CHAPTER: 3

Industrial Processes & Scale up Techniques Brief manufacturing Process,

Reaction Scheme

Industrial Manufacturing methods & flow chart of API

1. Ranitidine
2. Atenolol
3. Amlodipine
4. Metformin
5. Amoxycillin Trihydrate
1. Ranitidine Hydrochloride :
Brief Description of Ranitidine HCl
Stage – 1
Preparation of crystofer base-intermediate in SS reactor. Charge furfuryl alcohol
paraformaldehyde, dimethylamine HCl in presence of chloroform. Stir for 2/3 hrs. in alkaline
water and separate chloroform layer is stirred and slowly caustic is added, adjust pH ~ 10.5 to
11. The reaction mass is extracted I chloroform and then washed with water. Distill off
chloroform layer and remove traces by vacuum crude crystofer base is dried to get pure
crystofer base.
Step -2
2 (5 –(dimethyl amino)methyl-2-furanyl methyl thio) ethyl amine (cystofer base).
Condensed with N-Methyl -1 methylthio-2-nitroethylene amine (NMSM) at 30-40°C under
vacuum. The reaction mass is taken in chloroform and combined chloroform layer is distilled
off and IPA is added to it at 40°C and distilled off to obtain Ranitidine base. Which is
charcoalized in IPA and filtrate treated with Dry HCl gas at 15°C to form Ranitidine HCl. (pH ~6)
which is cooled to 10 °C and then centrifuged and washed with chilled IPA. Ranitidine HCl is
dried at 60-65°C under vacuum then shifted and packed in polythene bags and with proper
label and send for QC analysis.
Chemical Synthesis of Ranitidine Hypochloride:
Flow Chart of Manufacturing Process:
STAGE I (Cystofer Base- Intermediate)
Chloroform (CSM)
Dimethylamine HCl
Paraformaldehyde
SS REACTOR Separation & Distill of CFM
Furfuryl Alcohol Check pH (7.0)
D.C.C. (catalyst)
Cysteamine Hydrochloride
Caustic lye
Extraction

SS REACTOR
Chloroform Removal of impurities

Reaction Mass + SS REACTOR

Aqueous Layer Check pH (About 10.7)
Caustic Layer

Chloroform
SS REACTOR
(Chloroform Extraction) Combined Chloroform Layer
and wash with water
(Reaction Mass)

Chloroform Layer SS REACTOR Distillation of Chloroform

Under Vacuum
Crude Cystofer Base

HVD REACTOR
Crude Cystofer Base PURE CYSTOFER BASE
STAGE – II (Ranitidine Base)
RO Water SS REACTOR
NMSM 30-40°C / Under High
Cytofer Base Vacuum for 6 Hrs.
Reaction Mass

Reaction Mass
Chloroform GL REACTOR
(Chloroform Extraction) Combined Chloroform layer

Combined Chloroform Layer SS REACTOR Chloroform Recovery

Isopropyl Alcohol (Under Vacuum up to 40°C)
Distill of IPA/Under Vacuum 40°C

RANITIDINE BASE
STAGE III: (Ranitidine HCl)

Ranitidine Base GL REACTOR Filter through Sparkler

Isopropyl Alcohol Filter with High flow bed
Charcoal

Filtrate
Isopropyl alcohol GL REACTOR
Dry HCl gas (15°C) pH 9.8 to 6.0 (final 6.0)
Ranitidine HCl for seeding Temperature 10°C

Wash with chilled Isopropyl GL REACTOR

Alcohol

CENTRIFUGE
Mother Liquor
(IPA Recovery)

