DISSOLUTION METHODS, FORMULATION &
PROCESSING FACTORS, CORRELATION OF IN-
VIVO DATA WITH IN VITRO DISSOLUTION DATA:-

SUBMITTED TO
DEPARTMENT OF PHARMACEUTICS

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Dissolution is a process of mass transfer of solid into the
solvent. It is a multiple process involving heterogeneous
swinging reaction/interaction between the phases of solute-
solute, solute-solvent and solvent-solvent interface.

Dissolution Methods:-

Categorized into two methods:-

➢ Official methods
➢ Non official methods

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➢OFFICIAL METHODS:-
Apparatus are used according to standards specified. The USP
includes seven apparatus design for drug release and
dissolution testing of immediate release and for oral dosage
form, for extended release, enteric coated, transdermal drug
delivery system.

Methods are listed below:-

•Rotating basket method
•Paddle method
•Flow-through method
•Reciprocating cylinder method
•Paddle over disk method
•Rotating cylinder method
•Reciprocating disk method

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Apparatus four:-flow through cell

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ADVANTAGES:-

•Infinite sink condition can be achieved hence low soluble
drugs studies can be done.

•It is easy to change pH of media during test, avoiding
hot spots as seen in basket method.

•Minimum dwell time, avoiding problems of degradation
of drug during process.

•Ease of sampling and automation of data reduction.
•Adaptability to current USP calibrators.

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DIS-ADVANTAGES:-

•Large volume of media is required.

•Control of constant flow rate is difficulty.

•Clogging results in damage to equipment.

•Pump should produce pulse free flow.

•Pressure may build up due to clogging hence
pressure transducer should used to regulate
pressure and to maintain constant flow rate.

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➢NON- OFFICIAL METHODS:-

Tracking of dissolution from different dosage form is
some times is not possible with the existing official
methods. So several non-official methods are designed for
dissolution testing.

These includes,

•Percutaneous absorption technique.

•Rotating bottle method for sustained release dosage form.

•Dialysis system.

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PERCUTENOUS ABSORPTION TECHNIQUE:
•Percutaneous absorption is related to the absorption across
the skin.
Percutaneous absorption methods are currently used to study
transfer kinetics through membranes.
•These are useful in testing membrane characteristics and
studying absorption through skin.
•These are generally use for patches, the patches generally
mounted in same position as the simulated skin membrane
and serves as the donor side of the system.
•Some of the tech. that are used in percutaneous absorption
measurement includes side-by-side, the Franz cell, and flow
through cell design.

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ROTATING BOTTLE METHOD:-

•This is probably the oldest method used for sustained
release dosage forms.

•The system consists of 12 small bottle attached to a
horizontal shaft that rotates at a slow rate of 6-50 rpm.

•The whole assembly is placed in a constant water bath.

•Each bottle consists of 60 ml of dissolution fluid that is
decant through a 40-mesh screen after each sampling
period and is replaced by fresh fluid.

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DIALYSIS SYSTEM:-

•In this case very poorly soluble drugs, where perfect sink
condition would necessitate a huge volume of solvent with
conventional methods, a different approaches utilizing
dialysis membranes, was tried as a selective barrier
between the fresh solvent and the cell compartment
containing the dosage form.

•It has been used with some success in case of other
dosage form such as suspensions, creams and ointments.

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Factors affecting dissolution rate:-

1. Factors related to Physicochemical Properties of Drug.

2. Factors related to Drug Product Formulation.

3. Processing Factor.

4. Factors Relating Dissolution Apparatus.

5. Factors Relating Dissolution Test Parameters.

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Factor related to physicochemical properties of drug:-

1. Particle size of drug
– There is a direct relationship between surface area of drug and its
dissolution rate. Since, surface area increases with decrease in particle
size, higher dissolution rates may be achieved through reduction of
particle size.

– E.g. Micronisation of non-hydrophobic drug like griseofulvin leads to
increase in dissolution rate.

– Micronisation of hydrophobic powders can lead to aggregation and
floatation, when powder is dispersed into dissolution medium.

