Crystallization

Definition:

It is the (natural or artificial) process of formation of solid crystals precipitating from a solution, melt or more rarely deposited directly from a gas.

Crystallization is also a chemical solid-liquid separation technique in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs.

Process of crystallization:
There are two major events in the process of crystallization

a. Nucleation
b. Crystal growth

Nucleation:
A step where the solute molecules dispersed in the solvent start together into clusters on the nanometer scale. These become stable under the current operating conditions.
However, when the slucters are not stable they redissolve. Therefore, the clusters need to reach a critical size in order to become stable nuclei.
It is at the stage of nucleation that the atoms arrange in a defined and periodic manner that defines the crystal growth.

Crystal growth:
It is the subsequent growth of the nuclei that succeed in achieving the critical cluster size.
Supersaturation:
Nucleation and crystal growth continue to occur simultaneously while the supersaturation exists.

Supersaturation is the driving force of the crystallization hence the rate of nucleation and growth is driven by the existing supersaturation in the solution.

Once the supersaturation is exhausted, the solid-liquid system reaches equilibrium and the crystallization is complete.

Polymorphism:
Many compounds have the ability to crystallize with different crystal structures a phenomenon called polymorphism.

Each polymorph is in fact a different thermodynamic solid state crystal polymorphs of the same compound exhibit different physical properties such as dissolution rate, shape and melting point etc.

So, polymorphism is of major importance in industrial manufacture of crystalline product.

Artificial method for crystallization:
For crystallization to occur from a solution, it must be supersaturated. This can be achieved by solution cooling, addition of a second solvent to reduce the solubility of the solute (techniques known as antisolvent or drawn out), chemical reaction or change in pH being the most common methods used in industrial practice.

Other methods such as solvent evaporation can also be used.

Applications:
Crystal production such as powdered slat for food industry, silicon crystal wafer production and production of sucrose from sugar beet, where the sucrose is crystallized out from an aquous solution.

Purification:
Crystallization separates out a product from a liquid (feedstream) often in extremely pure form by cooling the feedstream or adding precipitants which lower the solubility of the desired product so that it forms crystals.

Well formed crystals are expected to be pure because each molecule or ion must fit perfectly into the crystal as it leaves the solution.

Apparatus for crystallization:
Tank crystallizers:
Saturated solutions are allowed to cool in open tanks. After a period of time the mother liquid is drained and the crystals removed. In this method, nucleation and size of crystal are difficult to control. Labor costs are high.

Scrapped surface crystallizers:
One type of scraped surface crystallizer consists of Swensen-Walker crystallizer consisting an open of an open trough 0.6 meter wide with a semicircular bottom having a cooling jacket outside.

A slow speed spiral agitator rotates and suspends the growing crystals on turning the blades pass close to the walls and break off any deposits or crystals on the cooled wall.

Adsorption

Definition:

“it is a phenomenon in which accumulation of a substance at the boundary on interface between the hetergenous phases takes place.”

Explanation:
It is difficult from absorption, as the absorption is the distribution of a substance throuth the bulk solution while adsorption is a surface phenomenon.

Sorption:
It is sometimes very difficult to define clearly the interface of highly porous solids, so for these system the term sorption is used as we cannot distinguish wether it is adsorption or absorption.

The substance that is attached to the surface of the solid is called adsorbate and the surface on which it gets adsorption is called adsorbent.

Occurance:
Adsorption can occur on following interfaces:

• Solid/Liquid
• Solid/gas
• Liquid/gas
• Liquid/liquid

Since adsorption is a surface phenomenon. The most effective adsorption are those with high surface area e.g. finely divided solids.

Positive adsorption:
Adsorption shows the ratio of a substance at the interface and the bulk phase if the concentration of the substance at the interface is greater. Than the concentration of the substance in bulk phase then it is called as positive adsorption.

Negative adsorption:
If the volume concentration of substance is higher than the concentration of bulk is known as negative adsorption.

