Solubility and dissolution

⚫ Learning objectives
⚫ Upon completion of this topic, you should be able to answer the
following questions:
⚫ What is a solution?
⚫ What is the difference between solubility and dissolution?
⚫ What variables control a solute’s solubility?
⚫ What variables control dissolution?
⚫ What do solubility and dissolution have to do with each other?
⚫
 Solubility, dissolution, and dissolution rate

⚫ Solubility and dissolution are different concepts, but are related.

Solubility is the capacity of a solute to dissolve in a pure
solvent. This means the maximum amount of solute that the
pure solvent can hold in solution, at specified environmental
conditions. Beyond this saturation concentration, a solute
cannot further dissolve in the amount of solvent provided. It can
exist tenuously in a supersaturated condition, but will eventually
revert to the solvent’s true capacity. But what occurs between
solutes and solvents that best shows the variability observed in
solubilities in a given solvent?
Solubility definition

* Quantitative term :the concentration of solute in a saturated solution /

maximum concentration in a certain solvent at a certain temperature.

* Qualitative term: spontaneous interaction of two or more substance

to form a homogenous ( molecular or ionic ) silva toon or dissolution
process
Solubility, dissolution, and dissolution rate

⚫ Solubility is a thermodynamic process: the

system will tend to arrive at a point of lowest
potential energy (PE) (Gibbs free energy),
which is most thermodynamically stable. When
we speak of solubility, it is understood to mean
the ultimate outcome, without regard to how
fast it occurs. Solubility provides us with
important information, but it only tells us the
endpoint, not how long it takes to get there.
Solubility, dissolution, and dissolution rate

⚫ Solutes vary not only in the extent to which they will

dissolve, but also how quickly they will reach their
respective solubility limits. Solubility and dissolution
rate are two distinct phenomena. Dissolution rate is
a kinetic process. A solute may have poor solubility
in a solvent, yet its dissolution rate may be rapid.
Conversely, a solute can be very soluble, yet require
a respected amount of time to arrive at the final,
saturation concentration.
 Dissolution

⚫ Most medicinal drugs are formulated into

tablets, capsules or other forms of medicine.
Formulating a medicine means mixing the
medicinal drug with other ingredients (called
excipients) according to a prescribed recipe
(the formulation). These ingredients have a
number of purposes in a tablet, for example,
they might help bind the tablet together,
control the rate of release of the drug and
improve the taste of the tablet.
 Dissolution

⚫ Dissolution of a tablet involves its disintegration into

smaller and smaller particles from which the
medicinal drug is released more and more rapidly.
The speed at which a medicinal drug is released
from a tablet or capsule and dissolves in solutions
that mimic fluids in the GI tract is an increasingly
important measurement. Knowledge of this rate of
dissolution contributes to the formulation,
development and regulatory approval of medicines.
It is also important for quality control, checking that
the tablets from a production run have the required
characteristics.
 Dissolution

⚫ The process of dissolution followed by absorption

determines, in part, the bioavailability of the drug.
The rate of dissolution can be determined in vivo by
taking samples of a person’s plasma or urine and
measuring the drug concentration in them.
⚫ However, this is not appropriate for routine
measurements on the vast numbers of compounds
investigated during drug discovery and development.
Instead, in vitro tests are used. Fluids in the body are
simulated and dissolution experiments carried out in
laboratory glassware. Conditions for these tests are
carefully defined in pharmacopoeias.
 Dissolution

⚫ Dissolution of a tablet depends on:

⚫ the size of the granules of medicinal drug;
⚫ the structure of the tablets and the nature of the
excipients used in the formulation;
⚫ the pH of fluids in the GI tract.

⚫ It also depends on temperature, but since body

temperature is always 37 °C (or very close)
temperature is not a factor in this situation
 Solubility and absorption

⚫ To be absorbed across cell membranes or

pass through intercellular pores a medicinal
drug must be in solution. The rate at which a
drug gets into solution is important, but if its
solubility is low its pharmacokinetic and
pharmacodynamic properties might be
adversely affected.
 Solubility and absorption

⚫ It has been said that low solubility is top of

the list of undesirable properties of a
potential medicinal drug. So being able to
measure solubility and, if necessary, modify
a compound to alter its solubility without
affecting its therapeutic properties is
important.
 Solubility and absorption

