Annexures GCPL 1 List of Annexures Annexure – I Plant Layout Annexure – II Manufacturing Process Annexure – III Details of Storage of Solvents Annexure – IV Water Balance & Details of Treatment and disposal of Effluent Annexure – V Details of Treatment and Disposal of Solid Waste Annexure – VI List of Raw materials & Quantity of Consumption Annexure – VII Point Source Emissions – Stack Emission Characteristics Annexure – VIII Details of Fugitive Emissions Annexure – IX Risk Identification Annexure – X Topo Map & Administrative Set-up Map
82
Embed
Annexures 3 GCPLenvironmentclearance.nic.in/writereaddata/Online/TOR/05...Calculated quantities of calcium gluconate & Boric acid dissolved in DM Water, filtered, spray dried, sieved
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Annexures GCPL 1
List of Annexures Annexure – I Plant Layout
Annexure – II Manufacturing Process
Annexure – III Details of Storage of Solvents
Annexure – IV Water Balance & Details of Treatment and disposal of Effluent
Annexure – V Details of Treatment and Disposal of Solid Waste
Annexure – VI List of Raw materials & Quantity of Consumption
Annexure – VII Point Source Emissions – Stack Emission Characteristics
Annexure – VIII Details of Fugitive Emissions
Annexure – IX Risk Identification
Annexure – X Topo Map & Administrative Set-up Map
Annexures GCPL 2
ANNEXURE – I PLANT LAYOUT
Annexures GCPL 3
Annexures GCPL 4
Annexures GCPL 5
ANNEXURE – II MANUFACTURING PROCESS
Annexures GCPL 6
Manufacturing Process
Exis t in g
Calcium Gluconate
Gluconic Acid procured from market is neutralized with Calcium carbonate, filtered,
crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Calcium Gluconate
Gluconic acid is neutralised with Calcium carbonate, filtered, crystallised, centrifuged,
dried, milled and packed.
Alternate process
NEUTRALISATION FILTERATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
GLUCONO DELTA LACTONE + CaCO3 + WATER
(NEUTRALISATION) FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
Annexures GCPL 7
Sodium Gluconate
Gluconic acid brought from the market is neutralised with Sodium bi-carbonate, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Sodium Gluconate
Gluconic acid is neutralised with Sodium carbonate / Sodium Bicarbonate, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
NEUTRALISATION FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
GLUCONIC ACID +
SODIUM CARBONATE /
BICARONATE
(NEUTRALISATION)
FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 8
Potassium Gluconate
Gluconic acid brought from the market is neutralized with Potassium carbonate, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Potassium Gluconate
Gluconic acid is neutralised with Potassium carbonate / Potassium Bicarbonate, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
NEUTRALISATION FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
GLUCONIC ACID +
POTASSIUM CARBONATE
/ BICARONATE
(NEUTRALISATION)
FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 9
Magnesium Gluconate
Gluconic acid brought from the market is neutralised with Magnesium carbonate, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Magnesium Gluconate
Gluconic acid is neutralised with Magnesium carbonate, filtered, concentrated, crystallised,
centrifuged, dried, milled and packed.
Alternate process
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
NEUTRALISATION FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
GLUCONIC ACID +
MAGNESIUM CARBONATE
(NEUTRALISATION) FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 10
Zinc Gluconate
Gluconic acid brought from the market is neutralised with Zinc carbonate/Zinc Oxide,
filtered, concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Zinc Gluconate
Gluconic acid is neutralised with Zinc carbonate/Zinc Oxide, filtered, concentrated,
crystallised, centrifuged, dried, milled and packed.
Alternate process
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
NEUTRALISATION FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
GLUCONIC ACID + ZINC
CARBONATE / ZINC OXIDE
(NEUTRALISATION) FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 11
Manganese Gluconate
Gluconic acid brought from the market is neutralised with Manganese carbonate/
Manganese Oxide, filtered, concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process for the manufacture of Manganese Gluconate
Gluconic acid is neutralised with Manganese carbonate/ Manganese Oxide, filtered,
concentrated, crystallised, centrifuged, dried, milled and packed.
Alternate process
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
NEUTRALISATION FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
CONCENTRATION
GLUCONIC ACID +
MANGANESE CARBONATE /
MANGANESE OXIDE
(NEUTRALISATION)
FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 12
Calcium Lactate
Lactic Acid is neutralised with Calcium carbonate, filtered, crystallised, centrifuged, dried,
milled and packed.
Calcium Glubionate
In this process, calculated quantities of both Calcium Gluconate and Calcium Lactobionate
are charged in the blender and mixed, sieved and packed.
Alternate Process for the manufacture of Calcium Glubionate
Calculated quantities of Calcium Gluconate and Calcium Lactobionate are mixed in DM
water, filtered, dried, sieved and packed.
NEUTRALISATION FILTRATION CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
BLENDING SIEVING PACKING
MIXING SIEVING PACKING FILTERING DRYING
Annexures GCPL 13
Calcium Lacto Gluconate
In this process, calculated quantities of Calcium Lactate and Calcium Gluconate are charged
in the blender and mixed, sieved and packed.
