CRYSTALLINITY
AS A PART OF
PREFORMULATION STUDY
CONTENTS
INTRODUCTION
CLASSIFICATION OF SOLIDS
AMORPHOUS
POLYMORPHS
SOLVATES
CLATHRATES
COMPARISON OF CRYSTALLINE AND AMORPHOUS FORMS
CRYSTAL STRUCTURE AND MORPHOLOGY
MODIFICATION OF CRYSTAL HABIT AND ITS
CHARACTERIZATION
CRYSTALLIZATION
ANALYTICAL METHOD FOR CHARACTERIZATION
IMPORTANCE IN PREFORMULATION STUDIES
LATEST TECHNIQUE DEVELOPMENTS
REFERENCES
STUDY QUESTIONS
2
INTRODUCTION
A crystal is a solid in which the
constituent atoms, molecules, or ions are
packed in a regularly ordered, repeating
pattern extending in all three spatial
dimensions.
The study of the crystalline form as a
part of preformulation studies is termed
as crystallinity studies.
3
CLASSIFICATION OF CHEMICAL
COMPOUND
Solids
Crystalline
Amorphous
(Non-crystalline)
Single entity
Polymorphs
Enantiotropic Monotropic
Molecular adducts
Non-stoichiometric
Inclusion compounds
Channel
Layer
Cage
(Clathrate)
Stoichiometric
compounds
Hydrates
Solvates
4
AMORPHOUS COMPOUND
They have atoms or molecules randomly placed as in a
liquid. They are typically prepared by:



Lyophilization. E.g. Fluprednisolone in tert-butanol.
Rapid quenching of chloramphenicol palmitate solution in
hydrophilic solvent.
Rapid quenching of melted chloramphenicol palmitate in the
refrigerator to -10◦
Precipitation is also used to prepare the amorphous prompt
insulin zinc suspension.
5
Amorphous forms are of :

Higher thermodynamic energy
Greater solubility and dissolution rate.
But due to high energy they are unstable and
revert back to a stable form.
Eg. Amorphous novibiocin suspension.
Agents like

methylcellulose,
polyvinylpyrollidone, and

several alginic acid derivatives such as sodium alginate and

propylene glycol algin are used to prevent such condition.
6
POWDER X-RAY DIFFRACTION
PATTERN
7
POLYMORPHS
Many drug substances can exist in more than one
crystalline form with different space-lattice arrangements.
This phenomenon is known as polymorphism and the
different crystalline forms as polymorphs.


