Crystallization

Crystallization is a natural process, to separate a solid from the impure aqueous solution of crystals. A substance’s atoms or molecules arrange themselves into a well-defined three-dimensional lattice during the crystallization process, which lowers the system’s overall energy. A substance crystallizes when its atoms or molecules take on distinct angles that bind them together. Crystallization is a technique for purifying chemicals. an approach to removing solids from a solution. A solid substance dissolves in a liquid when they are combined and heated. The point at which further solids cannot dissolve is achieved as more solids are incorporated into the liquid. The fluid is referred to as a saturation solution, and this is known as a saturation point.,

What is Crystallization?

Crystallization is a natural process that happens when the materials solidify from a liquid, or as they precipitate out of a liquid or gas. This process can be carried out by causing a physical change, like a change in temperature, or a chemical change like acidity. 

The crystallization process is carried out on the basis of the size and shapes of the molecules involved, and their chemical properties. Crystals can be made out of 1 species of atom, different species of ions, or even huge molecules like proteins. Some big molecules have a difficult time going through the crystallization process, as their internal chemistry is not symmetrical or interacts with itself to avoid crystallization.

The unit cell is known as the smallest unit of the crystal. It is the base form of atoms or molecules upon which more units can be attached. Think of this as a children’s building block, to which other blocks can be joined. Crystallization goes on as if the blocks are getting attached in all directions. Some of the materials are from differently shaped crystals, which results in great variation in the shape, size, and color of various crystals.

Examples of Crystallization

Some common examples of crystallization are listed below:

• The crystallization of water forms ice cubes and snow.
• The crystallization of honey when it is placed in a jar and exposed to suitable conditions.
• The formation of stalagmites and stalactites (especially in caves).
• The deposition of gemstone crystals.

Crystallization Process 

The crystallization process consists of two major events. One is nucleation and the other is crystal growth which both are driven by thermodynamic properties also as chemical properties. Nucleation is the primary step where the solute molecules or atoms dispersed within the solvent start to collect into clusters, that become stable under the present operating conditions. These stable clusters constitute the nuclei. Therefore, the clusters got to reach a critical size so as to become stable nuclei. It’s at the stage of nucleation that the atoms or molecules are arranged in a defined and periodic manner that defines the crystal structure.

Crystal growth refers to the increase in the size of the nuclei which is able to achieve the critical cluster size. Many compounds have the power to crystallize with some having different crystal structures, a phenomenon called polymorphism. Certain polymorphs can be metastable, meaning that although it’s not in thermodynamic equilibrium, they are kinetically stable and requires some input of energy to initiate a change to the equilibrium phase.

Theory of Crystallization

The three major stages in the process of Crystallization are:

1. Supersaturation of the solution: It can be done in three ways: Heating the solution, Cooling the solution, and Salting it out.
2. Nucleation: This takes place in several steps. During their random motion, the atoms/ molecules/ ions will come closer to one another and forms aggregates called Clusters. These clusters will combine to form an EMBRYO. In this stage, only the lattice formation begins. These embryos combine to form NUCLEI. From nuclei, crystals are formed.
3. Crystal Growth: Once the crystals are formed, nuclei formation stops and crystal growth begins.

Types of Crystallization

The process of Crystallization of two different types based on the development of supersaturation, they are:

Cooling Crystallization

When the product’s solubility increases significantly with rising temperature, cooling crystallization is attractive. In similar circumstances, cooling crystallization usually uses less energy than evaporative crystallization. Saturated solution at 30°C by cooling it to 0°C the precipitation occurs when a large crystal mass is precipitated after the hydration of water.

Evaporative Crystallization

In evaporative crystallization, the solvent’s evaporation causes the crystallization to occur. At constant temperature the precipitation of crystals by increasing the solute concentration above the solubility threshold. The solute/solvent mass ratio is increased using the technique of evaporation.

