Ministry Of Higher Education And Scientific Research

Al- Qadissiya University

College Of Engineering
Chemical Engineering Department
2017-2018

(Production of Erythromycin)

A Project Submitted To The College Of Engineering Al- Qadissiya

University In Partial Fulfillment Of The Requirement For The Degree Of
Bachelor Of Science In Chemical Engineering.

Done by :
Shahad Mahmood Mohamed & Zahraa Fawzee Kareem

Under the supervision of :

Dr. Salih Rushdi

~ i ~
 ‫اﱃ ﻗﺪوﰐ وﱃ ‪ ،‬وﻧﱪاﳼ ا ي ﯾﻨﲑ درﰊ ‪ ،‬اﱃ ﻣﻦ رﻓﻌﺖ‬
‫ر ٔﳼ ﺎﻟﯿ ًﺎ اﻓ ﺎرا ﺑﻪ‪ٔ ........‬ﰊ اﻟﻌﺰﺰ‬
‫إﱃ اﻟﱵ راﱐ ﻗﻠﳢﺎ ﻗ ﻞ ﻋﯿ ﳱﺎ و اﱃ ﴭﺮﰐ اﻟﱵ ﻻ ﺗﺬﺑﻞ اﱃ اﻟﻈﻞ‬
‫ٔوي اﻟﯿﻪ ﰲ ﰻ ﲔ‪ٔ .......‬ﱊ اﳊﺒ ﺔ‬
‫ٔﻗﻮل ﳍﻢ‪ٔ :‬ﻧﱲ وﻫﺒﳣﻮﱐ اﳊﯿﺎة وا ٔﻣﻞ واﻟ ﺸ ٔة ﲆ ﺷﻐﻒ ﻃﻼع‬
‫واﳌﻌﺮﻓﺔ‬
‫إﱃ اﻟﺸﻤﻮع اﻟﱵ ﺗﻨﲑ ﱄ اﻟﻄﺮﯾﻖ إﺧﻮﰐ و ٔﴎﰐ ﲨﯿﻌ ًﺎ‬
‫إﱃ ﰻ ﻣﻦ ﻠﻤﲏ ﺣﺮﻓ ًﺎ وﲻﻞ ٕ ﻼص ﺑﻐﯿﺔ اﲤﺎم ﻫﺬ اﻟﻌﻤﻞ‬
‫اﱃ ٔﺳﺘﺎذ اﻟﻔﺎﺿﻞ ﺣﻔﻈﻪ ﷲ‬
‫وا ﲑا اﱃ ﳇﯿﺔ اﻟﻬﻨﺪﺳﺔ ﻗﺴﻢ اﻟﻬﻨﺪﺳﺔ اﻟﻜﳰﯿﺎوﯾﺔ‬

‫~ ‪ ~ ii‬‬
 ‫ﺸﻜﺮ ﷲ اﻟﻌﲇ اﻟﻘﺪ ﺮ ا ي ٔﻧﻌﻢ ﻠﯿﻨﺎ ﻧﻌﻤﺔ اﻟﻌﻘﻞ وا ﻦ‬
‫ووﻓﻘ ﺎ اﱃ اﳒﺎز ﻫﺬا اﻟﻌﻤﻞ ‪...‬‬
‫ﻻ ﺴﻌﻨﺎ ﺑﻌﺪ ﳤﺎء ﻣﻦ ا ﺪاد ﻫﺬا اﻟﺒﺤﺚ ٕاﻻ ٔن ٔﺗﻘﺪم‬
‫ﲜﺰﯾﻞ اﻟﺸﻜﺮ وﻋﻈﲓ ﻣ ﻨﺎن ٕاﱃ ٔﺳﺎﺗﺬﰐ اﻟﻔﺎﺿﻠﲔ ‪.‬‬
‫ﰻ اﻟﺸﻜﺮ واﻟﺘﻘﺪ ﺮ ﻟ ٔ ﺳ ﺘﺎذ ورﺋ ﺲ ﻗﺴﻢ اﻟﻬﻨﺪﺳﺔ اﻟﻜﳰﯿﺎوﯾﺔ‬
‫ٔ‪.‬م‪.‬د ﺻﺎﱀ ﻋﺒﺪ اﳉﺒﺎر ﺻﺎﱀ‬
‫ا ي ﺗﻔﻀﻞ ٔﴍاف ﲆ ﻫﺬ اﻟﺒﺤﺚ ‪ ،‬ﺣ ﺚ ﻗﺪم ﻟﻨﺎ ﰻ‬
‫اﻟﻨﺼﺢ و رﺷﺎد ﻃﯿ ﻓﱰة ﺪاد ﺳﺎﺋﻠﲔ ﷲ ان ﳛﻔﻈﻪ‬
‫وﯾﻮﻓﻘﻪ‪.‬‬
‫~ ‪ ~ iii‬‬
Table of contents:
LIST OF TABLES: .................................................................................................................... vii
LIST OF FIGURE ......................................................................................................................viii
Abstract: ................................................................................................................................ ix
Chapter one............................................................................................................................. 1
Introduction: ................................................................................................................................... 2
1.1) General Structure: ..................................................................................................................... 4
1.2) Uses: ....................................................................................................................................... 5
Medical uses: .................................................................................................................................. 5
1.3) Available Forms of Erythromycin:............................................................................................... 5
1.4) The physical and chemical proper es of erythromycin : ............................................................... 8
Chapter TWO ........................................................................................................................ 11
2.1) Preparation of erythromycin: ................................................................................................. 12
2.1.1) Materials.......................................................................................................................... 12
2.1.2) S. erythraea Fermentation ................................................................................................. 12
2.1.3) Isolation & Extraction of Erythromycin : ............................................................................... 13
2.2) Some examples of preparation of erythromycin: ..................................................................... 15
Chapter Three ....................................................................................................................... 20
3.1) Process Description: ................................................................................................................ 21
3.2) Material Balance..................................................................................................................... 23
Sodium sulfate........................................................................................................................... 23
3.2.1. Fermenta on (Bio reactor): ................................................................................................. 28
3.2.2. Vessel: .............................................................................................................................. 30
3.2.3. Filter: ................................................................................................................................ 32
3.2.4. Extractor: .......................................................................................................................... 34
3.2.5. Decanter: .......................................................................................................................... 36
3.2.6. Vessel ............................................................................................................................... 38
3.2.7. Crystallizer : ....................................................................................................................... 39
3.2.8. Filter : ............................................................................................................................... 41
3.2.9. Dryer : .............................................................................................................................. 43
3.3) Energy Balance ........................................................................................................................ 44
Sodium sulfate........................................................................................................................... 44
3.3.1. Fermentation (Bio reactor): ................................................................................................. 45
3.3.2 Dryer : ............................................................................................................................... 47

~ iv ~
Chapter Four ......................................................................................................................... 49
Design of Equipment's : .................................................................................................................. 50
4.1) Design of fermenter ................................................................................................................. 50
4.2.1) Chemical design: ................................................................................................................... 52
Volume of fermenter: ................................................................................................................... 52
Dimensions................................................................................................................................... 54
4.1.2) Mechanical Design: ............................................................................................................... 56
Cylindrical Section: ....................................................................................................................... 56
Domed head : .............................................................................................................................. 58
Design of Flat Ends ........................................................................................................................ 60
Weight load .................................................................................................................................. 61
Weight of plate : .......................................................................................................................... 63
Skirt supports ............................................................................................................................... 65
Wind loading ................................................................................................................................ 65
Bending moment at base of skirt : ................................................................................................. 66
Criteria design: ............................................................................................................................. 69
Analysis of stresses: ...................................................................................................................... 69
Base ring and anchor bolts: ........................................................................................................... 71
4.2) Design of crystallizer ................................................................................................................ 75
4.2.1) Chemical design: ................................................................................................................ 80
Determine the super saturations and .................................................................. 80
Determine the crystallizer volume , diameter & height : ............................................................... 81
4.2.2) Mechanical design of crystallizer : ........................................................................................ 83
Determine the thickness (Cylindrical Section): 83
Weight load .................................................................................................................................. 84
Weight of insulation: .................................................................................................................... 85
Skirt supports: .............................................................................................................................. 86
Wind loading ................................................................................................................................ 87
Bending moment at base of skirt : ................................................................................................. 88
Criteria design: ............................................................................................................................. 90
Analysis of stresses ....................................................................................................................... 90
Base ring and anchor bolts: ........................................................................................................... 92

~ v ~
Chapter Five .......................................................................................................................... 95
COST ESTIMATION: ................................................................................................................ 96
Estimation of total investment cost: .......................................................................................... 97
1. Direct cost ................................................................................................................................... 97
2. Indirect cost: ................................................................................................................................ 99
Fixed capital investment ........................................................................................................ 100
Total capital investment: ....................................................................................................... 101
1. Fixed charges: ........................................................................................................................... 101
2. Direct production: ...................................................................................................................... 102
3. General expenses: ...................................................................................................................... 103
Total production cost: ........................................................................................................... 104
Gross earnings and rate of return: ............................................................................................ 104
Reference:........................................................................................................................... 106
‫ اﻟﻣﺧطط اﻟزﻣﻧﻲ ﻹﻧﺟﺎز اﻟﻣﺷروع‬...................................................................................................... 108

~ vi ~
LIST OF TABLES

Table (1.1) : properties of Streptomyces ............................................................................................. 3

Table (1.2) : properties of erythromycin .............................................................................................. 9

Table (1.5) : Physical and chemical proper es of internal materials ................................................ 10

Table (3.2.1) : proper es of component ........................................................................................... 23

Table (3.2.2) : Material balance of Fermenter ................................................................................... 29

Table (3.2.3) : Material balance of vessel 1. ..................................................................................... 31

Table (3.2.4) : Material balance of lter 2. ........................................................................................ 33

Table (3.2.5) : Material balance of Extractor. .................................................................................... 35

Table (3.2.6) : Material balance of Decanter ..................................................................................... 37

Table (3.2.7) : Material balance of vessel 2. ..................................................................................... 38

Table (3.2.8) : Material balance of crystallizer. ................................................................................ 40

Table (3.2.9) : Material balance of lter 3. ........................................................................................ 42

Table (3.2.10) : Material balance of Dryer. ........................................................................................ 43

Table (3.3.1) : proper es of component ............................................................................................ 44

Table(3.3.2) : Energy Balance for Fermenter & Dryer ....................................................................... 48

