nft presentation
TRANSCRIPT
NITROFURANTOIN
A
PresentationOn
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
N
NH
ON+
O-
O
N
O
O
NitrofurantoinMolecular 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 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%.
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
NH2
O
NH2 + NH2 NH2 OH2
hydrazine hydrate (1:1)
urea
O
NH2NH NH2
+O
CH3
CH3
Stage - I
AcetoneSemicarbazide
ROUTE OF SYNTHESISStage - I CH3
O
OH
H+
CH3
CH3
N NH
O
NH2
2-(propan-2-ylidene)hydrazinecarboxamide
(Acetone Semicarbazone)
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
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
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 23ATo make provision of additional rows for drying record
in 23A stepTo 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)
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)
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)
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. 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.
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. Fast heating should avoided, it leads into the
frothing.
14. Acetone recovery should be between 70-80 L.
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
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.
IMPURITY PROFILE (23B)
Related substance by TLC
1. NFDA – limit NMT 1%
2. Unidentified impurity – NMT 1%
Nitrofurazone By HPLC – NMT 6%
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.
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
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)
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. 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.
CF-01
RE-37
PROCESS FLOW DIAGRAM OF NFT (23D)
HOT UF WATER
DMF
NFT(23C)
DMF+WATER TD-19
NFT(23D)
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.
IMPURITY PROFILE (23D)
Related substance by TLC
1. NFDA
NMT – 1%
2. Nitrofurazone
By HPLC – NMT 0.01%
NITROFURANTOIN ROUTE
23D NFT PURE (ANHYDROUS)
26C NFT MACRO
26D NFT MACRO
28A NFT MONO
28B NFT MONO
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
FLOW DIAGRAM OF POWDER PROCESSING OF 26C
TD-19 SI-05
Drying at 1200C / 3 hrs Sieving through 420,180 & 75µ 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 – 140°C.
Dry the product at 135– 140°C 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 (5-8°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.
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)
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).
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
FLOW DIAGRAM OF POWDER PROCESSING OF 28B
VD-14
Packing
JM
HG-04
SI-05
THANK YOU
Special Thanks to
Mr. Mandar Dixit
Mr. Vishal Patil