Research Article

Manufacturing process with Chemical Reactions

and mass Balance for 6 Pharmaceutical Drugs
Ashok K Rathoure1, Savita Goyal Aggarwal2
Abstract
Diclofenac is a non-steroidal anti-inflammatory drug. Bifonazole is a substituted imidazole antifungal
agent structurally related to other drugs in this group. It possesses a broad spectrum of activity in vitro
against dermatophytes, moulds, yeasts, dimorphic fungi and some Gram-positive bacteria. Aceclofenac is
used to relieve pain in the conditions like osteoarthritis, rheumatoid Arthritis and ankylosing spondylitis.
Clotrimazole is used to treat yeast infections of the vagina, mouth and skin such as athlete’s foot, jock
itch and body ringworm. It can also be used to prevent oral thrush in certain patients. Dihydralazine
sulfate is a vasodilator and an antihypertensive agent. It relaxes arterial smooth muscle by inhibiting the
accumulation of intracellular free calcium. By relaxing vascular smooth muscle, vasodilators act to decrease
peripheral resistance. Pyridoxine hydrochloride is the 4-methanol form of Vitamin B6 which is converted
to Pyridoxal phosphate which is a coenzyme for synthesis of amino acids, neurotransmitters (serotonin,
norepinephrine), sphingolipids, aminolevulinic acid. Here, we have presented the manufacturing process
along with mass balance for 6 pharmaceutical drugs.

Keywords: Aceclofenac, Bifonazole, Clotrimazole, Drugs, Diclofenac Sodium, Pyridoxine Acetonide

Hydrochloride

Introduction
Pharmaceutical Drugs are defined as chemical substances used for treating, curing and preventing different types of
diseases. Commonly referred as medicines or medication, pharmaceutical drugs are used in the medical diagnosis,
treatment, prevention or curing disease. The product has very high specific demand as API bulk drugs products are
especially used to relieve pain, swelling (inflammation) and joint stiffness caused by arthritis. It is essential that API bulk
drug products are safe, effective and of good quality, and are prescribed and used rationally.

The pharmaceutical industry is an important component of health care systems throughout the world; it is comprised
of many public and private organizations that discover, develop, manufacture and market medicines for human
and animal health (Gennaro 1990). The pharmaceutical industry is based primarily upon the scientific research and
development (R&D) of medicines that prevent or treat diseases and disorders. Drug substances exhibit a wide range
of pharmacological activity and toxicological properties (Hardman, Gilman and Limbird 1996; Reynolds 1989). Modern
scientific and technological advances are accelerating the discovery and development of innovative pharmaceuticals
with improved therapeutic activity and reduced side effects. Molecular biologists, medicinal chemists and pharmacists
are improving the benefits of drugs through increased potency and specificity. These advances create new concerns
for protecting the health and safety of workers within the pharmaceutical industry (Agius 1989; Naumann et al. 1996;
Sargent and Kirk 1988; Teichman, Fallon and Brandt-Rauf 1988).

Eco Group of Companies, Surat (GJ) India.

1

GRD IMT, 214, Rajpur Road, Dehradun UK - 248001, India.

2

Correspondence: Dr. Ashok K Rathoure, Eco Group of Companies, Surat (GJ) India.

E-mail Id: asokumr@gmail.com

How to cite this article: Rathoure AK, Aggarwal SG. Manufacturing process with Chemical Reactions and mass Balance for 6
Pharmaceutical Drugs. J Durg Dis Dev 2017; 1(1): 54-64.

© ADR Journals 2017. All Rights Reserved.

