DRUG DISSOLUTION

Delivered by
Dr. Dhaval J. Patel

1
 CONTENTS
• Definition
• Theories of Drug Dissolution
• Noyes-Whitney’s Dissolution rate law
• Factors affecting Drug Dissolution
• Study of various approaches to improve
dissolution of poorly soluble drug
• In-vitro dissolution testing models
• In-vitro-In-vivo correlation
• References
2
Definition-
• Dissolution is a process in which a solid
substance solubilizes in a given solvent i.e.
mass transfer from the solid surface to the liquid
phase.

• Rate of dissolution is the amount of drug

substance that goes in solution per unit time
under standardized conditions of liquid/solid
interface, temperature and solvent composition.

3
 Theories of Drug Dissolution

I. Diffusion layer model/Film Theory

II. Danckwert’s model/Penetration or

surface renewal Theory

III. Interfacial barrier model/Double barrier

or Limited solvation theory.

4
I. Diffusion layer model/Film Theory :-

• It involves two steps :-

a. Solution of the solid to form stagnant film or

diffusive layer which is saturated with the drug

b. Diffusion of the soluble solute from the stagnant

layer to the bulk of the solution; this is r.d.s in
drug dissolution.
5
6
• The rate of dissolution is given by Noyes and
Whitney:
dc
= k (Cs- Cb)
dt

Where,
dc/dt= dissolution rate of the drug
K= dissolution rate constant
Cs= concentration of drug in stagnant layer
Cb= concentration of drug in the bulk of the
solution at time t
7
 Modified Noyes-Whitney’s Equation -

dC = DAKw/o (Cs – Cb )
dt Vh

Where,
D= diffusion coefficient of drug.
A= surface area of dissolving solid.
Kw/o= water/oil partition coefficient of drug.
V= volume of dissolution medium.
h= thickness of stagnant layer.
(Cs – Cb )= conc. gradient for diffusion of drug.
8
• This is first order dissolution rate process, for
which the driving force is concentration gradient.

• This is true for in-vitro dissolution which is

characterized by non-sink conditions.

• The in-vivo dissolution is rapid as sink conditions

are maintained by absorption of drug in systemic
circulation i.e. Cb=0 and rate of dissolution is
maximum.

9
• Under sink conditions, if the volume and surface
area of the solid are kept constant, then

dC
= K
dt

• This represents that the dissolution rate is

constant under sink conditions and follows zero
order kinetics.

10
Dissolution rate under non-sink and
sink conditions.
zero order dissolution
under sink condition

first order dissolution under

Conc. of dissolved drug

non-sink condition

Time

11
• Hixon-Crowell’s cubic root law of
dissolution takes into account the particle
size decrease and change in surface area,

W01/3 – W1/3 = Kt
Where,
W0=original mass of the drug
W=mass of drug remaining to dissolve at
time t
Kt=dissolution rate constant. 12
 II. Danckwert’s model/Penetration or
surface renewal Theory :-

• Dankwert takes into account the eddies or

packets that are present in the agitated fluid
which reach the solid-liquid interface, absorb
the solute by diffusion and carry it into the bulk
of solution.

• These packets get continuously replaced by

new ones and expose to new solid surface
each time, thus the theory is called as surface
renewal theory.
13
14
• The Danckwert’s model is expressed by
equation

dC =
dm = A (Cs-Cb). γD
V dt
dt

Where,
m = mass of solid dissolved
Gamma (γ) = rate of surface renewal

15
III. Interfacial barrier model/Double barrier or
Limited solvation theory :-

• The concept of this theory is explained by

following equation-

G = Ki (Cs - Cb)
Where,
G = dissolution rate per unit area,
Ki = effective interfacial transport constant.
16
• Factors affecting Drug Dissolution :-

A. Factors relating to the physicochemical

properties of drug.

B. Factors relating to the dosage forms.

17
A. Factors relating to the physicochemical
properties of drug-

i. Solubility-
• Solubility plays important role in controlling
dissolution from dosage form.

• From Noyes-Whitney equation it shows that

aqueous solubility of drug which determines its
dissolution rate.
18
ii. Particle size and effective surface area
of the drug –

• Particle size and surface area are inversely

related to each other.

Two types of surface area –

Absolute surface area which is the total
surface area of any particle.
Effective surface area which is the area of
solid surface exposed to the dissolution
medium.
19
• Effective surface area is directly related to the
dissolution rate.

