CRYSTALLIZATION

 

Syllabus: Introduction, importance. Theory – nucleation, crystal growth, Mier’s theory. Classification, principles underlying the design and operation of Swenson-Walker, Krystal, Vacuum and growth type of crystallisers. Study of different operation variables in the vacuum and growth type crystallizers.

 

Questions

1.      Discuss the Mier’s theory of crystallization.     (2000)                                                                              [8]

2.      Describe the design and operation of Krystal crystalliser. (2000)                                                                   [8]

3.      What are the different types of nucleation. How are nucleation rates predicted? How is crystal size distribution controlled in industrial crystallisers? (1999)                                                                                 [6]

4.      Derive an expression for crystal growth. Explain the law of crystal growth. (1998)                                    [5]

5.      Sketch and explain working of an evaporator-crystalliser. (1998)                                                                  [5]

6.      A solution containing 30% MgSO₄ and 70% H₂O is cooled to 18⁰C. During cooling 5% of the total water in the system evaporate. How many kilograms of crystals are obtained per kg of original mixture? Crystals formed are MgSO₄, 7H₂O. Concentration of mother liquor is 24.5% anhydrous MgSO₄. (1998)           [6]

7.      Write the importance of crystallization in the bulk production of fine and drug chemicals. Classify the crystallizers and write their uses. [1997]                                                                                [4+4+2]

8.      With the help of a neat diagram, explain the working of Krystal crystallizer. [1996]                                  [8]

9.      Write note on Mier’s supersaturation theory.    [1996]                                                                              [8]

10.   Write a note on Mier’s theory on crystallization. [1995]

11.   Classify crystallization on the basis of attainment of supersaturation.. Discuss in detail any two crystallizers.[1994] [12]

 

INTRODUCTION

Crystallization

Crystallization is the formation of solid particles within a homogeneous phase. It may occur as the formation of solid particles in a vapor, as in snow; as solidification from a liquid melt, as in the manufacture of large single crystals; or as crystallization form liquid solution.

Crystal

A crystal is a regular polyhedral form, bounded by smooth faces, which is assumed by a chemical compound, due to the action of its interatomic forces, when passing, under suitable conditions, from the state of a liquid or gas to that of a solid.

[N.B. A polyhedral form simply means a solid bounded by flat planes (we call these flat planes CRYSTAL FACES). "A chemical compound" tells us that all drugs are chemicals. The last half of the definition tells us that a crystal normally forms during the change of matter from liquid or gas to the solid state. In the liquid and gaseous state of any compound, the atomic forces that bind the mass together in the solid state are not present. Therefore, we must first crystallize the compound before we can study it's geometry. Liquids and gases take on the shape of their container, solids take on one of several regular geometric forms. These forms may be subdivided, using geometry, into six systems. ]

Crystal Lattice is defined as a three dimensional network of imaginary lines connecting the atoms or molecules.

The distance between the center of two atoms (or molecules) is called length of unit cell and the angle between the edges of a unit cell is called as lattice angle.

Crystal Forms

Crystal lattice can be classified according to the angles between the faces. There is only finite number of symmetrical arrangements possible for a crystal lattice, this is termed as crystal forms.

The ability of a compound to exist in different crystal forms is known as polymorphism.

[N.B. The types of crystal-forms has no relationship to the relative sizes of the faces since the relative development of the faces are not constant, only the angles between the faces remain constant. ]

There are six types of crystal forms, depending on the arrangement of the faces expressed as crystal axes and angles between the axes.

1.      Cubic - The three crystallographic axes are all equal in length and intersect at right angles (90 degrees) to each other. [a = b = c]

2.      Tetragonal - Three axes, all at right angles, two of which are equal in length (a and b) and one (c) which is different in length (shorter or longer). Note: If c was equal in length to a or b, then we would be in the cubic system.

3.      Orthorhombic - Three axes, all at right angles, and all three of different lengths. Note: If any axis was of equal length to any other, then we would be in the tetragonal system

4.      Hexagonal - Four axes, three of the axes fall in the same plane and at 60⁰ to each other. These 3 axes, labeled a1, a2, and a3, are the same length. The fourth axis, termed c, may be longer or shorter than the ‘a’ axes set. The c axis also passes through the intersection of the a axes set at right angle to the plane formed by the a set.

5.      Monoclinic - Three axes, all unequal in length, two of which (a and c) intersect at an oblique angle (not 90 degrees), the third axis (b) is perpendicular to the other two axes. Note: If a and c crossed at 90 degrees, then we would be in the orthorhombic system.

