Crystallization

 

Syllabus:

Characteristics of crystals like – purity, size, shape, geometry, habit, forms. Factors affecting them.

Solubility curves and calculations of yields. Material and heat balances around Swensen Walker Crystallizer.

Supersaturation theory and its limitations. Nucleation mechanisms, crystal growth.

Study of various types of crystallizers: Tanks, Agitated batch, Swensen Walker, Single vacuum, circulating magma and Krystal crystallizer. Caking of crystals and its prevention, numerical problems on yields.

 

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

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

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

·        The units that constitute the crystal structure are atoms, ions or molecules.

·        Ions with opposite charges are bonded together by electrostatic attraction e.g. Na⁺ and Cl^– ions bonded in NaCl crystals.

·        Atoms are bonded together by covalent bonds e.g. C atoms are bonded by covalent bonds in diamond and graphite.

·        Molecules of organic compounds are bonded by van der Waal’s force and / or hydrogen forces. E.g. Naphthalene, p-hydroxy benzoic acid.

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] e.g. Sodium chloride and potassium chloride crystals.

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. Urea and potassium dihydrogen phosphate crystals.

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 e.g. Barium sulphate crystals.

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.  Ice and thymol crystals.

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. Sucrose and Ephedrine chloride crystals.

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. Phenolphthalein and Copper sulphate.

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 e.g. Nalidixic acid

Columnar e.g. Fluorocortisone acetate

Blade e.g. Resorcinol

Plate e.g. Naphthalene

Tabular e.g. Tolbutamide

Equant e.g. Sodium chloride etc.

Purity of crystals

A well formed crystal is nearly a pure chemical. Some times it retains mother liquor when removed from the final magma. If the product contains crystal aggregates then considerable amount of impure mother liquor may be entrapped inside the product. When this mother liquor is dried on the crystals, contamination results.

In practice most of the mother liquor is removed from the crystals by centrifuging or filtration and the balance is removed by washing with fresh solvent.

IMPORTANCE OF CRYSTALLIZATION

·        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.

Factors affecting the crystal habit

1. Presence of another substance in the 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.

2. Solvent:

Griseofulvin crystallized out from acetone has different crystal habit than when crystallized from benzene or chloroform.

3. Rate of cooling:

Acicular or needle-like crystals are produced when the solution is cooled very slowly. Fluffy and small crystals are produced when the solution is cooled very fast.

THEORY OF CRYSTALLIZATION

Mechanism of crystallization

The formation of crystals from solution involves three steps:

A.     Supersaturation

B.     Nucleation (or nucleus formation)

C.     Crystal growth

A. Supersaturation

When the concentration of a compound in its solution is 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 escess compound may be precipitated out or crystallize.

Supersaturation 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 in situ

4.      Addition of a substance, which is more soluble in solvent than the solid to be crystallized.

B. Nucleation

Nucleation refers to the birth of very small bodies of molecules from which the crystal forms.

·        In solution, solute molecules, ions or atoms remain in constant random motion. This is due thermodynamic energy of the solution system.

·        When the solute particles (molecules, atoms or ions) moves and collide over each other they may form aggregates. This aggregates are called clusters. These are loose aggregates, which usually disappear quickly.

·        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.

·        Some embryo may grow to such a size that it remains in thermodynamic equilibrium with the solution. They do not revert back to clusters. These bodies are called nucleus (plural is nuclei).

 

C. 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.  From the bulk solution a solute particle (molecule, atom or ion) diffuse through this stagnant layer and then reaches the surface of the crystal. This 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.

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, nuclei formation is extremely rapid.

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.

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

·        Here the curve AB is the ordinary solubility (equilibrium) curve. It  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 points nuclei cannot form and crystallization cannot start.

Limitations of the Mier’s theory

1.      According to Mier’s theory, crystallization starts at super-solubility 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.

[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. ]

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.

[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.]

5.      During crystallization the solution may become contaminated with dust, particles from container etc. Nucleation may be initiated from these foreign particles also.

Solubility curves

Solubility of a solute depends on the temperature. When the solubility (of a saturated solution) of a solute is plotted against temperature the curve is known as solubility curve. Temperature is plotted in X-axis and solubility is plotted in Y-axis. The metastable condition is shown by dotted line.

The following solubility curves may be observed with various solutes:

1.      Curve-1 represents potassium nitrate (KNO₃). This is most common type in which the solubility of a substance increases with temperature.

2.      Curve-2 represents sodium chloride (NaCl). The solubility increases with increase in temperature, but to a marginal extent.

3.      Curve-3 represents sodium thiosulphate (Na₂S₂O₃). Here solubility increases rapidly with temperature. But inflections are observed in the curve to represent different hydrates.

4.      Curve-4 represents sodium carbonate (Na₂CO₃). This curve is unusual. Here solubility of sodium chloride increases with temperature, if it is in hydrated form.. Once the compound turns in to mono-hydrate form, its solubility decreases.

Calculation of yields

A solution of a substance is taken. The concentration of the solute in the solution is noted.