Table (4.1.1) : weight of fermenter .................................................................................................... 53

Table (4.2.1) : weight of crystallizer ................................................................................................... 63

Table(5.1): Economic Summary for Cases 1-5 .......................................................................... 96

Table (5.2): Cost of equipment for 2017-2018 .......................................................................................... 97

Table (5.3): Erythromycin price ............................................................................................................. 104

~ vii ~
LIST OF FIGURES:

Fig. (1.2): General Structure of erythromycin .............................................................................. 4

Fig(1.2) Tablets of Erythromycin .................................................................................................. 6

Fig (1.3) Powder of the Erythromycin .......................................................................................... 6

Fig (1.4) erythromycin ointment ................................................................................................... 7

Fig. (2.1): Cultivation of Streptomyces erythreus and biochemical changes during the
fermentation period of erythromycin. ....................................................................................... 13

Fig. 3.1. PFD for the Preliminary Process Design for Erythromycin. ................................... 22

Fig(4.1.1) : Design of Batch fermenter reactor .......................................................................... 51

Fig. (4.1.2): Cultivation of Streptomyces erythreus and biochemical changes during the
fermentation period of erythromycin. ....................................................................................... 55

Fig. (4.2.1) ; Batch Agitated Crystallizers ................................................................................... 76

Fig(4.2.2) Miers solubility curve.................................................................................................. 80

Fig (4.2.3). skirt-support designs. ............................................................................................... 87

Fig (5.1): Chart for Recommended Case ........................................................................................ 105

~ viii ~
Abstract:
This research studies the production of erythromycin produced from
bacteria Streptomyces. In general, erythromycin product is the first
substance to be introduced into the manufacture of drugs and antibiotics. In
order to produce erythromycin bacteria, we need nutrients. In this research,
we used dextran and soybean oil with propanol as a catalyst for
fermentation. These substances enter the fermenter(bio reactor) where the
basic process of fermentation is done 3 to 7 days using the batch process.
The components then pass through its chain of isolation, separation and
drying until it has obtained solid erythromycin.
We concluded that the average rate of meals per year was 33Batch/year.
The total amount of erythromycin we got at the end was approximately
31 kg.
In this research we also studied in detail the design of the fermented and
drying equipment to know many important things of design such as sizes,
diameters and weights.
We found in the end that the cost of setting up a plant for the erythromycin
industry is 211,361.062 $

~ ix ~
 Chapter one

~١~
Introduction:
Erythromycin was discovered in 1952 by Mcguire and coworkers from a
strain of Streptomyces erythreus.

It belongs to the group of Macrolide antibiotics.

Macrolide antibiotics slow the growth of, or sometimes kill sensitive

bacteria by reducing the production of important proteins needed by the
bacteria to survive. It has an antimicrobial spectrum similar to or slightly
wider than that of penicillin and is often used for people who have allergy
to penicillin. It is used to treat many different types of infections caused by
various bacteria , inhibit the bacterial endocarditis and attacks of rheumatic
fever, Also inhibit the respiratory tract infections.
The commonly used macrolides are:
 Erythromycin.
 Clarithromycin.
 Roxithromycin.
 Azithromycin.

Erythromycin is an antibiotic useful for the treatment of a number of

bacterial infections. This includes respiratory tract infections, skin
infections, chlamydia infections, pelvic inflammatory disease, and syphilis.
It may also be used during pregnancy to prevent Group B streptococcal
infection in the newborn. Erythromycin may be used to improve delayed
stomach emptying. It can be given intravenously and by mouth. An eye
ointment is routinely recommended after delivery to prevent eye infections
in the newborn.

Erythromycin is produced using Streptomyces.

~٢~
Streptomyces is a genus of Gram-positive bacteria that grows in various
environments, with a filamentous form similar to fungi. The morphological
differentiation of Streptomyces
involves the formation of a layer of hyphae that can differentiate into a
chain of spores. This process is unique among Gram-positives, requiring a
specialized and coordinated metabolism. The most interesting property of
Streptomyces is the ability to produce bioactive secondary metabolites such
as antifungals, antivirals, antitumoral, anti-hypertensives.

Table (1.1) : properties of Streptomyces

Property Name Description of the Property or
value
Molecular Formula C21H36O5
Molecular Weight: 368.514 g/mol
Density 0.1 g/cm3
IUPAC Name: 4-hexadecanoyl-3-hydroxy-2-
(hydroxymethyl)-2H-furan-5-one

Colony characteristics Gram Positive, Aerial Mycelia

Pigmentation Cream light brown color

pH 9.0
Heat capacity 231.29 kj / k . kg

~٣~
 1.1) General Structure:
Erythromycin contains three characteristics parts in the molecule:
1) A highly substituted macrocyclic lactone: aglycone.
 It is a macrocyclic compound containing 14-membered lactone ring
with 10 asymmetric centers
2) A ketone group.
3) An amino desoxysugar: glycon, and in some of the macrolides, a
neutral desoxysugar which are glycosisically attached to the aglycone
ring.
 The two sugars are namely: L-Cladinose and D-Desoamine.
 Its chemical formula is C37H67NO13.

Fig. (1.2): General Structure of erythromycin

~٤~
 1.2) Uses:
 Drug of choice in corynebacterial infections: diphtheria,
corynebacterial sepsis, erythrasma.
 In respiratory, neonatal, ocular, or genital chlamydial infections.
 Treatment of community-acquired pneumonia.
 Penicillin substitute in penicillin allergic individuals.
 Prophylaxis against endocarditis during dental procedures in
individuals with valvular heart disease.

Medical uses:
Erythromycin can be used to treat bacteria responsible for causing
infections of the skin and upper respiratory tract, including Streptococcus,
Staphylococcus, Haemophilus and Corynebacterium genera. The following
represents MIC susceptibility data for a few medically significant bacteria:

 Haemophilus influenzae: 0.015 to 256 μg/ml

 Staphylococcus aureus: 0.023 to 1024 μg/ml
 Streptococcus pyogenes: 0.004 to 256 μg/ml
 Corynebacterium minutissimum: 0.015 to 64 μg/ml

1.3) Available Forms of Erythromycin:

Erythromycin is available in enteric coated tablets, slow release capsules,
oral suspensions, opthalmic solutions, ointments, gels and injections.
 Erythromycin base (Capsules, tablets).
 Erythromycin ethylsuccinate (Oral suspension,tablets).
 Erythromycin stearate (Oral suspension,tablets).

~٥~
 Fig(1.2) Tablets of Erythromycin

 For injection the available combinations are:

‫ ـــ‬Erythromycin Gluceptate
‫ ـــ‬Erythromycin lactobionate

Fig (1.3) Powder of the Erythromycin

~٦~
 For corporeal use
‫ ـــ‬erythromycin base (ointment)

Fig (1.4) erythromycin ointment

~٧~
1.4) The physical and chemical properties of erythromycin
:
Erythromycin is a therapeutically useful, wide range antibiotic produced by
a strain of Streptomyces erythreus . A brief description of some of its
properties has been given .It is a crystalline, colorless compound which is
slightly soluble in water but dissolves easily in most of the common organic
solvents. Crystals are obtained readily from aqueous acetone, aqueous
alcohol or chloroform. Other solvents have been employed but those
mentioned are the most useful. Crystals can be obtained from aqueous
solution, but in this solvent solubility varies inversely with temperature in
the ordinary temperature range.
The molecular weight of erythromycin was estimated by two independent
methods. The free base, two salts and two other derivatives were subjected
to X-ray crystallographic analysis. Five independent molecular weight
values were calculated. The average value derived for the molecular weight
of the free base was 736. Maximum deviation from, the average was 6
units. This method has a possible maximum error of 2%.
The apparent molecular weight of erythromycin also was determined by
titration, using a technique which is precise to 0.10 % . The value obtained
was 738.1 .

1.4.1) Composition:
Standard-grade erythromycin is primarily composed of four related
compounds known as erythromycins A, B, C, and D. Each of these
compounds can be present in varying amounts and can differ by lot.
Erythromycin A has been found to have the most antibacterial activity,
followed by erythromycin B. Erythromycins C and D are about half as
active as erythromycin A. Some of these related compounds have been
purified and can be studied and researched individually.

~٨~
1.4.2) Synthesis:
Over the three decades after the discovery of erythromycin A and its
activity as an antimicrobial, many attempts were made to synthesize it in
the laboratory. The presence of 10 stereospecific carbons and several points
of distinct substitution has made the total synthesis of erythromycin A a
formidable task. Complete syntheses of erythromycins’ related structures
and precursors such as 6-deoxyerythronolide B have been accomplished,
giving way to possible syntheses of different erythromycins and other
macrolide antimicrobials. Woodward successfully completed the synthesis
of erythromycin A.

Table (1.2) : properties of erythromycin

Property Name Description of the Property

or value
Molecular Weight 733.937 g/mol

Heat capacity 0.315(kj/k.kg)

Density 1.226 kg/m3

pKa 8.8

Color Hydrated crystals from water.

Crystals from water.
White or slightly yellow crystals or powder.
Odor Odorless

Taste Bitter

Melting Point 212 to 219° F (NTP, 1992)

191 °C

~٩~
Solubility less than 1 mg/mL at 72° F (NTP, 1992)
Water Solubility 2000mg/L at 28°C
Very soluble in acetone, ethyl ether, ethanol,
chloroform
Vapor Pressure 2.12x10-25 mm Hg at 25oC

Decomposition When heated to decomp it emits toxic fumes

of nitric oxides.

pH pH (saturated solution): 8 to 10.5;

pH < 4 is destructive

1.5) Physical and chemical properties of internal materials

Table (1.3) properties of component:

Compound Molecular Molecular weight Density Heat capacity
formula (kg/kmole) (KJ/Kg . K)
(kg/L)

n-propanol C3H8O 60.09 803 2.396

Soybean oil ‫ــــــــ‬ 920 917 0.627

Dextran C18H32O16 504.44 1800 1.244

Water H2O 18 1000 4.186

Streptomyces C21H36O5 368.514 `100 ‫ـــــــ‬

~١٠~
Chapter TWO

~١١~
 2.1) Preparation of erythromycin:
This part will describe the fermentation of S. erythraea and the principle
steps for the isolation of erythromycin. [from Biotechnol. Prog. 1998, 14, 561-566]

2.1.1) Materials
1) Saccharopolyspora erythraea, S. erythraea sp.
(industrial strain)
2) Water
3) Soybean oil
4) Dextrin or Sucrose
5) NaOH
6) Butyl acetate
7) H2SO4
8) N-propanol

2.1.2) S. erythraea Fermentation

 Conditions were set as follows:

 Fermentation is carried out in stirred tank

fermenter.

