PHA6113 LEC 2APH

PHYSICAL PHARMACY
BY: A.B, C.C, H.B, N.A, R.P
● Pharmacokinetics
WEEK 1 - Study of the behavior of the
Introduction to Physical Pharmacy drug once inside the body
- Study of: Absorption,
INTRODUCTION TO PHYSICAL Distribution, Metabolism
PHARMACY and, Excretion of drugs in
● In physical pharmacy we study the the body
different physical and chemical ● Biopharmaceutics
properties of substances - Is the study of the factors
● How do pharmacists decide which influencing the bioavailability
dosage form to formulate? of a drug in humans/animals
○ The physical and chemical - Bio - life
properties of substances - Availability - present
would predict what would - Uses information to optimize
happen if we combine therapeutic activity of
materials such as dusting products
powder, cream, gel, lotion,
ointment, paste, liniment etc. ● Physical Pharmacy
and if it is possible for us to ○ Deals with physicochemical
convert them into a specific principles underlying the
dosage form development of a successful
dosage form
OVERVIEW OF PHARMACEUTICS ○ Area of Pharmacy which
● What is Pharmaceutics? deals with the quantitative
- Is a branch of the and theoretical principles as
pharmaceutical sciences that applied to the pharmacy
deals with: practice
a. Investigation of ○ Contributes to the design of
physical and a dosage form
chemical properties ○ Aids pharmacist to predict
of drug molecules ■ Solubility
b. Design, fabrication ■ Stability
and evaluation of ■ Compatibility
drug delivery systems ■ Rate of absorption
c. Monitoring how drug ■ Duration of action of
products are drug products
absorbed,
distributed, ● Examples of Principles
metabolized and ○ Newton’s law - flow
excreted in the body properties of preparation (do
● Dosage Forms they flow? Are they fluid or
- Art and science of viscous?)
formulation and manufacture ○ Surface tension - absorption
of dosage forms and drug of preparation
delivery systems

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: A.B, C.C, H.B, N.A, R.P
○ Optical activity and refractive g/cc
index - identifying
substances and determining Y Surface F/L = dynes/cm
purity (gamma tension M-L/T2-L or or
○ Reaction kinetics - rate at ) M/T2 g/s2
which a reaction takes place,
W Work or Fs = Dynes-cm
stability
energy M-L2/T2 or erg

UNITS AND DIMENSIONS

--------------------------------------------------
Symbol Quantity Dimension CGS
Unit

L Length L cm

T Time T s

M Mass M g

DERIVED UNITS
● Uses basic units
● Combination of two or more basic
units as a measurement
Symbol Quantity Dimension CGS Unit

A Area L2 cm2

V Volume L3 cm3
(L x W x H)

S or V Speed or L/T cm/s

Velocity

a Accelerati V/T = L/T2 cm/s2

on

F Force Ma = M - g-cm/s2
L/T2 or
dynes

P Pressure F/A = dynes/cm2

M-L/T2-L2 or or
M/L-T2 g/cm-s2

p Density M/L3 g/cm3

g/mL

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
● Dipole-dipole forces (Keesom
WEEK 2 Forces)
States of Matter Related to - occurs when polar molecules
Pharmaceutical Formulations possess permanent dipoles
(interactive molecules with a
INTERMOLECULAR FORCES partial positive charged-end
● Happens when molecules interact and a partial negative
with each other and create an charged-end interact)
attraction or repulsion force - The energy resulting from
this reaction can range from
ATTRACTIVE FORCES 1 to 7 kcal/mole.
● essential for molecules to come - Examples of molecules are
together, they are inversely water, hydrochloric acid,
proportional to the distance that alcohol, acetone, and
separates two molecules phenol.
● The greater the distance the lesser
the force will be. ● Dipole induced dipole forces
● The lesser the distance the greater (Debye Forces)
the force will be. - occurs when polar molecules
● ADHESIVE FORCE: attractive force produce a temporary
when different molecules are electric dipole in nonpolar
attracted to each other molecules that polarize
● COHESIVE FORCE: attractive force easily.
when like molecules are attracted to - This force of attraction is
each other. known to be weaker, with its
energy ranging from 1 to 3
REPULSIVE FORCES kcal/mole.
● Proportional to an exponential - generally lower in energy, but
relationship with the reciprocal of multiple interactions can
the distance separating the have a stabilizing effect on
molecules. states of matter
● This force act to separate molecules - Examples are ethylacetate,
● Opposite of attractive force. methylene chloride, and
ether.
LENNARD-JONES POTENTIAL THEORY
● phenomena that allows a state of ● Induced dipole-induced dipole or
equilibrium which balances the Dispersion forces (London Forces)
forces of attraction and repulsion. - come from molecular internal
vibrations in nonpolar
VAN DER WAALS FORCES molecules producing
● Force of attraction for molecular attraction that originates
interactions involving solubility, from synchronized
complexations, and other kinds of fluctuating dipoles between
physical bonding phenomena. neighboring atoms.

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
- energy of this attractive force HYDROPHOBIC INTERACTIONS
is 0.5 to 1 kcal/mole ● ​Forces of attraction between
- This force of attraction is nonpolar molecules and molecules
temporary, is produced from in water.
the asymmetry of electrons ● This interaction is critical for the
in the nucleus, and is structure and stabilization of
responsible for the molecules such as proteins
liquefaction of gases. (nonpolar amino acids) and
- often found in the aliphatic amphiphiles (polar and nonpolar
regions of lipid bilayers as moieties).
well, although other ● Nonpolar molecules are considered
interactions also help to to be “water-fearing” which results
stabilize the bilayer structure in their hydrophobic interactions.
- Nonpolar molecules ● This is due to the disruption of the
exhibiting this are organic hydrogen bonding network between
compounds such as carbon water molecules when
disulfide, carbon non-hydrogen bonding nonpolar
tetrachloride, and hexane. molecules are introduced into water
● To minimize this disruption,
ION DIPOLE FORCES reorientation of water molecules
● When polar molecules are attracted happens to reestablish a hydrogen
to either positive or negative bonding network.
charges. ● Nonpolar molecules are considered
● Has an energy ranging from 1 to 7 “water-fearing,” leading to their
kcal/mole. “hydrophobic” interactions, which
● An example is a quaternary are the source of the hydrophobic
ammonium with tertiary amine. effect.

