissolution testing
using the basket and paddle methods to allow maximum
discriminatory power.
PADDLE METHOD
BASKET METHOD
If the rotational speed is too low, it will leads to a low
dissolution rate. However, if the rate of rotation is too fast,
the test will not be able to discriminate the differences
between the acceptable and not acceptable formulations or
batches.
 The common stirring speed used for Apparatus I is50–100
rpm, while with Apparatus II the common stirring speed is
50–75 rpm.
 All dissolution tests should be performed at physiological
temperature (37±0.5◦C).
The test duration ranges from 15 min to 1 h.
DISSOLUTION METHOD FOR QUALITY CONTROL
OF MODIFIED-RELEASE DOSAGE FORM
DISSOLUTION MEDIA
• same as that used for
Media immediate release
dosage form
used

• more than one dissolution

Dissoluti media with different pH
values
on test • to simulate the change in
pH along GI tract.
 APPARATUS AND TEST CONDITIONS
• Basket and Paddle Method
Apparatu
s used
• Reciprocating cylinder may be used

Operatin
• very similar to those used for immediate
g
condition
release
s

• test duration, which may be as long as

Exception 12h for extended release products.
Limitations of Quality Control Dissolution Tests
Limitations
There are some issues regarding the current use of
dissolution tests that were developed for QC ,because
these dissolution tests are developed to provide a
maximum discriminatory power to assess any formulation
changes and manufacturing process deviations. they are
often overly discriminating, meaning that the differences
detected by these dissolution tests may not have any
clinical relevance.
Cont…
For instance, in the FDA-sponsored studies of metoprolol ,
although the slow-dissolving tablets of metoprolol failed
the USP dissolution test, the in vivo pharmacokinetic
studies showed that all metoprolol tablets were
bioequivalent with their corresponding formulations
regardless of their in vitro dissolution rates. Thus, these
clinically insignificant differences detected by the overly
discriminating dissolution test often lead to the rejection of
batches that may have an acceptable clinical performance.
Cont…
As a consequence, without a detailed knowledge on how
dissolution affects the bioavailability of the drug product,
these specifications are usually set to be very tight to
assure the product quality and consistency by identifying
any possible subtle changes in the product attributes
before in vivo performance is affected. These shortcomings
further facilitate the need for the development of
biorelevant dissolution tests.
Cont…
Dissolution tests used for QC can also be subjected to the limitation of being
nondiscriminating.

REASON:
 This limitation becomes evident if testing conditions are not selected appropriately (e.g., the
agitation rate or surfactant level). This situation is best illustrated by the case of mebendazole.

EXAMPLE:
 Mebendazole, which is a broad-spectrum anthelmintic drug, exists in three polymorphic forms
(A, B, C) that display solubility and therapeutic differences. Among these three forms,
polymorph C is therapeutically favored. Despite these differences, the three polymorphs
produced similar dissolution profiles using a dissolution method that employed 0.1N HCl with
1% SLS. Specifically, all these dissolution profiles met the specification in which 75% of the
drug dissolved within 120 min.
 It has been understood that the use of a large amount of SLS in the dissolution medium
eliminates the differences in the dissolution rates of mebendazole polymorphs.
PRECISION AND ACCURACY FACTORS:
The precision and accuracy of dissolution testing are often very sensitive to several
subtle operational controls. These include the agitating element, vibration, stirring
element alignment, stirring rate, dosage form position, sampling probes, position, and
filters. These factors may have a significant effect on the dissolution measurement if
they are not controlled properly.

 EXAMPLE:
 For instance, the study of non disintegrating double layered tablets containing salicylic
acid indicates that the stirring rate and basket placement influence the drug dissolution
in the basket apparatus .

In addition, the hydrodynamics in the paddle apparatus have been shown to be very
complex and vary with site in the vessel . Therefore, the exact location where the tablet
lands after it is dropped into the vessel may have a considerable influence on the
velocity profile around the tablet and hence its dissolution behavior.
 Biorelavant Dissolution Testing
•To achieve an adequate estimate of in vivo release behavior for solid dosage
forms, the relevant physiological conditions, in addition to the physicochemical
properties of a drug substances are important during the development of a
biorelevant dissolution testing system.

•For this biorelevent dissolution method is used which account for the following
factors to reflect the physiological conditions in the GI tract:
pH Conditions
composition of the GI contents
Volume of the GI contents
Transit times
Motility pattern
Dosing conditions (e.g., administered with food)
It is important to first review the concept and application
of the in vitro–in vivo correlation on the biorelevant
dissolution testing development

This correlation describe the relationship between an in

vitro property of a dosage form and a relevant in vivo
response. In general, the physicochemical property or in
vitro property of a dosage form is the in vitro dissolution
profile.
In Vivo–In Vitro Correlations
 The major objective of using biorelevant dissolution methods is to establish in
vivo–in vitro correlation (IVIVC) so that in vitro dissolution data can be used to
predict bioavailability.
 Four correlation levels are defined:
 Level A: a point-to-point relationship between in vitro dissolution rate and in
vivo input rate of the drug from the dosage form.
 Level B: a comparison of the mean in vitro dissolution time to in vivo residence
time or the mean in vivo dissolution time.
 Level C: a single point relationship between a dissolution parameter (t50%,
t90%,
 Multiple-level C: a correlation that relates one or several pharmacokinetic
parameters of interest to the amount of drug dissolved at several time points of
the dissolution profile.
 Among all levels of correlation, Level A is the most meaningful for
predicting purposes, since it provides a relationship that directly
links in vivo drug absorption to in vitro dissolution. This level of
correlation should be valid for a reasonably wide range of values of
formulation and manufacturing parameters that are essential for
the drug release characteristics. This level can be used as a
surrogate for in vivo performance of a drug product.
The Importance of BCS on Biorelavant
Dissolution Testing
The BCS, which was proposed by Amidon et al. (1995),
emphasizes the contribution of three fundamental
factors, dissolution, solubility, and intestinal
permeability, to the rate and extent of drug absorption
for solid oral dosage forms.