⚫ The solubility of a compound is the quantity

present in a saturated solution in contact with
an excess of undissolved solid. This is
equilibrium solubility. Traditionally, it is
measured by the shake-flask method.
Excess compound is shaken with a solvent
until a saturated solution is produced with an
excess of the solid compound present. It is
an accurate but very time-consuming
method.
 Solubility and absorption

⚫ Pharmacologists also measure kinetic

solubility. Precipitation is induced, for
example, by changing the polarity of the
solvent and the concentration at which a
precipitate first appears is measured. It can
be defined as the solubility at the time when
an induced precipitate forms. So, for
example, a solution might be slowly
evaporated until a solid begins to precipitate.
 Factors affecting solubility

⚫ So why are some compounds more soluble

than others? Solubility is often said to be a
physical change, but it does involve chemical
bonds being broken and new ones formed.
Like all change, the dissolution of a solid in a
solvent is governed by: thermodynamic
factors; kinetics factors.
 Factors affecting solubility

⚫ Thermodynamic factors are summarised by

the equation: ∆G = ∆H − T∆S where ∆G =
change in free energy / J ∆H = change in
enthalpy / J ∆S = change in entropy / JK−1 T
= temperature / K The more negative ∆G, the
more thermodynamically feasible the
change.
 Factors affecting solubility

⚫ In any dissolution, the entropy of the system increases (∆S is

positive) and so is a driver for change. The stronger the bonds
in a solution compared with the bonds in the solvent and the
solid, the more negative the enthalpy change (∆H). This is the
other thermodynamic driver for change. The activation energy
of the dissolution process is the kinetic barrier to a solid
dissolving. However, the process is rather more complicated
because it happens at the surface of the solid, and the
chemistry of the surface of a solid differs to that of the bulk
solid. Nonetheless the ionic or molecular structures of solids
and the solvated species they form in solution provide a
valuable insight into solubility.
 Dissolution rate

⚫ Dissolution is the process by which a solid

substance goes into solution and may be regarded
⚫ as being composed of two consecutive stages.
⚫ First an interfacial reaction between solid and
solvent breaks up the solid crystal for crystalline
substances and opens the amorphous lattice for
amorphous substances. This creates cavities in the
solvent, a so called phase change, molecules of
solid become molecules of solute.
 Dissolution rate

⚫ Secondly the solute molecules are transported away from the

interface through a boundary layer by means of diffusion or
convection. The boundary layer is close to a wetted surface and
is static or very slow moving because of friction and attraction
forces, mass transfer her is slow.

⚫ Thus a concentration gradient arises with a decreasing profile

from the saturated solution, Cs in direct contact with the solid to
the concentration C of the bulk
 Dissolution rate

⚫ Overall rate of dissolution will depend on the slowest

step, the first interfacial reaction is approximately
instantaneous, rate determines step is the diffusion
through the boundary layer. Fick’s law of diffusion
states that the change in concentration is directly
proportional to the concentration difference over the
diffusion layer.
⚫ J = D dc/dt
 Dissolution rate

⚫ Noyes-Whitney equation describes the

dissolution from a single spherical particle,
it’s a qualitative theory of diffusion kinetics for
a heterogeneous reactions and is derived
from Fick’s law.
⚫ J = D [(Cs-C)/d] S
⚫ d is delta
 Dissolution rate

⚫ Nernst & Brunner developed the so-called

‘stagnant film theory’, a combination of
Noyes-Whitney equation and Fick's law of
diffusion.
⚫ J = dw/dt . 1/A
⚫ dw/dt = DA/h (Cs-C); lamda = h
 Dissolution rate

⚫ where dw/dt is the dissolution rate, D is the

diffusion constant, Cs and C are the solubility
and bulk concentration respectively, A is the
surface area and h is the diffusion layer
thickness
 Intrinsic rate of dissolution

⚫ Dissolution is dependent on many factors, both

intrinsic and extrinsic. The definition of intrinsic
dissolution rate, IDR is the dissolution rate when
extrinsic factors are held constant for a pure
substance.
⚫ IDR is influenced by Intrinsic factors, especially
particle-size distributions. Intrinsic factors are
defined by the solid state properties of the pure
substance, such as:
 Intrinsic rate of dissolution

