Executive Summary

The design problem addressed by our group is a design of a production plant engaged in the bio
synthesis Penicillin V. The design presented covers the whole production process beginning
from the sterilization to drying of the final product. The location of the site selected from a multi
criteria decision making analysis is Hamabanthota.

The final product is in the form of potassium penicillin V powder, which is the active ingredient
in oral penicillin. The plant is expected to have an effective capacity of 3500kg of potassium
penicillin V powder per year, which is equal to the annual Sri Lankan demand, according to the
market survey.

Since the fermentation process takes approximately 7 days, it is not practical to carry out the
process in a continuous manner. Therefore, the total process is divided into two stages where
fermentation is carried out in a batch process in 40 batches annually and the fermented broth is
stored. Downstream processing is carried out 300 days per annum in a continuous basis from
the stored fermented broth.

The included pages contain preliminary literature survey, market research, site selection and
the mass balance for each unit operation in the selected unit operation. Energy calculations are
carried out for sterilization, cooling, fermentation and drying units since their temperatures
have to be maintained above or below ambient conditions. The recycling of material is not
considered in the mass balance.

1
 Table of Contents

Executive Summary........................................................................................................................................................ 1
CHAPTER 1- PRELIMINARY STUDY

1. Introduction to the Project................................................................................................................................. 4

2. Literature Survey............................................................................................................................................... 5
2.1. Applications of Penicillin V....................................................................................................................... 5
2.2. Demand Prediction...................................................................................................................................... 6
2.3. Raw Materials................................................................................................................................................ 8
2.4. Production Process...................................................................................................................................... 9
2.5. Comparison of Processes................................................................................................................... 13
3. Environmental Concerns and Safety Hazards..................................................................................... 16
4. Plant Location and Site Selection............................................................................................................. 17
5. Process Description............................................................................................................................................ 26
CHAPTER 2- MASS AND ENERGY BALANCE

6. Batch Size and Flow Rate Calculation.......................................................................................................... 28

6.1. For the Batch Section................................................................................................................................ 28
6.2. For the continuous section..................................................................................................................... 29
7. Unit Operations – Batch Section.................................................................................................................... 30
7.1. Sterilization.................................................................................................................................................. 30
7.2. Cooling............................................................................................................................................................ 32
7.3. Fermentation............................................................................................................................................... 34
7.4. Storage............................................................................................................................................................ 40
8. The Unit Operations – Continuous section................................................................................................ 41
8.2. Cooling Unit.................................................................................................................................................. 44
8.3. Acidification...................................................................................................................................................... 46
8.4. Centrifugal Extractor................................................................................................................................ 49
8.5. Re Extraction............................................................................................................................................... 52
8.6. Precipitation................................................................................................................................................. 55
8.7 Basket centrifugation............................................................................................................................... 64
8.8 Fluid Bed Dryer........................................................................................................................................... 67
9. Summary................................................................................................................................................................. 73
10. List of References............................................................................................................................................ 78

2
 CHAPTER I

PRELIMINARY
STUDY

3
 1. Introduction to the Project

Penicillin is a secondary metabolite of fungus ''Penicillium'' that is secreted in the stationary

phase in the life of the fungus. According to the variety of the fungus and the composition of the
medium, either benzyl penicillin (penicillin G) or phenoxymethyl penicillin (penicillin V) is
produced. Various other natural penicillins occur, but are not important. (Laulence and Bennet
1980).

The general structure of penicillin is as follows and the ‘R’ group characterizes the type of
penicillin.

Figure 1.1: General structure of penicillin (Sambamurthi and

Table 1.1: Types of penicillin (Sambamurthi and Kar 2006)

-R group Name Mode of administration

CH2-O-C6H6 Penicillin V Oral
CH2-C6H6 Penicillin G Intravenous

Out of the two major types of penicillin, this study is based on the synthesis and the industrial
production of Penicillin V from microbial species. In this context, a demand prediction along
with a literature review on the applications, process identification, environmental concerns and
site selection is discussed in this document.

4
 2. Literature Survey

2.1. Applications of Penicillin V

Penicillin V is used for both for the prevention and treatment of a wide range of infections
majorly caused by bacteria. The principal organisms against which penicillin V is used are
streptococcus, pneumococcus, gonococcus, treponema and clostridia. Some examples of the
deceases caused by the above microorganisms are as follows.

 Strep throat
 Tonsillitis
 Scarlet fever
 Red lesions of skin (caused by group A streptococcus)
 Trench mouth
 Infection of the middle ear (caused by streptococcus and pneumococcus)
 Throat irritation
 Acute infection of the nose
 Throat or sinus
 Upper respiratory infection (caused by pneumococcus and Streptococcus)
 Inflammation of the gums and mouth
 For infection prevention from tooth extraction and rheumatic fever prevention
(Laulence and Bennet 1980).

The antibiotic nature of penicillin arises because it interferes with the synthesis of the
peptidoglycan layer of the cell wall which normally protects the bacterium from the
environment. Since the cell wall thus formed is weak, the osmic pressure difference between the
outer environment and the cell interior cause the cell to swell and then explode. Penicillin is
only effective against multiplying organisms since resting organisms do not form a new cell wall
(Laulence and Bennet 1980).

The dose of penicillin V is 250-500mg per every 4 hrs (Laulence and Bennet 1980). Allergies for
penicillin V occurs in all forms up to 10% of patients, principally itching rashes, eczematous or
urticarial. Anaphylactic shock though rare can be fatal.

5
 2.2. Demand Prediction
For the demand prediction, penicillin consumption in Sri Lanka for eight consecutive years was
considered. The data was obtained from the Medical Supplies Division, Ministry of Health Sri
Lanka. The population data were taken from the Department of Census and Statistics.

Table 2.1: Penicillin consumption in Sri Lanka

Demand Population Per capita demand

Year
(kg) (million) (kg)
2006 4484.75 19.86 225.82
2007 6904.75 20.04 344.55
2008 6140.75 20.22 303.70
2009 4873.25 20.45 238.30
2010 4091.38 20.65 198.13
2011 4735.25 20.87 226.89
2012 3872.00 20.33 190.46
2013 4978.25 20.48 243.08

400
350
Per capita consumption (kg)

300
f(x) = − 10.95 x + 22260.33
250 R² = 0.26
200
150
100
50
0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Year

Figure
2.1: Variation of Penicillin consumption in Sri Lanka

After 2007, the consumption of penicillin demonstrates a decreasing pattern. Though the
population of the country has increased, the decrease in demand may have occurred due to the
use of alternative antibiotics. This substitution is mainly due to penicillin resistance; penicillin
allergies and the frequent necessity of administer penicillin (one dosage per every 4 hrs.)

Table 2.2: Substitutions for Penicillin

6
 Disease Substitute
Amoxicillin
Clarithromycin
Pharyngitis and
Azithromycin
Tonsillitis
Cetin (Cefuroxime Acetyl)

Skin or Skin Structure Keflex (Cephalexin)

Infections Merrem I.V. (Meropenem)
Maxipime (cefepime)

For the prediction of the penicillin demand on 2020, the linear decreasing pattern of the
penicillin demand observed from 2006 to 2013 was considered.

300
f(x) = − 10.95 x + 22260
250
Per capita consumption (kg)

200

150

100

50

0
2004 2006 2008 2010 2012 2014 2016 2018 2020 2022
Year

Figure 2.2: Predicted penicillin demand

It has been predicted that the population of Sri Lanka in year 2020 would be 26.73million.
Therefore, according to the above prediction, the penicillin demand in 2020 would be 3500
kg/year.

2.3. Raw Materials

2.3.1. Different strains of penicillin

7
Initially, Penicillium notatum was used for penicillin synthesis but later Penicillium baculatum,
Penicilluim cyaneo fulvum and Penicillium chrysogenum. Due to the high yield, Penicillium
chrysogenum is used in the industrial scale today and strains to which mutations are done with
UV-radiations, X-rays, and mechlorethamine are also available . This study is based on the
Penicillium chrysogenum strain.

2.3.2. Raw materials for fermentation media

For the growth of the Penicillium strain in the media, several nutrients are essential including a
carbon source, proteins, phosphates, nitrates, sulfates, potassium, magnesium and moisture. A
high amount of initial glucose given as a carbon source inhibits the penicillin production
therefore it has to be fed continuously in intervals during the fermentation process. A carbon
source can be of many forms ranging from glucose, lactose and sucrose while protein can be
provided by corn steeping liquor, wheat steeping liquor, corn gluten and synthetic mixtures of
amino acids. Nitrates of sodium calcium and magnesium can be used while magnesium sulphate
and zinc sulphate are used. Sometimes, in the industrial production of penicillin, industrial
media containing all the nutrients together (Pharmamedia) are also used.

Though every process contains these basic ingredients, the form in which they are added varies
from process to process.

8
 2.4. Production Process

2.4.1. Process 1
As mentioned in the book of ‘Pharmaceutical Biotechnology’ by K. Sambamurthy and Ashutosh
Kar the followings are the raw materials needed for production of Penicillin.

 Penicillium gene  Calcium carbonate

 Penicillinase enzyme  Corn steep liquor
 Lactose  Soy oil
 Glucose  Water
 Ammonium sulfate  Sulfuric acid
 Phenyl acetic acid  Organic solvent
 Potassium dihydrogen phosphate  Sodium hydroxide

Block diagram

Steam Enzymes

Nutrients Sterilization Fermentation Filtration

Oxygen
Condensate Microorganisms
Methyl isobutyl ketone

Re-extraction Back extraction Extraction Acidification

NaOH Butyl acetate Sulfuric acid

Back extraction Crystallization Drying

Hot air
NaOH

Figure 2.3: Block diagram of penicillin production (Sambamurthy and Kar 2006)

9
The above process flow can be further described as follows. First the nutrients consisting of
corn steep liquor, glucose and lactose are sterilized using steam. While sterilization the pH value
should be between 5.5 and 6.0. It is then sent to the fermenter together with Penicillium
microorganisms. Fermentation process is done for about 80 hours until the pH come up to a
value of 8. Fermentation is done with higher lactose content of 4 to 5% with vigorously
increased aeration and agitation environments. Penicillin would not be the only product of
fermentation whereas some weak organic acids, organic liquids and solids may be formed.
Penicillin production is sensitive to pH fluctuations during fermentation and therefore it is
necessary to maintain pH of 7 by adding calculated amount of either diluted sulfuric or sodium
hydroxide. Finally the Penicillinase enzyme is added to the fermenter broth (Sambamurthy and
Kar 2006).