 The temperature was set to 34 °C; the pH controlled so as not to exceed

7.2.

 The length of fermentation is 3-7 days.

 The feed was added to the reactor volume; and the pressure was set to 0.1
bar.

 Addition of n-propanol increases the production of erythromycin.

 Samples were drawn aseptically through a cross flow filter assembly .

 Daily samples of 50 or 100 mL were drawn to determine the erythromycin titer.

 Samples were stored at -20 °C.

~١٢~
 Fig. (2.1): Cultivation of Streptomyces erythreus and biochemical changes during
the fermentation period of erythromycin. [from H . G. OSMAN 1968]

2.1.3) Isolation & Extraction of Erythromycin :

 Adjust the pH of approx 5 kg of whole broth with 20% NaOH to
10.7.

 Remove the biomass by first centrifugation for 30 min at 4°C.

 Add 1.5% butyl acetate and stir the mixture in Extrector for 10 min at
4°C.

 Stop stirring and separate phases by centrifugation (5 min with

2000g).
 Collect the organic phase and determine the erythromycin content
by HPLC ( High-performance liquid chromatography ).
 Adjust the pH to 9.5 using NaOH.

~١٣~
 Cool the mixture to 10C for 3-8 h under mild agitation for the
crystallization of the erythromycin–isothiocyanate
 Filter the suspension from The dehydrate crystals of erythromycin

 Dry overnight at 50C under vacuum.

~١٤~
2.2) Some examples of preparation of erythromycin:
2.2.1) Preparation of erythromycin:

An inoculum broth is prepared having the following composition:

Material composition:
Starch 32 lbs
Soybean meal 10 lbs
Corn steep solids 10 lbs
Sodium chloride 10 lbs
Calcium carbonate 6 lbs
Water 250 gals

The broth is placed in an iron tank of 350 gallon capacity and is sterilized
by heating it under pressure at a temperature of about 120° C. for 30
minutes. The sterilized broth is cooled and
inoculated aseptically with spores of Streptomyces erythreus. The organism
is grown in the broth at about 26° C. for a period of 45 hours. During the
growth period the broth is stirred and aerated with sterile air in the amount
of about 0.5 volume of air per volume of culture broth per minute.

In a 1600-gal1on iron tank is placed a fermentation broth having the

following composition:
Material composition:
Starch 153 lbs
Soybean meal 153 lbs
Corn steep solids 51 lbs
Sodium chloride 33 lbs
Calcium carbonate 51 lbs
Water 1200 gals

~١٥~
The culture broth is sterilized by heating it under pressure at about 120° C.
for about 30
minutes. The broth is cooled and the above inoculant culture is added
aseptically. The organism is grown in the broth for 4 days at a temperature
of 26° C. During the growth period the broth is stirred and sterile air is
blown through the broth at a rate of about 0.5 volume of air per volume of
broth per minute.

2.2.2) Preparation of erythromycin complex

An inoculum broth is prepared having the following composition:

Material composition:
Starch 30 lbs
Soybean meal 30 lbs
Corn steep solids 10 lbs
Sodium chloride 10 lbs
Calcium carbonate 6 lbs
Water 250 gals

The broth contained in an iron tank of 350 gallon capacity is sterilized by

heating it under pressure at a temperature of about 120° C. for 30minutes.
The sterilized broth is cooled and is inoculated under aseptic conditions
with the spore form of Streptomyces erythreus. The organism is grown in
the broth at about 26°C. for a period of 35 hours. During the growth period
the broth is stirred, and is aerated with sterile air in the amount of about
one-half volume of air per volume of culture broth per minute. By the end
of the growth period a good growth of the vegetative form of the organism
is obtained.

~١٦~
2.2.3) Preparation of erythromycin from erythromycin
complex:
1 g. of erythromycin complex is suspended in 100 ml. of water and the
suspension is adjusted to about pH 6.3 by the addition of dilute
hydrochloric acid. The aqueous mixture is extracted
with chloroform and the extracted aqueous solution is adjusted to about pH
9.8 with aqueous sodium hydroxide. The alkaline solution is extracted twice
with equal-volume portions of amyl acetate, the amyl acetate extracts are
combined, and are evaporated to dryness in vacuo. The residue of
erythromycin base is recrystallized from aqueous ethanol.

2.2.4) Preparation of erythromycin complex in shake flask:

A Streptomyces erythreus, is produced by growing the organism on a

nutrient agar slant. The spores are recovered as a water suspension by
layering the slant with a small amount of water and gently scraping the
spores from the slant surface. About 1 ml. of the spore-suspension thus
obtained is used for inoculating under sterile conditions the following
sterilized culture medium:

Material Medium:
Glucose 1.5 g

Soybean meal 1.5 g

Corn steep solids 5g
Sodium chloride 5g
Calcium carbonate 2g
Water 100 ml

~١٧~
The inoculated culture medium is incubated at about 27° C. for about 48
hours until good vegetative development is observed.
fermentation culture medium having the following composition:

Material composition:
Starch 30 g
Soybean meal 30 g
Corn steep solids 10 g
Sodium chloride 5g
Calcium carbonate 2g
Water 2l

The flasks containing the inoculated culture media are placed in an

incubator room maintained at a temperature of about 28° C. and shaken for
about 80-90 hours on a reciprocal shaker having a 2" stroke, and run at a
rate of 114 complete excursions per minute. From time to time samples of
the culture medium are tested for the amount of the antibiotic activity
contained therein. When the amount of antibiotic activity attains a value of
about 200 meg/ml. of broth, the broths in the shake flasks are pooled, and
are filtered to remove the mycelium. The antibiotic activity is recovered
from the broth in the form of erythromycin complex by extracting the broth
twice with equal volumes of butanol, and evaporating the butanol to dryness
in vacuo. The solid erythromycin complex which is left as a residue is
purified by recrystallizing it several times from aqueous acetone.

~١٨~
2.2.5 Purification of erythromycin complex by carbon
adsorption:

One liter of filtered cultured broth obtained by the shake flask procedure
described in 1.6.4 is treated with 2 g. of acid treated (an activated carbon)
prepared by stirring the carbon in five times its weight of 5 percent acetic
acid for fifteen minutes, filtering off the carbon, and washing it with 25
times its weight (dry) of water. The carbon-broth mixture is stirred for
about one-half hour, the carbon is filtered off, and is washed with 500 ml.
of water. The activated carbon is stirred with 500 ml. butanol to elute the
erythromycin complex. The mixture is filtered to remove the carbon, and
the butanol filtrate which contains the complex is evaporated azeotropically
to dryness. The residue of erythromycin complex is purified by
recrystallizing it from aqueous ethanol.

~١٩~
 Chapter Three

~٢٠~
 3.1) Process Description:
Figure 3.1. shows the process flow diagram for the batch erythromycin
plant.
 The batch starts with sterilization followed by pumping deionized
water into the fermenter, R-101.
 The water is heated to 34°C by heater, E-102.
 Then soybean oil, Dextrin and n-propanol, the main nutrients for
erythromycin production, are dissolved in the water by the agitator in
R-101.
 The solution is then inoculated aseptically using spores of
Streptomyces erythreus from a seed tank V-101, and the cells are
allowed to grow using the nutrients and air supplied.
 The inlet air is added to fermenter, R-101, using a compressor, C-101,
at a rate of 0.4 volume air/minute/volume broth .
 The air is filtered and sterilized by a small air filter, F-101, to prevent
other microorganisms from entering the fermentation process. As the
compression of the air causes the temperature to rise, the air is cooled
using cooling water in E-101.
 After the 216 h fermentation period, the contents are pumped by P-
102 into V-103, where the pH is adjusted from 7.5 to 10.7 by adding
NaOH.
 The mixture are then filtered from the solid cell Streptomyces
erythreus in F-102 .
 The erythromycin is then extracted from the broth using butyl acetate
in EX-101 .
 Then the broth removed from the erythromycin in Dc-101.

~٢١~
 The erythromycin-rich water is then sent to V-104, where it is mixed,
using a static mixer, with a sodium hydroxide solution to adjust the
pH of the mixture to 9.5, thereby decreasing the solubility of
erythromycin in the solution.
 The solution is sent to CR-101, and erythromycin crystals are formed
by using seeding of erythromycin.
 The crystals are separated using a filter, F-103, and excess butyl
acetate & sodium hydroxide is removed.
 The crystals of erythromycin then dried from a few amount of butyl
acetate in D-101, a vacuum tray dryer.

Fig. 3.1. PFD for the Preliminary Process Design for Erythromycin

~٢٢~
 3.2) Material Balance

Capacity = 1000 kg/year

Operation Time = 300 year/day

*
Time =216 hr [from Biotechnol. Prog. 1998, 14, 561-566 Wolfgang Minas]

300 × 24
No. of Batch = = 33 /
216
1000
Total amount of Erythromycin = = 30.3 = 31 Kg/Batch
33

Table (3.2.1) properties of component

Compound Molecular Molecular

formula weight (kg/kmole)
Sulfuric acid H2SO4 98.079
n-propanol C3H8O 60.09
Soybean oil ‫ــــــــ‬ 920
Dextran C18H32O16 504.44
Water H2O 18
Streptomyces C21H36O5 368.514
Butyl acetate C6H12O2 116.16
Sodium hydroxide NaOH 39.997
Erythromycin C37H67NO13 733.937
Sodium sulfate Na2SO4 142.04

~٢٣~
Amount of component need for fermentation:
Amount of streptomycin (stream 3) :

Amount of streptomycin (kg) Amount of erythromycin (Kg)

3.2 7.4

X 31

X = 13.41kg
X= 0.0364 Kmol

Amount of n-propanol (stream 7) :

Amount of n-propanol (liter) Amount of erythromycin (Kg)

2.4 7.4

X 31

X=10.054liter
X=8.0734 kg
X=0.1344 kmol

~٢٤~
 Amount of soybean oil (stream 4) :
Amount of soybean oil (kg) Amount of erythromycin (Kg)

