Innovative R&D Models for Generic Crop Protection Chemical Companies

Dr. Surendra BhatiaSenior Technical Advisor – Sapec Group

sbhatia@agro.sapec.pt

11th April 2013

Outline

1. Milestone Method- From Concept to Commercial Manufacturing.

2. Technical Grade Manufacturing3. Formulation Development4. Analytics/Registration requirements for

EU/Brazil

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.

Defining Milestones

• A project can be divided in to three phases:

• Concept Phase• Creation Phase• Realization Phase

Division of ProjectConcept Phase Go

/No go

Creation Phase Go/No 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 SOPsM3 Analysis-

5BA , PCPM11 Safety

StudiesM19 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 TrialsM7 Documen-

tationM15 Basic design

Concept

Agrochemicals

Category

Conventional Products Modern Products

Group Application rates(g/Hectare)

Group Application rates(g/Hectare)

Herbicides Phenoxides(Older)TriazinesUreas

500-2500200-3000500-2000

Phenoxides(Newer)ImidazolinesSulfonyl Ureas

100-20050-10010-100

Fungicides DithiocarbamateMorpholines

250-3500750-1000

TriazolesStroliburins

5-25050-200

Insecticides OrganochlorinesOrganophosphates

100-10000200-5000

PyrethroidsNeonicotinoids

5-25050-200

Off Patent Molecules- Fungicides

• Boscalid• Cyflufenamid• Flumorph• Dimethomorph• Orysastrobin• Pyraclostrobin• Trifloxystrobin• Prothiaconazole• Simeconazole

Off Patent Molecules- Herbicides

• Dimethanamid P• S-Metolachlor• Formasulfuron• Monosulfuron• Mesosulfuron• Oxaziclomefone• Pyribenzoxim• Fentrazamide• Benzobicyclon

Off Patent Molecules- Insecticides

• Spirodiclofen• Thiamethoxam• Xiaochonogthion• Flonicamid• Bifenazate• Dinotefuran• Profurite aminium• Pyridalyl

SULFONYL UREAS :

TRIAZOLES

STROLIBURINS

NEONICOTINIDES

FOP Series

X O

R3R2

R1

O

CH3

OR4

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

ONH

New Opportunity with Old Knowhow and Old Product

3 CH3OH + PCl3 P (OCH 3)3

Trimethyl Phosphite

OH P

Cl Cl

Cl

+ PH

O O

O

HCl+ +Cl

3 2

diethyl phosphonateMolecular Weight: 138,10

Monocrotophos Intermediate

Fosetyl Aluminium

Old Molecules- New Opportunities

• 2,4- D Choline salts ↓

• Can this knowledge be suitably used for other acids like

Glyphosate FOP family

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

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.

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.

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 polymerizationc. These methods are used extensively in India by Coating Industries . d. Why not follow same principles for agchem.

Chemistry requirements for the registration

• Physicochemical Properties• 5-Batch Analysis for Technical• 5- Batch analysis for the formulation.• Spectral Studies.

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.

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.

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.

Challenges – 4 Pillars

1. GLP Labs – NABL accreditation.2. Shift from Batch Process to Continuous

Process3. Shift to Green Chemistry4. Novel Formulations