⚫ • Crystal habit
⚫ • Crystallinity
⚫ • Amorphism
⚫ • Polymorphism
⚫ • Pseudo-polymorphism
⚫ • Particle size and surface area
⚫ The above are predetermined factors which are different for
each substance. Extrinsic factors, test conditions, which can be
applied to different compounds and show similar trends, need
to be addressed further. Because changing them also produces
different results.
 Intrinsic rate of dissolution

⚫ IDR is the rate of dissolution of pure

substances when extrinsic factors as the
following are kept constant;
⚫ Agitation •
⚫ Surface area of tablet or sample
⚫ • Temperature
⚫ • pH
⚫ • Buffer strength
⚫ • Viscosity of the dissolution medium
⚫ • Ionic strength of the dissolution medium
 Intrinsic rate of dissolution

⚫ IDR is the rate of mass transfer per area of

dissolving surface and should be independent of
boundary layer thickness and volume of solvent,
assuming sink conditions( 10) C < CS . Usually
expressed in terms of mg per minute per 2 cm . The
Flow Though Cell is accepted in the pharmaceutical
industry as a dissolution system when determine
dissolution rates. Because there is an established
model for dissolution of linear flow past stationary
objects. The Flow Though Cell also has the ability to
run multiple experiments simultaneously.
 Dissolution rate vs Intrinsic rate of
dissolution

⚫ “Dissolution rate'' is best used to represent the

speed (the dimension is amount/time)

⚫ The intrinsic dissolution rate is the dissolution

rate from a unit surface area of the solid drug (the
dimension is amount/area/time), but not the
dissolution rate of an undissociated species.
Intrinsic solubility

Intrinsic solubility:
Intrinsic solubility is the solubility of undissociated species of the
drug.Intrinsic solubility can be measured at a pH where the compound
does not dissociate.Intrinsic solubility is a critical concept in
determining the BCS class of a compound.
 Intrinsic solubility

AB solid AB solution A+ B
⚫ The equilibrium solubility relationship for a non-electrolyte
where the equilibrium constant, Ko, is also known as So, the
intrinsic solubility:
⚫ K0 = (AB)soln/ (AB)solid = So
⚫ The total solubility observed represents the sum of the
equilibrium concentrations of all species present. For a non-
electrolyte, the total solubility is the intrinsic solubility.
⚫ Non-electrolytes, and strong electrolytes where neither A nor B
is acidic or basic, generally do not display solubility
characteristics that are directly dependent upon pH. But most
drugs are weak bases and around 20% are weak acids and
only 5% are non-ionic. ‘
 Intrinsic solubility

⚫ In the pharmaceutical industry, the intrinsic solubility is measured to

indicate absolute solubility
⚫ Measurements are taken at two temperatures :
⚫ first at C o 4 to ensure physical and chemical stability for short-term
storage. A minimum in aqueous solubility can be observed at C o 4
because of a maximum of water density.
⚫ The second temperature of interest is C o 37 , to support
biopharmaceutical evaluation.
 Intrinsic solubility

⚫ The HendersonHasselbalch equations are used to find the

intrinsic solubility for weak bases and acids.
⚫ pH = pKa + log10 [B]/ [BH]
⚫ pH = pKa + log10 [A]/ [HA]
⚫ A saturated aqueous solution of the salt of a weak base has a
concentration equal to the intrinsic solubility of the salt, and it
will be relatively acidic (it will have a pH usually more that 2
units below the pKa of the weak base). The intrinsic solubility of
the weak base is the lowest observed solubility, and it will be
observed when pH is more than 2 units above the pKa.
 Solubility definitions

⚫ The descriptive terms for the approximate solubility’s of Pharmacopeial

and National Formulary substances given by United States
Pharmacopeia, USP 23 is presented below.
⚫ Very soluble ≤1 ≥1000 ≥2,5 ≥0,025
⚫ Freely soluble 1 to 10 1000 to 100 2,5 to 0,25 0,025 to 0,0025
Soluble 10 to 30 100 to 33 0,25 to 0,08 0,0025 to 0,0008
⚫ Sparingly soluble 30 to 100 33 to 10 0,08 to 0,025 0,0008 to 0,00025
⚫ Slightly soluble 100 to 1000 10 to 1 0,025 to 0,0025 0,00025 to
0,0000025
⚫ Very slightly soluble 1000 to 10,000 1 to 0,1 0,0025 to 0,00025
0,000025 to 0,0000025
⚫ Practically insoluble, or Insoluble ≥10,000 ≤0,1 ≤0,00025
≤0,0000025
 What is disintegration?