4.8 7.4

X 31

X=20.11 kg
X=0.02 kmol

Amount of Dextrin (stream 5) :

Amount of Dextrin (kg) Amount of erythromycin (Kg)

7.2 7.4

X 31

X=30.162 kg
X= 0.0598 kmol

~٢٥~
 Amount of H2SO4 (stream 6) :
Amount of H2SO4 30% , H2O Amount of erythromycin (Kg)
70% (liter)
7.2 7.4

X 31

X = 30.2 liter
H2SO4 = 9.1 liter = 16.744 Kg = 0.171 kmol
H2O = 21.14 liter = 21.14 Kg = 1.1744 kmol

Amount of water (stream 1) :

Amount of water (liter) Amount of erythromycin (Kg)

40.8 7.4

X 31

X=170.92 liter =170.92 kg = 9.486 kmol

H2O = 9.486+1.1744 = 10.67 kmol

~٢٦~
 Amount of Air (stream 2) :

Amount of Air (liter/min ) Amount of erythromycin (Kg)

0.37 7.4

X 31

X=1550 liter/min

The pressure=1.1 bar =1100 mbar

R = 83.14472 L.bar.K-1.mol-1
T = 34 Co = 34 + 273 = 307 K
V= 1550 L/min
PV=nRT
P×V 1100 × 1550
n= = = 66.87 mol
R × T 83.14472 × 307

~٢٧~
 3.2.1. Fermentation (Bio reactor):
Air

1) Water Water
2)Air
F 8 Bactria(strep.)
3)Bactria(strep.) R-101 Soybean oil
4) Soybean oil Dextran
(١
5) Dextran H2SO4
6) H2SO4 n-propanol
7) n-propanol Erythromycin
Inert

F=stream(1+2+3+4+5+6+7)
Excess=1.2
Amount of dextran= 1.2 x 0.0598 = 0.072 kmol
Amount of soybean oil = 1.2 x 0.02= 0.024
The air enters with (F) and out from the top (no effect)
Amount of air = 66.8 kmol
In=out
F=stream 8 = 288.816 kg

~٢٨~
Table (3.2.2) : Material balance of Fermenter.
Component F 8
Mole Mass (kg) Mole (kmol) Mass (kg)
(kmol)
H2SO4 0.171 16.772 0.171 16.772
n-propanol 0.135 8.112 0.135 8.112
Dextrin 0.072 36.319 0.015 7.567
Soybean oil 0.024 22.08 0.005 4.6
Water 10.661 191.898 10.661 191.898
Bacteria(strep.) 0.037 13.635 0.037 13.635
Erythromycin --- --- 0.0422 31
Inert --- --- 0.034 15.232
Total 11.1 288.816 11.1 288.816
Air (mole /min) 66.8 --- --- ---

~٢٩~
 3.2.2. Vessel:
NaOH
Na2SO4
H2SO4 9 Dextran
Dextran
Water
Water
Soybean oil
Soybean oil 8 V-101 10 n-propanol
n-propanol
Bactria(strep.)
Bactria(strep.)
Erythromycin
Erythromycin
Inert
Inert

2NaOH + H2SO4 Na2SO4 + 2H2O

H2SO4 = 0.171 kmol
2NaOH = 0.171 x 2 = 0.342 kmol
Na2SO4 = 0.171 kmol
2H2O = 0.171 x 2 = 0.342 kmol
Total H2O = 10.661+ 0.342 = 11.003 Kmol
In=Out
Stream8 + stream9 =stream10
288.816 + 13.679 = 302.49 kgl

~٣٠~
Table (3.2.3) : Material balance of vessel 1.
Component 8 9 10
Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg)
H2SO4 0.171 16.772 --- --- --- ---
NaOH --- --- 0.342 13.679 --- ---
Na2SO4 --- --- --- --- 0.171 24.289
n-propanol 0.135 8.112 --- --- 0.135 8.112
Soybean oil 0.005 4.6 --- --- 0.005 4.6
Dextrin 0.015 7.567 --- --- 0.015 7.567
Water 10.661 191.898 --- --- 11.003 198.054
Bacteria(strep.) 0.037 13.635 --- --- 0.037 13.635
Erythromycin 0.0422 31 --- --- 0.0422 31
Inert 0.034 15.232 --- --- 0.034 15.232
Total 11.1 288.816 0.342 13.679 11.442 302.49

~٣١~
 3.2.3. Filter:
Na2SO4
n-propanol Water 98%
11
10 Erythromycin
Soybean oil F-102
Na2SO4
Bactria(strep.)
Dextran n-propanol
Water Soybean oil
Erythromycin 12 Dextran
Inert Inert
Water 2%
Bactria(strep.)

Amount of water in stream[12] = Amount of Bsctira in stream

[12] x 0.02
0.042 x 0.02 =0.0009 kmol
Amount of water in stream [11] = Amount of water in stream
[10] - Amount of water in stream [12]= 11.003 – 0.0009 =
11.002 kmol
In=Out
Stream10= stream 11+ stream12
302.49 kg
288.836+13.651=302.49 kg

~٣٢~
Table (3.2.4) : Material balance of filter 2.
Component 10 11 12
Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg)
Na2SO4 0.171 24.289 --- --- 0.171 24.289

n-propanol 0.135 8.112 --- --- 0.135 8.112

Soybean oil 0.005 4.6 --- --- 0.005 4.6
Dextrin 0.015 7.567 --- --- 0.015 7.567
Water 11.003 198.054 0.0009 0.016 11.002 198.036
Bacteria(strep.) 0.037 13.635 0.037 13.635 --- ---
Erythromycin 0.0422 31 --- --- 0.0422 31
Inert 0.034 15.232 --- --- 0.034 15.232
Total 11.442 302.49 0.038 13.651 11.405 288.836

~٣٣~
 3.2.4. Extractor:
Butyl acetate

Water
Erythromycin 11 14
Erythromycin(98%)
Na2SO4 EX-101 Butyl acetate(98%)
n-propanol
Soybean oil
Dextran
Inert 15

Water
Erythromycin(2%)
Butyl acetate(2%)
Na2SO4
n-propanol
Soybean oil
Dextran
Water
Inert

Add 1.5% Butyl acetate [from Biotechnol. Prog. 1998, 14, 561-566 Wolfgang Minas]

In=Out
Stream11+stream13= Stream14+stream15
288.836 + 19.863 = 49.637 + 259.35
=308.7 kg

~٣٤~
Table (3.2.5) : Material balance of Extractor.
Component 11 13 15 14
Mole Mass Mole Mass Mole Mass Mole Mass
(kmol (kg) (kmol (kg) (kmol) (kg) (kmol) (kg)
) )
Na2SO4 0.171 24.28 --- --- 0.171 24.289 --- ---
9
n-propanol 0.135 8.112 --- --- 0.135 8.112 --- ---

Soybean oil 0.005 4.6 --- --- 0.005 4.6 --- ---

Dextrin 0.015 7.567 --- --- 0.015 7.567 --- ---

Water 11.00 198.0 --- --- 11.002 198.036 --- ---

2 36
Butyl --- --- 0.171 19.863 0.004 0.465 0.167 19.399
acetate
Erythromy 0.042 31 --- --- 0.001 0.734 0.0412 30.238
cin 2
Inert 0.034 15.23 --- --- 0.034 15.232 --- ---
2
Total 11.40 288.8 0.171 19.863 11.367 259.035 0.208 49.637
5 36

~٣٥~
 3.2.5. Decanter:

Erythromycin 14
Butyl acetate 17 Erythromycin
DC-101 Butyl acetate
15
Water
Erythromycin
Butyl acetate
Na2SO4
16
n-propanol
Soybean oil
Dextran Water
Water Na2SO4
Inert n-propanol
Soybean oil
Dextran
Water
Inert

In=Out
Stream14 + stream15 = Stream16 + stream17
259.035 + 49.637 = 259.035 + 49.637
=308.7 kg

~٣٦~
Table (3.2.6) : Material balance of Decanter.

Component 14 15 16 17
Mole Mass Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg) (kmol) (kg)
Na2SO4 0.171 24.28 --- --- 0.171 24.28 --- ---
9 9
n-propanol 0.135 8.112 --- --- 0.135 8.112 --- ---

Soybean oil 0.005 4.6 --- --- 0.005 4.6 --- ---

Dextrin 0.015 7.567 --- --- 0.015 7.567 --- ---

Water 11.002 198.0 --- --- 11.00 198.0 --- ---

36 2 36
Butyl 0.004 0.465 0.167 19.3 0.004 0.465 0.167 19.39
acetate 99 9
Erythromy- 0.001 0.734 0.0412 30.2 0.001 0.734 0.0412 30.23
cin 38 8
Inert 0.034 15.23 --- --- 0.034 15.23 --- ---
2 2
Total 11.367 259.0 0.208 49.6 11.36 259.0 0.208 49.63
35 37 7 35 7

~٣٧~
 3.2.6. Vessel :
NaOH

18

19 Erythromycin
Erythromycin 17
V-102 Butyl acetate
Butyl acetate NaOH
NaOH

In=Out
Stream17 + stream18 = stream19
49.637 + 6.839 = 56.476 kg

Table (3.2.7) : Material balance of vessel 2.

Component 17 18 19
Mole Mass Mole Mass Mole Mass (kg)
(kmol) (kg) (kmol) (kg) (kmol)
Erythromycin 0.0412 30.238 --- --- 0.0412 30.238

Butyl acetate 0.167 19.399 --- --- 0.167 19.399

NaOH --- --- 0.171 6.839 0.171 6.839

Total 0.208 49.637 0.171 6.839 0.3792 56.476

~٣٨~
 3.2.7. Crystallizer :
Seeding of Erythromycin(1%)

20

Erythromycin 19 21
CR-101 Erythromycin
Butyl acetate
Butyl acetate
NaOH

Amount of seeding of erythromycin in [20] = Amount of

erythromycin in[19] x 0.01= 0.0412 x 0.01 = 0.0004 kmol
Amount of erythromycin in [21] =
Amount of seeding of erythromycin in [20] + Amount of seeding of
erythromycin in [19] = 0.0004+ 0.0412 = 0.0416 kmol
In = out
Stream19 + stream20 = stream21
56.476 + 0.294 = 56.77 kg

~٣٩~
Table (3.2.8) : Material balance of crystallizer.