• Greater the effective surface area, more intimate

the contact between the solid surface and the
aqueous solvent and faster the dissolution.

20
 iii. Polymorphism and amorphism –

• When a substance exists in more than one

crystalline form, the different forms are
designated as polymorphs and the phenomenon
as Polymorphism.

• Stable polymorphs has lower energy state,

higher M.P. and least aqueous solubility.

• Metastable polymorphs has higher energy state,

lower M.P. and higher aqueous solubility.
21
• Amorphous form of drug which has no internal
crystal structure represents higher energy state
and greater aqueous solubility than crystalline
forms.
• E.g.- amorphous form of novobiocin is 10 times
more soluble than the crystalline form.

• Thus, the order for dissolution of different solid

forms of drug is –

amorphous > metastable > stable

22
 IV. Salt form of the drug-

• Dissolution rate of weak acids and weak bases

can be enhance by converting them into their
salt form.

• With weakly acidic drugs, a strong base salt is

prepared like sodium and potassium salts of
barbiturates and sulfonamides.

• With weakly basic drugs, a strong acid salt is prepared

like the hydrochloride or sulfate salts of alkaloidal
drugs.
23
 iv. Hydrates/solvates –

• The stoichiometric type of adducts where the

solvent molecules are incorporated in the crystal
lattice of the solid are called as the solvates.

• When the solvent in association with the drug is

water, the solvate is known as hydrate.

• The organic solvates have greater aqueous

solubility than the nonsolvates.
• E.g. – chloroform solvates of griseofulvin is more water
soluble than their nonsolvated forms
24
 Factors contributing to the faster dissolution
rate of a drug

a. Reduction of particle size.

b. An increase in drug solubility
c. Absence of aggregation and agglomeration
between the fine crystallites of pure drug.
d. Excellent wettability and dispersibility of a drug as
the encircling soluble carrier readily dissolves and
causes the water to contact and wet the particles.
e. Crystallization of the drug in metastable form after
solidification from the fused solution which has
high solubility
25
B. Factors relating to the dosage forms –

i. Pharmaceutical excipients –

 Vehicle
 Diluents
 Lubricants
 Binders
 Surfactants
 colorants

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 ii. Manufacturing processes -

Method of granulation –

Wet granulation

Direct compression

Agglomerative phase of
communication (APOC)
27
  Compression Force :-
Rate of drug dissolution

A B C D

Compression force

Influence of compression force on dissolution rate of tablet

28
Intensity of packing of capsule contents –

• Diffusion of GI fluids into the tightly filled

capsules creates a high pressure within the
capsule resulting in rapid bursting and
dissolution of contents.

• On other hand, it shows that capsule with finer

particles and intense packing have poor drug
release and dissolution rate due to decrease in
pore size of the compact and poor penetrability
by the GI fluids.
29
IN-VITRO DISSOLUTION
TESTING MODELS

30
 INTRODUCTION
 Alternative to in vivo bioavailability determination

 Dissolution testing – Official in pharmacopeias

 Quantify the extent of release of drug

 Routinely used by Q.C. and R&D

 Q.C. Evaluate – batch consistency

 R&D Prediction of drug release

31
FACTORS TO BE CONSIDERED
WHILE DESIGNING OF A
DISSOLUTION TEST

32
 Factors relating to the
dissolution apparatus
Design of the container

Size of the container

Shape of the container

Nature of agitation

Speed of agitation

Performance precision of the apparatus

33
 Factors relating to the
dissolution fluid
Composition

Viscosity

Volume

Temperature

Sink condition

34
DISSOLUTION MEDIUM EXAMPLE
Water Ampicillin caps., butabarbital
sodium tabs.
Buffers Azithromycin caps.,
paracetamol tabs.
HCL solution Cemetidine tabs.
Simulated gastric fluid Astemizole tabs., piroxicam
caps.
Simulated intestinal fluid Valproic caps., Glipizide tabs.

Surfactant solution Clofibrate caps, danazol caps

35
 Process parameters
• Method of introduction of dosage form

• Sampling techniques

• Changing the dissolution fluid

36
37
 Classification
• There are basically three general
categories of dissolution apparatus :

1. Beaker methods

2. Open flow-through compartment system

3. Dialysis concept

38
1. BEAKER METHODS

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 Rotating Basket Apparatus
(Apparatus 1)
 It is basically a closed-compartment, beaker
type apparatus.
 It comprising of a cylindrical glass vessel with
hemispherical bottom of one litre capacity
partially immersed in a water bath.
 A cylindrical basket made of #22 mesh is located
centrally in the vessel at a distance of 2 cm from
the bottom and rotated by a variable speed
motor through a shaft.