6.      Triclinic - The three axes are all unequal in length and intersect at three different angles (any angle but 90 degrees). Note: If any two axes crossed at 90 degrees, then we would be describing a monoclinic crystal.

Crystal Habits

Crystal is a polyhedral solid with number of planar faces. The arrangement of these faces is termed as habit. The crystal habit may change due to changes in rate of deposition, shielding of certain faces, presence of impurities in mother liquor.

e.g. NaCl crystallizes out from aqueous solution with cubic faces only. On the other hand, if NaCl is crystallized from aqueous solution containing a small amount of urea, the crystals are found to have octahedral faces.

Different crystal habits are acicular, columnar, blade, plate, tabular, equant etc.

IMPORTANCE

·        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).

·        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.

·        Desalination of seawater by crystallization method requires only 1/7^th of the energy required by distillation process.

THEORY OF CRYSTALLIZATION

In the formation of crystals two steps are required:

(i) nucleation:               i.e. the birth of a new solute particle and

(ii) crystal growth:         i.e. the growth of the nucleus to macroscopic size.

            For nucleation and crystal growth the solution should be supersaturated that involves Mier’s supersaturation theory.

Mier’s supersaturation theory

Mier and Issac proposed a theory explaining a relationship between supersaturation and spontaneous crystalization.

Mier’s theory points out that

(i)     the greater the degree of supersaturation, the more chance is of nuclei formation,

(ii)   if the super-saturation passes a certain range of values, nucleus formation is extremely rapid.

Assumption:

A solution is taken which is free from any solid particles – neither of solute particle nor any foreign particle.

The theory can be explained with the help of solubilty - supersolubility diagram.

Here the curve AB is the ordinary solubility (equilibrium) curve represents the maximum concentration of solutions that can be obtained by bringing solid solute into equilibrium with solvent.

            If a sample of solution having a temperature and composition of point C is cooled in the direction of CD, it first crosses the solubility curve AB, but no nucleus will be formed. When it reaches some where in the neighbourhood of the point D (according to Mier’s theory) crystallization begins. As the crystallization proceeds the concentration of the solution follows roughly according to the curve DE and reaches the solubility curve.

            In the absence of any solid particles the curve FG represents the limit at which nucleus formation begins spontaneously and, consequently crystallization starts – this line (FG) is called the super solubility curve. According to Mier’s theory at any point between C and D point nuclei cannot form and crystallization cannot occur.

Limitations of the Mier’s theory

            It is doubtful that any exact line such as FG can be drawn that defines the appearance of nucleation because:

It has been shown that if

(a) the time be long enough,

(b) the volume of the solution be large enough,

[N.B. Formation of nuclei depends on the accidental collisions of molecules of solutes into aggregates large enough to persist in the solution. Hence if the volume of the solution is large then the probability of this type of accidental collisions increases. Hence nuclei appears more quickly in large volume solution than from small sample of solution. ]

(c) there be particles of the solute, or

[N.B. Mier’s theory is base on the postulation that the solution consists of pure solvent and pure solute without the presence of any solid particles, whether of solute itself or of any foreign material. In presence of any such solid particles it has been found that crystallization occurs well before the line FG.]

(d) any foreign solid particles be introduced (even in colloidal and amorphous material) crystallization can occur. Hence in practice the existence of a fixed super solubility curve such as FG according to Mier’s theory is no longer possible.

NUCLEATION

            Nucleation refers to the birth of very small bodies of new phase within a supersaturated homogeneous existing phase. Nucleation may take the following steps:

            (a) Primary nucleation

            (b) Secondary nucleation

Primary nucleation

Primary nucleation may be of two types:

            (a) Homogeneous nucleation     (b) Heterogeneous nucleation

Homogeneous nucleation

            When nucleation occurs in a homogeneous solution i.e. free from any solid particles – the phenomenon is called a homogeneous nucleation.

·        Crystal nuclei may form from various kinds of particles: molecules, atoms or ions.

·        Because of their random motion, several of these particles may associate to form a cluster. Clusters are loose aggregation which usually disappears quickly.

·        Enough particles may sometime associate into a lattice-arrangement – called an embryo. Embryos have short lives and revert to clusters or individual particles.

·        But, if the supersaturation is large enough, an embryo may grow to such a size that it will be in thermodynamic equilibrium with the solution. It is called a nucleus, which is the smallest association of particles that will not redissolve and can grow to form a crystal. The number of particles required for a stable nucleus ranges from a few to several hundreds.

·        The sequence of stages in the evolution of a crystal is :

Cluster                   ®           Embryo                  ®           Nucleus                 ®           Crystal

Ostwald ripening

            Thermodynamically a small particle possesses a significantly higher surface free energy per unit mass than large ones.