– E.g. hydrophobic drugs like aspirin, phenacetin and phenobarbital
shows decrease in dissolution rate, as they tend to adsorb air at the
surface and inhibit their wettability

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2. DRUG SOLUBILITY
– Solubility of drug plays a prime role incontrolling its
dissolution from dosage form. Aqueous solubility of
drug is a major factor that determines its
dissolution rate.
– E.g. Poorly soluble drug :griseofulvin, spironolactone
Hydrophilic drug :neomycin

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3. Solid state characteristics
-Solid phase characteristics of drug, such as amorphicity, crystallinity, state
of hydration and polymorphic structures have significant influence on
dissolution rate.

-Anhydrous forms dissolve faster than hydrated form because they are
thermodynamically more active than hydrates. E.g. Ampicillin anhydrate
faster dissolution rate than trihydrate.

– Amorphous forms of drug tend to dissolve faster than crystalline materials.
E.g. Novobiocin suspension, Griseofulvin.
– Metastable(high activation energy) polymorphic form have better
dissolution than stable form.

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4. Salt formation:-
-It is one of the common approaches used to increase drug solubility and
dissolution rate. E.g. sodium and potassium salts of Penicillin G,
phenytoin, barbiturates etc.
– While in case of Phenobarbital, dissolution of sodium salt was
slower than that of weak acid.

Dissolution and absorption of an acidic drug administered in salt form
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Factors related to drug product formulation:-

1. Binders and granulating agents:-
– In general, the hydrophilic ( aqueous) binders show better
dissolution profile with poorly wettable drugs like phenacetin by
imparting hydrophilic properties to the granule surface.
– Large amounts of such binders increase hardness
and decrease disintegration / dissolution rates of
tablets. Rate of dissolution of

phenacetin from ▲powder, ●
granules, and ○ tablet in
diluted gastric juice.

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2. Disintegrants:-
– Disintegrating agent added before & after the granulation affects the
dissolution rate.
-E.g. Phenobarbital tablet showed that when copagel (low viscosity grade
of Na CMC) added before granulation decreased dissolution rate but if
added after did not had any effect on dissolution rate.
– Microcrystalline cellulose is a very good disintegrating agent
but at high compression force, it may retard drug dissolution.
– Starch is not only an excellent diluent but also superior
disintegrant due to its hydrophilicity and swelling property

Effect of starch content on
dissolution rate of salicylic
acid tablet, ○ 5 %, ● 10 % and × 20 %
starch in granules.

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3. Effect of lubricants / anti-frictional agents:-

-The nature, quantity, and quality of lubricants added can affect the
dissolution rate.

-Lubricants are hydrophobic in nature (several metallic stearate & waxes)
which inhibit wettability, penetration of water into tablet so decrease in
disintegration and dissolution.

-The use of soluble lubricants like SLS and Carbowaxes promote drug
dissolution.

– E.g. Magnesium stearate, a hydrophobic lubricant, tend to
retard the dissolution rate of salicylic acid tablet, whereas sodium lauryl
sulfate enhances its dissolution, due to its hydrophobic but surface activity,
which increases wetting and better solvent penetration into tablet.

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(A) Effect of magnesium
stearate ondissolution rate
of salicylic acid from
rotating disc made from
fine salicylic acid powder, ○
3 % Mg. Stearate, ● no
lubricant added

(B) Effect of lubricant on dissolution
rate of salicylic acid contained in
compressed tablet, × 3 % Mg.
Stearate
, ● no lubricant, and ○ 3 % Sodium
lauryl sulphate.

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4. Coatings:-
– In general, the deleterious effect of various coatings on drug
dissolution from a tablet dosage form is in the following order:
Enteric coat > Sugar coat > Non- enteric film coat.

5. Buffers:-
– Buffers are sometimes useful in creating the right atmosphere for
drug dissolution, e.g. buffered aspirin tablets.

6. Complexing agents:-

– A complexed drug may have altered stability, solubility, molecular
size, partition coefficient and diffusion coefficient.
– E.g. Enhanced dissolution through formation of a soluble complex of
ergotamine tartarate-caffeine complex and hydroquinone-digoxin
complex.

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Processing factors:-
1. Method of granulation:-
– Wet granulation has been shown to improve the dissolution rate of poorly
soluble drugs by imparting hydrophilic properties to the surface of
granules.

– A newer technology called as APOC “Agglomerative Phase of
Comminution” was found to produce mechanically stronger tablets
with higher dissolution rates than those made by wet granulation. A
possible mechanism is increased internal surface area of granules
produced by APOC method.