What comes next is the most important recovery process. Microbes and solution containing
penicillin is filtered in a rotary vacuum filter. The filtered biomass can be used as an animal feed
while the filtrate is acidified using sulfuric acid to decrease the pH value to 2 - 2.5. Acidification
is done to get the anionic form of penicillin and it easily dissolves in lower pH than in higher pH
solutions. Importantly, recovery should be able to extract penicillin at a high yield as much as
possible. Therefore this process consists of four stages of extraction. First stage of extraction is
done with an organic solvent such as butyl acetate or amyl acetate. Then it is back extracted to
an aqueous solution of KOH or NaOH, simultaneously to get the penicillin salt. For high
purification, it is re-extracted to the organic solvent, methyl isobutyl ketone. A back extraction
to an aqueous solution is done again to extract penicillin. Organic solvents can be recovered by
distillation. Finally it is crystallized by cooling and washed and dried to get the final product
(Sambamurthy and Kar 2006).

2.4.2. Process 2
As adapted from Heinzel et al 2006 followings are the raw materials needed for production of
Penicillin V.

 Penicillum Crysogenum  Potassium Acetate

 Glucose (Energy Source)  Sulfuric acid (Sulfur source)
 Ammonia (Nitrogen source)  Oxygen (Respiration)
 Water (Microbial metabolism)  Phenoxy acetic acid
 Water  Butyl Acetate
 Sulfuric Acid  Sodium Hydroxide
Medium (pharmamedia, trace metals, phenoxy acetate) and the glucose solution are prepared
separately in two tanks. They are sterilized in the continuous heat sterilizer and fed to the
fermenter. Air is compressed and filter sterilized and fed to the fermenter for aeration.

10
In the fermenter, biomass and penicillin V are produced, consuming the carbon sources, the
precursor, and the mineral salts. After the fermentation, the bioreactor content is transferred to
the harvest tank for storage.

Biomass is removed initially in the rotary vacuum filter. In the centrifugal extractor penicillin is
extracted into butyl acetate. Prior to extraction, the cell-free broth is acidified to a pH of around
3 using sulfuric acid and cooled to minimize degradation during acid extraction. After the
extraction, the remaining aqueous solution is neutralized with sodium hydroxide and
discharged.

Penicillin is re-extracted into acetone/water. Potassium acetate is added and penicillin V

potassium salt precipitates. The precipitates are separated and washed in the basket
centrifugation. In the fluid-bed dryer, the penicillin is dried with air and the final product stored
in tank (Heinzel et al., 2006).

11
 Penicillium
Cooling water Chrysogenum Oxygen Filter aid
Steam

Glucose, Ammonia,
Sulfuric acid, water, Heat Fermentation (Fed Storage Bio mass removal
oxygen, Phenoxy Sterilization Cooling Batch, 156 h) 24 24 0C Rotary vacuum filter Solids
acetic acid (120 0 C for 25 24 0C 0
C pH 5.5 - 6 pH 5.5 - 6
min)

Exhaust air
Steam condensate
Sulfuric/ Phosphoric acid
Water Butyl acetate

Butyl
Acetate Centrifugal Acidification Cooling Liquid
Re extraction extraction pH 3 00 C
phase ammonia

Aqueous phase

Potassium Basket Storage

Fluid bed
Acetate Precipitation centrifugation drying

Aqueous phase Hot air

Figure 2.4: Block diagram of penicillin production process (Heinzel et al., 2006)

12
 2.5. Comparison of the methods

Comparison of Methods was done by Visual Promethee software

2.5.1. Visual PROMETHEE

PROMETHEE is a Multi Criteria Decision Making (MCDM) analysis method designed to evaluate several
possible actions or options according to multiple and conflicting criteria and rank them from the best to
the worst. The ranking is done by calculating a preference flow (Phi value) by pair wise comparison of
every decision based on each criterion.

A weight is allocated to represent the relative importance of each criterion. A preference function has to
be defined for each criterion. It translates the differences of pairwise comparison into degrees of
preferences. A Usual preference function can be allocated for criteria with no threshold limit. It is
generally applied for qualitative criteria where the highest or lowest value is preferred. Linear and V
shape preference flows are appropriate for quantitative criteria which varies linearly and a threshold
limit is existing. The indifference threshold of a V shape may be zero while it may differ in Linear
configuration. A Level preference function is best suited for qualitative measurements with more than
five levels while the Gaussian configuration is an alternative to Linear preference function but with a
smoother variation.

The positive preference flow (Phi+) measures how much an action is preferred over the other
ones. It is a measure of the strengths of an action. The larger the Phi+, the better is the action.
The negative preference flow (Phi-) measures how much the other actions are preferred to the
action considered. The smaller the Phi-, the better is the action. The net preference flow (Phi) is
the balance between the positive and negative preference flows. It thus takes into account the
aggregate of both the strengths and the weaknesses of the action. Hence, Phi can be either
positive or negative and the option with the highest Phi value is concluded as the best (Carmody
et al 2006)

2.5.2. Process Comparison

When process 1 and 2 are compared, only minor changes could be observed. In process 1, the medium
for fermentation is assembled in the manufacturing process from crude raw materials while in process
2 an industrially manufactured medium is used. Since crude raw materials like corn steeping liquor is

13
not available in Sri Lanka at a lower cost, it is worthier to use an industrially manufactured
fermentation medium with lesser contamination. In process 2, prior to extraction, the mixture is cooled
to avoid the destruction of penicillin since it is very sensitive to heat while process 1 does not contain
such a step.

Some considerable differences could be observed in the downstream processing in the two methods. In
process 1, there are four liquid - liquid extraction stages which may require a higher amount of solvents
but create a higher purity, while process 2 has only 2 liquid – liquid extraction stages. Further, process
1 does not specify the crystallization method of penicillin while process 2 indicates clearly that it is
through precipitation.

According to US patent 2719149, a penicillin recovery efficiency of 92% has been achieved through the
downstream processing procedure in process 2 while the extraction method in process 2 has given a
penicillin recovery efficiency of 91% according to US patent 2 488 559. But when the fermentation time
is considered, process 1 completes the fermentation in a shorter period of time which is a positive
attribute because increased fermentation affects in the increased overhead cost of a production facility
and also the energy consumption.

More importantly, process 1 is concerned on penicillin G production while process 2 is on penicillin V

production. A breakdown of the parameters of each process for multi criteria decision making is given
in the following table.

Table 2.3: Parameter comparisons of processes

Process 1 Process 2
Relevancy Low High
Contamination High Low
Recovery efficiency 91% 92%
Cooling Not available Available
Data availability Low High
Fermentation time 80h 156 h

A multi criteria decision making analysis was done for above two methods through Visual Promethean
Academic.

14
 Table 2. 4: The Promethee Analysis

Relevancy is measured qualitatively with a 5 point scale. Since the most relevant process is preferred,
the ‘max’ is given under preference. The preference function is selected as ‘Level’ according to the
Promethee guidelines since it is a qualitative measurement.

Recovery is measured quantitatively. Since the highest recovery is preferred, the ‘max’ is given under
preference. The preference function is selected as ‘Linear’ according to the Promethee guidelines since
it is a quantitative measurement.

Similar to relevancy, contamination and data availability are measured qualitatively, while
fermentation time is analyzed quantitatively with the preference being the minimum fermentation
time. Since data availability is more important than other parameters in the design task, a weight 0f ‘2’
is allocated while all other parameters are given a weight of ‘1’ each.

From the Promethee analysis, the following Promethee table was obtained with the rankings and the
relevant phi values

Table 2.5: Promethee Table

15
From the above analysis, it is seen that Process 2 has the highest net Phi value. Therefore, it was
selected for the plant design.

16
 3. Environmental Concerns and Safety Hazards

Most of the wastewater produced is discharged in the downstream processing stages; after
broth filtration, extraction and separation after crystallization. The waste water contains
impurities such as butyl acetate, other nutrients and traces of penicillin. These waste water
streams should be treated properly at a biological waste water treatment plant. A high amount
of organic matter in the waste streams may lead to high microbial growth if released directly to
surface water streams and may cause depletion in dissolved oxygen in water. In addition,
excessive amounts of penicillin in waste water may destroy favorable microorganisms in the
biological water treatment plant leading to its malfunctioning.

Apart from that, the organic liquids such as butyl acetate that do not dissolve in water may form
a layer on the surface water if added to natural resources, that will reduce the dissolved oxygen
levels in water leading to adverse effects such as anaerobic digestion of organic and inorganic
constituents leading to odors. In addition, the acetic acid formed during precipitation, may
increase the acidity in water therefore it is necessary to neutralize the effluent water stream.
Likewise, many different aspects have to be considered, when the effluent water from the plant
is treated. Hence effluent water is the most prominent environmental hazard in the Penicillin V
production plant

Out of the gas phase effluents, carbon dioxide dominates. The direct release of carbon dioxide to
the atmosphere during fermentation may contribute to green house effect. In addition to the
raw material inputs, energy consumption also contributes to the environmental impact.
Sterilization of raw materials is done by steam which has to be produced through a boiler
operation, which leads to the consumption of petroleum fuels. Further, the flue gas from the
boiler if not treated properly may result in the release of gases such as carbon dioxide and
sulfur dioxide contributing towards acid rains. But since the batch of penicillin produced is
small, the impact is relatively small when compared with mass scale industries.

In order to facilitate cooling in the downstream processing of penicillin, a refrigeration p that

lant is required. The refrigerant used should be selected in such a way that it affect minimally to
the ozone layer depletion. A refrigerant like ammonia is preferred over chloro - fluoro carbons.