2. Alternate Process for the m anu facture of Ca lciu m La ct o Glucon a t e
Calculated quantities of Calcium Lactate and Calcium Gluconate are mixed in DM water,
filtered, dried, sieved and packed.
3. Alternate Process for the m anu facture of Ca lciu m La ct o Glucon a t e
Calculated quantities of Gluconic Acid, Lactic Acid are reacted with calcium carbonate,
filtered, dried, sieved and packed.
4. Alternate Process for the m anu facture of Ca lciu m La ct o Glucon a t e
MIXING SIEVING PACKING FILTERING DRYING
BLENDING SIEVING PACKING
GLUCONIC ACID + LACTIC
ACID + CaCO3
(NEUTRALISATION) FILTRATION SIEVING
PACKING
DRYING
GLUCONO DELTA LACTONE
+ LACTIC ACID + CaCO3
(NEUTRALISATION) FILTRATION SIEVING
PACKING
DRYING
Annexures GCPL 14
Calcium Lactobionate
Calculated quantities of Lactose, Sodium bromide, Calcium Carbonate are mixed in water,
electrolysed, filtered, vaccum concentrated, crystallised with alcohol, centrifuged, milled,
dried and packed in bags/ Fibre drums.
ELECTROLYSIS FILTRATION
CRYSTALLISATION
PACKING MILLING DRYING CENTRIFUGING
VACCUM
CONCENTRATION
LACTOSE,
SODIUM BROMIDE,
CALCIUM CARBONATE,
DM WATER
Annexures GCPL 15
Calcium Borogluconate :
1. Calculated quantities of calcium gluconate and Boric acid are charged in the blender
and mixed sieved & packed.
2. Alternate Process
Calculated quantities of calcium gluconate & Boric acid dissolved in DM Water, filtered,
spray dried, sieved & packed.
Ferrous Gluconate :
BLENDING SIEVING PACKING
CALCIUM
GLUCONATE +
BORIC ACID +
DISSOLVED IN DM
WATER
FILTERED DRIED
PACKED SIEVED
CALCIUM
GLUCONATE +
FERROUS
SULPHATE + DM
WATER
FILTERATIO
N
CONCENTRATIO
N
PACKING MILLING
DRYING
Annexures GCPL 16
Man u factu rin g P rocess
P roposed
1 IRON SUCROSE
Ferr ic Chlor ide is dissolved in wa ter and sodium bica rbona te solu t ion is added
to precipita te fer r ic hydroxide which is filt ered.
Above fer r ic hydroxide is mixed with sucrose and hea ted to get iron sucrose in
solu t ion . Which is concent ra ted to get th ick mass which is added with vigorous
st ir r ing to DNS and then methanol to precipita te iron sucrose solid. This is
cent r ifuged and slur r ied with DNS and acetone aga in to remove the impur it ies.
The wet materia l is dr ied under vacuum, pulver ized, redr ied, milled, blended as
needed and packed.
Raw material:
Ferric Chloride
Sodium carbonate
Sucrose
DNS denatured spirit
Methanol
Acetone
Raw m ateria l con su m ption per kg of ou tpu t
Ferric Chloride = 0.2 kg / kg
Sodium Carbonate = 0.04 kg / kg
Sucrose = 2 kg / kg
DNS = 8 L / kg
Methanol = 5 L / kg
Acetone = 1 L / kg
Annexures GCPL 17
P ROCESS FLOW CHART
Sodium carbona te
solu t ion
MLR collect ion
Hea t
DNS
MLR collect ion
methanol
DNS
Acetone MLR collect ion
Water + Ferric Ch loride
Filtration of Ferric
h ydroxide
Ferric h ydroxide Cake +
Su gar
Con cen trated
Filtration
Filte r Mass
Filtration
Vacu u m Dryin g
Millin g , Blen din g & P ackin g
Annexures GCPL 18
2. CALCIUM DOBESYLATE
Stage-I: Sulphur ic acid is a dded to a suspent ion of hydroquinone in ethylene di
ch lor ide. After the su lfona t ion , water is added and aqueous layer separa ted.
Stage-II: aqueous layer is neut ra lized with a slur ry of ca lcium carbona te in
wa ter , cent r ifuged to separa te ca lcium sulfa te.
Liquid from cent r ifuge is concent ra ted, ch illed, the product filt ered and washed
with isopropanol and dr ied.