Component 19 20 21
Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg)
Erythromycin 0.0412 30.238 0.0004 0.294 0.0416 30.532

Butyl acetate 0.167 19.399 --- --- 0.167 19.399

NaOH 0.171 6.839 --- --- 0.171 6.839

Total 0.3792 56.476 0.0004 0.294 0.3796 56.77

~٤٠~
 3.2.8. Filter :
Erythromycin 21 23 Erythromycin
F-103
Butyl acetate Butyl acetate
NaOH (2%)
(wet solid)
22

Butyl acetate
NaOH
(liquids)

Amount of butyl acetate in [23]= Amount of erythromycin in [23]

x 0.02
= 0.0416 x 0.02 = 0.0008 kmol
Amount of butyl acetate in [22]= Amount of butyl acetate in [21] -
Amount of butyl acetate in [23]
= 0.167 - 0.0008 = 0.166 kmol
In = out
Stream21 = stream22 + stream23
54.77 kg
26.145 + 30.625 = 54.77 kg

~٤١~
Table (3.2.9) : Material balance of filter 3.
Component 21 22 23
Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg)
Erythromycin 0.0416 30.532 --- --- 0.0416 30.532

Butyl acetate 0.167 19.399 0.1662 19.306 0.0008 0.093

NaOH 0.171 6.839 0.171 6.839 --- ---

Total 0.3792 56.77 0.3372 26.145 0.0424 30.625

~٤٢~
 3.2.9. Dryer :

Butyl acetate

24

23 25
Erythromycin
D-101 Erythromycin
Butyl acetate

In=Out
Stream23 = stream24 + stream25
30.625 kg
0.093 + 30.532 = 30.625 kg

Table (3.2.10) : Material balance of Dryer.

Component 23 24 25
Mole Mass Mole Mass Mole Mass
(kmol) (kg) (kmol) (kg) (kmol) (kg)
Erythromyci 0.0416 30.532 --- --- 0.0424 30.532
n
Butyl acetate 0.0008 0.093 0.0008 0.093 --- ---

Total 0.0424 30.625 0.0008 0.093 0.0424 30.532

~٤٣~
 3.3) Energy Balance
The general energy balance equation is

+ + =

In this project we don't have velocity or height or movement parts, so

= = =0

So that the general equation will be

=
= 2 1

( )=

Table (3.3.1) properties of component

Compound Molecular Molecular Heat
formula weight capacity
(kg/kmole) (KJ/Kg .
K)
Sulfuric acid H2SO4 98.079 1.34
n-propanol C3H8O 60.09 2.396
Soybean oil ‫ــــــــ‬ 920 0.627
Dextran C18H32O16 504.44 ‫ـــــــــــ‬
Water H2O 18 4.186
Streptomyces C21H36O5 368.514
Butyl acetate C6H12O2 116.16 1.938
Sodium hydroxide NaOH 39.997 3.93
Erythromycin C37H67NO13 733.937 0.315
Sodium sulfate Na2SO4 142.04 0.903

~٤٤~
 3.3.1. Fermentation (Bio reactor):
Air

1) Water Water
2)Air Bactria(strep.)
3)Bactria(strep.) F 8 Soybean oil
4) Soybean oil R-101 Dextran
5) Dextran H2SO4
6) H2SO4 n-propanol
7) n-propanol Erythromycin
Inert

F=stream(1+2+3+4+5+6+7)
= 120℃ & 105℃ ,
120℃ = 2706

105℃ = 2683.4
= 25℃
= 34℃
=
= 0.0147 0.01367 + 0.01164 2.396
. .
+ 2 10 0.847 + 6 10 1.244
. .
+ 0.914 4.186 + 3 10 0.627
. .
= 3.86
.

= 288.816( ) 3.86 307( ) 298( )

.
= 10033
~٤٥~
 =

10057( )= 2706 2683.4

10057 ( )
=
22.6( )

= 444

~٤٦~
 3.3.2 Dryer :
Butyl acetate

24

23 25
Erythromycin
Butyl acetate
D-101 Erythromycin

0.0416 231.29 0.0008 225.11

= +
0.0424 . 0.0424 .

= 231.1
.
+ = +
+
= ( ) + ( )

30.625( ) 231.1 [333( ) 298( )] +

.
= 0.093( ) 225.11( ) [333( ) 298( )]
.
+ (30.532( ) 231.29 [333(k) 298(k)])
.
= 207.8 = 207800

~٤٧~
Table(3.3.2): Energy Balance for Fermenter & Dryer

Equipment's Qin Qout

(KJoule ) (KJoule )
Fermenter 10033 10033

Dryer 207800 207800

~٤٨~
 Chapter Four

~٤٩~
 Design of Equipment's :

4.1) Design of fermenter

(bioreactor):

A bioreactor may refer to any manufactured or engineered device

or system that supports a biologically active environment.
In one case, a bioreactor is a vessel in which a chemical process is
carried out which involves organisms or biochemically active
substances derived from such organisms. This process can either
be aerobic or anaerobic. These bioreactors are commonly
cylindrical, ranging in size from liters to cubic meters, and are
often made of stainless steel.

A bioreactor may also refer to a device or system meant to grow

cells or tissues in the context of cell culture. These devices are
being developed for use in tissue engineering or biochemical
engineering. [ from https://www.slideshare.net/zahiduet43/design-of-stirred-batch-reactor]

~٥٠~
Fig(4.1.1) : Design of Batch fermenter reactor

~٥١~
 A+B→C+D
Dextrin + soybean oil → erthromycin + inert
The yeast being used is Experimental research paper, for a
conversion of 100%,the time taken for the batch reaction is 216 hrs.
the following equation was then used to calculate the entire batch
time.
Where,

Total time for batch(t ):216 hrs.

4.2.1) Chemical design:

 Volume of fermenter:

Conversion=100%
Batch time=216 hrs.
No .of fermenters used=2
Working pressure of Vessel(p)=1.1 bar
Temperature of Reaction 34 ℃.
Mass flow rate in(ml)=288.816 kg/batch

Density of Material in fermenter(ρ ) = ∑X ρ

~٥٢~
ρ = Xρ + Xρ + Xρ + Xρ
+ Xρ + Xρ
ρ (1 × 1840 + 1 × 803 + 1 × 917 + 1 × 1800 + 1
× 1000 + 1 × 100)

ρ 6460 kg/m
Mass flow rate × Total timefor batch
V =
ρ
288.816 × 216
V =
6460
V = 9.657 m
We allow 75% of volume of fluid as the free space in the
fermenter.
Hence;
With 75% allowance;
V = .

9.657
V =
0.75
V = 12.9 m

~٥٣~
 Dimensions:

H
= 1.5
D
D
V =π H
4

D
V =π (1.5 × D)
4
3
× π × (D )
8
V = 12.9 m
Hence; putting in above equation;
D=2m
H=3m
Now;
Height of Dished Bottom=1m
Total Height=3+1=4 m

~٥٤~
Fig. (4.1.2): Cultivation of Streptomyces erythreus and biochemical changes during
the fermentation period of erythromycin.

~٥٥~
 4.1.2) Mechanical Design:
For the calculation of wall thickness we have to calculate the total
pressure which is the sum of static pressure and operating pressure
of the fermenter

Static pressure P = ρ gH
6460 × 9.81 × 3
P =
1000
Total pressure at base= Ps + P
= Ps + P
Maximum allowable pressure = 0.75 × 200
P = 150

 Cylindrical Section:
Design temperature 100oC(212oF)
Design pressure=10 bar
Design pressure take 10% above operating pressure Design
pressure
P=10.1 bar
P=1.01N/mm2
From Table(14-2);maximum allowable
stress(S)= 13.3 × 10 P = 92 N/mm2

~٥٦~
 Joint Efficiency; ( From table 13.3 (vol.6))
E =1
Corrosion allowance=2 mm
Material= Stainless steel(316).

t= .
Eq.(13.44) vol.6 Page(816)

t = shell thickness in [mm]

N
p = maximum working pressure [ ]
mm
D = wide diameter of shell [mm]
N
S = maximum allowable stress
mm
E = Joint Efficiency
1.01 × 2 × 1000
t=
2 × 92 × 1 1.2 × 1.01
t = 11 mm
add corrosion allowance 11+2=13 mm

~٥٧~
  Domed head :
Flat plates are used as covers for many ways. Formed flat ends,
known as “flange-only” ends, are manufactured by turning over a
flange with a small radius on a flat plate, Figure 13.9a. The corner
radius reduces the abrupt change of shape, at the junction with the
cylindrical section; which reduces the local stresses to some extent:
“Flange-only” heads are the cheapest type of formed head to
manufacture, but their use is limited to low-pressure and small-
diameter vessels. Standard tori spherical heads (dished ends) are
the most commonly used end closure for vessels up to operating
pressures of 15 bar. They can be used for higher pressures, but
above 10 bar their cost should be compared with that of an
equivalent ellipsoidal head. Above 15 bar an ellipsoidal head will
usually prove to be the most economical closure to use. A
hemispherical head is the strongest shape; capable of resisting
about twice the pressure of a tori spherical head of the same
thickness. The cost of forming a hemispherical head will, however,
be higher than that for a shallow tori spherical head. Hemispherical
heads are used for high pressures .

~٥٨~
1)
PD
t=
4SE 0.4 Pi
1.01 × 2 × 1000
4 92 × 1 0.4 × 1.01

t = 5.5 mm

2)
PD
t=
2SE 0.2Pi

1.01 × 2 × 1000
2 × 92 × 1 0.2 × 1.01

t = 11 mm

3)
R =d=D =2m
Knuckle=6%Rc=0.06×2
=0.12 m

~٥٩~
 0. .885 Pi Rc
t =
SE 0.1 Pi

0.885 × 1.01 × 2 × 1000

t=
92 × 1 0.1 × 1.01

t = 19.5 mm

Design of Flat Ends

C P
t=D
SE

0.25 × 1.01
t = 2 × 1000 ×
92 × 1

t = 117.5 mm

~٦٠~
  Weight load

The major sources of dead weight loads are:

1. The vessel shell.
2. The vessel fittings: man ways , nozzles.
3. Internal fittings: plates (plus the fluid on the plates); heating and
cooling coils.
4. External fittings: ladders, platforms, piping.
5. Auxiliary equipment which is not self-supported; condensers,
agitators.
6. Insulation.
7. The weight of liquid to fill the vessel. The vessel will be filled
with water for the hydraulic pressure test; and may fill with process
liquid due to disoperation.
Note: for vessels on a skirt support, the weight of the liquid to fill
the vessel will be transferred directly to the skirt. The weight of the
vessel and fittings can be calculated from the preliminary design
sketches. The weights of standard vessel components:
heads, shell plates, many ways, branches and nozzles, are given in
various handbooks;
Magueys (2001) and Brownell and Young (1959).
For a steel vessel, we use the equation :

~٦١~
 = 240 ( + 0.8 )
Where:

W = total weight of the shell, excluding internal fittings, such as

plates(N),

C = a factor to account for the weight of nozzles, man ways,

internal supports, etc. ; which can be taken as :
= 1.08 for vessels with only a few internal fittings,
= 1.15 for distillation columns, or similar vessels, with several
Many ways, and with plate support rings, or equivalent fittings.

