PHYSICOCHEMICAL PROPERTIES OF
DRUG MOLECULES
By
Dr. S. Adebayo
Monday, April 13,
2015
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Polymorphism
 A function of internal
arrangement/structure of crystalline
solids
 Polymorphic substances exist in more
than one packing arrangement
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 McCrone’s Law states that every
compound has different polymorphic
forms, and that, in general,the
number of forms known for a given
compound is proportional to the time
and money spent in research on that
compound.
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Polymorphism
 Occurrence of more than one morphic
form
 Monotropic
 Enantiotropic
 Amorphism
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Crystal habit
 The outward appearance of a crystal
 Independent of morphic forms
 Can be defined on the basis of variations on
the themes of 7 systems:
 Cubic, tetragonal, orthorhombic, monoclinic,
riclinic, trigonal, hexagonal
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Angles & lengths that describe
crystal habits
Crystal
Angle of axes
Length of axes
Examples
Cubic (regular)
α = β = γ = 90º
x =y =z
NaCl
Tetragonal
α = β = γ = 90º
x =y ≠z
NiSO4
Orthorhombic
α = β = γ = 90º
x ≠y ≠z
K2MNO4
Monoclinic
α = β = γ ≠ 90º
x ≠y ≠z
Sucrose
Triclinic (asymmetric)
α ≠β ≠ γ ≠ 90º
x ≠y ≠z
CuSO4
Trigonal (rhombohedral)
α = β = γ ≠90º
x =y =z
NaNO3
Hexagonal
Z at 90º to base
-
AgNO3
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Vector illustration of Angles and lengths of
axes that describe crystal habits
z
x
α = between length & breadth
y
β = between breadth & height
γ = between length & height
Crystal Systems
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Crystal Morphology & Habit
Monoclinic
simple
monoclinic
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centered
monoclinic
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Rhombohedral
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Tetragonal (Wulfenite)
simple tetragonal
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body-centered
tetragonal
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Tetragonal
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Orthorhombic xtals
basesimple
centered body-centered face-centered
orthorhombic orthorh orthorhombic orthorhombic
ombic
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Orthorhombic (Danburite)
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Granular e.g. Tungstate (CaWO4)
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Acicular
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Monoclinic (Realgar)
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Hexahedral (Vanadinite)
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SEM OF BREADFRUIT & CORN STARCH
POWDERS (Adebayo & Itiola, 2005; 2008)
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Scanning Electron micrographs of (A) Bitter yam, (B)
Chinese yam, (C) Round leaf yellow yam, (D) Sweet yam
and (E) Negro yam (Riley, Adebayo et al (2008)
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Crystal habit and drug
properties
 Changes in crystal habit can
influence:
 dissolution rate,
 powder flow
 compressibility.
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 can have
significant effect on
processability and
use of dosage
forms.
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Crystal habit and drug
properties …
 Effect on dissolution rate can be explained
by the changes in surface to volume ratio
 Transition from regular to acicular
(‘needle’) shape crystals (e.g. aspirin) may
be reflected as poor flow property.
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Origin of Crystal Habit
 Habit is determined by the rate of growth of
different faces of a crystal.

Hence, it can be altered by changes in
crystallization process.
 Generally, the fastest growing faces tend to grow
out of existence:

Will be the smallest faces on the final crystal

the slowest growing faces will dominate the final structure.
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Origin of Crystal Habit …
 Solvent of crystallization –
 crystallizing solvent may
preferentially favour
interaction with different
faces and consequently alter
the crystal habit.
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Origin/changes in crystal habit
 The presence of impurities - may be caused by:
 impurities
 breakdown products
 synthetic
mixture
precursors
in
the
crystallization
 a deliberate addition of impurities (e.g. SAAs)
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(Fairbrather, J. E. & Grant, JWD,
1974, JPP 30: 19p & JPP 31: 27p)
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Crystal Defects
 Imperfections due to point defects or
dislocations during packing of lattice
 Due to addition or accidental presence of
low conc. of impurities
 Can cause major changes in:




