In this slide, you will learn about what is polymorphism, types, and properties of polymorphism, the application of polymorphism in pharmaceutical industries, polymorphism of several drugs. Hope you will like it.

1. Presentation on
POLYMORPHISM
Submitted to:
Dr.Mohammad Hossain Shariare
Associate Professor
Department of Pharmaceutical Sciences
North South University
Submitted By:
Name ID
Md. Muhib Islam Sarkar 1821381649
Israt Jahan 1821408649
Afsana Akter 1821414049
Sadia Haque Shoily 1821099649
S.M.M. Sharif Nowaz Antu 1821420049

6. ENANTIOTROPY
 1.Reversible phase
transition
 2.Metastable to stable
 3.Lower melting point
has lower heat of fusion
MONOTROPY
1. Irreversible phase
transition
2. metastable to stable
3.Higher melting point has
higher heat of fusion

7. 4.Lower melting form is
thermodynamically stable below
the transition tempareture and high
m.p From is stable above the
transition tempareture
4.Higher melting form is always
thermodynamically stable form

8. Properties of polymorphs
Packing
properties
Thermodynamic
properties Kinetic
properties
Spectroscopic
properties
Surface
properties
Mechanical
properties

9. Stability characteristics of polymorph
 Depending upon relative stability there
are two forms of polymorph-
1)Stable form Less aqueous
solibility
2)Meta stable form High aqueous
solubility

10. STRUCTURAL APPREANCE OF
POLYMORPHISM
 Polymorphs can exist in different crystalline shape.

11. STRUCTURAL APPREANCE OF
POLYMORPHISM
 Different crystal forms of polymorphs of a
particular substance exhibit significance
differences in physical properties and chemical
reactivities.
 Exhibit difference in stabilities.

12. STRUCTURAL APPREANCE OF
POLYMORPHISM
 Paracetamol is known to have three
polymorphs.
Stable Form
1
Monoclinic
Meta stable form
2
Unstable form 3
Orthorhombic

13. Method to identify
polymorphism
:Optical crystallography
• Use in the identification of polymorphs crystal esist in
isotropic and anisotropic form
• Isotropic examine the velocity of light is same in all
direction.
• Anisotropic crystal have 2 or 3 different light
velocities or refractive index.
• Video recording system and polarizing microscope
filted during according to heating and cooling stage for
investigating polymorph.

14. X ray diffraction method
• It provide the most complete information about solid state.
• By this method one can identify the unit cell dimension &provide
specific differences between crystalline forms of given compound.
• In an X-ray diffraction measurement a crystal is mounted on a
goniometer and gradually rotated while being bombarded with X-ray
producing a diffraction pattern of regularly spaced sports known as
reflections.
• It is tedious time consuming so it is not used or unsuitable for
routine use.
• This method is based on the scattering of X-ray by crystals

15. Hot stage microscopy: Using this technique fluid phase
transformation as a function of temperature is observed. Generally
silicon oil hot stage microscopy is used for detection of pseudo
polymorphs.
NMR technique: In this technique, powder sample must be
rotated at a special angle with respect to magnetic field.

16. FTIR technique : It has been used to quantify binary mixtures of
polymorphs. In identification of polymorphs , only solid
samples (as mineral oil mulls & KBr pellets) can be used .
• In solutions polymorphs of a compound have identical spectra .
• Advantages: - Rapid.
• Technique is qualitative & quantitative.
• Dilatometry: Measure change in volume caused by thermal or chemical
effect.Using dilatometry the melting behaviour of Theobroma Oil
was studied .Extremely accurate but tedious , time consuming and
not widely used .

17. • Microcalorimetry: Used to characterize thermodynamic properties of
different molecules.
•
Thermal methods: a}DSC[Differential scanning calorimetry]
b}DTA[Differential thermal analysis]c} TGA [thermal gravimetric
analysis]
This method measures heat loss or gain from physical or chemical
chages occurring in sample which is recorded as a function of
temperature as substance is heated at uniform scale.
Advantage:
• I Thermodynamic parameter can be evaluated.
• II Heat of Transition from one polymorph to the other
Ref:https://www.slideshare.net/MahendraMahi28/polymorphism-142600438

18. Application of polymorphism
in pharmaceutical industry
To avoid manufacturing problem
For improvement of therapeutic activity of drug
To prevent loss of raw material
For better bioavailability of drug

19. Manufacturing
Problem
The knowledge of solid state properties in an early stage of
development helps to avoid manufacturing problems, to
fine the tune the performance of drugs and provides space
for innovations.
E.g.-Famotidine which is an excellent
histamine
H2 receptor antagonist is also found to exist in two
different polymorphic forms-
1.Metastable polymorph B
2.Stable polymorph A

20. Suspension
In preparation of suspension use of a wrong polymorph of a drug, a phase
conversion from the metastable to stable polymorph may occur. This result
in crystal growth and caking of suspension.
E.g.- cortisone acetate was one of the most difficult polymorphic
problems to solve.