~٦٢~
H = height, or length, between tangent lines (the length of the
cylindrical section), m,

g =gravitational acceleration, 9.81 m/s2,

t =wall thickness, 13mm

D = mean diameter of vessel

D = (D + t) × 10
D = (2 + 13 × 10 )
D = 2.013 m
H =3m
t = 13 × 10 m
W = 240 × 1.15 × 2.013 (3 + 0.8 × 2.013) × 0.013
W = 33.299 KN
W = 33299.2779 N

Weight of plate :
π
Plate area = × (D )
4
π
Plate area = × (2)
4
= 3.142 m
weight of a plate = 1.2 × Area
~٦٣~
= 1.2 × 3.142
weight of a plate = 3.8 KN
2plates = 2 × 3.8 = 7.6 KN

 Weight of insulation:
Mineral wool density= 130 kg/m3
Take height between tangent lines = 3 m
= 70
Approximate volume of insulation = π D h
= × 2 × 3 × 0.07 = 1.319
= 1.319 × ×
= 1.319 × 9.81 × 130 = 1682.72
∶
= 2 × 28043.8 = 3365.44
= 7.6 + 33.299 + 3.36544 = 278.6

~٦٤~
Table (4.1.1): weight of fermenter :
Total weight of fermenter KN
Weight of shall 33.299
Weight of plate 7.6
Weight of insulation 3.36544
Total Weight 278.6

Skirt supports
The method used to support a vessel will depend on the size, shape,
and weight of the vessel; the design temperature and pressure; the
vessel location and arrangement; and the internal and external
fittings and attachments. Horizontal vessels are usually mounted on
two saddle supports; Figure 13.22. Skirt supports are used for tall,
vertical columns; Figure 13.23 (vol.6) . The supports must be
designed to carry the weight of the vessel and contents, and any
superimposed loads, such as wind loads. Supports will impose
localized loads on the vessel wall, and the design must be checked
to ensure that the resulting stress concentrations are below the
maximum. allowable design stress. Supports should be designed to
allow easy access to the vessel and fittings for inspection and
maintenance . For straight cylindrical skirt θ = 90 made of carbon
steel .

Wind loading

Take dynamic wind pressure(Pw) = 1280 N/m2,corresponding to

160 kph(100mph)

~٦٥~
 D , including insulation=
D = D + D [t + t]
Assume (thickness)=70 mm- (0.07m)
D = 2 + 2 × [(0.07 + 0.013 )] = 2.17 m
F = loading (per linear meter) = P D

F = 2777.6 N/m

F
M = H
2
2777.6
M = ×3
2

M = 12499.2 N. m

Bending moment at base of skirt :

Take height between tangent lines = 3 m

height of reactor = 3 m

total height = 3 + 3 = 6 m

M
Bending M = (total height)
2
.
=6 ×

M = 224.9856 KN. m
~٦٦~
 4M
σ =
π(D + t ) t D

σ = bending stress in the skirt

M = maximum bending moment
D = inside diameter let, = 2 m
t = thickness = 13 mm
4 × 2249856 × 10
σ =
π × (2000 + 13) × 13 × 2000

σ = 51692 N/mm

W
σ = (D + t ) t
π
σ = the dead weight stress in the skirt
t = thickness = 13 mm
W = total weight
π
Approximate weight = × D × ρgH
4
π
= × 2 × 6460 × 9.81 × 3
4
Approximate weight = 597272.68 N
Approximate weight = 597.272 KN

~٦٧~
 Total Weight
= Approximate weight
+ Total weight of fermenter Analysis of stresses

Total Weight = 597.272 + 278.6 = 875.872 KN

W( )
σ ( )
=
π (D + t ) t

597272.68
σ ( )
=
π (2000 + 13) × 13
σ ( )
= 7.265 N/mm

W( )
σ ( )
=
π(D + t ) t
278.6 × 1000
σ ( )
=
π (2000 + 13) × 13

σ ( )
= 3.388 N/mm

~٦٨~
 Criteria design:

maximum σ ( .)
= σ +σ ( )

σ = 51692 + 7.265 N = 51699.3 N/mm

( )

maximum σ ( )
= σ σ ( )

= 51692 3.388 = 51688.6 N/mm

 Analysis of stresses:

1- pressure stresses:

1.01 × 2 × 1000
4 × 13
= 38.85 /

=
2
1.01 × 2 × 1000
2 × 13
= 77.69 /

~٦٩~
 2- Dead weight stress:
W
σ =
π (D + t ) t
875.872 × 1000
σ =
π × (2000 + 13) × 13
= 10.654N/mm2

3- Bending stresses:
D =D +2t
D = 2 × 1000 + 2 × 13
= 2026 mm
π
I = D D
64
π
I = (2026 2000 )
64
I = 4.16 × 10 mm

M Di
σ = +t
Iv 2
12499.2 2 × 1000
σ = + 13
4.16 × 10 2
= ±13.3 N/mm

~٧٠~
 Base ring and anchor bolts:

Bolt circle diameter =1.44 m

Circumference of bolt circle = 1.44 π

. × ×
Number of bolt required = = 3.142

Closest multiple of 4= 8 bolt

Take both design stress = 92 N/mm2

M = 224.9856 KN. m

Take W= Weight of vessel (operating valve)= 3079.05265 ×

1000 N

A = (4 × M × D – W) Eq.13.92 vol.6 Page(848)

×

where A = area of one bolt at the root of the thread, mm ,

N = number of bolts,
F = maximum allowable bolt stress, N/mm ;

~٧١~
typical design value 92 N/mm2
M = bending (overturning) moment at the base, N.m,
W = weight of the vessel, N,
D = bolt circle diameter, m

~٧٢~
 1 4 × 224985.6
A = – 278600 = 418 mm2
8 × 92 1.44
A ×4
B lt root dia. = = 23 mm
π

Total compressive load on the base ring per unit length

F = + Eq.13.93 vol.6
Page(848)

× .
F = + = 115955.7 N/m
× ×

Taking the bearing pressure as 5 N/mm2

L = Eq.13.94 vol.6
Page(848)

where L =base ring width, mm (Figure 13.29 vol.6),

F = the maximum allowable bearing pressure on the concrete

foundation pad,

which will depend on the mix used, and will typically range from
3.5 to7 N/mm2 (500 to 1000 psi).

~٧٣~
Taking the bearing pressure as 5 N/mm2

.
L =
×

=0.0232 m2

Take the skirt bottom diameter as 4m

Skirt base angle θ = tan = 75.96℃

. ( – )

Keep the skirt thickness the same as that calculated for the
cylindrical skirt. Highest stresses will occur at the top of the skirt;
where the values will be close to those calculated for the cylindrical
skirt. Sin 75.96℃ =0.97, so this term has little effect on the design
criteria

~٧٤~
 4.2) Design of crystallizer
(Batch Agitated Crystallizers):

The crystallizer body is equipped with a centrally located agitator, cooling

pipes. The upper part of the vessel is cylindrical and closed at the top. The
lower part of the vessel is conical and its bottommost part is used to drain
out final magma. Magma is defined as the slurry containing product crystal
and saturated mother liquor. Hot concentrated solution of a substance is
induced in the crystallizer and it is agitated with the impeller. Cold water
flows though the cooling coils to transfer heat from the hot solution. Cold
water transfers heat due to heat of crystallization too. As temperature drops,
super saturation is achieved that initiates crystallization
Rate of production of crystals is low due to batch process. Since
temperature at the surface of cooling coil is least so rapidly formed crystals
get deposited on the surface of cooling coil and cause hindrance in heat
transfer rate. These are the disadvantages of agitated batch crystallizer.
After certain period of growth, magma is transferred to centrifuge where
crystals are separated from mother liquor [from : J. N Y V L T , J. W. MULLIN 1977]

~٧٥~
 Fig. (4.2.1) ; Batch Agitated Crystallizers

In the design of crystallizer the total crystal number, surface area and the
mass mean size are affected by the mean residence time and the rates of
nucleation and crystal growth respectively. By making overall mass balance
around the crystallizer The rate at which solute is removed from solution is
balanced by the rate of mass crystallization. Thus:
Rate of change of mass in solution = rate of mass crystallization

~٧٦~
 Q(CIN - COUT) = QMT (1)
the mass deposition rate is also equal to the total flux of solute adding to the
crystal surface , i. e ∶
QMT = RGATV (2)

Where RG = ( ) is the mass flux of solute from the solution to the crystal
surface which is related to the (linear) crystals growth G = ( ) rate by:

RG = G (3)

Where F is the overall crystal shape factor of a crystal density , so:

A V = Q(CIN COUT) (4)

Where the total crystal surface area in the slurry, AT can be determined
from second moment of the crystal size distribution:
A =f nL dL = 2f n (Gτ) (5)

Thus the linear crystal growth rate is given by:

( IN OUT)
G= 2
(6)
S c ∫

i.e.
( IN UT)
G= (7)
T

The level of super saturation (S) is also changes.

If it is assumed, for simplicity, that the crystal growth exhibits linear
kinetics i.e.

= (8)

The solving for S between equations (7) & (8) gives

~٧٧~
 ( IN OUT)
S= (9)
T

Thus τ↑, ↓. In the other words a change in crystallizer residence time has a
corresponding but opposite effect on the level of super saturation.
The nucleation rate is given by :

= (MT) (10)

Thus τ↑, ↓ ↓ but how does this affect the mean crystal size? Since the
order of nucleation is usually more than that of growth, the nucleation rate
decreased relatively more with an increase in τ . thus the mean size
increases despite the lower growth rate.