HYDROGEN BONDING
● An electrostatic attraction between DIFFERENT STATES OF MATTER
molecules and parts of molecules, it
is a strong type of dipole dipole GASEOUS STATE
interaction ● Have no regular shape, are capable
● It can either be intermolecular or of filling all available space, are
intramolecular attraction of a compressible, and they are invisible.
hydrogen atom to a strong ● Held together by weak
electronegative atom such as intermolecular forces and they have
oxygen, nitrogen, fluoride, and higher kinetic energy that produces
sulfur. rapid motion.
● The small size of the hydrogen atom ● As we have observed in our
accounts for the intense environment, we can’t see gas
electrostatic field it creates molecules unlike liquids and solids
● Gases such as oxygen, nitrogen,
and hydrogen at normal temperature
and pressure can be defined by the

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
ideal gas laws such as Boyle’s law ● Characterized by shape, particle
and Charles’ laws. size, and melting point; some solids
● Weak IMF, Strong KE are volatile enough to have a
● Boyle’s Law: sublimation point.
P1V1=P2V2 ● Sublimation is the transition of a
○ States that for one mole of substance directly from the solid to
gas at a fixed temperature the gas state without passing to
the product of pressure and liquid state
volume is a constant ● Other characteristics: surface,
● Charles's Law: energy, hardness, elastic properties,
V1/T1= V2/T2 compaction and porosity
● Combined Charles and Boyle: ● There are also three main types of
PV/T = constant solids namely crystalline,
● General Gas Equation: amorphous, and polymeric
PV = (constant (R) x (T) ● Strong IMF, Weak KE

LIQUID STATE Gases: ↓ IMF - ↑ KE

● Occupies a definite volume and In terms of IMF: Solids > Liquids > Gases
takes the shape of the container Solids: ↑ IMF - ↓ KE
required to hold it. ● The relationship of the
● Denser than gases and possess less intermolecular forces found in the
kinetic energy than do gases. different states of matter is inversely
● considered less compressible than proportional to the kinetic energy
gases and more compressible than that they posses
solids.
● Liquids flow very readily, and the TYPES OF SOLID MATERIALS BASED
flow is influenced by friction. They ON THEIR STRUCTURES
can also be frozen (become solids),
have boiling points (become gases), CRYSTALLINE SOLIDS
and have vapor pressure and ● particles that are arranged in a
surface tension. definite repeating pattern and are
● Solids > Liquids > Gases generally classified based on the
nature of the forces that hold its
SOLID STATE particles together.
● Characterized as having a fixed ● These forces are primarily
shape and being nearly responsible for the physical
incompressible compared to gases properties of solids
and liquids. ● Four Major Types:
● Have strong intermolecular forces ○ Ionic
and therefore very little kinetic ○ Metallic
energy. ○ Covalent Network
● In solids the atoms vibrate in fixed ○ Molecular Solids
position about an equilibrium
position and so there is little
translational motion

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
NONCRYSTALLINE SOLIDS CRYSTALLINE FORMS VS.
● another name for amorphous AMORPHOUS FORMS
solids
● particles with no ordered internal CRYSTALLINE AMORPHOUS
structure and are arranged
randomly. RATE OF
CHEMICAL FASTER RATE SLOWER RATE
● Amorphous solids have two DEGRADATION
distinguishing characteristics.
○ Produce fragments with PHYSICAL
MORE STABLE LESS STABLE
STABILITY
irregular often curve surfaces
when cleaved or broken SOLUBILITY LESS SOLUBLE
MORE
○ Poorly defined patterns when SOLUBLE

exposed to x-rays because DISSOLUTION SLOWER RATE FASTER RATE

their components are not
arranged regularly
● The liquid phase is rapidly cooled POLYMORPHS VS. POLYMORPHISM
● Almost any substance can solidify in
amorphous forms POLYMORPHS
● Some solids are intrinsically ● chemical entities, including
amorphous because their pharmaceutical agents, that may
constituents either do not fit exist in more than one crystalline
together well enough to form a structure
stable crystalline lattice or they ● have different physical properties,
contain impurities that disrupt the which includes melting points,
lattice solubilities, densities, and stability.
Below is a figure that illustrates the
POLYMERIC SOLIDS intermolecular bonding pattern and
● have very complex structures molecular orientation observed for
because they are made up of Ritonavir polymorphs. (Figure 2-9)
entangled linear macromolecules
that interact with one another
through physical and weak forces
● Have nothing to do with ordered or
disordered arrangements
● The emergent properties of a frozen
mixture of polymers will generally lie
between those crystalline and
amorphous solids
● Also known as intermediates ● For example, the two different forms
of ritonavir have significantly
different solubilities in ethanol/water
mixtures, as shown in Figure 2-10

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
POLYMORPHISM
● ability of a substance to crystallize
into multiple forms of crystalline
structures.
● The changes in the crystalline
structure is based on the
intermolecular bonding patterns,
conformational changes in the
molecule, and/or changes in the
molecular orientation of the
neighboring molecules in the solid.
● polymorphism is the process, while
polymorphs are the products of that
.
process
● Table 2-4 for aripiprazole shows
the difference in the densities and
LATTICE UNITS OF
melting point. Other drug
CRYSTALLINE SOLIDS
substances with multiple forms are
● In crystalline solids, the molecules
summarized in Table 2-5.
or atoms are arranged in repetitious
three-dimensional lattice units
infinitely throughout the crystal.
● There are seven common lattice
units, often referred to as the unit
cell, as shown in Figure 2-8. They
are defined by the length (a, b, c)
and angles (α, β, γ) of the lattice.