Wet Ranitidine HCl DRYER

Under High Vacuum
Temperature 60-65°C

COMPACTER
GRANULATOR
SIFTER

BLENDING

PACKING
2. Atenolol:
Brief Manufacturing Process of Atenolol
STAGE I-
In clean SS reactor NAOH solution (~ 2.5 %) is charged and slowly PHPA (parahydroxy phenyl
acetate, PHPA) is charged at Room temperature and then cooled the reactor to 10 °C by
applying brine solution to the reactor externally. Epichlorohydrin is added at 5-10 °C in 2 hrs.
and maintained it for 3-5 hrs. temperature is raised to RT (~ 28°C) and the reaction mass is
centrifuged in SS centrifuge. Wash the cake with DM water till pH ~ 7.0 to 7.5 of washing. Spin
dry.
STAGE II- Manufacturing of Atenolol
In clean SS reactor change Mono Isopropyl amine (MIPA) at 0-5°C. Add slowly DM water and
wet Epoxide (stage 1) under stirring. Heat the reaction mass to 35°C and maintain for 4 hrs.
apply steam and slowly distill out MIPA up to 80 °C. After remove traces of MIPA under
vacuum. Add DM water and adjust pH with HCl clear solution is observed. Add charcoal and
maintain temperature for 2hrs. cool to 40-45°C and filter enough by flow bed and transfer the
clear solution in a clean reactor. Wash the charcoal bed with hot DM water till no ppt with
NaOH solution. Heat the clear filtrate to 40-45 °C and stir for 1 hr. cool the filtrate to room
temperature and slowly add caustic solution till pH 11 to 11.5. Atenolol precipitation out. Cool
the reaction mass to 10°C and maintain for 2hrs. to obtain maximum precipitation centrifuge
the product in SS Centrifuge (36” to 48”). Wash the cake with chilled DM water(0- 5°C) till the
product is free from chlorides and alkalinity of ML below 0.2 % spray dry the product for 1 hr
and unload the product. Dry the product at 90-95 °C for 6-8 hrs. in dryer. Mill the product in
multimill. Unload in double polythene bags and weight it. Label it properly and send the
sample for analysis in QC.
Synthetic Route for the synthesis of Atenolol
1. Manufacturing of Epoxide

OH
O CH 2Cl

+ NaOH +
O
H 2N

P HP A EP ICHLOROHYDRIN

O
O
O

H 2N

EP OXIDE

2. Manufacturing of Atenolol

O
O
O

+ (H3C) 2CH NH 2
H 2N

EP OXIDE ISOP ROP YLAMINE

OH

O NH
O CH(CH3) 2

H 2N

AT ENOLOL
Flow Chart of Manufacturing Process

STEP I: PHAPA TO EPOXIDE

PHPA

DM WATER

EPICHLOROHYDRIN

SS REACTOR

CENTRIFUGE

EPOXIDE (WET)
 Epoxide to Atenolol

EPOXIDE

MIPA

DM WATER

Excess MIPA SS REACTOR

HYDROCHLORIC
SS REACTOR ACID

CENTRIFUGE

ACTIVATED
SS TANK CHARCOAL

NEUTCH
FILTER

NaOH SOLN.
SS VESSEL

CENTRIFUGE WATER WASH

DRYER

ATENOLOL
3. Amlodipine Besilate:
Brief Description of Manufacturing Process of Amlodipine Besilate-
The manufacturing process has been given for a typical batch of 200.00 kg. the process is
an eight-stage reaction. Phthalic anhydride reacts with 2 amino ethanol to form
phthalimido ethanol. Phthalimido ethanol on reaction with 4- Chloro acetoacetate forms 6-
Phthalimido, ethoxyaxeto acetate. 6- Phthalimido, 4- ethoxyaceto acetate on reaction with
O-Chlorobenzoate forms Methyl amino crotonate. Methyl acetoacetate on reaction with
Ammonia forms (2- amino, 1- propylene) acetate which on reaction with methyl amino
crotonate forms phthaloyl amlodipine. Phthaloyl amlodipine on hydrolysis gives
Amlodipine base. Amlodipine base on further reaction with Benxylsulfonic Acid forms
Amlodipine besilate which is then purified by charcolisation and recrystalization from
Dichloromethane to get pure amlodipine Besilate. The product is then in acuum Tray Dryer
in different lots. The dried product is then subjected to sieving through desired mesh size,
send for final QC check and then material is issued for packing. All the critical process
parameters and reaction conditions are well defined. The flow chart of the manufacturing
process is given on preceding pages, it clearly indicate that the synthesis is carried out in
eight stages.
Synthetic route for synthesis of Amlodipine Besilate
 Cl

