States of Matter
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.