Raw m ateria l:
Hydroquinone
Sulphuric acid
Calcium carbonate
Ethylene di chloride
Isopropanol
Raw m ateria l con su m ption per kg of ou tpu t
Hydroquinone = 1.2 kg
Sulphuric acid = 1.6 kg
Calcium carbonate = 1.6kg/kg
Ethylene di chloride = 4L/kg
Isopropanol = 2L/kg
Annexures GCPL 19
P ROCESS FLOW CHART
Stage -1
su lphur ic acid
layer separation
Stage -II
ca lcium carbona te
cen trifu ge
concen trated
ch illed
isopropanol
Hydroqu in on e + e th ylen e d i
ch loride
Aqu eou s layer
Liqu id from cen trifu ge
Crystallisation
Dryin g
Cen trifu gation
Millin g , Blen din g & P ackin g
Residu e
Annexures GCPL 20
3. TIEMMONIUM METHYL SULPFATE (TMS)
Morpholine is reacted with 2-acetyl th iophene and p-formaldehyde in the
presence of hydrochlor ic acid in dena tured spir it (DNS) to get the cor responding
mannich base as HCl sa lt . The above HCl sa lt is basified in toluene to get the
corresponding mannich ketone base. This is reacted with phenyl magnesium
bromide in tet rahydrofuran to get t iemmonium hydrochlor ide which is pur ified
using methanol slur ry. The pure hydrochlor ide is conver ted to base and t rea ted
with dimethyl su lfa te in acetone to get the t iemmonium methyl su lfa te. This is
dr ied in a vacuum oven, milled, blended and packed.
Raw m ateria l:
Morpholine
2- Acetyl thiophene
P-Formaldehyde
Hydrochloric acid
Denatured spirit (DNS)
Phenyl magnesium bromide
Dimethyl Sulfate
Tetrahydrofuran
Methanol
Toluene
acetone
Raw m ateria l con su m ption per kg of ou tpu t
Morpholine = 1 kg / kg
2- Acetyl th iophene = 1.5 kg / kg
P-Formaldehyde =0.7 kg / kg
Hydrochlor ic acid = 5.7 kg / kg
Dena tured spir it (DNS) = 6L / kg
Phenyl magnesium bromide =2.3 kg / kg
Dimethyl Sulfa te =0.5 kg / kg
Annexures GCPL 21
Methanol = 3L/kg
Tetrahydrofuran = 2L/kg
Toluene = 8 L/kg
Acetone = 5L/kg
P ROCESS FLOW CHART
Con. HCl
Reflux
MLR collect ion
Phenyl magnesium bromide
Con. HCl
Methanol MLR collect ion
Dimethy su lpha te
MLR collect ion
Morph olin e + 2- Ace tyl
th ioph en e + P -Form aldeh yde
+DNS
Cool, Cen trifu gation ,
Bas ification
Keton e Base
Qu en ch in g ice w ater
Cen trifu gation
Basification w ith Am m on ia
Cen trifu gation
Vacu u m Dryin g
Annexures GCPL 22
4 ETHAMSYLATE
Stage-I: Sulphur ic acid is added to a suspent ion of hydroquinone in ethylene di
ch lor ide. After the su lfona t ion , water is added and aqueous layer separa ted.
Stage-II: aqueous layer is neut ra lized with diethylamine, concent ra ted, ch illed,
the product filt ered and washed with isopropanol and dr ied.
Raw m ateria l:
Hydroquinone
Sulphuric acid
Diethylamine
Ethylene di chloride
Isopropanol
Raw m ateria l con su m ption per kg of ou tpu t
Hydroquinone =0.8 kg/kg
Sulphuric acid = 1.5 kg/kg
Diethylamine = 1.6 L/kg
Ethylene di chloride = 2.3L/kg
Isopropanol = 0.5L/kg
Millin g , Blen din g & P ackin g
Annexures GCPL 23
P ROCESS FLOW CHART
Stage -I:
Suphur ic acid
wa ter
layer separation
s tage -II
diethylamine
con cen tration
isopropanol
h ydroqu in on e + e th ylen e d i
ch loride
Su lph on ated m ass
Aqu eou s layer
Crystallisation
Dryin g
Cen trifu gation
Ch ill, re s idu e
Annexures GCPL 24
5 TOLPERISONE HCl
Mixture of 4-methyl propiophenone, piper idin e, and hydrochlor ic acid hea ted to
reflux in 1,3-dioxalone. After the react ion is over , dilu ted with ethyl aceta te and
chilled with st ir r ing. Product formed is cen t r ifuged, washed with ethyl aceta te.
The crude product is pur ified with methanol and ethyl a ceta te using charcoa l.
Raw m ateria l:
1.4-methyl propiophenone
2. piper idine
3.1,3-dioxalone
4. conc. hydrochlor ic acid
5. ethyl aceta te
6. methanol
Raw m ateria l con su m ption per kg of ou tpu t
1.4-methyl propiophenone 1.0 kg
2. piper idine 0.6 kg
3.1,3-dioxalone 1.5 kg
4. conc.hydrochlor ic acid 0.025 L
5. ethyl aceta te 3 L
6. methanol 1.0 L
Millin g , Blen din g & P ackin g
Annexures GCPL 25
P ROCESS FLOW CHART
Reflux
ch ill
stage-1
charcoa l
filt er
4-m eth yl
propioph en on e+piperid in e+
HCl + 1,3-d ioxolan e
Dilu te w ith e th yl ac tate
Cen trifu gation
Dissolve s tage -1 in m eth an ol
cen trifu gation
Filtrate , con cen trate , add
e th yl ace tate , ch ill
Vacu u m dryin g
Annexures GCPL 26
6. a . CALCIUM GLYCEROP HOSP HATE
Stage – I: Epichlorohydr in is hydrolised with dilu te acid, and reacted with
Tr i sodium phospha te, to get Crude sodium Glycerophospha te.