40
 Contd…..

All metal parts like basket and shaft are

made of stainless steel 316.

41
 Rotating Paddle Apparatus
(Apparatus 2)
 Here, basket is replaced with a stirrer.

 A small, loose, wire helix may be attached to

the dosage form that would otherwise float.

 The position and alignment of the paddle are

specified in the official books.

42
 The Reciprocating Cylinder
Method (Apparatus 3)
 This method adopts the USP disintegration
“basket and rack” assembly for the dissolution
test.

 The disks are not used.

 This method is less suitable for precise

dissolution testing due to the amount of agitation
and vibration involved.

 E.g. Chlorpheniramine ER tablets,

Carbamazepine chewable tablet 43
44
 Paddle over Disk method
(Apparatus 5)
 Modification of Apparatus 2.

 Here, stainless steel disk designed for holding

transdermal system at the bottom of the vessel.

 The disk/device should not sorb, react with, or

interfere with the specimen being tested.

 The disk holds the system flat and is positioned

such that the release surface is parallel with the
bottom of the paddle blade.
45
46
 Cylinder method (Apparatus 6)

 Same as apparatus 1,except to replace the

basket and shaft with a S.S. cylinder stirring
element.

 Temperature - 32 ± 0.5°

 The dosage unit is placed on the cylinder.

 Distance between the inside bottom of the

vessel and cylinder is maintained at 25 ± 2 mm.

47
 Reciprocating Holder method
(Apparatus 7)
The assembly consists of a set of
calibrated solution containers, a motor and
drive assembly to reciprocate the system
vertically.

Various type of sample holder are used.

48
 Advantages of the Beaker
Methods
The basket method is the most widely
used procedure which confines the solid
dosage form to a limited area which is
essential for better reproducibility.

It is advantageous for capsules as they

tend to float at the surface thus minimizing
the area exposed to the dissolution fluid.

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 Limitation of the Beaker Methods
 Clogging of the basket screen by gummy particles.
 Tendency of the light particles to float.
 Sensitivity of the apparatus to variables such as
vibration, eccentricity, etc.
 Rapid corrosion of the SS mesh in presence of
HCl.
 Sensitivity of the apparatus to any slight changes
in the paddle orientation.
 Non-reproducible position of the tablets at the
bottom of the flask.
50
 2. OPEN FLOW-THROUGH
COMPARTMENT SYSTEM
 The dosage form is contained in a small vertical
glass column with built in filter through which a
continuous flow of the dissolution medium is
circulated upward at a specific rate from an
outside reservoir using a peristaltic or centrifugal
pump.

 Dissolution fluid is collected in a separate

reservoir.

 E.g. lipid filled soft Gelatin capsule

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53
 Advantages
No stirring and drug particles are exposed
to homogeneous, laminar flow that can be
precisely controlled. All the problems of
wobbling, shaft eccentricity, vibration,
stirrer position don’t exist.

There is no physical abrasion of solids.

Perfect sink conditions can be maintained.

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 Disadvantages

Tendency of the filter to clog because of

the unidirectional flow.
Different types of pumps, such as
peristaltic and centrifugal, have been
shown to give different dissolution results.
Temperature control is also much more
difficult to achieve in column type flow
through system than in the conventional
stirred vessel type.
55
 3. DIALYSIS SYSTEM
Here, dialysis membrane used as a
selective barrier between fresh solvent
compartment and the cell compartment
containing dosage form.

It can be used in case of very poorly

soluble drugs and dosage form such as
ointments, creams and suspensions.

56
57
58
 THE ROTATING FILTER
METHOD
It consists of a magnetically driven rotating
filter assembly and a 12 mesh wire cloth
basket.

The sample is withdrawn through the

spinning filter for analysis.

59
 ROTATING FLASK
DISSOLUTION METHOD
This consists of a spherical flask made of
glass and supported by a horizontal glass
shaft that is fused to its sides.

The shaft is connected to a constant

speed driving motor.

