PRODUCT:

BISPYRIBAC
SODIUM

1. PURPOSE:

To Establish the documented procedure for manufacturing of Bispyribac sodium as per the
specified process.

2. SCOPE:
This SOP is applicable for the manufacturing of Bispyribac sodium as per the specified process.

3. RESPONSIBILITY:

Designation Responsibility
All the employees To follow the procedure of training.
In-Charge-Production Production Incharge to ensure the proper execution
Head Production Overall responsible for implementation of SOP.

4. DEFINITION OF TERMS

I. SOP: Standard Operating Procedure

II. PRD: Production
III. QA: Quality Assurance
IV. QC: Quality Control
V. IP: In process
VI. RM: Raw Material
VII. PPE’s: Personal Protective Equipment’s
VIII. MSDP: 2-Methylsulfonyl-4,6-dimethoxypyrimidine

5. SAFETY INSTRUCTION FOR BISPYRIBAC SODIUM MANUFACTURING:

Raw Material Hazard Precautions & First Aid PPE’s

Dihydroxy Benzoic Causes skin irritation. Avoid breathing dust. Safety glasses with
Acid Causes serious eye IF IN EYES: Rinse cautiously with side shields.
irritation. water for several minutes. Remove Wear chemical
Action Prepared By Reviewed By Approved By
Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
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 PRODUCT:
BISPYRIBAC
SODIUM

May cause respiratory contact lenses, if present and easy to protective gloves,
irritation. do. Continue rinsing. e.g., PVC
If breathed in, move person into Wear safety footwear
fresh air. If not breathing, give
artificial respiration. Consult a
physician.
In case of skin contact: Wash off
with soap and plenty of water.
Consult a physician.
In case of eye contact: Rinse
thoroughly with plenty of water for
at least 15 minutes and consult a
physician.
If swallowed: Never give anything
by mouth to an unconscious person.
Rinse mouth with water. Consult a
physician

2-Methylsulfonyl-4,6- Not a hazardous Avoid dust formation. Avoid Safety glasses with
dimethoxypyrimidine substance or mixture breathing vapors, mist, or gas. side shields.
according to Wear chemical
Regulation (EC) No. protective gloves,
1272/2008 e.g., PVC
Wear safety footwear
Dimethylformamide Flammable liquid and Avoid breathing Wear personal
vapor dust/fume/gas/mist/vapors/spray protective
Causes serious eye Keep away from heat/sparks/open equipment/face
irritation flames/hot surfaces. - No smoking protection
May damage the Use only outdoors or in a well- Safety glasses with
unborn child ventilated area side shields.
Harmful in contact IF exposed or concerned: Get Wear chemical
with skin or if inhale medical attention/advice protective gloves,
IF INHALED: Remove victim to e.g., PVC
fresh air and keep at rest in a Wear safety footwear
position comfortable for breathing
Skin: Call a POISON CENTER or
doctor/physician if you feel unwell

Action Prepared By Reviewed By Approved By

Name

Department R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

Wash contaminated clothing before

reuse
IF ON SKIN (or hair): Take off
immediately all contaminated
clothing. Rinse skin with
water/shower
IF IN EYES: Rinse cautiously with
water for several minutes. Remove
contact lenses, if present and easy to
do. Continue rinsing If eye irritation
persists: Get medical
advice/attention
In case of fire: Use CO2, dry
chemical, or foam for extinction
Toluene Highly flammable Obtain special instructions before Wear personal
liquid and vapor. use. protective
May be fatal if Keep away from heat, hot surfaces, equipment/face
swallowed and enters sparks, open flames, and other protection
airways. ignition sources. No smoking. Safety glasses with
Causes skin irritation. Avoid release to the environment. side shields.
May cause drowsiness In case of skin contact: Take off Wear chemical
or dizziness. immediately all contaminated protective gloves,
Suspected of clothing. Rinse skin with water/ e.g., PVC
damaging the unborn shower. Consult a physician. Wear safety footwear
child. After eye contact: rinse out with
May cause damage to plenty of water. Call in
organs (Central ophthalmologist. Remove contact
nervous system) lenses.
through prolonged or If swallowed After swallowing:
repeated exposure. caution if victim vomits. Risk of
aspiration! Keep airways free.
Pulmonary failure possible after
aspiration of vomit. Call a physician
immediately.
Potassium Carbonate Causes skin irritation Wash face, hands and any exposed Wear personal
Causes serious eye skin thoroughly after handling protective
irritation Wear protective gloves/protective equipment/face
May cause respiratory clothing/eye protection/face protection
Action Prepared By Reviewed By Approved By
Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

