Chapter 2
States of Matter
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
1
Contents
Binding forces between molecules
• Intramolecular forces
• Intermolecular forces
States of matter
• The liquid state
• Solids and the crystalline state
• The liquid crystalline state
• The supercriticial fluid state
• Phase equilibria & the phase rule
2
Binding forces between molecules
Intramolecular forces
Intermolecular forces
Binding forces
4


Intramolecular forces

Ionic bonds

Covalent bonds

Polar covalent bonds
Intermolecular forces

Van der Waals forces

Ion-dipole & Ion-induced dipole Forces

Hydrogen bonds
Cohesion
Adhesion
Repulsive & attractive energies
5
Fig. 2-1
Chemical bonds
6

Ionic bonds

Covalent bonds

Polar covalent bonds
Van der Waals forces
7
Neutral Molecule
Induced-Dipole
London
Induced-Dipole
Dipole
Keesome
Dipole
Induced-Dipole
Debye
Dipole
Ion-dipole & ion-induced dipole forces
8
Na+
Dipole
Cl-
Dipole
Na+
Induced-Dipole
Hydrogen bonds
9
Fig. 2-4
States of matter
The liquid state
The liquid state
11

Liquefaction of gases

Critical Temperature


Above this temperature, a liquid can no longer exist.
Critical Pressure

The pressure required to liquefy a gas at its critical temperature

Ex) H2O (647 K, 218 atm)
He (5.2 K, 2.26 atm)
Aerosols
12
1 atm
1 - 6 atm
Drug + Propellant
Vapor pressure of liquids
13
V.P. vs. Temp.
Fig. 2-5
Clausius-Clapeyron equation
14

The relationship between the vapor pressure and the
absolute temperature of a liquid
P1 H v (T2  T1 )
log 
P2 2.303RT1T2
∆𝐻𝑣 1
ln 𝑃 = −
+ 𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡
𝑅 𝑇
Eqn 2-15
Eqn 2-16a
H: Heat of vaporization
States of matter
Solids & the crystalline state
Crystal systems
16

Cubic (NaCl)
입(등)방정계

Tetragonal (Urea)
정방정계

Hexagonal (Iodoform)
육방정계

Rhombic (Iodine)
사방정계

Monoclinic (Sucrose)
단사정계

Triclinic (Boric acid)
삼사정계
* Fast track – Physical Pharmacy
Alexander T Florence and David Attwood
Crystal structures
17

Ionic & atomic crystal


Molecular crystal


Hard, brittle and high m.p.
Soft and low m.p.
Metallic crystal
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Polymorphism (다형)
18
• Polymorphic
Some elemental substances exist in more than one crystalline form

Formulation of polymorphs

Nature of solvent

Difference of
physicochemical properties

Crystal shape

Optical property

Temperature

Rate of cooling

Heating

Solubility

Boling

Dissolution rate

Solid state stability

Van der Waals forces

Hydrogen bonds
Psudopolymorphs (solvates)
Polymorphism
19

Spiperone

2 polymorphs
Dimer (molecules in pairs)
Nondimerized molecules
X-ray powder diffraction pattern
20
Form I
Form II
Losartan
고혈압치료제(MSD 코자)
Polymorphism
21

Theobroma oil (cacao butter)

4 polymorphism forms (Polymorphs)
α - form
γ - form
15
β - form
β' - form
20
25
30
Melting point, ºC
35
40

γ - form – melting at 18 ºC, unstable

α - form – melting at 22 ºC , unstable

β' - form – melting at 28 ºC , unstable

β - form – melting at 34.5 ºC, stable  Used for stable suppository
Polymorphism
22
Enantiotropic polymorphism
• The change from one form to another is reversible.
Metastable form
Stable form
Monotropic polymorphism
• The transition takes place in one direction only.
Metastable form
Stable form
Amorphous solids
23
Def) Amorphous solids may be considered as supercooled
liquids in which the molecules are arranged in a
random manner somewhat as in the liquid state.
Crystals (except cubic crystals)
• Anisotropic – show different characteristics in
various directions along the crystal
Amorphous solids (+ cubic crystals)
• Isotropic – exhibit similar properties in all directions
Amorphous solids
24


Differ from crystalline solids

Tend to flow when subjected to sufficient pressure

Do not have definite melting point
Ex) Novobiocin acid

Crystalline form : poorly absorbed
 No activity

Amorphous form : readily absorbed
 Therapeutically active
Amorphous form: prompt action
Crystalline form: long action
Insulin zinc suspension(Lente)
AF:CF=30:70 24h effect
Insulin formulation
X-ray diffraction
25

Laue or Transmission method

Bragg or Reflection method
Boiling point & Melting point
26
짝수
홀수
Fig. 2-14


Van der Waals forces
Hydrogen bonds
States of matter
The liquid crystalline state
Liquid crystals
28

State of matter that have properties between those of a
conventional liquid and those of a solid crystal
Thermotropic liquid crystal
• Phase transition into liquid crystal phase as
temperature is changed.
Lyotropic liquid crystal
• Phase transition as a function of both temperature
and concentration
Thermotropic liquid crystals
29

