2. Solubility of Solids in Liquids
Systems of solids in liquids are the most frequently and most important type of
pharmaceutical solutions.
With discussing the solubility of solids in liquids, it is worth considering the
process of drug dissolution.
Dissolution: is a process by which a substance goes into the solution state.
Salt + Water Salt-Water
Solubility: is an inherent property of a substance. It is the capacity of a solute to
dissolve in a pure solvent.
2
Solubility, Dissolution, and Dissolution rate
3. 3
The dissolution of a therapeutic agent in water
involves several key molecular steps:
• Removal of a molecule of the drug from the solid
state,
• Formation of a cavity within the solvent and
• Accommodation of the drug molecule into the
formed cavity. This process involves
(endothermic processes) and the formation of a
bond between the solute and the solvent (with the
subsequent liberation of energy).
Dissolution
Fig.1. Conceptual visualization of Dissolution
4. 4
For either dissolution mode, and in order for dissolution to occur- with or
without an accompanying chemical reaction – the solute particle size is first
reduced. This initiates the process of dissolution.
This process is measured as rate.
The Noyes-Whitney equation describes dissolution in a single equation.
Dissolution
5. Stagnant layer= الطبقة
الراكدة
Fig.2. Dissolution of a solid drug particle in a solvent.
(C s = concentration of drug in the stagnant layer,
C = concentration of drug in the bulk solvent.)
5
Dissolution
6. An equation known as the Noyes-Whitney equation in 1897 was
developed to define the dissolution from a single spherical particle.
The rate of mass transfer of solute molecules or ions through a static
diffusion layer (dm/dt) is directly proportional to the area available
for molecular or ionic migration (A), the concentration difference
(Cs-C) across the boundary layer, and is inversely proportional to
the thickness of the boundary layer (h).
where the constant k1 is known as the diffusion coefficient, D/h, and
has the units of m/s, which is related, in part, to the viscosity of the
solvent.
6
Noyes-Whitney equation
Fig.3. Diagram of boundary layers and concentration
change surrounding a dissolving particle.
7. 7
unit
symbol
parameter
mg/sec
dm/dt
Solute dissolution rate
mg
m
mass
sec
t
Time
m2 or cm2
A
Surface area of the solute
particle
m or cm
h or d
Thickness of the
concentration gradient
mg or moles/ L
Cs
Particle surface
(saturation)concentration
mg or moles/ L
C
Concentration in the bulk
solvent solution
m2/sec ,cm2/sec or m/sec,
cm/sec
D or k1
Diffusion coefficient
Fig.4. Noyes- Whitney parameters for
dissolution rate.
Noyes-Whitney equation
8. 8
A preparation of drug granules weighing 0.95 g and having a total surface area of 0.28m2(0.28 × 104 cm2)
is allowed to dissolve in 500 mL of water at 25°C. After the first minute, 0.76 g has passed into solution. The
quantity D/h can be referred to as a dissolution rate constant, k.
If the solubility, Cs, of the drug is 15 mg/mL at 25 °C, what is k?
Example1
9. 9
Calculate the rate of dissolution (dM/dt) of relatively hydrophobic drug particles with a
surface area of 2.5 × 103 cm2 and a saturated solubility of 0.35 mg/mL at 25°C (77°F) in water.
The diffusion coefficient is 1.75 × 10–7 cm2/sec, and the thickness of the diffusion layer is 1.25
μm. The concentration of drug in the bulk solution is 2.1 × 10–4 mg/mL.
Example2
Answer: 21.06mg/sec
10. 10
DissolutionRate
Aqueous solubility can also play a critical role in the rate of dissolution of drug and release from dosage forms. The rate at
which a solute dissolves was described in quantitative terms by Noyes and Whitney and the equation can be written in the
following way:
From the Noyes Whitney equation, dissolution rate is seen to be directly proportional to the aqueous
solubility, Cs, as well as the surface area, A, of drug exposed to the dissolution medium. It is common
practice, especially for low-solubility drugs, to increase dissolution rate by increasing the surface area of a
drug. This can be done through particle size reduction.
If drug surface area is too low, the dissolution rate may be too slow and absorption can become dissolution
rate limited.
For high-solubility drugs, the dissolution rate is generally fast enough that a high drug concentration is
achieved in the lumen and extensive particle size reduction is not needed.
