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NITROFURANTOIN A Presentat ion On By Mr. Deepak Sawant & Mr. Amit Satvidkar

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Page 1: NFT Presentation

NITROFURANTOIN

A

PresentationOn

By

Mr. Deepak Sawant &

Mr. Amit Satvidkar

Page 2: NFT Presentation

INTRODUCTION

It is an antibiotic usually used in treatment of

urinary tract infection. It is often used against

E coli bacteria .

Market brand name is Furadatin, macrobid,

macrodatin ,nitrofur mac,nitromacro etc.

Page 3: NFT Presentation

STRUCTURE

N

NH

ON+

O-

O

N

O

O

NitrofurantoinMolecular Formula – C8H6N4O5

Molecular Weight – 238.16

Page 4: NFT Presentation

DOSAGE

The normal adult dose of nitrofurantoin is 50 to 100 mg four times daily for seven days.

If a long-acting preparation is used then the dose is 100 mg twice daily.

The pediatric dose is 5–7 mg/kg/day in four divided doses

or when in 25 mg/5ml oral suspension then pediatric dose is 3 mg/kg/day in four divided doses

Nitrofurantoin should be taken with food, as this improves the absorption of the drug by 45%.

Page 5: NFT Presentation

MECHANISM

The mechanism of action of nitrofurantoin is unique and complex. The drug works by damaging bacterial DNA, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoproteins (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity.

Page 6: NFT Presentation

NITROFURANTOIN SIDE EFFECTS

Nitrofurantoin can cause Nausea, upset stomach, vomiting Mild diarrhea that is watery or bloody Rust-colored or brownish urine Fever, chills, body aches Vaginal itching or discharge.

Page 7: NFT Presentation

PRECAUTIONS

Nitrofurantoin must be taken with food and in rare cases can cause bleeding in the stomach, vomiting and other gastrointestinal disruptions

Patients should be informed that nitrofurantoin colours urine a dark orange-brown; this is completely harmless.

Nitrofurantoin should not be given to pregnant women after 38 weeks of pregnancy, or who are about to give birth because it can cause haemolytic anaemia to baby

Page 8: NFT Presentation

ROUTE OF SYNTHESIS

NH2

O

NH2 + NH2 NH2 OH2

hydrazine hydrate (1:1)

urea

O

NH2NH NH2

+O

CH3

CH3

Stage - I

AcetoneSemicarbazide

Page 9: NFT Presentation

ROUTE OF SYNTHESISStage - I CH3

O

OH

H+

CH3

CH3

N NH

O

NH2

2-(propan-2-ylidene)hydrazinecarboxamide

(Acetone Semicarbazone)

Page 10: NFT Presentation

ROUTE OF SYNTHESISStage - II

ClO

CH3

O

methyl chloroacetate

CH3

CH3

N NH

O

NH2 +

Na O CH3CH3 OH

DMF

CH3

CH3

NN

NHO

O

Acetone Semicarbazone

1-aminohydantoin derivative

Page 11: NFT Presentation

CH3

CH3

NN

NHO

O+ ON

+O

-

O

O

O

O

CH3

OCH3

N

NH

ON+

O-

O

N

O

O

H2SO4

ROUTE OF SYNTHESISStage - II

Nitrofurantoin

NFDA

1-aminohydantoin derivative

Page 12: NFT Presentation

REGULATORY INFORMATION & CHANGE CONTROL OF NITROFURANTOIN

1) We have to submitted DMF of NFT macro crystal USP at 13th July 2001, DMF NO.15504

2) DMF of NFT monohydrate USP at 30th April 2003, DMF NO.16505

3) We are supplying our NFT thr.watson to Amneal & sciele U.S.customer, they got ANDA approval for NFT oral suspension at June 2011

Page 13: NFT Presentation

CHANGE CONTROL IN NFT

CCP No. DQCCC080021:this change control is regarding STP as per CQA/001-02

CCP NO.DPRCC080091:23C & 23D step BMR revised under this change control

CCP NO. DPRCC080099:To use recycled DMF along with F.DMF for diss.in 23c

To revise BMR of 23D to increase input Qty.CCP No. DPRCC110033 :To incorporate provision of

glass line reactors RE-79 in 23ATo make provision of additional rows for drying record

in 23A stepTo revise % yield of 23D step

Page 14: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23A)

1. Preparation of dilute Sulphuric acid should be done

by slowly addition of H2SO4 in 10 0C Chilled water.

2. For reaction, water should be charged exactly 275

Litre including water present in Hydrazine Hydrate.

3. During charging of Hydrazine Hydrate by vacuum

stop stirring to avoid flashing.

4. Temperature should be taken slowly up to 78

within 1.5 hours.

