Recrystallization is a separation technique used to separate compounds based on their different solubilities at different temperatures. Usually, recrystallization is used to separate compounds with significantly large differences in volumes, i.e. to separate impurities from a pure solvent. For this, recrystallization is better to be called a purification technique than a separation technique.
The solubilities of compounds increase with an increase in temperatures. This property of solids is used to purify precious solids from impurities. The desired size of crystals, shape, quality, yield and optimized forms are the product of the recrystallization process.
Typically, products are separated from chemical reactions when there is a mixture of reactants, by-products, and main desired products.
In short, recrystallization is the dissolution of crystals to recrystallize again and achieve the desired shape, yield, and purity of a crystalline compound.
The root of recrystallization, Crystallization itself
While recrystallization means ‘again crystallization’, crystallization is a process of solid crystals formation by the orderly arrangement of atoms into lattice type crystalline shaped structures.
Crystallization is achieved through precipitation from a solution, freezing, or sometimes direct deposition from a gas.
Crystallization occurs in two steps, which are the last steps of recrystallization as well.
- Crystal growth
Nucleation is the creation of a spherical center or origin on which crystal growth can start. A gas bubble, a dust particle, and even crystals of the desired solute may serve the purpose of nucleation.
Crystal growth deals with what happens afterward. Starting from the first layer of atomic arrangement on nucleation source, to the development of whole crystal lattice is termed crystal growth.
Saturation and Supersaturation
A solution with a maximum amount of solute present at a particular temperature is called a saturated solution. A supersaturated solution is similarly a saturated solution but as the word super suggests, at high temperatures. It means that a supersaturated solution is in fact a highly saturated solution at high temperatures.
Recrystallization involves supersaturation as an integral part, explained in the procedure section.
So in fact, the recrystallization process is the crystallization of a solid from a supersaturated solution by annealing (bringing the temperature down slowly).
The cooling of materials at a considerable rate with respect to time, after taking it to a temperature above its recrystallization temperature is termed annealing or seasoning.
It is a process that alters the microstructure of a material by the phenomenon of heat change. Annealing usually changes the physical properties of the material but sometimes the effects may further go to chemical properties.
Types of recrystallization
Recrystallization involves several different types of approaches for the purification process based on the condition of the solution and on the solid required to be recrystallized.
1. Single solvent recrystallization
It is the recrystallization from a single solvent also called the normal recrystallization. The compound to be purified along with the impurity is solvated into a solvent of suitable nature i.e. having the ability to dissolve both impurity and solute. When a saturation point is reached at a higher temperature, the solution is left to cool down.
At a certain temperature, the solubility of solute certainly drops down and it is no longer invisible. Crystals start to appear in number on cooling as the solubility is related inversely to the temperature.
In ideal conditions, there is no need to worry about the impurities because their solubilities never decrease due to the temperature drop. This is because the impurities are considered perfectly soluble in a given solvent. In reality, however, this whole process is repeated several times to achieve good purity.
The recrystallization process can start because of:
- The temperature drop
- Adding a seed crystal inducing crystals to appear
- Scratching glass container walls, leading to a minute crystal appearance that induces recrystallization called nucleation.
Crystals may always differ somehow depending on the environmental conditions, rate of cooling, experience, and the nature of solvent.
2. Multi solvent recrystallization
Recrystallization involving more than one solvent is termed multi-step recrystallization.
A solution of solute and impurity is prepared in the first solvent assuming that both solute and impurity are soluble in that solvent at a given temperature. A second solvent is then added to the solution, capable of solvating either the solute or impurity. This separates impurities from desired solutes one way or the other.
The principle and extraction procedure of the multi-step recrystallization is similar to the single stepped but the difference arises when a second solvent is added to the solution of the first solvent, solute, and the impurities.
Extension in types of recrystallization
3. Hot filtration recrystallization
Hot filtration crystallization is an extension of the recrystallization process discussed above. If an insoluble material is present along with desired solute and impurity in the analytical sample, simple recrystallization is not enough to achieve purity or good yield.
