[STATES OF MATTER] PHYSICAL PHARMACY

DEFINITION OF TERMS:  Boiling - a form of evaporation where conversion from the liquid state to the vapor state
 Ionization- is the process by which an atom or a molecule acquires a negative or occurs within the body of the liquid through bubble formation
positive charge by gaining or losing electrons.  Boiling Point - The temperature at which vapor pressure of liquid equals atmospheric
 Deionization- the removal of ions. The term is generally used with respect to removal pressure. Also considered as the temperature at which thermal agitation can overcome
of ions from water. the attractive forces between molecules of a liquid.
 Hygroscopicity – the measurement of the ability of a powder/solid material to absorb  Normal Boiling point - is the temperature at which a liquid boils under a pressure of
water 760 mmHg
 Deliquisence – ability of hygroscopic powders/solid material (lyophilized) to absorb SOLID
water to form a solution.  particles are tightly packed
 Elasticity- is a physical property of a material where the material returns to its original  PE dominance
shape after being deformed.  definite shape and volume
 Gas – is a substance that exists in the gaseous state even at room temperature, eg. O2  virtually incompressible
,CO2  very small thermal expansion
 Vapor - is a substance that is liquid or solid at room temperature and that passes into  does not flow
the gaseous state when heated to a sufficiently high temperature. eg. Menthol and  diffusion occurs extremely slow; vibration is at fixed position
ethanol LIQUID
 Vapor pressure – the pressure exerted by a vapor in equilibrium with the solid or liquid  particles of liquids are randomly packed, but are near enough apart to slide over one another.
phase of the same substance. But do not move with enough energy to separate.
 Boiling point- temperature at which the pressure exerted by the surroundings upon  PE = KE
a liquid is equaled by the pressure exerted by the vapor of the liquid; under this condition,  indefinite shape, definite volume
addition of heat results in the transformation of the liquid into its vapor without raising the  does not expand to fill container
temperature.  Not easily compressible
 Evaporation- conversion of a substance from  flows readily
the liquid or solid phase into the gaseous (vapor) phase. If conditions allow the formation  diffusion occurs slowly
of vapor bubbles within a liquid, the vaporization process is called boiling. GAS
 Enthalpy - heat content of a material or the state of matter (increasing enthalpy from particles of gases are very far apart and move freely

solid to liquid to gas) KE dominance

 Entropy – a measure of the degree of total randomness (also increases as materials go indefinite shape and volume

from solid to liquid to gas) compressible (compress with pressure & expand w/ changes in temperature)

 Propellant - liquefied or mixture of liquefied gases, that supplies the necessary pressure Diffusion within a gas occur rapidly (spread apart in order to homogeneously distribute itself

within an aerosol system to expel material from the container & in combination with other throughout the container)
components to convert the materials into the desired physical form.  Relatively low density and viscosity
 Lattice - a regular repeated three-dimensional arrangement of atoms, ions, or molecules MESOPHASE
in a metal or other crystalline solid.  “Mesos” – middle
 Birefringence - is the optical property of a material having a refractive index that 1. PLASMA
depends on the polarization and propagation direction of light. These optically anisotropic o are superhot and superexcited atom
materials are said to be birefringent. o ionized gas
 a property association with crystals. The light passing through a material is divided into o a very good conductor of electricity and is affected by magnetic fields.
two components with different velocities and hence different refractive index. o like gases have an indefinite shape and an indefinite volume.
o easily compressible because there is a great deal of free space between particles.
2. LIQUID CRYSTALLINE
o Lies between liquid and crystalline states
3. SUPERCRITICAL FLUID
o exist under high pressure and temperature and has a properties that are intermediate
BIREFRINGENCE between those liquid and gases. Ex. methylene chloride, CO2

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 [STATES OF MATTER] PHYSICAL PHARMACY

BOSE EINSTIEN CONDENSATES  ∆Hf

 Supercold and superunexcited atoms  MP
 Gas condensation at billions of degree above absolute zero temp., superatom is formed which Change of state: LIQUID to GAS
can’t be separated creating a blob. (special elements are involve to create BECs )  heat of vaporization – the heat that is absorbed when water vaporizes at the
CHANGES IN THE STATE OF MATTER normal boiling point. It is also the heat absorbed when 1g or mole of liquid is
vaporized
 ΔHv or Molar heat of vaporization – the heat absorbed by 1 mole of liquid when
it passes into the vapor state
 Latent Heat of Vaporization - quantities of heat, heat that is taken up when the
liquid vaporizes and also the heat that is lost when the vapor condense to liquid
 Heat of combustion- the heat involved in the complete oxidation of 1 mole of a
compound at 1 atmospheric pressure
PRINCIPLE:

