;SLJQPOCJPQCDMCCIPWC

1. CRYSTALLISATION
SUBMITTED TO : Dr. Amita Joshi Rana
SUBMITTED BY : Sanjana Bisht
M. Pharm - II sem

2. CONTENT
• Definition of crystallization
• Importance of crystallization
• Crystal and crystal lattice
• Mechanism of crystallization
• Factor affecting crystallization
• Polymorph
• Crystal hydrate and solvate
• Isomorph
• Application

3. CYRSTALLISATION
• Crystallization can be defined as the process through which the
atoms/molecules of a substance arrange themselves in a well-defined three-
dimensional lattice and consequently, minimize the overall energy of the
system. When a substance is subjected to crystallization, its atoms or
molecules bind together through well-defined angles.
• On adding a solid substance in a liquid and stirring it, the solid dissolves in
the fluid. But when added more and more solid to the liquid, a point comes
after which no more solid dissolves in the liquid. This point is called a
saturation point and the fluid is called a saturation solution

4. IMPORTANCE
• Purification of drug
• 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 .

5. CRYTAL LATTICE
• The crystal lattice is the symmetrical three-dimensional structural
arrangements of atoms, ions or molecules (constituent particle) inside
a crystalline solid as points. It can be defined as the geometrical
arrangement of the atoms, ions or molecules of the crystalline solid as
points in space.

6. CRYSTAL LATTICE OF NaCl

9. IMPORTANCE OF CRYSTALLISATION
• Purification
• Improve bioavailability of the drug and choose the most stable form
• A crystalline powder is easily handled , stable , posses good flow properties
and an attractive appearance .

12. SUPERSATURATION
• When the concentration of the compound in its solution is greater than the
saturation solubility of that compound in that solvent the condition is known
as super saturation .
• This is an unstable state
• From this supersaturates solution the excess compound may be precipitated
out or crystallize .

13. Super saturation can be achieved by the following methods :
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 .

14. • The driving force needed for the nucleation and growth of a crystal is referred to as
supersaturation and is defined as the difference in chemical potential between a
molecule in solution and that in the bulk of the crystal phase: µ = µs − µc where µs
is the chemical potential of a molecule in solution and µc is the chemical potential
of the molecule in the bulk crystal. Following thermodynamics can be expressed as
µ = kT ln S
• where k is the Boltzmann constant, T is the absolute temperature, and S is the
supersaturation ratio. When µ > 0 the solution is said to be supersaturated, meaning
that nucleation and/or growth is possible, whereas when µ < 0 the solution will be
undersaturated and dissolution will take place.

15. MIER’S SUPERSATURATION THEORY
• In the year 1927, Miers, SIR, H.A. postulated a theory on super saturation. Miers theory
explains growth of nuclei with respect to super solubility and solubility curve under some
limitations
• . Let us know first about solubility curve. When equilibrium is attained at final temperature,
mother liquor becomes saturated in crystallization process and rate of formation of nucleus
is balanced by the rate of dissolution of nucleus.
• The equilibrium relationship is the solubility curve. Solubility data for different solids had
been expressed as function of temperature. Solubility chart displays various types of profiles
like curves with positive and high slope (KNO3), positive and very low slope (NaCl),
negative slope (MnSO4−H2O).

16. • For most of the materials, solubility curves follow firstly i.e. high and positive
slope. Solubility curve represents the maximum concentration of solutions
that can be obtained by bringing solute into equilibrium with solvent. This
curve represents final concentration of mother liquor toward which
supersaturated solution approaches. Super saturation is attained by
decreasing temperature of highly concentrated solution or decreasing
amount of solvent by evaporation or by both.

17. AB − super solubility curve, CD − solubility curve, E − Feed
location, under saturation, F−solution cools to saturation, G −
Metastable zone, nucleation begins, H− Concentration

18. NUCLEATION
• nucleation, the initial process that occurs in the formation of a crystal from
a solution, a liquid, or a vapour, in which a small number of ions, atoms, or
molecules become arranged in a pattern characteristic of a crystalline solid,
forming a site upon which additional particles are deposited as the crystal
grows.