Use of high-solubility salts is commonly undertaken to facilitate rapid dissolution in the GI tract.
A
11. 11
Drugs must be in their molecular form to be absorbed through membranes, to be distributed
throughout the circulation, to interact with their targets, and to be metabolized and excreted.
Therefore, the solubility of the drug is a fundamental physicochemical property and its dissolution
is a fundamental physicochemical process.
Fig.5. Steps of drugs disintegration and dissolution to
reach Absorption site.
Dissolution
13. 13
• its molecular nature (e.g., presence of polar functional groups),
• its state of ionization at the pH of the body fluid (with the ionized form being more water-soluble),
• and its crystallinity (with the weaker polymorph being more water-soluble).
Factors that tend to affect a drug’s solubility in body fluids include:
• the physicochemical properties as drug’s water solubility and particle size (with smaller particles
generally dissolving more quickly),
• the formulation factors, and
• the physiologic factors of the human being. It is very important to analyze the physicochemical and the
formulation variables to achieve reproducibility االنتاج إعادة قابلية in results from batch to batch.
The rate and extent of the dissolution of a drug can be affected by:
Notes
14. 14
The U.S. Food and Drug Administration mandates dissolution testing for the quality control of
pharmaceutical products.
The United States Pharmacopeia (USP) has established specific guidelines for dissolution studies of
different dosage forms.
Dissolution testing is an important tool to evaluate batch-to-batch uniformity of formulations.
As more and more patient-specific formulations are compounded in community and clinical pharmacy
settings, dissolution studies are performed in some compounding facilities to ensure the quality of the
final product.
Dissolution testing
16. 16
USP Dissolution testing
As shown in Figure 8, the USP testing procedure varies with the apparatus used for dissolution.
Apparatus 1 (Rotating Basket): The most common
type of USP dissolution testing equipment, the
rotating basket system, consists of a cylindrical
stainless-steel basket and shaft assembly. The
basket and shaft are made to resist corrosion even
in a harsh acidic medium.
Apparatus 2 (Paddle): The assembly of this
apparatus is very similar to that of apparatus 1,
except that a paddle and a shaft are used as the
stirring element.
Fig.8. United States Pharmacopeia–approved dissolution systems.
Apparatus 3 (Reciprocating Cylinder): This
apparatus consists of a set of flat-bottomed
cylindrical glass vessels equipped with a
reciprocating cylinder that houses the sample to
be tested.
17. 17 Fig.8. United States Pharmacopeia–approved dissolution systems.
USP Dissolution testing
Apparatus 4 (Flow-Through Cell): This system
consists of a reservoir of dissolution medium that is
pumped into a flow cell containing the sample.
Apparatus 5 (Paddle over Disk): This apparatus is
especially suitable for the measurement of drug release
from topical and transdermal dosage forms such as
patches. It consists of a sample holder or
disk assembly that sits at the bottom of the glass
vessel.
Apparatus 6 (Cylinder Method): This system is
modified from apparatus 1 and is designed for testing
the dissolution properties of transdermal patches.
Instead of a basket, a stainless-steel cylinder is used
as a sample holder.
Apparatus 7 (Reciprocating Disk Method): Also used
for testing the release of drug from transdermal
systems, apparatus 7 consists of a motor drive
assembly that reciprocates.
19. 19
Quality Control Test
According to the USP guidelines, dissolution analysis is an important quality control test for pharmaceutical
products.
Dissolution studies with solid dosage forms, for instance, are performed to provide the total time for release
of the drug. The USP drug monographs provide detailed guidelines for dissolution studies, including
volume, the dissolution medium, pH, ionic strength, and the rotational speed of the basket (apparatus 1) or
paddle (apparatus 2).
Periodically, samples of the dissolution medium are removed, and the dissolved drug is analyzed according
to the assay described in the USP.
SIGNIFICANCE OF DISSOLUTION
STUDIES
Diffusion Layer Model
Upon their introduction into a beaker or administration
into the gastrointestinal tract, most tablets
undergo a process of disintegration to produce granules.
These granules deaggregate to form a fine powder.
Due to an increase in surface area, a large portion
of dissolved drug will originate from the fine powder
formed due to deaggregation, and once dissolved, the
drug can be absorbed across the gastrointestinal tract into systemic circulation. Dissolution of drug from
the powder particle into a large excess bulk medium
can be described by the diffusion layer model
(Fig. 5-7).