The insoluble material has to be filtered out when the whole mixture is in solution form and the only thing filterable is the insoluble material. A filter paper serves the purpose but the filtration assembly needs to be kept warm in order to assure no crystallization of the desired solute.
If solute were to crystallize before passing through the filter paper, it would be lost and the whole purpose of recrystallization will go in vain.
Seeding is also an addition to the already suitable recrystallization process whether single or multi-step. The saturated solution needs an induction to start the crystallization process, which could be served by adding a seed.
A seed is something on which nucleation could take place leading to crystallization. A single crystal of desired solute or even adust particle may serve the purpose.
5. Scratching glass container
Similar to seeding, vibrations originating from scratching glass containers may also lead to the desired arrangement of solute molecules together, leading to the crystallization stimulus.
Some theories suggest that this scratching is a part of the seeding process as small glass particles wither away from the glass surface when scratched. These particles serve as seeding sites and the phenomenon of nucleation begins.
6. Single perfect crystals
Perfect crystals have always been difficult to make. Small amounts of analytes and slow development of crystals can grow perfect crystals. Some techniques used for the goal are:
- Slow evaporation of the solvent (Single step recrystallization)
- Slow evaporation of the volatile solvent (Multistep recrystallization)
- Slow diffusion of solvents by applying evaporation condensation mechanism for the second solvent (Multistep recrystallization)
- Applying interface delay for the two solvents to intermix (Multistep recrystallization).
- By some specially designed solvent delivery/intermixing equipment.
The single perfect crystals once made are stored in sealed containers. X-ray crystallography and several other techniques can only be done on such pure and perfect crystals. These crystals also account for the crystal lattices of pure compounds.
Seven step procedure for recrystallization
Recrystallization if carefully organized, can lead to great results. This implies the uses, crystallographical applications, yielding, and several other optimal conditions requiring procedures.
The seven step recrystallization procedure is considered best by chemists and equipment manufacturers.
1. Solvent vs solute screening
Before the recrystallization process begins, a suitable solute-solvent system needs to be designed. It includes the relative solubility of a particular solute and its insolubility criterion like crystallization temperature.
Moreover, the disposal costs, the function of temperature, and environmental impacts are also taken into consideration.
2. Selection of crystallization method
The selection of crystallization method may prove to be very important because it entirely controls whether the crystals will form or not.
(a) Cooling recrystallization
The solute-solvent system having high solubility at higher temperatures and considerably low solubility at lower temperatures can proceed through cooling crystallization. The main criterion controlling this process is the function of temperature. The solutes that decompose at higher temperatures shall not be put up on the cooling recrystallization method.
(b) Anti solvent recrystallization
Other than temperature function, an anti-solvent agent may be implied. Anti solvent recrystallization involves dissolving the solute in a solvent which is later crystallized due to the miscibility of anti-solvent and solvent chemicals.
This technique is however lesser advantageous than cooling recrystallization because the introduction of a new solvent species makes it harder for crystals to be separated at the end.
(c) Evaporative recrystallization
The evaporation recrystallization is usually implied on volatile solvents when anti-solvent agents are not workable. With decreasing solvent concentration supersaturation starts to establish eventually leading to recrystallization. Nucleation can be induced by inserting crystals of the solute or just gas bubbles may serve the purpose. Several other seeding techniques can be used mentioned above.
(d) Precipitative / reaction recrystallization
The solute compounds synthesized during a chemical reaction can be precipitated by increasing their concentration in the solution. It can be achieved by decreasing concentrations of other reagents via acid/base neutralization. This type of crystallization method is useful when solute components are synthesized during a reaction and the by-products are acids or bases.
3. Managing supersaturation
An important step is the decision of the supersaturation limit. In recrystallization, the amount of solute dissolved in a certain amount of solvent at a given temperature accounts for saturation. Consequently, if the amount of solute dissolved exceeds a certain limit at a given temperature, the condition is called supersaturation.