○ The cubic system exhibits

the highest symmetry and
● It is estimated that 89% of the triclinic system exhibits
pharmaceuticals will exhibit different the lowest symmetry.
solid forms. ○ Crystals may be units of
atoms, molecules, or ions
(Table 2-3).

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
○ chemical reactivity
○ apparent solubility
○ dissolution rate
○ vapor pressure
○ density
● These properties can have a direct
effect on the ability to process
and/or manufacture the drug
substance and the drug product, as
well as on drug product stability,
dissolution, and bioavailability.
● Influence on Solubility,
Dissolution, and Bioavailability
(BA) and Bioequivalence (BE)
○ Drug substance molecules ○ Since polymorphic forms
are usually found in the differ in their internal solid
lower-symmetry systems states structure a drug
due to their relatively large substance that exist in
size compared to smaller various polymorphic forms
inorganic systems, such as can have different aqueous
sodium chloride (NaCl). solubilities and dissolution
rates
IMPACT OF POLYMORPHISM IN ○ When there are differences in
DRUG PRODUCTS the apparent solubilities
● Polymorphism is the ability of a there may be differences as
substance to exist into multiple well on the drug product
forms of crystalline structures bioavailability and
○ A form of isomerism since bioequivalence
the crystalline structure ● Influence on Manufacturing of the
shares the same formula but Drug Product
has different arrangements ○ Can exhibit different physical
or conformations of the and mechanical properties
constituents in the crystal including hygroscopicity,
lattice. particle shape, density,
● It is an influential phenomenon in flowability and compactibility
the pharmaceutical sciences as it ○ Can affect processing of the
can significantly influence a variety drug substance and/ or
of properties of an active manufacturing of the drug
pharmaceutical ingredient, thus, it product
can affect the quality, safety, and ○ The effect of polymorphism
efficacy of a drug product. on pharmaceutical
● Polymorphic forms of a drug processing also depends on
substance have different physical the formulation and the
properties which includes: manufacturing process
○ melting points

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
○ Polymorphic forms of the ● Higher boiling point indicates
drug substance can also greater intermolecular forces and
undergo phase conversion less vapor pressure
when exposed to a range of
manufacturing processes HEAT OF VAPORIZATION
such as drying, milling, ● represents the thermal energy
micronization, wet absorbed (a positive value) to cause
granulation, pre-drying and the hydrogen bonding in liquid water
compaction to break and release the free
○ Exposure to environmental molecules that transform into the
condition such as humidity gaseous state.
and temperature can also ○ Water at 100°C (212°F) =
induce polymer conversion 𝚫Hv (water)BP = 9720
● Influence on Stability cal/mole
○ The most thermodynamically ● In the process of vaporization, for
stable polymorphic form of a the molecule to leave the surface of
drug substance is chosen a liquid and pass into the air above
during development, based it, the forces of attraction between
on the minimal potential for non-surface molecules and liquid
conversion to another must be overcome
polymorphic form and on its ● To overcome: energy must be
greater chemical stability supplied to the liquid in the form of
○ However as a drug product heat. The heat absorbed 1g or 1
solubility is affected a mole of liquid vaporized is the heat
multitude of factors, the FDA of vaporization
said that the stability of the
drug product and not the INTERMOLECULAR FORCES: RELATED
stability of the drug TO THE HEAT OF VAPORIZATION AND
substance polymorphic form TO MOLECULAR WEIGHT
should be the most relevant ● ↑ Higher molecular weight =
measure of drug quality ↑ More intermolecular points of
contact = ↑ Stronger Intermolecular
RELATIONSHIP BETWEEN HEAT OF interactions = ↑ Higher heats of
VAPORIZATION, BOILING POINT, AND vaporization = ↑ Higher Boiling
THE MAGNITUDE OF points = ↓ Lower vapor pressure
INTERMOLECULAR FORCES

BOILING POINT OF A LIQUID

● temperature at which the vapor
pressure of a liquid equals the
atmospheric pressure.
● measures the temperature at which
a chemical or substance boils

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
RELATIONSHIP OF THE HEAT OF the temperature until it reaches
FUSION AND MELTING POINT OF again another phase change, where
SOLIDS TO THE MAGNITUDE OF it remains constant again
INTERMOLECULAR FORCES
HEAT OF FUSION
MELTING POINT OF A SOLID ● heat required to increase the
● temperature at which the solid interatomic or intermolecular
changes into a liquid distance in the solid state to form
the liquid state.
○ 𝚫Hf Values are positive as
heat is absorbed.
■ It becomes negative
when liquid turn into
solid (freezing)
○ Water at 0°C (32°F) = 𝚫Hf
(water)MP = 1436 cal/mole.
● Amount of energy required to
change a solid into a liquid
● Intermolecular forces are related to
the heat of fusion and to molecular
● When a solid material is heated to
weight.
its melting point, the temperature
○ For structurally related
does not rise until the entire solid
compounds (ex:
has passed into the liquid state.
Polyethylene glycols)
■ ↑ Stronger
intermolecular forces
= ↑ Higher molecular
weights = ↑ Higher
heat of fusion = ↑
Higher melting points
(Relationship: Directly
proportional)
■ Larger molecules
have more electrons
● As heat is added temperature and are affected by
increases except for a couple of the london dispersion
level regions where a phase change forces more than
takes place small molecules with
● During phase changes heat is still less electron
being added but during the phase ■ A molecule with a
change that energy causes the larger chain length
change in phase and the experiences stronger
temperature does not rise london dispersion
● Whilst the phase change is force because larger
complete the heat again increases molecules have more