Ease of processing
Chemical reactivity
Dissolution
Bioavailability
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Obtaining the right habit
 The preformulation scientist should
consider the optimum form of habit
 Possibly influence crystallization
procedures to ensure optimum
properties are not serendipitous
but rather a result of crystal
engineering.
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Characterization of crystal
habits
 Crystal habit & morphology can best
be studied by microscopic techniques.
 Standard light microscopes fitted with
polarizing filters and phase contrast
facilities can allow easy examination
of crystals and quantification of habit
and size.
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Characterization of crystal
habits…
 Studies on crystal properties generally involve standard
tests such as:
 melting point to indicate crystal purity and crystal
form
 thermal analysis.
 Crystal habit can be deduced from photomicrography
 For photomicrography, image may be enhanced
by using polarized light.
 Scanning electron micrography.
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Optical isomers
 Preferred isomer should be identified
 Any other isomers are regarded as
impurities
 Column based systems now available
for determination
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Setting acceptance criteria for drug
substance & drug products
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Concepts/Terminologies Relating to
Crystalline Phenomenon – Familiarize
yourself with them
Rate of crystallization
Polymorphism"
Rate of transition
Crystal habit
Crystal growth
Crystal morphology
Crystal structure
determination
 Interplanar spacing
 Association in the solid
state
 Solid state structure
properties







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 Melting pressure
 Freezing point
 Glass transition
temperature
 Phase diagram
 Long spacing
 Reorientation in the solid
state
 Spin polarization
 Nuclear spin conversion
 Structure of the solid
 Dimensions of the unit
cell
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Polymorphism in
pharmaceuticals
 Polymorphism is important in the
development of pharmaceutical
ingredients.
 Many drugs are regulatory approved
based on a single crystal form or
polymorph.
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Crystal Properties and
Solubility
 Majority of substances are crystalline in nature: their
molecules are packed in an ordered and reproducible
manner.
 Excipients also vary from crystalline material to
armophous polymers.
 Very few samples are, however, entirely
homogenous:
 drugs will at least be partially armophous
 polymers will be partially crystalline.
 The extent of crystallinity will affect their physical
properties to a significant extent.
Polymorphism and Solubility
 BP 2001 defines polymorphism as the
occurrence of more than one morphic
forms.
 It is a function of the internal
arrangement/structure of crystalline
solids.
 A polymorphic substance therefore exists
in more than one packing arrangement.
Types of polymorphism
 Two types of polymorphism have been
identified:
 Monotropic polymorphism – Those for which
only one form is stable, irrespective of
temperature and pressure and the metastable
form would revert to the stable form with time.
 Enatiotropic polymorphism – Different forms are
stable under different external conditions:
 change in temperature and pressure determine
the form that is stable (Lund, 1994).
Monotropic polymorphs
 Different monotropic polymorphs
 often have different melting points with the
most stable form having the highest melting
point.
 They also exhibit different x-ray diffraction
patterns and IR spectra and dissolution rate.
 In some cases, these differences in properties
may affect the –
 handling characteristics of the material,
 the stability of formulated preparations
 bioavailability.
Occurence
 Occurrence of polymorphism can not be
predicted because it can be induced in many
materials at appropriate conditions.
 Moreover, its absence is difficult to
demonstrate by a single specific test.
 The metastable forms usually have:
 faster dissolution rate
 apparently greater equilibrium solubility
 considerably greater bioavailability.
Polymorphic transition
 Metastable form is not stable and will revert
to the stable form.
 Transition in polymorphic form can be
gradual and time-dependent and can be
accelerated by increase in temperature,
humidity or energetic treatment as in
processing of powder.
 Therefore, unit processes such as mixing,
milling and tabletting can induce changes in
crystal type and, hence, change the physical
and potential biopharmaceutical properties
of the drug.
Need for control of morphic forms
 Necessary during processing of –
 active ingredients
 excipients
 during production of formulated products
 to ensure the correct physical and
biopharmaceutical characteristics of the
product.
Control of morphic forms ..
 Great care is needed to determine –
 which polymorph is present,
 under what condition
 how long it will be stable.
 A useful stress test for a drug substance is to –
 ball-mill it for a defined time
 check for any change in polymorphic form
through DSC analysis.
Armophism
 Like polymorphism, transition from
armophous to crystalline forms and vice
versa may have significant effect on
dissolution.
 Solubility of armophous drugs can be
higher than that of crystalline form by a
factor of 10s or 100s.
Hancock & Parkes (2000) – Pharm. Res. 17: 397
– 404
Pseudopolymorphism
 Caused by changes in crystallization process which
results in inclusion of solvent molecules in the crystal
thereby producing solvates or hydrates.