The flask is placed in a constant

temperature water bath and rotates about
its horizontal axis.
60
 ROTATING AND STATIC DISK
METHODS
 The compound is
compressed into non
disintegrating disc
 Mounted – One surface
is exposed to medium
 Assumption – Surface
area remains constant
 Used to determine the
intrinsic dissolution rate
61
Dissolution, Pharmaceutical Product Interchange
ability and Biopharmaceutics Classification

API properties

Dissolution:
An interplay of three
groups of factors

Formulation Analytics
Design In-Vitro Drug Release
Applications of Dissolution in the
Pharmaceutical Industry
1. As a formulation design aid (since formulation can profoundly affect
dissolution behaviour)

2. As a quality control measure immediately after production for batch

release

3. As a quality control measure to check performance during the shelf life

4. To predict performance under various dosing conditions („biorelevant“
methods)

5. To verify that the quality of a product is not adversely affected when there
is a change in excipients or manufacturing method (can sometimes be used
instead of a pharmacokinetic study)

6. To obtain approval for a multisource drug product („generic“ version of an

existing drug product) – in certain cases a pharmacokinetic study is not
required.
 1. Dissolution as an aid to formulation in
the Pharmaceutical Industry

The dissolution of the pure API is determined. If this is too slow for
the target release rate from the API, the formulation has to be
enhanced to improve the release characteristics.

Dissolution SGFsp
chloroquine diphosphate dissolved / % of label claim

100
90 Itraconazole
80
80
70

dissolved (%)
60
60 50
40
30
40
20
10
Resochin Tabletten, film coated tablets
20 Chlorochin 250 mg Berlin-Chemie, film coated tablets 0
Weimerquin Tabletten, uncoated tablets
chloroquine diphosphate drug substance
0 30 60 90 120 150 180 210 240
0 time (min)
0 10 20 30 40 50 60
SD Pharmacoat 603 SD Luviskol VA64
Chloroquine
time / min chlqphos_drug_ph68
PM Pharmacoat 603
Sporanox (2X100mg)
PM Luviskol VA64
2&3 . Dissolution as a quality control
measure for batch release, and to ensure
continued quality during the shelf life.
Here it is important to have a well-designed dissolution test that
can detect batches with poor quality without rejecting batches of
adequate quality.
The USP and, recently, the International Pharmacopeia, make
recommendations for specific drug products
WHO Standard dissolution method for highly soluble APIs

– Paddle Apparatus
– 500 mL
– SIFsp/IP Phosphate Buffer pH 6.8
– 75 Rpm
– 37 °C
– Sampling at 30 min.

• Specification:
– >85 % release within 30 min.
Dissolution, Pharmaceutical Product Interchangeability and
Biopharmaceutics Classification

WHO Standard dissolution method for highly soluble APIs

– Paddle Apparatus
– 500 mL
– SIFsp/IP Phosphate Buffer pH 6.8
– 75 Rpm
– 37 °C
– Sampling at 30 min.

• Specification:
– >85 % release within 30 min.
Widely used for: Why the Paddle Apparatus?
• Tablets and capsules
(can also be used for
pellets, MR dosage
forms)

Advantages:
• easy to use, robust
• long experience
• Many examples in USP

Disadvantages:
• possibility of coning
• Method of choice for
IR – dosage forms
• Why 500 mL medium?
– Corresponds approximately to the
volume of the contents in the upper
GI tract in the fasting state plus a
glass of water.
• Why 75 rpm?
– Avoids coning problems in most
cases
– For most drugs and drug products
studied to date, if there is no coning,
the results are very similar at 50 and
100 rpm.
Volumes in the upper GI tract after two types
of meals
• Why 37°C?
– Corresponds to the temperature of the GI
fluids
– For transdermal products a lower
temperature, usually 32°C is used, since
this is closer to skin temperature.

• Why a pH 6.8 Phosphate buffer?