Drugs like barbiturates have polymorphic forms.
Also steroid hormones have 42 and sulphonamides have 30
polymorphic forms.
8
SOLVATES
(PSEUDOPOLYMORPHISM)
Solvates are molecular complexes that have incorporated the
crystallizing solvent molecule in their specific lattice position
and in fixed stoichiometry.
Estradiol forms highest number of solvates with all 30
solvents.
Other eg are erythromycin, chloramphenicol, ampicillin,
sulphanilamide etc.
Solvates can be distinguished from polymorphs by observing
bubbles of gas in silicon oil upon heating.
9
CLATHRATES
A clathrate is a single-phased solid with two distinct
components: the host and the guest.
The guest is retained in the closed cavities provided by the
crystalline structure of the host.
Thus it is a non-stoichiometric molecular adduct.
The major classes of clathrates are hydroquinone clathrates,
water clathrates, phenol clathrates etc.
10
PHARMACEUTICAL APPLICATIONS
OF CLATHRATES:PURIFICATIONSEPARATION OF RARE GASES-
SEPARATION OF OPTICAL ISOMERSSTORAGE OF INERT GASES-
MODE OF ACTION OF ANESTHETICS[ JPS-1975, 64, 1264.]
11
COMPARISON OF THE MECHANICAL PROPERTIES
OF THE COMPACTS OF THE CRYSTALLINE AND
AMORPHOUS FORMS OF A DRUG SUBSTANCE
CRYSTALLINE FORM AMORPHOUS FORM
More ductile (low
indentation hardness
value)
Least ductile (high
indentation hardness
value)
Form compacts with
highest tensile
strength
Compacts have low
brittleness value
Form compacts with lowest
tensile strength
Require higher
compression stress
Require lower compression
stress
Compacts have high
brittleness value
12
COMPARISON OF SOLUBILITY OF
CRYSTAL, SOLVATE AND HYDRATE:
Amorphous form more soluble than a corresponding
crystalline form.
The dissolution rates of hydrates are less than corresponding
anhydrous crystalline form. E.g gluthethimide, theophylline,
caffeine, succinyl sulphathiazole, phenobarbitol.
The dissolution rates for organic solvates are higher than
corresponding pure crystaline form. E.g. 1,4-dioxane solvate
of nifedipine shows better solubility than dihydrate form.
So organic solvates should be preferred in place of pure
crystals which solves both problems, solubility and stability,
but only if ICH guidelines about limits of organic residues
permit.
13
Crystals are of two types:Irregularly shaped crystals known as anhedral or
allotriomorphic.
Definite shaped crystals bound by plane faces known as
euhedral or idiomorphic.
Any crystal is characterized by its internal structure and
habit. Habit is the description of the outer appearance of a
crystal whereas the internal structure is the molecular
arrangement within the solid.
14
CRYSTAL SYSTEM
(INTERNAL STRUCTURE)
The most symmetric system is cubic system.
Other six systems, in order of decreasing symmetry, are
hexagonal, tetragonal, rhombohedral (also known as
trigonal), orthorhombic, monoclinic and triclinic.
Thus there are fourteen types of unit cell called as the
Bravais lattices.
We can identify the various planes of crystal using the
system of Miller indices.
15
CRYSTAL HABIT
There are five types of crystal habit widely recognized:
Platy: plates
Tabular: moderate expansion of two parallel faces
Prismatic: columns
Acicular: needle-like
Bladed: flat acicular
These occur in all the seven systems.
16
Crystal habit
can be quantitatively expressed in terms of aspect ratio (AR).
AR defined as the ratio of length to width and values of AR
approaching 1 (spherical or cube shape) are considered to be
pharmaceutically good.
It is preferable to keep the AR values below 5 so as to avoid
problems with flow.
AR in polar solvents was as high as 9.4 in comparison with
5-6 in non-polar solvents.
[JPP-2007, 59, 29-39.]
17
METHODS OF MODIFICATIONS OF CRYSTAL HABIT
Excessive supersaturation. E.g. transform a prism or
isodiametric crystals to needle shape.
Cooling rate and agitation. E.g. naphthalene gives thin
plates if rapidly cooled whereas slow evaporation yields
prisms.
The crystallizing solvent. E.g. resorcinol produces needles
from benzene and squat prisms from butyl acetate.
Addition of co-solvents or solutes. E.g. sodium chloride is
cubic but urea produces octahedral habit.
Crystal habit can also be modified by adding
impurities or ‘poisons’; for example, sulphonic acid dyes alter
the crystal habit of ammonium, sodium and potassium
nitrates.
18
CHARACTERIZATION OF HABITS
The angle between two crystals faces can be described
in two ways:

Included or edge angle between two faces,

Interfacial or polar angle, the angle between the normals to
the faces of the crystal.
Interfacial angle is of importance in crystallography.
They are measured by instruments known as goniometers.
19
CRYSTALLIZATION



Crystallization is a chemical solid-liquid separation
technique, in which mass transfer of a solute from the
liquid solution to a pure solid crystalline phase occurs.
The crystallization process consists of two major
events:
Nucleation
Homogenous
Heterogenous
Crystal growth
20
Supersaturation is the driving force of the
crystallization
This can be achieved by various methods, with
1) solution cooling,
2) addition of a second solvent to reduce the solubility of the
solute (technique known as anti-solvent or drown-out)
3) chemical reaction
4) change in pH being the most common methods used in
industrial practice.
Other methods, such as solvent evaporation, can also be
used.
21
ANALYTICAL METHODS FOR
CHARACTERIZATION OF SOLID FORMS
METHOD