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
phases where they EUTECTIC MIXTURES AND ITS
can be attracted to IMPORTANCE IN DOSAGE
other molecules FORMULATION
■ Because of the
strong intermolecular
forces it will require
more energy to break
the IMF thus increase
of heat of fusion and
melting point takes
place
● For compounds that are not
structurally similar
○ Melting points are dominated
by intermolecular
interactions rather than
EUTECTIC POINT
molecular weight.
● Lowest temperature at which the
○ Ex: Urea (MW = 60 g/mole)
existence of the liquid phase is
has a melting point of
possible.
approximately 134°C while
Stearic acid (MW = 284.5
EUTECTIC MIXTURE
g/mole) which melts at
● Composition of at least two solid
69.6°C.
components that produces a
○ Urea has strong hydrogen
change of phase to liquid at a
bonding interactions in the
certain temperature
solid state whereas stearic
● Several mixtures of pharmaceutical
acid largely interacts through
solids will liquefy at a given
van der Waals forces in the
temperature and composition
aliphatic chain.
○ In the diagram there is solid
● ↑ Higher melting points = ↓
A and solid B
Decreased solubility
○ Solid A has a higher melting
(Relationship: Indirectly proportional)
point while Solid B has a
○ Reason: Because of the
lower melting point but at
increase in the strength of
some point they both melted
the bonds in the crystal
at the same time which is the
lattice of the solids.
eutectic temperature
(eutectic point: red dot)
● Eutectic mixtures can create
problems when one is compounding
with powders.
○ Mixing the eutectic
components with the
powders helps prevent
liquefaction. However, it may
be preferable to form the

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., S.G.
liquid eutectic mixture prior
to mixing with the powders
to allow the powder particles
to adsorb the liquid eutectic.
○ During manufacturing it is
necessary to predict
formation of eutectic and
avoid manufacturing
problems, if any.
○ Ex. during tablet compaction
the heat produced in the
punch and dye cavities may
lead to fusion and melting of
tablet powder compact
leading to manufacturing
defect
○ Thus knowledge of eutectic
points of powder
components may help avoid
these problems
● Another utility of eutectics is found
with the increased skin transport
rates with the combination of
lidocaine (for anesthesia) (MP: 68°C
to 69°C or 156.2°F) and prilocaine
(MP: 37°C to 38°C or 100.4°F).
○ When mixed together, an oil
is formed that is
incorporated into a cream to
provide dermal anesthesia
on intact skin within several
minutes of application.

COMMON EUTECTICS

EUTECTIC MIXTURE TEMPERATURE OF

THE EUTECTIC, °C

Testosterone-menthol 40

Cholesterol-menthol 40

Enthol, camphor, ~25°C (room

phenol thymol, and/or temperature
chloral hydrate

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., & S.G.
● Ex: a substance described as
WEEK 3 “soluble” requires between 10 to
SOLUBILITY 30 parts (mL) of solvent to dissolve
1 part (g) of solute
SOLUBILITY ● Very slightly soluble to slightly
● Concentration of a solution when soluble: weak electrolytes such as
the solvent has dissolved all the phenobarbital, atropine, and aspirin
solute that it can at a given ● Very soluble: salts of weak acids
temperature and weak bases
● The amount of substance that will ● Examples:
be dissolved in a given amount of
solvent at a specific temperature.
● Physical property, and varies with
temperature having an almost
exponential relationship
● As a general rule “Like dissolves ● Solubility values for solutes reported
like” in the literature often are given as
○ Polar solute will dissolve in per weight of solvent or per volume
polar solvent. of solvent
○ Nonpolar solute will dissolve ● Expressions such as grams of solute
in nonpolar solvent. in 100 grams of solvent and 1 g of
solute in a volume of solvent are
common in pharmaceutical
references

MISCIBILITY
● Used to refer to the solute when it is
a liquid and will form a solution with
a solvent over any concentration
Descriptive Terms of Solubility range
● The solubility of solid solutes in ● It refers to the ability of a liquid
liquid solvents is an important solute to dissolve in a liquid solvent
consideration in the preparation, and they generally mix without
storage, and use of liquid continuously making a
pharmaceutical formulations and homogeneous solution.
products ● Compared to solubility which has
degrees, miscibility has none and
only the word miscible is used
● Water mixed with alcohol (no
division)- miscible
○ Both substances are liquid
○ When combined they form a
uniform solution
● Mineral oil with water (shows
division) -immiscible

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., & S.G.
○ Clear division between oil lattice structure so that it will
and water separate into ions or molecules to
get into the individual ion or
Descriptive Terms of Miscibility molecule necessary to form a
● The miscibility expression for liquid solution
solute in liquid solvents is found for ● The solvent (usually water) takes in
liquid solutions that mix together at energy to break apart its hydrogen
any concentration bonds
● There are no degrees of miscibility, ○ Allows solute to come in
only the word miscible is used contact with adjacent
molecules of water
SATURATED SOLUTION vs ● When solute and solvent works
SUPERSATURATED SOLUTION hand in hand together, by taking in
● Saturated Solution energy to be able to form a solution
○ Contains the maximum ● When solute and solvent come
possible amount of solute together, energy is releases
that a given solute can give
at a given temperature Heat of Solution
● Supersaturated Solution ● the overall energy exchanged
○ a solution that has more than between the solute and the solvent
the maximum amount of ○ Can be either positive or
solutes that can be negative
dissolved in a solvent at a ○ Greatly affects the solubility
given temperature of the solute
○ It contains the amount of
solute greater than that Exponential proportionality for the effect of
required for a saturated temperature of solubility:
solution. 𝑆α𝑒 =
−∆𝐻𝑠𝑜𝑙
○ When solute is added 𝑅𝑇
crystals readily from around Unit: moles/L
the solute added
○ E.g. Caffeine Equation to predict the effect of
temperature on solubility:
𝑆(𝑇2) 𝑇2−𝑇1
PRINCIPAL FACTOR THAT AFFECTS THE 𝑙𝑜𝑔 =
∆𝐻𝑠𝑜𝑙𝑛
( )
SOLUBILITY 𝑆(𝑇 )
1
2,303 𝑇1𝑇2

