IMPORTANCE,

APPLICATION,
FACTORS AFFECTING DISSOLUTION RATE,
THEORIES OF DISSOLUTION
&
OFFICIAL DISSOLUTION TESTS
 INTRODUCTION
• Dissolution is defined as the process by which
a solid substance enters in the solvent to
yield a solution.
OR
• Dissolution is the process by which a solid
substance dissolved.
OR
• Fundamentally, it is controlled by the affinity
between the solid substance and solvent.
 IMPORTANCE & APPLICATION
• Dissolution testing evaluated critical parameter such as
– Predict adequate bioavailability
• Help to avoid batch to batch variation
• QC and IPQC test.
• Selection of best formulation &comparison of excipient effect
on dosage form
• In vivo – in vitro co-relation
• Regulatory requirement of official test
• F1 & F2 (similarity dissimilarity) value help to get comparing
dissolution pattern of test with market product
• A.N.D.A. & N.D.A. required dissolution test.
• Sometimes modification is also required for better invivo
predictability:
 FACTORS AFFECTING DISSOLUTION RATE

SIX MAIN CLASSES

• Factor related to the physicochemical
property of the drug
• Factor related to drug product formulation
• Factor related to dosage form
• Factor related to dissolution testing device
• Factor related to dissolution test
parameters
• Miscellaneous factor
 Factor related to physicochemical
property
I. Solid phase characteristics
 Amorphicity & crystallinity
 Amorphous form of drug usually greater solubility
&higher dissolution rate as compared to
crystalline form.
• Polymorphism
• Co precipitation &/or Complexation
• Co precipitation as well as complexation are
use for enhancing the dissolution rate of drug
due to,
– Formation energetic amorphous drug phase or
– Drug being molecularly dispersed or
– Formation of co accervates
• e.g. Hydroflumethiazide – PVP co precipitate has
four times more solubility than crystalline drug.
IV. Particle size
• If the drug hydrophobic reduction in particle size may
lead to decrease in effective surface area and hence
slower the rate of dissolution.
V. Salt formation
• by salt formation to increase the solubility
 Factor Related To Drug Product Formulation
(Solid Dosage Form)
• Diluent & Disintegrant
• Studies of starch on dissolution rate of salicylic acid tablet

• excipient dilution (drug/excipient ratio).

 Granulating agent and Binder
• e.g. Phenobarbital tablet granulated with gelatin
solution, Na – carboxymethyl cellulose or polyethylene
glycol 6000 as binder.
• Also depend on conc. of binder.

• Water soluble granulating agent Plasdone give

faster dissolution rate than with gelatin.
 Disintegrating agent
• Studies of various disintegrating agents on Phenobarbital
tablet
Lubricants
• Surfactant
• e.g. treated cassava starch with SLS/polysorbate – 80
in sulfadiazine tablet
• Effect of certified water – soluble dyes on
the dissolution rate
• Effect of coating component on tablet
dissolution
 Factor Related To Dosage Form
• Manufacturing procedure (granulation)
• Granule size
Drug excipient interaction
• The dissolution of prednisolone found to depend
on the length of mixing time with Mg-stearate
Compression force
• The compression process influence density, porosity,
hardness, disintegration time & dissolution of tablet

