Solubility of drugs

SOLUBILITY OF DRUGS
Presented By:
Mahewashsana A. Pathan,
R.P. College of Pharmacy, Osmanabad

SOLUBILITY
“The concentration of a substance (solute) that
dissolves in a given volume of solvent at a certain
temperature to form a homogenous solution.”
OR
“The spontaneous interaction of two or more
substances to form a homogenous molecular
dispersion.”
2

Definitions
• Solute: a component which dissolved in the solvent,
present in less amount in the solution.
• Solvent: a component in which solute is dissolved,
present in more amount than solute.
• Solution: A system in which solutes are completely
dissolved in solvent & form a homogenous molecular
dispersion.
• Saturated solution: Solution in which the solute in
solution is in equilibrium with solid phase.
• Unsaturated solution: Solution containing dissolved
solute in concentration below that necessary for
complete saturation.
• Supersaturated solution: Solution containing more of
the dissolved solute than it would normally contain.
3

SOLUBILITY EXPRESSIONS
Sr.
No.
Description forms
( Solubility)
Parts of solvent required
for one part of solute
1 Very soluble (VS) <1
2 Poorly soluble (PS) 1-10
3 Soluble 10-30
4 Sparingly soluble (SPS) 30-100
5 Slightly soluble (SS) 100-1000
6 Very slightly soluble (VSS) 1000-10000
7 Practically insoluble (PI) >10000
4

MECHANISM OF SOLUTE SOLVENT INTERACTIONS
“LIKE DISSOLVES LIKE”
Sr.
No
Nature of
Solvent
Mechanism of solubility Example
1. Polar a. High dielectric
constant
b. H- bond formation
c. dipole interactions
Water+ ethanol
2. Non-polar weak van der waal’s
forces
Fats, oils, alkaloidal
bases + CCL4,
benzene
3. Semi-polar induce certain degree of
polarity
Acetone increase
solubility of ether in
water
5

IDEAL SOLUBILITY PARAMETERS
‘Ability of a liquid to act as a solvent’
1) Hildebrand solubility parameter (δ)
“square root of cohesive energy density”
δ= √△Hv- RT/ Vm
2) Hansen solubility parameter (δt)
δt= δd + δp + δh
6

Solvation / Dissolution
“ Interaction of a solute with the solvent, which leads
to stabilization of solute species in the solution”
+ve solvation energy= endothermic dissolution
-ve solvation energy= exothermic dissolution
7

Association
“Chemical reaction in which the opposite electric
charge ions come together in solution & form a
distinct chemical entity”
Classification according to nature of interaction:
1. Contact
2. Solvent shared
3. Solvent separated
8

FACTORS INFLUENCING SOLUBILITY
1. Temperature
2. Nature of solvent ( like dissolves like)
3. Pressure
4. pH
5. Particle size
6. Crystal structure
7. Molecular structure
8. Solute- solvent interactions
9. Addition of substituent
10. Common ion effect
11. Solubilizing agents 9

SOLUBILITY OF GASES IN LIQUIDS
Henry’s law:
‘Solubility is directly proportional to partial pressure
of gas at a constant temperature’.
S= KP
10

SOLUBILITY OF LIQUIDS IN LIQUIDS
1. Completely miscible liquids:
E.g. Water+ ethanol, Glycerine+ Alcohol, benzene+ CCL4
2. Partially miscible liquids:
E.g. Phenol+ water.
3. Completely immiscible liquids:
E.g. Mercury+ water.
11

RAOULT’S LAW
“The partial pressure (Pi) of each component in a
solution is equal to the mole fraction of the
component & the vapour pressure of the pure
component”
Pi = xP
Or
P = pAxA + pBxB
12

IDEAL SOLUTIONS
“ Solutions which obey Raoult’s law in all the solute
composition in a solvent”
13

REAL/ NON IDEAL SOLUTIONS
“Solutions which do not obey Raoult’s law over entire
range of composition”
Negative deviation
PA < Xa P
△H < 0
△V < 0
Positive deviation
PA > Xa P
△H > 0
△V > 0 14

AZEOTROPES
(Constant boiling mixtures)
MINIMUM BOILING
AZEOTROPES
+ve deviation from Raoult’s law
MAXIMUM BOILING
AZEOTROPES
-ve deviation from Raoult’s law
15

FRACTIONAL DISTILLATION
16
• Seperation of mixtures into its component parts.
• Seperation of two miscible liquid, having different b.p.