            Hence the solubility of small crystals are several times higher than the larger ones.

            So when the small and large crystals are both present in a solution, the smaller crystals will dissolve and the larger one will grow until the smaller crystals disappear. This phenomenon is called Ostwald ripening.

Expression for rate of nucleation

            The rate of nucleation, form the theory of chemical kinetics, is given by the following equation:

J = nucleation rate,

R = gas constant = 8.314 x 10⁷

A = frequency factor

T = temperature, ⁰K

DG = Overall excess free energy between the solid particle of solute and solute in solution.

Heterogeneous nucleation

            When microscopic solid particles (called seed) are present in the solution the rate of nucleation becomes rapid. Actually the solid particles catalyze the nucleation rate by reducing the energy required for nucleation. Atmospheric dust may act as seed. (These seeds do not possess the same crystal structure of solute.)

Secondary nucleation

            If the nuclei are formed due to the presence of existing (macroscopical) crystals in the magma then the nucleation is called secondary nucleation.

By two ways secondary nuclei may occur:

            (i) Fluid shear nucleation

            (ii) Contact nucleation

Fluid shear nucleation

            When supersatureated solution moves past the surface of growing crystal at a substantial velocity, the shear stresses in the boundary layer may sweep away embryos or nuclei and thus appear as new crystals.

Contact nucleation

            Collisions between existing crystals with each other or with the walls or with the walls of the crystallizer and rotary impellers or agitator blades

·        usually breaks the microscopic dendritic growth on the surface of the growing crystal to form more clusters and embryos,

·        and hits the clusters of solute particles to become organized into crystals.

CRYSTAL GROWTH

Crystal growth takes place in two steps:

(i)     Diffusional step:      Solute molecules or ions from the supersaturated solution diffuses through the                                     liquid phase to reach the crystal surface.

(ii)   Interfacial step:       On reaching the surface the solute molecules or ions are accepted by the                                           crystal and organized into space lattice.

Derivation of individual and overall growth coefficient

            A molecule is under going two steps – diffusional and interfacial. In both the steps the molecule is experiencing driving forces.

y = mole fraction of solute in the bulk

y’ = mole fraction of solute at the interface

y_s = mole fraction at on the surface of the crystal

    = saturation solubility of the solute

where   y_s  <  y’ <  y.

(y  – y’)            is the driving force due to which the molecule is diffusing         through the liquid to reach the surface of the crystal.

(y’ –  y_s)is the driving force due to which the interfacial step is taking place.

Equation for mass transfer (at the diffusion step)

The equation for mass transfer may then be written as

                    eqn. 1

where   N_A = molar flux, moles per unit time per unit area

             = rate of mass transfer, mol / h            

            s_p  = specific surface area of crystal (vol per unit mass)

            k_y = mass-transfer coefficient

Equation for surface reaction

[N.B. Let us make an analogy of eqn (1) and (2) with V = IR equation where     V = potential difference                                                  = the driving force                                              I  = current = flux                                              R = resistance Say for eqn. (1) ,   and  ]

                 eqn. 2

where,  k_s = coefficient of surface reaction

So the resistances for the two steps are

  and   

If the over all resistance of those two steps are K then             

or,                 or,          or,

Growth rate

For an invariant crystal the volume of the crystal v_P is proportional to the cube of its characteristic length L; i.e.     v_P  =  a L³. where  ‘a’ is a constant.

If r_M is the molar density and the mass of the crystal is ‘m’ then

            m  =  v_P r_M = a L³ r_M      .

Differentiating the above equation

             

The growth rate is denoted by the symbol G

N.B. For a sphere  ,  here diameter, d = characteristic length of a sphere, L For a cube                        , here side, x = characteristic length of a cube. i.e.

For a cubical or spherical crystal, the specific surface area, s_P =  6 v_P / L = 6 a L².

Hence, the overall resistance,

So, the growth rate of crystal,

CLASSIFICATION OF CRYSTALLIZERS

Crystallization equipment is classified by the methods by which supersaturation is bought about. These are as follows:

1. Supersaturation by cooling alone

A. Batch processes

(i) Tank crystallizers

(ii) Agitated batch crystallizers

B. Continuous processes

(i) Swenson-Walker

(ii) Other

2. Supersaturation by adiabatic cooling

A. Vacuum crystallizers

(i) without external classifying seed bed

(ii) with external classifying seed bed

3. Supersaturation by evaporation

A. Salting evaporators

B. Krystal evaporators

TANK CRYSTALLIZER

Procedure

            Hot , nearly saturated solutions are kept in open rectangular tanks in which the solution stood while it cooled and crystals are deposited. No seed is given. Some times rod or strings are hung in the tanks to give the crystals additional surfaces on which the crystals may grow and to keep major part of the product above the bottom of the tank where the sediment is collected (actually the sediment is the source of impurity).