1. tighter bonding
2. higher compression force cause
deformation crushing
or fracture of drug particle or convert a
spherical granules into disc. Shaped particle
3.& 4. both condition
• Deaggregation
• Deaggregation is prerequisite for dissolution
• Deaggregation controls the rate of dissolution
• Storage of dosage form
 Factor Related To The Dissolution Testing
Device
Agitation
• Agitation changes hydrodynamic condition & flow pattern
• Relation ship between intensity of agitation & rate of dissolution.
• K = a (N) b
• Where N = speed of agitation
• K = dissolution rate
• a & b are constant
• Vibration
• The speed of rotation device officially 100 rpm.
• Periodical variation in rpm might result in possible
disturbance in rotational acceleration this phenomenon
is known as torsional vibration.
• Stirring element alignment
• The USP / NF XV states that the axis of the stirring
element must not deviate more than 2 mm from the
axis of the dissolution vessel
• Tilt in excess of 1.5 0 may increase dissolution
rate from 2 to 25%.
• Flow pattern disturbance
• The geometry and alignment of stirring device, external vibration
rotational speed, thermometer, distance of basket or paddle
from the lowest point of the bottom of the round bottom flask
are affecting on the flow pattern.
• Sampling Probe, Position & Filter
• Sampling probe can affect the hydrodynamic of the system
• Position of sampling, USP / NF state that sample should be
removed at approximately half the distance from the basket or
paddle to the dissolution medium and not closer than 1 cm to
the side of the flask
• Filter material must be saturated with the drug by repeated
passage to avoid losses that might go undetected during the test
sampling.
 Factor Related To Dissolution Test
Parameter
• Temperature
• USP /NF specifies that the dissolution medium must be held at 370C (±0.5)
& for topical 25 - 300 (320±0.5).
• Dissolution medium
• Effect of dissolution air on dissolution medium
 Altering PH
 Dissolved air tends to release slowly in form of tiny air bubble
that circulate randomly and affect hydrodynamic flow
pattern
 Specific gravity decrease thus floating of powder thus wetting
and penetration problem.
• Dissolution media composition & PH
 Addition of Na – sulfate decrease the dissolution rate.
 Addition of urea increase dissolution rate.
 Various Official Dissolution Test
• Solid dosage form (tablet & capsule)
• I.P. & E.P.
• Apparatus I – paddle apparatus
• Apparatus II – basket apparatus
• B.P. & U.S.P.
• Apparatus I – basket apparatus
• Apparatus II – paddle apparatus
• B.P. & E.P.
• Apparatus III – flow through cell apparatus
• Conditions ( for all)
– Temp. - 37±0.50C
– PH - ±0.05 unit in specified monograph
– Capacity – 1000 ml
– Distance between inside bottom of vessel and paddle/basket is maintained
at 25±2 mm.
• Apparatus III – Reciprocating cylinder
• Consist of a cylindrical , that bottom vessel that
accommodate a glass reciprocating cylinder whose end
are close with a polypropylene mesh screen.
• The dosage unit placed in reciprocating cylinder & the
release of drug into solvent within the cylinder measured.
• Apparatus IV – flow through cell
• Used flow though cell with a filter system, through which
the dissolution medium is pumped.
• Temp. for both apparatus III & IV at 37±0.50C.
Apparatus V – Paddle over disk.
The disk assembly design to minimize to any dead volume.
The disk assembly is located at 25±2 mm from the bottom the
paddle.
Apparatus VI – cylinder
Used basket apparatus except that the basket and shaft are replaced
with a stainless steel cylinder stirring element.
Apparatus VII – (reciprocating holder )
Use solution container in which a specifically designed disk sample
holder may be made to reciprocating.
For apparatus V,VI&VII
Procedure carried out at 32±0.50 C. (because deliver system are used
on the skin)
 MODEL DEPENDENT AND MODEL INDEPENDENT
METHOD TO COMPARE DISSOLUTION PROFILE
WITH SIMILARITY AND DISSIMILARITY FACTORS
Approach Method Parameter/equation
Ratio of percent dissolved
Model-independent Ratio test procedures Ratio of are under dissolution curve
Ratio of mean dissolution time
Difference factor (f1)
Pair wise procedures
Similarity factor (f2)
Model-dependent Zero-order % diss = kt
First-order % diss = 100 (1 – e-kt)
Hixson-Crowell % diss = 100 [1-(1- kt/4.6416 mg1/3) 3
Higuchi % diss = kt0.5
Quadratic % diss = 100(k1t2 + k2t)
Weibull % diss = 100 [1 – e- (t/)]
Gompertz % diss = A e-e-k (t-)
logistic % diss = A / [1+e-k(t-)]
 GRAPHICAL METHOD
In this method we plot graph of Time V/S
concentration of solute (drug) in the
dissolution medium or biological fluid.
 120

100
% Metoprplol dissolved

80

60

40

20

0
5 10 15 20 25 30 45
Time in minutes
A B C D
 DETERMINING DISSOLUTION PROFILE SIMILARITY

 A minimum of 12 dosage units must be evaluated .

 similarity factor (f2).

 similar when the f2 value is _50.

 To allow the use of mean data, the coefficient of variation

should not be more than 20% at the earlier time points (e.g., 10
minutes), and should not be more than 10% at other time points.