Types of adsorption:
There are two types of adsorption:

Physical adsorption

Negative adsorption

1. Physical adsorption:
In physical adsorption the adsorbate is attached with adsorbent by Vander Waals or Electrostatic weak forces and it is characterized by low heat of adsorption.

Physical adsorption of gases is common at low temperature and high pressure. The gas in the adsorbent layer is in equilibrium with the gas molecule. In the bulk gas the equilibrium depends upon the nature of the adsorbent.

2. Chemical adsorption:
This involves the chemical combination of adsorbate at the surface of adsorbent. It is characterized by high heat of adsorption and unlike physical adsorption is irreversible. In many cases the chemical adsorption is slow because the molecule has to acquire an energy of interaction before they can react with the adsorbent, the rate of uptake will increase with increase of temperature.

Factors affecting the adsorption:

Solubility of adsorbate:
The adsorption is inversely proportional to the solubility of the adsorbate in the adsorbent.

Adsorption α 1/Solubility

pH:
it does not effect the adsorption directly pH of the solution affect the degree of ionization.

Usually the drug with a single molecule has more adsorption.

Nature of the adsorption:
Nature of the adsorbent have major effect on the adsorption by increasing the surface area, the adsorption rate could be increased. It can be increased by making it porous or finely divided.

Temperature:
Adsorption is an Exothermic process so increase in temperature will decrease. The adsorption and vice versa.

Pressure:
Adsorbed amount of adsorbate is directly proportional to the pressure applied.

Efflorescence

It is the loss of water from a crystal.


It means “to flower out” in French.

It is the spontaneous loss of water (or solvent) from a hydrated or solvated salt to the atmosphere on exposure to air, which occurs when the aquous tension of the hydrate is greater than the partial pressure of the water vapor in the air.

Efflorescent:
Denoting a crystalline body that gradually changes to a powder by losing its water of crystallization on exposure to a dry atmosphere.

Explanation:
If the vapor pressure of a hydrated salt is greater than the pressure exerted by the water vapor in the surrounding atmosphere than the salt will attempt to attain equilibrium with its surroundings and therefore tend to lose water to form a lower hydrate or an anhydrous salt.

This phenomenon is known as efflorescence.

The pressure of water vapor in the atmosphere is about 13.33 x 10^2 N/m^2 at 293 K.

Therefore hydrates with vapor pressure greater than this will tend to exhibit efflorescence and be unstable provided that the lower hydrate that if formed still exerts a vapor pressure greater than the surrounding atmosphere.

If this is not so then water will be taken up from the atmosphere by the lower hydrate as fast as it is formed and the final equilibrium will depend on the rates at which water is lost or taken up the two hydrates.

Examples:

The behavior of the various forms of sodium carbonate may be represented by the following scheme:

Na2CO3.10H2O (v.p = 32 x 10^2 N/m^2 at 293K) --> (Spontaneous dehydration i.e. efflorescence)  Na2CO3.H2O (v.p. = 16 x 10^2 N/m^2 at 293K)--> (efflorescence not observable because anhydrous salt is rapidly hydrated) --> Na2CO3 (anhydrous) (v.p. = 0)

Since the vapor pressure exerted by the decahydrate is much greater than that of normal atmosphere. It loses water by the process of efflorescence and is converted to the monohydrate.

The vapor pressure of the later is still above that of the atmosphere but further apparent loss of water does not occur. Since the anhydrous salt is rehydrated at a faster rate than dehydration of the monohydrate.

Similarly, vapor pressure of Glauber’s salt (Na2SO4.10H2O) normally exceed that of the water vapor in the atmosphere these salts effloresce and their surface assumes a powdry appearance. Blue stone or blue vitriol (CuSO4.5H2O)is a blue crystalline solid that when exposed to air slowly loses water of crystallization from its surface to form a white layer of anhydrous copper (II) sulfate.

Factors affecting efflorescence:
The vapor pressure of hydrated salts, and therefore the rate of efflorescence increases with rise in temperature.

Pressure of vapors.

