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LATEST TECHNOLOGY

IN

Safe handling & Recovery

OF

Solvents in Pharma

Industry

TYPICAL SOLVENT USE IN Pharma Industry

Usage of solvents in an API process development is for:

• Diluent to carry out reaction

• To produce high purity product

• Consistent quality of the product

• Higher yields

• Volume efficiency

• Operability• Solvent are used about 80 to 90% of mass

• Solvents are dominant in determining the toxicity of the process

• RISK FACTORS

• Safety• Environmental Impact

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Solvent use

DEVELOPMENT STAGE

Scientist have to considerSolubility – selection basis.

� Polarity – refers to s separation of electric charge.

� Volatility – tendency to vaporize at different temperatures.

� Cost and easy availability.

� Melting/Boiling points.

� Viscosity- resistance of a fluid.

� Flash Point

� Corrosiveness.

� Reactivity.

� Environmental health and safety

SAFETY

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Green chemistry solvent guide

Preferred

� Water

� Acetone

� Ethanol

� 2-Propanol

� 1-Propanol

� Ethyl acetate

� Isopropyl acetate

� Methanol

� MEA

� 1-Butanol

� t-Butanol

Usable

� Cyclohexane

� Heptanes

� Toluene

� t-Butyl Methyl ether

� Isooctane

� Acetonitrile

� 2-MeTHF

� Xylenes

� DMSO

� Acetic acid

� Ethylene Glycol

Undesirable

� Pentane

� Hexane's

� Di-Isopropyl ether

� Di-ethyl ether

� Dichloromethane

� Chloroform

� Dichloroethane

� DMF

� N-Methyl pyrolidine

� Pyridine

� Di methyl acetamide

� Dioxane

� Di methoxy ethane

� Benzene

� Carbon Tetra chloride.

SOLVENT IMPACT

Solvent forms a major role in API

– Cost

– Safety & Hazard

– Handling & storage

– Utility consumption

– Environmental Impact

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ECONOMY

Consumption of 2000 Lts per batch for 10 batch a month

Reduction by 5%

Recovery improvement by 10%

Will save

Rs 3.0 Lakhs per month for a 10 batch/month operation directly

(reduction, steam cost & recovery improvement)

The saving in manpower, storage, handling and environment is bonus.

Solvent reduction methods

• Choosing right solvent- reduce multiple solvent

handling.

• Combine steps of reaction to reduce solvent use -

Telescoping.

• Process loss by better handling

• Wash and reuse where ever possible

• Recover and recycle where ever possible.

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Optimization of Solvent Use

• Greener solvent selection & substitution

• Reduce solvents carbon footprint

• Elimination of highly hazardous solvents

• Solvent reduction

• Recovery techniques

• Novel approaches to separations

• Novel reaction media (ionic liquids)

• Solid-state chemistry

• Bio catalytic routes

Solvent recovery methods

• Wash and reuse.

• Simple boil over and reuse.

• Distill and purify – binary/ azeotropic

/fractional (atmospheric/pressure or

vacuum)

• Per vaporation techniques

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SAFE HANDLING

• Close loop hamdling and avoid mannual and drum

handling.

• Proper earthing while handling

• Avoid flexible piping and use hard pipes.

• Do not charge solvent into hot reactors/systems.

• Keep the condenser temperatures within control and

monitor them periodically.

• Store solvent in cool and dry place.

Solvent Recovery Improvements

• Better utility and design of the distillation system.

• High vacuum distillation– better recovery , yield and purity of the product – key factors- Joints, vacuum system.

• Use of vent condenser in Reactors.

• De scaling frequently of the heat exchangers and reactor jackets.

• Use of molecular sieve for removal of moisture.

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Per vaporation methods

• Is only membrane process where phase transition occurs.

• The heat of vaporization has to be supplied.

• The mass transport is achieved lowering the activity of the permeating component on the permeate side by: gas carrier, vacuum or temperature difference.

• The driving force is the partial pressure difference of the permeate between the feed and permeate streams.

• The permeate pressure has to be lower than the saturation pressure of the permeant to achieve the separation.

Gas carrier Pervaporation

Vacuum Pervaporation

Temperature difference

Pervaporation

Figure 2. Schematic draws of pervaporation processes.

Per vaporation Applications

Usually used for the chemical process industry, but there are other areas of application

� Food.� Farmaceutical industries� Enviromental problem� Analytical application

Since there are many applications a classification that can be useful is given below:

Aqueous mixtures

• Removal of water from organic solvents.

• Alcohols from fermentation broths (ethanol, butanol, etc..)

• Volatile organic contaminants from waste water (aromatics, chlorinated hydrocarbons)

• Removal of flavor and aroma compounds.

• Removal of phenolic compounds.

Non-aqueous mixtures

• Alcohols/aromatics (methanol/toluene)

• Alcohols/aliphatics (ethanol/hexane)

• Alcohols/ethers (Methanol/MTBE)

• Cyclohexane/benzene

• Hexane/toluene.

• Butane/butene.

• C-8 isomers (o-xylene, m-xylene, p-xylene, styrene).

{{

Volatile organic compounds from water

Dehydration

}}

Polar/Non polar

Aromatics/Aliphatic}}Saturated/Unsaturated

Isomers

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Mechanism of Transport

• Pervaporation involve a sequence of three steps:

• Selective sorption

• Selective diffusion through the membrane.

• Desorption into a vapor phase on the permeate side.

Because of its characteristics, pervaporation is often mistakenly considered as a kind of extractive distillation but VLE ≠ Solution-Diffution mechanism.

Figure 3. Comparison between VLE and pervaporation

Summary Per vaporation

Advantages

� Low energy consumption.

� Low investment cost.

� Better selectivity without thermodynamic limitations.

� Clean and close operation.

� No process wastes.

� Compact and scalable units.

Drawback

� Scarce membrane market.

� Lack of information.

� Low permeate flows.

� Better selectivity without thermodynamic limitations.

� Limited applications:

� Organic substances dehydration.

� Recovery of volatile compounds at low concentrations.

� Separation of azeo tropic mixtures.

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Summary Per vaporation

Membranes: Composite membranes with an

elastomeric or glassy polymeric top layer.

Thickness: ≈ 0.1 to few µm (for top layer)

Pore size: Non-porous

Driven force: Partial vapor pressure or activity

difference.

Separation principle: Solution/Diffusion

Membrane material: Elastomeric and glassy.

Applications: � Dehydration of organic solvents.

� Removal of organic compounds from

water.

� Polar/non-polar.

� Saturated/unsaturated.

� Separation of isomers.