Temperature EFFECT OF TEMPERATURE ON THE

● principal factor that influences the SOLUBILITY OF A DRUG ACCORDING
solubility of the drug or the TO THE HEAT OF THE SOLUTION
equilibrium solubility ● temperature increase does not fully
● nearly exponential rise or fall of guarantee the increased solubility of
temperature with solubility is related a solute, it all depends whether the
to the exchange of energy that enthalpy is positive or negative
occurs during solution formation
● As solid solute dissolves, it takes in
energy to break apart the crystal

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PHA6113 LEC 2APH
PHYSICAL PHARMACY
BY: N.A., H.B., & S.G.
Positive Heat (ENDOTHERMIC) Dielectric properties
● If the heat of the solution is positive, ● Relates to the ability to store charge
a solvent at a higher temperature i.e., indicate how well ions are
will dissolve more solute than it will shielded from each other and the
at a lower temperature. ability of the solvent to coordinate
● The net energy from breaking and and stabilize ions e.g., water has a
forming bonds results in heat energy very high dielectric constant, which
being absorbed into the system as allows salts to dissolve and
the solute dissolves dissociate in its presence.
● As the temperature increases the ● Higher solvent dielectric constant =
solubility increases more polar

Negative Heat (EXOTHERMIC)

● If the heat of the solution is
negative, a solvent at a higher
temperature will decrease the
solubility of the solute i.e., heat must
be released for the solute to
dissolve.

Hydrogen Bonding
● important component of solubility
because of the formation of
intermolecular bonds that hold a
substance in solution
● The presence of hydrogen bonding
between molecules of a substance
indicates that the substance is
polar, therefore, soluble in polar
solvents.
INFLUENCES OF A DRUG’S CHEMICAL ● Any compound with functional
STRUCTURE ON ITS SOLUBILITY groups such as -OH, -NH, and -SH
can form hydrogen bonds and be
Dipole Moment attracted to water, and can therefore
● Substances with strong dipole increase a drug molecule’s water
effects are said to be polar therefore solubility.
having its charge separated
permanently (negative on one side, PARTICLE SIZE
positive on the other). ● The reduction in the size of particles
● Higher dipole moment = higher beyond normal particle sizes to
solubility in polar solvents due to micronization can influence
charge distribution and orientation solubility.

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● Micronization 5. cis (z) Isomer is more soluble than
○ Process of reducing the trans (e) isomer; cis has a lower
particle size melting point. CIS isomer has high
○ E.g a micronized drug may melting point.
have an increase in solubility 6. Increasing unsaturation increases
over a drug that is not solubility in polar solvents.
micronized 7. Anhydrous solutes are more soluble
○ increases solubility if the than those that are crystalline.
process breaks down the
crystal lattice of the solid SOLUBILITY PRODUCT CONSTANT (𝐾𝑠𝑝)
■ Crystal Lattice- it is ● is a constant that is equal to the
the one that holds the product of the equilibrium
solute together and concentrations of dissolved ions of
increases the energy a salt, with each ion raised to its
required to separate stoichiometric coefficient.
the ions or molecules ● Example:
for solution formation. ○ Solubility product constant
● Breaking the bonds in the crystal
lattice by micronization will reduce
the energy required to separate the
solute from itself and increase
solubility.

GENERAL SOLUBILITY RULES

1. Like dissolves like
○ The greater the similarity
between the solute and the
solvent (similar ● Solubility of calcium
physical-chemical carbonate at in water at 25°C
−5
properties), the greater the is 9. 5𝑥10 𝑚𝑜𝑙𝑒𝑠/𝐿
solubility. (practically insoluble)
2. Solubility in water is increased by
increasing the capacity of the
solute for H bonding with polar
groups (Ex: OH, NH2, SO3H,
COOH)
3. Solubility in water is decreased with
an increase in the number of
carbon atoms in the solute
○ (Ex: an increase in molecular
weight without increasing
polarity)
4. For many organic molecules, a high
melting point means low water
solubility.

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WEAK ACIDS AND WEAK BASES Weak Bases
● In weak bases, if the pH is raised,
Weak Acids [H+] decreases and S decreases.
● do not dissociate completely in ● If the pH is lowered, [H+] increases
solution and the molar solubility increases.
● does not donate all of its hydrogen
ions (H+) in a solution
● have very small values for Ka (and
therefore higher values for pKa)
compared to strong acids, which
have very large Ka values (and
slightly negative pKa values)

Weak Bases
● basic substances that do not
completely dissociate into their
constituent ions when dissolved in INFLUENCE OF TEMPERATURE IN THE
solutions. SOLUBILITY OF LIQUIDS IN LIQUIDS
● Therefore, when dissolved in a ● An example of this is the preparation
solution, a part of the weak base of 10% phenol in water solution.
dissociates into hydroxide anions ● It is stated that at the temperature of
and the relevant conjugate acid, 25 °C, the 10% phenol in water
and another part remains solution is immiscible and cannot
undissociated inside the solution. be prepared but when the
temperature is increased to 37 °C
INFLUENCE OF pH CHANGE IN THE near the body temperature it
SOLUBILITY OF WEAK ACIDS AND becomes a solution.
WEAK BASES IN WATER
● Weak Acids
○ In weak acids, if you
increase the pH the molar
solubility will increase.
○ If [H+] is increased, the molar
solubility decreases, and if
[H+] is decreased (higher pH),
the molar solubility increases

