States of Matter

Aseel Samaro
 States of Matter
 Binding Forces Between Molecules
 Solids and the Crystalline State
 Phase Equilibria and the Phase Rule
 Objectives of the lecture
After completion of this chapter, the students should be able to:
Describe the solid state , crystallinity, solvates and polymorphism
Understand phase equilibria and phase transitions between the three
main states of matter
Understand the phase rule and its application to different systems
containing multiple components.
 Comparison of Gases, Liquids and Solids
 Gases are compressible fluids. Their molecules are widely separated.
 Liquids are relatively incompressible fluids. Their molecules are more tightly packed.
 Solids are nearly incompressible and rigid. Their molecules or ions are in close contact
and do not move.

In order for molecules to exist in aggregates in gases, liquids

and solids Intermolecular forces must exist
 Repulsive and Attractive Forces
 As two atoms or molecules are brought closer
together, the opposite charges and binding
forces in the two molecules are closer
together than the similar charges and forces,
causing the molecules to attract one another.

 The negatively charged electron clouds of

molecules largely govern the balance
(equilibrium) forces between the two
molecules
 Ideal Gas Equation
1
Boyle’s law: P a V (at constant n and T)

Charles’ law: V a T (at constant n and P)

Avogadro’s law: V a n (at constant P and T)

P1V1 P2V2 R is the gas

T1
= PV = nRT
T2 constant
 Gaseous state
 The conditions 0 0C and 1 atm are called standard temperature and
pressure (STP).

 Experiments show that at STP, 1 mole of an ideal gas occupies 22.414

L.

PV = nRT
PV (1 atm)(22.414L)
R= =
nT (1 mol)(273.15 K)

R = 0.082057 L • atm / (mol • K)

 Gaseous state
What is the volume (in liters) occupied by 49.8 g of HCl at STP?

1 atm ≈ 760.001 mm-Hg T = 0 0C = 273.15 K

P = 1 atm
PV = nRT
1 mol HCl
n = 49.8 g x = 1.37 mol
nRT 36.45 g HCl
V=
P
1.37 mol x 0.0821 L•atm
mol•K
x 273.15 K
V=
1 atm

V = 30.7 L

9
 Gaseous state

P1V1 P2V2
=

T1 T2
 Liquefaction of Gases
 The critical temperature (Tc) is the temperature above which the gas cannot be
made to liquefy, OR is the temperature above which the liquid cannot longer exist

 The critical pressure (Pc) is the minimum pressure required to liquefy a gas at its
critical temperature.

 critical temperature (Tc) of water is 374°C, or 647 K, and its critical pressure is
218 atm,
 SOLIDS & CRYSTALLINE STATE
Pharmaceutical Drugs: more than 80% are solid formulations
 Solids and the crystalline state
 A crystalline solid possesses rigid and long-range order.

 In a crystalline solid, atoms, molecules or ions occupy specific

(predictable) positions.

 An amorphous solid does not possess a well-defined arrangement

and long-range molecular order.
 Classification of Solids

Crystalline Amorphous

 Amorphous
A unit cell is the basic repeating structural unit of a crystalline solid.

lattice
point
At lattice points:
• Atoms
• Molecules
• Ions

Unit Cell Unit cells in 3 dimensions

The crystal lattice of sodium chloride NaCl

Na Cl
 Crystal forms
The various crystal forms are divide to basic 7 unit according to its symmetry
NaCl urea iodoform

iodine

Be3Al2(SiO3)6
sucrose Boric acid
 Types of Crystals
Ionic Crystals
• Lattice points occupied by cations and anions
• Held together by electrostatic attraction
• Hard, brittle, high melting point
• Poor conductor of heat and electricity

CsCl ZnS CaF2

Covalent Crystals
• Lattice points occupied by atoms
• Held together by covalent bonds
• Hard, high melting point
• Poor conductor of heat and electricity

carbon
atoms

diamond
graphite
Metallic Crystals
• Lattice points occupied by metal atoms
• Held together by metallic bonds
• Soft to hard, low to high melting point
• Good conductors of heat and electricity

nucleus &
inner shell e-

mobile “sea”
of e-

Cross Section of a Metallic Crystal

 Polymorphism
 Some elemental substance such as C
and S ,may exist in more than one
crystalline form and are said to be
allotropic, which is a special case of
polymorphism