– Corresponds to one of the three pH values
stipulated by the FDA in its biowaiver
guidance
– Both the USP and IP buffers have good
buffer capacity. Nevertheless, the pH
should be checked at the end of the
experiment.
 Case Example: Doxycycline hyclate
USP Method
Paddle Apparatus, 75 rpm
Paddle 4.5 cm above the vessel
• Solubility: bottom
– SGFsp pH 1.2 40.1 mg/mL 900 mL de-ionized water
– Aq. puricata > 50.0 30 min. for Capsules, 90 min. for
Tablets
mg/mL
– SIFsp pH 6.8 28.7 mg/mL

• Dose – 230 mg
• Permeability:
– Bioavailability: 95 % WHO Method
Paddle Apparatus, 75 rpm
– Cmax, p.o. admin. 2–3 h Standard paddle position
500 ml pH 6.8 phosphate
buffer
>85% release in 30 min.
Comparison of dissolution results for products
that contain 230.8 mg Doxycycline hyclate
120

120

doxycycline dissolved / % of label claim

100
doxycycline dissolved / % of label claim

100
80

80
60

60 40

doxy 200 von ct, ct-Arzneimittel GmbH, batch B20499

Doxycyclin STADA 200 mg Filmtabletten, STADApharm GmbH, batch 5611
40 20 Azudoxat 200 mg, Azupharma GmbH & Co., batch 11608
Doxy-Diolan 200, BRAHMS Arzneimittel, batch 0011
doxy 200 von ct, ct-Arzneimittel GmbH, batch B20499 Doxy-Wolff 200, DR. AUGUST WOLFF Arzneimittel, batch 106010
Doxycyclin STADA 200 mg Filmtabletten, STADApharm GmbH, batch 5611
Azudoxat 200 mg, Azupharma GmbH & Co., batch 11608 0
20 Doxy-Diolan 200, BRAHMS Arzneimittel GmbH, batch 0011
0 10 20 30 40 50 60 70 80 90 100
Doxy-Wolff 200, DR. AUGUST WOLFF Arzneimittel GmbH, batch 106010
time / min
doxycyc_sif

0
0 10 20 30 40 50 60 70 80 90 100 110 120 130
time / min doxycyc_water

WHO Method
USP
Method
• Why a specification of 85% in 30
min?
– Corresponds to the specification stipulated
by the FDA in its biowaiver guidance
– During development of the method, it is
advisable to generate a dissolution profile
(e.g. samples at 10, 20, 30, 45 and 60
mins) so that the dissolution is adequately
characterized
– For determination of bioequivalence, it
must be shown that the dissolution profile
of the test product varies by less than 10%
from the comparator product (usually by f2
comparison)
 Dissolution tests proposed for
Pharm. Int.
100

doxycycline dissolved / % of label claim

• Chloroquine phosphate and 80

sulfate
60
• Doxycyline hyclate
• Ethambutol dihydrochloride 40

doxy 200 von ct, capsules

• Isoniazid 20
Doxycyclin STADA 200 mg Filmtabletten, film coated tablets
Azudoxat 200 mg, uncoated tablets
Doxy-Diolan 200 mg, film coated tablets

• Metronidazole Doxy-Wolff 200, film coated tablets

doxycycline hyclate drug substance

• Primaquine diphosphate 0
0 10 20 30 40 50 60
time / min doxycyc_drug_sif

• Pyrazinamide
• Rifampicin
However, many APIs are poorly soluble, creating
dissolution problems
Some dissolution test options for poorly soluble
drugs
1. Adjust the pH of the medium
2. Add a surfactant to the medium
3. Increase the volume of the dissolution medium
4. Increase the duration of the dissolution test
Some dissolution test options for poorly soluble
drugs: Adjust the pH of the medium
pH-dependent solubility:
weak base

100000 61202
100
16011
10000
80

% Freisetzung
1000 559 SGF pH2
60
124 Acetatpuffer pH5
100
40
Conc. (mg/l)

10 3,9
1,7 20
1 0,4
0
0,1 0 30 60 90 120 150 180
pH 1.2 pH 2 pH 3 pH 4 pH 5 pH 6.5 pH 8
Zeit (min)
Some dissolution test options for poorly soluble
drugs: Add a surfactant to the medium

Increasing levels of sodium lauryl sulfate (0.1-1%) increase

dissolution of danazol (left panel)
Some dissolution test options for poorly soluble
drugs: Increase the volume of the medium

Using the Flow-Through tester,

volumes of up to several liters
can be used.
 4. Dissolution to predict performance
under various dosing conditions:
One question that often comes up is whether the API release is
affected by coadministration of a meal.