SUBLIMATION IN FREEZE DRYING OR LYOPHILIZATION

- Widely used in the pharmaceutical and diagnostic industries for the manufacturing of
heat-sensitive drugs as most common approach in making a sterilized powder.
Categories of change: - Is a dehydration technique, which enables liquid or slurry products, which have
1. Endothermic change of state - change of state in which heat energy is absorbed. Ex. previously been frozen to be dried under a vacuum
melting sublimation, evaporation - Process where drug suspended in water is frozen and then dried by sublimation
2. Exothermic change of state- change of state in which heat is given off. Ex. freezing, process.
condensation and deposition The Phase Diagram
Changes from SOLID to LIQUID
 Freezing point – temperature at which a liquid passes into the solid state. Also the melting
point of a pure crystalline compound.
o Hence, freezing point and melting point of a pure crystalline solid is defined as the
temperature at which the pure liquid and solid exist in equilibrium.
 Normal freezing or Melting point- temperature of the equilibrium mixture with an external
pressure of 1 atm.
 Melting point- temperature at which a solid passes into the liquid state. The heat added
during the melting process does not bring about a change in temperature until all of the solid
has disappeared.
Clapeyron: Heat of fusion
 Heat of fusion - the heat required to increase the interatomic or intermolecular distances in
crystals, thus allowing melting (increase molecular motion)
 Hf or molar Heat of Fusion – Heat absorbed when 1 mole of solid changes into 1 mole of
liquid.
 Latent heat of fusion- the heat absorbed when 1 gram of solid melts or the heat liberated
when it freezes

GENERALIZATION: Phase Diagram

 Molecular weight  is a plot of pressure (P or ln P) vs temperature (T). Display the phase of the substance at
 Intermolecular forces various pressures & temperatures & the places where equilibria exist between phases.

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 [STATES OF MATTER] PHYSICAL PHARMACY

 It is a common way to represent the various phases of a substance and the conditions under
which each phase exists.

 Lines on the diagram represent conditions (T,P) under which a phase change is at equilibrium.
 That is, at a point on a line, it is possible for two (or three) phases to coexist at equilibrium. In
other regions of the plot, only one phase exists at equilibrium.
Triple Point
 At the triple-point temperature, T3, and triple-point pressure, P3, three phases can coexist at
equilibrium.
point having definite temperature and pressure, at which soild, liquid and vapor phase of a
chemical entity are able to coexist indefinitely.
Critical Point
 At a temperature above the critical temperature, Tc, and a pressure above the critical
pressure, Pc, it is no longer possible to distinguish between the gas and liquid phases. At T >
Tc and P > Pc the substance is referred to as a super-critical fluid.

GAS
Kinetic molecular theory for Ideal Gas Critical Pressure
1. Gases are composed of particles called molecules. Applies to low pressure and high  the pressure required to liquefy a gas at its critical temperature.
temperature.  This also the highest vapor pressure that a liquid can have.
2. 2. The particles of the gas do not attract one another, but rather move with complete Critical temperature
independence. (at low pressure)  the temperature above which a gas cannot be liquefied.
3. 3. The particles exhibit continuous random motion owing to their kinetic energy.  Rough measure of the attractive forces between molecules
4. 4. The molecules exhibit perfect elasticity, that is, there is no net loss of speed after they  Temperature above the critical value, molecules possess sufficient kinetic energy so that no
collide with one another and with the walls of the confining vessel amount of pressure can bring them within the range of attractive forces that cause the
particles “stick” together

METHODS OF GAS LIQUEFACTION

1. Subject to intense cold by the use of freezing mixtures.

2. adiabatic expansion –allowing ideal gas to expand that no heat can enter the system. May be
achieved by Dewar or Vacuum, flask
3. Joule – Thomson effect – Precool the gas before allowing it to expand. Cooling effect happens
when highly compressed nonideal gas expands into region of low pressure. The drop of temp.
results from the energy expended in overcoming the cohesive forces of attraction between the
Van der Waals theory for Real gas molecules.
1. Real gases are not composed of infinitely small and perfectly elastic non-attracting spheres. Ex. liquid oxygen and liquid air
Instead, they are composed of molecules of a finite volume that tend to attract one another. 4. High pressure in a closed chamber that is maintained below the critical temperature.
Ex. Pharmaceutical Aerosol
LIQUEFACTION OF GAS:
 Principle: High pressure and low temperature : Reduced pressure, molecules expands &
liquids reverts to a gas.
 The further a gas is cooled below its critical temperature, the less pressure is required to
liquefy it.

