Solubility

Department of pharmaceutics
presented by Zainab Eassa Jassim
PhD candidate
Solubility: is the analytical composition of a saturated solution
expressed as a proportion of a designated solute in a designated
solvent. This may be stated in various units of concentration such as
molarity, molality, mole fraction, mole ratio, mass (solute) per volume
(solvent), and other units.
 Terms require consideration

-Saturated solution
-molarity
-molality
-mole fraction
-mole ratio
› The solubility of a substance depends on the physical and
chemical properties of the solute and solvent and on
temperature, pressure, and the presence of other chemicals
(including changes to the pH) of the solution.

› Simply stated, it is the amount of a substance that will

dissolve in a given amount of another substance
 › Solubilization: Solubilization is the formation of a
thermodynamically stable, isotropic 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
 Terms require consideration
›- Isotropic solution
-electrostatic force
-van der Waals forces
-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).
 Thermodynamic Solubility

› Thermodynamically, the process of solubilization involves breaking

of existing bonds, intramolecular (solute–solute, solvent–solvent),
› making of intermolecular bonds (solute–solvent). The first step can
be viewed as a physicochemical reaction that reaches equilibrium
rapidly, resulting in the saturation,
› i.e., reaching solubility (Cs) and described by the classical Gibbs free
energy (ΔG):
› Solute (drug) + solvent (aqueous medium) = solubilized
solute (drug)
› ΔG = ΔH − TΔS
› where ΔG is the Gibbs free energy, ΔH is the net enthalpy
change, and ΔS is the net entropy change.
› Based on the thermodynamic principles and Gibbs
free energy, it can be explained that the first step is
extremely rapid, if not instantaneous, while the
second step, i.e., diffusion, is slow, thus making
solubilization a diffusion-controlled process
 Equilibrium solubility
› Rate of solubilization in the barrier becoming the rate-limiting step,
and diffusivity will be dependent on the solubility of the solid solute
Cs

› This process of solubilization is referred to as

› “interfacial barrier model,”
› “double-barrier mechanism,”
› or “limited solvation theory,”
 Schematic representation of the boundary layer adjacent to the surface of a
solubilizing solid and the concentration gradient across the stagnant, barrier, or
boundary layer, where St is the equilibrium solubility of the solid solute Cs and
C is the concentration of the solute in the bulk solution.
› The rate of solubilization, dM/dT, can be computed
as follows:
dM∕dT = k(i) ⋅ (Cs − C)
› where k(i) is the effective interfacial transport
constant, 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
› 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.
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.
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
› 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
Domain of solubilization and solubility in drug
development.
 pH-dependent solubility profile
› It is important to note that the poorly water-soluble drug
substances, in general, exhibit a pH-dependent solubility
profile, While the drug is soluble in a pH range but
precipitates at a specific pH (pHmax), i.e., significant
decrease in its solubility.

› Should this pHmax be in the physiological environment

where the drug is likely to get absorbed,
Schematic representation of a pH-solubility profile of a basic drug.
• Differential scanning calorimetry DSC as a technique
where the heat flow rate difference (mW = mJ/sec)
into a sample and reference material is measured, is
used to measure enthalpy changes due to changes in
the physical and chemical properties of a material as a
function of temperature or time.
• Measure heat absorbed or liberated during heating or
cooling