The solution is evaporated or cooled to make it supersaturated solution. The excess solute crystallizes out of the solution and the mother liquor at the end of the crystallization process is nothing but a saturated solution. The solubility is the saturation solubility at that temperature. This saturation solubility at that temperature is determined from the solubility curve.

During evaporation some amount of solvent is evaporated.

Material may crystallize out in pure form or as hydrates.

Problem:

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.

Solution

In the original mixture

MgSO4                 30% x 1000kg     = 300kg

Free water            70% x 1000kg     = 700kg

Total                                                   = 1000kg

Water evaporated = 5% of free water in the original mixture = 5% x 700kg = 35kg

MgSO₄ crystallizes out in the form of  MgSO₄, 7H₂O (7 molecules of crystal water)

Let, m kg of (MgSO₄, 7H₂O) crystal forms from 1000kg of original mixture.

Molecular weight of MgSO4 = 120.4 and MgSO₄, 7H₂O = 246.5

Therefore, m kg MgSO₄, 7H₂O crystal contains        m kg of  MgSO₄.               = 0.488 m kg MgSO₄.

and         m kg water                       = 0.511 m kg H₂O

In the final mixture

MgSO₄, 7H₂O crystal                       = m kg

MgSO₄ left in the mother liquor    = (300 – 0.488m) kg

Water left in the mother liquor      = (700 – 35 – 0.511m) kg = (655 – 0.511m) kg

From the solubility curve of MgSO₄ in water it is found that at 18⁰C the solubility of MgSO₄ is 24.5%.

So in the final mixture at 60⁰F       MgSO⁴                  =             24.5kg

                                                            Free water            =             (100 – 24.5) kg  = 75.5 kg

Therefore,                          Solving this equation will yield, m = 261 kg

CRYSTALLIZERS

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

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

Construction:     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.

Working principle:           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.

Use:

Krystal crystallizer is preferred when large quantities of crystals of controlled size is required. For example in sodium chloride and magnesium sulphate crystallization.

CAKING OF CRYSTALS

What is caking?

Caking can be defined as the process of formation of clumps or cakes when crystals are improperly stored.

Crystal powders can absorbs moisture when the humidity of the air is above the critical humidity. Below this critical humidity the crystals do not absorbs moisture while above the critical humidity the crystals absorbs moisture and forms a saturated solution on the surface of the crystals. When temperature of the crystals are cooled (due to some reason) or the water is evaporated from the surface, the extra solute crystallize out and thus may form solid bridges in between two adjacent crystals, called crystal bridges. Thus the crystal particles will join together to form hard aggregate. This aggregates or lumps are called caking.

Problems of caking

After caking the flow properties of the powder decreases. Powder will not flow uniformly from the hopper into the die-cavity of tablet punch machine. Capsule filling will not be uniform. Filling of pouches will not be uniform.

Factors affecting caking

1.      Size of the crystals: Smaller crystals have a greater tendency of caking than larger crystals because powder of smaller crystals have less void so greater number of contact points. More the number of contact points greater number of crystal bridges will be formed.

2.      Shape of the crystals: Spherical shape posses the least possible points of contacts than any other form. Hence, the distorted crystals tends to more caking than spherical particles.

3.      Humidity: The higher the humidity of the atmosphere to which crystals are exposed, more will be the rate of caking.

4.      Time of exposure to moisture: The higher the time of exposure, the more will be the caking, provided that the atmosphere has humidity more than critical humidity.

5.      Impurities in the crystals: The crystals may be coated with impurities from the mother liquor. This may increase the value of critical humidity. For example MgCl₂ and CaCl₂ alters the critical humidity of NaCl crystals.

6.      Melting points of crystals: If the melting point of the crystals are near room temperature then at slightly high temperature they will melt and at low temperature they will fuse to form crystals and thus increases caking.

7.      Temperature fluctuations: When temperature is increased solubility of crystals increases. Subsequent decrease of temperature will produce a supersaturated solution from which crystals will be precipitated. So fluctuations of temperature produce crystals rapidly.

Prevention of caking

1.      Crystals must be more spherical in shape, with least points of contact.

2.      Crystals must be larger in size with more voids ad must be of a narrow size distribution (i.e. must be more uniform in size).

3.      Crystals are packed and stored in atmosphere where the humidity is less than critical humidity.

4.      Crystals may be coated with powdery inert material to prevent absorption of moisture like NaCl is coated with magnesia (MgO) or tricalcium phosphate

Questions

1.      What are crystal forms? Classify them. [2+2]

2.      What is crystal habit? Give example. What are the factors affecting the crystal habits. [2+2+3]

3.      Write short note on purity of crystals. [3]

4.      Write the theory of crystallization. [6]

5.      Discuss the Mier’s theory of crystallization. What are its limitation? [8]

6.      What do you mean by solubility curve of a compound? Give examples. [4]

7.      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. [6]

8.      Describe the design and operation of Swensen-Walker crystallizer with diagram. [8]

9.      Describe the design and operation of vacuum crystallizer with diagram. [8]

10.   Describe the design and operation of Krystal crystalliser with diagram. [8]

11.   What is caking of crystals? What are the factors affecting caking of crystals? How caking can be prevented? [2+5+3]






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