CRITICAL SOLUTION TEMPERATURE
(CST)
18
Application- determination of CST used for test the
purity of phenol & other such substances.

NERNS’T DISTRIBUTION LAW
( PARTITION COEFFICIENT)
“ If a solute distributes
between two immiscible
solvents at a constant
temperature then the
ratio of its concentration
in two solvents is a
constant value”.
K= C1/ C2
19

Deviation from the distribution law has been
attributed if-
1. There is alterations in the mutual solubility of two
liquids as a result of increasing concentration.
2. If molecular state of the solute get change in the
two solvents. The change in molecular state
include;
a) When solute undergoes association in one of the
solvents,
b) When solute undergoes dissociation in the solvent.
20

Limitations of distribution law:
• Solute should not react with any of the solvents.
• Solute must not undergo any change in its
molecular state in the solvents.
• Temperature should be constant throughout the
experiment.
• Solute concentration are noted after equilibrium
is established.
• Solute concentration in both solvents is low. The
law does not hold when concentrations are high.
21

Applications of distribution law:
• Seperation of organic substances from aqueous
solutions.
• In metallurgical operations.
• Useful in the study of complexation, hydrolysis of
salts.
• Useful in determination of association and
dissociation.
22

DISSOLUTION AND DRUG RELEASE
• Dissolution is the process by which a solid substance
enters the solvent phase to yield a solution.
• Absorption is the process of transporting the drug
substance from the GIT into the systemic circulation.
• Drug release for absorption decreases in following
order: solution> suspension> capsules > tablet
24

THEORIES OF DISSOLUTION
1. Diffusion layer model
2. Danckwert’s model
3. Interfacial barrier model
25

DIFFUSION LAYER MODEL (Film theory)
• When solid goes into dissolution medium, a thin film
adhere to surface of solid particle called stagnant
layer or diffusion layer.
dC/dt = k ∆C
dC/dt = rate of diffusion
K= rate constant
∆C= concentration of
solid at any point at time t.
26

DANCKWERT’S MODEL (SURFACE RENEWAL
THEORY)
V. dC/ dt = A (Cs – Cb) × √ D
dC/dt = dissolution rate
A= surface area of dissolving body
Cs= saturation solubility
Cb = bulk concentration
D= diffusion coefficient
V = volume of dissolution medium
27

INTERRACIAL BARRIER MODEL
• In this, dissolution is a function of solubility rather
than diffusion.
• An intermediate concentration exist at the interface
as a result of solvation mechanism.
• Rate of dissolution is-
dC/dt = K (Cs-Cb)
28

Processing
factors
Factors
relating to
Dissolution
media
Factors
related to
drug
product
FACTORS AFFECTING DISSOLUTION
Physicochemical
properties of drug
29
Factors
relating to
Dissolution
apparatus

Physicochemical properties of drug
1. Drug solubility- minimum aqueous solubility of 1% is needed to
avoid potential solubility limited absorption problems.
2. Particle size- reducing the particle size increases surface area and
solubility therefore higher is the dissolution.
3. Salt formation- it is is common approach used to increase the
solubility and rate of dissolution of the drug sodium salts dissolve
more readily than their corresponding in soluble acids for example
sodium and potassium salt of penicillin G, sulfonamides,
phenytoin, barbiturates, etc.
4. Solvates & hydrates- the anhydrous compounds are highly soluble
as hydrate for example anhydrous and hydrate forms of ampicillin.
30

5. pH effect- rate of dissolution increases while increasing the pH
solution.
6. Polymorphism and amorphism: Amorphous>metastable>stable
7. Co-Precipitation- the rate of dissolution of sulfathiazole could be
significantly increased by coprecipitating the drug with povidone.
8. Complexation- complexation of drug in GIT alter rate of absorption.
9. Wetting- wettability e of hydrophobic drugs measure by contact
angle high contact angle means poor wettability and vice versa a bile
salt decrease contact angle of poorly soluble drugs in GIT and further
increase dissolution rate.
31