Apart from boiler operation and steam handling, the safety considerations in the plant are less
since unit operations are conducted near ambient conditions.

17
 4. Plant Location and Site Selection

Plant location and site selection is the predominant action when designing a plant and there are
many criteria that should be considered because of initiation cost, operating cost and
environment regulation as well as other legal regulations should be satisfied. The key identified
criteria for this design are as follows,

 The marketing area

 Raw material supply
 Availability of utilities: water, fuel, power
 Availability of suitable land
 Environmental impact and effluent disposal
 Climate[ CITATION Cou00 \l 1033 ]

At the beginning, according to population density, five locations were selected to analyze best
site location based on above criteria.

Table 4.1: Population density of selected sites

Index Plant location Population density

/ (persons per km2)
A Puttalum 248
B Kurunegala 336
C Trincomalee 159
D Anuradapura 120
E Hambanthota 230

4.1.1. Marketing area

This consideration is important fact for the cost transportation of finished products to the
consumers. Penicillin V is a pharmaceutical industry which has low volume production
therefore this consideration will be less important because it depends on the volume of
production[ CITATION Cou00 \l 1033 ].

18
In our case, there is no specific market area and we have to distribute products all over the
country therefore, total distance from the plant to the each capital of the provinces were
calculated and those values are used for Visual Promethee.

Table 4.2: Distance from selected sites to main cities

Distance from the plant to each capitals/ km

Plant location

Anuradhapura

Total distance
Trincomalle

Rathnapura
Kurunegala
Colombo

Badulla
Kandy

Jaffna

Galle
A 150 157 244 85 178 90 200 266 283 1653
B 90 53 159 111 162 - 117 302 200 1194

C 264 181 248 104 - 162 273 230 365 1827

D 201 150 231 - 104 111 219 193 302 1511
E 239 242 144 361 363 246 133 535 130 2393

4.1.2. Raw material availability

The availability and price of raw materials are major facts that determine the site location and
which are more important to deal with bulk raw materials. But, we are dealing with low volume
raw materials in this production[ CITATION Cou00 \l 1033 ]. But, this consideration will be taken
into the account by given the appropriate consideration relatively other facts. Because, required
raw materials should be imported therefore plant location will be close to the harbor.

Glucose/Sucrose is a major raw material and we decided to get it from sugar industry in sri
lanka due to cost of importing material. The distances are calculated between site location and
nearest sugar factory. Other materials are imported the distance are calculated with nearest
harbor.

19
 Plant location Distance from Distance from Distance to nearest
Colombo harbor to Hambanthota harbor harbor
the plant/ km to the plant/ km
A 139 331 139
B 102 243 102
C 263 355 263
D 200 362 200
E 248 1 1
Table 4.3: Distance analysis to harbors

Distance from Distance from

Distance to nearest
Plant location Sewanagala to the Palwaththa to the
sugar factory/km
plant/ km plant/ km
A 287 294 287
B 198 208 198
C 360 280 280
D 306 285 285
E 45 93 45
Table 4.4: Distance analysis for sugar supply

4.1.3. Environmental consideration

Waste generation and waste disposal in a plant is an adverse effect on environment. Waste
disposal difficulties and full filling the environmental legal requirement should be considered in
this fact when selecting a site.

CO2 emission and biomass sludge emission are major environmental aspects associated with
production of Penicillin V plant. Biomass sludge can be used as animal feed and also as a
fertilizer by using sludge treatment plant and effluent water can be discharge to a nearest water
body. Proximity is calculated and qualitatively assessed relative to each site location.

Distance to the nearest waste water discharging

Plant location point Remark
Stream, creek, river Sea
A 15 2.5 Very good
B 6.4 75 Average
C 10 5 Good
D 4 75 Good

20
 E 4.8 1 Very good
Table 4.5: Availability of water

4.1.4. Utilities

Production of Penicillin v is involved with chemical processes so water as a utility will be more
important for cooling and other process purposes. Therefore plant should be located near the
resource of water with reliable quantity.

Electricity will be needed for plant operation but consumption of electricity in this case is
comparatively less than electrochemical processes involved plant. Electricity is taken from
national electricity grid and it does not depend on location[ CITATION Cou00 \l 1033 ].

Water is important utility for production of penicillin but the required amount is considerably
high therefore the location of a nearby water resource is a must. The proximity to a water
resource is considered environmental impact. But here we only consider the quality of water
and treatment cost to meet our process specification. Finally we use qualitative method for this
consideration.

Table 4.6: Utilities

Site location Remarks

A Average
B Good
C Average
D Average
E Average

4.1.5. Availability of suitable land

The land which should be flat, well drained, suitable load bearing characteristics and sufficient
land area should be satisfied for the proposed plant and further expansion when selecting a
suitable land[ CITATION Cou00 \l 1033 ].

Table 4.7: Land availability

Site location Remarks
A Good
B Average

21
 C Good
D Good
E Good

4.1.6. Climate

Climate is an important fact when locating a plant because some adverse climatic conditions
such as abnormal low and high temperature, winds, earthquakes, will lead to additional cost of
operation. Therefore, these considerations will be taken into account in this plant design.

Table 4.8: Climate Analysis

Site location Remarks

A Good
B Average
C Good
D Bad
E Average

Considering above considerations, plant site was selected according to multi criteria decision
making software.

The Promethee analysis criteria matrix (Table 4.9) is constructed with data from Tables 4.3 –
Table 4.8.

Table 4.9: The Promethee Analysis

22
 Figure
4.1: The Promethee Rainbow

The Promethee Rainbow (Figure 4.1) shows that Hambanthota has the highest net Phi value
(Denoted in X axis) and raw material 1 and 2, Environmental impact, land availability, and
population density has affected towards the positive Phi value, while climate, utility and the
marketing area has affected towards a negative Phi value. From the above multi criteria
decision making analysis, Hambanthota is the suitable plant location

23
CHAPTER II

MASS AND
ENERGY
BALANCE

24
Notations
Symbo
Description Unit
l
CP Heat capacity kJ/kg.K
hfg Latent heat of steam kJ/kg
HG Enthalpy of gas streams kJ/kg
HS Enthalpy of solid streams kJ/kg
∆Hrxn Standard heat of reaction kJ
m Mass flow rate kg/day
M Molar mass kg/kmol
n Molar flow rate mol/day
QW Heat loss from wall kJ
0
T Temperature C
V Volume L
x Mass fraction -
X Moisture content kg/kg
y Yield -
Y Absolute humidity kg/kg
ρ Density kg/L
Λ Latent heat of vaporization kJ/kg

Abbreviations

A - Ammonia AP - Aqueous phase

AA - Acetic acid B - Biomass

AI - Acetate ions BA - Butyl acetate

25
CD - Carbon dioxide P - Penicillin

e - Effluent PA - Potassium acetate

G - Glucose PAA - Phenoxy acetic acid

i - inlet PI - Penicillin ions

K - Potassium ions PP - Potassium Penicillin

precipitate
o - Outlet
S - Steam
O - Oxygen
SA - Sulfuric acid
OP - Organic phase
W - Water

5. Process Description

Based on the Multi Criteria Decision Making (MCDM) study conducted during the initial stages
of the assignment, the production process (Figure 5.1) adapted from Heinzel et al (2006) is
used in the process design.

26
The raw materials used in the process are as follows.

Penicillin strain
 Penicillum Crysogenum

Raw materials for media

 Glucose (Energy Source)  Sulfuric acid (Sulfur source)
 Ammonia (Nitrogen source)  Oxygen (Respiration)
 Water (Microbial metabolism)  Phenoxy acetic acid

Extraction Solvents
 Water  Butyl Acetate

pH adjusters
 Sulfuric Acid  Sodium Hydroxide

Precipitation agent
 Potassium Acetate

27
 CO2
Penicillium
Cooling water Chrysogenu Filter aid
Steam Oxygen
m

Glucose, Ammonia,
Sulfuric acid, water, Heat Fermentation (Fed Storage Bio mass removal
oxygen, Phenoxy Sterilization Cooling Batch, 156 h) 24 24 0C Rotary vacuum filter Solids
acetic acid (120 0 C for 25 24 0C 0
C pH 5.5 - 6 pH 5.5 - 6
min)

Cooling water
Steam condensate
Water Butyl acetate Sulfuric/ Phosphoric acid

Butyl
Acetate Centrifugal Acidification Cooling Liquid
Re extraction extraction pH 3 00 C
phase ammonia

Aqueous phase

Potassium Basket Storage

Fluid bed
Acetate Precipitation centrifugation drying

Aqueous phase Hot air

Figure 5.1: Block diagram of Penicillin production process

28
6. Batch Size and Flow Rate Calculation

6.1. For the Batch Section

 The included unit operations:
Sterilization, cooling, fermentation and storage
 The total input flow rate of raw materials:
881.36 kg/ batch (Calculated in the fermentation unit operation, page 40)

Table 6.1: The composition of the input raw materials to the batch section as calculated in the
fermentation unit operation

Component Flow rate (kg/batch)

Glucose 127.02
Sulfuric acid 28.81
Ammonia 15.30
Phenoxy acetic acid 51.40
Oxygen 23.33
Water 635.50
Total 881.36

6.2. For the continuous section

 The included unit operations : All the downstream processes

29
  Annual Demand : 3500 kg
 Number of operating days : 300 days
 Peniciliin V produced per day : 3500/300 kg/day
: 11.67 kg/day
 The total input flow rate of raw materials : 133 kg/ day

(Calculated in MS Excel by mass balancing till the required output is obtained.)

By multiplying the above flow rate (133 kg/ day) by the mass fractions of each constituent
calculated in the storage unit (page 43), the obtained compositions of the inlet mass flow to the
continuous section are as follows.