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INFLUENCE OF SOLVENTS
ON SOLUBILITY

Strong Electrolytes
● Strong acids and bases and their
salts are soluble in water. The polar
nature of water attracts the ions and
forms a solution. Nonelectrolytes
● High-molecular-weight organic
drugs that do not dissociate or
associate in water are generally
soluble in organic solvents and have
little or no solubility in water.
● Among the exceptions to this
● Table interpretation: generalization would be sugars such
○ Shows the variation in as dextrose
solubility for water, alcohol,
acetone SOLVENT EFFECTS ON THE SOLUBILITY
○ Acetone has low dielectric OF WEAK ELECTROLYTES IN
constant and no hydrogen BUFFER SOLUTIONS
bonding ● The addition of alcohol to a buffered
○ Alcohol has low dielectric aqueous solution of a weak
constant but has hydrogen electrolyte increases the solubility of
bonding but does not the uncharged species by adjusting
solubilize these inorganic the polarity of the solvent to a more
organic ions due to their favorable value.
strong crystal lattice in their ● Being less polar than water, alcohol
solid state decreases the dissociation of a
○ Acetone and Alcohol have weak electrolyte, and the
low values because they concentration of the drug as the ion
have low dielectric constant in water goes down as the
compared to water. dissociation constant is decreased.
------------------------------------------------
Weak Electrolytes
● Weak acids and bases with high
molecular weight (MW) are often
not soluble in water. Cosolvents
such as alcohol, propylene glycol,
and polyethylene glycol or mixed
solvent systems are required for
solubility.
● Table 5-8 shows the solubility of the
weak acid and its sodium salt.

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the bulk of the solution
WEEK 4 (rate determining step).
Dissolution and Partitioning
Noyes-Whitney Relationship
Dissolution & Solubility ● Noyes Whitney relationship is based
from widely known textbooks that a
particle size or a surface area
Dissolution Solubility
influences its dissolution rate
Fundamental Fundamental inversely.
physicochemical physicochemical ○ The bigger the particle size,
process. property the slower it dissolves.
○ The smaller the particle size,
Rate of solute Capacity of solute to the faster it dissolves.
dissolving in a be dissolved in a
solution (also a solvent in the Hixon-Crowell Cube-Root Relationship
quality control test) presence of a salt
● Based on the assumption that the
Concentration of a dissolution occurs normal to the
Process by which a solute when the surface of the solute particles
solid enters into a solvent has dissolved ● agitation is uniform all over the
solution in the all the solute that it exposed surfaces and there is no
presence of a solvent can at a given stagnation, and the particle of
temperature solute retains its geometric
shape.
Involves a
Involves a kinetic
thermodynamic
process USP Dissolution Testing Apparatus 1 &
process
Apparatus 2
Where the solute ● Should be carried out on a daily
Outcome of
dissolves in a solvent basis in the quality control
dissolution
to form a solution department of any pharmaceutical
company
Effect of the Following factors on the ● This method is used to monitor the
Rate & Extent of the dissolution of drug quality of the capsules and the
tablets that are produced in the
Diffusion Layer Model market
● Diffusion Layer Model is based on ● A drug can only go to the market
absence of any reactive or after it passes the dissolution test
chemical forces consisting of two and is approved
consecutive steps:
○ Formation of stagnant film Apparatus I (Rotating Basket)
or diffusion layer ● Most common type of USP
○ Diffusion of soluble solute dissolution testing apparatus or
from the stagnant layer to equipment.

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● Consists of a cylindrical-steel ● Most common rotational speed for
basket and shaft assembly this system.
○ Rotating basket system ○ 100 rpm
● Standard basket is made with ● A speed-regulating motor shaft
40-mesh (381 um) openings and basket assembly are selected
○ Take note that many sizes of and maintained at a specific rate
openings and basket are specified in the individual
available monograph
● The composition and volume of
dissolution are also specified in the
individual monograph.
● Typically 900mL of 0.1M HCl is used
to simulate the pH of the gastric
● Used for: fluid
○ Dissolution studies of ● Periodically, small volumes of the
capsule, suppositories, and dissolution medium are withdrawn
tablets and analyzed to find the
■ Have low density concentration of dissolved drug.
■ Tend to float on the ● The cumulative amount and percent
dissolution medium of dissolution as a function of time
■ The ones that are calculated by using appropriate
dissolves slowly standard curves.
● How to use:
○ The Sample is placed in a Apparatus II (Paddle)
basket, the assembly is ● The assembly of this apparatus is
inserted into a 1L glass similar to apparatus 1, except that
vessel. the paddle and a shaft are used as
○ The entire system is the stirring element.
maintained at a temperature ● The paddle is coated with
of 37°C. ○ teflon
○ any other inert material
● Paddle is shaped to minimize
turbulence during stirring.