Factors related to Dissolution apparatus:
1. Agitation- speed of agitation generate a flow at liquid solid
interface between solvent and drug in order to prevent turbulence
agitation should be maintained at a relatively low rate.
2. Stirring element alignment- the USP/NF states that axis of the
stirring element must not deviate more than 0.2 mm from the axis
of dissolution vessel which defines centring of stirring shaft to
within +/-2 mm till in excess of 1.5 increase dissolution rate from 2
to 25%.
3. Sampling probe position- USP states that sample should be
removed at approximately half the distance from the basket or
paddle to the dissolution media and not closer than 1cm to the
side of the flask.
32

Factors related to dissolution media
1. Temperature- drug solubility is temperature dependent. Generally a
temperature of 37°+-0.5 is maintain during dissolution of oral dosage
forms and suppositories. However for topical preparations temperature
as low as 30 degree and 25 degree have been used.
2. pH of medium- pH varies with different locations in the GIT and further
influence saturation solubility of ionizable drugs specific gravity decrease
leads to floating of powder which leads to wetting and penetration
problems.
3. Dissolution media composition- the composition of dissolution media
also affect Dissolution rate. E.g. Addition of sodium sulphate decrease
the dissolution rate and addition of urea increase dissolution rate.
4. Volume of dissolution medium and sink conditions- volume generally
used are 500, 900, 1000ml and simulated gastric fluid pH- 1.2. simulated
intestinal fluid PH- 6.8. 33

Factors related to to drug product:
1. Disintegration- disintegrating agents are added before and after the
granulation affects the dissolution rate for example microcrystalline cellulose
is very good disintegrating agent but at high compression force it may retard
drug dissolution.
2. Binders- the hydrophilic binder increase dissolution rate of poorly wettable
drugs but large amount of binder increased hardness and decrease
disintegration or dissolution rate of tablet.
3. Lubricants- these are hydrophobic in nature which inhibit wettability
penetration of water into tablet so decrease in disintegration and dissolution
use of soluble lubricant like SLS promote drug dissolution.
4. Surfactants- they enhance dissolution rate of poorly soluble drugs due to
lowering of interfacial tension.
5. Effect of coating component on tablet dissolution- coating ingredient
specially shellac and cellulose acetate phthalate, etc have significant effect on
dissolution rate of coated tablet.
34

Processing factors:
1. Method of granulation- granulation process in general
enhances dissolution rate of poorly soluble drug.
2. Compression force- the compression force influence density,
porosity, hardness disintegration time and dissolution of
tablet.
3. Drug excipient interaction- the interaction occur during any
unit operation such as mixing, milling blending, drying, &
granulation results change in dissolution
35

DISSOLUTION APPARATUS
Basket apparatus (USP Apparatus 1):
• Cylindrical basket attached to a motor &
metallic shaft.
• Basket is of stainless steel, type 316.
Coated with gold. Its thickness should be
not more than 2.5mm.
• Basket holds the sample & rotates in a
hemispherical vessel containing the
dissolution medium.
• Vessel capacity is 1000ml, made of glass
or transperant material.
• Theventire vessel is immersed in a
constant temperature bath set at 37°C.
37

Paddle Apparatus (USP Apparatus 2):
• Consist of a special, coated paddle
used as a source of stirring.
• Attached vertically to a variable
speed motor.
• Sample(tablet or capsule) placed
into the bottom of the dissolution
flask.
• Common operating speed for
apparatus 2 is 50 rpm for solid oral
dosage forms & 25 rpm for
suspension.
• Generally preferred for tablets.
38

Apparatus 3 (Reciprocating cylinder):
Suitable for- extended release drug products.
39

Apparatus 4 (Flow through cell):
Suitable for- drug products containing low water soluble drugs.
40

Apparatus 5 (Paddle over disk):
Suitable for- Transdermal drug products
41

Apparatus 7 (Reciprocating disk):
43

MATHEMATICAL MODELS OF DRUG RELEASE:
• These are used to evaluate the kinetics & mechanism of drug
release from the dosage forms.
• The model that fits the release data is selected based on
correlation coefficient value in various models.
44