Table 6.2: The composition of mass input to the continuous section

Mass Mass
Component
fraction (kg/day)
Penicillin 0.10 13.84
Water 0.82 108.98
Bio mass 0.04 4.90
Glucose 0.02 3.01
Sulfuric acid 0.01 0.68
Ammonia Trace 0.36
Phenoxy acetic acid 0.01 1.22
Total 1.00 133.00

7. Unit Operations – Batch Section

7.1. Sterilization

7.1.1. Introduction
Sterilization is a heat transfer operation from superheated steam to fermentation media prior to
send to the fermenter. Even though sterilization can be done by filtration, irradiation, sonic
vibration or chemical cleansing, heating is the most widely used sterilization method

30
(Gopalakrishnan & Detchanamurthy, 2011). Superheated steam is used as heating medium and in
this study it is assumed that steam will only dissipates its latent heat. Superheated steam at 3 bar
and 133.50C is employed.

7.1.2. Design conditions

The assumptions made for the calculations were as follows.

 Heat loss through the sterilizer to the environment is negligible.

 Superheated steam will only dissipate latent heat.
 Heat capacity of Phenoxy acetic acid is similar to water.

Table 7.1: Input conditions to the sterilizer

Mass Inlet Temp. Heat capacity

Component Reference
(kg/batch) (°C) (kJ/kg.K)
Glucose 127.02 27 211.3 Boerio-Goates 1991
Sulfuric 28.81 27 1.34 Engineering Tool Box
Ammonia 15.30 27 4.52 Haar and Gallagher 1978
Phenoxy A. acid 51.40 27 4.18 Assumed similar to water
Oxygen 23.33 27 0.92 Air Liquide 2014
Water 635.50 27 4.18

Desired output is to sterilize the media up to 120 0C by heat sterilization. Outlet mass is same as
inlet.

Latent heat of steam at 3 bar and 133.50C = 2164 kJ/kg (Steam tables)

7.1.3. Energy balance

mG,1 mSA,1
mG,1 mSA,1
mA,1 mPAA,1
UNIT 1 mA,1 mPAA,1
mO,1
Sterilization mO,1

mS,1 Condensed steam

Superheated steam

31
 Figure 7.1: Block diagram of sterilization

Apply energy balance to the sterilizer,

Heat dissipated by super heated

= Heat absorbed by the media
steam
m S , 1 h fg = ( mG , 1 C P , G +mSA , 1 C P , SA +m A ,1 C P , A +m PAA, 1 C P , PAA +mO , 1 C P , O ) ∆ T
mS , 1 h fg = (127.02 ×211.3+ 28.81×1.34 +15.30 ×4.52+51.40 × 4.18+23.33 ×0.92
m S , 1 h fg = 2.78 ×106 kJ /batch
mS , 1 2.78× 106
= kg /batch
2164
= 1284.66 kg /batch

7.2. Cooling

7.2.1. Introduction
Similar to sterilization, cooling is also a heat transfer operation from sterilized media to cooled
water. Sterilized media need to be cooled prior send to the fermenter if not Penicillin production
will not occur. Cooled water at 40C will be using to cool the media up to 240C.

7.2.2. Design conditions

The assumptions made were,

 Heat transfer from environment to cooling water is negligible.

 Heat capacity of Phenoxy acetic acid is similar to water.

Table 7.2: Input conditions to the cooler

Component Mass Inlet Temp. Heat capacity Reference

32
 (kg/batch) (°C) (kJ/kg.K)
Glucose 127.02 120 211.3 Boerio-Goates 1991
0
Desired output is to cool the
Sulfuric media
28.81 up to 24
120C by cooling water.
1.34 Outlet mass is same as inlet.
Engineering Tool Box
Ammonia 15.30 120 4.52 Haar and Gallagher 1978
Phenoxy A. acid 51.40 120 4.18 Assumed similar to water
Oxygen 23.33 120 0.92 Air Liquide 2014
Water 635.50 120 4.18

7.2.3. Energy balance

mG,2 mSA,2
mG,2 mSA,2
mA,2 mPAA,2
UNIT 2 mA,2 mPAA,2
mO,2
Cooling mO,2

mCW,2
Cooling water

Figure 7.2: Block diagram for cooling

Apply energy balance to the cooler,

Heat absorbed by cooling

water
m CW ,2 C P ,CW ∆T CW
mCW ,2 C P ,CW ∆T CW
m CW ,2 C P ,CW ∆T CW
mCW ,2
= Heat removed from the media
= ( mG , 2 C P , G +mSA , 2 C P , SA +m A ,2 C P , A +m PAA ,2 C P ,PAA +mO , 2 C P , O ) ∆ T
= (127.02 ×211.3+ 28.81×1.34 +15.30 ×4.52+51.40 × 4.18+23.33 ×0.9
= 2.86 ×10 6 kJ /batch
2.86 ×10 6
= kg /batch
4.18 ×(20−4)
= 4.28 × 104 kg /batch

33
 7.3. Fermentation

7.3.1. Introduction
Fermentation is the most important part of the biosynthesis of Penicillin V. Fermentation is
conducted in a fed batch reactor process with Penicillin Chrysogenum strain at pH 5.5 and 24 0C.
The pressure is at ambient conditions.

7.3.2. Design conditions

As adapted from (Heinzel et al 2006)

Biomass yield per oxygen (Y ¿¿ B/O)¿ 1.56 g/g

Penicillin V yield per glucose(Y ¿¿ P /G) ¿ 0.81 g/g

Penicillin V yeild perphenoxy acetic acid (Y ¿¿ P/ PAA) ¿ 2 g/g

Overall reaction efficiency 85%
Biomass composition of final product per unit volume of
0.045 kg/l
water

Table 7.3: Properties of components as adapted from Najafpour 2007

Component Molar Mass (kg/kmol)

Penicillin 350
Water 18
Bio mass 117
Glucose 180
Sulfuric 98
Ammonia 17
Phenoxy acetic acid 152

7.3.3. Calculation of stoichiometric coefficients

The chemical reaction in the production of penicillin V as adapted from Najafpour 2007 is as
follows.

34
a C 6 H 12 O 6 + b H 2 S O 4 +cN H 3 +d C 8 H 8 O 3+ eO2 → C16 H 18 O 5 N 2 S+ fC O 2+ g H 2 O+ hC 4 H 7 O 3 N

Considering
Glucose + Sulfuricyield Ammonia + Phenoxy acetic acid + Oygen → Penicillin + Carbon dioxide + Water
acid +factors
Y
+BiomassP/ G = mp
mG
= np× M P
nG × M G
0.81 = 1× 350
a ×180
a = 2.4
Similarly
Y P/ PAA = mp
mPAA
2 = 1 ×350
d × 152
d = 1.15

Y B/ O = mB
mO
1.56 = 117 ×h
Eqn1
32× e
Applying molar balance to nitrogen
C = 2 +h Eqn 2
Applying molar balance to Sulphur
B = 1
Applying molar balance to Carbon
6a +8d = 16 + f + 4h Eqn3
Applying molar balance to Hydrogen
12a + 2b + 3c + 8d = 18 + 2g + 7h Eqn 4
Applying molar balance to Oxygen
6a + 4b + 3d + 2e = 5 + 2f + g +3h Eqn5
By solving equations 1, 2, 3, 4 and 5
C = 3.06
E = 2.48
F = 3.36
G = 11.89
H = 1.06

Therefore the production reaction of Penicillin V is as follows

2.4 C 6 H 12 O6+ H 2 S O4 +3.06 N H 3+ 1.15C 8 H 8 O3 +2.48 O2 → C16 H 18 O5 N 2 S+3.36 C O 2 +11.89 H 2 O+1.06 C 4 H 7

Considering 2.4 moles of glucose as basis

Mass of glucose reacted at 100% efficiency = 2.4 × M G
= 2.4 × 180

35
 = 432 g
= 367.2 g
Mass of glucose reacted at 85% efficiency
Mass of glucose remaining = 432 - 367.2
= 64.80 g
Mass of Penicillin formed = 1 ×350 × 85 %
= 297.5 g
Mass of glucose required per a unit mass of = 432
penicillin 297.5
= 1.45 g/g
Annual penicillin demand = 3500 kg
Penicillin produced per batch if 40 = 3500/40
batches are operated
= 87.5 kg
Glucose required per a batch = 1.45 × 87.5
= 127.02 kg

Similar to the above calculation the masses of the reactants required, products formed and the reactants
remaining per batch can be calculated

7.3.4. Mass Balance

Table 7.4: Masses of reactants required, remaining and products formed per batch

Input Output (kg/batch)

Component
(kg/batch) Remaining Reactants Products
Glucose 127.02 19.06 -
Sulfuric 28.81 4.32 -
Ammonia 15.30 2.30 -
Phenoxy acetic acid 51.40 7.71 -
Oxygen 23.33 3.50 -
Penicillin - - 87.50
Carbon Dioxide - - 36.96
Water - - 53.51
Bio mass - - 31.01

36
 Total 245.86 245.86

mO,3,O
mCD,3,O
mP,3,o mW,3,o
mW,3i mA,3,o mPAA,3,o
mA,7,i mPAA,7,i mSA,3,o mG,3,o mB,3,o
mSA,C,7,i mG,7,i Vw
UNIT 3
Fermentation

Figure 7.3: Block diagram of the fermentation

Biomass composition of final product = 0.045 kg/l water

31.01 0.045 kg/l water
=
Vw
Vw = 689 L
Mass of water produced through reaction = 53.50 kg/ batch
53.50
Volume of water produced through reaction =
ρw
53.50
=
1
= 53.50 L
Volume of additional water required = 689 - 53.50
= 635.50 L
Mass of additional water required = 635.50 ×1
= 635.50 kg/batch

7.3.5. Energy Balance

Table 7.5: Heat capacity values of reactants and products of fermentation reaction

Component Specific heat (kJ/kg.K)

Penicillin 142
Biomass 92.05
Sulfuric acid 1.34
Phenoxy acetic acid 4.18
Carbon dioxide 0.8
Oxygen 0.92
Glucose 211.30
Ammonia 4.52
Water 4.18

37
The energy balance is based on 1st law of thermodynamics assuming isothermal operation and no
net work done.

Energy out = Energy in + generation-consumption-accumulation

δQ=−∆ H rxn

−∆ H rxn =∑ m prodout , j C pj ∆ T −∑ mreactant , i C pi ∆ T

¿ { 87.50 ×142+36.96 ×0.86 +689.00 ×4.18+ 31.01× 95.15+19.06 ×211.30+ 4.32× 1.34+2.30 × 4.52+7.71× 4.18
}

= ( 536794.08−716003.45 ) kJ

=1.79 ×105 kJ

Taking temperature of cooling water at outlet as 23°C, the requirement would be,

Q=mC p ∆T

1.79 ×105
m=
4.18 ×(23−20)

m=1.43 ×10 4 kg/batch

Component kg/batch Component kg/batch

Cooling water 14300 CO2 36.96
Total 14300 Total 36.96

Component kg/batch
Component kg/batch Penicillin 87.50
Glucose 127.02 Bio mass 31.01
Sulfuric 28.81 Glucose 19.06
Ammonia 15.30 Sulfuric 4.32
PA acid 51.40 Ammonia 2.30
Oxygen 23.33 PA acid 7.71
Water 635.50 Oxygen 3.50
Total 881.36 Water 689.00
Total 844.40
38
 Figure 7.4: Summary of mass flow rates of the fermenter

7.4. Storage
7.4.1. Introduction
Since the produced carbon dioxide and remaining oxygen in the fermenter are directly emitted to
the atmosphere, the remaining solid and liquid ingredients are stored in order to be used in the
continuous process.

