ALL ABOUT CRYSTALLIZATION CRYSTALLIZATION BASICS OF CRYSTAL PREPARATION OF CRYSTAL APPLICATION AND ALL.

1. CRYSTALLIZATIO
N
1

2. PRESENTED BY: AZMIN M MOGAL ( M PHARM; SEM-II)
GUIDED BY: Mrs. MONIKA KAKADIYA
DEPARTMENT: Pharmaceutical chemistry
SUBJECT: Pharmaceutical process chemistry
SUBJECT CODE: MPC204T
TOPIC: Crystallization
COLLEGE: Shree Dhanvantary Pharmacy College, kim
2

3. • Crystallization is a separation technique that is used to separate solid that
has dissolved in a liquid. The solution is warmed in an open container,
allowing the solvent to evaporate, leaving a saturated solution.
As the saturated solution is allowed to cool, the solution will separate out
of the solution and crystals will start to grow. The crystals can be collected
and allowed to dry.
• The size of the crystals depends on the rate of cooling;
1.Fast cooling: Large number of small crystals.
2. Slow cooling: Smaller number of large crystals.
3

4. DEFINITIO
N:
“Crystallization is a chemical solid–liquid
separation technique, in which mass
transfer of a solute from the liquid solution
to a pure solid.”
4

5. •Spontaneous arrangement of the particle
into a repetitive order.
•i.e regular geometric patterns.
5

6. CRYSTALS
:
• Crystal can be
defined as a solid
particle, which is
formed by the
solidification process
under suitable
environment in which
structural units are
arranged by a fixed
geometric pattern or
lattice. CRYSTAL STRUCTURE OF NaCl
6

7. • The smallest Geometric portion, Which repeats to build up the
whole crystal is called a UNIT CELL.
7

8. In the Crystal, the
angle between the two
perpendiculars to the
intersecting faces is
termed as the axial
angle.
Axial length can be
defined as distance
between the centre of
two atoms.
8

9. • A definite number of symmetrical arrangement are
possible for a crystal lattice and these may termed
as crystal forms or crystal system.
• A chemical substance may exists more than one
crystalline form is called polymorphs and these
phenomenon is called polymorphism.
9

10. Methods of Polymorph Preparation
Most of the polymorphic transitions occur spontaneously or by induction of
some specific conditions, and generally require a complete solid-state
characterization of the API and the excipients. Now-a-days, there is an increased
interest between the formulation and medicinal scientists to explore the various
possibilities of the polymorphic transitions in-situ and exformulation, generally
as a component of preformulation studies. Therefore, many new methods have
been investigated to induce the polymorphic transitions and this section will
discuss a few most employed ones in brief. Figure 3 highlights the frequently
reported methods for the polymorphic transitions in the APIs or so-called
methods to prepare polymorphs.Most of these methods are neither novel nor
new, but extension of the routinely employed crystallization techniques for
various organic molecules including proteins.
10

11. 11

12. • Crystalline solid have definite shapes and orderly arrangement
of the unit.
• They have low solubility and dissolution.
• Amorphous Solid: They do not have specific shape Amorphe
means without form Randomly arrangement of solid particles in the
structure.
12

13. • CRYSTAL
HYDRATES:Some drugs have greater tendency to associate with water.
•The resulting product or substance is called Drug hydrates
e.g. Na2CO3. 10H2O
13

14. • CRYSTAL
SOLVATES:
Some drugs have greater tendency to associate with Solvents to
produce crystalline forms of solvates
•The solvates are also called pseudomorphs.
•ISOMORPHS :
When two or more substances posses the same crystalline form
they are called as isomorphs.
14

15. CHARACTERISTICS OF CRYSTAL:
1. Crystal lattice
2. Crystal system or
forms
3. Crystal habit
15

16. CRYSTALLIZATION PROCESSES:
A) Cooling Crystallization
B) Evaporative Crystallization
16

17. COOLING
CRYSTALLIZATION
:
• The cooling crystallization can be applied when the solubility
gradient of the solution increases steeply with falling temperature or
when a vaporization of the solvent has to be avoided.
EVAPORATIVE
CRYSTALLIZATION:
• Generating crystals by evaporating a solution at const. temperature
• Most of the industrial crystallizers are evaporative
17

18. CRYSTALLIZERS:
Crystallizer can be of 3 types:
•Batch type crystallizer
•Continuous type crystallizer
•Forced circulation type crystallizer
18

19. 19

20. A typical
laboratory
technique for
crystal formation
is to dissolve the
solid in a
solution in which
it is partially
soluble, usually
at high
temperatures to
obtain
supersaturation.
The hot mixture
is then filtered to
remove any
insoluble
impurities. The
filtrate is allowed
to slowly cool
20