CHO

NCH2CH2OCH2CO C COOC2H5

CH
O
Cl

Methyl Aminocrotonate
NH2

CH3 C=CH COOCH3

Cl
H3CO2C CO2CH2CH3 o

H3C N CH2OCH2CH2 N
H
o
Phthaloyl Amlodipine

Hydrolysis

Cl
H3CO2C CO2C2H5

H3C N CH2OCH2CH2NH2
H
Amlodipine Base

Cl
SO3H
H3CO2C CO2C2H5

H3C N CH2OCH2CH2NH2
H
Amlodipine Besylate
Flow Chart of Manufacturing Process:

STAGE - I

Pthalic Anhydride, Reactor Heat 100°C ( 30 minutes)

2 Amino Ethanol
Maintain 168° – 172°C (3 hrs)

Reactor Phthalimido Ethanol

(Stage I Product)

STAGE II

Reactor
Liq. NH3, Stir 20°C (2 hrs)
Methyl Aceto Acetate

Heat 40° – 45°C (1 Hr)

Reactor
Cool 0-5°C (1 Hr)

Centrifuge Wash
(Stage II product)
 STAGE -III

Toluene Sodium Hydride Reactor Flow of N2 Gas

Methanol and Dry Ice Reactor Cool 0°C

Stage I product Reactor Cool Cool – 12° to – 15°C

4 Chloro Ethyl Reactor Stop adding Ice &

Aceto Acetate maintain temp 0°- 5°C

Methanol & Water Reactor Stir ( 15 hrs) RT Stop N2

Gas Addition

Reactor Heat 40°- 45°C (1 hr)

Vacuum Stage III product

 STAGE – IV
Stage III product Benzene, catalyst Reactor Heat (70-80 °C)
Ortho Chloro Benzaldehyde

D. M. Water Reactor Stir (15 min)

Organic Layer Reactor Wash, distill organic layer

(Stage IV Product)

STAGE - V
Stage IV Reactor Stir RT (30 min)
Product, Glacial Acetic Acid

Stage II Product Ethyl, Reactor Over 45 minutes

Amino Ortonate in 3 Lots 15- 20 °C

Centrifuge 30-35°C Wash with Acetic

acid & Hexane (Stage V
Product)
 STAGE - VI
Stage V Product, Flask Stir 40-45°C (10 hrs)
Mono Methyl amine (30%)

Centrifuge (Stage VI Product)

STAGE – VII
Stage VI Product, Flask R.T.
DM Water, BSA

Wash the residue

Filter (Stage VII Product)

STAGE - VIII
Stage VII Product Flask Removes Impurities
In Methylene Chloride

Methylene Chloride Flask Apply Vacuum & Distill Traces

Of MeCl2

Ethyl Acetate Flask Stir for 2 hrs.

Filter & Wash the product ( Amlodipine besilate) with Ethyl Acetate
4. Metformin Hydrochloride:

Stage – I
In glass lined reactor (GLR) charge O-xylene, Dimethyl amine hydrochloride, Dicynodiamide
are heated at ~ 100°C, slowly heat to 135-137°C by exotherm. Maintain for 4-6 hrs, cool to
90°C and add DM water slowly cool and settle for aqueous layer for further processing.

Repeat above process in another GLR and aqueous layer in another reactor (GLR) charge
channel and heat to 80-85 °C for 1 hrs. and then filter with through high flow bed and wash
with hot DM water.

