Crystallization

Vijay Kumar Tirukkachi

 Solids are characterized by incompressibility,

rigidity and mechanical strength. Molecules, atoms or ions that make up a solid are closely packed and held together by strong forces. Based upon the arrangement of molecules, atoms or ions, solids may be of two types a. Amorphous solid b. Crystalline

 An amorphous solid is a substance whose

constituent units do not posses an orderly arrangement over a long range. These are sometimes referred to as super cooled Liquids due to disorderly arrangement like liquids. A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an ordered pattern extending in all three spatial dimensions.

Differences between amorphous and crystalline solids

Crystalline solids
1 2 Have definite geometrical shape Anisotropic : their physical properties like refractive index, thermal and electrical conductivity are different in different direction Have Sharp melting Point Crystals are cleaved along preferred direction with plane surface. 1 2

Amorphous solid
Have no definite geometrical shape Isotropic : their physical properties are same in all directions.

3 4

3 4

Have no Sharp melting Point Amorphous solids on cleavage results irregular surface.

Importance Of Crystallization
During the manufacture of drugs, after the

reaction is completed in solution resulting in the formation of a drug or its intermediate, it must be crystallized out of the solution. This is necessary because crystallization if properly carried out results in the separation of a pure from of the material. In small scale Purity and yield Commercial scale Size, Range of Size and Shape.

Crystal Forms and Crystal Habit

Crystal habit is description of outer appearance of

crystal.
Crystal habit & internal structure of drug can

affect bulk & physicochemical properties of a molecule.

Changes in internal structure usually alters

crystal habit. Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit.

Different types of Crystal forms

INTERNAL STRUCTURE OF A COMPOUND

Crystalline

Noncrystalline

Polymorphs (Single molecules)

Molecular Adducts Nonstoichiometric Complexes StoichiometricComple xs (Pseudopolymorphism ) Hydrates

Enantiotropi c

Monotropic

Organic Solvates

Fig. Classification of internal structure of a compound

Crystallization
Crystallization is a technique which chemists use

to purify solid compounds. Crystallization is based on the principles of solubility: compounds (solutes) tend to be more soluble in hot liquids (solvents) than they are in cold liquids. If a saturated hot solution is allowed to cool, the solute is no longer soluble in the solvent and forms crystals of pure compound. Impurities are excluded from the growing crystals and the pure solid crystals can be separated from the dissolved impurities by filtration.

CRYSTAL GROWTH MECHANISM

Crystal growth is a layer by layer process, which

involves creation of nuclei, followed by growth of nuclei into macroscopic crystals.

The formation of crystals from solutions involves

three steps A. Supersaturation B. Nucleus formation C. Crystal growth

Supersaturation: When the solubility of a compound in a solvent exceed the saturation solubility, the solution becomes supersaturated and the compound may crystallize. Nucleation : once supersaturation is achieved, nucleation is a next essential step for crystallization to occur. in supersaturated solution to form a clusters and to give lattice arrangement finally to form a nuclei this process called as nucleation. Types: primary nucleation Secondary nucleation

Crystal growth : Crystal growth As stable nuclei form, they grow into macroscopic crystals. This portion of the crystallization process is known as crystal growth. This process consists of several stages through which the growth units pass. These include the following: 1. Adsorption of the growth unit at the impingement site.
2. Diffusion of the growth units from the site of

impingement to a growth site.

 If the solution is free from all types of solid particles,

the solution will not begin to crystallize until it has supercooled considerably past the curve AB. According to Meirs supersaturation theory, somewhere in the neighborhod of point D, crystallization begins and the concentration of the substance in solution then roughly follows curve DE. The super solubility curve FG represents the limit at which nucleus formation begins spontaneously and crystallization can start. At any point along the line CD, nuclei formation cant take place and no crystallization occurs.

Conditions for Miers Supersaturation Theory

Solvents must be pure

Free from solid solute particles

Free from foreign solid materials Free from entry of any dust particles Soft crystals shouldnt form during the process Should not be any fluctuation in temperature

Limitation of Miers Theory

It is better to consider the critical supersolubility range not

as a definite line but as an area. If sufficiently long time is given, nuclei can form well below the supersolubility curve. If the nucleus formation depends upon accidental collision of solute molecules, it is possible that the larger the volume of the solution the greater is the chance for such collision. As long as the nucleus formation depends upons accidental combination of the solute molecules to form permanent aggregates, the line FG cannot be drawn. Foreign solid particles or isomorphic particles act as nuclei. But Miers theory deals only with pure solution comparatively free from every particles of solid matter. Greater the degree of supersaturation , the greater is the

Thermodynamics of crystallization
The nature of a crystallization process is governed by

both thermodynamic and kinetic factors, which can make it highly variable and difficult to control. Factors such as impurity level, mixing regime, vessel design, and cooling profile can have a major impact on the size, number, and shape of crystals produced. Whether considering nucleation or growth, the reason for the transformation from solution to solid is the free energy of the initial solution phase that is greater than the sum of the free energies of the crystalline phase plus the final solution phase.