Produced when certain substances are heated

Three types of thermotropic liquid crystals
Nematic (thread-like) liquid crystals


Orientate with long axes parallel, but not ordered into layers

Mobile and orientated by electric or magnetic fields
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
Thermotropic liquid crystals
30
2. Smectic (soap-like) liquid crystals

Arrange with long axes parallel, also arranged into layers

Viscous and not oriented by magnetic fields
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
Thermotropic liquid crystals
31
3. Cholesteric (chiral nematic) liquid crystals

Formed by several cholesteryl esters

Stack of very thin two-dimensional nematic-like layers
Nematic-like layer
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
Thermotropic liquid crystals
32
Smectic Liquid Crystals
Nematic Liquid Crystals
Cholesteric Liquid Crystals
Lyotropic liquid crystals
33


The liquid crystalline phases that occur on increasing the
concentration of surfactant solutions
As increase of concentration of surfactant

Spherical micelle  elongated or rod like micelle
 hexagonal phase (middle phase)
 cubic phase (with some surfactants)
 neat phase (lamellar phase)
* Physiochemical Principles of Pharmacy 4th edition
Alexander T Florence and David Attwood
States of matter
The supercritical fluid state
Supercritical fluid
35

Intermediate between those of liquids and gases
Gas-like property
• Better ability to permeate solid substances
Liquid-like property
• High densities that can be regulated by pressure

Pressure↑
 Density of the gas↑, Ability to dissolve compounds↑
Supercritical fluid
36
Fig. 2-16
Supercritical fluid
37

Pharmaceutical applications

Extraction

Crystallization

Preparation of formulations

Preparation of polymer mixtures

Formulation of micro- and nanoparticles
Example
38

Decaffeination of coffee

Traditionally, solvents like methylene chloride have been used.
 Expensive, toxic

Utilization of supercritical CO2
 Reduced cost and toxicity

Adding water to supercritical CO2  Reduced the loss of the flavor
Supercritical fluid
39
Fig. 2-17
States of matter
Phase equilibria & the phase rule
The phase rule
(계를 완전히 설명하기 위하여 고정해야 하는 변수들의 최소한 자유도의 수)
41
𝐹 =𝐶−𝑃+2

F is the number of degrees of freedom in the system

C is the number of components

P is the number of phases present
Phase diagram for water
42
Fig. 2-22
Condensed systems
43

Systems in which the vapor phase is ignored and only
solid and/or liquid phases are considered are termed
condensed systems
Two component systems containing
liquid phases I
44
Water vs.
Phenol
Upper Consolute
Temperature
Fig. 2-23
Two component systems containing
liquid phases II
45
Water vs Triethylamine
Fig. 2-24
Water vs Nicotine
Fig. 2-25
Two component systems containing solid &
liquid phases: Eutectic mixtures
46

Eutectic mixture

A mixture of chemical compounds has a single chemical
composition that solidifies at a lower temperature than any
other composition.

Eutectic point

The component ratio that
exhibits the lowest observed
melting point
Typical phase diagram of eutectic mixture
Two component systems containing
solid & liquid phases
47
Fig. 2-26
Eutectic mixtures
48

Eutectic Mixture of Local Anesthetics (EMLA)

The eutectic system of Lidocaine / Prilocaine

Eutectic point – 1:1 mixture

Eutectic temperature – 18 ºC

A mixed local anesthetic that can be used for topical application
EMLA Cream (AstraZeneca)
Menthol + Testosterone
Solid dispersion
49

Definition

The dispersion of one or more active ingredients in an inert
carrier or matrix at solid state
Solid dispersion type
Matrix
Drug
*
**
I
Eutectics
C
C
II
Amorphous precipitations in
crystalline matrix
C
A
III
Solid solutions
C
M
I
V
Glass suspension
A
C
V
Glass suspension
A
A
V
I
Glass solution
A
M
* A: matrix in the amorphous state, C: matrix in the crystalline state
** A: drug dispersed as amorphous clusters in the matrix, C: drug dispersed as crystalline particles in the matrix,
M : drug molecularly dispersed throughout the matrix
Solid dispersion
50

Solid solution

Each solid phase contains both components

A solid solute is dissolved in a solid solvent

Higher, lower, or unchanged melting behavior depending
upon the degree of interaction between components

Mixed amorphous or glass solutions

Molecular dispersion of one component in another where
the overall solid is amorphous

Exhibit an intermediate glass transition temperature
Solid dispersion
51

Advantages




Reduction of particle size
Increased wettability of the material
Reduced aggregation and agglomeration
Increase in solubility of the drug
 Facilitating the dissolution and
the bioavailability of poorly
soluble drugs
Rate of solution of griseofulvin solid solutions,
eutectic and crystalline material
Phase equilibria in threecomponent systems
52
𝐹 =𝐶−𝑃+2


𝐹 =3−1+2=4
Condensed system & constant temperature
 𝑭=𝟐
Triangular diagrams
53
Fig. 2-27
Triangular diagram of microemulsion
54
Partially Miscible Liquids
55
Fig. 2-28
Solvent effects
Fig. 2-29
Temperature effects