1. Zero order release:
• Drug dissolution from dosage forms
that do not disagregate & release the
drug slowly.
Q = Qo + Ko t
Where, Q= amount of drug dissolved in
time t,
Qo = initial amount of drug
Ko = zero order release constant
• Describe dissolution of- transdermal
systems, matrix tablets with low
soluble drugs in coated form, etc.
45

2. First order release:
log C = log Co – kt / 2.303
Where, C- amount of drug let in the matrix
Co- initial amount of drug in matrix
K- first order rate constant
• Data obtained are plotted as log cumulative% of drug release
remaining Vs time.
46

3. Higuchi model:
• Based on following hypothesis-
1. Initial drug concentration in matrix is higher than drug solubility.
2. The diffusion takes place only in one dimension.
3. Drug particles are much smaller than system thickness.
4. Matrix swelling and resolution are negligible.
5. Drug diffusibility is constant.
6. Sink conditions are attend.
Q= A √D (2C – Cs) Cs t
Where, Q- amount of drug release
D- diffusion coefficient
C- initial drug concentration
Cs- drug solubility in the matrix media.
. Q= Kh √t
Where, Kh- Higuchi Dissolution constant. 47

4. Hixon-crowell model:
• Particles’ regular area is proportional to to the
the cube root of its volume.’
48

5. Korsemeyer- peppas model:
Mt/ Ma = K t^n
Where, Mt/ Ma= fraction of drug release
n= diffusional exponent for drug
release.
• Value of ‘n’ characterize the release
behaviour.
49
No. n Diffusion mechanism
1 > 0.45 Fickian
2 0.45< n < 0.89 Non-fickian
3 0.89 Case II (relaxational) transport.
4 >0.89 Super case II

DIFFUSION PRINCIPLES IN
BIOLOGICAL SYSTEMS

DIFFUSION
“Mass transfer of individual molecules of a substance caused by
random molecular motion, associated with a driving force
such as the concentration gradient”
OR
“ A physical process that refers to the
net movement of molecules from
a region of high concentration to
lower concentration under the
influence of concentration gradient.”

Diffusion phenomena applied in pharmaceutical
sciences include:
• Release of drug from dosage form
• Ultrafiltration, microfiltration, dialysis, hemodailysis.
• Permeation & distribution of drug in living tissues
• Estimation of molecular weight of polymers
• Prediction of absorption & elimination of drug.

TYPES OF DIFFUSION
1. Passive diffusion:
• Net moment of material from an area of high concentration
to an area of low concentration.
• The difference between high and low concentration is
termed as concentration gradient.
• Diffusion will continue until the gradient has been
eliminated.

2. Facilitated (carrier mediated) diffusion:
• It is moment of molecules across the cell
membrane via special transport proteins
that are embedded within the cellular
membrane.
3. Active transport:
• Movement of molecules across a
membrane from a region of lower
concentration to higher concentration,
against the concentration gradient.
4. Filtration:
• Movement of solvent or solute
molecules, influenced by hydraulic
pressure.

LAWS OF DIFFUSION
• Derived by Adolf Fick in 1856.
FICK’S FIRST LAW OF DIFFUSION:
“Diffusion flux is directly proportional to concentration gradient
under the assumption of steady state diffusion”
J= -D dc/dx
Where,
J= diffusion flux (g/ sq. cm/s)
D= Diffusion coefficient or diffusivity
( cm sq/sec)
dc= change in concentration of material
( g/cubic cm)
dx= change in distance (cm)
• Diffusion flux (J) is mass transfer through a unit
Cross section area in unit time.
J= dM/S dt

FICK’S SECOND LAW OF DIFFUSION:
“Change in concentration with time in a particular
region is proportional to the change in concentration
gradient at that point in the system.”
dc/dt = -dJ/dx

MEASUREMENT OF DIFFUSION
Franz Diffusion cell

• Franz cell apparatus contain two chambers separated by a
membrane.
• Donor chamber consist of known concentration of solute.
• Receptor chamber contain fluid from which samples are taken at a
regular interval for analysis.
• Temperature is maintained at 37˚C.
• Membrane maybe of excised tissue, tissue constructs & cadaver
tissue to synthetic membranes.
• When experiment starts, solute from donor chamber diffuses
through membrane into receptor chamber.
• From receptor chamber, solution is periodically removed for
analysis.
• The test determine amount of diffusant that has permeated the
membrane.
• The solution of receptor chamber is replaced with new solution
after each sampling.

