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CRYSTALLINITY AND POLYMORPHISM

CRYSTALLINITY AND POLYMORPHISM:
Crystal habit and internal structure of a drug can affect bulk
and physicochemical properties, which ranges from flowability to chemical
stability. Habit is the description of outer appearance of a crystal. Whereas
the internal structure is the molecular arrangement within the solid.
Changes with internal structure usually alter crystal habit.
Eg. Conversion of sodium salt to its free acid form produce both; a
change in internal structure and crystal habit.
Depending on the internal structure a compound can be classified as
1.

Crystalline

2.

Amorphous

Crystals are characterized by repetitious spacing of constituent atoms

or molecules in a three dimensional array. In case of amorphous forms
atoms or molecules are randomly placed as in a liquid. The amorphous
forms are usually of higher thermodynamic energy than the crystalline
form. Upon storage, the amorphous forms tend to convert to more stable
crystalline forms. So due consideration should be given for these changes.
Eg: The amorphous forms of Novobiocin was found to be well
absorbed, however when formulated into a suspension, convert into more
stable crystalline form and results in poor absorption.
A polymeric form may contain stiochiometric or non stiochiometric
solvents. If the solvent is water, the complex is called a hydrate. The term
hemihydrates, monohydrate, dihydrate etc describe hydrate forms with
molar equivalence of water. A compound not containing any water molecule
within its crystal structure is termed as anhydrous. Anhydrous forms are
more soluble; Conversion of anhydrous form to hydrous form within dosage
form

may

reduce

the

dissolution

rate

and

extent

of

absorption.

Identification of possible hydrate compounds is important since their

aqueous

solublities

can

be

significantly

less

than

anhydrous

form.

Conversion of anhydrous form to hydrate with in dosage form may reduce

dissolution and extent of absorption of drug.
Eg:

Anhydrous

form

of

Ampilcillin

produced

higher

blood

concentration than the trihydrate form of Ampilcillin.

Non stoichiometric adducts such as inclusions or clatharates involve
entrapped solvent molecules with in crystal lattice. This adduct is
undesirable because of its lack of reproducibility and should be avoided for
development.
POLYMORPHISM:
Polymorphism is the ability of the compound to crystallize as more
than one distinct crystalline species with different internal structure.
Different crystalline forms are called Polymorphs. Polymorphs may be of
two types :(a) Enantiotropic
(b) Monotropic
When the change from one form to another is reversible it is called as
enantiotropic If transition take place in only one direction is called as
monotropic. Chemical stability and solubility changes due to polymorphism
can have impact on drugs bio-availability. Most of the pharmaceutical
products exhibit polymorphism Eg. Sulfonamides and steroids.
Eg: Cortisone acetate is available in 5 different polymorphic forms.
Among this 4 are unstable, if they are used in the preparation of suspension
in presence of water, it changes to stable form, accompanied by caking of
the crystals. So we should select stable form for the preparation of
suspension. The amorphous form of Novabiocin was found to be well
absorbed. However when formulated into a suspension a reversion of
metastable state to more stable crystalline form occurs resulting in poor
absorption.

In case of Calcium pantothenate the preferred form is the crystalline

form. In the preparation of multivitamin formulation, calcium pantothenate
is granulated with other ingredients. If the amorphous form is used during
granulation, polymorphic transformation may occur and it makes the
granulating mass stick, making further process impossible.
The parameters routinely investigated are: - Number of polymorphs
that exist, relative degree of stability of various polymorphs, presence of a
glassy state, stabilization of metastable

forms, temperature stability

ranges for each polymorph, solubilities etc. Polymorphic forms are

physically more stable then others. They have high melting point, least
aqueous solubility

& lowest energy.

Remaining polymorphs called

Metastable forms i.e. they have low melting point, high aqueous solubility,
& high energy. Therefore metastable forms are preferred in formulation.
Eg. Chloramphenicol exist as A, B, C; B form is preferred
Riboflavin has I, II, III forms; III rd form shows 20 times more water
solubility than I. Therefore dissolution of different solid forms of drug is
Amorphous > metastable > stables
Polymorphic stability is also needed to predict long term physical
stability of dosage forms.
Eg. Capping like cracking in tablets of anhydrous crystalline carbochromen
hydrochloride upon storage under high humidity conditions. This was
determined to be due to transformation of the anhydrous form into a
dihydrate form
The following techniques are widely used to study polymorphs:
1. Dissolution: Metastable forms are detectable because they have a faster
dissolution rate.
2. X-Ray

diffraction:

Crystalline

materials

in

powder

form

give

characteristic x-ray diffraction patterns made up of peaks in certain

positions and varying intensities. Each powder pattern of the crystal lattice
is characteristic for a given polymorph. The sample is examined as
presented and sample size is small.

3. Infra red spectroscopy: Different packing arrangements will affect the

energy of the molecular bonds thus altering the I.R.Spectra. Solid samples
must be used since polymorphs of a compound have identical spectra in
solution.
4. Differential scanning calorimetry (DSC) and differential thermal analysis
(DTA).

These methods have been used extensively to identify

polymorphs. In both methods, the heat loss or gain resulting from physical
or chemical changes occurring in a sample is recorded as a function of
temperature as the substance is heated at uniform temperature. Enthalpic
changes i.e. both endothermic and exothermic are caused by phase
transitions. Fusion, sublimation, solid-solid transition and water loss
generally

produce

endothermic

effects

while

crystallization

causes

exothermic effects. Thermal analysis enables evaluation of thermodynamic

parameters governing the system.
5. Dilatometry
Dilatometry measures the change in volume caused by thermal or chemical
effects. It has been used to follow the melting behavior of theobroma oil by
measuring the specific volume of both rapidly and slowly cooled theobroma
oil as a function of increasing temperature. This technique is extremely
accurate, however it is extremely tedious and time consuming. It is not
widely used.
6. Hot stage microscope
Upon heating to the phase transition point, the crystal undergoes a
change

in

the

birefringence

and/or

appearance.

