Crystal Properties and
Polymorphism
Most marketed pharmaceutical drugs exist in the molecular crystalline form .
Crystalline Form:
The drug molecules precipitates out of the solution in an ordered arrangement
The arrangement of the molecules in a crystal determines its physical
properties and so greatly influences key drug properties such as dissolution
rate and stability as well as the processing and formulation of solid
pharmaceuticals. *
* Nature Reviews Drug Discovery( 57- 42 ,3 January 2004 | ) doi/10.1038:nrd1280
Polymorphism:
Many drug substances can exist in more than one
crystalline form.
The different crystal forms are called polymorphs.
.
Types of the polymorphs:
1. True polymorph
Crystals made up of drug molecules only
2. Pseudo polymorph or Solvate :
The crystals entrap solvent molecules in a
specific lattice to give a solvate or pseudo
polymorph ( if entrapp water , it called
hydrate ).
Preparation of polymorph:
They are prepared via appropriate manipulation of
conditions of crystallization.
These conditions include:
a) Nature of the solvent
b) Temperature
c) Rate of cooling
Amorphous Form:
The solute precipitates out of the solution in a
random arrangement.
Preparation:
a)Shock cooling
b) Sudden change in the composition of the solvent of
crystallization .
c) Lyophilization
Crystalline Properties of drugs
So pharmaceutical drugs/pharmaceutical
excipients exist in:
Crystalline form or Amorphous form
if polymorph either
True polymorh or Solvate
(pseudopolymorh)
Difference between different
polymorphs:
Different polymorphic differ from each other in many
physical properties, such as
a) crystal shape ( can be observed by microscopy)
b) true density *
c) solubility and dissolution
d) compaction behavior
e) flow properties
f) solid state stability.
g)Thermal crystal transition (changes in crystal arrangement under
gradient increase of temperature)
It is necessary to search for different polymorphic
with maximum stability and bioavailability.
Techniques for studying crystal properties
1)Microscopy and hot-stage microscopy* .
2) X-ray diffraction :
single-crystal x-ray and powder x-ray diffraction.
3) Thermal analysis.
So Based on the crystal properties of drugs
This session highlights the interpretation of the
crystalline analysis of drugs and their interaction
with pharmaceutical excipients
using the techniques 2 and 3 *
2) x-ray diffraction :
a) Single-crystal x-ray:
It involves the x-ray diffraction of a single crystal.
It provides the most complete information about the drug solid crystal
state.
It is, however, tedious, time consuming, and, hence, unsuitable for routine
use
b) Powder x-ray diffraction : (the main judge of the crystallinity)
rapid and relatively simple, and is the method of choice.
X-ray diffraction pattern is unique to each
polymorphic form (fingerprint)
Amorphous materials do not show any patterns or show one
or two broad peaks.
Powder x-ray diffraction does not always indicate if the
crystalline material is a true polymorph (anhydrous) or
a solvate (hydrous)
Powder x-ray diffraction patterns of amorphous, anhydrous
crystalline and crystalline trihydrate forms of epicillin.
Halo patteren with low
intenisty broad hump
Intenisty
(counts/ Sharp
second, diffraction
cps) peaks
(degrees)
Like drugs and
pharmaeutical Contains both
excepients crystalline and
amorphous
Crystalline regions
e.g: polymers
Or a physical
mixture between
crystalline and
amorphous
material
3) Thermal analysis using :
Differential scanning calorimetry(DSC)
A) Device B) DSC thermogram and thermal transitions
Heating rate: 2 or 5 or 10◦C/min.
Sample : solid, liquid, gas
Atmosphere: nitrogen because increasing temperature along with
oxygen exposure can lead to oxidative and pyrolytic effects to the
sample
Thermal transitions
They're the changes that take place to the crystal structure of
the drug or excipient sample when you heat it.
Thermal transitions include:
1. Melting which is an endothermic transition
2. Crystallization which is an exothermic transition
3. The glass transition a very weak endothermic transition
unique to thermograms of polymers.