Danazol dissolution Danazol absorption

 5.&6. Dissolution to obtain (continued)
approval to market a drug product

In certain circumstances, dissolution testing

can serve as a surrogate for a
bioequivalence study in humans. This is
referred to as a „biowaiver“.
One example is when a change has to be
made to the formulation or manufacture of
an existing product
Another example is in the approval of a
new multisource product.
 „Must have“ Literature
• „Handbookof Dissolution Testing 3. Auflage“
Roy Hanson & Vivian Gray
Published by Dissolution Technologies (2005)
www.dissolutiontechnologies.com
• „Pharmaceutical Dissolution Testing“
Edited by J. Dressman & J. Krämer
Published by Taylor and Francis
www.taylorandfrancis.com
• General Chapter on Dissolution Testing (United
States Pharmacopeia)
IN VITRO IN VIVO
CORRELATION

84
 INTRODUCTION
• Key goal in development of dosage form is good
understanding of in vitro and in vivo
performance of dosage form
• Formulation optimization requires altering some
parameters – bioavailability studies
• Delay in marketing, added in time and cost
• Regulatory guidance developed to minimize the
additional bioavailability studies
• The guidance is referred as in vitro in vivo
correlation

85
 IVIVC BASIC
• Simply a mathematical model describing the
relationship b/w in vitro and in vivo properties of
drug
• In vitro – in vivo correlation can be achieved
using
Pharmacological correlation
Semi quantitative correlation
Quantitative correlation

86
 DEFINITION
• USP definition
“The establishment of rational relationship b/w a biological
property or a parameter derived from a biological
property produced by a dosage form and
physicochemical property of same dosage form”

• FDA definition
“It is predictive mathematical model describing the
relationship b/w in vitro property of dosage form and a
relevant in vivo response”
87
 IMPORTANCE
• Serves as a surrogate of in vivo and assist in
supporting biowaivers

• Validates the use of dissolution methods and

specification

• Assist in QC during mfg and selecting the

appropriate formulation

88
 LEVELS OF CORRELATION
• Level A correlation
• Level B correlation
• Level C correlation
• Multiple level C correlation
• Level D correlation

89
 Level A correlation
• Highest category 120
correlation 100
• Represents point to 80
point relationship % Drug
60
• Developed by two Absorbed
40
stage procedure
20
 Deconvulation
0
 Comparison 0 20 40 60 80 100 120
• Purpose – define % Drug Dissolved
direct relationship
90
 Level B correlation
• Utilizes the principle of statistical moment
analysis
MDTvitro is compared with MRTvivo
• No point to point correlation
• Does not reflect the actual in vivo plasma level
curves
• Thus we can not rely to justify the formulation
modification, mfg site change and excipient
source change.

91
 Level C correlation
• Dissolution time point (t 50%,t 90% ) is
compared to one mean pharmacokinetic
parameter ( Cmax ,tmax ,AUC)
• Single point correlation
• Weakest level of correlation as partial
relationship b/w absorption and dissolution
is established
• Useful in the early stages of formulation
development
92
 Multiple level C correlation
• It reflects the relationship b/w one or several
pharmacokinetic parameter of interest and
amount of drug dissolved at several time point of
dissolution profile
• Base on
 Early
 Middle
 Late stage
93
 1. Develop formulation with different release rates
2. Obtain in vitro dissolution profile and in vivo
concentration profile of these formulation

TWO STEP APPROACH ONE STEP APROACH

94
Approaches to improve dissolution of poorly
soluble drug –
Lipid based formulations –
• These include lipid solutions, micro-emulsions.
• Lipid solutions consist of drug dissolved in
vegetable oil or in triglycerides.
• The high lipophilicity facilitates absorption into the
intestinal lymphatics and then to the systemic
circulation.
• The presence of surfactant in this formulation
causes the enhanced absorption due to membrane
induced permeation changes.
95
Size reduction technology –

• Surface area increases by decreasing particle

size which results in higher dissolution rate.

• Reduction in particle size can be accomplished

by micronization, cryogenic and supercritical
fluid technology.

96
 Functional polymer technology –

• This technique enhance the dissolution rate of

poorly soluble drug by avoiding the lattice energy of
the drug crystal.

• These polymers (amberlite, duolite) are ion

exchange materials that interact with the ionizable
molecules of the surrounding medium and
exchange their mobile ions of equal charge with
surrounding medium reversibly.

• The resultant complex, known as resinate can be

formulated as suspension, dry powder or tablet.
97
 Porous microparticle technology –

• The poorly water soluble drug is embedded in a

microparticle having a porous, water soluble,
sponge like matrix. when mixed with water, the
matrix dissolves, wetting the drug and leaving a
suspension of rapidly dissolving drug particles.