Stage –II : To the Above crude Sodium Glycerophospha te solu t ion , Ca lcium
chlor ide is added to get Crude Ca lcium Glycerophospha te
Stage – III : crude Ca lcium Glycerophospha te is washed with DNS: Water
mixture to get Pure Ca lcium Glycerophospha te, which is cent r ifuged and dr ied.
Raw m ateria l:
1. Epichlorohydrin
2. Trisodium phosphate
3. Calcium chloride
4. Denatured spirit (DNS)
Raw m ateria l con su m ption per kg of ou tpu t
1. Epichlorohydrin =1.5 kg / kg
2. Trisodium phosphate = 6 kg / kg
3. Calcium chloride = 2 kg / kg
4. Denatured spirit (DNS) = 5L / kg
Millin g , Blen din g & P ackin g
Annexures GCPL 27
P ROCESS FLOW CHART
Stage - I
Reflux
Hot condit ion
Stage -II
Calcium chlor ide
Stage -III
DNS: Water
Epichlorohydrin + water
Reaction w ith Trisodiu m
ph osph ate
Ch arcoal treatm ent &
Filtration
Reaction w ith calc iu m
ch loride
Dryin g
Cen trifu gation & Slu rry
w ash
Millin g , Blen din g & P ackin g
Annexures GCPL 28
6.b. MAGNESIUM GLYCEROP HOSP HATE
Stage – I: Epichlorohydr in is hydrolised with dilu te acid, and rea cted with
Tr i sodium phospha te, to get Crude sodium Glycerophospha te.
Stage –II : To the Above crude Sodium Glycerophospha te solu t ion ,Magnesium
ch lor ide is added to get Crude Magnesium Glycerophospha te
Stage – III : crude Magnesium Glycerophospha te is washed with DNS: Water
mixture to get Pure Magnesium Glycerophospha te, which is cent r ifuged and
dr ied
.
Raw m ateria l:
4. Epichlorohydrin
5. Trisodium phosphate
6. Magnesium chloride
7. Denatured spirit (DNS)
Raw m ateria l con su m ption per kg of ou tpu t
8. Epichlorohydrin =1.5 kg / kg
9. Trisodium phosphate = 6 kg / kg
10. Magnesium chloride = 3 kg / kg
11. Denatured spirit (DNS) = 5L / kg
Annexures GCPL 29
P ROCESS FLOW CHART
Stage - I
Reflux
Hot condit ion
Stage -II
Magnesium chlor ide
Stage -IV
DNS: Water
Epichlorohydrin + water
Reaction w ith Trisodiu m
ph osph ate
Ch arcoal treatm e nt &
Filtration
Reaction w ith Magn es iu m
ch loride
Dryin g
Cen trifu gation & Slu rry
w ash
Con cen tration
Annexures GCPL 30
6. c . SODIUM GLYCEROP HOSP HATE
Stage – I: Epichlorohydr in is hydrolised with dilu te acid, and reacted with
Tr i sodium phospha te, to get Crude sodium Glycerophospha te solu t ion which is
concent ra ted and filt ered to get Crude sodium Glycerophospha te
Stage – II : crude Sodium Glycerophospha te is washed with DNS: Water
mixture to get Pure Sodium Glycerophospha te, which is en t r ifuged and dr ied
.
Raw m ateria l:
1. Epichlorohydrin
2. Trisodium phosphate
3. Denatured spirit (DNS)
Raw m ateria l con su m ption per kg of ou tpu t
4. Epichlorohydrin =1 kg / kg
5. Trisodium phosphate = 6 kg / kg
6. Denatured spirit (DNS) =5L / kg
Millin g , Blen din g & P ackin g
Annexures GCPL 31
P ROCESS FLOW CHART
Stage - I
Reflux
Hot condit ion
DNS
Stage -II
DNS: Water
Epichlorohydrin + water
Reaction w ith Trisodiu m
ph osph ate
Ch arcoal treatm ent &
Filtration
Crysta llisation
Dryin g
Cen trifu gation & Slu rry
w ash
Con cen tration
Annexures GCPL 32
7 FENSPIRIDE HYDROCHLORIDE
MANUFACTURING FLOWCHART:
Stage -1:
1-(2-ph en yle th yl)-4-p iperidon e
Hydroch loric ac id
Water, ce n trifu ge , dry
S tage -II : Fen spiride Hydroch loride Cru de
Zin c Du st
bas ify w ith Aq. am m on ia
Dich lorom eth an e
Con cen tration
Toluen e , Die th y l carbonate
w ater, to lu en e
ac id ify ,
Hydroch loric ac id
cool, cen trifu ge , dry
Millin g , Blen din g & P ackin g
Nitrom eth an e+ DMSO +
P otass iu m Carbon ate , 0 deg .C
Stage -1
Meth an ol + Stage -1+
Hydroch loric ac id , <5 deg .C
Dich lorom eth an e layer
to lu en e layer
Stage -II
Res idu e
Annexures GCPL 33
S tage -III: P u rification
S tage -II
Heat
Ace ton e
Cool & Cen trifu ge ,
Man u factu rin g process for th e Fen spiride Hydroch loride :
Stage -I: 4-(n it romethyl)-1-phenethylpiper idin -4-ol is prepared by react ing 1-(2-
phenylethyl)-4-piper idone with n it romethane and potassium carbona te in
dimethylsu lfoxide. stage-1 is isola ted by quenching in wa ter Cent r ifuging.