7.4.2. Data
Table 7.6: Input masses into storage from fermenter

Component Amount (kg/batch) Mass fraction

Penicillin 87.50 0.10
Water 689.00 0.82
Bio mass 31.01 0.04
Glucose 19.06 0.02
Sulfuric 4.32 0.01
Ammonia 2.30 Trace
Phenoxy acetic acid 7.71 0.01
Total 840.89 1

39
 8. The Unit Operations – Continuous section

8.1 Rotary vacuum filter

8.1.1. Introduction
Rotary vacuum filters use vacuum to drive the liquid (filtrate) through the deposited cake of solids
and it is a continuous process but they have periodically stop to change the filter cloths. Drum filter
is made by large hollow drum around with the filter medium is fitted. This drum is partially
submerged in a tank of slurry and filtrate sucked through the filter cake by inside the drum while
wash water is spraying to the drum surface. There are several methods used for removing
deposited cake from drum. They are knives, strings, air jet and wires (Svarovsky, 1977).

8.1.2. Design conditions

The assumptions made were

 3% filter aid (Shuler and Kargi, 2001)

 97% yield can achieved [3% of penicillin goes with biomass] (Heinzle et al., 2007)
 3% of Filter aid goes with biomass

The input mass flow rates to the continuous section as given in table 6.2.

Table 8.1: Input as flow rates to the rotary vacuum filter

Mass flow
Component Phase
rate (kg/day)
Biomass Solid 4.90
Penicillin Liquid 13.84

40
 Water Liquid 108.98
Glucose Liquid 3.01
Sulfuric Liquid 0.68
Ammonia Liquid 0.36
Phenoxy acetic acid Liquid 1.22
Total - 133

8.1.3. Mass Balance

mw,4,i mB,4,o
mt,4,i UNIT mp,4,o
5Filtration

Figure 8.1: Block diagram for vacuum filter

Filter aid ¿mw,4,i¿ = 4.90 × 0.03

= 0.15 kg /day
Input (mt,4,i) = 133.00 kg/day
Bio mass output (mB,4,o) = Solid ∑ +liquid parts
Bio mass + 3% of liquid constituents
= 4.90+ 0.03 ×(13.84 +108.98+3.01+0.68+0.36+ 1.22)
= 8.75 kg /day
¿+Gen = Out + Loss+ Acc
mw,4,+¿ mt,4,i = mB,4,o +¿ mp,4,o

mp,4,o = mw , 4 ,i +mt , 4 , i−mB , 4 , o

mp,4,o = 0.15+133.00−8.75
mp,4,o = 124.40 kg/day

41
Component kg/day
Penicillin 13.84 Component kg/day
Water 108.98 Filter aid 0.15
Bio mass 4.90 Total 0.15
Glucose 3.01
Sulfuric 0.68
Ammonia 0.36
PA acid 1.22 Component kg/day
Total 133.00 Penicillin 13.42
Water 105.85
Glucose 2.92
Sulfuric 0.66
Component kg/day Ammonia 0.35
Bio mass 4.90 PA acid 1.18
Penicillin 0.42 Total 124.40
Water 3.27
Filter aid 0.00
Glucose 0.09
Ammonia 0.01
PA acid 0.04
Sulfuric 0.02
Total 8.75

Figure 8.2: Summary of mass flow rates of the vacuum filter

42
 8.2. Cooling Unit

8.2.1. Introduction
Cooling is done to enhance the efficiency of Penicillin purification in the latter stages of the
downstream extraction processes. The inlet to the cooling unit is liquid phase outlet from the
vacuum filter. By applying energy balance the mass flow rate of ammonia is found.

8.2.2. Design conditions

The assumptions are

 C p Value of penicillin is equal to C p value of water.

 There is no energy loss, accumulation or generating.
 Saturated liquid of ammonia at -30 0 C used as refrigerant and it converts to saturated vapor
at -100 C after passing heat exchanger.

Table 8.2: Properties of the input components

Inlet Heat Mass flow Heat

Outlet
Component temp. capacity rate absorbed
temp. (0C)
(0C) (kJ/kg.K) (kg/day) (kJ)
Glucose 27 0 211.30 13.42 -76586.70
Sulfuric 27 0 1.34 0.66 -24.00
Ammonia 27 0 4.52 0.35 -42.97
Water+Filetr aid 27 0 4.18 105.85 -11946.13
Penicillin 27 0 4.18 13.42 -1515.06
Phenoxy acetic acid 27 0 4.18 1.18 -133.53
Total - - - 134.90 -90248.39

Data for liquid ammonium used are,

 Inlet temperature of ammonia : -300C

 Outlet temperature of ammonia : -100C
 Enthalpy at the inlet temperature : 44.7 kJ/kg
 Enthalpy at the outlet temperature : 1433.0 kJ/kg

8.2.3. Mass Balance

mA,6 (TA,6,i , hA,6,i ) UNIT 6 mA,6 (TA,6,o , hA,6,0 )

mp,6 (Tp,6,i , Cpw) Cooling unit mp,6 (Tp,6,0 , Cpw)
43
 Figure 8.3: Block diagram for cooling

Calculation: Apply energy balance to the above unit,

¿+Gen = Out + Loss+ Acc

¿ = Out
m A , 6 h A , 6 ,o−m A ,6 h A ,6 ,i = 90248.39
= 90248.39
m A, 6
(h A ,6 , o−h A ,6 ,i)
= 90248.39
m A, 6
(1433.00−44.70)
m A, 6 = 65.01 kg/day

Component kg/day
Ammonia 65.01
Total 65.01
Component kg/day Component kg/day
Penicillin 13.42 Penicillin 13.42
Water 105.85 Water 105.85
Glucose 2.92 Glucose 2.92
Sulfuric 0.66 Sulfuric 0.66
Ammonia 0.35 Ammonia 0.35
PA acid 1.18 PA acid 1.18
Total 124.40 Total 124.40

Figure 8.4: Summary of mass flow rates of the cooler

44
 8.3. Acidification

8.3.1. Introduction
In the final product it is necessary to separate penicillin enzyme completely from the impurities.
This is done by extracting penicillin enzyme into an organic phase such as butyl acetate (C 6H12O2) at
low pH values, since penicillin is more soluble in butyl acetate at such pH values than in water. In
order to reduce the pH, acidification is done by adding an acid such as sulfuric acid (H 2SO4).

8.3.2. Design conditions

Desired output pH = 3 (Heinzel et al 2006)

Input pH = 5.5 (pH inside the fermenter)

Table 8.3: The input mass flow rates to the acidifier and densities as adapted from Najafpour 2007

Component Mass flow rate Density /(kg/L)

(kg/day)
Penicillin 13.42 3.42
Water 105.85 1.00
Glucose 2.92 1.54
Sulfuric acid 0.66 1.84
Ammonia 0.35 0.597
Phenoxy acetic acid 1.18 1.22

For acidification purpose 98% (w/w) pure sulfuric acid is employed.

8.3.3. Mass Balance mSA,7,i

VsA
mP,7,I mW,7,i
mA,7,i mPAA,7,i mP,7,o mW,7,o
mSA,C,7,i mG,7,i mA,7,o mPAA,7,o
Vi mSA,7,o mG,7,o
UNIT 7 Vo
Acidification

Figure 8.5: Block diagram for acidification

45
Volume calculation

Vi = V P ,i +V W , i+V A ,i +V PAA ,i +V SA ,C ,i +V G , i
m P ,7 ,i m W ,7 ,i m A , 7 ,i m PAA , 7 ,i
+ + +
= ρP ρW ρA ρPAA
+ mSA ,C ,7 ,i mG , 7 ,i
+
ρ SA PG
= 13.42 105.83 2.92 1.18 0.35 1.18
+ + + + +
3.42 1 1.54 1.84 0.597 1.22
Since pH = −log ¿ ¿
Considering the inlet

5.5 = ¿−log ¿ ¿
Inlet ¿ = 10−5.5 mol/L
Similarly outlet ¿ should be = 10−3 mol/L
¿ in sulfuric acid added = 2× Purity × Density
M SA
= 2× 1000× 0.98 ×1.84
mol
98
= 36.80 mol/L

+¿¿
Applying molar balance to H

Moles of H +¿¿ Coming ¿ the cooler ¿ + [ Moles

=
[ ¿ ] H +¿ ¿ Added
of[ Moles ] Leaving ]
of H +¿¿

(Inlet ¿ = Outlet ¿
¿

Applying volume balance

Vi + Vs = Vo

Therefore

(Inlet ¿ = Outlet ¿
¿

(10¿¿−5.5 ×113.59)¿ +¿ ) = 10−3 ×(113.59+V s)

Vs = 3.1 ×10−3 L/day

46
 m SA , 7 ,i = V s × ρSA
= 3.1 ×10−3 × 1.84
= 5.7 g/day
Applying mass balance to sulfuric acid
m SAC ,, 7 ,i +m SA , 7 ,i = m SA , 7 ,o
m SA , 7 ,o = 0.66 + 5.7 ×10−3
= 0.67 kg/day

The mass of other components do not change throughout the process.