Reduction of efflorescence:
Since the instability that arises from efflorescence is caused by the loss of water vapor. The common method of minimizing such deterioration involves the use of containers that present the loss of water vapor.

The additional precautions of using well filled containers with a minimum amount of atmosphere above the efflorescent material and storage in a cool place are also advisable.

Lyophilization

It is also referred to as “freeze-drying”, “sublimation-drying” or “cryodesiccation”.


Definition:
It is the process of isolation of a substance (solid) from solution by freezing it and evaporating the ice under vacuum (by sublimation).

Process of lyophilization:
In the process of lyophilization, water or any other solvent is removed from a frozen solution by sublimation caused by reduction of the temperature and pressure to values at a lower level than the triple point.

Under the application of these conditions, heat applied is used as latent heat and the ice converts directly to the vapor state (by the process of sublimation).

Practically, the following features must be taken into account.

Temperature and pressure are necessary to be at a lower level than the triple point and it is usually -10 ºC to -30 ºC and 10 N/m2 to 30 N/m2 respectively. To achieve this pressure, the vapors must be removed or else the vapor pressure will affect this pressure.

Stages of the freeze-drying process:
Following stages are found in lyophilization:

1. Freezing
2. Vacuum
3. Primary drying
4. Secondary drying
5. Packaging

Freezing:
The material is usually frozen before the application of vacuum. A number of methods are used in freezing of the material.

In shell freezing, the bottle is partially filled with the material to be frozen. It is placed in a refrigerator almost horizontally and rotated slowly. In this way the material freezes along side the walls of the bottle and resulting in large area for heat transfer and sublimation.

In vertical spin freezing, small crystals of ice are produced. In this method, the bottles are first placed in a moderate coldness and rotated quickly in vertical position in a constant flow of very cold air. This result in the liquid becoming super cooled and freezing occurs rapidly.

Vacuum:
Vacuum pumps are used to create the vacuum and reducing the pressure sufficiently.

On small scale, two-stage rotary pumps are used while on large scale ejector pumps are used.

Primary drying:
During the primary drying, two important processes are followed i.e. (1) vapors are removed by applying (2) the latent heat of sublimation. The apparatus similar to the vacuum oven can be used.

Heat transfer is crucial in this process as the extra heat may cause the material to melt and less heat may cause the process to be prolonged or no sublimation. So, heat transfer must be controlled.

Vapor removal is important to reduce a change in pressure. On the small scale, vapor is removed by using desiccant such as phosphorus pentoxide or by using a small condenser. And on the large scale condensation is helpful to remove vapors and by using pumps such ejector pumps.

The rate of drying in lyophilization is very low showing that the rate of drying of ice is about 1 mm depth per hour.

Secondary drying:
The primary drying may leave about 0-5 % of moisture in the solid, which can be removed by secondary drying process.

In this method, temperature may raise above 0 ºC to break any type of physico-chemical interactions between the frozen material and the water molecules resulting in the removal of the moisture.

High temperature can be used, as the risk of hydrolysis is negligible in the secondary drying because the secondary drying is an ordinary vacuum drying phase.

Packaging:
After the completion of freeze-drying process, vacuum is usually removed by the application of an inert gas such as nitrogen before the material is tightly closed. Great care is needed in the packaging of freeze dried products. Containers must be tightly closed to protect from moisture.

Freeze-drying equipment:
There are three types of freeze-dryers:

1. Rotary evaporators
2. Manifold freeze-dryers
3. Tray freeze-dryers

Uses:
Aqueous solutions and/or dispersions of oxygen-sensitive or heat-sensitive drugs, biologicals such as blood products (such as peptides, proteins), antibiotics (other than penicillin), vaccines (such as BCG, yellow fever, smallpox) and enzyme preparations (such as hyaluronidase) and microbiological cultures are usually freeze-dried.

After freeze-drying and packing the material in a vial, the material can be stored, shipped and reconstituted later to the primary form for the use as injection.

It increases the shelf life of some of the pharmaceuticals for many years.