Stage -II: Fenspir ide hydrochlor ide crude is prepared by the reduct ion of
stage-I with zinc dust and hydrochlor ic acid, basifica t ion with aqueous
ammonia and ext ract ing with dich loromethane. Dichloromethane ext ract is
concent ra ted to get 4-(aminoethyl)-1-phenylpiper idin -4-ol, which is reacted
with diethylca rbona te in the presence of sodium methoxide to get Fenspir ide
base. This is t rea ted with Hydrochlor ic acid to get Fenspir ide hydrochlor ide
crude.
Stage -III: Fenspir ide HCl crude dissolved in methanol , t rea ted with Act ivated
ca rbon . filt ered, filt ra te concent ra ted completely, Acetone is added , solid
cent r ifuged, dr ied under vacuo <60 deg.C , milled ,sieved and packed.
Meth an ol
Con cen trate
Dryin g, m illin g , S ievin g+
packin g
Annexures GCPL 34
8 CLOZAPINE :
MANUFACTURING FLOW CHART
2-ch loro ben zoic ac id
reduct ion
wa ter +sodium dith iona te
s tage -1
cyclisa t ion , xylene
s tage -2
N-m eth ylp iperazin e , TiCl4
s tage -3
recrysta llisation
Brie f process description : Stage -1:
4-chloro-2-n it ro an iline is reacted with 2-chloro bezoic acid and th e resu lt ing
product is reduced in -situ with sodium dithiona te in wa ter to get 2-( 4-ch loro
-2-am in o d iph en ylam in o)ben zoic ac id s tage -1
S tage -2:
Stage-1 is cylised in refluxing xylene to get 8-ch loro-5H-ben zo-
[b,e ][1,4]d iazepin e -11-10H-on e
Stage -3:
4-ch loro-2-n itro an ilin e
+potass iu m carbonate
+DMF
2-( 4-ch loro -2-am in o
d iph en ylam in o)benzoic ac id
8-ch loro-5H-ben zo-
[b,e ][1,4]d iazepin e -11-10H-on e
cru de c lozapin e
pu re c lozapin e
Dryin g, s iev in g an d
packin g
Annexures GCPL 35
Stage-2 is reacted with N-methyl piperazine in presence of t it an ium
tet rachlor ide to get crude clozapine (stage-3)
Stage -4: pu re c lozapin e
Crude clozapine is pur ified to pure clozapine by dissolving in methanol ,
charcolising, filt er ing, concent ra t ing and cooling. The product is cent r ifuged,
dr ied under vacuum below 60 deg.C , milled , sieved and packed.
9 NIFUROXAZIDE MANUFACTURING FLOW CHART:
Syn th es is of Nifu roxazide :
Nitrofu rfu ral d iace tate
Heat
4-hydroxy benzohydrazide
Hydroch loric ac id
Heat & Cool
Cen trifu ge
Meth an ol
Cen trifu ge
Man u factu rin g procedu re for Nifu roxazide :
Nit rofufura l Diaceta te reacts with 4-hydroxy benzohydrazide in the presence of
su lfur ic acid in DNS to form the Nifuroxazide.
Water +Su lph uric ac id+
DNS
Reaction m ass
Reaction m ass
Wet cake , re flu x
Dryin g, m illin g , s iev in g,
packin g
Annexures GCPL 36
10 OXETACAINE MANUFACTURING FLOW CHART:
Stage -I:
Su lfu ric ac id
wa ter
Cen trifu ge , dry
S tage -II: Methyla t ion
Dim eth yl su lfate
P otass iu m h ydroxide
Heatin g
Water
Extraction & Disti llation
Stage -III:
P EG-400
h eatin g Sodiu m Hydroxide
d ich loro e th an e
Water
Extraction
Layer separation
Ch loroace ty l ch loride
Sodiu m h ydroxide
Extraction & Disti llation
Dimethyl benzyl carbinol +
Acetonitrile
S tage -I+ Tolu en e
Dim et
s tage -1
Reaction Mass
Res idu e
Stage -II
Reaction Mass
Organ ic layer
Res idu e
Annexures GCPL 37
S tage -IV: Oxetaca ine crude
Etan ol am in e Tolu en e
Sodiu m Hydroxide
Heatin g
Water
Extraction , layer separation
Hydroch loric ac id
Extraction , layer separation
Am m on ia
Cen trifu ge , dry
S tage -V: Purifica t ion
Isopropyl a lcoh ol
Water
Cen trifu ge
Man u factu rin g P rocess of Oxe tacain e :
S tage -1: Dimethyl benzyl ca rbinol is reacted acetonit r ile and su lfur ic acid to
get stage-I.