Page 15: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23A)

5. Scrub liberated NH3 gas by dipping vent pipe of

reaction vessel below appropriate surface of H2SO4

solution.(To avoid the chance of back pressure)

6. During temp. maintaining of 10 hr, mild reflux

should be maintained (Target temp. 980 C)

7. At time of cooling to reaction vessel, first remove

the vent pipe from H2SO4 solution to avoid back-

sucking.

8. After completion of reaction ,completely remove

insoluble salt (biuret) by sparkler filter.

Page 16: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23A)

9. Clear filtrate in acetone should be done at

temperature 70-130 C.

10. PH should be adjusted to 4.7-4.9 by aqueous

1:1 Acetic acid solution.

Page 17: NFT Presentation

PROCESS FLOW DIAGRAM OF ASC (23A)

RE-46

CF-24

RE-45

SF-14

CLEAR FILTRATE

WATER

HYDRAZINE

HYDRATE

UREA

INSOLUBLES

TO RE-79FOR SCRUBBING

NH3

N2 GAS

CH3COOH

Acetone

FD-12

NFT(23A)

Page 18: NFT Presentation

1631101862 1631101876655

660

665

670

675

680

685

690

695

700

705

675

700

670 670

Actual Weight

Plot of Batch Vs Output

NFT (23A)

Page 19: NFT Presentation

IMPURITY PROFILE (23A)

Biuret

NMT – 1%

Semicarbazide

NMT – 4%

Individual unidentified impurity

NMT – 1.5%

Page 20: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23B)

1. Clean reaction vessel by Methanol reflux then

dry it under vacuum at 800C by steam.

2. Take 0.5 kg nitrogen pressure in reactor and

release it through reflux limb, charging nozzle,

reactor vent and bottom valve.

3. The K.F. of DMF should be less than 0.2 %

4. The K.F. of Methanol should be less than 0.1%

5. Pressure suit should be used for Sodium

Methoxide charging.

Page 21: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23B)

6. Check for proper earthing and bonding.

7. Sodium methoxide should be charge within 20-

30 minutes under nitrogen atmosphere.

8. Methanol addition should be done below 700 C

temp. within 90 minutes.

9. After ASC charging maintain temperature 65- 700

C for 30 minutes and solution should be clear.

10. MCA addition should be done at 68-700 C and

control temp. by brine circulation.

Page 22: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23B)

11. NFDA should be charged at temperature 650 C,

it should be stable.

12. After NFDA charging give 3 minutes deep

steam jerk for acetone recovery.

13. Fast heating should avoided, it leads into the

frothing.

14. Acetone recovery should be between 70-80 L.

Page 23: NFT Presentation

PROCESS FLOW DIAGRAM OF NFT (23B)

RC-80

CF-25

RE- 72/76 RE- 81/62

DIST. ACETONE

FD-12

NFT(23B)

SODIUM METHOXIDE

DMF

METHANOL

NFDA

H2SO4

MCA

ASC

Page 24: NFT Presentation

1631

1020

53

1631

1020

92

1631

1020

94

1631

1021

06

1631

1021

38

1631

1021

52108

110

112

114

116

118

120

122

124

126

128

118118118118118118118118118118118118

Actual WtStandard Wt

Output Range- 107-130 Kg.

NFT (23B)

Plot of Batch Vs Output.

Page 25: NFT Presentation

IMPURITY PROFILE (23B)

Related substance by TLC

1. NFDA – limit NMT 1%

2. Unidentified impurity – NMT 1%

Nitrofurazone By HPLC – NMT 6%

Page 26: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23C)

1. Appropriate quantity of DMF and 23B step should be charged as per standards.

2. Before charcoalisation, check for dissolution and it should be clear.

3. Appropriate quantity of Hot UF water (Temp. 90-950C) addition should be done at temperature 1050

C.

4. After UF water addition solution should be clear.

5. Gradually cool up to 2-50 C.

6. Wash wet cake with chilled DMF.

7. Recycle DMF of previous batch should be used for dissolution. It helps to achieve better yield.

Page 27: NFT Presentation

RE-29

CF-01

RE-37

SF-11

RECYCLED DMF

PROCESS FLOW DIAGRAM OF NFT (23C)

DMF WASH

HOT UF WATER

CHARCOAL

DMF

NFT(23B)

ML TANK

Page 28: NFT Presentation

1631

1020

86

1631

1021

07

1631

1021

45

1631

1021

50

1631

1021

64180

190

200

210

220

230

240

250

220 220 220 220 220

Actual WtStandard Wt

Output Range- 190-250 Kg.

Plot of Batch Vs Output.

NFT (23C)

Page 29: NFT Presentation

IMPURITY PROFILE (23C)

1. NFDA

NMT – 1%

2. Individual unidentified impurity

NMT – 0.1%

3. Nitrofurazone

By HPLC – NMT 0.7%

Page 30: NFT Presentation

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23D)

1. DMF should be charged as per calculation.

2. Solution should be clear before and after hot

UF water addition.

3. Rate of hot UF water addition should be

constant , it help to improve crystal size.