irritation protection Safety glasses with

Avoid breathing side shields.
dust/fume/gas/mist/vapors/spray Use Wear chemical
only outdoors or in a well-ventilated protective gloves,
area e.g., PVC
IF INHALED: Remove victim to Wear safety footwear
fresh air and keep at rest in a
position comfortable for breathing
Call a POISON CENTER or
doctor/physician if you feel unwell
IF ON SKIN: Wash with plenty of
soap and water If skin irritation
occurs: Get medical advice/attention
Take off contaminated clothing and
wash before reuse
IF IN EYES: Rinse cautiously with
water for several minutes. Remove
contact lenses, if present and easy to
do. Continue rinsing If eye irritation
persists: Get medical
advice/attention
32% HCl May be corrosive to Wear protective gloves/ protective Wear personal
metals. clothing/ eye protection/ face protective
Causes severe skin protection. equipment/face
burns and eye damage. IF SWALLOWED: Rinse mouth. protection
May cause respiratory Do NOT induce vomiting. Safety glasses with
irritation. IF IN EYES: Rinse cautiously with side shields.
water for several minutes. Remove Wear chemical
contact lenses, if present and easy to protective gloves,
do. Continue rinsing. e.g., PVC
IF exposed or concerned: Wear safety footwear
immediately call a POISON
CENTER or doctor/ physician.
Methanol Highly flammable Keep away from heat, hot surfaces, Wear personal
liquid and vapor. sparks, open flames, and other protective
Toxic if swallowed, in ignition sources. No smoking. equipment/face
contact with skin or if Wear protective gloves/ protective protection
inhaled. clothing/ eye protection/ face Safety glasses with
Action Prepared By Reviewed By Approved By
Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

Causes damage to protection/ hearing protection. side shields.

organs (Eyes, Central IF SWALLOWED: Immediately call Wear chemical
nervous system). a POISON CENTER/ doctor. protective gloves,
IF ON SKIN (or hair): Take off e.g., PVC
immediately all contaminated Wear safety footwear
clothing. Rinse skin with water.
IF INHALED: Remove person to
fresh air and keep comfortable for
breathing. Call a POISON CENTER/
doctor.

6. INPUT QUANTITY TABLE FOR MANUFACTURING OF BISPYRIBAC

SODIUM

Sr. No. RAW MATERIAL QUANTITY (KG) QUANTITY (LTR)

1. Dihydroxybenzoic Acid 100 Kg 72.9 Ltr
2. DMF 152 Kg 161 Ltr
3. Toluene 870 Kg 1003 Ltr
4. Potassium carbonate 268 Kg 110.3 Ltr
5. 2-Methylsulfonyl-4,6- 346 Kg 262.7 Ltr
dimethoxypyrimidine
6. Water for filtration 1600 Kg 1600 Ltr
7. Water for HCl treatment 1000 Kg 1000 Ltr
8. 32% Hydrochloric Acid 95 Kg 80.5 Ltr
9. Methanol 400 Kg 505 Ltr
10 Methanol for washing 100 Kg 126 Ltr
11. 47% NaOH 65 Kg 43 Ltr
12. Total Quantity 4990 Kg 4964.4 Ltr

OUTPUT QUANTITY
Sr. No. OUTPUT QUANTITY (KG) QUANTITY (LTR)
1 BISPYRIBAC SODIUM ~250 Kg ~170 Ltr

Action Prepared By Reviewed By Approved By

Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

7. GENERAL CHECKPOINTS
Inspection of Equipment’s
I. Inspect the reactor and ensure that it is empty, leak proof and there is no residual mass of last batch
into the reactor.
I. Close the bottom valve of the reactor. In case of material is to receive in drums/bags, verify
the label of Raw material, quantity by weighing the quantity on calibrated weighing
balance.
II. Ensure that all the utilities and instruments are working properly.

Inspection of Raw Material.

I. Weigh the batch quantity of raw material which is to be charge from drums/bags and
arrange the material near charging point.
II. Check the CAS No. of Raw material before charging.

8. OPERATING PROCEDURE
STEP-I: CARBAMATE INTERMEDIATE FORMATION
• Inspect the reactor and ensure that it is empty, leak proof and there is no residual mass of
last batch into the reactor.
• Ensure that all the utilities and instruments are working properly.
• Charge weighted quantity of DMF in SS reactor at ambient temperature and start the
utility circulation in condensers.
• Start the agitator and charge weighted quantity of Toluene in SS reactor at ambient
temperature.
• Charge weighted quantity of Dihydroxy benzoic acid under stirring followed by
potassium carbonate through manhole at ambient temperature.
• Stir the reaction mass for 10-15 minutes after RM charging.
*Note: Exothermicity of 3-5 °C may observe after potassium carbonate charging.
• Now gradually increase the temperature of reaction mixture upto 110-115°C by providing
steam circulation in reactor jacket.
• Once temperature is reached keep the reaction mixture under reflux for 3-4 Hrs. to
separate the water from azeotropic mixture.
• Cool the reaction upto 40°C by circulating cooling water in reactor jacket.
Action Prepared By Reviewed By Approved By
Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

