Crystal Properties and Polymorphism.ppt

crystal properties and polymorphism

1. Crystal Properties & Polymorphism
Crystal habit & internal structure of a drug can affect bulk and
physicochemical properties ranging from flowability to stability.
Crystal Habit: The description of the outer appearance of the crystal.
Ex: Platy, Tubular, Needle, Prismatic, Bladed, Planar, Tabular, etc…
Internal Structure: Molecular arrangement within the solid.
A single internal structure of compound can have several different
habits depending on the environment of crystal growth.

2. Crystal Properties & Polymorphism
Internal Structure can be classified in several ways.
Chemical Compound
Habit Internal Structure
Crystalline Amorphous
Single CrystalPolymorph Molec. Adduct
Stio. Ch. MetricNon Stio. Ch. Metric
Layer CageChannel

3. Crystal Properties & Polymorphism
Crystalline Compound are characterized by repetitious spacing of
constituent atoms in three dimensional array.
Amorphous forms have atoms or molecules randomly placed as in
liquids.
Crystalline substances exists in any one of the three forms.
Non Stoichiometric adducts such as inclusion complexes or clathrates
involve entrapment of solvent molecules which are undesirable and
non reproducible
Stoichiometric adducts are commonly referred to as solvates. These
have incorporated a crystallizing solvent in its crystal lattice.
Ex: Hemi Hydrate, Mono, Di, Tri Hydrate, etc…

4. Crystal Properties & Polymorphism
Polymorphism is the ability of the compound to crystallize as more
than one distinct crystalline species with different internal lattice.
Many drugs show this property of polymorphism and these different
forms are called as Polymorphs.
A solid occasionally crystallizes entrapping solvent molecules in a
specific lattice position in a fixed stoichiometry resulting in a solvate
or pseudo polymorph.

5. Crystal Properties & Polymorphism
Many drugs can be prepared in a particular polymorphic form by
manipulation of conditions of crystallization like
•Nature of solvent
•Temperature
•Rate of Crystallization
•Rate of Cooling
Different polymorphic forms of a given solvent differs from each
other with respect to physical properties like
Density, Size, Shape, Compaction Behavior, Flow Properties,
Solubility and Dissolution.

6. Crystal Properties & Polymorphism
Polymorphism has a profound effect on the following properties of
drug molecule.
•Physical Stability
•Chemical Stability
•Tableting Behavior
•Dissolution and Bioavailability

7. Crystal Properties & Polymorphism
Physical Stability:
Drug substances exists in two or more polymorphic forms.
Only one form is thermodynamically stable at a given temp. & press.
Other forms would convert to the stable form with time.
This transformation is slow or rapid.
When the transition is slow it is called Meta Stable Form.

8. Crystal Properties & Polymorphism
In general stable polymorph exhibit highest melting point.
Polymorphic transformations can occur during
•Grinding
•Granulation
•Drying
•Compression
Ex: Digoxin, Spironolactone, Estradiol undergoes
polymorphic
changes during communation.
Phenyl Butazone undergoes polymorphic changes during
grinding and compression.

9. Crystal Properties & Polymorphism
Granulation entails the use of solvent which leads to the formation of
solvates and drying can lead to formation of amorphous compounds.
Ex: Calcium Pantothonate preferred form is crystalline but in the
preparation of multi vitamin tablets an amorphous form which
readily reverts to stable form when wetted with verity of solvents.

10. Crystal Properties & Polymorphism
Chemical Stability: Some of the drugs are prone to degradation in
solid state. The physical form of the drug influences rate of
degradation.
Ex: Aztreonam – Manobactum Antibiotic exists in to forms.
 - Needle like,  - Dense Crystalline form.
In presence of high humidity (75% RH)  form degrades by
hydrolysis of  lactum ring and half life is reduced to six months.
Where as  form is stable in the same condition up to several years.

11. Crystal Properties & Polymorphism
Tableting Behavior:
The important factors to be considered in manufacturing of tablets are
•Flow of powder
•Compaction behavior
•Tensile Strengths
•Density
•Morphology
•Shape & Size

12. Crystal Properties & Polymorphism
Two polymeric forms of same drug can differ in these properties.
Morphology of crystal depends on crystal habit which interns is
influence by impurity, concentration, rate of crystallization.
Solubility and Bioavaioulability:
Difference in the rate of dissolution and solubility's of different
polymeric forms is well established.
When absorption of a drug is dissolution rate limited a soluble and
faster dissolving form can be used to improve the rate and extent of
bioavaioulability.
Ex: Choloramphenicol A & B
 &  forms of cholortracycline

13. Crystal Properties & Polymorphism
Techniques for study of crystals and polymorphs:
•Microscopy (Hot Stage)
•Infrared Spectroscopy
•Single Crystal X – ray Crystallography
•Thermal Analysis – DSC
•X – ray Powder Diffraction
•Dilatometry

14. Crystal Properties & Polymorphism

15. Crystal Properties & Polymorphism