Stage -I1: Stage-I methyla ted with dimethyl su lfa te in the presence of
potassium hydroxide in toluene to stage-II.
Stage -II1: Stage-II hydrolyzed with sodium hydroxide and reacted with
ch loroacetyl ch lor ide to stage-III.
Stage -IV: Stage-III react ed with ethanol amine in the presence of sodium
hydroxide in toluene to stage-IV (Oxetaca ine crude).
Stage -V: Oxetacine crude crude pu r ified using Isopropyl a lcohol and water to
get pure Oxetaca ine
Residu e
Reaction
Organ ic layer
Acid ic layer
s tage -IV
Stage -IV
Dryin g, m illin g , s iev in g,
packin g
Annexures GCPL 38
11 BENFOTIAMINE
Mixture of th iamine HCl and or thophosphor ic acid is hea ted and phosphorous
pentoxide is added slowly over a per iod. Dilu ted by a dding wa ter and
Hydrolysed by hea t ing to reflux
The above solu t ion is basified with sodium hydroxide and t rea ted with benzoyl
ch lor ide in methylene di ch lor ide a t low tempera ture. After the react ion ,
cent r ifuged to remove inorganics, the MLR is concent ra ted and filt ered. The
filt ra te is acidified to get the crude benfot iamine which is cent r ifuged and
washed with water .
crude product is dissolved in dilu te sodium hydroxide, charcolised, filt ered,
acidified to get the pure product which is cent r ifuged, washed with wa ter ,
methanol and spin dr ied. The wet mater ia l is dr ied under vacuum, pulver ized,
milled, blended as needed and packed.
Raw m ateria l:
1. th iamine HCl
2.or thophosphor ic acid
3.phosphorous pentoxide
4.Sodium hydroxide
5.benzoyl ch lor ide
6.Hydrochlor ic acid
7.methylene ch lor ide
8.methanol
Raw m ateria l con su m ption per kg of ou tpu t
1. th iamine HCl 2.5 kg
2.or thophosphor ic acid 3.5 kg
3.phosphorous pentoxide 2.5 kg
4.Sodium hydroxide 2.5 kg
5.benzoyl ch lor ide 1.5 kg
6.Hydroch lor ic acid 2.5 L
7.methylene ch lor ide 5.0 L
Annexures GCPL 39
8.methanol 2.0 L
P ROCESS FLOW CHART
Phosphorous pentoxide
hea t
wa ter
reflux, cool
benzoyl ch lor ide
in DCM
hydrochlor ic acid
Hydrochlor ic acid
Th iam in e HCl +
orth oph osph oric acid
Reaction m ixtu re
Reaction m ixtu re+ sodiu m
h ydroxide
Cen trifu gation
Cen trifu gation
Millin g , Blen din g & P ackin g
Above so lid + aq. sodiu m
h ydroxide
Ch arcoalise , fi lte r
Cen trifu ge , MLR con cen trate
Vacu u m dryin g
Annexures GCPL 40
12 CALCIUM FOLINATE
Folic acid dissolved in wa ter and t rea ted with sodium borohydr ide under
cooling. The mixture is quenched in to hydrochlor ic acid and then formyla ted
using formic acid. The react ion solu t ion is concent ra ted under vacuum and
cent r ifuged to get stage-1(formyl folic acid). Stage-1 is reacted with
t r iethylamine in wa ter and then conver ted to the cor responding ca lcium sa lt
using ca lcium chlor ide. The product is precipita ted by adding DNS. The crude
product is pu r ified using water and DNS. Washed with acetone and dr ied. The
wet product is dr ied under vacuum, milled and sieved and packed.
Raw m ateria l:
1. folic acid
2. sodium borohydr ide
3. conc. HCl
4. t r iethyl amine
5. ca lcium chlor ide
6. DNS
7.acetone
8.formic acid
9. Methanol
Raw m ateria l con su m ption per kg of ou tpu t
1. folic acid 2.5 kg
2. sodium borohydr ide 5 kg
3. conc. HCl 7 L
4. t r iethyl amine 2 L
5. ca lcium chlor ide 2 kg
6. DNS 75 L
7.acetone 5 L
8.formic acid 70 L
Annexures GCPL 41
9. methanol 5L
P ROCESS FLOW CHART
Sodium boro hydr ide
Formic acid
Stage -1
t r iethylamine
DNS
ca lcium chlor ide
Qu en ch in to HCl
Filtration , con cen tration
Ce n trifu gation
Stage -1 in w ater
Dryin g u nder vacuu m
Millin g , s iev in g Blen din g &
P ackin g
Reaction m ixtu re
cen trifu gation
recrysta llisation
cen trifu gation
Folic ac id in w ater
Annexures GCPL 42
13. TRIMETAZIDINE HYDROCHLORIDE
Stage -I: Synthesis of Tr imetazidine Hydrochlor ide crude
P iperazin e
5% P alladiu m on Carbon
Hydrogen ator
Centrifu ge , Con cen trate
Tolu en e ,w ater
Extraction , layer separation
isopropan olic HCl,cool
Centrifu ge , dry
S tage -II: Purifica t ion of Tr imetazidine crude
Meth an ol
ac tivated carbon
h eat, fi lte r
concen trate
Ace ton e
Cen trifu ge
Man u factu rin g procedu re for Trim etazid in e Hydroch loride :
Stage -I: 2,3,4-t r imethoxy benza ldehyde and piperazine is condensed and
reduced using Pa lladium on ca rbon and Hydrogen gas and isola ted as ,
t r imetazedine hydrochlor ide crude
2,3,4-trim eth oxy
ben zaldeh yde
+ Meth an ol
Reaction m ass
Res idu e
Tolu en e Layer
S tage -I
Stage -I
fi ltrate
Res idu e
Dryin g, Millin g , S ievin g,
packin g
Annexures GCPL 43
Stage -II: Stage-I pur ified by dissolving in methanol, charcolisa t ion , filt ra t ion ,
concent ra t ion . pure Tr imetazidine hydrochlor ide. is isola ted by adding acetone.