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 [STATES OF MATTER] PHYSICAL PHARMACY

James Dewar on
Adiabatic
expansion of gas:
Gas Liquefaction

PHARMACEUTICAL SOLIDS
SOLIDS

CRYSTALLINE AMORPHOUS POLYMERIC

Unit cells Examples
Simple cubic Sodium chloride
Tetragonal Urea
Orthothrombic Ritonavir form II
POLYMORPHS AMORPHOUS
Rhombohedral Iodine
Monoclinic Sucrose, Ritonavir form I
Triclinic Boric acid
Hexagonal Iodoform
HYDRATES/ AMORPHOUS
SOLVATES DISPERSION
CRYSTAL LATTICE:
There are seven systems of crystal structures, which are also called lattices or space lattices:
1. Cubic or Isometric - This shape includes octahedrons and dodecahedrons as well as cubes.
SALTS/COCRYSTALS 2. Tetragonal - These crystals form prisms and double pyramids. The structure is like a cubic
crystal, except one axis is longer than the other.
3. Orthorhombic - These are rhombic prisms and dipyramids that resemble tetragons but without
square cross-sections.
4. Hexagonal - Six-sided prisms with a hexagon cross section.
5. Trigonal - These crystals have a 3-fold axis.
6. Triclinic - Triclinic crystals tend not to be symmetrical.
7. Monoclinic - These crystals resemble skewed tetragonal shapes.

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 [STATES OF MATTER] PHYSICAL PHARMACY

Type Structural Intermolecul Typical Properties Examples

Particles ar forces Rigid and incompressible Usually rigid and cannot be compressed to
Hardnes Melting Other prop. any appreciable extent. However graphite is
s point soft because of its unusual structure.
Metallic Cations & Metallic soft to Low to Lustrous, ductile; malleable, Na, Mg, Give clean cleavage,i.e, break into pieces with They give irregular cleavage
delocalized bonds very high very good conductors of heat Al,Fe,Sn,C plane surfaces
electrons hard; and electricity u,Ag,W Have definite heat of fusion Do not have a definite heat of fusion.
Anisotropic – their mechanical & electrical Isotropic – they have similar physical
Ionic Cations and Electrostatic Hard Moderate Nonconductors as solid, good NaCl,MgO, properties depend on the direction along which properties in all directions because the
Anions attractions to very electric conductors as liquids, NaNO3
they are measured. constituents are arranged in random manner.
high many are soluble in polar
solvents like water Polymorphism usually happens
Network Atoms Covalent Most Either Most are nonconductors of C(diamond Both have amorphous & crystalline properties:
covalent bonds are very sublime or electricity ,  Paraffin
hard melt at graphite),  Beeswax
very high SiC,AlN,Si  Petrolatum
temp. O2
Molecular Atoms or Dispersions Soft Extremely Sublime in many cases, He,Ar,H2,C PROPERTIES OF SOLID
Nonpolar nonpolar forces low to soluble in nonpolar solvents O2,CCl4,CH
1. Isotropic - exhibit similar properties in all directions. Ex. Amorphous substances, Cubic
molecules moderate 4,I2
Polar Polar Dispersion Soft Low to Soluble in some polar and (CH3)2O, crystals
molecules forces and moderate some nonpolar solvents CHCl3,HCl 2. Anisotropic – crystals other than cubic, are showing different characteristics in various
dipole-dipole directions along the crystal. (ex. Change of color from blue to yellow depending on the
attractions orientation of the crystals, refractive index, crystal growth, rate of solubility).

I.CRYSTALLINE SOLIDS
H-bonded Molecules Hydrogen soft Low to Soluble in some H-bonded H2O,NH3
with H- bonds moderate solvents and some polar
bonded to solvents
F,O,N

COMPARISON: Crystalline vs Amorphous Note: The hardness and strength of metals depends in the kind of imperfections or lattice defects in
Crystalline Solids Amorphous solids the crystals.