Disadvantages

1.      Crystal growth is very slow.

2.      Crystals formed are large and interlocked, so mother liquor along with impurity gets entrapped within the crystals.

3.      The floor space required and the amount of material tied up in this process are both large.

AGITATED BATCH CRYSTALLIZER

Procedure

            It is a tank with a central shaft running through it. Water is circulated through the cooling coils, and the solution is agitated by the propellers on the central shaft. Product is collected at the bottom of the crystallizer.         It is a batch process.

Advantages

·        The agitation increases the rate of heat transfer and keeps the temperature of the solution uniform through out the crystallizer.

·        Agitation keeps the smaller crystals in suspension and allows them to grow uniformly– thus finer crystals can be obtained.

Disadvantages

·        It is a batch process or a discontinuous one.

·        Since the solubility is least at the cooling surface hence the crystals growth is more rapid on the cooling coils. Thus the crystals deposited on the cooling coils reduces the heat transfer rate.

SWENSON-WALKER CRYSTALLIZER

Description:      It consists of an open trough (A) 2 ft wide, with a semicylindrical bottom. A water jacket (B) is welded to the outside surface of the trough. Inside the trough a slow speed, long pitch, spiral agitator (C) is fitted as close as possible to the bottom of the trough. The agitator rotates at a speed of 7 rpm.

This apparatus is built in units of 10 ft length. Several such units are joined together to give increased capacity.

Procedure:        This is continuous type crystallizer. The hot supersaturated solution is fed at one end of the trough, and the cooling water is flows in the jacket, but in counter current (i.e. opposite to the flow ) to the solution. As the hot solution flows along the trough it is cooled and crystals are formed. Agitator prevents an accumulation of the crystals on the cooling surface and, lift the crystals and shower them through the solution. In this manner perfectly individual crystals are formed.

            At the end of the crystallizer there may be an over flow gate where the mother liquor and the crystals are overflowed in a draining table or drain box,, from which the mother liquor is separated and fed in the crystallizer again. The crystals are sent to centrifuge.

            In another method an inclined screw conveyor lifts the crystals and the wet crystals are send to the centrifuge.

VACUUM CRYSTALLIZER

Principle:         Under vacuum the boiling point of a liquid reduces. So under vacuum a liquid boils under its normal boiling point. If a warm saturated solution is introduced into a vessel in which a vacuum is maintained and the feed temperature is above the (reduced) boiling point of the solution then the solution so introduced must flash (sudden evaporation) and be cooled due to adiabatic evaporation (taking the latent heat from the solution). Cooling will cause supersaturation and thus crystallization. Evaporation will increase the yield.

            Vacuum crystallizers are often operated continuously, but they can also be operated batch-wise.

Construction

            A simple vacuum crystallizer contains no moving parts. The crystallizer is a cone-bottomed vessel (A). The feed enters at any suitable point (B) of the crystallizer and the vapor leaves at point C to go to the vacuum producing equipment. Under vacuum the feed flashes (rapid evaporation) and due to ebullition (formation of bubbles) in the crystallizer the crystals are kept in suspension until they become large enough to fall into the discharge pipe (D), from which they are removed as slurry by a pump (E). 

            There is sometimes a tendency for the feed to short-circuit to the discharge pipe without being flashed (i.e. the feed enters and directly flows into the discharge pipe). For this reason two propellers (F) are installed in the crystallizer to keep the solution thoroughly stirred to prevent the feed solution from reaching the discharge pipe without flashing.

KRYSTAL CRYSTALLIZER

Construction and working principle

            Here A is the vapor head, and B is the crystallizing chamber. For the first time solution is fed into the suction end of the pump (C). Pump sends the feed solution to the heater or cooler (D). The feed then is introduced in the vapor head (A). The vapor is discharged to a condenser and vacuum pump. The operation is so controlled that the crystals are not formed in the vessel A, but the vessel A is prolonged into tube E extended almost to the bottom of vessel B. At the lower part of the vessel B the crystals are formed and are suspended in the liquid. The supersaturated liquid formed in nozzle E passes to vessel B and an upward flow maintains the suspension at the bottom of vessel B.

            At the bottom coarser crystals remain and becomes finer at the top. The coarser crystals are drawn out form time to time through G. The finest crystals, remaining at the top flows again through connection F to the pump which is sent again into the heater or cooled D.




CRYSTALLIZATION---------DOWN LOAD--------ORIGINALL


PHARMACEUTICS THEORY