Tools and Strategies for Green API

Manufacturing

Dr MG (Deepak) Palekar

Head- Strategy & Technology

deepak.palekar@stepsol.com

Sustainable Development

It is the pattern of resource use that aims to meet human

needs while preserving the environment so that these

needs can be met not only in the present but also for

generation to come.

Sustainable Development in Pharma

Sustainable Development =

Green Chemistry

+ Process Intensification

+ Water Management

- Global Reporting Initiative (GRI) reports for SD

Process Intensification

Any engineering development that leads to

a substantially smaller, cleaner, safer and

more energy efficient technology.

Advantages of Sustainable Development

• Lower resource consumption (Carbon/ Water/ Energy

Footprint)

• Higher productivity (equipment & manpower)

• Lower waste/ effluent generation

• Risk reduction (legal, regulatory, social)

• Improved process Process patent

• Enhanced value proposition, improved image

• Preferred supplier status (with some customers)

• Lower cost of production higher profitability

Approach

Reactants/ Raw Materials

A + B + Solvent + Additive C + D +

Solvent

Down-Stream Processing

Filtration/ Solvent extraction/

Crystallization/ Distillation/ Drying

Effluents & Waste (RM, by-

products, solvents, catalyst, water)

Organic chemistry can give conversion

as per stoichiometric principles;

the competitive edge is gained by

mastering down-stream processing!

Strategy - Approach

• Front End (Maximize Atom Efficiency/ Reduce

Waste) - Selectivity/ Yield Improvement, Solvent selection,

Heterogeneous/ bio-catalyst, Process intensification & DSP

• Back End (Reduce Effluents) - Recovery of RM/ By-

Product/ Solvents, Waste treatment, Water recycle/ management

Need a focus on Sustainable Development/ Green

Chemistry through a Champion and/ or a Team, which

will define the objectives & monitor the progress.

Tools

• Green Chemistry (Organic Synthesis/ Heterogenous

Catalysis/ Biocatalysis/ Solvents/ Water)

• Process Intensification (Reactor design/ Mixing/

Reaction kinetics/ Heat exchange/ Productivity increase per

batch)

• DownStream Processing/ Technologies (Nanotech,

Cavitation, Microwave, Chromatography)

Tools

• Biocatalysis

• Solvents

• Water

• Cavitation

• Chromatographic Separation

• Reactor Design

Biocatalysis

Advantages:

• Milder reaction conditions (typically up to 60 C and atmospheric

pressure)

• High selectivity (stereo/ region/ chemical)

• Increased productivity (shorter route of synthesis)

• Higher purity product (low/ no impurities)

• Lower cost of downstream processing (simpler purification, lesser

impurities, lower solvent usage)

• Can be immobilized and reused

There are around 150 biocatalytic processes currently in commercial

use in chemical/ pharma industry. New scientific developments in

genomics as well as in protein engineering will facilitate tailoring of

enzyme properties to increase that number significantly in future.

Biocatalysis- Commercial Enzymes

Enzyme Class Reactions Applications

Oxidoreductase • C=O and C=C reduction

• Reductive amination of C=O

• Oxidation of C-H,C=C, C-N and C-O

• Atorvastatin intermediate

• Montelukast

Transferase Transfer of functional groups such as

amino, Acyl, phosphoryl, methyl,

glycosyl, nitro & sulphur groups

• Sitagliptin

• Cyclodextrin from starch

Hydrolase Hydrolysis of esters, amides, lactones,

lactams, epoxides, nitriles & reverse

reactions

• Diltiazem intermediate

• Resolution of chiral

chemicals

Lyase Addition of small molecules to double

bonds such as C=C, C=N and C=O

Statin Intermediates

Isomerase Isomerisations such as racemizations,

epimerizations & rearrangement

reactions

HFCS from glucose

Biocatalysis- Industrial Successes

Pregabalin/ Pfizer• Low protein loading(0.8%)

• Higher throughput

• All reactions conducted in water; significant reduction in solvent

• E-factor improved from 86 to < 20

• Starting material reduction, Mandelic acid usage eliminated

• Energy usage reduced by > 80%

Sitagliptin/ Merck• > 10% increase in overall yield.

• > 50% increase in productivity.

• ~ 20% reduction in total waste.

• Elimination of heavy metal use

• Reduction in total manufacturing cost.

Solvent Usage

• Typically 1 kg of API uses 22 kgs of solvent; can add up

to 80-90% of total mass of API material balance

• 1 kg of solvent 1.5 kg CO2, and 2.25 kgs total air

emission

• Top 10 solvents constitute 90% of waste in pharma

industry in USA (methanol, Dichloromethane, Toluene,

Acetonitrile, Chloroform, N,N-DMF, N-Methyl-2-

Pyrrolidone, MTBE, Cyclohexane, Formic Acid)

• Solvent implications over life cycle: Purchase cost,

energy, waste generated; Cost to use/recycle (energy

and associated costs) and Disposal cost and emissions

Solvent Selection

• Recyclability (boiling point, azeotrope formation)

• Health hazards (exposure limit/ toxicity)

• Flammability & explosion safety

• Stability and reactivity (peroxide formation, acidity/

basicity effect)

• Regulatory

Expanding GSK’s solvent selection guide – embedding

sustainability into solvent selection starting at medicinal chemistry

Richard K. Henderson et. al.

Royal Society Chemistry, 2011.