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PHYSICAL PHARMACY
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● Variable-speed motor six articles to provide the total time
○ Holds paddle and shaft for release of the drug.
assembly is held ● The USP drug monographs
● Rotational speed controlled provide detailed guidelines for
○ 50 rpm for tablets and 25 dissolution studies
rpm for suspensions ○ Volume
● How to use: ○ dissolution medium
○ The assembly is inserted into ○ pH, ionic strength
a large glass vessel that ○ rotational speed of the
holds the dissolution basket (apparatus I) and
medium and maintains it at paddle (apparatus II).
37 °C. ● Periodically, the samples of
● For effective dissolution studies dissolution medium are removed,
for apparatus 2 and the dissolved drug is analyzed
○ Dosage form must sink to according to the assay also
the bottom of the glass prescribed by the USP
vessel ● The cumulative amount and percent
○ Remain at least 2 cm away labeled drug are calculated and
from the bottom of the plotted as a function of time.
paddle
● For products, such as capsules, that Dissolution, Absorption, and
float in the medium, a sinker made Bioavailability
of platinum wire is wrapped around ● When a dosage form reaches its
the formulation to keep it floating. intended site for absorption, the
○ Make sure that the sinker formulation must release the
does not affect the active ingredient absorbed in the
dissolution property of the systemic circulation.
dosage form. ● For oral dosage forms (e.g. tablets)
○ disintegration into granules
IMPORTANCE OF DISSOLUTION → the deaggregation into
STUDIES fine powders
○ increases exposure of the
Quality Control Test drug particles and enhances
● According to the USP guidelines dissolution.
dissolution studies is a very ● After dissolution,
important quality control test in any ○ The drug is absorbed →
pharmaceutical product systemic circulation through
● Dissolution studies with solid the hepatic portal vein.
dosage forms are performed with

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○ “rate-limiting step”-slowest Ionized Non-ionized
step in the sequence which
determines the rate of which Hydrophilic Lipid -soluble
the drug reaches the system Less absorption More absorption
circulation which is a process
of dissolution and
● The more water-soluble a drug will
absorption.
be, the less absorption it will have
● For hydrophilic drugs
● The more lipid soluble a drug will be,
○ salt forms, dissolution in the
the more absorption it will have
aqueous medium is usually
● Ionization state of the drug
very rapid
depends on the pH of its
○ absorption process becomes
environment where dissolution will
the rate-limiting step.
occur
○ The drug solution may
● Although dissolution rate increases
accumulate at the absorption
with ionization, Drugs are absorbed
site or may be prematurely
more efficiently when it is in an
eliminated from the body.
unionized state
● For hydrophobic drugs,
● Weakly basic drugs, dissolution can
○ dissolution process is usually
occur in the stomach, however they
the rate limiting step.
are absorbed better from the
○ The bioavailability of many
upper intestine
hydrophobic drugs is
determined by the rate at
2. Particle Size
which the drug dissolves in
● Noyes-Whitney relationship
the aqueous medium since
○ ↑ rate of dissolution of
dissolution profiles of the
particles (dM/dt) = ↑ surface
drug can be manipulated
area (S) (directly proportional)
through physicochemical
○ Rate of dissolution is directly
formulation changes
proportional to the surface
area
FACTORS AFFECTING THE RATE &
EXTENT OF THE DISSOLUTION OF ● ↓ particle size = ↑ surface area
DRUG (inversely proportional)
● In poorly soluble drugs, decreasing
Physicochemical Properties of the Drug its particle size can greatly improve
the dissolution rate and
1. Ionized vs. non-ionized forms bioavailability after oral
administration

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● Anhydrous form of a drug will
dissolve faster than its crystal
hydrate form
● Example:
○ Ampicillin trihydrate
■ Less absorbed after
oral administration
compared to its
anhydrous form due
to the faster
dissolution rate

Formulation Factors
● One known method of decreasing ● Affects the rate and extend the
particle size dissolution of drug
○ Micronization increases the 1. Solid Dosage Form
effective surface area ● Drugs in tablet and
available for dissolution capsule formulations need to
● Micronized form drugs dissolve in the gastrointestinal
○ Nitrofurantoin fluid for absorption across the
○ Griseofulvin mucosal tissue and into systemic
○ Chloramphenicol circulation to occur.
○ Dissolution process of
3. Crystalline State tablets, particularly for poorly
● Crystalline drugs dissolve more soluble drugs, is dependent
slowly in water than in amorphous on disintegration and
forms. deaggregation to form fine
● Polymorphism particles.
○ Drugs like corticosteroids ● Tablet disintegration is affected by
can undergo changes in their the addition of binding agents
crystalline structure. during wet granulation.
● Polymorphic transition can ● Increase Dissolution process
sometimes lead to the slower ○ Polymeric binders such as
dissolving of a drug, this is because poly(N-vinylpyrrolidone) and
it changes from a faster dissolving sodium
crystalline structure to a slower form carboxymethylcellulose
■ Can increase the rate
of dissolution of

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hydrophobic drug ○ Settling
particle through an ○ Aggregation
enhanced wetting ○ change in the crystalline
effect on the surface structure upon aging of
○ Diluents (starch & lactose) suspensions.
■ in tablet and capsule ● Upon settling and aggregation
dosage forms ○ ↑ in the effective particle size
■ Can increase the will ↓ the dissolution rate.
dissolution rate of ● In terms of aging
hydrophobic drugs in ○ Aging of suspensions occurs
both tablets and when they have been on the
capsules. This is shelf for a long time
probably due to an because there is an
increase in effective equilibrium between the solid
surface area available drug and the saturated
for dissolution of the solution.
drug in the presence ○ As time progresses, the drug
of diluents in a saturated solution can
● Decrease Dissolution process precipitate in a different
○ Lubricating agents (stearic crystalline form or as larger
acid & magnesium stearate) crystals with a potential
○ Decreases dissolution consequence of altered
process by creating a drug dissolution
hydrophobic layer on the ● Effects of having an old/aged
particles that impedes their suspension
interfacial interaction with the ○ drug particles in aged
aqueous medium. suspensions tend to dissolve
more slowly.
2. Suspension & Emulsions ○ The viscosity of suspensions
● Dissolution is an important quality affects the dissolution of the
control test for suspension drug, as solute diffusion
formulations. decreases with increasing
● Dissolution of drugs is the rate- viscosity.
limiting step in the absorption ○ Ex. some suspensions
process from the gastrointestinal intended for intramuscular
tract. and subcutaneous
● Several important factors that administration are the same
influence the dissolution of drugs: to have higher viscosity after