The crystals differ in properties from the non-solvated sample
just like the different polymorphic forms.
 referred to as ‘Pseudopolymorphs’
 Different solvates of the same drug can produce different
blood concentrations from administered solid oral dosage
form.
 Unlike polymorphs in which morphic forms with the
lowest melting point usually produce the highest blood
concentration,

solvates or anhydrous forms may produce higher
concentrations depending on the particular drug.
Types of Polymorphism
 Packing polymorphism - polymorphism existing as
a result of difference in crystal packing
 An example of an organic polymorph is glycine which
is able to form monoclinic and hexagonal crystals.
 Conformational polymorphism - Polymorphism
resulting from the existence of different conformers of
the same molecule
 Pseudopolymorphism - the different crystal types
are the result of hydration or solvation.
Polymorphism in
pharmaceuticals Case Studies
 GlaxoSmithKline defended its patent
for the polymorph type II of
Ranitidine (Zantac).
 For Medicine administered orally as a
crystalline solid, dissolution rates
depend on the exact crystal form of a
polymorph.
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Polymorphism in
pharmaceuticals ….
 Polymorphism is not always well
understood.
 In 2006 a new crystal form was discovered of maleic
acid 124 years after the first crystal structure
determination
 Maleic acid is a chemical manufactured on a
very large scale in the chemical industry and is
a salt forming component of drug molecules.
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Polymorphism in
pharmaceuticals ….
 The new crystal type is produced when a caffeine maleic acid co-crystal (2:1) is dissolved in
chloroform and the solvent is allowed to evaporate
slowly.

Both polymorphs consist of sheets of molecules connected
through hydrogen bonding of the carboxylic acid groups
 in form I the sheets alternate with respect of the net
dipole moment
 in form II the sheets are oriented in the same direction.
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Polymorphism in
pharmaceuticals ….
 Polymorphism is also established for
aspirin
 A new crystal type was found following
attempt to co-crystallization of aspirin and
levetiracetam from hot acetonitrile.
 Form II is only stable at 100 K and reverts to
from I at ambient temperature.
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Polymorphism in
pharmaceuticals ….
 In form I two salicyl molecules form
centrosymmetric dimers through the
acetyl groups with the (acidic) methyl
proton to carbonyl hydrogen bonds
 In the newly discovered form II each
salicyl molecule forms the same
hydrogen bonds but then with two
neighboring molecules instead of one.
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Polymorphism in
pharmaceuticals ….
 With respect to the hydrogen bonds
formed by the carboxylic acid
groups both polymorphs form
identical dimer structures.
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Disappearing Crystal Crystal
Polymorphs
 The drug Paroxetine was subject to
a law suit that hinged on such a pair
of identical polymorphs
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References

Florence, A. T. & Attwood, D. Physicochemical
principles of pharmacy, PhP London, 2006

Investigating the latent polymorphism of maleic acid
Graeme M. Day, Andrew V. Trask, W. D. Samuel
Motherwell and William Jones Chemical
Communications, 2006, (1), 54 - 56 DOI:
10.1039/b513442k

↑ The Predictably Elusive Form II of Aspirin Peddy
Vishweshwar, Jennifer A. McMahon, Mark Oliveira,
Matthew L. Peterson, and Michael J. Zaworotko J.
Am. Chem. Soc.; 2005; 127(48) pp 16802 - 16803;
(Communication) DOI: 10.1021/ja056455b
Physicochemical Properties of Drug
Molecules
THANK YOU FOR YOUR ATTENTION
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