physicochemical_properties_of_drug_molecules

1. PHYSICOCHEMICAL PROPERTIES OF DRUG
MOLECULES
1

2. Polymorphism
A function of internal arrangement/structure of crystalline solids
◦ Polymorphic substances exist in more than one packing arrangement
Wednesday, March 1
2, 2025
2

3. Wednesday, March 1
2, 2025
3
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.

4. Polymorphism
Occurrence of more than one morphic form
◦ Monotropic
◦ Enantiotropic
◦ Amorphism
Wednesday, March 1
2, 2025
4

5. 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
Wednesday, March 1
2, 2025
5

6. Angles & lengths that describe crystal
habits
Wednesday, March 1
2, 2025
6
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 K2
MNO4
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

7. Vector illustration of Angles and lengths of axes
that describe crystal habits
z
x
y
α = between length & breadth
β = between breadth & height
γ = between length & height

8. Crystal Systems
Wednesday, March 1
2, 2025
8

9. Crystal Morphology & Habit

10. Monoclinic
Wednesday, March 1
2, 2025
10
simple
monoclinic
centered
monoclinic

11. Rhombohedral
Wednesday, March 1
2, 2025
11

12. Tetragonal (Wulfenite)
Wednesday, March 1
2, 2025
12
simple tetragonal
body-centered
tetragonal

13. Tetragonal
Wednesday, March 1
2, 2025
13

14. Orthorhombic xtals
Wednesday, March 1
2, 2025
14
simple
orthorhombic
base-
centered
orthorh
ombic
body-centered
orthorhombic
face-centered
orthorhombic

15. Orthorhombic (Danburite)
Wednesday, March 1
2, 2025
15

16. Granular e.g. Tungstate (CaWO4)
Wednesday, March 1
2, 2025
16

17. Acicular
Wednesday, March 1
2, 2025
17

18. Monoclinic (Realgar)
Wednesday, March 1
2, 2025
18

19. Hexahedral (Vanadinite)
Wednesday, March 1
2, 2025
19

20. Wednesday, March 12,
2025
20
SEM OF BREADFRUIT & CORN STARCH POWDERS
(Adebayo & Itiola, 2005; 2008)

21. 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)
Wednesday, March 1
2, 2025
21

22. Crystal habit and drug
properties
Changes in crystal habit can influence:
◦ dissolution rate,
◦ powder flow
◦ compressibility.
Wednesday, March 1
2, 2025
22
 can have significant effect on
processability and use of dosage
forms.

23. 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.
Wednesday, March 1
2, 2025
23

24. 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.
Wednesday, March 1
2, 2025
24

25. Origin of Crystal Habit …
Solvent of crystallization –
◦crystallizing solvent may preferentially
favour interaction with different faces
and consequently alter the crystal
habit.
Wednesday, March 1
2, 2025
25

26. Origin/changes in crystal
habit
The presence of impurities - may be caused by:
◦ impurities
◦ breakdown products
◦ synthetic precursors in the crystallization mixture
◦ a deliberate addition of impurities (e.g. SAAs)
Wednesday, March 1
2, 2025
(FAIRBRATHER, J. E. & GRANT, JWD, 1974,
JPP 30: 19P & JPP 31: 27P)
26

27. 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
Wednesday, March 1
2, 2025
27

28. 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.
Wednesday, March 1
2, 2025
28

29. 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.
Wednesday, March 1
2, 2025
29

30. 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.
Wednesday, March 1
2, 2025
30

31. Optical isomers
Preferred isomer should be identified
Any other isomers are regarded as impurities
Column based systems now available for determination
Wednesday, March 1
2, 2025
31

32. Setting acceptance criteria for drug
substance & drug products
Wednesday, March 1
2, 2025
32

33. 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
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
Wednesday, March 1
2, 2025
33

34. 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.
Wednesday, March 1
2, 2025
34

35. 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.

36. 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.

37. 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).

38. 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.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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

44. 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.

45. 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.

46. 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.
Wednesday, March 1
2, 2025
46

47. 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.
Wednesday, March 1
2, 2025
47

48. 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.
Wednesday, March 1
2, 2025
48

49. 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.
Wednesday, March 1
2, 2025
49

50. 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.
Wednesday, March 1
2, 2025
50

51. Polymorphism in pharmaceuticals ….
With respect to the hydrogen bonds formed by the carboxylic acid
groups both polymorphs form identical dimer structures.
Wednesday, March 1
2, 2025
51

52. Disappearing Crystal Crystal
Polymorphs
The drug Paroxetine was subject to a law suit that hinged on such a pair
of identical polymorphs
Wednesday, March 1
2, 2025
52

53. 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

54. Physicochemical Properties of Drug Molecules
Wednesday, March 1
2, 2025
54
THANK YOU FOR YOUR ATTENTION