Solubility

Department of pharmaceutics
presented by
Zainab Eassa Jassim
Renata A. Al sattar
PhD candidate

Supervised by
Prof. Dr Mowafaq M. Ghareeb
Outlines

› Solubility definition
› Solubilization process
› Factors affecting on solubility
› Methods of solubility Enhancement
› pH-solubility profile
› Classification of drug according to solubility
› Polymorph and determination of its solubility by DSC
Solubility:
 Simply stated, it is the amount of a substance that will
dissolve in a given amount of another substance

 is the analytical composition of a saturated solution

expressed as a proportion of a designated solute in a
designated solvent.
› The solubility of a substance depends on the
physical and chemical properties of the solute and
solvent and temperature, pressure, and the
presence of other chemicals (including changes to
the pH) of the solution.
 › Solubilization:
› Solubilization is the formation of a
thermodynamically stable solution of a substance
(the solute), normally insoluble or slightly soluble
in water, by the addition of a solubilizer, such as a
surfactant.
-
› Solvation:
› It is any stabilizing interaction of a solute and the
solvent or a similar interaction of groups of an
insoluble material with solvent that general involve
electrostatic forces and van der Waals forces and
chemically more specific effects such as hydrogen
bond formation.
 Theories of Solubilization
› There are two steps for solubilization :

(1) phase transition of solid into molecular (liquid) state of

the solute at the interface on contact of liquid solvent
resulting in a layer of saturated solution at the interface, and
2) transport of the molecules from the saturated solution
layer into the bulk of the liquid solvent medium by the
process of diffusion.
This two-step process of solubilization is commonly referred
to as the “diffusion layer model ”.
Schematic representation of solubilization from a planar surface of
the solid solute where Cs is the solubility, Cb is the bulk solution
concentration, and h is the thickness of the diffusion barrier (layer).
 “Danckwerts model” or surface
renewal theory
› The affinity between solute and solvent is expressed by
means of random packets of solvent reaching the solid–
liquid interface assisted by eddy diffusion and getting
attached to the interface.
› These packets absorb the solute and get saturated
following which they leave the interface and are replaced
by fresh packets of the solvent.
 “Danckwerts model” or surface
renewal theory

Schematic depiction of Danckwerts model (surface renewal

theory), where Cs is the equilibrium solubility of the solid
solute and C is the concentration of the solute in the bulk
solution
 “Danckwerts model” or surface
renewal theory
 This process results in the absence of boundary
layer and a constant film that is being continuously
replaced by fresh solvent.
 As long as there is excess solvent, the solution will
not be saturated.
 “Danckwerts model” or surface
renewal theory
› The rate of solubilization can be computed using the
following equation

› where A is the surface area, Cs is the equilibrium solubility

of the solid solute, C is the concentration of the solute in
the bulk solution, 𝓇 is the rate of surface renewal, and D is
the diffusivity
 Solubility: Challenges in Drug Development

Essentially, three main objectives, for characterizing the solubility and

the process of solubilization of the drug substance :
(i) possess sufficient aqueous solubility with respect to the dose to be
administered,
(ii) achieve safe and effective bioefficacy (e.g. BA, BE),
(iii) establish and demonstrate quality specifications and QC of the
finished dosage form
 Types of Solubility
› Intrinsic solubility
› Apparent solubility
› Thermodynamic solubility
› Kinetic solubility
 Intrinsic solubility

› The intrinsic solubility is defined as the solubility of

the unionized form of the molecule.
› The relationship of pH and solubility of an
ionizable molecule is described by the Henderson
Hasselbalch equation.
 Intrinsic solubility

› Taking the base-species Hendersone Hasselbalch equation

where S refers to the solubility of the drug and So is the
intrinsic solubility, i.e. the solubility of the unionized form of
the drug
pH–solubility profile for a compound with a single, basic
pKa value of 5. The four regions of pH-dependent solubility
are the salt plateau, pHmax, ionized compound, and un-
ionized compound
 Apparent solubility

› It is often assumed to be the highest concentration

observed during a solubility experiment.
dependent on the environmental factor such as pH
and ionic strength.
› Higher apparent solubility is typically observed
from solids with a higher energy state (eg,
metastable or amorphous solids)
 Thermodynamic solubility

› The concentration of the solute in the solvent at which this

equilibrium is reached is defined as the thermodynamic
solubility.
› “shake-flask”method is typically considered as the
standard method for determining the thermodynamic
solubility
 Thermodynamic solubility

› Determining the thermodynamic solubility in

polymers using melting point depression-based
methods have been reported analyzed by
differential scanning calorimetry (DSC)
 Kinetic solubility

› is defined as the point at which the aqueous

component can no longer solvate the drug.

› it measures a precipitation rate rather than

solubility.

› Solubility results obtained from kinetic

measure_x0002_ments might not match the
thermodynamic solubility results
 methods of solubility determination
All methods used for solubility determination
primarily consist of two parts:
saturating the solvent with the solute
 measuring the amount of solute present per unit
of the solvent at that saturation state.
 methods of solubility determination
› The traditional shake-flask method
Classification of drug according to solubility
Generalized and dimensionless definition of
solubility without regard to any type of solvent –
aqueous or otherwise –
Biopharmaceutics Classification System
 Biopharmaceutics Classification System
› BCS classifies the drug substance on its aqueous solubility
and intestinal permeability.