4. Finally wash wet cake with chilled UF water up

to DMF odour is very faint.

Page 31: NFT Presentation

CF-01

RE-37

PROCESS FLOW DIAGRAM OF NFT (23D)

HOT UF WATER

DMF

NFT(23C)

DMF+WATER TD-19

NFT(23D)

Page 32: NFT Presentation

1631

1021

53

1631

1022

27

1631

1022

36

1631

1022

42

1631

1022

710

50

100

150

200

250

300

220203.15 202

238.81215.05

135 135 135 135 135

Actual WtStandard Wt

NFT (23D)

Plot of Batch Vs Output.

Output Range- 94-177 Kg.

Page 33: NFT Presentation

IMPURITY PROFILE (23D)

Related substance by TLC

1. NFDA

NMT – 1%

2. Nitrofurazone

By HPLC – NMT 0.01%

Page 34: NFT Presentation

NITROFURANTOIN ROUTE

23D NFT PURE (ANHYDROUS)

26C NFT MACRO

26D NFT MACRO

28A NFT MONO

28B NFT MONO

Page 35: NFT Presentation

FLOW DIAGRAM OF NITROFURANTOIN (26C&D/28A&B)

VACUUM

AIR VENT AIR VENT

ML

RE-48

RE-47

CONDENSOR

CF-11

CONDENSOR

RC-82

SF-10

RC-71

Page 36: NFT Presentation

FLOW DIAGRAM OF POWDER PROCESSING OF 26C

TD-19 SI-05

Drying at 1200C / 3 hrs Sieving through 420,180 & 75µ sieves

Page 37: NFT Presentation

FLOW DIAGRAM OF POWDER PROCESSING OF 26D

TD-19 HG-04

Drying at 135-1400C / 3 hrs

PACKING

Page 38: NFT Presentation

CRITICAL PARAMETERS OF NFT MACRO (26C)

Reactor RPM should be 65. Water content of Acetic acid & UF water should be

20%. Solution should be clear at 105 + 10C. There should

not be any floating particles. At constant temperature between 101.5 to 1020C, do

the seeding with about 200 gm seed. Cooling rate after seeding i.e. from 102 to 970C should be NMT 1.250C/hr & from 97 to 850C should

be NMT 30C/hr. Sudden cooling will not give proper size of crystals.

Acetic acid distillation rate & temperature i.e. for initial 2 hrs is 1.38 to 1.56 L/hr & after 2 hrs 1.66 to

2.15 L/hr & temp. should be between 85 to 890C.

Page 39: NFT Presentation

CRITICAL PARAMETERS OF NFT MACRO (26D)

Initially dry the product with steam (pressure 7 –10 kg/ cm2) in jacket for about 3 hrs.

After 3 hrs, start heaters & increase the temperature to 135 – 140°C.

Dry the product at 135– 140°C for about 3 hrs.

Page 40: NFT Presentation

CRITICAL PARAMETERS OF NFT MONO (28A)

Solution should be clear at 103 + 10C. There should not be any floating particles.

Fast cooling is to be done. Brine should be filled at 68 + 30C. If product of specific crystal size is to be

obtained, then charge chilled (5-8°C) UF water about 170 litre in about 1 minute when temp. of reactor reaches around 94°C.

Wash the wet cake with UF water till practically no odour of acetic acid is persists.

Page 41: NFT Presentation

NFT MONO (28A)PLOT OF BATCH VS OUTPUT

1631

1019

28

1631

1019

36

1631

1022

44

1631

1022

46

1631

1022

52

1631

1022

54

1631

1022

5636.0

36.5

37.0

37.5

38.0

38.5

39.0

wet wt.Standard wt 35 - 40 Kg (Wet)

Page 42: NFT Presentation

CRITICAL PARAMETERS OF NFT MONO (28B)

Distill out water at 70 - 85°C. Wash the wet cake with UF water till

practically no odour of acetic acid is persists. Dry the wet cake by circulating hot water at

40 – 45°C in the heat exchanging coils of the vacuum tray dryer till water content by KF of the product is between 6.5 to 7.5%.

KF of the product should be between 6.5 to 7.5% because one mole of water is to be retained (as monohydrate in Nitrofurantoin Monohydrate).

Page 43: NFT Presentation

NFT MONO (28B)PLOT OF BATCH VS OUTPUT

1631

1019

26

1631

1019

37

1631

1022

78

1631

1022

79

1631

1022

99

1631

1023

0064.0

65.0

66.0

67.0

68.0

69.0

70.0

Dry Wt.Standard Wt. 66 - 72 Kg

Page 44: NFT Presentation

FLOW DIAGRAM OF POWDER PROCESSING OF 28B

VD-14

Packing

JM

HG-04

SI-05

Page 45: NFT Presentation

THANK YOU

Special Thanks to

Mr. Mandar Dixit

Mr. Vishal Patil