 Note :-When both test and reference products dissolve 85% or

more of the label amount of the drug in 15 minutes using all
three dissolution media recommended above, the profile
comparison with an f2 test is unnecessary
 SIMILARITY FACTOR, F2

• This is the most simple model

independent mathematical approach to
compare dissolution profile.

Where Rt & Tt are cumulative % dissolved at of selected n points of

reference & test product respectively.
 Press coated

TIME REFERENCE A R1-F1 (R1-F1)2

0 0 0
30 0 0
60 0 0
90 0 0
120 0 0
150 2.32 1.9
180 2.32 2.42
210 2.52 3.02
240 4.22 4.08
270 4.18 4.26
300 6.24 5.88
330 100.28 98.98
360 99.98 99.92
390 100.25 100.1
TIME REFERENCE A R1-F1 (R1-F1)2
0 0 0

30 0 0
60 0 0
90 0 0
120 0 0
150 2.35 0.98
180 2.35 1.98
210 2.55 2.44
240 4.26 3.85
270 4.2 4.44
300 7.21 7.34
330 100.02 98.22
360 98.64 99.1
390 98.85 100.2
 THEORIES OF DISSOLUTION
• Several theories to explain drug dissolution
– Diffusion layer model / film theory
– Dankwert‘s model / penetration or surface
renewal theory
– Interfacial barrier model / double barrier
or limited salvation theory
 Diffusion layer model / film theory
• This process of dissolution by diffusion with out
reactive or chemical force
• Consist of two consecutive steps
• Solution of the solid to form a thin film or layer at
the solid / liquid interface called as stagnant film
or diffusion layer which is saturated with the
drug this step is usually rapid (instantaneous).
• Diffusion of the soluble solute from the stagnant
layer to the bulk of the solution this step is slower
and is therefore the rate determine step in the
drug dissolution.
Equation (A) is based on fick’s first law of diffusion &
constant surface area
• Brunner incorporated fick’s first law of diffusion
and modification of the Noyes – Whitney’s
equation to
 Sink condition
• In vivo condition, there is no conc. build up in the
bulk of the solution and hence no retarding effect on
the dissolution rate of the drug i.e. Cs>>Cb and sink
condition maintain.
• Sink condition can be achieved by,
– Bathing the dissolving solid in fresh solvent from time to time.
– Increase the volume of dissolution fluid.
– Removing the dissolved drug by the organic phase e.g. hexane or
chloroform.
– Adding a water miscible solvent such as alcohol
– By adding selected adsorbents to remove the dissolution drug.
• Noyes Whitney’s equation assumes that surface area should remain
constant during the dissolution.
• Hixson and Crowell’s cubic root low of
dissolution for change in surface area on dissolution
due to decrease in particle and decrease in surface
area.
W01/3 – W1/3 = kt
W0 = original mass of drug
W = mass of drug remaining to dissolve at time t
K = dissolution rate constant
Dankwert’s Model (Penetration Or
Surface Renewal Theory)
This model assume that transport of solute away from the solid
surface is achieve by means the agitated fluid consisting of
macroscopic mass of eddies or packets reach the solid/liquid
interface in a random fashion due to eddy currents.
 Interfacial barrier model (double
barrier or limited salvation theory
• Based on salvation mechanism & solubility rather than
diffusion.
• The interfacial barrier model can be extended to both
diffusion layer model and the Dankwert’s model.
 Introduction to
BCS and
dissolution study
 INTRODUCTION OF BCS

 BCS provides a scientific approach for

classifying dug compounds based on solubility as
related to dose and intestinal permeability in
combination with dissolution properties oral
immediate release dosage forms.

 According to BCS, drugs are classified into four

classes.
Class I : High solubility – High permeability
These drugs exhibits high absorption number and high
dissolution number.
Rate limiting step is gastric emptying rate.

Class II : Low solubility – High permeability

Absorption for class II drugs is usually slower than class I
and occurs over a longer period of time.
Rate limiting step is in-vivo drug dissolution.
Class III : High solubility – Low permeability

Here permeability is the rate limiting step for absorption.

Since the dissolution is rapid, the variation is attributed to
alteration of physiology and membrane permeability rather
than dosage form factors.