Advantages of lyophilization:
1. Decomposition and hydrolysis of the product is reduced as a result of prevention of the enzyme action due to very low temperature.
2. Oxidation is reduced as a result of high vacuum and less air.
3. The product is light and porous as the original solution was frozen and there is no incorporation of extra materials.
4. As the product is porous so this results in more solubility.

Disadvantages of lyophilization:
1. The high porous nature (results in more solubility) and highly dried state results in a highly hygroscopic product. So special conditions are required up to packaging.
2. The process is very slow and requires expensive instruments and plants.

Elutriation

The word “Elutriation” is derived from the Latin word “elutriare” meaning “to wash out”.

Definition:
It is the separation, purification or removal of something from a mixture by decanting, straining or washing.

Process of elutriation:
In the process of elutriation, the movement of the fluid, generally water or air, is in the opposite direction to that of the sedimentation process.

Types of elutriation:
According to direction:

Vertical elutriation:
In the gravitational process, the larger particles present in water (or any other liquid) will move vertically downwards with the affect of gravity while the small particles in the fluid travels straight up with the fluid. This is a type of vertical elutriation.

Horizontal elutriation:
If a water current of suspended particles is flowed through a settling chamber. The particles that move out of the water current are collected in the bottom of the chamber. This is a type of horizontal elutriation.

Centrifugal elutriation:
In this case the water current is caused to spin with some force resulting in the large centrifugal force on the suspended particles. The heavier particles will settle to the walls of the elutriator or to the bottom.

The DorrClone is an example of a centrifugal-type of classifier.

According to the type of fluid:

• Air elutriation

• Water elutriation

If the velocity of the fluid is smaller than the velocity of setting down of the particles then the particles will settle downwards. On the other hand, if the velocity of the fluid is larger than the velocity of setting down of the particles then the particles will be carried up along with the fluid.

Air elutriation will give precise separation of the particles and in less time than water elutriation.

Factors affecting elutriation:

Elutriation is affected by the

• velocity of the fluid

• the particle size : As the small sized particles will flow (upward) along the fluid while the large sized particles will move downwards (against the velocity of the fluid).

• position of the particle in the (tube containing) fluid

• density of the particle

In a tube, there exist different velocities i.e. the velocity is largest in the centre and is smallest along the walls of the tube. So the small sized particles move upward, when in the centre and in the meantime they are also pushed towards the wall of the tube. Where the velocity is smaller and here the small sized particles start to move downwards.

Process of removal of particles:

If the upward flow of the water (or any other liquid) is slightly increased, the small sized particles (which move down slowly) will move along the movement of the water (i.e. upward) and will be removed from the water. In this process, the medium sized particles will remain immobile and the heavier particles will continue to move downward.

The upward flow of water will then again be increased and the next smallest size particles will be removed. And in this way, particles of different sizes will be separated and obtained.

Centrifugation

It refers to the process of sedimentation by using centrifuge machine.

Basic idea behind centrifugation:
Centrifugation is based on the widely known idea of sedimentation by the use of centrifugal force, which represents a force that apparently moves a spinning or rotating object away from the axis of rotation in a curved path.

Centrifugal effect:
The processes using centrifugal force (F) can be described by the equations involving the gravitational constant (G). In this case, it is easy to determine the centrifugal force in the terms of the ratio of the centrifugal force to the gravitational force. In addition, this ratio represents the centrifugal effect (C).

Centrifugal effect (C) shows that how many times the centrifugal force is larger than gravitational force.

C = 2.013 dn^2

Where
d = diameter of rotation
n = speed of rotation

Here in this equation, “n” has the value in “s-1” and “d” has the value in “m”.


This equation shows that centrifugal effect is directly proportional to the diameter and to the square of the speed of the rotation i.e. greater will be the diameter of the tube or container more will be centrifugation and similarly for the speed of rotation.

Factors affecting centrifugation:

Centrifugation is basically affected by centrifugal effect. Moreover, nature of the liquid medium in which the particles are placed also affects the centrifugation.