› The drug substance is considered highly soluble when the

highest dose is soluble in ≤250 mL of aqueous media in the
pH range of 2–6.8.

› The drug substance is considered as highly permeable

when the absolute BA considering the extent of intestinal
absorption is determined to be ≥90%.
Domain of solubilization and solubility in drug
development.
 Polymorphism

› chemical compounds often display the ability to

crystallize out as more than one structure.

› The different polymorphic forms may result in the solid

having significant differences in chemical and physical
properties, such as melting point, dissolution rate,
bioavailability, solubility, etc.,
› The thermodynamic relationships between polymorphic
systems can be classified according to a number of
thermodynamic laws that were first developed by Burger
and Ramberger.

From these rules, two distinct classes of polymorphic

systems have been developed:
›
monotropic and enantiotropic.
 Monotropic

Where only one polymorph is stable below the

melting point, the free energy and solubility curves
do not cross, and there is no reversible transition
between the polymorphic forms below the melting
point.
 Enantiotropic

Where a transition point exists below the melting

point (above and below this, different polymorphic
forms are stable), and this transition is reversible.
The free energy and solubility curves of an
enantiotropic system cross before the melting point
and are equal at the crossing point.
 The purpose of the work
Determining the solubility of both stable and
metastable polymorphs
- carbamazepine (forms I and III)
- glycine (α and γ forms)
- -mefenamic acid (forms I and II)
› using differential scanning calorimetry (DSC).
 Sample Preparation and Procedure

› Determination of appropriate temperature range in

order to reduce the experimental time.

› Sample pan containing a quantity of solute then

solvent is added with the help of a micropipet.

› Reference pan containing The same amount of

solvent
› The sample is first heated or cooled to an initial
temperature, the sample is heated and held at the
temperature until equilibrium has been achieved.

› Finally it is cooled, using the same rate, to the

initial temperature and held at this starting
temperature until equilibrium has been achieved
 Sample Preparation and Procedure

After pretreatment, the sample is then heated at a

fixed rate, 0.1-10 K/min, to reach the final
temperature, which is much higher than the
expected solubility temperature. The solution is then
maintained at this temperature until equilibrium has
been achieved. Equilibrium time over all steps is
about 30 min.
 Estimation of Solubility from a Heat Flow Curve

This figure shows that as the

temperature increases, dissolution
occurs, and the heat flow curve
decreases. At the point of complete
dissolution, the heat flow of the
system increases, and it is at this
point by using the heat flow curve
derivative that it is possible to
determine Tsat, which is equal to
the solubility of the system.

Typical DSC curve and its derivative for solubility measurement

(Adipic acid-water, 38.37 wt %, 1 K/min).
 The temperature at the point of
intersection of the two tangents is
estimated by dropping a
perpendicular line to the x-axis.
This point of intersection with the
x-axis is equal to the solubility
point at the particular
concentration of the sample.

Solubility determination for data extracted

 Determining the Solubility of a Metastable Form

Determining the solubility of a metastable form (i.e.,

form II) uses the same basic technique as for a stable
form where a predetermined quantity of the
metastable form is placed in the solvent of choice
and heated at a fixed rate (0.08 K/min).
The only difference between the stable and the
metastable form measurement is that unlike the
stable form there is no pretreatment (temperature
cycling) for the metastable form.
› The reason for this is that if the system is pretreated
then the metastable form can convert to a more
stable form during the recrystallization that occurs
in the cooling phase.
Enantiotropic system
The main concern in using DSC to determine the
solubility of a metastable form is that the heat flow
signal is a function of various parameters (e.g., heat
of solution, mass of solute/ solvent, and heating
rate) and that the heating rate used in the
metastable measurement may affect the heat flow
signal
 Thermodynamic Relationship of the Various Polymorphic
Forms.

The thermodynamic relationship (i.e., monotropy or

enantiotropy between the polymorphic forms of
carbamazepine (forms I and III), glycine (α and γ),
and mefenamic acid (forms I and II)) was
determined by plotting the solubility data using the
van’t Hoff equation
 T = is the experimental temperature
x = the mole fraction

R = gas constant Tm is the melting temperature

van’t Hoff plot of polymorphic forms I and III of
carbamazepine.
Solubility of Carbamazepine Forms I and III in 2-Propanol
van’t Hoff plot of polymorphic forms I and II of
mefenamic acid
Solubility of Mefenamic Acid in Ethyl Acetate
van’t Hoff plot of polymorphic forms α and γ of glycine
Solubility of Glycine in Water
 Conclusion
› The ability of DSC to accurately measure the solubility of
both a stable and a metastable form.

› DSC also enables the thermodynamic relationship between

the two systems to be identified (i.e., monotropy or
enantiotropy).

› The benefit of being able to determine the solubility of a

less stable polymorphic form and hence its thermodynamic
relationship with a more stable form
Thank you