20. • The rate of nucleation (i.e., the number of nuclei formed per unit time per
unit volume) can be expressed by an Arrhenius-type equation:

21. • where A also depends on supersaturation. A typical plot of J as a function of
supersaturation (S) . It can be seen in this plot that the nucleation rate is
virtually zero until a critical value of supersaturation is achieved, after which
the rate increases exponentially. This critical supersaturation (µc) defines the
so-called metastable zone where crystal growth can proceed without
concomitant nucleation taking place.

23. CRYSTAL GROWTH
• Crystal growth is the series of processes by which an atom or a molecule is incorporated into the
surface of a crystal, causing an increase in size. These different processes can be summarized into
four steps
• 1) transport of atoms through solution;
• 2) attachment of atoms to the surface;
• 3) movement of atoms on the surface;
• 4) attachment of atoms to edges and kinks.
• The first process is the so-called transport process, whereas 2–4 are referred to as surface
processes (and may involve several substeps). Since these different steps normally occur in series,
the slowest process will control the overall crystal growth. Therefore, growth can be transport
(when step 1 is the slowest) or surface controlled (when steps 2–4 are the slowest).

24. FACTOR AFFECTING
CRYSTALLISATION
• In making icings, frostings, or candy like fondant and fudge, it is necessary to
crystallize the sugar solution. For crystallization to occur, nuclei must form in
the solution. To these nuclei the material of the solution is added to form
crystals. Both the rate of formation of nuclei and the rate of crystallization
are affected by the nature of the crystallizing substance, the concentration,
the temperature, agitation, and the impurities present in the solution .

26. • Nature of the crystallizing substance: Some substances like salt crystallize
readily from water solution. It requires only a very slight super-saturation to
start nuclear formation, and all excess salt in the solution beyond the
saturation point is precipitated as crystals. Some substances do not form
nuclei or crystallize so readily as salt. With sucrose it is often necessary to
have a considerable degree of supersaturation before crystallization
commences. Sucrose crystallizes more readily than levulose.

27. • Formation of nuclei: Nuclei cannot form and crystallization cannot occur except from a
supersaturated solution. The formation of nuclei, that is the uniting of atoms to form
nuclei, is influenced by several factors. If a solution is left to stand, a few nuclei may form
spontaneously in various places, and from these nuclei crystallization proceeds. When only a
few nuclei develop spontaneously in the solution, the crystals grow to large size. Usually
nuclei formation and crystallization do not begin immediately after supersaturation occurs.
* The rate of nuclear formation may be favored by specks of dust in the solution. Agitation
or stirring of a solution increases the rate of nuclear formation. A drop in temperature at
first favors, and then retards, the formation of nuclei. Instead of spontaneous formation of
nuclei, seeding a solution may be used to start crystallization.

28. • Seeding: When crystals of the same material are added to start crystallization the
process is called seeding. These crystals serve as nuclei for crystal growth.
• If the quantity of crystals added is large and the size of the crystals small, it serves
as many nuclei in the solution and the resulting crystals are small.
• If the quantity of material added is very small, the nuclei formed are few in number
and the crystals formed are large. One may think of all crystals as being large
enough to be visible, whereas many of them may be very small, so small in fact that
they may float in the air.
• If crystals are floating in the air there is the possibility that they may serve to seed
solutions, and thus start crystallization.

29. • Temperature at which crystallization occurs: It is a well-known fact that, in
general, chemical precipitates come down more coarsely crystalline if
crystallized at high temperatures. The sugars follow this general rule. Other
things being equal, i.e., concentration, etc., the higher the temperature at
which crystal formation occurs, the coarser the crystals formed.

30. • Concentration of the solution: A more concentrated solution favors the formation
of nuclei. Fondant syrup cooked to 114°C. Contains less water and is more
concentrated than one cooked to 111°C. Thus nuclei form more readily in the one
cooked to 114°C. Large, wellshaped crystals form more readily if the degree of
supersaturation is not too great. The most favorable supersaturation for crystal
growth, of a sucrose solution boiled to 112°C, is that between 70° and 90°C.
Although crystallization occurs in a very short time when the syrup is stirred at
these temperatures, the crystals formed are larger than when the syrup is cooled to a
lower temperature. Supersaturation and a low temperature are desirable for the
development of small crystals.