• This is the core technology applied as HDDS

(Hydrophobic Drug Delivery System). These
drug particles provide large surface area for
increased dissolution rate.
98
• The hydrophilic solubilization technology
(HST) for poorly soluble drugs uses a
lecithin and gelatin based water soluble
coating to improve dissolution and
hydration of lecithin-gelatin coat forms
micelles which improve oral bioavailability
of the insoluble drugs.

99
 Controlled precipitation technology –

• In this process, the drug is dissolved in a water

miscible organic solvent and then dispersed into
aqueous medium containing stabilizers (HPMC,
cellulose ethers, gelatin)

• The solvent dissolves in water and causes

precipitation of the drug in the form of micro-crystal

• The stabilizers control particle growth and

enhances the dissolution rate of poorly soluble
drug due to large surface area hydrophilized by the
adsorbed stabilizer.
100
 Inclusion complexes –

• These complexes can be prepared with

β-cyclodextrin and HP-β-CD.

• The required quantity of β-CD is weighed and

water added to get consistancy.

• To the mass weighed quantity of the drug is

added. The mixture is kneaded in a glass mortar
for 1 hr. and then completely dried in hot air
oven at 60oC for 2 hrs. The dried mass is sieved
through mesh no. 120
101
 Solid dispersions –

• It is defined as the dispersion of one or more

active ingredients in an inert carrier or matrix at
solid state prepared by the fusion or melting
solvent method.

• Carriers for solid dispersion-

 Sugars- dextrose, sorbitol, mannitol.
 Acids- Citric acid, tartaric acid, succinic acid.
 Polymeric materials- PEG 4000, PEG 6000,
HPMC, polyvinyl pyrrolidone.
102
  Methods of preparation –

1. Melting method/Fusion method –

• In this method, the physical mixture of a drug and

water soluble carrier was heated directly until it is
melted, which was then cooled and solidified
rapidly in an ice bath.
• To facilitate faster dissolution, the melt was
poured in the form of thin layer onto a stainless
steel plate and cooled by flowing air or water on
opposite side of plate.
• The final solid mass is then crushed, pulverized
and sieved. 103
 2. Solvent method –

• Solid solutions or mixed crystals can be prepared

by dissolving a physical mixture of two solid
components in a common solvent, followed by
evaporation of the solvent.

• Thermal decomposition of drugs or carriers can be

prevented because of low temperature.

• E.g. – solvent dispersions of β-carotenes-PVP,

griseofulvin –PVP, tolbutamide-PVP, etc.
104
 3. Melting-Solvent method –

• The drug is first dissolved in a solvent and

then the solution is incorporated directly into
the melt of the carrier.

• A liquid drug such as methyl salicylate,

Vitamin-E, clofibrate can be formulated as a
solid dosage form and mixing it with melted
liquid of PEG-6000 and cooling the mixture.

105
  Simple Eutectic mixtures –

• Rapid solidification of fused liquid of two

components which shows complete liquid
miscibility and negligible solid-solid solubility
yields a simple eutectic mixture.

• When a eutectic is exposed to GI fluids, both

poorly soluble drug and carrier may crystallize
out in very small particulate size.

106
  Solid solution :-

• It is made up of a solid solute molecularly

dispersed in a solid solvent. The two
components crystallize together in a
homogenous one-phase system and thus they
are referred to as mixed crystals or molecular
dispersions.

• They are generally prepared by fusion method

where a physical mixture of solute and solvent
are melted together followed by rapid
solidification.
107
• The two mechanisms suggested for rapid
dissolution of molecular dispersions –

i. When the binary mixture is exposed to water,

the soluble carrier dissolves rapidly leaving the
insoluble drug in a state of microcrystalline
dispersion of very fine particles.

ii. Solute and solvent molecules randomly

arranged themselves to form crystal lattice,
when dissolution fluid is exposed to such crystal,
soluble solvent molecules get dissolved in
dissolution fluid and leaves behind insoluble
drug molecules.
108
 Glass solutions and glass suspensions –

• It is a homogenous glassy system in which a

solute dissolves in a glassy solvent.

• Glass solution is metastable and it amorphous

to x-ray diffraction.