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2. Compression force:-
-The compression process influence density, porosity, hardness,
disintegration time & dissolution of tablet.

– The curve obtained by plotting compression force versus rate of
dissolution can take one of the 4 possible shapes:-

1. tighter bonding increases hardness
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

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Factors related to dissolution apparatus:-

1. AGITATION:-

-Rate of dissolution depends on type of agitation used, the degree of
laminar and turbulent flow in system, the shape and design of stirrer.

– Speed of agitation should be such that it prevent turbulence
and sustain a reproducible laminar flow, which is essential for obtaining
reliable results.

– So, agitation should be maintained at a relatively low rate.

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2. SAMPLING PROBE POSITION & FILTER:-

-Sampling probe can affect the hydrodynamic of the system.

-USP states that sample should be removed at approximately half the
distance from the upper surface of basket or paddle and surface of
dissolution medium and not closer than 1 cm to the side of the flask.

3. STIRRING ELEMENT ALIGNMENT:-

– The USP / NF states that the axis of the stirring element must not deviate
more than 0.2 mm from the axis of the dissolution vessel.

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Factors related to dissolution test parameters:-

1. Vibration:-
-The excessive vibration of dissolution apparatus increases dissolution
rates.

2. Vessel design and construction:-
-Plastic vessels provide more perfect hemisphere than glass vessels.

3. Temperature control:-
-Should be maintained at 37 ± 0.5 º C

4. Dissolution medium parameters:-
– Surface tension, pH, Viscosity, De-aeration

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CORRELATION OF IN-VIVO DATA WITH IN-VITRO
DISSOLUTION DATA:- (IVIVC)

# According to Food & Drug administration:
IVIVC is a predictive mathematical model describing therelationship
between an in-vitro property of a dosageform and a relevant in-vivo
response.

# According to FDA 1977 on bioavailability & bioequivalence stated that
dissolution test the preferred in-vitro test should be correlated with in-vivo
data.

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•The in-vitro property is the rate or extent of drug dissolution or release
while the in-vivo response is the plasma drug concentration or amount of
drug absorbed.

• It establishes relationship between biological property (pharmaco-dynamic
effect & plasma drug concentration) and physicochemical property of drug
substance such as dissolution rate.

• The in-vitro dissolution characteristics are dependent on the physical
properties of active pharmaceutical ingredients, the drug dissolution,
hydrodynamics of dissolution apparatus & dissolution media.

▪ UNLESS THE INVITRO DISSOLUTION REFLECTS THE INVIVO
PERFORMANCE THE RESULTS OBTAINED WILL HAVE NO
RELEVANCE.

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OBJECTIVES:-
1) To ensure batch to batch uniformity in physiological performance by

utilizing in-vitro experimental data.

2) To serve as a tool in developing new, efficacious and safe dosage form.

3) It assumes great imp. Especially for such formulations which contains
drugs having narrow therapeutic window.

(Eg: Diltiazem , carbamazepine& Nifedipine ) or variable therapeutic
response (Eg: Theophylline, digoxin etc.,)

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IVIVC CAN BE ACHIEVED USING:-

A) Pharmacological correlations based on clinical observations.

B) Semi-quantitative correlation based on drug blood level or urinary
excretion data.

C) Quantitative correlation arising from absorption kinetics & calculation
of an invivo absorption rate constants.

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DIFFERENT METHODS OF IVIVC:-

➢Simple point type

➢ Comparison of Profiles

➢ Simple Point Type:- The percentage of drug dissolved
in a given time is correlated with the bioavailability of the
drug product.

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COMPARISON OF PROFILES:-

In vivo Data:

•Plasma concentration time profile.
•Pharmacokinetic parameters.
• Percent drug absorbed time profile.
• Statistical movement analysis.

In vitro Data:

•Percent drug dissolution profile.
•Kinetic parameters.
• Percent drug dissolved time profile.
•Statistical movement analysis.

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IN VIVO DATA IN VITRO DATA
 Plasma concentration time  Percent drug dissolution profile.

profile  Kinetic parameters.
 Percent drug dissolved time

 Pharmacokinetic parameters.
profile.