Apparatus for centrifugation (Centrifuges):
Container is the most important part of centrifugation apparatus i.e. centrifuges. This container is used for the placement of a mixture or solution of solid and liquid or of a solution of two liquids.

This container is then rotated at greater speed resulting in the separation of the ingredients of the mixture takes place by the use of centrifugal force.

Mechanism for the separation in the apparatus of centrifugation:
A mixture of liquid or solid in a liquid of low density can be separated as the material of larger density is thrown in the outward direction to the bottom of the tube or container with a larger force. This results in the separation of pure, low-density liquid as a transparent or purified supernatant liquid which forms upper layer.

Types of centrifuges:

There are two basic types of centrifuges:

1. Sedimentation

2. Filtration

Sedimentation centrifuges:

The basic principle, in the sedimentation type of centrifuges, is difference in the densities of the ingredients of the mixture. In these types of centrifuges, the particles are settled to the wall by the action of the centrifugal force.

These types of centrifuges are used for the separation of ingredients of the mixture of solid in liquid as well as liquid in liquid.

Two types of centrifuges are based on the principle of sedimentation:

1. Bottle centrifuge

2. Disc type centrifuge

Bottle centrifuge:
It is mostly used centrifuge machine in the laboratories. It consists of a vertical rotating rod that causes the “bottle-type” containers or test tubes, which are fixed symmetrically, to be rotated in a horizontal plane resulting in the separation of the materials of varying densities. The vertical rod is rotated usually by means of electric motor. Sometimes, gas turbines can also be used for the rotation.

Disk type centrifuge:
It consists of vertical pile of thin conical disks, which are arranged in the manner of one on the top of another. The sedimentation of the particles takes place in the space between neighbouring cones. In this way, settling distance is greatly reduced, thereby increasing the rate at which the particles in the material are separated. The cones are adjusted in such a manner that heavier material moves down the surface easily upon reaching the inner surface of the cone.

Filtration centrifuges:

These types of centrifuges are used for the separation of the mixture of solid in liquid only performing the operation similar to the filtration process. These are also sometimes referred to as clarifiers.

It is same in the basic operation to the sedimentation types of centrifuges but instead of solid containers or tubes, it contains a porous wall or perforated containers or baskets, which causes the liquid phase to pass through it but keeps the solid phase on it.

Centrifuge based on the principle of filtration is “Basket centrifuge”.

Basket centrifuge:
Basket centrifuge consists of a porous wall and rotor which is cylindrical and tubular in structure. The porous wall is some times replaced by one or more of the fine mesh screens. The fluid go through the screen where as the particles larger in size are left on the screen.

Application of centrifugation:

Centrifugation is used for the separation of ingredients of a mixture of solid in liquid or liquid in liquid as the degree of separation achieved by centrifugation is of greater amplitude than the action due to gravity.

It is important specifically when the separation by normal filtration methods is difficult such as in the separation of fluids of highly viscous nature.

In the pharmaceutical research, it is considered as an important tool in determining the stability of emulsions.

Bottle centrifuge can be used for:

1. Finding the sediments present in crude vegetable and mineral oils
2. Determination of the butterfat content in the milk
3. Various clinical trials and tests

Disk type centrifuge can be used for refining of vegetable oils by removing soap stock

Basket centrifuge can be used for:

1. Drying and washing of several different kinds of crystals and fibrous materials
2. The preparation of cane sugar.

Micelles

These are aggregates of surfactant molecules or ions in a solution or liquid colloid. These aggregates are made up of the water loving surface and an inner fatty core.

Micelle formation is done at a well defined concentration that is the critical micelle concentration.

Usually surface active agents behave as normal compounds in dilute solution but at certain reasonably well defined concentrations relatively sharp changes occur in the physical properties of these solutions.


These changes are attributed to the association of the amphipathic molecules or iond into aggregates of colloidal dimensions that are known as micelles.

Ionic and non-ionic substances that exhibit this type of behavior are referred to collectively as association colloids.

Critical Micelle concentration and micellar structure:
The minimum concentration at which physical properties of solutions of association colloids marked changes is known as critical micelle concentration. It is abbreviated as CMC.