Supersaturation is the point where a slight induction of seeding leads to crystallization which is why it needs to be managed carefully by suitable solubility range solvent and temperature.
4. Thermodynamics along with kinetics
For any chemical reaction, thermodynamics and kinetics are the only two parameters that govern the yield, percentage efficiency, and rate of a reaction. For the recrystallization procedure to yield a good amount of product, the crystals, these two parameters need to be dealt with.
Thermodynamics has the main role because it is the function of solubility change with the temperature that began the recrystallization concept in the first place. However, the kinetics of a reaction can be significantly effective on recrystallization when the product to be crystallized is being formed in the saturated solution.
5. Seeding procedure
For desired crystalline properties, a good strategy needs to be designed in order to start nucleation and control the growth over it. Three types of such results can be predicted with the mentioned strategies.
- Very small crystals originate in uncontrolled and not planned seeding.
- Small crystals are seen in less controlled seeding
- Large crystals are observed upon total control over the seeding process and good strategy.
At this point, crystals have already arranged their lattices and precipitation starts to occur.
6. Solid/Liquid separation
After the crystals are visible as precipitates, the mother liquor needs to be removed or evaporated. Filtration is generally preferred when nonvolatile solvents are used because heating can damage crystals as well.
Filtration is generally followed by the washing of crystal cake (filtration residue) is done by a volatile solvent. This solvent is preferably an antisolvent for the mother liquor.
At this stage fully established crystals are visible but they do not show all characteristic properties.
Dring the crystal residue cake after being washed leads to perfect crystals. It is done by evaporated removal of solvent. Methods like vacuuming and heating can also be implemented to dry crystals depending on the nature of crystals.
Thermally stable crystals are therefore more easily and efficiently dried.
Applications of recrystallization
Some of the applications of the recrystallization process are:
- Purification of crystalline materials.
- The study of compaction and flowability of compounds in different environments and temperatures.
- Development of pharmaceutical products. For example, ibuprofen, paracetamol, are purified using the recrystallization process.
- To study the impact of crystal habit on pharmaceutical products.
- The action mechanism and regeneration of drugs study.
- Bioavailability and wettability study of certain chemical compounds.
- Control of texture of certain crystals.
- Separation of isomers based on the difference in their solubility as a chemical property i.e. resolution of a racemic mixture of opposite natured compounds.
- Preparation of microsized drug compounds by micro crystallization
- Nanoparticle synthesis involving in pulmonary drug delivery mechanisms.
- Comparative study for the solubility of two or more solute components for chiral recognition and other aspects etc.
- The compaction and nucleation study.
- Polymorphism study, the ability of a crystalline structure to exist in more than one crystalline arrangement.
Craig tube-A useful equipment for small scale recrystallization
A Craig tube is an apparatus sued for small scale recrystallization invented by Lyman C. Craig. It generally consists of a test tube and a stopper to protect solution chemicals from atmospheric contamination. The compounds used for the synthesis of such equipment is preferably inert one like PTFE (Polytetrafluoroethylene).
Craig tube is generally privileged due to the high purity of the recrystallized product and its relative dryness.
Limitations of recrystallization process
Recrystallization is a very useful method although there are some limitations:
- The solubilities of solutes are of great concern because they change over changes in the environment and impurities.
- Analyte material must already be much pure otherwise recrystallization does not proceed smoothly.
- The desired crystalline compound must be in a solid-state at stable conditions. This is the reason, many crystalline structures cannot be crystallized by this procedure.
- Recrystallization is not an absolute process. It means that some of the solute remains in the solvent whether how low the solubility of that compound is at that temperature. This limitation doesn’t matter for compounds that are just being analyzed in a laboratory. However, for the pharmaceutical industry and other absolute concentration dependent techniques, it is a matter of great concern.
Such limitations must always be considered while planning on adopting this technique for analytical or purification procedures.
How to perform a simple recrystallization procedure?
A simple recrystallization procedure requires supersaturation of a soluble chemical compound and then slow cooling provided that the solubility of that soluble chemical decreases significantly at low temperatures.