Class IV : Low solubility - Low permeability

This drugs exhibits lots of problems for effective oral

administration.
Possibilities of shifting the solubility – dissolution characteristics form a very
poorly soluble drug to D.S within the range of values encountered in the Human
GI track
 AIM OF BCS
• To provide regulatory tool for replacing certain
bioequivalence studies by accurate in-vitro
dissolution tests.
This will reduce the cost in drug development
process, also reduce unnecessary drug exposure in
healthy objects.
• To provide guidance for industry.
 BASIC REQUIREMENTS OF BCS

• It must predict the in-vivo dissolution system

well.
• Rate limiting step for in-vivo absorption must
be well defined.
• Limits for permeability and solubility must be
balanced.
• In-vitro methods should be sufficiently robust
for correct classification.
 PROBLEMS WITH BCS

• Every chances of misclassification.

• It is based on highest dose what about smaller

doses of same product.

• Today it is intended only for IR products that

are absorbed through out intestinal tract.
 INDUSTRIAL IMPLEMENTATION OF
BCS

 Since class- I drugs are having high solubility &

permeability, their biowaiver request is granted by
FDA.
 Potential Cost Savings.
To examine this number of BE studies performed by
industry per year was examined.
 Indirect Savings.
-time saving
-clinical resources are freed to be applied elsewhere.
 CLASS BOUNDARIES
 Highly soluble when highest dose strength is
soluble in 250 ml or less water over
a pH range of 1 to 7.5
 Highly permeable when extent of intestinal absorption

is 90 % or higher.

 Rapidly dissolving when not less than 85% of labeled

amount of drug substance dissolves
within 30 min using USP apparatus I
at 100 rpm in volume of 900 ml or less in
each of following media
(1) 0.1 N HCL or USP simulated gastric fluid
without enzymes.
(2) a 4.5 pH buffer
(3) a 6.8 pH buffer or simulated intestinal fluid USP without enzymes.
 SOLUBILTY DETERMINATION

• By pH – solubility profile of test drug in

aqueous media with a pH range of 1 to 7.5
• Shake flask or titration method.
• Analysis by validated stability indicating
assay.
 PERMEABILITY DETERMINATION

 Extent of absorption in humans:

1.Mass-balance pharmacokinetic studies.
2.Absolute bioavailability studies.

 Intestinal permeability methods:

1.In vivo intestinal perfusions studies in humans.
2.In vivo intestinal perfusion studies in animals.
3.In vitro permeation experiments with excised human or animal
intestinal tissue.
4.In vitro permeation experiments across epithelial cell monolayer

 The most common in-vitro cell culture technique used to assess

permeability is the CaCo –2 ( human colon carcinoma ) cell live or
sub-clone ( e.g. Tc-7) based estimates .
 SUGGESTED IMPROVEMENTS OF BCS

• BCS could be reduced into two classes.

• Class-I Permeation rate limited absorption:

Drugs with in-vivo Kdiss > in-vivo Kpe belong to class I
regardless fa.

• Class-II Dissolution rate limited absorption:

Drugs with in-vivo Kdiss< in-vivo Kpe belong to class II.
Here in-vivo BE studies are required.
 BCS CONTAINING SIX CLASSES

Bergstrom et al. carried out a study, in which BCS containing

six Classes was used,

• Solubility was classified as “high” or “low”

• Permeability was classified as “low”, “intermediate” or
“high”.
Gohel suggested third dimension to BCS, i.e.
chiral conversion.