MATERIAL REQUIRED
per SAMPLE
1mg
1mg
Microscopy
Fusion methods
(hot stage microscopy)
Differntial scanning calorimetry
(DSC/DTA)
Infrared spectoscopy
X-ray powder diffraction
Scanning electron microscopy
Thermogravimetric analysis
Dissolution/solubility analysis
2-5mg
2-20mg
500mg
2mg
10mg
mg to gm
22
IMPORTANCE OF CRYSTALLINITY
IN PREFORMULATION STUDIES
EFFECT ON SOLUBILITY & BIOAVAILABILITY
Antibiotic novobiocin is inactive in crystyalline form while
amorphous form has 10 times more solubility and hence
more bioavailable.
23
EFFECT ON INSULIN
NO TYPE OF INSULIN
.
FORM OF
INSULIN
ONSET
OF
ACTION
DURATION OF
ACTION
1
Prompt insulinzinc suspension
(semilente)
Amorphous
fast
Short
2
Extended
insulin-zinc
suspension
(ultralente)
Insulin-zinc
suspension
(lente)
crystalline
slow
Long
3
30%amorphou fast
s+
70%crystalline
Intermediate
24
CHEMICAL STABILITY


At instances crystalline form are more stable than
amorphous form.
e.g. crystalline forms of penicillin G as potassium or sodium
salt are more stable.
SUSPENSION SYRINGEABILITY

A suspension of plate shaped crystals may be injected
through a needle with a greater ease than one with needle
shaped crystals of same dimensions.
25
EFFECT ON GRANULATION


Sulphathiazole can exist in different crystalline forms . Form
III has water adsorption of 0.046 mg/m2 & form I has water
adsorption of 0.031 mg/m2 so form III shows better wetting
and so easy granulation.
Use of amorphous form of calcium pentothenate in multivitamin tablets prepared by wet granulation process, is not
desirable because polymorphic transformation makes the
granulation mass sticky, making futher granulation
virtually impossible.
26
HARDNESS OF TABLET


Sulphamerazine is available in two different crystalline
forms SMZ-I & SMZ-II. SMZ-I forms harder tablets than
SMZ-II at same compression pressure and so it shows
delayed release.
Both these forms can be used in single tablet by compression
coating in which the core is formed of SMZ-I and coat is
made up of SMZ-II to get repeat action.
27
EFFECT ON CONSOLIDATION


Substances possessing the cubic lattice arrangement were
tabletted more satisfactorily than those with rhombohedral
lattice.
The isotropic nature of former group contribute to better
tabletting because no alignment of particular lattice planes
is required. In addition provide three equal planes for stress
relief at right angles to each other.
28
DIRECTLY COMPRESSIBLE EXCIPIENTS


The DC grade excipients are microgranulations, since they
consist of masses of small crystallites randomly embedded
in a matrix of glue-like (often amorphous) material.
Such a combination imparts the desired overall qualities
which results in strong tablet by providing a plastically
deforming component (the matrix) to relieve internal
stresses and strongly bonding surfaces (the faces of
crystallites) to enhance consolidation.
29
POLYMORPHIC TRANSFORMATION



Many drugs undergo polymorphic transformation during
various processes. E.g. during grinding drugs like digoxin,
estradiol, spironolactone, phenylbutazone undergo
transformation.
By granulation of theophylline with water converts into
monohydrate from anhydrous form.
Similarly by drying and compression also drugs undergo
change in their form.
30
LATEST TECHNIQUE DEVELOPMENTS IN
CRYSTALLIZATION
SPHERICAL CRYSTALLIZATION

It has been developed by Yoshiaki and co-workers.
It is a solvent exchange crystallization method in which
crystal agglomeration is purposefully induced through the
addition of third solvent termed as “Bridging liquid” which
act as granulating agent.
31
It is a novel technique
to improve compressibility,
good flowability and
bioavailability of pharmaceuticals.
Moreover tablets formed have greater mechanical strength
and lower friability.
Various drugs have been successfully undergone this
process to acquire improved micromeritic properties and
thus have shown increased dissolution rate like
salicylic acid,
mefenemic acid,
aminophylline,
tolbutamide.
[Pharmaceutical Research-1994, 11(4)]32
METHODS OF SPHERICAL CRYSTALLIZATION

SIMPLE SPHERICAL CRYSTALLIZATION
E.g. spherical crystallization of salicylic acid from ethanol by
addition of water, using chloroform as bridging unit.

QUASI-EMULSION-SOLVENT-DIFFUSION METHOD
E.g. antirheumatic drug bucillamine was crystallized as
spheres by this method using HPMC. Also controlled
release microspheres of ibuprofen with acrylic polymers
was accomplished by this method.