21. Creams
When creams are prepared with the active ingredient
suspended in the cream base, use of the wrong polymorph
can result in a phase inversion to a more stable phase. As a
consequence, crystal growth can occur in the vehicle
yielding gritty, cosmetically unacceptable creams or
products in which the active ingredient is unevenly
distributed.

22. Solution
Flynn has reported some problem in the formulation of a
parenteral solution of a drug. In this instance,
determination of the water solubility of the compound
indicated the drug to be adequately soluble for the
concentration required in the formulation. Stability studies
on the formulation quickly turned up the presence of
precipitate.

23. Suppositories
The polymorphic changes of a suppository base could result
in a product that undergoes a change in its melting
characteristics. If the suppository base is of the type that
depends on melting at body temperatures to release the
active components of the formulations a relatively small
change in its melting point could have severe
consequences.

24. Polymorphism and Generically
Equivalent Dosage Forms
If the rate of absorption of the active ingredient in an oral
preparation is dissolution-rate dependent, the use of a
compound exhibiting polymorphism may lead to good or
bad consequences. The successful utilization of a
polymorph of significantly greater thermodynamic activity
(solubility) than the stable modification may provide, in
some instances, therapeutic blood levels from otherwise
inactive drugs.

25. Polymorphism of several drug
Drug Substance Polymorphism Aspect Bioavailability Issues in human
body
Ritonavir 1.Antiretroviral drug belonging to
protease inhibitor class and used
to treat HIV-1 infection
2.Exhibits conformational
polymorphism
Having total 5 forms
2 years after the launch of first
ritonavir product, several batches
failed dissoulation specifications
because the presence of a
different polymorphic form having
50% lower intrinsic solubility of
reference form
Oxytetracycline 1.It is a broad spectrum antibiotic
2.Exist in 2 different forms
1. Oxytetracycline showed
differences in patients' blood
levels
2. Differences in in vitro
dissolution of tablets

26. Continue….
Drug Substance Polymorphism Aspect Bioavailability Issues in human
body
Axitinib 1.It is a tyrosine kinase inhibitor
of endothelial growth factor of
tumor thus prevents growth of
cancer
2.60 solvates and 5 anhydrous
forms were discovered
1.The commercial formulation
under trade name INLYTA which
contains the stable anhydrous
form
Atrovastatin Calcium 1.Inhibitor of 3-hydroxyl-3-
methylglutaryl-coenzyme A
reductase
2.Strong ability to lowering blood
cholesterol
1.Ustable
2.The hydroxyl acid form is
converted to lactone form that is
15 times less soluble than the
hydroxyl form
3.After oral administration, the
absolute bioavailability of
atorvastatin is only 14%
Chloramphenicol Palmitate 1.It is a prodrug of
chloramphenicol with antibiotic
properties
2.Exibits 3 forms: Stable,
Metastable, Unstable
1.Metastable form dissolves faster
than stable form
2.Low serum levels for the stable
polymorph were observed.
Ref.:www.semanticscholar.org

27. Structure of some drug substances:
Ritonavir Oxytetracyclin Axitinib
Atrovastatin Calcium
Chloramphenicol
Palmitate

28. Regulatory consideration
 A sponsor of an Abbreviated New Drug Application (ANDA) must have
information in the context of generic product and innovator product
equivalency.
 Three decision trees for solid oral dosage forms or liquid suspensions are
provided for evaluating when and how polymorphs of drug substances should be
monitored and controlled in ANDA submissions.
 Case studies from ANDAs are provided which demonstrate the irrelevance of
polymorphism to the determination of drug substance “sameness”.
 In case of approval a new drug,US FDA states appropriate analytical procedures.
(Ref.:sciencedirect.com)

29. Conclusion
 Polymorphism have such serious consequences for the bioavailability of drugs
with low aqueous solubility
 polymorphic forms of a drug differ in the physicochemical properties
 To check purity/integrity of the API
 maintain the potency
 huge scope for further research
 Difference in the solubility and melting point
 Metastable form may lead to preferential choice of a polymorph other than
stable form

30. References
 Polymorph Impact on the Bioavailability and Stability of Poorly Soluble
Drugs:Roberta Censi, Piera Di Martino
https://www.sciencedirect.com/science/article/abs/pii/S0169409X03002
242
Wikipedia
https://www.semanticscholar.org/paper/Polymorph-Impact-on-the-
Bioavailability-and-of-Censi-
Martino/45efb7ee5d2393679561197104856379c075fa29