⚫ To disintegrate a substance involves breaking it into

small chunks, particles and molecules. Disintegration
is a process with which substances are broken down
into tiny fragments to improve their solubility.
Compounds are disintegrated in chemical reactions.
At times the process of disintegration can integrate
with dissolution where a solid substance
disintegrates into small pieces while dissolving in a
solvent until it forms a uniform solution of the solute
and the solvent.
 Disintegration

⚫ In the pharmaceutical industry, there is a

disintegration test undertaken on drugs to make
them ready for absorption into the blood stream. For
any dosage to be absorbed by the body, it has to be
in a solution. The disintegration process breaks
down the drug into tiny fragments or granules to
improve its solubility. Disintegration time is the time
needed for the drug to break into fragments under
certain conditions. Some disintegration tests are
done with simulated gastric or intestinal fluid to see
how the dosages will perform when ingested.
 What is dissolution?

⚫ This is the process through which solid, gaseous or

liquid substances dissolve in a solvent to produce a
solution. However, for the substances to dissolve in
a solvent, both the solute and the solvent must be
compatible. For instance, a polar substance may not
dissolve in a non-polar solvent. Amongst other
solvents, water is the universal solvent that is good
in dissolving many substances. Gas solvents can
only dissolve gas solutes.
 Dissolution

⚫ The solution formed by dissolution process is often a

uniform one. There are factors that can expedite the
dissolution and these include the temperature.
Dissolution is a kinetic process, so the kinetic energy
resulting from increased temperature will speed up
the process of dissolving a solute in a solvent. The
intermolecular forces of the solute will be broken with
ease. If the solute and the solvent can absorb the
visible light, the solution yielded can have color.
 Dissolution

⚫ For solid substances dissolving in a solvent,

shaking and stirring can expedite the
dissolution process. Other substances may
not readily dissolve so they may need some
manual breaking, and that is where
disintegration comes in to break the
substances into tiny chunks prior to the
dissolution.
 Dissolution

⚫ Like disintegration and even more often,

dissolution is a common process used in
pharmaceutical industry in the manufacturing
of drugs. A dissolution test is a normal
standard required in the development of solid
oral tablets. It helps in detecting any changes
in physical properties of drugs, more
especially the active pharmaceutical
ingredient (API).
 Dissolution

⚫ The solubility of tablets in liquids is subject to the

effectiveness of the dissolution rate. Some tablets
readily dissolve without any full or partial
disintegration. A tablet should also be permeable
through the intestine walls to be absorbed into the
blood circulation. Such factors prompt dissolution
tests to be conducted regularly in drug
developments. Poor solubility impedes the
dissolution rate and bioavailability. In such cases
disintegration is important to precede dissolution,
and grind the substances.
 Key differences between dissolution
and disintegration

⚫ Definition
⚫ Disintegration is a process of breaking down a
substance into tiny fragments to improve its solubility
in a solvent. The process is used predominantly in
pharmaceutical and chemical industries. Dissolution,
on the other hand, is a process through which
solutes dissolve in a solvent. Dissolution is also used
predominantly in pharmaceutical industries to check
how soluble a drug is in the body.
 Factors affecting each process

⚫ The hardness, binders, fillers and lubricants

are some of the factors that affect
disintegration of the substance when
breaking down the cohesive forces that bind
it together. Temperature is a factor that can
affect dissolution in a good way by expediting
the process. The effects of fillers and binders
can also affect the rate of dissolution of a
particular substance.
 Application

⚫ Both processes can be applied on the same

substances. However, disintegration seems
to be applicable on large solid substances.
On the other side, dissolution can be applied
on solids, liquids and gases. Gases can
dissolve in gas solvents. A solid with low
solubility may require disintegration first.
 Summary of Disintegration Vs.
Dissolution

⚫ Disintegration is a process of breaking solid substances into

small granules.
⚫ Both processes can be used in the pharmaceutical industry in
the development of drugs
⚫ Dissolution testing has become a norm in the development of
solid oral drugs
⚫ Dissolution can be a form of disintegration as it also breaks
substances into tiny particles. But, often, the solution yielded
from dissolution is uniform and the particles cannot be
observed with a naked eye.
⚫ Disintegration may be needed to disintegrate tough solid
substances that do not readily dissolve in solvents.