Class Solubility Permeability Chiral Conversion

I High High A High*

B Low*
II Low High A High
B Low
III High Low A High
B Low
IV Low Low A High
B Low
 Research Gate
• Case Studies 1: We demonstrated in vivo bioequivalence between the pilot batch and
the reference product. We did the dissolution test of the pilot batch using the
dissolution conditions specified in the FDA database, and we obtained slightly lower
results. When we run the dissolution test with peak vessels, the results show some
improvement. Can we use peak vessels in this case?
• Case Studies 2: What dissolution medium can be used with poorly water-soluble
drugs (BCS Class 2)? If the drug substance is not soluble in that medium, how should
the standard solutions for the calibration curve be prepared?
• Case Studies 3: Which solvents can be employed to prepare the standard solution to
be used in the quantitative procedure in dissolution testing? Is it mandatory to use
the dissolution medium?
• Case Studies 4: I am preparing a film containing sumatriptan. How should I select the
composition of the dissolution medium?
• Case Studies 5: Most of the dissolution tests use 900 mL of medium. How was this
volume defined? Is there any correlation with the volume of gastric fluid in humans?
• Case Studies 6: I am working with a gastroretentive drug delivery system for a
fixed combination product. Drug A has absorbance in 0.1 N HCl while drug B does
not. Can I use two separate media for the fixed combination product, 0.1 N HCl for
drug A and water for drug B?
• Case Studies 7: We are developing a floating tablet, and it remains floating in the
dissolution vessel during the entire test. Is it mandatory that the tablet should
remain on the bottom of the dissolution vessel?
• Case Studies 8: I am working on a project to enhance the solubility of a drug that is
insoluble in water. I am uncertain on how to develop the dissolution test; I would
like to use phosphate buffer as dissolution medium, but the drug is not soluble in
this buffer.
• Case Studies 9: Is a dissolution test needed for the active substance as a single
component in a capsule dosage form, or would a disintegration test be adequate?
• Case Studies 10: How is the dissolution sample solution determined? We find that
in some tests, the samples withdrawn from the vessel need to be diluted as part of
the quantitative procedure.
 BIOWAIVERS
 Means to waive off doing bioavailability and bioequivalence
studies.
 Conditions for justifying request of biowaiver .
1. Drug must be highly soluble & permeable.
2. Must be stable in GIT.
3. Product is designed not to be absorbed in oral cavity.
4. Must not have narrow therapeutic index.
5. Excipients used in IR solid dosage forms must have no
significant effect on rate & extent of oral drug absorption .
 BIOWAIVER EXTENSIONS

(1) For class II drugs:

 Here in-vivo dissolution is rate limiting step.
 If in-vivo dissolution can be estimated in
vitro, it is possible to establish IVIVC.
But experimental methods are difficult
to design & validate because no. of in-vitro
process involved.
 Key determinant for class II drug absorption
is the solubility in the absorbing region of
intestine.
• So, change in formulation is required.
Add SLS to mimic solubilization in vitro and
maintenance of sink condition in vivo resulting
from continuous absorption.

• Addition of various surfactants concentration in

dissolution media may be adequate for quality
control but not sufficient for predicting in-vivo
dissolution.
 (2) For class III drugs:
 drugs shows permeability limited absorption

 It has been contended that there are equally

compelling reasons to grant biowaivers to class
III drugs as class I drugs.

 If the dissolution of class III drugs is rapid

under all physiological pH conditions, it is
expected that they will behave like oral solution
in-vivo and in-vivo bioequivalence study is
generally waived off for oral solutions.
• Recent survey of FDA data of over 10 BCS
class III drugs shows that most commonly used
excipients in oral solid dosage forms have no
significant effect on absorption.

• Class III drug products containing significant

amount of GIT transit affecting or permeability
changing excipient should be excluded from
consideration of biowaivers.
 For E.g..
 SLS, fatty acids, steroidal detergents changes
membrane permeability.
 Mannitol, sorbitol can reduce small intestine transit
time.
 Isoniazid which lies at borderline of BCS class I &
III. Its biowaiver is recommended when the test
product meets WHO requirements for “Very rapidly
dissolving” and contains only excipients commonly
used in isoniazid products.
 BIORELEVANT DISSOLUTION MEDIA

• Biorelevant in vitro dissolution testing is useful for qualitative

forecasting of formulation and food effects on dissolution and
availability of orally administered drug.

• It is used to ensure that the in vitro test mimic the in vivo as

closely as possible.

• This media can provide more accurate simulation of

pharmacokinetic profiles than SGF or SIF.
 DISSOLUTION MEDIA

 Primary require for selection of dissolution media is that, it

should be able to reflect in vivo situations when it is used to
establish an IVIVC
 For Class I and III drugs, use of simple aqueous media such as
SGF without enzymes or SIF without enzymes is
recommended.
 For Class II and III drugs, use of biorelevant media for
dissolution testing is recommended.
They are: 1) SGF plus surfactant
2) Milk with 3.5 % fat to
stimulate fed state condition
3)FaSSIF is used for poorly
soluble drugs.
FACTORS AFFECTING SELECTION OF DISSOLUTION MEDIUM.

 PH of the dissolution medium.

 Surface tension of dissolution medium.

 Viscosity of the dissolution medium.

 Presence of uncreative and reactive additives in the

dissolution medium.

 Volume of the dissolution medium and sink

conditions.