Physical forms
(Crystallinity,
amorphousness and
polymorphism
•Characteristics
•Crystal habit and internal structure affects the flowability and
stability.
•Melting point
•Molecules gained sufficient energy from the heating process to
overcome the attractive forces that hold the crystal together.
•Crystals with weak forces holding the molecules together have
low
melting point while crystal with strong lattice have high melting
points.
•How crystals are formed?
•Cool a molten sample to below the melting point e.g. lipids,
semisolid matrix.
•Crystallization of solid from solvent – by removing the liquid by
• Polymorphism:
•Change in crystallization conditions e.g. change in stirring;
different solvents or presence of impurities.
•Alternative packing arrangement is occurred for the same
Molecule and they are polymorphic forms.
•By looking packing arrangement we can say that
[Link] densities due to spacing of molecules.
[Link] melting points because of internal structure.
[Link] milling and compaction properties.
[Link] dissolution properties.
• Monotropic polymorphism - Only one polymorphic form is
stable and any other polymorph that is formed will eventually
convert to the stable form.
• Enantiotropic polymorphism - Under different conditions
(temperature and pressure) the material can reversibly
transform between alternative stable forms.
• In case of monotropic polymorphism, the true stable form has
the highest melting point and all other forms are described as
metastable (exist for very short times or many months before
they convert to the stable form).
• High melting point (stable form) have strong lattice; hard to
remove a molecule and low dissolution rate.
• Low melting point (metastable form) have weak lattice; easy to
remove a molecule and high dissolution rate.
• Polymorphism and bioavailability
• Polymorphic form must be well controlled in order to ensure
that the bioavailability is the same each time the product is
made, and throughout the shelf-life of the product.
• it is essential to check for the existence of polymorphism and
ensure that they use the same appropriate polymorphic form.
• Hydrates and solvates:
• If the solvent is water - hydrate (hemi, mono di and trihydrate).
• If it is other than water – solvates (ethanolate).
• “Hydrates have lower dissolution rate than anhydrous”
• Amorphous state:
• Material is solid but no existence of repetitive long range order.
• As no crystal lattice to break hence no melting point is shown
by amorphous materials.
• Large molecular weight substances (polymers) – amorphous or
semi crystalline.
• Low mol. wt. substances – they are amorphous when solidify
rapidly or spray dried.
• Glass transition temperature (Tg)
• It’s a temp. boundary above which the substance is soft, flexible
and rubbery and below it becomes hard, brittle and glassy. i.e.
state above Tg is rubbery and below is glassy state. Further
heating starts the substance to flow.
• Plasticizers – Lowers the Tg e.g. Glycerin, sorbitol, dibutyl
sebacate, dibutyl pthalate.
• Techniques used to study crystallinity, amorphousness,
Tg:
• Differential scanning calorimetry
• X-ray diffractometry
DSC of polymorphic material
DSC thermogram
XRD diffraction pattern
References
• AULTON, M. E. (2007). Aulton's pharmaceutics: the design and
manufacture of medicines. Edinburgh, Churchill Livingstone .
• Images reproduced from thesis of Ms. Snehal Borade and Ms.
Monali More (Guide: Dr. M. P. Patil)