 Polymorphism is the ability of a

substance to exist in more than one
crystal structure
Polymorphism is the ability of a substance to exist in more than one
crystal structure

Polymorphs: when two crystals have the same chemical composition

but different internal structure (molecular packing –molecular
conformation or / and inter or intra molecular
interactions)modifications or polymorphs or forms

Pseudo polymorphs : different crystal forms have molecules of the

same given substances and also contain molecules of solvent
incorporated into a unique structure (solvates or hydrates (water))
 The most common example of polymorphism

carbon
atoms

High T and p
diamond graphite

Diamond is metastable and converts very slowly to graphite

 Solid State : Polymorphs

Mono-component systems: Polymorphs

Multi-component systems
 Cocrystal
 The simplest definition of a cocrystal is a crystalline structure made
up of two or more components in a definite stoichiometric ratio,
where each component is defined as either an atom, ion, or
molecule.
 Principle of polymorphism
 When the change from one form to another is reversible, it is said to
be enantiotropic.

 When the transition takes place in one direction only—for example,

from a metastable to a stable form—the change is said to be
monotropic.
 Solvates
 Pharmaceutical synthesis include purification and crystallization,
residual solvent can be trapped in the lattice.
 This result in the formation of cocrystal or solvate.

 The presence of residual solvent may affect dramatically the

crystalline structure of the solid depending on the type of inter.
molecular forces that the solvent may have with crystalline solid
 Polymorphism
Melting point Photochemical reactivity
Vapor pressure Thermal stability
Hardness Filtration and drying characteristics
Optical, electrical magnetic Dissolution rate
properties Bioavailability
Color Physical and chemical stability
IR spectra
NMR spectra

Solubility and melting point are very important in pharmaceutical

processes including dissolution and formulation.
 Amorphous Solid
 An amorphous solid does not possess a well-defined arrangement and long-range
molecular order.
 Amorphous substances, as well as cubic crystal, are isotropic, that is, they exhibit
similar properties in all direction.

AMORPHOUS SOLIDS
Solids that don’t have a definite geometrical shape are known as Amorphous Solids.
1. In these solids particles are randomly arranged in three dimension.
2. They don’t have sharp melting points.
3. Amorphous solids are formed due to sudden cooling of liquid.
4. Amorphous solids melt over a wide range of temperature
 Amorphous or crystalline & therapeutic
activity
 The crystalline from of the antibiotic novobiocin acid is poorly
absorbed and has no activity, where the amorphous form is readily
absorbed and therapeutically active, due to different dissolution rate.
 Crystallization
General crystallization conditions
􀁺Solvents –different polarities
􀁺Concentration of the solutions (super saturated, saturated, diluted)
􀁺Cooling speed (quenching, slow)
􀁺Temperature (room or lower than room temperature)
 Polymorphism and Industry/ Pharmaceutical

API Final Form

Crystallization Granulation

Filtration Drying

Drying Compaction

Milling Tableting

Bulk API Drug Product

Stability
 Polymorphism and Industry/
Pharmaceutical
 Fluoxetine HCl, the
active ingredient in the
antidepressant drug
Prozac.

 co crystal which will

have increased solubility
compared to the
crystalline form
 Celecoxib

 CELECOXIB is a nonsteroidal anti-inflammatory drug

 However it was found that the higher bioavailability was shown by the amorphous state

 The downfall of the amorphous state was its stability.

 This was due to the structural relaxation.

 This was enhanced by mixing it with polymers like PVP, which helped in stabilizing the
amorphous system (Piyush Gupta et al. 2004, Piyush Gupta et al. 2005).

