A Presentation

On

NITROFURANTOIN
By

Mr. Deepak Sawant & Mr. Amit Satvidkar

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.

STRUCTURE
O H N N N O
+

Nitrofurantoin
Molecular Formula C8H6N4O5 Molecular Weight 238.16

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 57 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%.

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.

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.

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

ROUTE OF SYNTHESIS
Stage - I
O NH2 H2N urea O O H3C CH3
Semicarbazide Acetone

H2N

NH2

H2O

hydrazine hydrate (1:1)

H2N

NH

NH2

ROUTE OF SYNTHESIS
Stage - I
H3C OH O

H3C N H3C NH O

NH2

2-(propan-2-ylidene)hydrazinecarboxamide
(Acetone Semicarbazone)

ROUTE OF SYNTHESIS
Stage - II
H3C N H3C NH
O

NH2

Cl

CH3

O Acetone Semicarbazone
Na O CH3 H3C

methyl chloroacetate

DMF
OH

O H3C N N H3C

H N O

1-aminohydantoin derivative

ROUTE OF SYNTHESIS
Stage - II
O H3C N N H3C H N O O
-

O N
+

+
O

O O H3C O

CH3

1-aminohydantoin derivative

H2SO4
O

NFDA
H N N O

N O

Nitrofurantoin

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

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 23A To make provision of additional rows for drying record in 23A step To revise % yield of 23D step

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.

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.

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.

PROCESS FLOW DIAGRAM OF ASC (23A)

TO RE-79 FOR SCRUBBING NH3 CLEAR FILTRATE N2 GAS Acetone CH3COOH

UREA
WATER HYDRAZINE HYDRATE

RE-46

RE-45

SF-14

CF-24

FD-12

INSOLUBLES

NFT(23A)

NFT (23A)
705
700 695 700

690
685 680 675 670 670 Actual Weight Standard Wt

675
670 665

660
655 1631101862 1631101876

Plot of Batch Vs Output

IMPURITY PROFILE (23A)

Biuret NMT 1%

Semicarbazide NMT 4%

Individual unidentified impurity

NMT 1.5%

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. 4. 5.

The K.F. of DMF should be less than 0.2 % The K.F. of Methanol should be less than 0.1% Pressure suit should be used for Sodium Methoxide charging.

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.

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. 14.

Fast heating should avoided, it leads into the frothing. Acetone recovery should be between 70-80 L.

PROCESS FLOW DIAGRAM OF NFT (23B)

METHANOL

RC-80

MCA

DIST. ACETONE

DMF SODIUM METHOXIDE ASC

H2SO4

NFDA

RE- 72/76

RE- 81/62

CF-25

FD-12

NFT(23B)

NFT (23B)
128 126 124 122 120 118 116 114 118 118 118 118 118 118 118 118 118 118 118 118 Actual Wt Standard Wt

Output Range107-130 Kg.

112
110 108

Plot of Batch Vs Output.

IMPURITY PROFILE (23B)

1. 2.

Related substance by TLC NFDA limit NMT 1% Unidentified impurity NMT 1%

Nitrofurazone By HPLC NMT 6%

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23C)

1.

2.

3.

4. 5. 6. 7.

Appropriate quantity of DMF and 23B step should be charged as per standards. Before charcoalisation, check for dissolution and it should be clear. Appropriate quantity of Hot UF water (Temp. 90-950C) addition should be done at temperature 1050 C. After UF water addition solution should be clear. Gradually cool up to 2-50 C. Wash wet cake with chilled DMF. Recycle DMF of previous batch should be used for dissolution. It helps to achieve better yield.

PROCESS FLOW DIAGRAM OF NFT (23C)

HOT UF WATER

NFT(23B)
DMF CHARCOAL

RE-29

RE-37

DMF WASH

SF-11

CF-01

RECYCLED DMF

ML TANK

NFT (23C)
250 240

230
220 210 200 190 180 220 220 220 220 220

Output Range190-250 Kg.

Actual Wt Standard Wt

Plot of Batch Vs Output.

IMPURITY PROFILE (23C)

1.

NFDA
NMT 1%

2.

Individual unidentified impurity NMT 0.1%

3.

Nitrofurazone By HPLC NMT 0.7%

CRITICAL PROCESS PARAMETER/ SAFETY PRECAUTIONS (23D)

1. 2.

DMF should be charged as per calculation. 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.

PROCESS FLOW DIAGRAM OF NFT (23D)

DMF NFT(23C) HOT UF WATER

RE-37

DMF+WATER

CF-01

TD-19

NFT(23D)

NFT (23D)
300 250 200

238.81 220
203.15 135 202 135 135 215.05

Output Range94-177 Kg.

150
100 50 0

135

135 Actual Wt Standard Wt

Plot of Batch Vs Output.

IMPURITY PROFILE (23D)

1.

Related substance by TLC NFDA NMT 1%

2.

Nitrofurazone

By HPLC NMT 0.01%

NITROFURANTOIN ROUTE

23D NFT PURE (ANHYDROUS)

26C NFT MACRO 28A NFT MONO

26D NFT MACRO 28B NFT MONO

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

VACUUM AIR VENT AIR VENT

CONDENSOR

CONDENSOR

RC-71

RE-48

RE-47

RC82 CF-11
SF10

ML

FLOW DIAGRAM OF POWDER PROCESSING OF 26C

TD-19

SI-05

Drying at 1200C / 3 hrs

Sieving through 420,180 & 75 sieves

FLOW DIAGRAM OF POWDER PROCESSING OF 26D

TD-19

HG-04

Drying at 135-1400C / 3 hrs PACKING

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.

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

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 (5-8C) UF water about 170 litre in about 1 minute when temp. of reactor reaches around 94C. Wash the wet cake with UF water till practically no odour of acetic acid is persists.

37.0

36.0

36.5

37.5

38.0

38.5

39.0

NFT MONO (28A) PLOT OF BATCH VS OUTPUT

1631101928 1631101929 1631101936 1631101965 1631102244 1631102245 1631102246 1631102247 1631102252 1631102253 1631102254 1631102255 1631102256 1631102321 wet wt. Standard wt 35 - 40 Kg (Wet)

CRITICAL PARAMETERS OF NFT MONO (28B)

Distill out water at 70 - 85C. 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 45C 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).

NFT MONO (28B) PLOT OF BATCH VS OUTPUT

70.0 69.5 69.0 68.5 68.0 67.5 67.0 66.5 66.0 65.5 65.0 64.5 64.0

Dry Wt. Standard Wt. 66 - 72 Kg

FLOW DIAGRAM OF POWDER PROCESSING OF 28B

VD-14
JM

HG-04

SI-05

Packing

THANK

YOU

Special Thanks to

Mr. Mandar Dixit

Mr. Vishal Patil