Factors Affecting Crystallization 

• Presence of another substance: 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. 
• Solvent: The solvent with moderate solubility is preferred for crystallization. The presence of benzene can help crystal growth. Avoid highly volatile solvents.
• Nucleation: Crystals initially form via “nucleating events”. After a crystallite has nucleated it must grow. Nucleation sites are necessary for the formation of crystals. Excess nucleation sites cause smaller average crystal sizes. 
• Crystal Growth: Crystals grow by the ordered deposition of the solute molecules onto the surface of a pre-existing crystal. Crystal growth is facilitated by the environment changing slowly over time. Keep crystal growth vessels away from sources of mechanical agitation (e.g. vibrations). Set up away from vacuum pumps, hoods, doors, drawers, and so on.
• Rate of cooling/Time: Quality crystals grow best over time in near-equilibrium conditions. The longer the time, the better the crystals. Faster crystallization is not as good as slow crystallization. Faster crystallization higher chance of lower quality Crystals.

Application of Crystallization

Crystallization is a key component of almost all processes in the manufacturing of small-molecule pharmaceuticals. It is essential in both processing and pharmaceutical development. Since the properties of a solid material (polymorphism) can dramatically affect the process or the product’s compliance and effect (dissolution rate for example), monitoring and controlling the isolation of solids for the various applications through crystallization is of paramount interest.

So crystallization is used in:

• Purification of drug
• Better processing characteristics
• Ease for handling
• Improved physical stability
• Sustained release
• Improved bioavailability
• Preparation of organic and inorganic API 8- separation of API from galenical extracts
• Manufacturing of pure API by high yield

FAQs on Crystallization

Question 1: Define Crystallization.

Answer:

Crystallization is a natural process that happens when the materials solidify from a liquid, or as they precipitate out of a liquid or gas. This process can be carried out by causing a physical change, like a change in temperature, or a chemical change like acidity. 

Question 2: What is Water of Crystallization? 

Answer:

The definite amount of water associated with hydrated crystals which is an integral part of the crystal is known as water of crystallisation.  

For Example, Blue vitriol CuSO₄.5H₂O, Glauber salt Na₂SO₄.10H₂O, etc.

Question 3: Name a decahydrate crystalline salt. 

Answer:

Washing soda (Na₂CO₃.10H₂O) is a decahydrate crystalline salt.

Question 4: Differentiate between Crystallization and Evaporation?

Answer:

Here are some important differences between Crystallization and Evaporation:

Crystallization	Evaporation
Crystallization is the process of formation of solid Crystals Precipitating from a solution, melting, or more rarely deposited directly from a gas.	Evaporation is a type of vaporization of a liquid that occurs only on the surface of a liquid.
Is used when the soluble solid does not decompose upon strong heating	Is used when the soluble solid contains water of crystallization.
Drawback: any soluble impurities may also be present after evaporation.	Advantage: pure solid is collected in the form of crystals.
Example: Seawater Evaporating and forming into clouds.	Example: Dry Ice.

Question 5: How Crystallization is different from Recrystallization?

Answer:

Recrystallization is done to crystals formed from a crystallization method. However, Crystallization is a separation technique. Recrystallization is used to purify the compound received from crystallization.

Question 6: What are the types of Crystallization?

Answer:

The process of Crystallization of two different types based on the development of supersaturation, they are:

1. Cooling Crystallization – When the product’s solubility increases significantly with rising temperature, cooling crystallization is attractive. In similar circumstances, cooling crystallization usually uses less energy than evaporative crystallization. 
2. Evaporative Crystallization – In evaporative crystallization, the solvent’s evaporation causes the crystallization to occur. At constant temperature the precipitation of crystals by increasing the solute concentration above the solubility threshold. 

Question 7: Insoluble impurities from the solution during crystallization are removed by?

Answer:

Filtration is the process of separating small particles of solid matter from a liquid, by causing the liquid to pass through the pores of some substance, called a filter. Insoluble impurities from solution during crystallization are removed by filtration as the insoluble solid particles passed through the filter.

Question 8: What are the Advantages of Crystallization?

Answer:

The key advantages of crystallization are listed below.

• A product of high purity can be obtained from one single step via the process of crystallization.
• The dry products formed from crystallization can be directly packaged and stored.
• The energy requirements and the operating temperatures of this process are relatively low.