J. Durg. Dis. Dev. 2017; 1(1) Rathoure AK et al.

Table 1.Pharmaceutical Drugs and their uses

S. No. Drugs Uses Reference
1. Diclofenac Non-steroidal anti-inflammatory drug. Goa and Chrisp 1992; Kurowski and
Sodium Dunky 1992; Merlos, et al. 1996;
Vietri et al. 2000; Klabunde et al.
2000; Kato, M., et al. 2001.
2. Aceclofenac Used in osteoarthritis, rheumatoid Arthritis and Garg et al., 2007; Semalty et al.,
ankylosing spondylitis 2010;
3. Clotrimazole Used to yeast infections of the vagina, mouth and Crowley and Gallagher (2014)
skin such as athlete’s foot, jock itch, and body
ringworm
4. Di-hydralazene A pyridazine antiadrenergic agent, Barry et. al., (1984); Knowles et.
sulphate Nonsympatholytic vasodilatory antihypertensives. al., (2004)
5. Bifonazole Antifungal agent Lackner and Clissold, 1989;
Hanneke et al., 2007
6. Pyridoxine 4-methanol form of Vitamin B6 work as Manuchair Ebadi (2007); Sarfaraz,
Acetonide co-enzyme for synthesis of amino acids, (2009).
Hydrochloride neurotransmitters etc.

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Rathoure AK et al. J. Durg. Dis. Dev. 2017; 1(1)

Table 2.Raw Material required for Manufacturing of 6 pharmaceutical drugs

S.No. Substance Physical State Storage
1. 2,6 Di-chloro phenol Solid Drums
2. Potassium Carbonate Solid Bags
3. Toluene Liquid Tanker
4. Aniline Liquid Tanker
5. Sodium Methoxide Liquid Tanker
6. Chloro Acetyl Chloride Liquid Drums
7. Sulphuric acid Liquid Carboys
8. Aluminum Chloride Solid Drums
9. Hydro Chloric acid Liquid Carboys
10. Caustic soda Solid Bags
11. Sodium Hydro Sulphide Solid Drums
12. Charcoal Solid Bags
13. Iso Propyl Alcohol Liquid Tanker
14. EDTA Solid Bags
15. Tertiary Butanol Liquid Drums
16. N-N Di methyl aniline Liquid Drums
17. Sodium bi carbonate Solid Bags
18. T- Butyl Chloro Acetate Liquid Drums
19. T- Butyl Ammonium Bromide Solid Drums
20. Formic acid Liquid Tanker
21. Acetone Liquid Tanker
22. Caustic flakes Solid Bags
23. Ortho Chloro Phenyl Di phenyl Chloro methane Solid Drums
24. Imidazole Solid Drums
25. Tri ethyl Amine Liquid Drums
26. Phthalodinitrile Solid Drums
27. Hydrazine hydrate Liquid Drums
28. Acetic acid Liquid Carboys
29. Methanol Liquid Tanker
30. Bifonazole Solid Drums
31. Pyridoxine Hydro Chloride Solid Drums
32. Diglyme Liquid Drums
33. Phosphorous oxy-chloride Liquid Carboys

Diclofenac Sodium treat a headache that has already begun. It will not prevent
headaches or reduce the number of attacks.
Diclofenac is used to relieve pain, swelling (inflammation)
and  joint stiffness  caused by  arthritis. Reducing these Manufacturing Process
symptoms helps you do more of your normal daily activities.
2, 6-Dichlorophenol is reacted with MMCA, Aniline
This medication is known as a nonsteroidal anti-inflammatory
and Chloro Acetyl Chloride and AlCl3 to yield (2, 6 -
drug (NSAID). Diclofenac is used to treat mild to moderate
Dichlorophenol) Indolinone is hydrolyzed using isopropyl
pain, or signs and symptoms of osteoarthritis or rheumatoid
alcohol and sodium hydroxide to give crude Diclofenac
arthritis. The Cataflam brand of this medicine is also used
Sodium. This on purification using deminerlised water
to treat menstrual cramps. Diclofenac powder (Cambia) is
and isopropyl alcohol gives the pure Diclofenac Sodium.
used to treat a migraine headache attack. Cambia will only

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Rathoure AK et al. J. Durg. Dis. Dev. 2017; 1(1)

(1.0) Mass Balance of Dichlofenac Sodium

Waste Water: 165.64 kgs

2,6 DCP: 3000 kgs Carbon dioxide: 404.90 kgs
K2CO3: 1269.93 kgs REACTOR
Toluene (F): 309.6 kgs Toluene Recovered: 2786.4 kgs
Toluene (R): 2786.4 kgs (9362.86 KGS)
Distillation Distillation residue: 77.4 kgs
Loss: 232.2 kgs