~٧٨~
Where the relative kinetic order i is given by

= (17)
And

b
kR = (18)

Or, in terms of population density

n0 = = kR M G (19)

Combining the equations for mass balance , mean size and kinetics for the
solids hold up gives (for j=1)

MT = 6fV ρC [k M G ]( ) (20)

And the growth rate requires to achieve a desired dominant size id given by
:

G= (21)

And since τ = , the corresponding residence time is

τ= (22)

And the crystallizer volume (capacity) is given by :

= (23)

~٧٩~
4.2.1) Chemical design:

 Determine the super saturations and :

For super saturation from cooling crystallization defined the super

saturations as follows for crystallization by cooling
S = CT - CT(super cooling) / CT(super cooling)
Where,
CT : is the solubility at temperature T.
CT(super cooling) : is the solubility of super cooling degree.
The super cooling with (5 ℃) given the best growth rate with a good face
structural of crystals.
So we adopted this super cooling degree in our design.
kg Erythromycin
The solubility at (5 ℃)= 29.73
kg butyl actate

kg Erythromycin
The solubility at (25 ℃) = 16.421
kg butyl actate

. .
S= = 44.77 %
.

Fig(4.2.2) Miers solubility curve

~٨٠~
Dominant product crystal size :
=3
=50
∶ .
:
The growth rate (G) can be found from the figure between G and super
saturations (S) :
G= 5* 10-8 m/s
L 50 10
= =
3G 3 5 10
= 333.33

 Determine the crystallizer volume , diameter & height

:
=
V : the crystallizer volume (capacity)
: the volumetric flow rate
m
V=
ρ
Total time for batch(t ) = 8 hrs.
Working pressure (p) = 1.1 bar
Mass flow rate=56.77kg/batch

~٨١~
 Density of Material in crystallizer(ρ ) = ∑X ρ
ρ = Xρ + Xρ + Xρ .

ρ = 4212 kg/m
.
V = = 0.0135 (m /s)

=333.3 × 0.0135 = 4.492

We allow 75% of volume of fluid as the free space in the crystallizer.
Hence;
With 75% allowance;
.
v= .
= = 5.989 m
.

No .of crystallizers used=2

.
v= = = 2.995 m

V= D H,

H
=3
D
π
5.989 = D × 3
4
D = 1.2709 m
H = 3.8127 m

~٨٢~
 4.2.2) Mechanical design of crystallizer :

 Determine the thickness (Cylindrical Section):

Design temperature 50oC(122oF)
Design pressure=10 bar
Design pressure take 10% above operating pressure Design pressure
P=10.1 bar
Corrosion allowance=2 mm
Material= Stainless steel(316).

t= Eq.(13.44) vol.6 Page(816)

.

t = shell thickness in [mm]

N
p = maximum working pressure [ ]
mm
D = wide diameter of shell [mm]
N
S = maximum allowable stress
mm
E = Joint Efficiency
1.01 × 1.2709 × 1000
t=
2 × 92 × 1 1.2 × 1.01
t = 7 mm
add corrosion allowance 7+2=9 mm

~٨٣~
  Weight load

The major sources of dead weight loads are:

1. The vessel shell.
2. The vessel fittings: man ways , nozzles.
3. Internal fittings: plates (plus the fluid on the plates); heating and cooling
coils.
4. External fittings: ladders, platforms, piping.
5. Auxiliary equipment which is not self-supported; condensers, agitators.
6. Insulation.
7. The weight of liquid to fill the vessel. The vessel will be filled with water
for the hydraulic pressure test; and may fill with process liquid due to
disoperation.
Note: for vessels on a skirt support, the weight of the liquid to fill the vessel
will be transferred directly to the skirt. The weight of the vessel and fittings
can be calculated from the preliminary design sketches. The weights of
standard vessel components:
heads, shell plates, many ways, branches and nozzles, are given in various
handbooks;
Magueys (2001) and Brownell and Young (1959).
For a steel vessel, we use the equation :
W = 240 C D (H + 0.8 D ) t
W =total weight of shell ,excluding internal fittings ,such as plates.
w = a factor to account for the weights of nozzles , manways , internal
supports etc. , which can be taken as :
= 1.08 for vessels with only a few internal fittings,
= 1.15 for distillations columns, or similar vessels, with several
Many ways, and with the plate support rings, or equivalent fittings.
H = height , or length, between tangent lines (the length of the cylindrical
section) , m.
g = gravitational acceleration. 9.81 m/s2.
~٨٤~
t = wall thickness, mm
D = mean diameter of vessel

D = (D + t) × 10
D = (1.2709 + 9 × 10 )
D = 1.3 m
H =4m
t = 9 × 10 m
W = 240 × 1.15 × 1.3 (4 + 0.8 × 1.3) × 9 × 10
W = 16.275 KN
W = 16275 N

 Weight of insulation:
Mineral wool density= 130 kg/m
Take height between tangent lines = 4 m
t = 70 mm

Approximate volume of insulation = π D h t

= π × 1.3 × 5 × 0.07 = 1.429 m
Weight = 1.429 × g × Mineral wool density
1822.4037 N

~٨٥~
 Double this to allow for fittings WD ∶
WD = 2 × 18224.037 = 36448.074 N
Total weight = 16.275 + 36.448074 = 52.723074 KN

Table (4.2.1): weight of crystallizer

Total weight of Crystallizer KN

Weight of shall 16.275

Weight of insulation 36.448074
Total Weight 52.723074

 Skirt supports:
The method used to support a vessel will depend on the size, shape, and
weight of the vessel; the design temperature and pressure; the vessel
location and arrangement; and the internal and external fittings and
attachments. Horizontal vessels are usually mounted on two saddle
supports; Figure 13.22. Skirt supports are used for tall, vertical columns;
Figure 13.23 (vol.6) . The supports must be designed to carry the weight of
the vessel and contents, and any superimposed loads, such as wind loads.
Supports will impose localized loads on the vessel wall, and the design
must be checked to ensure that the resulting stress concentrations are below
the maximum. allowable design stress. Supports should be designed to
allow easy access to the vessel and fittings for inspection and maintenance .
For straight cylindrical skirt θ = 90 made of carbon steel .

~٨٦~
 fig 4.2.3. : skirt-support designs.

 Wind loading

Take dynamic wind pressure(Pw) = 1280 N/m2,corresponding to 160

kph(100mph)

D , including insulation=
D = D + D [t + t]
Assume t (thickness)=70 mm- (0.07m)
D = 2 + 2 × [(0.07 + 0.013 )] = 2.158 m
F = loading (per linear meter) = P D

F = 2762.24 N/m

F
M = H
2
2762.24
M = ×4
2

M = 22097.92 N. m
~٨٧~
  Bending moment at base of skirt :

Take height between tangent lines = 4 m

height of Crystallizer = 3 m

total height = 4 + 3 = 7 m

M
Bending M = (total height)
2
.
=7 ×

M = 541.39904 KN. m
4M
σ =
π(D + t ) t D
σ = bending stress in the skirt
M = maximum bending moment
D = inside diameter let, = 2 m
t = thickness = 13 mm
4 × 541399.04 × 10
σ =
π × (1300 + 9) × 9 × 1300
σ = 45009.28 N/mm
W
σ = (D + t ) t
π
σ = the dead weight stress in the skirt
t = thickness = 13 mm
W = total weight
π
Approximate weight = × D × ρgH
4
~٨٨~
 π
= × 1.3 × 4212 × 9.81 × 4
4
Approximate weight = 199849.3 N
Total Weight = 199849.3 + 52723.074 = 252572.37 N
W( )
σ ( )
=
π (D + t ) t

199849.3
σ ( )
=
π (1300 + 9) × 9
σ ( )
= 5.3997 N/mm

W( )
σ ( )
=
π(D + t ) t

52.723074 × 1000
σ ( )
=
π(1300 + 9) 9
σ ( )
= 1424.52 N/mm

~٨٩~
  Criteria design:

maximum σ ( .)
= σ +σ ( )

σ = 45009.28 + 5.3997 = 45016 N/mm

( )

maximum σ ( )
= σ σ ( )

= 45009.28 1424.52 = 43584.76 N/mm

 Analysis of stresses

1- pressure stresses
p D
σ =
4t
1.01 × 1.3 × 1000
4×9
= 36.47 N/mm
p Di
σ =
2t
1.01 × 1.3 × 1000
2×9
= 72.94 N/mm

~٩٠~
 2- Dead weight stress
W
σ =
π (D + t ) t
252572.37
σ =
π × (1300 + 9) × 9
= 6.824 N/mm2

3- Bending stresses
D =D +2t
D = 1.3 × 1000 + 2 × 9
= 1318 mm
π
I = D D
64
π
I = (2026 1300 )
64
I = 6.8 × 10 mm

M Di
σ = +t
Iv 2
22097.92 1.3 × 1000
σ = +9
6.8 × 10 2
= ±2.142 N/mm

~٩١~
  Base ring and anchor bolts:

Bolt circle diameter =1.44 m

Circumference of bolt circle = 1.44 π

. × ×
Number of bolt required = = 3.142

Closest multiple of 4= 8 bolt

Take both design stress = 92 N/mm2

M = 541.39904 KN. m

Take W= Weight of Crystallizer (operating valve)= 52.73074 KN

A = (4 × M × D – W) Eq.13.92 vol.6 Page(848)

×

where A = area of one bolt at the root of the thread, mm ,

N = number of bolts,
F = maximum allowable bolt stress, N/mm ;
typical design value 92 N/mm2
M = bending (overturning) moment at the base, N.m,
W = weight of the Crystallizer, N,
D = bolt circle diameter, m

~٩٢~
 1 4 × 541.39904 × 1000
A = – 52.73074 × 1000
8 × 92 1.44
= 1971 mm
A ×4
B lt root dia. = = 50 mm
π

Total compressive load on the base ring per unit length

F = + Eq.13.93 vol.6 Page(848)

4 × 541.39904 52.73074
F = + = 420.799KN/m
π × 1.3 π × 1.3

Taking the bearing pressure as 5 N/mm2

L = Eq.13.94 vol.6 Page(848)

where L =base ring width, mm (Figure 13.29 vol.6),

F = the maximum allowable bearing pressure on the concrete foundation
pad,
which will depend on the mix used, and will typically range from 3.5 to7
N/mm2 (500 to 1000 psi).
Taking the bearing pressure as 5 N/mm2

L =
×

= 8.3 × 10 m
Take the skirt bottom diameter as 4m

Skirt base angle θ = tan = 55.9℃

. ( – . )

Keep the skirt thickness the same as that calculated for the cylindrical skirt.
Highest stresses will occur at the top of the skirt; where the values will be

~٩٣~
close to those calculated for the cylindrical skirt. Sin 75.96℃ =0.83, so this
term has little effect on the design criteria.