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injection to slow drug release ○ A = plot of Q versus the
and dissolution square root of time
○ (t 1/2) = is constructed, and
3. Semisolid Dosage Forms the slope of the line is used
● Creams, gels, and ointments. to determine the release
● Basic components of these rate.
preparations include varying
amounts of active ingredient Physiological Factors
○ Hydrophobic (e.g. 1. Gastric emptying time and
oleaginous) Intestinal Transit Times
○ Hydrophilic (e.g., ● Can affect the dissolution and
water-miscible) base. effectivity of the drug
● Dissolution characteristics of a ● Nondigestible materials take around
semisolid dosage form drug is 15 min to 2 hrs to pass through the
dependent on the type of base stomach, all which depend on the
used. content of the stomach
● In vitro dissolution studies of ● Gastric emptying time
semisolid dosage forms typically ○ faster in a fasted state
involve examination of the release ○ slower in a fed state
rate of active ingredients from the ● Intestinal transit time usually takes
system as a function of time using in 1-4 hrs in the upper intestines.
vitro skin permeation models such ● Most drugs are absorbed in the
as the Franz cell. upper intestine (duodenum and
● The date are analyzed according to jejunum)
the square-root-of-time relationship Intestinal transit Type of food eaten
proposed by Higuchi: time affects along with the drug
1/2 can also affect
● 𝑄 = [2𝐴𝐶𝑠𝐷𝑡]
Drug dissolution Bioavailability
● WHERE:
○ Q = is the amount of drug Absorption Dissolution
released per unit surface
Bioavailability Drug transit and
area A (in mg/cm2 ), Tablet disintegration
○ Cs = is the saturated
solubility of the drug in the
2. Variability of pH
dissolution medium,
● The pH in various regions of the GI
○ D = is the diffusion
tract is important to drug
coefficient,
dissolution.
○ t = is time.
● pH

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○ Fasted stomach gastrointestinal membrane to
■ can be as low as 1.2 pass through the membrane
○ Fed state itself
■ can fluctuate to 3.5 ○ It has to be soluble in
and above hydrophilic or water loving
● ​pH in the intestines phase to get out of the
○ 5.4 pH in the small intestine membrane to proceed to the
○ 8.4 pH in the colon blood and in the systemic
● Weakly acidic drugs tend to circulation. Thus, most of the
dissolve less in the acidic pH of drugs move from a lipid
the stomach environment to the aqueous
● Weakly basic drugs tend to dissolve one.
better in the stomach ● States that a solute will distribute
itself between two immiscible
GENERAL PARTITION LAW solvents (oil and water) so that the
ratio of its concentration in each
solvent is equal to the ratio of its
solubility in each one.
● It is therefore a constant for a given
solute in the immiscible system at a
given temperature.
● Expressed as:
● If two immiscible liquids are mixed
and a solute is added the affinity of
the solute will be based on whether
it is hydrophilic or hydrophobic
● For instance, if the solute has a high
polarity, it means that it has an
affinity to the water or aqueous ● Applies only to the concentration of
phase. solvents common to both phases
● Same goes for the solute with low such as having the same chemical
polarity, it means that it will have structure in both phases
more affinity to the organic than that ○ Aqueous layer - buffered
to the aqueous phase aqueous solution
● For the drug to cross the membrane ○ Organic layer - immiscible
barrier organic solvent (octanol or
○ it must be dissolved in the an oily layer)
lipid material of the

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PARTITION COEFFICIENT ● Exist as cations and anions in aq.
● Ratio of concentrations of unionized Layer
drug distributed between organic ● Water-soluble - since they
phase and aqueous phase at completely dissociate in aqueous
equilibrium phase
● ↓ Solubility in organic, non-polar
solvents
● Partitioning in organic layer does not
● ↑ Kd = not very water soluble =
occur to any great extent
more soluble in organic solvent (oil
● Large cations/anions - may form an
phase)
ion pair in an organic phase
● ↓value of 𝐾𝑑= more water soluble =
Kd → 0
less oil soluble
Kd -> lower when water soluble due to the
complete dissociation of strong electrolytes
PARTITIONING ORIENTATION
● Recall: Inorganic Chemistry Apparent Partition Partition Coefficient
○ Strong acid/base - 100% Coefficient (K1d) (Kd )
dissociation pH-dependent pH-independent
○ Weak acid/base - partial
dissociation Determine Determine
distribution of distribution of ionized
○ Example: unionized components
components
HCl (SA):
Weak Electrolytes
● Partition depends on pH
In the presence of water, it
● pH < pKa for a weak acid; pH > pKa
fully dissociates, therefore,
for a weak base,
the reaction is irreversible.
● Recall: Kd is written as follows:

CH3COOH (WA):

It partially dissociates,
therefore, the reaction is
● For organic weak acid electrolytes in
reversible.
aqueous solution buffered at pH =
pKa or higher, apparent coefficient
Strong Electrolytes
● Completely dissociated in an may be calculated:
aqueous solution

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○ Shows the dependency to

pH or the H+ concentration
1
○ 𝐾𝑑 = 𝑎𝑝𝑝𝑎𝑟𝑒𝑛𝑡 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡
○ They do not fully dissociate
○ Still need to compute for the
unionized concentration
which concerns the apparent
coefficient
○ Apparent coefficient - pH
dependent
● For an organic weak base
electrolytes in aqueous solution
buffered at pH = pKa or lower,
apparent coefficient may be
computed using:

○ shows the dependency of

the apparent partition
coefficient on the hydrogen
ion concentration
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