Water: 4200 kgs REACTOR Distillation KCl Powder (by-product): 1371 kgs
KCl Solution: 5571.16 kgs (24.61%)
Waste water: 4200 kgs
Aniline: 1711.65 kgs Methanol Recovered: 3213 kgs
Sodium methoxide: 3975.44 kgs (25%) REACTOR Distillation Distillation residue: 89.23 kgs
Loss: 267.75 kgs
Methanol Recovered: 588.95 kgs
Water: 1600 kgs REACTOR Sodium Glycolate: 1803.67 kgs
Waste water: 1268.72 kgs
2,6 DCDPA: 4380.35 kgs 2,6 Di Chloro Di ethyl Amine: 4380.35 kgs Water: 1564 kgs
Toluene (F): 132.2 kgs
Toluene (R): 2189.8 kgs REACTOR HCl Gas: 671.61 kgs Scrubber 30% HCl: 2238 kgs
Chloro Acetyl Chloride: 2080 kgs
Soda ash: 29.25 kgs Distillation Toluene recovered: 2189.8 kgs
Sulphuric acid: 29.25 kgs Distillation residue: 58.05 kgs kgs
Water: 3600 kgs Loss: 133.17 kgs
Waste Water: 3600 kgs

Water: 7500 kgs FILTERATION & WASHING Wash Water: 7500 kgs

PADDLE VACCUM DRYER

N Chloro Acetyl (2,6 Di Chloro Di Phenyl Amine): 5787.87 kgs

Water: 1564 kgs

Aluminum Chloride: 2454.5 kgs GLASS LINED REACTOR HCl gas: 671.59 kgs Scrubber HCl (30%): 2238 kgs

Water: 8776.6 kgs

HCl: 292.50 kgs REACTOR Aluminum Chloride Solution (10-12%): 11523.6 kgs

Water: 5851.12 kgs

HCl: 292.50 kgs CENTRIFUGE Waste Water: 6143.62 kgs

Indolinone: 5115.10 kgs

Caustic: 736kgs
Sodium Hydro Sulphide: 175.53 kgs SS REACTOR
Water: 8776.66 kgs

Water: 2925.55 kgs CENTRIFUGE Waste Water: 11877.74 kgs

DICHLOFENAC SODIUM CRUDE:

Charcoal: 331 kgs
Water: 24496.5 kgs SS REACTOR
IPA: 331 kgs
EDTA: 9.93 kgs
SPARKLEER Waste Charcoal: 331 kgs

Water: 24496.5 kgs

IPA: 496.55 kgs CENTRIFUGE Waste Water: 49830.48 kgs

VACUM DRYER

DICLOFENAC SODIUM SALT: 5851.10 KGS

Figure 1.Mass Balance for Diclofenac Sodium

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J. Durg. Dis. Dev. 2017; 1(1) Rathoure AK et al.

Manufacturing Process for Aceclofenac Stage-2

Stage-1 Stage-I react with Diclofenac Sodium in presence of TBAB

in Toluene media, further react with formic acid and
T Butanol and Chloro Acetyl Chloride react in presence of reaction mass quenching in water and product is isolated
NN Dimethyl Aniline at low temperature. After reaction by filtration. Finally Crude Aceclofenac purified in ethyl
organics mass wash with water and sodium bicarbonate acetate and charcoal. Pure product isolated by filtration.
solution to get stage-1

Mass Balance of Aceclofenac Water: 1000 kgs

Caustic Flakes : 500 Kgs Water: 753 kgs
Chloro Acetyl Chloride : 1000 Kgs
T- butanol : 670 Kgs
NN Dimethyl Aniline (R) : 981.0 Kgs
GLASS LINED REACTOR GLASS LINED REACTOR HCl gas : 323.016 Kgs Scrubber HCl (30%): 1076 kgs
NN Di methyl aniline (F): 109 kgs
Sodium Bicarbonate : 15 Kgs
Water : 3000 Kgs
HCl : 20 Kgs GLASS LINED REACTOR NN Dimethyl Aniline Distillation
Recovery : 981.003 Kgs
Residue : 26.78 Kgs
Loss : 80.32 Kgs
T-butyl Chloro Acetone : 1331.85 Kgs Water : 4552.031 Kgs
Diclofenac Sodium : 1250 Kgs
T-butyl Chloro Acetate : 750 Kgs
Sodium chloride : 229.95 Kgs
TBAB : 15 Kgs GLASS LINED REACTOR
Water : 1875 Kgs Waste Water : 1875 Kgs
Formic Acid (F) : 180.81 Kgs
Formic acid (R): 1699.19 kgs GLASS LINED REACTOR