14 CALCIUM METHYLFOLATE
MANUFACTURING FLOWCHART:
Stage -I: Synthesis of Ca lcium Methylfola te crude
Sodiu m Hydroxide
sodiu m boroh ydride
ac id ification , cen trifu gation
Sodiu m Boroh ydride
Form aldeh yde
ac id ification , cen trifu gation
Calc iu m ch loride
Cen trifu gin g ,dryin g
S tage -II: P u rification of Calc iu m m ethylfo late :
Water
h ydroch loric ac id ,
Cen trifu ge
Sodium h ydroxide
Calc iu m ch loride
ca lc iu m ch loride
Cen trifu ge
Stage -I
so lid +w ater
P rocess w ater+ Folic ac id
Cen trifu gate
Dryin g, m illin g , s iev in g,
packin g
Cen trifu gate
crude CaMeF
Annexures GCPL 44
Man u factu rin g process for Calc iu m meth ylfo late :
Stage -I: A solu t ion of Folic acid in sodium hydroxide is reduced with Sodium
borohydr ide to get tet rahydrofola te, which is reacted with formaldehyde and
reduced aga in with sodium borohydr ide and then t rea ted with ca lcium
chlor ide to get Calcium methylfola te crude.
Stage -II: m eth yl fo lic ac id is prec ip itated by ac id ification of th e cru de
produ ct w h ich is redisso lved in Sodium hydroxide, charcoa lised, filt ered
and reprecipita ted as pure ca lcium methyl fola te by adding filt ered ca lcium
chlor ide solu t ion .
15 UBIQUINOL ACETATE
MANUFACTURING FLOWCHART: Pyridine , Zinc Dust Acetic Anhydride Cooling, acidification, n-heptane, layer separation concentration DNS Centrifuge Manufacturing Procedure of Ubiquinol acetate: Coenyme Q10 reduced with Zinc dust in the presence of Hydrochloric acid, reacted with acetic anhydride to get Ubiquinol acetate, which is extracted with n-heptane and isolated by addition of DNS.
Coen zym e Q10
n- heptane layer
residue
Drying, Milling, sieving, Packing
Annexures GCPL 45
16. STRONTIUM RANELATE
Stage-I: ethyl acetone dica rboxila te is made by react ing cit r ic acid with
ch lorosulfonic acid in methylene ch lor ide
Stage – II: ethyl acetone dica rboxila te is condensed with , Malano n it r ile and
Sulphur in presence of t r iethylamine to get stage-II
Stage –III: Stage –II is reacted with Methyl bromoaceta te and Potassium
carbona te in Acetone, and to get a lkyla ted Stage –II.
Stage –IV; Stage –III reacted with st ront ium hydroxide in wa ter under reflux
condit ion to get the fina l product which is washed with wa ter , dr ied, milled and
packed.
Raw m ateria l:
Triethylamine/Morpholine,
Methanol,
Malano nitrile
Sulphur
Acetone,
Potassium carbonate and
Methyl bromoacetate
Strontium hydroxide
isopropanol
Raw m ateria l con su m ption per kg of ou tpu t
Citric acid = 2 kg / kg
Chlorosulphonic acid = 2kg / kg
Methylene dichloride =2 L / kg
Morpholine = 1.8 kg / kg
Methanol = 8 L / kg
Malano nitrile = 0.6 kg / kg
Isopropanol = 2L/kg
Suphur = 0.2 kg / kg
Acetone = 8 L / kg
Potassium carbonate = 1.2kg / kg
Methyl bromoacetate = 1.3 kg / kg
Strontium hydroxide = 1.5 kg / kg
Annexures GCPL 46
P ROCESS FLOW CHART
Stage - I
Cit r ic acid
Water
Stage - II
Hot condit ion
Water
Stage -III
Hot condit ion
Methylene dichloride +
Chlorosulphonic acid
Qu en ch in g
Morph olin e + m ethan ol +
Malan o n itrile + Suph u r
Qu en ch in g
Ace ton e + P otass ium
carbon ate + Meth yl
brom oace tate
Filtration
Filtration & Con cen tration
Annexures GCPL 47
Stage -IV
Water
Hot condit ion
17. P HENYRAMIDOL HYDROCHLORIDE
Stage -1: Synthesis of Phenyramidol Hydrochlor ide crude
Styre n e Oxide
Water + Eth yl ace tate
Extraction , layer separation
IP A.HCl
Cen trifu ge
2-Am in opyrid in e +DMF + Lith iu m
am ide
Reaction mass
Organ ic layer
P h en yram idol Hydro ch loride cru de
s tage -1
Reaction w ith s tron tiu m
h ydroxide
Dryin g
Filtration
Millin g , Blen din g & P ackin g
Annexures GCPL 48
S tage -2 :Pure Phenyramidol Hydrochlor ide
Heatin g , fi ltration
Distillation
Aceton e
Man u factu rin g process for P h en yram idol h ydroch loride :
Stage -I: 2-Amino pyr idine reacts with styrene oxide in the presence of lith ium
amide to form the Phenyramidol hydrochlor ide crude.