 A new solid state form was developed by Pharmacia

 Furosemide
Two forms with significantly differing aqueous solubility and dissolution
rate
Oral bioavailability compromised

Giron lists >20 excipients that display polymorphism, including

– Lactose (anhydrous; also monohydrate)
– Aspartame (anhydrous; hydrate forms)
– Magnesium stearate (can affect lubrication of tablets)
 Bioavailability
 The rate and extent to which the active ingredient or active moiety is
absorbed from a drug product and becomes available at the site of
action.
 Bioequivalence
 The absence of a significant difference in the rate and extent to which
the active ingredient or active moiety in pharmaceutical equivalents
or pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar
conditions in an appropriately designed study.
Carbamazepine
 at least, six polymorphic white or almost white, crystalline
CHLORPROPAMIDE powder. It exhibits polymorphism. Practically insoluble in water
soluble in alcohol freely soluble in acetone and in dichlo-
blood-glucose-lowering drug romethane dissolves in dilute solutions of alkali hydroxides.
Protect from light.
AIDS drug ritonavir
 Polymorphism and Industry/ Pharmaceutical

 Theobroma oil (cacao butter ) is a polymorphic natural fat.

 Theobroma oil can exist in 4 different polymorphic forms of

which only one is Stabile
1. Unstable gamma form melting at 18°C
2. Alpha form melting at 22°C
3. Beta prime form melting at 28°C
4. Stable beta form melting at 34.5°C

 This is important in the preparation of theobroma

suppositories.

 If the oil is heated to a point where it is completely liquified

(about 35 C), the crystals of the stable polymorph are
destroyed & the mass does not crystallize until it is cooled to
15 C.

 The crystals that form are unstable & the suppositories melt
at 24 C.

 Theobroma suppositories must be prepared below 33 C.

 Polymorphism and Industry/ Pharmaceutical

Anhydrates together with salts form the majority of all drug formulations
About a half of all APIs used today are salts
Salts are stable and well soluble in polar solvents (first of all in water), because they contain ionic bond.
There is one more essential advantage of salts – their solubility is a function of pH. Since pH in the
gastrointestinal tract (GIT) vary between 1-7,5

atorvastatin calcium trihydrate

Each tablet contains Atorvastatin Calcium
Trihydrate equivalent to Atorvastatin 20 mg.
Phase Equilibria & The Phase Rule
 Phase
diagram –
Water
 Phase Equilibria & The Phase Rule: Definitions

 Phase Equilibrium: A stable phase structure with lowest free-energy (internal

energy) of a system, and also randomness or disorder of the atoms or molecules
(entropy).
 Any change in Temperature, Composition, and Pressure causes an increase in free
energy and away from Equilibrium thus forcing a move to another ‘state’
 Phase Definition
 A phase is defined as any homogeneous and physically distinct part of a system which is
separated from other parts of the system by interfaces.

 A part of a system is homogeneous if it has identical physical properties and chemical

composition throughout the part.

A phase may be gas, liquid or solid.

A gas or a gaseous mixture is a single phase.
Totally miscible liquids constitute a single phase.
In an immiscible liquid system, each layer is counted as a separate phase.
Every solid constitutes a single phase except when a solid solution is formed.
A solid solution is considered as a single phase.
Each polymorphic form constitutes a separate phase.
• Examples
1. Liquid water, pieces of ice and water vapour are present together.
The number of phases is 3 as each form is a separate phase. Ice in the system is a single phase even
if it is present as a number of pieces.

2. Calcium carbonate undergoes thermal decomposition.

The chemical reaction is: CaCO3(s)  CaO(s) + CO2 (g)
Number of phases = 3 : This system consists of 2 solid phases, CaCO3 and CaO and one gaseous
phase, that of CO2.

3. Ammonium chloride undergoes thermal decomposition. The chemical reaction is:

 NH4Cl(s) NH3 (g) + HCl (g) Number of phases = 2
 This system has two phases, one solid, NH4Cl and one gaseous, a mixture of NH3 and HCl.