Component kg/day Component kg/day

Penicillin 13.42 Penicillin 13.42
Water 105.85 Water 105.85
Glucose 2.92 Glucose 2.92
Sulfuric 0.67 Sulfuric 0.66
Ammonia 0.35 Ammonia 0.35
PA acid 1.18 PA acid 1.18
Total 124.41 Total 124.40

Component kg/day
Sulfuric acid 0.01
Total 0.01

Figure 8.6: Summary of mass flow rates of the acidifier

8.4. Centrifugal Extractor

8.4.1. Introduction
A centrifugal extractor, also known as an Annular Centrifugal Extractor (ACE) is used to mix
two immiscible liquids and extract the solute from one liquid phase to another. The separation of
phases occurs under gravity by rotating the mixture by means of a rotor. Heavier phase will move

47
towards the wall of the rotor while lighter phase remains close to the axis and thereby the
separation be done.

8.4.2. Design conditions

Assumptions are,

 No material generation, loss or accumulation of the system

 Water and butyl acetate are immiscible
 Only Penicillin is extracted into butyl acetate

Table 8.4: Input mass flow rates to the centrifugal extractor

Component Mass flow rate (kg/day)

Penicillin 13.42
Water 105.85
Glucose 2.92
Ammonia 0.35
Phenoxy acetic acid 1.18
Sulfuric acid 0.67
Total 124.40

 Extraction yield = 90% ( Najafpour 2007)

 Equilibrium constant of Penicillin
in butyl acetate: water = 25(Chemical Engineering II 2007)

8.4.3. Mass balance

Raffinate
(Aqueous phase) Extract
mWP,8,o (Organic phase)
xP,WP,8,o xW,8,o mOP,8,o
xG,8,o xA,8,o xP,OP,8,o
xPAA,8,o xSA,8,o xBA,8,o
UNIT 8
Centrifugal
Feed Extractor
(Aqueous phase)
mWP,8,I xP,WP,8,i xW,8,i Solventm
xG,8,i xA,8,IxPAA,8,i OP,8,i
xSA,8,i

48
 Figure 8.7: Block diagram for centrifugal extraction

Apply mass balance to Penicillin,

In + Gen = Out + Loss+ Acc

From above assumptions Gen = Loss = Acc = 0.

Therefore,

m ℘ ,8 , i x P ,℘,8 , i = ( m℘ , 8 ,o x P ,℘ , 8 ,o ) + ( mOP ,8 , o x P ,OP ,8 , o )

( m℘ , 8 ,o x P ,℘ , 8 ,o ) + ( mOP ,8 , o x P ,OP ,8 , o ) = 124.40 ×0.11
( m℘ , 8 ,o x P ,℘ , 8 ,o ) + ( mOP ,8 , o x P ,OP ,8 , o ) = 13.42 kg/day
For 90% yield,

( mOP , 8 ,o x P ,OP , 8 ,o ) = 0.9 × ( m℘ , 8 ,i x P ,℘ , 8 ,i )

= 0.9 ×13.42
= 12.08 kg /day
Therefore,

Amount of Penicillin∈water phase oultet = 13.42−12.08

= 1.34 kg /day
Outlet mass flow rate of water phase = 1.34+105.85+ 2.92+ 0.35+1.18+0.67
m ℘,8 , o = 112.32 kg /day
1.34
x P , ℘,8 , o =
112.32
= 0.01
For the equilibrium of outlet streams,

Mass fraction of Penicillin∈organic

phase
= 25
Mass fraction of Penicillin∈water
phase
( x P , OP )8 ,o
= 25
( x P ,℘ )8 , o
x P , OP ,8,0 = 25 ×0.01
= 0.25
Mass fraction of Penicillin∈organic Mass flow rate of Penicillin
= Mass flow rate of
phase (Penici llin+ solvent )
12.08
0.25 =
12.08+ ( m OP )8 , o
m OP ,8 , o = 28.35 kg /day

49
 Component kg/day Component kg/day
Butyl acetate 28.35 Penicillin 13.42
Total 28.35 Water 105.85
Component kg/day Glucose 2.92
Penicillin 12.08 Ammonia 0.35
Butyl acetate 28.35 PA acid 1.18
Total 40.44 Sulfuric acid 0.67
Total 124.40

Component kg/day
Penicillin 1.34
Water 105.85
Glucose 2.92
Figure 8.8: Summary of mass flow rates of the extractor
Ammonia 0.35
PA acid 1.18
8.5. Re Extraction Sulfuric acid 0.67
Total 112.32

8.5.1. Introduction
Penicillin enzyme in the organic phase has to be re extracted into an aqueous phase in order to
form the Penicillin V potassium salt which can then be precipitated. Re extraction is done at neutral
pH where penicillin is more soluble in water than in that of organic fluids (Najafpour 2007). The
extraction is single stage where a mixer and settler mechanism will be employed assuming that
butyl acetate and water are immiscible.

8.5.2. Design conditions

pH of solvent (Distilled water) =7

Temperature of solvent = 5 0C

The percentage penicillin recovery from re extraction = 90% ( Najafpour 2007)

Distribution coefficient of penicillin in Butyl acetate and

50
 water at pH7 = 0.1 (Chemical Eng. II, 2007)

Table 8.5: Input mass flow rates to the re extractor

Component Mass flow rate (kg/day)

Penicillin 12.08
Butyl acetate 28.35
Total 40.44

8.5.3. Mass Balance

Raffinate Extract
(Organic Phase) (Aqueous phase)
mBA,9,o mP,OP,9,o mW,9,o mP,AP,9,o

UNIT 9
Feed Re extraction
(Organic Phase) Solvent
mBA,9,i mP, OP,9,i mW,9,i

Figure 8.9: Block diagram of re extraction

Applying mass balance to penicillin

Mass of Penicillin in feed = Mass of Penicillin in raffinate
+
Mass of penicillin in extract

51
m P ,OP ,9 , i = m P ,OP ,9 , o +m P , AP ,9 , i
Considering extraction efficiency
m P , AP ,9 , o = mP ,OP ,9 , i × 90 %
= 12.08 × 90 %
= 10.87 kg/day
Therefore mP ,OP ,9 , o = 12.08 - 10.87
= 1.21 kg/day
Since water and butyl acetate are immiscible
m BA ,9 ,i = m BA ,9 , o
m BA ,9 , o = 28.35 kg/day
Since the extract and the raffinate are in equilibrium
( x¿¿ p)OP = Distribution Coefficient
¿
(x ¿¿ p) AP ¿
mP ,OP , 9 ,o = 0.1
m P ,OP , 9 ,o +mBA ,9 , o
mP , AP , 9 ,o
mP , AP ,9 , o +mW ,9 , o
1.21 = 0.1
1.21+28.35
10.87
10.87+ mW ,9 , o
m W , 9 ,o = 15.73kg/day
Since water and butyl acetate are immiscible
m W , 9 ,i = m W , 9 ,o
m W , 9 ,i = 15.73kg/day

Component kg/day
Penicillin 12.08
Butyl acetate 28.35
Total 40.44

Component kg/day
Water 15.73
Total 15.73 Component kg/day
Penicillin 10.87
Water 15.73
Total 26.61

Component kg/day
Penicillin 1.21
Butyl acetate 28.35
Total 29.56 52
 Figure 8.10: Summary of mass flow rates of the re extractor

8.6. Precipitation

8.6.1. Introduction
In precipitation, the penicillin enzyme is reacted with potassium acetate in a mixer settler
equipment, where the following reaction takes place.

Pen-COOK + CH3COOH
Pen-COOH + CH3COOK
Penicillin Acetic Acid
Penicillin Potassium acetate Potassium salt

(Peterfi et al 1999)

Due to the high concentration of Pen-COOK formed, it precipitates until the dissolved concentration
of Pen-COOK is equal to the critical concentration of precipitation at the relavent temperature.

The dissolved Penicillin potassium salt is present in water in the following form.

Pen-COOK Pen-COO- + K+

8.6.2. Design conditions

Table 8.6: Input mass flow rates to the precipitator and densities adapted from Najafpour 2007

Component Mass flow rate (kg/day) Density /(kg/L)

Penicillin 10.87 3.42
Water 15.73 1.00
Total 26.61 -

53
  Operation temperature = 5 0C (Heinzel et al 2006)
 Critical solubility of Penicillin potassium salt at 50C = 0.0502mol/L (Peterfi et al 1999)
 Purity of potassium acetate = 98% (Potassium Acetate 2008)
 Density of potassium acetate = 1.57 kg/L (Potassium Acetate 2008)

Table 8.7: Molar masses of different components

Component Molar mass/(kg/kmol)

Penicillin 3.42
Water 18
Potassium acetate 98
Potassium ion 39
Acetate ion 59
Acetic acid 60
Penicillin ion 449
Potassium Penicillin Precipitate 488

8.6.3. Mass Balance

nPA,10,i
VPA
nPI,10,o n,W,10,o
nP,10,i nA,10,o nK,10,o
nW,10,i nPP,10,o nAA,10,o
UNIT 10
Vi Precipitation Vo

Figure 8.6: Block diagram for precipitation

Volume calculation

Vi = V P ,i +V W , i
= m P ,10 , i m W ,10 ,i
+
ρP ρW
= 10.87 15.73
+
3.42 1.00
= 18.91 L/ day
= mP ,10 , i
n P ,10 , i
MP

54
 = 10.87× 1000
350
= 31.07 mol/day
From stoichiometry
n P ,10 , i :n PA ,10 ,i = 1:1
Therefore n PA ,10 ,i = 31.07 mol/day
Potassium penicillin formed n PP = 31.07 mol/day
Acitic acid formed n AA = 31.07 mol/day