Determination of critical micelle concentration:

(H. B. Klevens et al.)Critical micelle concentration (CMC) can be determined:
1. By Conductivity and transport number, which require the application of external electric forces.
2. Spectral dye method.
3. By solubilization studies which require the use of dyes or hydrocarbons.
4. By viscosity which involves the application of a shearing force.

Concept of formation of micelles is introduced to explain the apparent changes in osmotic properties and electrical conductivity with concentration in solutions of ionic associated colloids.

The conductivity indicated that a considerable degree of electrolytic dissociation was occurring in solution whereas the osmotic properties indicated that considerable aggregation of ions into single colligative units was also occurring above CMC.

Types of Micelles:
There are two basic types of micelles:

a. a small approximately spherical charged micelle which existed in all concentration i.e. above and below the CMC and which was largely responsible for the appreciable electrical conductivity and

b. a large undissociated lamellar micelle which only existed above the CMC and was responsible for the low osmotic properties at such concentrations.

Model of micelle:

Hartley’s model of spherical micelle

This model consists of a spherical charged micelle with a radius approximately equal to the chain length of the amphipathic ion.

The spherical type of micelle is now accepted as existing in all solutions of associated colloids at and just above the CMC.

However, in more concentrated solutions physical measurement for example X-ray diffraction, viscosity, light scattering indicate the existence of large asymmetric micelles.

How, large micelles are formed?
The rearrangement from spherical to larger and more widely separated asymmetric micelles has been ascribed to a reaction of the system in an effort to reduce the intermicellar repulsive forces that arise from the closer and closer approach of spherical micelles as the concentration of amphipathic material increases.

Different micellar shapes like rods and lamellae are also formed in different systems.

Stability and size of spherical micelles:
The cohesive force between water molecules is much stronger than either the attraction between the lipophilic parts of the surface active agents or the attraction between water and the lipophilic chains.

Therefore, the surface active agent tends to be squeezed out of solution in order to reduce the large degree of separation of water molecules that would be caused by the presence of many monomeric amphipathic molecules.

This effort which tends to cause a phase separation is counterbalanced to some extent by the hydrophilic nature of the polar groups.

In addition, the attractive forces between water molecules decay very rapidly with distance of separation since they are inversely proportional to somewhere between the fourth and seventh power of the distance.

Thus, the weak of separating water molecules by a relatively large distance of on the formation of a micelle is little different from that involved in the introduction of an amphipathic monomer.

Ionic surface active agent:
The electrical repulsion between adjacent similarly charged ions tends to disrupt the micelles of an ionic surface active agent.

In such a case, micelle formation is therefore dependent on the balance between this disruptive effect and the constructive “squeezing out of solution” effect.

Nonionic micelles:
Since, the electrical repulsive effect is absent in non-ionic micelles. Various suggestions have been made regarding the existence of a factor that would tend to oppose micelle formation for example cross sectional area and solvation of the hydrophilic group.

However, the precise nature of such a factor is still in doubt.

Association of ionic and non-ionic surface active agents:
The association of ionic and nonionic surface active agents is also aided by the “hydrophobic bonding” between the hydrocarbons chains.

This type of bonding involves vander waals forces of attraction, the effect of which is therefore of less significance than those mentioned previously.

In addition, an increase in temperature will have a disruptive effect on the formation of micelles since their rate of deaggregation will be increased.

The size of a spherical micelle depends on the structure of the surface active agent. In the model of the micelle, the radius is approximately equal to the length of the hydrocarbon chain.

If the diameter were to increase beyond this point then the unlikely structure would either include a space in the centre into which the hydrocarbon chains could not reach or the presence of some of the ionic groups between the hydrocarbon chains.

References:

H. B. Klevens. Critical micelle concentration as determined by refraction. The journal of physical chemistry, 1948.

Further Reading:

Dynamics of Surfactant Self-Assemblies: Micelles, Microemulsions, Vesicles and Lyotropic Phases (Surfactant Science) by Raoul Zana

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