AMMONIA DIFFUSION METHOD
Useful for amphoteric drugs like enoxacin.

NEUTRALIZATION METHOD
Tolbutamide dissolved in sodium hydroxide and HPEC
aqueous solution was crystallized using this method.
33
CONTROLLED CRYSTALLIZATION


Very useful method for getting microcrystals in very
narrow size range for hydrophobic drugs.
E.g. anti-inflammatory drug betamethasone dipropionate,
triamcinolone acetonide, beclomethasone. [JPS-2003, 92]
AMORPHOUS FORM STABILIZATION
NEUSILIN (amorphous magnesium aluminium silicate)
was milled in the ball mill with the drugs like
indomethacin, ketoprofen,naproxen and progesterone. The
amorphous form thus formed was more stable than normal
amorphous form and did not turned to crystalline form
easily.
Thus by using additives with high glass transition
temperature or by selective hydrogen bonding with the
stabilizing additives conversion of amorphous form to
crystalline form can be prevented.
34
[JPS-2003, 92(3)]
SUPER CRITICAL FLUID CRYSTALLIZATION


It is a novel technique used for selective production of
polymorphs and pseudopolymorphs from aqueous solution.
Glycine has three polymorphs and can be selectively
precipitated to either pure α- or β-glycine by this technique.
[Chemical Abstract, (2007), 147(12), 1058:258004m]
CHIRAL DRUGS

Resolution of chiral drugs and drug intermediate is done by
preferential crystallization.
35
[Chemical Abstract, (2007), 146(25), 1729:507024v]
CONCLUSION
Thus, with all examples of the effects of habits,
polymorphs, solvates and clathrates on optimising
pharmaceutical formulations, the crystal chemistry
has become a routine part of every pharmaceutical
company’s preformulation programme.
36
REFERENCES

Pharm. Dosage forms and drug delivery system , ANSEL, 100,151.

Pharm. Dosage forms, LACHMANN and LIBERMANN, 1, 26-30.

Modern pharmaceutics, BANKER,MARSHALL DEKKER INC.

Pharm Encyclopedia, 3, 399.

Pharm Encyclopedia, 12, 320-321.

Advanced pharmaceutical solids, CARSTENSEN, 110, 6.

Physical pharmacy, ALFRED MARTIN.

Industrial pharmacy, LACHMANN and LIBERMANN.

Physico-chemical principles of pharmacy, A.T.FLORENCE &
D.ATTWOOD, 8-10.
37
REFERENCES

Pharmaceutics-the science of dosage form design, M.E.AULTON, 142-

Pharmaceutical sciences, REMINGTON, 1358.

Journ. Of Pharm. Sciences, (2007), 96, 990.

Journ. Of Pharm. Sciences, (2006), 95, 26-30.

Journ. Of Pharm. Sciences, (2006), 95, 446.

Journ. Of Pharm. Sciences, (2006), 95, 1641.

Journ. Of Pharm. Sciences, (2003), 92, 35-46.

Journ. Of Pharm. Sciences, (1989), 78, 68-72.

Journ. Of Pharm. Sciences, (1987), 76, 471-474.
149.
38
REFERENCES

Journ. Of Pharm. Sciences, (1984), 73, 1407-1410.

Journ. Of Pharm. Sciences, (1975), 64, 1264.

Journ. Of Pharm. Sciences, (1963), 52, 781-791.

Journ. Of Pharmaceutics and Pharmacology, (1975), 28, 94.

Pharmaceutical research, (1994), 11.

Int. Journ.Of Pharm., (2002), 241, 73-85.

Advanced Drug Delivery Reviews, (2007), 59, 617-630.

Chemical Abstract, (2007), 147(12), 1058.

Chemical Abstract, (2007), 146(25), 1729.
39
STUDY QUESTIONS
1) Explain factors affecting crystal habit & its pharma
applications.
(1st internal 2005)
2)Crystallization is inhibited by PVP – Discuss.
(1st internal 2005)
3) Compare crystal and amorphous.
How solubilities of crystal hydrate & solvate differ?
(1st internal 2006)
4) Define: spherical crystallization.
(1st internal 2006)
5) Write a note on spherical crystallization.
(August 2006)
6) Write a note on crystallinity?
7) What are clathrates? Give its pharmaceutical applications?
40
41