31. • Rate of crystallization: To the nuclei formed in the solution new molecules
from the solution are deposited, in a regular order or manner, so that each
crystal has a typical shape. One side or face of a crystal may grow more
rapidly than another. The rate at which the nuclei grow to larger size is called
the rate of crystallization. The rate may be favored by the concentration of
the solution and its temperature; it may be hindered by foreign substances.

32. • Interfering substances: Some products can be added prevent the formation
and growth of crystals. These products such as cream, butter, egg white etc.,
are called interfering agents. The agents coat the crystals and prevent the
growth of large crystals.

33. Polymorph
• Certain drugs can exist in more than one crystalline form . Such a
phenomena is known as polymorphism . About 63 % of barbiturates ,67 %
of steroids and 40% of sulphonamides exhibit polymorphism .
• Although the drug is chemically indistinguishable in each form , polymorphs
differ significantly with respect to a number of properties such as density ,
melting point , solubility and dissolution rate .

35. HYDRATES
Hydrate, any compound containing water in the form of H2O molecules,
usually, but not always, with a definite content of water by weight. The best-
known hydrates are crystalline solids that lose their fundamental structures
upon removal of the bound water. Exceptions to this are
the zeolites (aluminum silicate minerals or their synthetic analogues that contain
water in indefinite amounts) as well as similar clay minerals, certain clays, and
metallic oxides, which have variable proportions of water in their hydrated
forms; zeolites lose and regain water reversibly with little or no change in
structure.

36. Examples of hydrates are Glauber’s salt (sodium sulfate decahydrate,
Na2SO4∙10H2O); washing soda (sodium carbonate decahydrate,
Na2CO3∙10H2O); borax (sodium tetraborate decahydrate, Na2B4O7∙10H2O); the
sulfates known as vitriols (e.g., Epsom salt, MgSO4∙7H2O); and the double salts
known collectively as alums (M+
2SO4∙M+3
2(SO4)3∙24H2O, where M+ is a
monopositive cation, such as K+or NH4+, and M3+ is a tripositive cation, such
as Al3+ or Cr3+).

37. Crystal solvate
• Crystal solvates tend to form during the process of crystallization with the help of a
solvent. The crystalline solids that contains the molecules of solvent inside their
crystal assembly (stoichiometrically or nonstoichiometrically) are known as solvates,
also inappropriately, pseudopolymorphs. When water is the solvent molecule, then,
the so formed solvates are termed as “hydrates”
• AMORPHOUS APIs :Producing Amorphous Active Pharmaceutical
Ingredients offers an enhanced drug release that is caused by the increase in
its dissolution rate . This improvement enables higher bioavailability and
bioactivity of such solid APIs.

38. • ISOMORPHS :
• When two or more substances posses the same crystalline form they are
called isomorph .
AMORPHOUS APIs :Producing Amorphous Active Pharmaceutical Ingredients offers an
enhanced drug release that is caused by the increase in its dissolution rate . This improvement
enables higher bioavailability and bioactivity of such solid APIs.

39. APPLICATION
• Purification of seawater
• Separation of alum crystals from impure samples
• In the pharmaceutical industry, crystallization is used as a separation and
purification process for the synthesis and isolation of co-crystals, pure active
pharmaceutical ingredients (API), controlled release pulmonary drug
delivery, and separation of chiral isomers.

40. APPLICATION
• Purification of drugs
• Better processing characteristics such as compressibility and wettability of
drug .
• Easy handling transport and storage
• Improve the bioavailability
• Drugs in different crystal from used in the production of certain sustained
release drug .

41. REFERENCE
• https://byjus.com/chemistry/crystallization/
• https://www.syrris.com/applications/what-is-crystallization-and-what-are-
the-methods-of-crystallization/
• http://epgp.inflibnet.ac.in/epgpdata/uploads/epgp_content/S000444FN/P
000546/M011693/ET/146279496638et.pdf
• https://www.researchgate.net/figure/Factors-which-affect-the-
crystallization-of-a-drug-substance_fig2_221927380

42. • https://application.wiley-vch.de/books/sample/352732514X_c01.pdf
• https://www.researchgate.net/figure/General-Methods-to-Prepare-
Polymorphs_fig3_280763463/download
• https://www.britannica.com/science/hard-water
• http://nsdl.niscair.res.in/bitstream/123456789/598/1/corrected%20crystalli
zation.pdf