Caking of crystals
The tendency of crystalline material to bind or cake

together is termed as caking of crystals. Caking is troublesome in bulk storage and in large container but most serious in small packages. The extent of caking may vary from formation of a loose aggregates to solid lumps that have to be crushed with considerable force. As consumer demand a free flowing product, prevention of caking is a serious problem for manufacturer. Caking is attributable to a small amount of dissolution taking place at the surface of the crystals and subsequent reevaporation of the solvent. The crystals become very tightly bonded together.

 If the crystals are large so that there are few

points of contact and there is a large free volume between the crystals so there is no appreciable bonding of the crystals, this will lead to caking minimization. If the crystals are fine or have small percentage of voids or are in contact with a moist atmosphere for a long time, sufficient moisture may be absorbed to fill the voids entirely with saturated solution and when this have been reevaporated, the crystals will lock into a solid mass of cake of crystal.

 Caking depends upon

1. Vapor pressure of the solution. If a saturated solution is brought into contact with air in which the partial pressure of water is less than the vapor pressure of the solution, the solution will evaporate. 2. Relative humidity On the other hand, if the air contains more moisture than this limiting amount, the solution will absorb water until it is so dilute that its vapor pressure is equal to the partial pressure of the moisture of the air with which it is in contact.

Following conditions are desirable to prevent caking. 1.Maintaining the highest possible critical humidity: Maximum critical humidity is often obtained by removing impurities such as CaCl 2 or MgCl 2 .These impurities have a lower critical humidity than the product desired. Presence of impurities absorb H 2 O from atmosphere and caking occurs. 2. Uniform crystals with maximum percentage of voids and fewest possible points of contact : To increase the percent of voids, it is not necessary to produce larger crystals but to produce a more uniform mixture. For a given crystal form and for absolutely uniform sized crystals, the percentage of voids is same irrespective of the crystal size. 3. Coating of crystals with inert materials: Inert materials like magnesia or tricalcium phosphate or anhydrous CaCl 2 can absorb moisture and are used to coat the crystals. But this is not always applicable.

Prevention of caking

Types of crystallization
Crystallization may occur naturally or artificially. Natural crystallization: There are many examples of natural process that involve crystallization. Geological time scale process Mineral crystal formation (gemstone), Stalactite/stalagmite, rings formation. Usual time scale process Snow flakes formation, Honey crystallization (nearly all types of honey crystallize).

Artificial Crystallization
Crystals can be produced artificially by any one of the following processes: 1.Supersaturation by cooling alone 2. Supersaturation by evaporation of the solvent 3. Supersaturation by adiabatic evaporation i.e. cooling and evaporation

4. Supersaturation by salting out

1.Supersaturation by cooling alone It is applicable for those substances that have a steep solubility curve where the solubility of the substance rapidly decreases with reduction in temperature. The solution is generally concentrated in a separated evaporator and then fed in to the crystallizer. Batch crystallizers i. Tank crystallizers ii. Agitated batch crystallizers Continuous crystallizers i.Swenson-Walker crystallizer

2. Supersaturation by evaporation of the solvent In the crystallization of substances like common salt where the solubility of curve is either flat or not too steep and the yield of the solid by cooling alone is negligible. Krystal crystallizer

3. Supersaturation by adiabatic evaporation i.e. cooling and evaporation This method is most important for large scale production. If a hot saturated solution is introduced into a crystallizer in which sufficient vacuum is maintained with the total pressure less than the vapor pressure of the solution at the temperature at which it is introduced, the solution must flash and be cooled by the resulting adiabatic evaporation, thus attaining the desired supersaturation crystallization. Vacuum crystallizers A. without external classifying seed bed B. With classifying seed bed

4. Supersaturation by salting out Supersaturation by salting out is carried out by adding another substance that reduces the solubility of the substance in solution to such an extent that the desired solute separates or crystallizes out of the solution.

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