Stage-II: Phenyramidol hydrochlor ide pur ified by using recrysta llisa t ion using
methanol and acetone to get pure Phenyramidol hydrochlor ide.
Meth an ol + Stage -1+activated
carbon
fi ltrate
Cen trifu gation , dryin g,
m illin g s iev in g & packin g
Res idu e
Annexures GCPL 49
18 IRON SORBITOL COMPLEX
MANUFACTURING FLOWCHART:
citric acid
basification with Sodium Hydroxide
Ferric Chloride
filter, adjust pH with Citric acid
DNS DNS
Procedure: a solution Sorbitol , dextrin and citric acid in water is heated and complexed
with Ferric chloride solution in the presence of sodium hydroxide. pH is adjusted with
citric acid , filtered . the complex is isolated by adding DNS. which is centrifuged and dried
Sorbitol + Water+dextrin
Reaction Mass
Filtrate
Centrifuge
Drying, Milling, Sieving, Packing
Annexures GCPL 50
19 NAFTIFINE HYDROCHLORIDE:
Stage -I: Naft ifine hydrochlor ide crude
Cin n am yl Ch loride
Heat, cen trifu ge
Hydroch loric ac id
Cen trifu ge , dry
Stage -II: Purifica t ion of Naft ifine hydroch lor ide
Cen trifu ge , con cen trate
Isopropyl a lcoh ol
cool, Cen trifu ge
Man u factu rin g P rocedu re for Naftifine Hydroch loride .
Stage -I: N-Methyl –naphthyl- methanamine reacted with Cinnamyl ch lor ide in
the presence of sodium bica rbonate in toluene to get Naft ifine hydrochlor ide
crude.
S tage -II: Stage-I pur ified by dissolving in methanol, charcolisa t ion , filt ra t ion
concent ra t ion and isopropyl a lcohol added to get Naft ifine hydrochlor ide.
N-Meth yl –n aph th yl
m eth an am in e
+Sodiu m Bicarbonate+ Tolu en e
Stage -II + Meth an ol+activated
carbon
s tage -1
re s idu e
Dryin g, Millin g ,
s iev in g
cen trifu gate
Annexures GCPL 51
20 ESMOLOL HYDROCHLORIDE MANUFACTURING FLOWCHART:
Stage-I
Malonic acid Heat Water Stage-II: hydrogen gas sulphuric acid concentration Stage-III: Sodium Hydride Epichlorohydrin Water , Ethyl acetate layer separation, concentration Stage-IV
Isopropylamine Concentration
Ethyl acetate, HCl filtration
Stage-V:
Ethyl acetate Acetone
Crystallization
4-Hydroxy benzaldehyde +
Pyridine
Reaction Mass
Centrifuge and Drying
Stage-I +
5% Pd/C + methanol
stage-II
Stage-II +
Dimethylformamide
Reaction
stage-III
Stage-III+ Methanol
Stage-IV
Esmolol Hydrochloride Centrifuge, Drying, Packing
Esmolol Base
Esmolol Hydrochloride
Crude
Annexures GCPL 52
Manufacturing procedure of Esmolol Hydrochloride:
Stage-I : 4-hydroxy benzaldehyde condensed with malonic acid in the presence of
pyridine to give the 3-(4-hydroxyphenyl)acrylic acid (Stage-I).
Stage-II : Stage-I reduced with Hydrogen and Pd/C to get 3-(4-
hydroxyphenyl)propanoic acid . Which is esterified with methanol to get
methyl-3-(4-hydroxyphenyl)propanoate (Stage-II).
Stage-III : Stage-II condensed with Epichlorohydrin in the presence of sodium
hydride to get methyl-3-[4-(3-chloro-2-hydroxypropoxy)phenyl]
propanoate (Stage-III).
Stage-IV : Stage-III condensed with isopropyl amine to get Esmolol base, which is
treated with hydrochloric acid to get Esmolol hydrochloride
Stage-V : Stage-IV is re crystallised from ethyl acetate and acetone to get pure