What is the aim of recrystallization?
The basic aim of recrystallization is the purification of crystalline solids. Impurities with different solubilities and insoluble contaminants (filtration) can be separated using a simple cooling recrystallization mechanism.
What happens to impurities during recrystallization?
In recrystallization, the impurities are essentially not crystallized with the desired chemical substance. They can be crystallized separately or depending on the importance and economic factors, they can simply be wasted with the solvent as a solution.
What are the uses of recrystallization techniques in the industry?
Recrystallization has set its root deep down in the pharmaceutical industry. The production, purification, separation, and study of crystal habit are all part of the recrystallization study.
Other important industries involving recrystallization as an important step are chemical, purification, and further analytical industries.
How to determine the rate of recrystallization?
The rate of recrystallization is inverse of the time required to attain half of teh overall crystallization. Orientation changes during deformation and formation are involved in the determination of the rate of recrystallization.
Will decrease or increase pH affect solubility in this recrystallization process?
Obviously, the changes in pH correspond to the solubilities of solutes because pH determines the ionic balance and environment of solutions. By changing this parameter, the crystallization process can both be delayed or induced.
What is the difference between recrystallization and titration?
Recrystallization is the process of separation of an element by first complete dissolution and then taking it out whether by titration, boiling, or any other process.
What is recrystallization temperature?
Recrystallization temperature is the certain temperature where the dissolved solute molecules tend to orient themselves and start growing in primary layers over seeds, the nucleation process.
It is also the temperature lower than the melting point of crystalline material at which the precipitation starts.
What is acetylsalicylate recrystallization?
Recrystallization of acetylsalicylate is the recrystallization over a controlled degree of supersaturation and temperature ranges depending on the nature of the solvent system. Ibuprofen and paracetamol are also crystallized by the same procedure.
What is recrystallization in metals?
Metal recrystallization is the process of replacement of deformed, rusty, and impure crystals of metals by perfectly formed, and pure crystals of the same metal atoms.
What is the equipment for recrystallization?
The recrystallization procedure requires the following equipment to begin:
- Solute and solvent and antisolvent (chemicals)
- A glass rod
- Volumetric flasks (100ml, 500ml, 1000ml, etc)
- A magnetic stirrer
- Filtration equipment (papers, stand, vacuum pump, etc)
- Drying agent, etc.
What is the best solvent for recrystallization?
Volatile solvents are better for recrystallization because they evaporate faster leaving the pure solute behind.
What is the difference between recrystallization and annealing of metal?
Recrystallization of metals is a process of purifying metal crystals by first preparing a supersaturated solution and then recrystallizing it. Now this recrystallization can occur normally like at room temperature while annealing requires controlled conditions where very slow cooling takes place.
What is the purpose of heating during recrystallization?
Heating during recrystallization is done to increase the solubility of the solute in the solvent. This increase is supposed to be more than the crystallization point of the specific solute.
Why is methanol used in the recrystallization of urea?
Methanol is used for the recrystallization of urea because it dissolves all the related impurities and has a good function of temperature for the solubility of urea itself. It means that it dissolves at the right temperature in methanol and crystallizes out upon cooling without impurities.
How to recrystallize a product from methanol?
Once a supersaturated solution of a substance has been made in methanol, it shall be left to cool at room temperature. Being volatile, the concentration of solvent will eventually decrease relatively increasing the concentration of the substance. This will automatically accomplish crystallization. Seeding and scratching may also be implemented to start the crystallization process.
What is the significance of recrystallization temperature in metal formation?
Recrystallization temperature is very important in metal formation as it controls the overall arrangement and nucleation of crystals. This temperature is actually the range where the solution phase of metal atoms end and the crystallization point arrives.
What is the difference between normalizing and annealing?
Normalizing is the cooling of a substance at room temperature while annealing refers to a controlled way of cooling the solution mixture. The difference in cooling time can lead to a different type of arrangement and consequently different sizes and purity of crystals.