DIFFUSION CONTROLLED RELEASE SYSTEM
1. Reservoir (laminated matrix) device:
• A hollow system containing an inner core
surrounded in water insoluble membrane.
• Polymer can be applied by coating or
encapsulation.
• Drug partitions into membrane &
exchanges with surrounding fluid by
diffusion.
• Drug will enter membrane, diffuse to
periphery & exchange with surrounding
fluid.
• Polymer content in coating, thickness of
coating & hardness of microcapsules are
rate controlling parameters.
• Release follow fick’s first law of diffusion.

2. Matrix (Monolithic) devices:
• Solid drug is dispersed or
distributed in an insoluble
matrix.
• Outer layer of drug is exposed to
bathing solution in which it is
first dissolved. Then drug
diffuses out of matrix.
• Matrix diffusion system are of
two types:
i. Rigid matrix
ii. Swellable matrix

In Vitro- In Vivo Correlation
( IVIVC )
61

Introduction:
• The term of IVIVC was first introduced in the late 1950 by Wagner et al.
USP definition of IVIVC:
“The establishment of a rational relationship between a
biological property, or a parameter derived from a biological property
produced by a dosage form, & a physicochemical property or
characteristic of the same dosage form.”
• FDA definition of IVIVC:
“A predictive mathematical model describing the relationship
between an in-vitro property of a dosage form & an in-vivo response.”
62

IMPORTANCE
• To serve as a surrogate for in-vivo bioavailability.
• To support biowaivers for bioequivalence testing.
• To validate the use of dissolution methods & set the dissolution
specifications.
• IVIVC proves an important research tool in the development of drug
delivery system.
• The IVIVC model facilitates the rational development & evaluation of
immediate or extended release dosage forms. Hence it acts as a tool
for formulation screening.
• To assist quality control for certain scale-up & post approval changes
(SUPAC).
• Reduction of regulatory burden.
• To reduce the number of human studies during the formulation
development.
63

APPROACHES FOR IVIVC
1. Correlation based on plasma level data
2. Based on urinary excretion data
3. Based on pharmacologic response
64

Levels of IVIVC
Level A
Level B
Level C
Multiple level C
Level D
65

Level In vitro In vivo
A Dissolution curve Absorption curve
B Mean Dissolution Time (MDT) Mean Residence Time (MRT),
MAT.
C Disintegration time, dissolution
rate, dissolution efficiency
Cmax, Tmax, Ka, AUC.
D Rank order or qualitative analysis Not useful for regulatory
considerations but for
formulation & process
development.
66

IVIVC Models
1. Convolution model
2. Deconvolution model
67

Types of correlation
1. Quantitative correlation
68
Y = mx + c
Where, y = in vivo parameter
X = in vitro parameter
m = slope of the relationship
c = intercept.
Ideally m = 1 & c = 0, indicating a linear relationship.
2. Rank order correlation

IVIVC development
Step 1
• the In vivo input profile of the drug from
different formulations is calculated from drug
concentrations in plasma.
Step 2
• the relationship between in vitro dissolution
and the in vivo drug input profile is determined
Step 3
• In this phase plasma drug concentration profiles are
predicted and compared to the observed time courses
for different formulations.
69

Validation of IVIVC Model
1. Internal
2. External
• Prediction error
For Cmax
%Prediction error (P.E.)= ( Cmax Observed – Cmax
Predicted ) / Cmax Observed * 100
For AUC:
%Prediction error (P.E.)= (AUC observed – AUC predicted
)/ AUC observed * 100
70

Biopharmaceutics classification system
(BCS)
71

APPLICATION OF IVIVC
• Application in drug delivery system
• In early stages of drug delivery technology development
• Formulation assessment: In vitro dissolution
• Dissolution specifications
• Future biowaivers
• IVIVC - Parenteral drug delivery
• Biowaivers
• Establishment of dissolution specifications
• Mapping
72

softwares
winNonlin-
IVIVC
Toolkit
GastroP;us v.
6.1 IVIVCPlus
PDx-
IVIVC
DDDPlus
V. 3.0
ivivc for
R
Kinetica
73

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