21. 21

22. MECHANISM OF
CRYSTALLIZATION:
Three major steps are involved in crystallization:
•Super Saturation.
•Nucleation.
•Crystal Growth.
22

23. 1.Super Saturation of the solution :
Supersaturation can be achieved by the
followingmethods:
1.Evaporation of solvent from the solution.
2.Cooling of the solution.
3.Formation of new solute molecule as a result of
chemical reaction
4.Addition of a substance, which is more soluble
in
solvent than the solid to be crystallized.
23

24.  When the concentration of a compound in its
solutionis greater than the saturation solubility of that
compound in that solvent the condition is known
as supersaturation.
This is an unstable state.
From this supersaturates solution the excess
compound may be precipitated out or crystallize.
24

25. susupersaturatipersaturatioonn
Under-saturation
(protein remains soluble; crystals dissolve)
Precipitatant concentration (salt, PEG etc.)
Nucleation zone
Precipitation zone
Solubility
curve
Metastable zone
Crystals grow,
but
Nuclei form
only infinitely
slowly
25

26. 2.Nucleation:
 Step where solute molecules dispersed in the solvent start
to gather into clusters on the nanometer scale.
 Some clusters may become so big that they may arrange
themselves in lattice arrangement. These bodies of
aggregates are called embryo.
 However, embryos are unstable and they may break into
clusters again.
 These stable structures together form a nuclei.
 It is at the stage of nucleation that atoms arrange in
periodic manner to form crystal structure.
26

27. 3.Crystal Growth:
“Crystal growth is a diffusion process and a surface phenomenon.
Every crystal is surrounded by a layer of liquid known as stagnant
layer.
•Once the crystals are formed, nuclei formation stops and crystal
growth begins.
•From the bulk solution a solute particle (molecule, atom or ion)
diffuse through this stagnant layer and then reaches the surface of
the crystal.
•These particles then organize themselves in the crystal lattice.
This phenomenon continues at the surface at a slow rate. This
process will happen if the bulk solution is supersaturated. 27

28. Crystallization Principles
Figure 1: Typical phase diagram. The components in
solution consist of the product (ordinate) and the
precipitating reagent (abscissa). The lines with arrows
out line one possible way of performing the
crystallization.
- The supersaturation must be above the a
certain value before nucleation will begin
- Metastable region : the supersaturation is
low that nucleation will not start
- Once the supersaturation has been raised
enough to be in the labile region, nucleation
can begin.
- At this point, crystals begin to grow, and the
supersaturation decreases
- If the supersaturation becomes too high, the
nucleation rate will be too great, and
amorphous precipitate will result.
28

29. 24
 Batch Crystallization
Process
 The change in solubility is accomplished by:
 decreasing the temperature of the solution
 Changing composition of solvent by adding a solvent
in
which the compound is insoluble
 In some cases crystallization is not achieved by a change
in solubility →reacti e crystallizatioŶǀ
 Formation of solid particles within a homogeneous phase by
modifying the solubility of the component of interest
V
Solutes
and
Solvents
j = 1..N
k = 1..M
Solutes
S
k
C
j
V
i
T
i
i
i
j =
1..N
k =
1..M
S
k
C
j
T
f
f
f
f
29

30. • Yields and material balance in crystallization
• The solution (mother liquor) and the solid crystals are in contact for
enough time to reach equilibrium. Hence, the mother liquor is saturated
at the final temperature at the final temperature of the process, and the
final process, and the final concentration of the solute in the solution can
be obtained from the solubility curve.
• The yield can be calculated knowing the initial concentration of solute,
the final temperature, and the solubility at this temperature.
• In making the material balances, the calculations are straightforward
when the solute crystals are anhydrous. Simple water and solute material
balances are made. When the crystallizations are hydrated, some of the
water in solution is removed with the crystals as a hydrate.
30

31. MIER’S SUPERSATURATION THEORY:
Mier and Issac proposed a theory explaining a relationship between
supersaturation and spontaneous crystallization.
Mier’s theory points out that :
•The greater the degree of supersaturation, the more chance is of
nuclei formation
•if the super-saturation passes a certain range of values, nuclei
formation is extremely rapid.
31

32. • Assumption:
1. The solute and the solvent must be pure.
2. The solution must be free from solid solute particles.
3. The solution must be free from foreign solid
particles.
32

33. Limitations of the Mier’s theory
1. According to Mier’s theory, crystallization starts at supersolubility
curve (FG). But the general tendency is that crystallization takes place
in an area rather than a line.
2. If the solution is kept for long periods, nucleation starts well below the
super-solubility curve.
3. If the solution is available in large volume, nucleation starts well below
the super-solubility curve.
4. Mier’s theory is applicable only when pure solute and pure solvent is
taken. In practice, it is impossible to get them in pure state.
5. During crystallization the solution may become contaminated with
dust, particles from container etc. Nucleation may be initiated from
these foreign particles also.
33