• Polyhydroxy molecules like sugars form

glasses which may be due to strong hydrogen
bonding prevent crystallization.
109
 Amorphous precipitations in a crystalline
carrier –

• The drug precipitate out in an amorphous form

in the crystalline carrier from a melting or
solvent method of preparation.

• Amorphous form produces faster dissolution

rate than crystalline form.

110
 EVALUTION OF PREDICTIBILITY
CORRELATION
• Demonstrate – in vitro dissolution characteristic
is maintained
• They focus the predictive performance or
prediction error
• Depending of intended application of IVIVC and
therapeutic index
– Internal evaluation
– External evaluation

(Cmax observed – Cmax predicted) × 100

% PE =
Cmax predicted
111
112
113
Biopharmaceutics Classification System

Absorption Number
A function of GI Permeability to Drug Substance

P  T
An   T   eff GI

R
GI

T ABS

114
 Biopharmaceutics Classification System

Effective permeability

P  T
An   T   eff GI

R
GI

T ABS
Residence time in GI
Radius of GI
Time required for
115
complete absorption
 Biopharmaceutics Classification System

Dose Number
A function of solubility of drug substance

D 
Highest Dose Unit
250 mL

 V 
Do   W ater


 C 
Solubility
Solubility

 
S
Issues

D / Vwater >> CS ~ High Do D / Vwater << CS ~ Low Do

116
 Biopharmaceutics Classification System

Dissolution Number
A function of drug release from formulation

 3D  C  T 
Dn    S
T     GI

 r    T 
2 GI

DISS

117
 Biopharmaceutics Classification System

Diffusivity Solubility
5x10-6 cm2/s

3D  C  T 
mg/mL


Dn    S
T     GI

 r    T 
2 GI

DISS

Residence time in GI
Particle Radius 180 min

25 mm Time required for

Density 118
3 complete dissolution
 Dissolution and IVIVC
• It has high discriminating power and able to
detect minor changes in manufacturing process
• Purpose
– Batch consistency
– Quality performance
– Guide to new formulation
• Dissolution apparatus
Apparatus 1 Rotating basket
Apparatus 2 Paddle method
Apparatus 3 Reciprocating cylinder
Apparatus 4 Flow through cell
119
• For IVIVC purpose dissolution profile of at least
12 dosage form each lot should be carried out

• Where Rt and Tt = cumulative % dissolved

for reference and test
• Values range from 0 to 100

120
 Bioavailability studies in developing
IVIVC
• Performed to characterize the plasma conc.
versus time profile
• Performed with sufficient no. of subjects
• Appropriate deconvulation technique is to be
applied for IVIVC

Wegner Nelson method Loo – Riegelman method

121
 Factors to be considered while
developing IVIVC
1. Stereochemistry

2. First pass effect

3. Food effect

122
 APPLICATION OF IVIVC
• Early development of drug product and
optimization

• Bio waiver for minor formulation and

process changes

• Setting dissolution specification

123
 References
• D.M.Brahmankar, Biopharmaceutics and
pharmacokinetics- A Treatise; Vallabh Prakashan,
page no. 20–31.
• Hamed M. Abdou, Dissolution Bioavailability &
Bioequivalence; MACK Publication, page no. 11-17,
53-84.
• Leon Shargel, Applied Biopharmaceutics &
Pharmacokinetics; 4th edition, page no. 132-136.
• The Indian Pharmacist, February 2008,
page no.10-12
124
 REFERENCES
United States Pharmacopoeia – 24, page no.:
1942 – 1951.
“Current perspectives in dissolution testing of
conventional and novel dosage forms”, by
Shirazad Azarmi, Wilson Roa, Raimar
Lobenberg, Int. jou. Of pharmaceutics
328(2007)12 – 21.
Alton’s pharmaceutics “ The design and
manufacturing of medicines”, by Michael E.
Alton, page no.: 21 – 22.
http://www.google.com

125
 REFERENCES
Text book of Biopharmaceutics and
pharmacokinetics, by Shobha Rani R. Hiremath.
Principle and application of Biopharmaceutics and
Pharmacokinetics, by Dr. H.P. Tipnis, Dr. Amrita
Bajaj.
“IVIVC : a ground discussion” by Kalaslar S.G.,
Yadav A.V. and Patil V.B., IJPER – vol. – 41, Dec.
2007.

Pharmaceutical Preformulation and Formulation,

by Mark Gibson page no.: 241 – 244.
126
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