A. POLYMORPHS
 Are chemically identical entities, including pharmaceutical agents that may exist in more than
one crystalline structure.
 One polymorph may be more biologically active than another polymorph of the same drug
Changes in crystalline forms arise from:
 Changes in the intermolecular bonding patterns
 Conformational changes in the molecules
 Molecular orientations between neighboring molecules in the solid.
POLYMORPHISM
 A condition or phenomenon when an elemental substances or solid material exist in more than
one form or crystal structure.
 Differences in: Stabilities, Melting points, Solubility , Rate of dissolution, X-ray crystals and
diffraction patterns

Have definite shape and geometrical form Don’t have definite geometrical shape
Have sharp melting point Melt over a wide range of temperature

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 [STATES OF MATTER] PHYSICAL PHARMACY
This illustration depicts eight of the
allotropes (different molecular
configurations) that pure carbon can  In solid, the two ionized compounds will interact in the lattice to form crystalline salt. The drug
take: substance can be a weak acid or a weak base. This compound in a salt is called counterion.
a) Diamond
b) Graphite
Counterions used in pharmaceutical salts in Marketed Products
c) Lonsdaleite
d) C60 (Buckminsterfullerene)
e) C540 (see Fullerene) Anion Counter for Weak Base Drugs Cation Counterion for Weak
f) C70 (see Fullerene) Acids Drugs
g) Amorphous carbon
h) single-walled carbon nanotube Hydrochloride Sodium

Sulfate Calcium
POLYMORPHISM: THEOBROMA CACAO BUTTER
 A polymorphous natural fat that is mainly consist of a single glyceride, that melts to large
Bromide Potassium
degree over a narrow temperature range of 34-36*C
POLYMORPHIC FORMS OF THEOBROMA OIL:
Maleate Meglumine
1. Gamma form - (mp.18 ‘C) - unstable
2. Alpha form - (mp. 22 ‘C)
3. Beta prime form - (mp. 28 ‘C) Mesylate Tromethamine
4. Beta form - (mp. 34.5 ‘C) – stable
CHANGES IN POLYMORPHIC FORMS Tartrate Magnesium
1. Enantiotropic – if refers to the reversible change from one form to another
2. Monotropic – it refers to a change that takes place in one direction only Acetate Zinc
ex. metastable to stable form
Citrate Lysine
B. HYDRATES AND SOLVATES
Phosphate Diethylamine
HYDRATES
 water is included in the lattice
 More commonly as drug substance D. COCRYSTALS
 Less soluble in water than anhydrous form.  A homogenous multicomponent phase of fixed stoichometry where chemical entities are held
SOLVATES / psuedopolymorphs together in a crystal lattice by intermolecular forces.
 crystals which contain solvent molecules formed from the crystallization of a substance in  Drug + cocrystal former
different solvent systems.


Not usually choose due to the possibilities of toxicity of common solvents
Example: Ethynylestradiol (Potent synthetic estrogen) crystallized (polymorphs 4 forms) from
the solvents acetonitrile, methanol & chloroform saturated with water
II. AMORPHOUS SOLIDS
C. SALT CRYSTALS A.AMORPHOUS SOLIDS
 A crystal when a lattice also accommodates other molecules, such as acids and bases to form
salts.
FORMATION:  These are supercooled liquids in which the molecules are arranged in a manner as in the
 When there is a pKa (acid ionization) difference of two between the molecules, a proton is liquid state.
transferred to form two ionized species, one with a positive charge and one with negative  Solids as amorphous when there is no long-range order over many molecular units to produce
charge. a lattice or crystalline structure.
 They dont’ have a definite melting points

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 [STATES OF MATTER] PHYSICAL PHARMACY

 Will flow if sufficient pressured is applied

LIQUID STATE
 Have faster rate of dissolution ( more soluble) than crystalline solids since there is no PROPERTIES OF LIQUIDS
crystalline lattice that needs to be broken before a material can be dissolved.  VAPOR PRESSURE
 Examples: Glass ( nonequilibrium solids )and synthetic plastic substances o A physical property that does not depend on: volume,weight of liquid, atmosprheric
pressure, presence of other vapors in the air.
B. AMORPHOUS DISPERSIONS o Dependent only in temperature
 An amorphous solid that is stabilized by a polymer or a combination of polymer(s) and or EQUILIBRIUM VAPOR PRESSURE:
surfactants. o Pressure of the saturated vapor above the liquid
 Has an increased in solubility with physical stability closer to that of a crystalline material. o Rate of vaporization equals the rate of condensation
 But may still crystallize in the solid state or in a solution.  SURFACE TENSION
 Ex. itraconazole, lopinavir/ritonavir, and etravirine LIQUID CRYSTALLINE STATE
 4th state of matter