 Percent drug absorbed time  Statistical movement analysi
profile. Percent drug dissolution profile:

 Statistic Plasma concentration  ·Percent drug dissolved at time
t.

time profile:
 ·Maximum drug dissolved at

 ·Plasma concentration at time t. tmax.
 ·Peak plasma concentration  ·Time taken for maximum

(Cmax). amount of drug to dissolve.
 ·Total amount of drug

 ·Time taken for Cmax (tmax).
dissolved.

 AUC0 t , AUC0 ∞  ·Time for a certain percentage
 Time for a certain percentage of drug to

of drug to reach al movement  dissolve such as t30%, t50%,
t90%, etc. s.

analysis
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IN VIVO DATA IN VITRO DATA
 the blood such as t30%, t50%,  Kinetic parameters:

t90%Pharmacokinetic  ·Dissolution rate constant.
parameters:

 ·Dissolution Percent drug
 ·Absorption rate constant. dissolved time profile:
 ·Elimination rate constant., etc·  ·Percent drug dissolved at time

Absorption half life. Statistical movement analysis:
 ·Elimination Percent drug  ·Mean Dissolution Time (MDT).

absorbed time profile: half life
 ·Percent drug absorbed at time

Statistical movement analysis:

 ·Mean Residence Time (MRT).

 ·Mean Absorption Time
(MAT).half life.

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PERCENT OF DRUG DISSOLVED VERSUS PERCENT OF DRUG
ABSORBED:-

• If a drug is absorbed completely after dissolution, a linear correlation may
be obtained and by comparing the percent drug absorbed to the percent
drug dissolved.

• In choosing the dissolution medium and use a slow dissolution stirring rate
so that invivo dissolution is approximated.

Eg: The drug Aspirin is absorbed rapidly and completely from GIT. Therefore
a change in the dissolution rate from a dosage form may be reflected in a
change in the amount and rate if drug absorption during the period of
observation.

•Differences in the dissolution rates of dosage forms will be reflected in the
rate and extent of the drug only if the drug absorption is dissolution rate
limited.

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DISSOLUTION RATE V/S ABSORPTION RATE:-

• If dissolution of the drug is rate limiting, a faster dissolution rate may
result in a faster rate of appearance of drug in the plasma. It may be
possible to establish a correlation between rate of dissolution and rate of
absorption of the drug.

• The absorption is more difficult to determine then peak absorption time.
Therefore, the absorption time may be used in correlating dissolution data
to absorption data.

•In the analysis of invitro invivo drug correlation rapid drug absorption may
be distinguished from the slower drug absorption by observation of the
absorption time for the preparation.

❑ Eg: In study involving three sustained released Aspirin products, the
dissolution time for the preparations were linearly correlated to the
absorptions times for various amounts aspirin absorbed.

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• The results from this study demonstrated that aspirin was rapidly
absorbed and it was very much depended on the dissolution rate for
absorption.

DIFFERENT STAGES IN IVIVC:-

Stage 1 IVIVC:

•represents a point-to-point relationship between in vitro dissolution rate
and in vivo rate of the drug from the dosage form.

•Super imposable absorption rate curves and mathematical descriptions
are similar.

•Alternative to in vivo method.

•Manufacturing method changes, formula,modification performed without in
vivo data.

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Stage 2 IVIVC:
•level B IVIVC utilizes the principles of statistical moment analysis.

In this level of correlation, the mean in vitro dissolution time (MDTvitro)
of the product is compared to either mean in vivo residence time (MRT)

Not point to point correlation
This level is not reliable to justify changes in manufacturing or formula

changes.

Stage 3 IVIVC:
➢Single point correlation

Relates dissolution time with pharmacokinetic property like AUC (AREA
UNDER CURVE).

Helps to develop formulations.

Stage 4 IVIVC: (multiple stage 4):
❑Amount of drug dissolved at different time intervals can be correlated with
many pharmacokinetic parameters.
❑Scale up and post approval changes(SUPAC) can be made to the
formulation.

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REFERENCE:-

•Subrahmanyam CVS ; Biopharmaceutics
pharmacokinetics; Delhi, Vallabh prakashan:2010.

• Brahmankar DM, Sunil B.Jaiswal; Biopharmaceutics &
Pharmacokinetics; Delhi, Vallabh prakashan: 2015.

• Patrick J.Sinko, Martins; physical pharmacy &
pharmaceutical science; 5th edition: 2006

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THANK YOU

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