34. SOLVENT SELECTION FOR CRYSTALLIZATION
CHOOSING A SOLVENT
The first consideration in purifying a solid by recrystallization is to find a
suitable solvent. There are four important properties that you should look for in
a good solvent for recrystallization.
The compound should be very soluble at the boiling point of the solvent and
only sparingly soluble in the solvent at room temperature. This difference in
solubility at hot versus cold temperatures is essential for the recrystallization
process. If the compound is insoluble in the chosen solvent at high
temperatures, then it will not dissolve. If the compound is very soluble in the
solvent at room temperature, then getting the compound to crystallize in pure
form from solution is difficult. For example, water is an excellent solvent for the
recrystallization of benzoic acid. At 10°C only 2.1 g of benzoic acid dissolves in 1
liter of water, while at 95 °C the solubility is 68 g/L.
34

35. The unwanted impurities should be either very soluble in the solvent at
room temperature or insoluble in the hot solvent. This way, after the
impure solid is dissolved in the hot solvent, any undissolved impurities
can be removed by filtration. After the solution cools and the desired
compound crystallizes out, any remaining soluble impurities will remain
dissolved in the solvent.
The solvent should not react with the compound being purified. The
desired compound may be lost during recrystallization if the solvent
reacts with the compound.
The solvent should be volatile enough to be easily removed from the
solvent after the compound has crystallized. This allows for easy and
rapid drying of the solid compound after it has been isolated from the
solution. 35

36. FACTORS AFFECTING CRYSTALLIZATION:
1. PRESENCE OF ANOTHER
SUBSTANCE
2.SOLVENT
3.NUCLEATION
4.CRYSTAL GROWTH
5.RATE OF COOLING
6.TIME
36

37. PRESENCE OF ANOTHER SUBSTANCE IN
MOTHER LIQUOR:
• Sodium chloride crystallized from aqueous solutions produces cubic
crystals.
• If sodium chloride is crystallized from a solution containing a small
amount of urea, the crystals obtained will have octahedral faces.
Both types of crystals belong to the cubic crystal form but differ in
habit.
37

38.  SOLVENT
CONSIDERATIONS:
• Moderate solubility is best (avoid supersaturation).
• Like dissolves like.
• Hydrogen bonding can help or hinder
crystallization.
• Presence of benzene can help crystal growth.
• Avoid highly volatile solvents.
• Avoid long chain alkyl solvents can be significantly
disordered in crystals.
• Choose solvents with “rigid geometries”.
38

39. NUCLEATION
:
• Crystals initially form via “nucleating events”.
• After a crystallite has nucleated it must grow.
• Nucleation sites are necessary.
• Excess nucleation sites cause smaller average crystal
size.
39

40. Crystal Growth:
•Crystals grow by the ordered deposition of the solute molecules onto
the surface of a pre-existing crystal.
•Crystal growth is facilitated by the environment changing slowly over
time.
•Keep crystal growth vessel away from sources of mechanical agitation
(e.g.
•vibrations).
•Set-up away from vacuum pumps, rotovaps, hoods, doors, drawers,
and so on
•Leave samples alone for 1 week, don't “check in” with it. Your
crystalsare not lonely
40

41.  TIME:
• Quality crystals grow best over time in near equilibrium
conditions.
• The longer the time, the better the crystals.
• Faster crystallization is not as good as slow crystallization.
• Faster crystallization higher chance of lower quality
crystals
41

42. 1. Purification of Drugs.
2. Better processing
characteristics.
3. Ease of handling.
4. Better chemical stability.
5. Improved physical stability.
6. Improved bioavailability.
7. Sustained release formulation.
8. Miscellaneous.
OBJECTIVES AND
APPLICATIONS :
42

43. IMPORTANCE OF CRYSTALLIZATION
 purification of drugs .
 improve bioavailability of the drug and choose the most stable form.
 a crystalline powder is easily handled ,stable , possesses good flow
properties and an attractive appearance .
 Crystallization from solution is important industrially because of the
 variety of materials that are marketed in the crystalline form.
 Crystallization affords a practical method of obtaining pure chemical
substances in a satisfactory condition for packaging and storing. A
crystal formed from an impure solution is itself pure (unless mixed
crystals occur).
43

44. • A drug may remain in different crystalline forms, some are stable, and
rests are metastable.
• The metastable forms have greater solubility in water, thus have better
bioavailability. By controlling the conditions during crystallization, the
quantity of metastable to stable forms may be controlled.
• After crystallization water or solvent molecules may be entrapped
within the crystal structure and thus form hydrates or solvates which
have different physical properties that may be utilized in various
pharmaceutical purpose.
• Particles with various micromeritic properties, compressibility and
wettability can be prepared by controlling the crystallization process.
44

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