III. POLYMERIC SOLIDS

 Properties of which are intermediate between the liquid and solid states
 They are also known as the mesophase or Liquid-Crystalline state or Plasma
 Are organic in nature
 Posses strong dipoles and easily polarizable groups
 Polymers are large molecules formed by a covalent assembly of small molecules (monomers)  Are elongated, rectilinear in shape and rigid
into a chain or network of repeating structural units.
Types: TYPES OF LIQUID CRYSTALLINE STATE
 Natural - Ex. ruber ( polyisoprene,), polypeptides and cellulose (and other polysaccharides or 1. SMECTIC
gums)  soap or grease-like.
Plastics used in packaging and devices Polyvinylchloride,  the molecules of this crystals are mobile in two directions and can rotate in one axis
 Synthetic polyethylene, polystyrene and Controlled release devices: polyvinyl
 Semisynthetic  Considered as the mesophase of the most pharmaceutical significance since it forms
acetate, polyactides and cellulose derivatives (methylcellulose and a ternary complex mixture with other additives
hydroxypropylmethylcellulose)  Usually used as component in emulsion employed in the solubilization of water-
insoluble materials to their highly viscous nature.
COMMON PHARMACEUTICAL POYMERS: 2. NEMATIC
name Common name  thread-like. The molecules can rotate only one axis but are mobile in three
dimensions.
Polyvinyl alcohol PVA 3. CHOLESTERIC
Methylcellulose Methocel A  a special case of nematic type. Incorporation of cholesterol and lipids in human
subendothelial macrophages leads to an insoluble liquid crystalline biologic membrane
Carbomer Carbopol that results to plaque formation
PE (Polyethylene)  Cholesteryl benzoate - was the first recorded type of liquid crystals by Reinitzer in
1888 that was derived through the application of heat. At 145 C, the solid formed a
Polyethyleneglycol, Polyethylene PEG
turbid liquid (the thermotropic liquid crystal) which only became clear, to give the
glycol
conventional liquid state at 179 C
Polypropylene (PP) 4. LYOTROPIC
Polymethylmethacrylate (PMMA) Plexiglass  These are liquid crystals obtained from the action of certain solvents on solids. Ex.
Salicylic acid
Polymethacylate Eudragit 5. THERMOTROPIC
 These are the forms of liquid crystals obtained from the application of sufficient heat
Poly (d,llactide) Polyactide.
on solids to form the mesophase

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 [STATES OF MATTER] PHYSICAL PHARMACY

SUPERCRITICAL FLUID Gas-Liquid-solid 3 F=C-P+2 (F=0) Invariant – the three phases is visible thus
 is a mesophase formed from the gaseous state where the gas is held under a =1-3+2=0 the system is completely defined. It lies with in the
combination of temperature and pressure that exceed the critical point of a
intersection bounding the three phases.
substance.
 As the pressure is raised higher, the density of the gas can increase without a
significant increase in the viscosity while the ability of the supercritical fluid to
dissolve compounds also increases.
USES: EUTECTIC MIXTURE:
 For extraction, crystallization, formulations of polymer mixtures and formation or  EUTECTIC POINT – the lowest temperature at which the existence of the liquid phase is
micro & nanoparticles possible
Common application:  Mixing eutectic mixtures or components with powders (MgO) helps prevent its liquefaction.
 Decaffeination of coffee & Tea using supercritical CO2  EUTEXIA – a phenomenon that results to liquefaction of when two solids are combined due to
lowering of temperature.
PHASE EQUILIBRIA AND THE PHASE RULE:
J. Willard Gibbs – formulated the phase rule which is a relationship for determining the least number of  Example of eutectic substances/powder: methanol, camphor, aspirin, paracetamol
intensive (independent) variables (temperature, pressure, density, and concentration) that can be
changed without changing the equilibrium state of the system. Or the least number required to define
the state of the system.
F =C – P + 2
Where:
 F = no. of degrees of freedom of the system ( this is the least number of intensive
variables ,Ex. temperature, concentration, pressure, density, etc.) , that must be fixed
to describe the system completely.
 C = no. of components ( this is the smallest number of constituents by which the
composition of each phase in the system can be expressed in the form of chemical
formula or equation)
 P = no. of phases (these represent the number of homogenous, physically distinct
portion of a system that is separated from other portions of the system by bounding
surface) Solid, liquid and gas
 The greater the number of phases in equilibrium, the fewer are the degrees of
freedom

System # of Degrees of Comments

phase freedom

Gas/Liquid/solid 1 F=C-P+2 (F=2) Bivariant – must fix two variables to define

= 1-1+2=2 the system. Lies within vapor, liquid or solid

Gas-liquid, 2 F=C-P+2 (F=1) Univariant – must fix one variable to define

liquid-solid, or =1-2+2=1 the system. Lies intermediate with between solid-
gas-solid liquid, liquid –vapor or solid vapor

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