Water : 3750 Kgs

Toluene (R) : 2553.12 Kgs
Toluene (F): 134.38 kgs
DRYER
Waste Water : 3750 Kgs
ANF Salt : 400.95 Kgs
Toluene Recovered : 2553.12 Kgs
Residue : 80.01 Kgs
Formic ML Toluene ML Distillation Loss : 77.025 Kgs

Distillation Formic Recovered : 1699.19 Kgs

Residue : 50 Kgs
Loss : 100.75 Kgs
Acetone (R): 1306.82 Kgs
Acetone (F): 145.2 kgs SS REACTOR Charcoal Sludge : 13 Kgs
Charcoal : 13 Kgs
Water: 960 kgs Acetone Recovered: 1306.82 kgs
Residue: 59.96 kgs
ANF Loss: 85.24 kgs
Waste water: 960 kgs

DRYER

Aceclofenac : 1391.50 Kgs

Figure 2.Mass Balance for Aceclofenac

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Manufacturing Process for Clotrimazole layer by water finally distill out Toluene to get Crude Clt CL.

Clt CL (Ortho Chloro Tritryl Chloride) and Imidazole is heated Crude Clt CL purified in Acetone and Activated charcoal
in Toluene in presence of Triethyl Amine, wash organics and pure product is isolated by filtration.

Mass Balance of Clotrimazole

Ortho -Chloro Phenyl Diphenyl

Toluene Recovered : 1143.80 Kgs
Cloromethane : 300 Kgs
Acetone Recovered : 1244.25 Kgs
Toluene (R) : 1143.80 Kgs SS REACTOR Loss : 198.45 Kgs
Toluene (F): 60.2 kgs Water: 81.59 kgs
Imidazole : 90 Kgs
TEA : 120 Kgs HCl gas : 34.97 Kgs
Water : 600 Kgs
Scrubber HCl (30%): 116.56 kgs
Acetone (R) : 1244.25 Kgs
CENTRIFUGE Waste water : 744.83 kgs
Acetone(F): 138.25 kgs

Charcoal : 10 Kgs GLASS LINED REACTOR

Acetone (R) : 1283.75 Kgs
Acetone (F): 128.37 kgs
SPARKLER FILTER Carbon Waste : 10 Kgs

GLASS LINED REACTOR Acetone Recovered : 869 Kgs

Acetone (Recovered) : 286.375 Kgs

CENTRIFUGE Loss : 128.375 Kgs

DRYER

CLOTRIMAZOLE : 330.2 Kgs

Figure 3.Mass Balance for Clotrimazole
Manufacturing of Bifonazole
Stage-I
Bifinyl and Benzoyl Chloride react in presence of AlCl3 in
EDC at low temperature. Reaction mass quenching in water
and HCl. Material should be isolated by filtration.
Stage -II
Stage-I react with sodium borohydrate in presence of NaOH
in IPA. Reaction mass acidify with HCl. Distilled out IPA and
add water in reaction mass. Product isolated by filtration.
Stage-III
Stage-II reacts with Imidazole in presence of Thionyl
Chloride in Toluene. Organic layer wash with water distilled
out Toluene to get Crude Bifonazole.
Crude materials purified in Acetone and Charcoal. Pure
materials isolated by filtration.