CRYSTALIZATION STEP –

Collect all the clear filtrate. Then add methanol and cool to 50-60°C and centrifuge the
material at RT. Spin dry and wash the cake with methanol. Unload and 1 hrs in lots and pack
in double polythene bags. Check the product in QC

Synthetic Route for synthesis of Metformin Hydrochloride

NH
CH3
CN + HN .HCl
H2N N CH3
H

Cyanoguanidine N,N-Dimethyl amine

(Dicyandiamide) Hydrochloride

O-Xylene

Me2N NH NH2
, HCl
NH NH

Metformin Hydrochloride
 Flow Chart of Manufacturing Process-

DCDA DCDA
DMA HCl DMA HCl
O- Xylene O- Xylene

GLASS LINED Reactor (R 1) GLASS LINED Reactor (R 1)

Reflux Reflux

GLASS LINED Reactor Water GLASS LINED Reactor

Aqueous Layer Aqueous Layer

Charcoal Reactor R7

Filtration

GLASS LINED Reactor R4

Concentration Water

Centrifuge Methanol

Metformin HCl, Wet

Fluidized Bed Dryer

Metformin Hydrochloride, E.P.

5. Amoxycillin Trihydrate:
Brief Manufacturing Process-
Stage –I
In SS reactor at low temperature (-40 to - 50°C) dane salt is reacted with TEA, with pivaloyl
chloride and stage –I product is formed.
Stage – II
In another SS Reactor at -3 to -5 °C. 6 APA in MDC is condensed with Triethyl amine to
form 6 APA salt.
Stage – III
Condensation of Stage I and Stage II in SS reactor at -30 to -35 °C given Stage III product.
Stage – IV & V
Stage III product is taken in SS reactor with purified water and pH is adjusted to 0.5 to 1.
Then above aqueous layer and organic layer MDC layer separated. Aq. Layer pH is
adjusted to 4.9 to 5.2 with Ammonia solution and the stage VI product is formed which is
washed and wet cake is dried in FBD to get pure Amoxycillin Trihydrate, which is
pulverized and packed and checked in QC as per specification (BP/EP)

Synthetic Route for synthesis of Amoxycillin Trihydrate

Stage – I

HO CH COOK HO CH COOCOC(CH3)3

NH + (CH3)3CCOCl NH
+ KCI
CH3 C CHCOOCH3 CH3 C CHCOOCH3

Stage- II
S
H2N S
CH3 H2N
CH3
O
N CH3 + (C2H5)3N
N CH3
O
COOH .
COOH (C2H5)3N
 Stage – III

S
H2N HO CH COOCOC(CH3)3
CH3
O
N CH3 + NH
.
COOH (C2H5)3N
CH3 C CHCOOCH3

O
S
HO CH C NH CH3
NH N CH3
+C(CH3)3COOH.(C2H5)3N
O
CH3 C CHCOOCH3
COOH

Stage IV & V

O
S
HO CH C NH CH3
NH N CH3
+ HCI + H2O
O
CH3 C CHCOOCH3
COOH

O
S
HO CH C NH CH3
. HCI + CH3COCH2COOCH3
NH2 N CH3
O
COOH
 Stage VI

O
S
HO CH C NH CH3
.
NH2 HCI N CH3 + NH4OH + 2H2O
O
COOH

O
S
HO CH C NH CH3
. 3H2O + NH4CI
NH2 N CH3
O
COOH
Flow Chart of Manufacturing Process:
Dichloromethane - 40°C
Dimethyl Acetamide SS Reactor
2- Ethyl Hexanoic Acid - 68°C
Dane Salt
Triethyl Amine Stage I Product
Pivaloyl Chloride

Dichloromethane
6 – Amino Penicillanic Acid SS Reactor - - 3 to – 2 °C
Triethyl Amine Stage II Product
Purified Water

SS Reactor
Stage II Product - 30 to -32°C
Stage I Product Stage III product

Purified Water SS Reactor pH 0.6 to 1.0

Stage III Product layer separation of
Hydrochloric Acid
aqueous
Stage IV to layer & organic layer
stage V

SS Reactor
Aqueous layer stage V pH 1.6 to 2.0
Ammonia solution pH 4.9 to 5.1
Stage VI product

Purified Water pH 0.6 to 1.0

Stage VI Product Centrifuge Wet Cake
ML

Wet Cake FBD Dried Product i.e

(Amoxicillin Trihydrate)
Pulverization

Packaging