Some elemental substances like carbon and sulphur exist in more than one crystalline form and therefore are said to be “polymorphic”.
Polymorphs ----> generally have
Different melting points.
Different x-ray diffraction patterns.
Different solubilities.
But are chemically identical.
Nearly all long chain compounds exhibit polymorphism.
Polymorphism in fatty acids ===> is due to different types of attachments between the carboxyl groups of adjacent molecules, this in turn modify the angle of tilt of the chains in the crystal.
Example 1:
A triglyceride, ----> Tristearin ===> proceeds from ===> Low melting metastatic alpha (α) form ===> trough ===> the Beta prime (β′) form ===> and finally to ===> Stable Beta (β) form (have a high melting point).
This transition cannot occur in opposite direction.
Example 2:
Theobroma oil or cocoa butter – a polymorphous natural fat.
Consist of mainly of single glyceride.
So melts to a large degree over a narrow temperature range of 34◦ – 36◦C.
Theobroma oil is capable of existing in four polymorphic forms.
1. Gamma form (γ), melts at 18◦C ----> Unstable form
2. Alpha form (α), melts at 22◦C
3. Beta prime form (β′), melts at 28◦C
4. Beta form (β), melts at 34.5◦ ----> Stable form
Configuration of fatty acid molecules in the crystalline state:
I.
II.
Rigelman has pointed out the relationship between polymorphism and preparation of cocoa butter suppositories.
If Theobroma oil heated to the point at which it is completely liquidified (about 35◦C.) ===> the nuclei of the stable β crystals are destroyed ===> and the mass does not crystallize until it is super cooled to about 15◦C.
Crystals that form are metastable γ, α and β′ forms and the suppositories melt at 23◦C - 24◦ C or at ordinary room temperature.
Proper Method of Preparation is:
Melting cocoa butter -----> at the lowest possible temperature about 33◦C.
The mass is sufficiently fluid to pour, yet the crystal nuclei of the stable β form are not lost.
The mass is cooled in moulds.
Stable suppositories are formed or produced which consists of β crystals and melts at 34.5◦C.
Polymorphism Applications:
Polymorphism has achieved significance in recent years, owing to the fact that different polymorphs exhibit different solubilites.
For slight soluble drugs it may affect the rate of dissolution.
As a result one polymorph may be more active therapeutically than other polymorphs of the same drug.
Aquiar et al showed polymorphic state of chloramphenicol palmitate have a significant influence on the biological availability of the drug.
Form II of sulfameter an antibacterial agent more active orally in humans than form III. But most marketed pharmaceutical preparations found to contain mainly form III.
Polymorphism can also be a factor in suspension technology.
Cortisone acetate exists in atleast 5 different forms, of which four are unstable in the presence of water and which changes to stable form.
This transformation usually accompanied by appreciable cracking of the crystals.
This should all be in the form of the stable polymorph before the suspension is prepared.
Heating, grinding under water and suspension in water are all factors that affect interconversion of the different cortisone acetate forms.
For a single drug determining the crystal structure and molecular conformations of different polymorphs is different.
Spiperone a potent antipsychotic agent having 2 polymorphs is used mainly in treatment of schizophrenia.
Molecular conformations of two polymorphs of Spiperone:
I.
II.
The difference between the 2 polymorphs is in the positioning of the atoms in the side chains and together with the manner in which each molecule binds to the neighbour spiperone molecules in the crystals.
It showed that crystal of polymorph II is made up of dimmers (molecules in pairs), whereas polymorph crystal I constructed of non-dimerized molecules of spiperone.
Difference in intermolecular vanderwaals forces and H-bonds were found to produce different crystals structures in antipsychotic compounds such as haloperidol and bromperidol.
Variability in H-bonding also contributes to polymorphism in sulphonamides.
Tamoxifen citrate an anti-estrogenic and anti-neoplastic drug used to treat breast cancer and postmenopausal symptoms.
It has 2 polymorphs.
One is stable referred to as form B is held in its molecular conformation in the solid state by H-bonding.
One carboxyl group of citric acid moiety donates its proton to the nitrogen atom on an adjacent tamoxifen molecule to bring about the H-bonding and to stabilize the molecular crystal of form B.
The other polymorph know as form A is a metastable polymorph of tamoxifen citrate.
Its molecular structure is less organized than that of stable B form.
An etanolic suspension of polymorph A spontaneously rearranges into polymorph B.
Carbamazepine used in treatment of epilepsy and trigeminal neuralgia (severe pain in the face, lips and tongue).
Beta polymorph of it can be crystallized from solvents of high dielectric constant such as aliphatic alcohols.
Alpha polymorph crystallized from solvent of low dialect constant such as CCl4 and cyclohexane.
Estrogens are essential hormones for development of female sexual characteristics.
When potent synthetic estrogenethynylestradiol is crystallised from the solvents acetonitrile, methanol and chloroform saturated with water four different crystalline solvents formed.
Ethynylestadiol known to exists in several polymorphic forms.
Thermal analysis infrared spectroscopy, x-ray studies shows that these forms are crystals containing solvent molecules thus should be classified as solvates rather than as polymorphs.
Solvates are sometimes called as pseudo-polymorphs; other related estradiol compounds may exists in true polymorphic forms.
When the change is from one form to another is reversible it is said to be enantiotropy.
When transition taken place in one direction only it is monotropic.
E.g.: from a metastable to stable form
Enantiotropism and monotropism are important properties of polymorphs.
Transition temperature in polymorphism is important because it helps to characterize the system and determine the more stable form at low temperatures.
Polymorphs at their temperatures have some free energy identical solubilities in a particular solvent and identical vapour pressures.
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