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Mass Balance of Bifonazole

Bifonazole Hydrochloride : 325 Kgs

Glacial Acetic acid : 310 Kgs GLASS LINED REACTOR
Water : 1300 Kgs

Water : 650 Kgs CENTRIFUGE Waste Water : 2294 Kgs

Acetone (R) : 1480 Kgs GLASS LINED REACTOR

Acetone (F): 100 kgs

SPARKLER

GLASS LINED REACTOR Acetone Recovered : 1323.25 Kgs

Acetone (F) : 83.28Kgs Acetone Recovered : 326.27 Kgs

Acetone (R): 169.52 kgs
CENTRIFUGE Loss : 183.28 Kgs

DRYER

BIFONAZOLE : 291 KGS

Figure 4.Mass Balance for Bifonazole

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Rathoure AK et al.
Manufacturing of Di Hydralazene Sulphate
Dihydrallazine Sulphate is also known as nepresol sulphate
or 1-4, dihydrazino-phthalazine sulphate is manufactured by
the condensation of phthalodinitrile (phthalic acid dinitrile)
with hydrazine hydrate in the presence of acetic acid glacial
in methyl alcohol. The base is then converted into the
soluble acetate and precipitated as sulphate containing
two molecules of water of crystallization. Phthalodinitrile is
reacted with Hydrazine Hydrate in Methanol with catalytic
quantity of Acetic Acid at 65 - 700 C to get Azinothalazine
J. Durg. Dis. Dev. 2017; 1(1)
base. This is converted into acetate by treating with
dilute Acetic Acid. The resulting solution is filtered where
the crude Dihydrallazine Sulphate is precipitated with
Sulphuric Acid. The crude Sulphate is dissolved in hot
water, treated with activated Carbon and filtered and the
clear filtrate cooled to get pure crystals of Dihydrallazine
Sulphate. The residue after recovery of Methanol from
the methanolic mother liquors is discarded or treatment
in effluent treatment plant. Gases generated from the 2nd
stage will be Scrubbed Off in Scrubber.
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Mass Balance of Di Hydralazene Sulphate

Phthalodinitrile : 100 Kgs
Hydrazine Hydrate : 205 Kgs GLASS LINED Methanol Recovered: 383.94 Kgs
Distillation Residue : 6.75 Kgs
Acetic Acid : 32 Kgs REACTOR Loss : 35.91 Kgs
Methanol (R) : 383.94 Kgs
Methanol (F): 42.66 kgs
Water : 300 Kgs CENTRIFUGE Water To ETP : 457 Kgs

DHY BASE : 148.44 KGS

DM Water : 3465 Kgs
Acetic Acid : 55 Kgs
Charcoal : 5.0 Kgs
GLASS LINED REACTOR
Sulphuric Acid : 90 Kgs
SPARKLER FILTER Charcoal : 5.0 Kgs

CENTRIFUGE Waste water: 3610 Kgs

DHY SULPHATE CRUDE : 225 KGS

DM Water : 2950 Kgs

Charcoal : 12.0 Kgs GLASS LINED REACTOR

SPARKLER FILTER Charcoal : 12.0 Kgs

Water : 300 kgs CENTRIFUGE Waste Water : 3250 Kgs

DRYER

DI HYDRALAZENE SULPHATE : 225 KGS

Figure 5.Mass Balance for Di-hydralazene sulphate

Manufacturing of Pyridoxine Acetonide Hydro Chloride
Pyridoxine Hydrochloride reacts with Acetone in presence of phosphorous oxychloride and Deglyme to obtain Pyridoxine
Acetonide Hydrochloride.

H3C N
O
OH
HO .HCl + POCl3 + CH3 C CH3 + Diglyme
OH
Acetone ( 58)
Pyridoxine
Hydro Chloride (205.64)

CH3
O
CH3
O
+ POCl3 + H2O + Diglyme
CH2OH
H3C . HCl
N

Pyridoxine Acetonide Hydro Chloride (245.64)

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Rathoure AK et al.
Mass Balance of Pyridoxine Acetonide Hydrochloride
Pyridoxine Hydro Chloride: 250 kgs
Acetone (R) : 333.93 kgs
Acetone (F):100.57 kgs
Diglyme: 50 kgs
Phosphorous Oxychloride : 188 kgs
Pyridoxine Acetonide Hydrochloride : 298.62 kgs
Figure 6.Mass Balance for Pyridoxine Acetonide hydro-chloride
Conclusion
The manufacturing of pharmaceutical drug products is
very much cautious phase and their use in the public. The
six drug products given here are commonly used by public
for treatment of various ailments.
Conflict of Interest: None
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GLASS LINED REACTOR
Acetone Recovered : 333.93 kgs
FILTERATION Loss : 37.10 kgs
ML TO ETP : 225.85 kgs
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Date of Submission: 2017-11-29
Date of Acceptance: 2017-12-30
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