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About Author:
Balbir Singh Negi
GM Regulatory Affairs
SHAH TC Overseas Private Limited, Delhi, INDIA
22 years of industrial Exp,
M.Sc, MBA, Doctor of Science

The usage of solvents in active pharmaceutical ingredients (API) and coating plants are very common in pharmaceutical industry. The organic solvents are mostly used in washing of product, cleaning of equipments and the reaction media for separation and purification. The cost reduction of the API products can be reduced by the distillation of mother liquor after establishing of yield in R &D, pilot plant and then in the commercial plant, the next process step is validation, done with fresh solvent of three consecutive batches and then done with three consecutive batches of recovered solvents from mother liquor. The product cost is mainly reduced by the distillation of product mother liquor or to do more research to reduce the quantity of solvent or manufacturing process without solvent.

The pharmaceutical companies are the largest users of organic solvents in India.Solvents are regularly present in theproduction processes. The pharmaceutical theyare usually used at any step of the synthesis pathwayof an active substance or excipients, and sometimesduring the drug product formulation process. Nowadays the every pharmaceutical industry have the own solvent distillation plants (SRP) to distilled the mother liquor of product.

Distillation is a process of separating mixtures based on differences in volatilities of components in a boiling liquid mixture and the vapour is cooled and condensed, the condensate will contain more volatile components. Distillation is a unit operation, or a physical separation process, and not a chemical reaction.

Distillation columns are designed to achieve this separation efficiently. Distillation is the most common separation technique which involves the heating andcooling of mother liquor.

The Different Types of Distillation
There are several methods of distillation depending on the procedure and the instrument setup. Each distillation type is used for purification of compounds having different properties. Following are the common types.

Simple Distillation
Simple distillation is practiced for a mixture in which the boiling points of the components differ by at least 70° C. It is also followed for the mixtures contaminated with non-volatile particles (solid or oil) and those that are nearly pure with less than 10 per cent contamination. Double distillation is the process of repeating distillation on the collected liquid in order to enhance the purity of the separated compounds.

Fractional Distillation
Those mixtures, in which the volatility of the components is nearly similar or differs by 25° C (at 1 atmosphere pressure), cannot be separated by simple distillation. In such cases, fractional distillation is used whereby the constituents are separated by a fractionating column. In the fractionating column, the plates are arranged and the compound with the least boiling point are collected at the top while those with higher boiling point are present at the bottom. A series of compounds are separated simultaneously one after another. Fractional distillation is used for the alcohol purification and gasoline purification in petroleum refining industries.

Steam Distillation
Steam distillation is used for the purification of mixtures, in which the components are temperature or heat sensitive; for example, organic compounds. In the instrument setup, steam is introduced by heating water, which allows the compounds to boil at a lower temperature. This way, the temperature sensitive compounds are separated before decomposition. The vapors are collected and condensed in the same way as other distillation types. The resultant liquid consists of two phases, water and compound, which is then purified by using simple distillation. Steam distillation is practiced for the large-scale separation of essential oils and perfumes.

Vacuum Distillation
Vacuum distillation is a special method of separating compounds at pressure lower than the standard atmospheric pressure. Under this condition, the compounds boil below their normal boiling temperature. Hence, vacuum distillation is best suited for separation of compounds with higher boiling points (more than 200°C), which tend to decompose at their boiling temperature. Vacuum distillation can be conducted without heating the mixture, as usually followed in other distillation types. For the separation of some aromatic compounds, vacuum distillation is used along with steam distillation.

Short Path Distillation
Thermal sensitive compounds can also be separated by following short path distillation. In this technique, the separated compounds are condensed immediately without traveling the condenser. The condenser is configured in a vertical manner between the heating flask and the collecting flask. Similar to vacuum type, the pressure is maintained below the atmospheric pressure. Short path distillation is used for the separation of organic compounds with high molecular weight, especially in the pharmaceutical industries.
Another method of classifying distillation is based on the column type used in the process. There are two types of distillation columns namely, batch and continuous. In the former case, the feed is provided in the batch wise manner; whereas, in the latter type, the feed to the column is introduced continuously. A continuous operation is used commonly in the industrial applications.

Mainly the pharmaceutical industry has batch distillation and continuous distillation.
The distillation plant is installed on the basis of mixture of solvents and type of less volatile solvents or high volatile solvents to be distilled.

Batch distillation
A batch still showing the separation of mixed two solvents in different ratio.
When methanol mother liquor mixed with 5 % of water and the distillate the pure methanol is recover with less percentage of water, depends on the rate of distillate and reflux maintained.
At end the residue is collected from the bottom of batch distillation still.

Continuous distillation
Continuous distillation is on-going regular mother liquor feed to the distillation column maintaining the feed rate, reflux and bottom cut, depends upon ratio of solvent mixed to be distilled. Most of the distillation plants are run through PLC programme logic computer.
The recovery of tetrahydrofuran continuous distillation is done with structure packed 10-15 meter height column, depends on the composition of mixture. Tetrahydrofuran distillation is critical as it generate the peroxides. The antioxidant Butylated hydroxy toluene (BHT),is mixed with the mother liquor feeding tank before the distillation.
Continuous distillation produces at least two output fractions, including at least one volatile distillate fraction, which has boiled and been separately captured as a vapor condensed to a liquid. There is always a bottoms (or residue) fraction, which is the least volatile residue that has not been separately captured as a condensed vapor.
Continuous distillation differs from batch distillation in the respect that concentrations should not change over time.
Continuous distillation can be run at a steady state for an arbitrary amount of time. For any source material of specific composition, the main variables that affect the purity of products in continuous distillation are the reflux ratio and the number of theoretical equilibrium stages (practically, the number of trays or the height of packing). Reflux is a flow from the condenser back to the column, which generates a recycle that allows a better separation with a given number of trays. Equilibrium stages are ideal steps where compositions achieve vapor-liquid equilibrium, repeating the separation process and allowing better separation given a reflux ratio. A column with a high reflux ratio may have fewer stages, but it refluxes a large amount of liquid, giving a wide column with a large holdup. Conversely, a column with a low reflux ratio must have a large number of stages, thus requiring a taller column.

Types of Continuous Columns
Continuous columns can be further classified according to: the nature of the feed that they are processing,

*binary column- feed contains only two components

*multi-component column- feed contains more than two componentsthe number of product streams they have

*azeotropic distillation- where the extra feed appears at the top product streamthe type of column internals

*tray column- where trays of various designs are used to hold up the liquid to provide better contact between vapour and liquid, hence better separation

*packed column- where instead of trays, 'packings' are used to enhance contact between vapour and liquid

1 Jagiellonian University, Faculty of Chemistry, Department of Analytical Chemistry, Ingardena 3, 30-060 KrakUw, Poland
2 PlivaKrakUw S.A., Mogilska 80, 31-546 KrakUw, Poland
*distillationan introduction by M.T. Tham
*Types of Distillation By NingthoujamSandhyarani



dear Sir,

This artical is really interesting...Great job!!