Some

problems

in

development that may result from inadequate investigation of polymorphic

drug forms are:
1.

Crystal growth in suspensions and creams, resulting in a product with

poor

uniformity,

appearance

and/or

biological

availability.

Eg.

Parenteral cortisone acetate suspensions cake if prepared with the

wrong polymorphic form.
2.

Precipitation of less soluble polymorphic form in liquid dosage forms.

3.

Poor bioavailability from a less soluble polymorph, eg, metastable

fluprednisolone implants has a higher absorption rate than the stable
form.

4.

Crystal

transitions

resulting

from

milling

or

wet

granulation,

producing changes in the physical and biological characteristics of the

dosage form.
5.

Poor chemical stability, eg. amorphous penicillin is less stable than the
crystal salt.

Crystal habit may influence such properties as:

1. Suspension stability and syringability:

plate shaped crystals will flow

through a needle or orifice much more readily than needle shaped

crystals.
2. Tableting properties - - These may be altered by crystal packing during
compression. Eg. Particle size of lactose has a considerable influence
upon tablet strength.
3. Dissolution Dissimilar crystalline habits may have different dissolution
rates depending on their surface area. Cubic and spherical particles
dissolve equally from all sides whereas other habits change their
shape factor during dissolution, altering the dissolution rate.
Various techniques are available for the investigation of the solid state .These
include:
1) Microscopy (Including hot stage microscopy)
2) Infrared spectrophotometry
3) Single-crystal X-ray
4) X-ray powder diffraction
5) Thermal analysis
6) Dilatometry.
7) Proton magnetic resonance (PMR)
8) Nuclear magnetic resonance spectroscopy (NMR)
9) Scanning electron microscopy (SEM)

MICROSCOPY:
This method is based upon the principle that when all substances that are
transparent when examined under microscope that has cross polarizing
filters with one or more than one referactive index, transmit light and
appear bright with brilliant colours.against the black polarized background.
And the colour depends upon the crystal thicknes and the difference in
refractive indices. The substance are either uniaxal having two refractive
indices or bixial having three principle refractive indices.(eg.:-Anisotropic)
and sometimes the substances does not tranmitts light through polarizing
filters and they apper black and they are having single refractive index.
Example:-Isotropic substance (Sodium chloride),Amorphous compounds,
crstyalline organic compounds Etc.
ADVANTAGES:-By this method we can study crystal morphology , differnce
between polymeric form.
DISADVANTAGE:- This method reqvire a well-traind optical crystallography.
HOT STAGE MICROSCOPY:The polarizing microscopfitted with a hot stage is usefull instrument for
investigating
polymorphisum,melting point,transition thermal temperature.
DISADVANTAGE: In this techniqe the organic molecules can degarade
during the melting process.
THERMAL ANALYSIS:Differential scanning calorimetry (DSC) and differential thermal
analysis(DTA) are particularly useful in the investigation of polymorphisum.
It measures the heat loss
or gain resulting from physical or chemical changes with in a sample as a
function of temperature . Example of endothermic process are fusion ,

boiling, sublimation, and vaporization. Example of exothermic process are

crystallization, degradation. This have many application in performulation
studies including purity, polymorphism, solvation, degradation, and
excipient compatibility. For characterizing crystal forms the heat of fusion
can be obtained from the area under the DSC-curve for the melting
endotherm. Similarly the heat of transition from one polymorph to another
may be calculated. A sharp symmetric melting endotherm can indicate
relative purity, where as broad assymmtric curve suggest impurities.
DRAWBACK:-Degradation during thermal analysis may provide misleading
results.
X-RAY:
Working : When a beam of nonhomopgenous x-rays is allow to pass tthrough a
crystal the x-ray beam is diffracted & it is recorded by means of photographic
plates . The diffraction is due to the crystal acting as a three dimensional
diffraction grating towards the x-ray. An important tecnique for establishing the
batch-to-batch reproducilibility of a crystalline form is x-ray powder diffraction
random orientation of a crystal lattice in a powder sample causes the x-rays to
scatter in a reproducible patter of peak intensities at distinct angles <teta >
relative to the incident beam each diffraction patter is characterstic of a specific
crystalline lattice for a given compound .An amorphous form does not produce a
pattern mixture of different crystalline forms can be analyzed using normalized
intensities at specific angles, with out are unique for each crystalline form. Single
Crystal X-ray provides the most complete information about the solid state. It is
tedious, time consuming & hence unsuitable for routine use.
IR SPECTROSCOPY:IR has the ability to differentiate isomers groups such as Cis-trans double
bond compound. The wavelength of the IR spectrum is 750-2500nm.
The sampling preparation

techniques for IR determination are solution,

drug dispersion in a potassium bromide pellt, nujol mulls,and direct

determination by FTIR which gives better qualtive determination .FTIR

uses asimple opticl device, an interferometer that allows the simultaneous
measurement

of

ferqvency.

The

ferqvency

is

calculated

with

the

mathematical technique called Fourier transformation.

NMRSPECTROSCOPY:NMR involves the ab sorpation

of electromagnetic radiation in the

radiofreqvency of a longer wave length spectrum. When a sample is placed

with atomic nuclei of hydrogen(H,protons) fluorine or phosphorous ina
magnetic field, absorpation of energy will occur the nuclei shift from the
preferred, high energy orientation ata particular ferqvency .thus a plot of
ferqvency versus intensity of radiation results in the NMR spectrum of a
material.