Tc
Tg
Tm
Glass Transition Temperature (Tg)
The temperature at which the amorphous material
transitions from the glassy state to the rubbery state
Glassy state is hard and brittle (vibrational motion)
while rubbery state (rotational motion) is soft and
flexible
Involves heat absorption resulting in molecules
mobility
Melting Temperature (Tm)
The temperature at which the crystalline material
transitions from the solid crystalline state
(vibrational movement) to the liquid state
(rotational movement)
Involves heat absorption resulting in
molecules mobility
Crystallization temperature (Tc)
Crystallization is an exothermic process in which
solid atoms or molecules are highly organized
into crystal structure.
Hence
Tg only: completely amorphous material
Tm only or with Tc: Crystalline material
Tg with Tm (optional Tc): Semicrystalline,
physical mixture
What do you think
about the DSC pattern
of a drug,
pharmaceutical
excepient and a
polymer?
What Can You Measure with DSC?
Qualitative analysis
◦ Fingerprinting of minerals, clays, polymers
Sample purity
◦ By Melting points
Glass transition temperature, Tg of polymers
Crystallization temperature, Tc
Compatibility study*
Encapsulation of drug in micro/nanoparticle*
Excipient Compatibility Study
Thermal analysis:
Differential scanning calorimetry(DSC)
• It is used to investigate any interactions between
components in a formulation.
• It is used in the selection of suitable chemically
compatible excipients.
Methodology:
It requires 5 mg of drug, in a 50% mixture with the
excipinents, to observe an interaction.
Mixtures should be examined under nitrogen to
eliminate oxidative and pyrolytic effects at a standard
heating rate (2, 5 or 10oC min-1) on the DSC apparatus.
Ex.1
Interpretation:
•If
there is no change in both drug and excipients peaks
•Or Transition of peak is not more than 50 C
i.e there is no interaction no incompatibilities & the
excipient is recommended
(intensity of peak may decrease due to dillution effect)
However An interaction on DSC will show as :
1)changes in melting point and/or the appearance of a transition
2) peak shape (there is gross broadening or elongation of an exo-
or endothermic change)
3)The appearance of new peaks.
4)The disappearance of peak
The excipients are then probably chemically reactive and
incompatible with the drug, the incompatibility should be
confirmed by TLC/IR.
Figure (5) Scheme to identify chemically compatible excipents using DSC
with confirmatory TLC.
Drug
No interaction
50%Mixture Recommended
DSC Interaction excipents
Excipents
TLC/IR
Significant
Alternative Yes No
breakdown
excipient
The advantages of DSC over TLC:
No long-term storage of the mixture is required prior
to evaluation
Where confirmation is required by TLC, samples
(50:50 mixtures of drug and excipents) should be
sealed in small neutral glass test tubes and stored for
either 7 days at 50oC or 14 days at 37oC.
Case study
A compatibility study between famotidine and some
excipients, (Primojel, Emcompress, Talc, Mg stearate
and Avicel PH 101) was carried out using differential
scanning calorimetry (DSC). The following
thermograms were obtained. Comment on the
thermograms regarding:
a) The presence of incompatibility.
b) The need for further investigations.
c) The excipients that you recommend for use with
famotidine.
Fig 1: Fig 2:
Observation: Drug ( famotidine) has Observation: Drug ( famotidine) has
melting endothermic peak at around melting endothermic peak at around
160 deg. 160 deg.
Primojel excipient show no peaks in Encompress excipient has melting
the study range. endothermic peak at 200 deg.
In the physical mixture, the peak of In the physical mixture, both peaks are
famotidine dissapeared, present with a slight shift less than 5 deg,
Interpretation and conclusion: they Interpretation and conclusion: they
may be incompatible, and need further are compatible and the excipient is
investigations using TLC/IR recommended
Fig 3:
Observation: Drug ( famotidine) has melting endothermic peak at around 160
deg.
In the physical mixture, the peak of famotidine was present as it is at the same
position all excipients appeared to have no peaks at the study range,
Interpretation and conclusion: they all (talc, mg stearate and avicel) compatible,
no need for further investigations they are all recommended
Tools required (phase
diagram):
Burette-
2 conical flask-
2 graduated ppette –
sucker
Pencil and rubber-
funnel-
calculator