The total acetic acid formed leaves the precipitator dissolved in water
Therefore n AA ,10,0 = 31.07 mol/day
m AA, 10,0 = n AA ,10,0 × M AA
= 31.07× 60
1000
= 1.86 kg/day

= nPA ,10 ,i × M PA
m PA ,10 ,i
1000× Purity
= 31.07 × 98
1000× 0.98
= 3.11 kg/Day
= m PA,10 , i
VPA
ρ PA
= 3.11
1.57
= 1.98 L/day
Total input volume = VPA + V i
VT = 1.98 + 18.91
= 20.89 L/day
Concentration of penicillin salt = nPP
formed VT
= nPP
VT
= 31.07
20.89
= 1.48 mol/L
The above calculated value exceeds the critical concentration at precipitation. Therefore,
precipitation takes place
Concentration of dissolved penicillin =
0.0502 mol/L (Critical concentration)
salt leaving the precipitator
The above concentration is equal to the concentratios of potassium and penicillin ions
dissolved
Therefore n PI ,10,0 = 0.0502 × V W

55
For the above calculation, the volume of the exit stream is assumed to be equal to the
volume of the water input, since a majority of penicillin precipitates reducing the liquid
volume in the precipitator
n PI ,10,0 = 0.0502 × 15.73
= 0.79 mol/Day
Therefore n K , 10,0 = 0.79 mol/Day
m K ,10,0 = n K , 10,0 × M K
= 39
0.79 ×
1000
= 0.03 kg/day

mPI , 10,0 = n PI ,10,0 × M PI

= 349
0.79 ×
1000
= 0.28 kg/day

Applying molar balance to penicillin

[ Moles ofinputpenicillin ] =
[ Moles of penicillin + Moles of penicillin
salt precipitated ] [ dissolved ]
n P ,10 , i = n PP ,10 , o+¿n ¿
PI ,10,0

n PP ,10 , o = n P ,10 , i−n PI ,10,0

= 31.07 – 0.79
= 30.28 mol/day

m PP , 10 ,o = n PP ,10 , o × M PP
= 30.28× 388
1000
= 11.75 kg/day

Applying mass balance to water

=
Water content
[
But
¿ ] [
Water input ¿ ℜextractor ¿ + ¿ potassium
acetate ] [ Water output ]

Water content =
¿ potassium mPA ,10 ,i × ( 1−Purity )
acetate
= 3.11× (1-0.98)
= 0.06

Therefore m w ,10,0 = m w ,10 ,i + 0.06

= 15.73 + 0.06
= 15.79 g/day

56
 8.6.4 Energy Balance
Prediction of Formation Enthalpy

According to Perry RH 1934, the heat of formation at the standard conditions is given by the
following equation.

∆ H f 298 = n
68.29 ∑ ¿ ∆ Hi Equation 1
i=1
Where
∆ H f 298 = Enthalpy of formation at 298 K in kJ/mol
n = Number of different atomic groups contained in the
molecule
Ni = Number of atomic group i contained in the molecule
∆ Hi = Numerical value of atomic group i obtained from the
Table 8.8

With reference to Perry RH 1934 and considering the molecular structure of penicillin V as per
Figure 1.1 the following table gives the data regarding heat of formation.

Table 8.8: ∆ Hi of different atomic groups

Type of the group Number of Groups ∆ Hi

2 -76.45
1 -20.64

2 29.89

2 82.23

1 -426.72
1 41.87
2 123.34
1 -138.16

2 -133.22

From equation 1

57
∆ H f 298 of PenicillinV = 68.29+ ( 2 ×−76.45 ) + (−20.64 )+ ( 2× 29.89 )

+ ( 2 ×82.23 )+ (−426.72 ) + ( 41.87 )+ (2 ×123.24 )

+ ( 138.16 ) + ( 2 ×−133.22 )
= -360.78 kJ/mol
Similarly
∆ H f 298 of Potassiumacetate = -722.6 kJ/mol
∆ H f 298 of Penicillin potassim salt = -523.9 kJ/mol
∆ H f 298 of acetic acid = -483.88 kJ/mol

Prediction of the Specific heat capacity

From Hurst and Harrison Method as per Perry RH 1934, the specific heat of a constituent can be
predicted from the following equation.

n
Cp =
∑ ¿ ∆ Ei Equation 2
i
Where
Cp = Molar heat capacity of the component at 298 K in J/mol.K
n = Number of different atomic groups contained in the
molecule
Ni = Number of atomic group i contained in the molecule
∆ Ei = Numerical value of atomic group i obtained from the
Table 8.9
With reference to Perry RH 1934 and considering the molecular structure of penicillin V as per
Figure 1.1 the following table gives the data regarding molar heat capacity.

Table 8.9: Data of different atomic groups

Atom Number of atoms ∆ Ei

C 16 10.89
H 18 7.56
O 5 13.42
N 2 18.74
S 1 12.36

From equation 2
Cp of Penicillin V at 298 K = ( 16 ×10.89 ) + ( 187.56 )+¿ 13.42) + (2×18.74 ¿+(12.36)
= 427.26 J/mol.K

58
Simillarly
Cp of Potassium acetate at 298 K = 109.38 J/mol. K
Cp of Penicillin salt at 298 K = 448.48 J/mol.K
Cp of Acetic acid at 298 K = 123.1 J/mol.K

Considering the following precipitation reaction,

Pen-COOK + CH3COOH
Pen-COOH + CH3COOK
Penicillin Acetic Acid
Penicillin Heat Potassium ∆ Hr =
of reactionacetate ∆ H f Products −∆ H f reactants
Potassium salt
(Sinnot RK 2005)

∆ Hr of the above reaction at 298 K = [ (−523.9 ) + (−483.88 ) ]−[ (−360.78 ) +(−722.6 ) ]

(∆ Hf values are predicted above)

= 75.6 kJ/mol

Heat of reaction at 5 0C ∆ H r 278 K = 278

∆ H r 298 K + ∫ ∇ Cpdt
298
Where
∇ Cp = CpProducts −Cp Reactants
(Perry RH 1934)

Since the solubility of Penicillin salt produced is very less, it could be assumed that the entire salt is
in solid form. In addition, the specific heat capacities of solids and liquids remain constant near the
critical temperature of 273 K( Sinnot RK 2005). Therefore it could be assumed that the Cp values
remain constant.

Heat of reaction at 5 0C ∆ H r 278 K = 75.6 +

278

∫ [ ( 448.48+123.1 ) −( 109.38+437.26 ) ]×10−3 dt

298
(Cp values are predicted above)
= 74.9 kJ/mol
Potassium penicillin formed n PP = 31.07 mol/day
Heat absorbed during precipitation = ¿31.07)
= 2327 kJ/day

From the above calculation, it could be seen that the precipitation of the Penicillin V salt is an
endothermic reaction which absorbs heat. Since precipitation should be carried out at 5 0C or below

59
that temperature, cooling water has to be provided in order to maintain the temperature. The heat
absorbed by the reaction will result in reducing the temperature of cooling water further.

Assuming that

Cp of cooling water = 4.18 kJ/kg.K

Inlet temperature of cooling water = 50C
Outlet temperature of cooling water = 10C
Mass of cooling water required = 2327
4.18 × ( 5−1 )
= 139.17 kg/day

Component kg/batch
Cooling water 139.17
Component kg/day Total 139.17
PP 3.11
Total 3.11

Component kg/day
Potassium ions 0.03
Component kg/day
Penicillin ions 0.28
Penicillin 10.87
Water 15.79
Water 15.73
Acetic acid 1.86
SubTotal 26.61
Pen-COOK preci. 11.75
Total 29.71

Figure 8.7: Summary of mass flow rates of the precipitator

60
 8.7 Basket centrifugation

8.7.2 Introduction
Basically basket centrifugation is an equipment use centrifugal force to separate solid particles
from liquid. Centrifugation is a process, which solid particles are sediment and separated from a
liquid using centrifugal force as a driving force. Depending on the rotational speed and distance
from the axis of rotation, the centrifugal force can be many times greater than the force of gravity,
allowing even very small particles or particles slightly denser than the fluid to settle. Operations
such as cake filtration, centrifugation, and bed drying are commonly employed for this purpose
(Bloch & Soares 1998).

8.7.2 Design conditions

The assumptions made were,

 Assume isothermal operation.

 Assume there are no accumulation, spill and leakage in the system.
 Assume there is no chemical reaction taking place.
 Assume that the separated penicillin salt crystals free of Potassium Acetate and Butyl
Acetate.
 Assume that the final moisture content is 9 % wet basis.
 Assume there is no need a washing stage because required amount of water for washing is
less than water entering at the inlet.

