Crystallization

Topics covered
 Crystallization and related terms.
 Polymorphism
 Significance in pharmaceutical systems
 Importance of the Topic: 2 Journals
(Int. J. Pharmaceutics & J.Pharm. Sci. 2006-2009 , 4 yrs, ~ 300 papers)
 Chemical Compound

Habit Internal structure

Crystalline Amorphous

Single entity Molecular adducts

Non-stoichiometric Stoichiometric
Polymorphs Inclusion complex Solvates (Hydrates)

Channel Layer Clathrate

Fig. Crystal Chemistry of a chemical compound.

Ref. J.K.Haleblian, J.Pharm.Sci., 64(8),1975
 Crystal
 Crystal: is a solid material, whose constituent atoms, molecules, or ions
are arranged in an orderly repeating pattern extending in all three spatial
dimensions.

 Crystal Habit: is the description of the outer appearance of a

crystal. If the environment of a growing crystal affects its external shape
without changing its internal structure (which affects the polymorphism of a
crystal), a different habit results.

 Crystallography: Scientific study of crystals

 Crystallization: Process of forming a crystalline structure from a
fluid or from materials dissolved in the fluid
Crystallization and related terms.
 Atoms and molecules tend to organize themselves into their most favourable
thermodynamic state, which under certain conditions results in their
appearance as crystals

 Crystal is characterized by a highly ordered arrangement of the molecules,

associated with which is a three-dimensional periodicity. The repeating 3d
patterns are ideally depicted as lattice.
 Process of crystal formation

 In the first step (termed Nucleation) tiny crystallites of the smallest

size capable of independent existence (termed nuclei) are formed.

 Molecules of the crystallizing phase then progressively attach

themselves to the nuclei, which then grow to form macroscopic
crystals in the process known as crystal growth.

 If the crystals are now allowed to remain in the saturated medium, the
smaller crystals, which have a slightly greater solubility tend to
dissolve. At the same time, the larger crystals, which consequently
have a lower solubility, tend to grow.
(This process of the growth of larger crystals at the expense of
smaller crystals is sometimes termed Ostwald ripening.)
 Ostwald Ripening

Crystal Growth

Nucleation

Fig. Process of crystallization

 Ostwald Ripening

<<disappear>>

diffusion diffusion diffusion diffusion

once a nucleus is formed at or beyond the critical size it will
continue to grow.
• It can either grow equally rapidly in all directions (Situation i),
• Or the growth may be impaired in one direction (Situation ii ), in which case a

plate results.
• If the growth is impaired in two directions, then a Needle results
TYPES OF CRYSTALS
 Polymorphism
The same...but...maybe
different
 LISTEN

SILENT
Haleblian & McCrone (1969), : Defined Polymorphism as
“A solid crystalline phase of a given compound in the solid
state”. This includes the existence of different conformers of
the same molecule in different polymorphic modifications.

Ref. JPS, 1969.

 Polymorphism

Molecular packing can vary by angle of tilt...

…and by chain packing
The polymorphs of a given compound have different
physicochemical properties :
 melting point,
 solubility and
 density and
 hence, can influence formulation & biopharmaceutical
properties of a drug
 Polymorphism

 Polymorphs are different crystalline forms of the same pure substance in which
the molecules have different arrangements and/or different conformations of
the molecules.

As a result

Polymorphic solids have different unit cells &

hence display different physical properties, including those due to packing, and
various thermodynamic, spectroscopic, interfacial, and mechanical properties.

[ For eg..Acetaminophen (Paracetamol, can exist as a monoclinic form, which

is thermodynamically stable under ambient conditions. The compound can also
be obtained as a less stable orthorhombic form]
 Types of Polymorphs
 Enantiotropic: One polymorph can be REVERSIBLY
changed into another one by varying the temperature or
pressure

 Monotropic : The change between the two forms is

IRREVERSIBLE.
Case Study of Fatty Acids

Stearic acid
18 carbon carboxylic acid
linear molecule

Oleic Acid
18 carbon carboxylic acid
single double bond puts a “kink”
O
C
HO
 List of Physical Properties that Differ Among Various Polymorphs
1. Packing properties
a. Density ,b. Refractive index, c. Hygroscopicity
2. Thermodynamic properties
a. Melting and sublimation temperatures, b. Enthalpy (i.e., Heat content),
c. Entropy, f. Free energy , i. Solubility
3. Spectroscopic properties
a. Electronic transitions (i.e., UV-visible absorption spectra)
b. Vibrational transitions (i.e., IR absorption spectra and Raman spectra)
c. Rotational transitions (i.e., Far IR or microwave absorption spectra)
d. Nuclear spin transitions (i.e., NMR spectra)
4. Kinetic properties
a. Dissolution rate, b. Rates of solid state reactions, c. Stability ,
5. Surface properties
a. Surface free energy ,b. Interfacial tensions c. Habit (i.e., shape)
6. Mechanical properties
a. Hardness , b. Compactibility, c. tableting ,d. Handling, flow, and blending
 Amorphous Forms
 Non-crystalline materials, i.e. no-long range order exists
Analytical Techniques used to study Crystallization

a) X-ray Diffraction
b) Fourier Transform- Infrared Spectroscopy
c) Differential Scanning Calorimetry
d) Microscopy including
 Optical Microscopy
 Scanning Electron Microscopy
 Atomic force Microscopy
e) Nuclear magnetic resonance
Significance
 Acetaminophen
Acetaminophen (30 g) was dissolved in 100 ml methanol at 40 °C. Precipitation was carried
out by adding 300 ml of water (5 °C) continuously over……..min under stirring

120 min. 30 min. 30 sec. 30 sec.

During this process, the temperature was lowered continuously to……..°C

10 °C. 20 °C 2 °C under stirring

over 2 h
The crystals were collected immediately
Small
Large Small plate-like
Large plate-like
Prismatic prismatic crystals
crystals
crystals crystals (=habit
(=habit IV)
(=habit II). (=habit III) V).
induce further crystallization and
crystal growth
Fig. . SEM and microscope pictures of acetaminophen. (a) Habit I; (b) habit II; (c) habit III; (d) habit IV; (e) habit V.
Ref.: B.W.Muller, International Journal of Pharmaceutics 244 (2002) 45–57
 Crystal Habit can affect the properties of a drug, for eg. Tableting
behavior, flowability and the tendency to stick to the punches
influencing the crystal habit of the drug.

 Even for drugs with bad compaction behavior, a habit can be

developed that shows better tableting properties.

 In the case of ibuprofen, a directly compressible form was found

(possible drug content 90%). Also, in the case of acetaminophen,
differences in tableting properties were observed. The importance of
the choice of the optimal crystal form was demonstrated. This has to
be carried out in the first steps of drug formulation development.
 Conclusion
 Crystallinity of a drug can influence the
process of manufacturing of dosage form ,
stability & its overall performance.
Thank You !!