4. A solution of NaCl in water Number of phases = 1

 Components
 The number of components of a system at equilibrium is the smallest
number of independently varying chemical constituents using which
the composition of each and every phase in the system can be
expressed.
• Examples
 Counting the number of components
1. The sulphur system is a one component system. All the phases,
monoclinic, rhombic, liquid and vapour – can be expressed in terms
of the single constituent – sulphur.

2. A mixture of ethanol and water is an example of a two component

system. We need both ethanol and water to express its
composition.
 An example of a system in which a reaction occurs and an equilibrium is established is the
thermal decomposition of solid CaCO3.

In this system, there are three distinct phases:

 Solid CaCO3
 Solid CaO
 Gaseous CO2

Though there are 3 species present, the number of components is only two, because of the
equilibrium:
 CaCO3 (s)  CaO(s) + CO2(g)

 Any two of the three constituents may be chosen as the components.

 If CaO and CO2 are chosen, then the composition of the phase CaCO3 is expressed as one mole of
component CO2 plus one mole of component CaO.

 If, on the other hand, CaCO3 and CO2 were chosen, then the composition of the phase CaO would
be described as one mole of CaCO3 minus one mole of CO2.
 Degrees of freedom (or variance)
 The degrees of freedom or variance of a system is defined as the
minimum number of variables such as:
temperature
pressure
concentration
which must be fixed in order to define the system completely.

F=CP+2
• Examples
1. A gaseous mixture of CO2 and N2.
Three variables: pressure, temperature and composition are required to define this system.
This is, hence, a trivariant system.

2. A system having only liquid water has two degrees of freedom or is bivariant. Both
temperature and pressure need to be mentioned in order to define the system.

3. If to the system containing liquid water, pieces of ice are added and this system with 2
phases is allowed to come to equilibrium, then it is an univariant system.

Only one variable, either temperature or pressure need to be specified in order to define
the system.
If the pressure on the system is maintained at 1 atm, then the temperature of the system
gets automatically fixed at 0oC, the normal melting point of ice.
 Phase Equilibria & The Phase Rule
 A phase diagram (Equilibrium Phase Diagram) summarizes the
conditions at which a substance exists as a solid, liquid, or gas.

 OR : It is a “map” of the information about the control of phase

structure of a particular material system.

 The relationships between temperature and the compositions and

the quantities of phases present at equilibrium are represented.
 The phase rule
 J.W. Gibbs formulated the phase rule, which is a general relation
between the variance, F, the number of component, C, and the
number of phases P, at equilibrium , for a system of any
composition:

 For a system in equilibrium The phase rule F=CP+2

 F : degree of freedom, the least number of intensive variable that

must be fixed (known) to describe the system completely
 Phase Rule relation to determine the least number of intensive
variable, that can be changed without changing the equilibrium state
of the system, or, alternately,
The least number required to define the state of the system, which is
called degree of freedom F.

 Intensive variable independent variable that do not depend on the

volume or the size, e.g.Temp., pressure
 Phase Equilibria & The Phase Rule
Components of a system

 Independent chemical species which comprise the system:

These could be: Elements, Ions, Compounds
E.g. Au-Cu system : Components → Au, Cu
Ice-water system : Component → H2O
Al2O3 – Cr2O3 system : Components → Al2O3, Cr2O3

 Component the smallest number of constituent by which the composition

of each phase in the system at equilibrium can be expressed in form of
chemical formula or equation
 The number of phases in a system is denoted P

(a)A gas, or a gaseous mixture is a single phase. P=1

(b) For a solid system, an alloy of two metals is a two-phase system (P=2) if the metals
are immiscible, but a single-phase system (P=1) if they are miscible---a homogeneous
mixture of the two substances---is uniform on a molecular scale.

