1. Innovative R&D Models for Generic Crop
Protection Chemical Companies
Dr. Surendra Bhatia
Senior Technical Advisor – Sapec Group
sbhatia@agro.sapec.pt
11th April 2013
2. Outline
1. Milestone Method- From Concept to
Commercial Manufacturing.
2. Technical Grade Manufacturing
3. Formulation Development
4. Analytics/Registration requirements for
EU/Brazil
3. Success Stories - India
• India has become the largest producer of Mancozeb.
• Synthetic Pyrethroids produced in India are being sold to
Innovative companies for Global sales.
• Backward integration of Triazoles has helped companies
produce these fungicides at competitive prices.
• Up gradation of manufacturing facility by use of DCS/PLC
systems.
• Waste water recycle by use of MEE and RO and many of the
producers have achieved the goal of ZLD(Zero Liquid
Discharge).
• Air monitoring standards are stringent and use of modern
PLC systems are being followed with full compliance.
• Consistency in Quality by implementation of ISO Systems.
4. Defining Milestones
• A project can be divided in to three phases:
• Concept Phase
• Creation Phase
• Realization Phase
5. Division of Project
Concept Phase Go
/No
go
Creation Phase Go
/N
o
go
Realization Phase
M0 Idea M8 Scale Up
Concepts
M16 Detailed Eng.
M1 Literature M9 Design Req. M17 Project Planning
M2 Lab trials M10 Pilot Trials M18 SOPs
M3 Analysis-
5BA , PCP
M11 Safety
Studies
M19 Setting up plant facility
M4 Proto type
prepared
M12 Pilot Plant
Results
M20 Raw Materials
M5 Safety
Studies
M13 Documentation M21 Hazop
M6 Cost M14 Cost M22 Plant Trials
M7 Documen-
tation
M15 Basic design
Concept
14. FOP Series
X O
R3R2
R1
O
CH3
O
R4
O
Sr.
No.
Name Substituents
X R1 R2 R3 R4
1 Chlorazifop N H Cl Cl H
2 Clodinafop N H Cl F H
3 Diclofop-methyl C H Cl Cl CH3
4 Cyhalofop C H CN F H
5 Fluazifop-P N H CF3 H H
6 Haloxyfop-P N H CF3 Cl H
7 Isoxapyrifop N H Cl Cl
O
N
H
15. New Opportunity with Old Knowhow and Old Product
3 CH 3OH + PCl 3 P(OCH 3)3
Trimethyl Phosphite
Monocrotophos Intermediate
Fosetyl Aluminium
16. Old Molecules- New Opportunities
• 2,4- D Choline salts
↓
• Can this knowledge be suitably used for other
acids like
Glyphosate
FOP family
17. Important Properties
• Crystal Polymorph Studies
• Cyclohexanedione Herbicides
• Cyprodinil fungicide
• Pyrimethalin
• There are new opportunities like
A. The development of Cocrystals.
N-heterocycles are good candidates.
B. Amorphous compounds
18. Formulations -WDGs
• Spray Fluid Bed Drier: Availability of local equipment at
manufacturing scale has made this technology viable
and the problem of dust due to wettable powders is
reduced.
• Can we extend this know-how to Chlorpyrifos DF?
• Hot Melt Extrusion is another opportunity to be
followed in place of extrusion for low melting
compounds by incorporating suitable polymers with
matching Tg.
19. Suspension Concentrates
• Mixtures as suspension concentrates are
popular in Europe.
• Oil based suspension concentrates are also
used in limited way.
• EU task force is looking at Essential oils which
are known to have bactericidal/Fungistatic
properties.
• Important oils used are: cottonseed
oil, cinnamon oil , Neem oil.
20. Microencapsulation
Syngenta has achieved success with
microencapsulated formulation of lambda
Cyhalothrin ( Zeon).
The process uses simple technique of
a. Interfacial polymerization
b. We can innovate by the use of Core and Shell
method followed in emulsion polymerization
c. These methods are used extensively in India
by Coating Industries .
d. Why not follow same principles for agchem.
21. Chemistry requirements for the
registration
• Physicochemical Properties
• 5-Batch Analysis for Technical
• 5- Batch analysis for the formulation.
• Spectral Studies.
22. Physico Chemical Properties
• Appearance
• pH Value acidity and alkalinity
• Explosive Properties and oxidizing Properties,
where relevant.
• Flash Point, Flammability, Autoflammability
where relevant
• Relative density where relevant
• Storage stability.
23. 5 Batch Analysis
• Phase 1: NON-GLP( During lab scale process
development)
a. Synthesis of the compound
b. Screening for active impurities
by LCMS/GCMS
c. Isolation of Active and impurities by
Prep HPLC/HPTLC.
d. Identification of the impurities.
24. 5 Batch Analysis- Phase 2
• During commercial Production:
• Production of 7 batches
• Impurities Synthesis
• Method development for Active ingredient
and Impurities( if NON-CIPAC).
• Quantification of active and impurities.
• Analysis
• Report.
25. Challenges – 4 Pillars
1. GLP Labs – NABL accreditation.
2. Shift from Batch Process to Continuous
Process
3. Shift to Green Chemistry
4. Novel Formulations