• Charge 173 kg of 2-Methylsulfonyl-4,6-dimethoxypyrimidine (First Lot) in reaction

mixture through manhole at 40°C under stirring.
• Heat the reaction mass gradually upto 110-115°C by providing steam circulation in
reactor jacket.
• Maintain the reaction mass at 110-115°C for 3 hrs. under reflux.
• Again, cool the reaction mass upto 40°C by circulating cooling water in reactor jacket.
• Charge 173 kg of 2-Methylsulfonyl-4,6-dimethoxypyrimidine (Second Lot) in reaction
mixture through manhole at 40°C under stirring.
• Heat the reaction mass gradually upto 110-115°C by providing steam circulation in
reactor jacket.
• Maintain the reaction mass at 110-115°C for 4-5 hrs. under reflux.
• Check sample after 5 hrs. of maintaining. If unreacted dihydroxybenzoic acid is less
than 0.2% then apply cooling otherwise continue reaction cooking till completion.
• Also separate the water from azeotropic mixture throughout the maintaining time.
• Once the reaction is completed cool the reaction mass upto 40°C and apply the vacuum to
reactor system.
• Start the recovery of toluene + DMF at mass temperature between 35-75°C under
vacuum.
• Collect the recovered solvent in assigned receiver system.
• After the recovery is completed release the vacuum and cool the reaction mass upto 40-
50°C.
*Note: After solvent recovery reaction mass will be very thick.
• Charge the weighted quantity of water in reaction mass at 40-50°C under stirring.
• Stir the reaction mass at 50-55°C for 1-1.5 Hrs.
• Transfer the reaction to Centrifuge System (SS Filter) for filtration.
• Make sure that Centrifuge Filtrate line is connected to ML collection tank.
• Filter the reaction mass through Centrifuge and unload the wet cake in Polybag for
further process.

STEP-II: REACTION WITH HCl AND FILTRATION

• Charge weighted quantity of water in MSGL reactor at ambient temperature
• Charge Stage-I wet cake in reactor and start the stirring.
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Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
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 PRODUCT:
BISPYRIBAC
SODIUM

• Now start the dosing of weighted quantity of 32% HCl from addition pot to reaction mass
at 30-35°C.
• Reaction mass temperature to be maintained by using cooling water circulation in reactor
jacket.
• Check the pH of reaction mass it should be around 2-2.5.
• Heat the reaction mass upto 50°C and maintain it for 1 Hr.
• Filter the reaction mass at same temperature through rubber coated filter. (As material is
acidic in nature)
• Wash the wet cake with weighted quantity of water and filter the wash ML.
• Unload the wet cake in polybag from filter for further process.

STEP-III: REACTION WITH 47% NaOH SOLUTION & FILTRATION

• Charge weighted quantity of Methanol in SS reactor at ambient temperature.
• Charge stage-II wet cake in reactor and start the stirring.
• Heat the reaction mass upto 40-45°C.
• Dose the weighted quantity of 47% NaOH solution to achieve pH upto 8-9 at 40-45°C.
• Once the pH achieved maintain the reaction at 40-45°C at for 2 Hrs.
• Now gradually cool the reaction mass upto 0-5°C by circulating brine through reactor
jacket.
• Maintain the reaction mass at 0-5°C for 1 Hr.
• After completing the maintaining transfer the reaction mass to centrifuge (SS Filter) for
filtration.
• Filter the reaction mass through Centrifuge and give weighted quantity methanol washing
to wet cake.
• Once the filtration is completed unload the wet Bispyribac Sodium in polybag.

STEP-IV: DRYING
• Prepare Tray Dryer (SS Dryer) and check the utility circulation.
• Fill the Dryer trays with measured quantity of Bispyribac Sodium wet cake.
• After complete filling apply the heating in Dryer upto 70-80°C.
• Start the drying of Bispyribac Sodium at 70-80°C.

Action Prepared By Reviewed By Approved By

Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date
 PRODUCT:
BISPYRIBAC
SODIUM

• Send the sample of material for M/C check. If M/C is less than 1% then apply cooling
upto 35-40°C and do the unloading of Bispyribac Sodium else continue the drying at 70-
80°C.
• Expected Dry Bispyribac Sodium = 250 Kg
*Note: Use Necessary PPE’s while manual unloading of dry Bispyribac Sodium.
• Properly Label the Dry Bispyribac Sodium bags.
• Keep the reaction & filtration system ready for next batch.

Action Prepared By Reviewed By Approved By

Name

Department Technology R&D Production R&D Technology

Designation Senior Officer Research Scientist General Manager Head -Chemistry Head -
& GLP Technology
Signature/
Date