Solvent Reduction

• Efficient recovery techniques

• Reduction in process steps (Biocatalysis, in-situ

reactions)

• Novel reaction media (Ionic liquids)

• Novel approach to downstream processing/

separations (Chromatography, cavitation)

• Efficient reactor design

Water: Risk for Business

• - Disruption in production & financial loss

• Increased cost

• Govt./ Regulatory interference on water quantity/ price

• Consents, Permits

•Image on issue of sustainability and equitable usage

• Freshwater shortage

Physical RiskReputational

Risks

Financial Risks

Regulatory Risk

Water availability not under control of corporates

Production delays,Limits on production

Strong community opposition to company activities

Financial loss due to non availability of water

Cavitation

Ultrasonic Cavitation- Crystallization (Particle Size distribution, crystal form)

- Milling (Fines control)

- Reaction (Higher reaction rate, improved selectivity/ yield)

Hydrodynamic Cavitation- Cooling Water treatment (no chemical usage, microbial growth/

scale formation control, lower corrosion, less water blow-down)

- Reaction (waste water treatment, oxidation)

Advantages: Continuous process, lower energy consumption, improved productivity

Challenges: Process Scale-up

Chromatographic Separation

Applications:

• Removal of impurities/ Purification of products (Sp. Chemicals/

Pharma intermediates/ APIs)

• Recovery of Solvent/ metal from waste

Advantages:

Cleaner process, improved yield, better quality of product, impurity can

be removed selectively minimal use of solvent, Continuous process

Challenges:

Initial investment can be high

Success Story

Based on material balance, identified areas of atom efficiency, process

improvements & waste reduction

• Reaction- Improved yield/ solvent usage/ reduced water usage

(Front end)

• Color Removal- Replace activated carbon by synthetic resin (DSP/

Chromatography/ lab scale)

• Crystallization & Milling- using ultrasound (DSP/ Pilot plant scale)

• Drying – Faster drying process (DSP)

• Waste- Recovery of By-product & Raw Material by chemical

process & metal by chemical process/ Chromatography (Back end)

• Waste- Recovery of solvent from vent/ handling losses (Back

end/ Chromatography)

Improved productivity/ quality of product, lower waste/ effluents.

* Processes marked in black bold are implemented on commercial scale

Reactor Design- Process Intensification

• Microreactor

• Mixers (Impinging Jet Mixer, Vortex Mixer, Static Mixer

• Spinning Disk reactor

• Rotating Packed bed

• Multifunctional membranes

• Microwave irradiation

• Ultrasound irradiation

• Cavitation Flow reactor (Bubble column reactor,

Downflow Gas Contactor)

Reactor Design- Successes

• Productivity increase by 10 to 25% in pharma intermediates/

specialty chemicals through Process Intensification/ Atom

Efficiency (increased batch size, better mixing, lower solvent

usage)

• Batch to continuous process for phosgenation using cascade

reactor leading to improved conversion/ yield/ product quality

• Continuous sulfonation using a plug flow reactor leading to higher

conversion & selectivity.

• Falling film reactor (continuous process) for a condensation reaction,

leading to higher conversion/ productivity and lower separation cost.

• Bubble column reactor for chlorination reaction instead of

stirred reactor, leading to higher conversion/ selectivity and

lower utility cost.

Downflow Gas Contactor

DGC is a downflow co-current device

consisting of a cylindrical upper

section and inverted conical lower

section (if required when using pure

gases)

Specially Designed Inlet (SDI)

High velocity liquid input through

the entry section generates intense

shear and energy; and produces a

highly agitated gas-liquid dispersion

with increased interfacial area and

improved mass transfer.

Suitable control system include

heating, cooling, dispersion level,

pressure, flow rates etc.

DGC- Bubble Dispersion

DGC Advantages

Lower power consumption

Smaller operating volumes

No foaming

Close 100% Gas utilisation

High gas hold-up: 40-50%

Accurate control of interfacial area

(upto 6000 m2/m3)

No internal moving parts

Tolerance to particulates

Ease of scale-up with no loss of

efficiency

Ease of automation and control

Simple, compact set-up with

flexibility of design

Industrial Applications

• Gas-Liquid and Liquid-liquid reactions (Hydrogenation,

Oxidation, Carbonylation, Ethoxylation, Chlorination, Biodiesel

production)

• Effluent treatment (COD/ BOD reduction, Wet Air Oxidation,

Non-biodegradable effluent)

• Gas Absorption (CO2 capture from Biogas/ Flue gas,

Ammonia recovery from waste)

UV Lamp 2.0kw

Flow Rate 10 L/min

Gas Flow Rate (O2 flow rate) 0.05 L/min

Temperature 330C

Pressure 0-8 bar

Operating Mode Batch

Volume Of DGC Reactor 17 Litre

Batch Volume 15 Litre

Residence time in DGC 1.5 min

Contact time O2- 42 sec

UV- 36 sec

CASE STUDY- PHARMACEUTICAL

WASTEWATER TREATMENT

COD reduction in DGC

STEP- Services Offered

• Process Intensification/ Process audits

• Improvements based on Green Technologies

• Environmental assessment

• Water footprint and sustainability studies

• ETP Audits

• Effluent treatment plant packages

• Pre-engineered Effluent treatment plants

• Environmental management plan

• Pre-tendering services for ETP/ STP

• Detailed project reports and Feasibility report

• Sanitary wastewater treatment & collection system

• Training

STEP- Customers

• BASF India

• Cadagua Ferrovial India Ltd.

• SNF, France

• Hindustan Unilever Ltd.

• Hindustan Coca Cola Beverages Ltd.

• Dr Reddy’s Labs

• Godrej & Boyce

• Aker Solutions/ Reliance Industries Ltd.

• Ernest & Young

• XCC/ World Bank

“Socialism collapsed because it did not allow the

market to tell the economic truth.

Capitalism may collapse because it does not allow the

market to tell the ecological truth.”

Oystein Dahle, former VP- Exxon (Norway & North

Sea) in ‘Hot, Flat & Crowded’- Thomas Friedman

Progress Step by Step

towards Sustainable

Development!