It has important implications in governing the

dissolution test design during the drug development.
According to the BCS, drug compounds are classified based
upon their solubility and permeability described as follows:

Class I: High Permeability, High Solubility

Class II: High Permeability, Low Solubility
Class III: Low Permeability, High Solubility
Class IV: Low Permeability, Low Solubility
BCS Class I compounds
 BCS Class I compounds (e.g., metoprolol) have a high
absorption number (An) and a high dissolution number (Dn),
 Indicating that the rate determining step for drug absorption is
likely to be dissolution or gastric emptying.
 This class of drugs is generally well absorbed if the drug is
stable or does not undergo first pass metabolism.
 For immediate-release products of Class I compounds, the
absorption rate is likely dominated by the gastric emptying
time, and no direct correlation between in vivo data and in vitro
dissolution data is expected.
Class II drugs
 Class II drugs (e.g., phenytoin) have a high absorption number
(An) and a low dissolution number (Dn).
 Dissolution is the rate limiting step for drug absorption.
 The influence of dissolution on absorption of BCS Class II drugs
can be classified into two scenarios:
 solubility-limited absorption
 dissolution-limited absorption
BCS Class III drugs
 For BCS Class III drugs (e.g., cimetidine), permeability is likely to
be a dominant factor in determining the rate and extent of drug
absorption.

 Developing a dissolution test that can predict the in vivo

performance of products containing these compounds is
generally not possible.
BCS Class IV drugs
 BCS Class IV drugs, which are low in both solubility and
permeability, present significant problems for effective oral
delivery.

 This class of drugs is generally more difficult to develop in

comparison to BCS Class I, II, and III drugs.
Biorelavant Dissolution Methods
 Biorelavant dissolution methods are designed to closely
simulate physiological conditions in the GI tract.

 The physicochemical properties of the drug substance (e.g.,

solubility) and its formulation (e.g., immediate- or extended-
release dosage forms) play a key role in selecting an
appropriate type of biorelevant dissolution medium (e.g., gastric
or intestinal medium)
Biorelavant Dissolution Media for Gastric
Conditions
 For BCS Class I drugs that are formulated in immediate-release dosage forms

or any products that dissolve rapidly and completely in an acidicmedium, it is

logical to use a dissolution medium that reflects the gastric conditions.
 pH, sufactants, enzymes and food can effect the dissolution.

 The pH in the stomach has a significant influence on the dissolution rate due

to its effect on the solubility of a drug substance.

 To simulate gastric conditions in the fasted state, the pH values of a gastric

dissolution medium should be in the pH range of 1.5–2.5.

Apparatus and Test Conditions for Simulating
the Stomach
 The basket and paddle methods are frequently used, in
conjunction with biorelavant media for gastric conditions, to
simulate the drug release in the stomach under fasted and fed
conditions.

 These two devices consist of a single vessel for each dosage

form and are operated with a fixed volume of a single medium,
they are best suited for drug products in which the majority of
drug release occurs in the same section of the GI tract.
 Paddle apparatus

Baskets & Shafts - Tablet Dissolution

Cont..
The duration of a dissolution test should reflect the time
available for dissolution in the stomach that is a function of
the emptying pattern, which can vary considerably
depending on the size of the solid particles as well as the
size and the content of the meal.
Biorelavant Dissolution Media for Intestinal
Conditions
 For poorly soluble drugs (e.g., BCS Class II drugs that are
neutral or weak acids), it may be more appropriate to use a
dissolution media that mimics the intestinal conditions.
 The pH values of intestinal conditions are considerably higher
than those of gastric conditions, and were measured to be in
the range of
 5.5–6.0 for the duodenum
 6.5 in the jejunum
 7 in the proximal
 7.5 in the distal ileum
Cont..
 A commonly used medium for simulating fasting conditions in
the proximal small intestine is fasted state simulated intestinal
fluid (FaSSIF).

 The dissolution rate of poorly soluble, lipophilic drugs may be

improved greatly in this medium in comparison to the
dissolution rate observed in simple aqueous solutions.
Biorelavant Methods for Extended-Release Dosage
Forms
 For extended-release drug products, the dissolution method
must capture, at minimum, the changes in composition, pH, and
residence times along the GI tract, since absorption of these
dosage forms takes place throughout the entire intestine.

 Different biorelevant dissolution media are used to assess the in

vivo release behavior of extended-release dosage forms.
Conclusions
 Dissolution testing is critical to the drug product development
and production. It is routinely used in QC as well as research
and development.
 In research and development, dissolution testing is used to
evaluate the performance of new formulations by measuring the
rate of drug release from dosage forms, examining the stability
of these formulations, and assessing formulation changes.
 dissolution testing is employed to provide some predictive
estimates of the drug release under physiological conditions by
establishing IVIVCs.