(c) For a liquid system, according to the solubility to decide whether a system consists of
one phase or of two.
For example, a solution of sodium chloride in water is a single phase.
A pair of liquids that are partially miscible or immiscible is a two-phase system(P=2)
Oil in water
 A way of understanding the Gibbs Phase Rule:
The degrees of freedom can be thought of as the difference between what you (can) control and
what the system controls

F = C+2  P

Degrees of Freedom = What you can control  What the system controls

Can control the no. of System decided how many

components added and P & T phases to produce given the
conditions
 F : degree of freedom, the least number of intensive variable that must be fixed
(known) to describe the system completely
 Degree of freedom (or variance) F is the number of variables (T, p, and/or
composition) that can be changed independently without changing the phases of
the system

a) At the triple point: b) liquid-solid curve

P = 3 (solid, liquid, and gas) P=2
C= 1 (water) 2+F = 1 + 2
P+F=C+2 F= 1
F = 0 (no degree of freedom) One variable (T or P) can be changed

c) Liquid
P =1
So F =2
Two variables (T and P) can be varied independently
and the system will remains a single phase
 One-component systems
Curve O-A Phase diagram of water
Vaporization
Condensation Critical point
218
Curve O -B
Melting

P (atm)
1
Freezing

Curve O -C 0.006
Sublimation

Deposition

O--Triple point =0 =100

374
F=CP+2
F=CP+2
Phase Diagram of Carbon Dioxide
 Condensed system: System in which the vapor phase is ignored and only
the solid and/or liquid phases are considered.

Two component system

 For two component system F can be 3, (3D model is needed), e.g. T, p and
concentration , usually we fix p = 1atm , the vapor phase is neglected, and F
is reduced to 2

 For three component system the pressure and temperature are fixed
Phenol water phase diagram
 Two component system containing liquid phase

 Tie Line : bc line: The line at which the system at

equilibrium will separate into phases of constant
composition, termed ‘conjugate phases’

 Lever Rule: a way to calculate the proportions of each

phase present on a phase diagram in a two phase field
(at a given temperature and composition).

e.g. for point d (24%)

 e.g. for point d (24%)

For every 10 g of liquid system 7.5 g phase A

in equilibrium in point d 2.5 g phase B water rich phase
contains water+ phenol(11%)
Example:
Mixed 24g phenol +76g water , T 50°C,
equilibrium
75 g phase A 25 g phase B Phenol rich phase
contains Phenol (63%)+ water
11% phenol 63 % phenol

0.11× 75 g=8.25 g 0.63× 25 g=15.75 g

phenol phenol
 The Critical Solution Temperature: CST
 Is the maximum temperature at which
the 2-phase region exists (or upper
consolute temperature).

 In the case of the phenol-water system,

this is 66.8oC (point h)

 All combinations of phenol and water >

CST are completely miscible and yield 1-
phase liquid systems.
 Systems Showing a Decrease in Miscibility with
Rise in Temperature

 A few mixtures, exhibit a lower critical

solution temperature (low CST), e.g.
triethylamine plus water. The miscibility
with in temperature.
 Systems Showing Upper and Lower CSTs
The miscibility with temp.

a certain temperature miscibility

starts to again with further in
temperature.

Closed-phase diagram, i.e.

nicotine-water system.
Two component system containing solid
and liquid phase (Eutectic Mixtures)

A :salol B: thymol

53%
A :salol B: thymol
 Eutectic mixture : Pharmaceutical Application

 EMLA® (lidocaine 2.5% and prilocaine 2.5%) Cream

 EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is an emulsion in which the oil
phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight.
This eutectic mixture has a melting point below room temperature and therefore
both local anesthetics exist as a liquid oil rather than as crystals
Three component system
Triangular Diagrams for three – component
systems
Birzeit University Physical Pharmacy PHAR 323 Dr. Hani
Shtaya
 Topics that we have covered:
1. Binding Forces Between Molecules
2. Repulsive and Attractive Forces
3. The Gaseous State
 The Ideal Gas Law
 Liquefaction of Gases
 Aerosols
4. Solids and the Crystalline State
 Crystalline Solids
 Polymorphism
 Solvates
 Amorphous Solids
5. Phase Equilibria and the Phase Rule
 Phase Rule
 Systems Containing One Component
 Condensed System
 Two-Component Systems Containing Liquid Phases
 Two-Component Systems Containing Solid and Liquid Phases : Eutectic Mixtures
 Rules Relating to Triangular Diagrams