~٩٤~
 Chapter Five

~٩٥~
 COST ESTIMATION:
Table(5.1): Economic Summary for Cases 1-5

Case 2 : Equipment=6.3 × 106 $

Batch /year Economic $

288 6.3 × 106
33 x
X=721875 $

Factor of Equipment = 50%

Fixed capital investment for cost index (2011)= = 1443750 $
.

Cost index for (2017 )=567.5

Cost index for (2011 )=585.7
present fixed capital investment
Present cost
index value at present time
= original cost
index value at time original cost was obtained

Present cost = 1443750 × ( 567.5/585.7)

Present cost = 1398887.016 $

~٩٦~
Table (5.2): Cost of equipment for 2017-2018

Estimation of total investment cost:

1- Direct cost

a- Purchased equipment cost:

(15 - 40% of FCI ) Assume 20 % of = 139887.016
= 139887.016 × 20 %

= 279777.4031 $

~٩٧~
 b- Installation cost:

(35 - 45% of PEC) Assume 35% ,where =

279777.4031 Purchased equipment cost

= × 35% = 279777.4031 × 35% = 97922.09109 $

c- Instrument and control installed:(6 -30% of PEC) Assume 12% of PEC

= × 12% = 279777.4031 × 12% = 33573.28837 $

d- Piping installation cost:(10 -80% of PEC) Assume 40%

= × 40% = 279777.4031 × 40% = 111910.9612 $

e- Electrical installation cost:(10 - 40% of PEC) Assume 20 % of PEC

= × 20% = 279777.4031 × 20% = 55955.48062$

f- Building process and auxiliary (10-70% of PEC) Assume 40 %

= × 40 % = 279777.4031 × 40% = 111910.9612 $

g- Service facilities:(30-80% 0f PEC) Assume 50 %

= × 50% = 279777.4031 × 50% = 13988.7016 $

~٩٨~
h- Yard improvement:(10-15% of PEC) Assume 12 %

= × 12% = 279777.4031 × 12% = 33573.28837 $

i- Land:( 4-8% of PEC) Assume 6%

= × 6% = 279777.4031 × 6% = 16786.6442 $

= + + + + + + + +

direct cost = 881298.8197 $

1. Indirect cost:

Expenses which are not directly involved with material and labor of actual
installation or complete facility

a- Engineering and supervision(5-30% of DC) Assume 15%

= × 15% = 881298.8197 × 7 % = 132194.823 $

b- Construction expenses: (10% of DC)

= × 10 % = 881298.8197 × 10 % = 88129.88197 $

c- Contractors fee(2-7% 0f DC) Assume 4 %

= × 4 % = 881298.8197 × 4 % = 35251.95279 $

~٩٩~
d- Contingency: (8-20% of DC) Assume 15 %

= × 15% = 881298.8197 × 15% = 132194.823 $

= + + +

= 387771.4807 $

 Fixed capital investment:

( )= +

( ) = 881298.8197 $ + 387771.4807$

( ) = 1269070.3 $

Working capital investment: 10 -20% of FCI Assume 10%

= × 10% = 1269070.3 × 10% = 126907.03 $

~١٠٠~
  Total capital investment:

Estimation of total product cost(TPC):

1. Fixed charges:

a- Depreciation: (10% of FCI for machinery)

= × 10% = 1269070.3 × 10% = 126907.03$

b- Local taxes: (3-4% of TPC= FCI) Assume 3.5 %

= ( = ) × 3.5% = 1269070.3 × 3.5% = 44417.4605 $

c- Insurances(0.4-1% of FCI) Assume 0.7 %

= × 0.7%=1269070.3 × 0.7%= 8883.4921 $

d- Rent: (8-12% of FCI) Assume 10%

= × 10% = 1269070.3 × 10% = 126907.03 $

= + + +
= 307115.0126 $
But, Fixed charges = (10-20% of TPC) Assume 15%
1269070.3 × 15% = 46067.25189$
= /0.2 × 100/20
= 1535575.063 $

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 2. Direct production:

a- Raw material: (10-50% 0f TPC) Assume 30%

= 1535575.063 × 30% = 460672.5189 $

b- Operating labor(OL): (10-20% of TPC) Assume 15%

= 1535575.063 × 15% = 230336.2595 $

c- Direct supervisory and electric labor (10-25% of OL) Assume 15 %
= 230336.2595 × 15% = 34550.43892 $
d- Utilities (10-20% of TPC) Assume 12%
= 1535575.063 × 12% = 184269.0076 $
e- Maintenance (2-10% of FCI) Assume 5%
= 1535575.063 × 5% = 69944.3508 $
f- Operating supplies (OS): (10-20% of maintenance) Assume 15 %

= 69944.3508 × 15% = 10491.65262 $

g- Laboratory charges (10-20% of OL) Assume 13%

= 230336.2595 × 13% = 29943.71374 $

h- Patent and royalties (2-6% of TPC) Assume 4%
=1535575.063 × 4% = 61423.00252 $

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i- Plant overhead cost: 50-70% of (OL+OS+M) Assume 60 %
= (230336.2595 + 10491.65262 + 69944.3508 ) × 60%
= 186463.3578 $

3. General expenses:
a- Administration cost: (40-60% of OL) Assume 50 %
= 230336.2595 × 50% = 115168.1298 $

b-Distribution and selling price (2-30% of TPC) Assume 12%

1535575.0632 × 12% =184269.0076 $

c- Research and development cost: (3% of TPC)

= 1535575.063 × 3% = 46067.25189 $

( ) = + +
= 345504.3893 $

manufacturing cost(MC)
= Product cost + fixed charges + Plant overhead expenses

= 1768105.673$

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  Total production cost:
= +
= 211361.062 $

 Gross earnings and rate of return:

Table (5.3): Erythromycin price

price per unit = 100$

= produce day rate

× number production days(in year) × price per unit

Total income = 1000 × 33 × 100

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Total income = 3300000 $
= Total income

= 3300000 2113610.062
= 1186389.938 $

= 50%
= –( × 50%)

= /

= 1186389.938 – (1186389.938 × 50%)

= 593194.969 $
= /
= 593194.969 /1269070.3
= 0.4674$

Fig (5.1): Chart for Recommended Case

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Reference:
1- b r a z j i n f e c t d i s . 2 0 1 2; " Antibiotics produced by Streptomyces"
2- Béatrice Biscans Université de Toulouse. CNRS -Laboratoire de Génie
Chimique UMR 5503 –FRANCE" Crystallization reactors"
3- Biotechnol. Prog. 1998, 14, 561-566 Wolfgang Minas, Peter Bru 1 nker, Pauli
T. Kallio, and James E. Bailey " Improved Erythromycin Production in a
Genetically Engineered
Industrial Strain of Saccharopolyspora erythraea"
4- Bunch, R.L., et. al “Erythromycin, its Salts, and Method of Preparation.”
Patent 2,653,899. April
14, 1953
5- BY EDWMH. FLY“, MAXV. SIGAL, JR., PAUL F. WILEYAND KOERTGERZON
RECEIVED JANUARY 16, 1954 " Erythromycin. I. Properties and
Degradation Studies"
6- Coulson & Richardson’s " CHEMICAL ENGINEERING VOLUME 6"
7- Gavin Towler , Ray Sinnott "Chemical Engineering Design Principles,
Practice and Economics of Plant and Process Design Second Edition”
8- H . G. OSMAN, A. A. ABOU-ZEID and A. A. EL-GAMAL (Eingegangen urn
3.1.1968) " Factors influencing the biosynthesis of erythromycin by
Streptomyces erythreus"
9- H.A. El-Enshasy a,*, N.A. Mohamed b, M.A. Farid b, A.I. El-Diwan Bioresource
Technology 99 (2008) 4263–4268 Improvement of erythromycin
production by Saccharopolyspora erythraea in molasses based medium
through cultivation medium optimization"
10- https://en.wikipedia.org/wiki/Erythromycin
11- https://pubchem.ncbi.nlm.nih.gov/compound/dextran
12- https://pubchem.ncbi.nlm.nih.gov/compound/erythromycin
13- https://www.slideshare.net/zahiduet43/design-of-stirred-batch-
reactor
14- J. N YV L T , J. W. MULLIN 1977 " Design of Batch Agitated
Crystallizers"
15- Kapil Nanakwani, Sameer R. Modi, Lokesh Kumar, Arvind K. Bansal
Thermochimica Acta 582 (2014) 77–85 " Role of thermodynamic, kinetic
and structural factors in the
recrystallization behavior of amorphous erythromycin salts"

~١٠٦~
16- M.Sc. Biotechnology Part II (Sem III) Paper III - Unit III Mumbai
University BY: Mayur D. Chauhan " Erythromycin"
17- M.Sc. Biotechnology Part II 2006 " Solubility of Erythromycin A
Dihydrate in Different Pure Solvents"
18- N. S. Tavare, Industrial Crystallization © Springer Science+Business
Media New York 1995 "BATCH CRYSTALLIZER"
19- Paolina Garbeva FEMS Microbiol Lett 342 (2013) 157–167 "
Taxonomic and functional diversity of Streptomyces in a forest
soil'
20- Rostamza M., 1Noohi A., *2Hamedi J. Received 15 July 2007; revised
17 Nov 2007; Accepted 1 Dec 2007 " Enhancement in production of
erythromycin by Saccharopolyspora
erythraea by the use of suitable industrial seeding-media"
21- Wolfgang Minas " Methods in Biotechnology, Vol. 18: Microbial
Processes and Products Production of Erythromycin With Saccharopolyspora
erythraea
22- X.ZOU et al., Response Surface Methodology for Optimization of the
Erythromycin …, Chem. Biochem. Eng. Q. 24 (1) 95–100 (2010)
23- Zhanzhong Wang, Jingkang Wang,* Meijing Zhang, and Leping Dang "
Solubility of Erythromycin A Dihydrate in Different Pure Solvents" J. Chem.
Eng. Data 2006, 51, 1062-1065

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