Table 8.10: Inlet conditions to the basket centrifugal seperator

Inlet mass flow
Component
(kg/day)
Penicillin crystals 11.75

61
 Penicillin ions 0.28
Acetic acid 1.86
Potassium ions 0.03
Water 15.79
Total 29.71

 Moisture content of final

= 9 – 25 % dry basis (Filorikyan & Vylinkina 1969)
separated solid
 Yield = 99% (Heinzle.E 2006)
 Molar mass of penicillin salt = 388 kg/kmol
 Molar mass of penicillin ions = 349 kg/kmol
 Molar mass of potassium ions = 39 kg/kmol

8.7.3 Mass balance

m11,i m11,o
xP,11,i UNIT 11 xP,11,o
xW,11,i Basket Centrifugation xW,11,o

m11,e
xP,11,e

Figure 8.8: Block diagram for basket centrifugation

Apply mass balance

m¿ +m gen = mout +macc + mloss

From above assumptions

m gen= 0 , m acc =0, m loss = 0

Therefore

m¿ = m out
[mass of penicillin crystals] + [mass of = [mass of penicillin crystals] + [mass of water in

62
penicillin ions] + [mass of acetic acid] + jlkj crystals] + [mass of effluent]
[mass of potassium ions] + [mass of water]

Mass of penicillin crystals in outlet = 11.75 x 0.99

= 11.63 kg /day

mass of water in crystals = 11.63 x 0.09

= 1.05 kg/day

Total mass balance

0.03 + 0.28 + 15.79 + 1.89 + 11.75 = 11.63 + 1.05 + m 11, e

m 11, e = 17.04 kg/day

Total water balance

[Mass of inlet water with crystals] = [Mass of outlet water with crystals]+[Mass of
fdnfddf effluent water]

15.79 = 1.05+m W , 11,e

m W , 11,e = 14.74 kg /day
Total Penicillin balance

[mass of penicillin in penicillin salts at = [mass of penicillin in penicillin salts at outlet] +

inlet] + [mass of penicillin ions at inlet] hhkjh[mass of penicillin ions at outlet]

349 349
11.75 x + 0.28 = 11.63 x + 17.04 x Xp,11e
388 388
Xp,11e = 0.02

Component kg/day Component kg/day

Potassium ions 0.03 Potassium ions 0.04
Penicillin ions 0.28 Penicillin ions 0.38
Water 15.79 Water 14.75
Acetic acid 1.86 Acitic acid 1.86
Pen-COOK preci. 11.75 Total 17.04
Total 29.71
Component kg/day
Penicillin crystals 11.63
Water 1.05
Total 12.68

63
 Figure 8.9: Summary of mass flow rates of the centrifuge

8.8 Fluid Bed Dryer

8.8.1 Introduction

Drying of pharmaceutical is one of the most sophisticated and expensive process in drying
technology, because pharmaceuticals are often heat sensitive materials, oxidation of the product
can take place in presence of normal atmosphere, and the contamination of the product must be
severely avoid. Fluid bed dryers are more commonly used for drying of penicillin crystals in
pharmaceutical industry.
The penicillin crystals are fluidized by using hot air and heat transfer and mass transfer occur
simultaneously inside the fluidized bed column. Dried product is taken out from the bottom of the
dryer after it comes to desired condition.

8.8.2 Design conditions

Wet solid at 50C is fed to the fluid bed dryer which contains 9% moisture on dry basis and it should
be reduced to 0.5% moisture on dry basis. 11.63 kg of penicillin crystals is the throughput per
batch. It is essentially to obtain a temperature for dried penicillin crystals which is below the

denaturation temperature of penicillin (56.80C ) crystals.

The assumptions are,

 Amount of dust penicillin in outlet gas stream is negligible. Therefore, amount of inlet feed
penicillin crystals is equal to amount of outlet dried penicillin crystals. There is no water loss.
 It is essentially assumed that the final solid temperature only rises up to dry bulb temperature
of outlet gas stream.
 Heat loss from the wall is taken as 5% of the enthalpy of inlet air (Mujudar, 2004).

The required data are,

 Specific heat capacity of Penicillin

crystal = 0.85 kJ/kg.K

64
  Average Specific heat capacity of water = 4.2 kJ/kg.K

 Specific heat capacity of air = 1 kJ/kg.K

 Latent heat of vaporization of water = 2370 kJ/kg (Mujudar, 2004)

8.8.3 Mass and energy balance calculations

UNIT 12
Fluid Bed
, Dryer

Figure 8.10: Mass balance for the fluid bed dryer

Notation:
Gg – Mass of dry air
Fs – Mass of dry Penicillin

Mass balance for continuous fluid bed dryer –well mixed

Water balance for the dryer

Amount of water removed form the solids = Total additional moisture in outlet gas stream

F s ( X ¿ −X out ) =Gg ( Y ¿ −Y out )

11.6 ( 0.09−0.005 )=G g ( Y out −0.005 )

11.63 ( 0.09−0.005 )
Gg =
( Y out −0.005 )
65
 (0.9885+Gg 0.005)
Y out =
Gg

Heat balance for continuous fluid bed dryer –well mixed

Energy Energy Energy Energy

[ ][ ][ ][ ][
¿ the + ¿ the
input air input solid
stream stream
= ¿ the
output air
stream
+ ¿ the
output
solid stream
Energy
+ loss ¿ the wall ¿
¿ ]
F s H s ,∈¿+G g H g,∈¿=F H + Gg Hg ,out +Q w ¿ ¿
s s ,out

Enthalpy for solid inlet and outlet can be obtained from following equations respectively

H s ,∈¿=¿ ( C ps + X¿ C l ) T s ,∈¿ ¿ ¿
¿

H s , out =¿ ( C ps+ X out Cl ) T s ,out ¿

Enthalpy for gas inlet and outlet can be obtained from following equations respectively

H g ,∈ ¿=¿ ( C pg +Y ¿ C l ) T g,∈¿¿ ¿
¿ + λY¿

H g ,out =¿ ( C pg +Y out Cl ) T g , out ¿ + λ Y out

Since Q w = 0.05G g H g ,∈ ¿¿ above equation can be simplified as follows

F s H s ,∈¿+G g H g,∈¿=F H + Gg Hg ,out +0.05 G g H g,∈ ¿ ¿ ¿ ¿

s s ,out

F s H s ,∈¿+0.95 G H g g,∈¿=F s H s ,out +G g Hg ,out ¿ ¿

Finding enthalpy of inlet and outlet for both streams

H s ,∈¿=¿ ( C + X¿ C l ) T s ,∈¿ ¿ ¿
¿
ps 66
 H s ,∈¿=¿ (0.85 +0.09 ×4.2 ) 5 ¿ ¿

H s ,∈¿=¿6.14 KJ / kg¿ ¿

For outlet solid enthalpy

H s , out =¿ ( C ps+ X out Cl ) T s ,out ¿

H s , out =¿ ( 0.85+ 0.005× 4.2 ) 28 ¿

H s , out =¿ 24.39 kJ / kg ¿

For inlet gas enthalpy

H g ,∈ ¿=¿ ( C pg +Y ¿ C l ) T g,∈¿¿ ¿
¿ +λY¿

H g ,∈ ¿=¿ ( 1+0.005 ×4.2 )67 ¿ ¿ +2370 × 0.005

H g ,∈ ¿=¿80.26 kJ / kg¿ ¿

For outlet gas enthalpy

H g ,out =¿ ( C pg +Y out Cl ) T g , out ¿ + λ Y out

Substitute for Y out in terms of Gg

(0.9885+ Gg 0.005) (0.9885+G g 0.005)

{
H g ,out =¿ 1+4.2 ×
Gg
28 ¿ + 2370 ×
Gg }
116.25 +Gg 0.588 2342.86+11.85 G g
H g ,out =¿ 28+
{ ( Gg
¿ +
Gg )} ( )
Substituting all values for following equation
F s H s ,∈¿+0.95 G H
g g,∈¿=F s H s ,out +G g Hg ,out ¿ ¿

11.63 × 6.14+0.95 ×G g × 80.26=11.63 ×24.39+ 40.438 G g +2459.1

Gg =76.01 kg

67
Absolute humidity at inlet

(0.9885+76.01× 0.005)
Y out =
76.01

Y out =0.018 kg/kg

Enthalpy of outlet gas stream

116.25 +76.01× 0.588 2342.86+11.85 ×76.01

{ (
H g ,out =¿ 28+
76.01
¿ + )} ( 76.01 )
H g ,out =¿ 72.79 kJ /kg ¿

Amount of water removed = F s ( X ¿ −X out )

= 11.63 ( 0.09−0.005 )

= 0.9885 kg

Amount of inlet water in solid stream = 11.63 × 0.09

= 1.0467 kg

Amount of water in outlet solid stream = (1.0467 -0.9885)

= 0.0582 kg

Total energy in input air stream = G g H g ,∈ ¿¿

= 76.01× 80.26

= 6100.36 kg

Total energy in output air stream = G g H g ,out

= 76.01× 72.79

= 5532.82 kJ

Total energy in input solid stream = F s H s ,∈¿¿

= 11.63 ×6.14

68
 = 71.40 kJ

Total energy in output solid stream = F s H s ,out

= 11.63 ×24.39

= 283.63 kJ

Total energy loss = 355.31 kJ

This calculation is done as a trial and error method by changing the inlet and out temperature of air
stream to satisfy with required energy to remove water from the penicillin crystals. Then, finally it

is obtained 670C as inlet temperature and 28 0C as outlet temperature.

Component kg/day
Hot air 76.01
Total 76.01

Component kg/day Component kg/day

Penicillin crystals 11.63 Penicillin crystals 11.63
Water 1.05 Water 0.06
Total 12.68 Sub total 11.69

Component kg/day
Hot air 76.01
Water 0.99
Total 77

Figure 8.11: Summary of mass flow rates of the dryer

69
 9. Summary

The summery of the overall mass balance for the entire process is tabulated in the following pages.
Since the plant operates separately on batch and continuous processes in upstream and
downstream processing stages, the mass flow rates are calculated separately for both the processes

70
71
 Batch Process

Figure 9.1: Process flow diagram of the batch process

72
 Table 9.1: Mass flow rates of the batch process

  Component
 

Phenoxy Acetic Acid

 

Carbon Dioxide
Sulfuric Acid

Ammonia

Penicillin

Bio mass
Glucose

Oxygen

Water

Total
1 127.02 28.81 15.30 51.40 23.33 - - 635.50 - 881.36
Line number

2 127.02 28.81 15.30 51.40 23.33 - - 635.50 - 881.36

3 127.02 28.81 15.30 51.40 23.33 - - 635.50 - 881.36
4 - - - - - - 36.96 - - 36.96
5 19.06 4.32 2.30 7.71 3.50 87.50 - 689.00 31.01 844.47

All values in kg/batch

73
 Continuous Process

Figure 9.2: Process flow diagram of the continuous process 74

 Table 9.3: Mass flow rates of the continuous process

  Component

Phenoxy Acetic
 

Potassium

Penicillin crystals
 

Potassium ions

Penicillin ions
Butyl Acetate
Sulfuric acid

Aetic Acid
Ammonia

Filter Aid
Penicillin

Biomass

Glucose
Water

Total
Acetate
Acid
6 13.84 108.98 4.90 3.01 0.68 0.36 1.22 - - - - - - - 133.00
7 - - - - - - - - - - - 0.15 - - 0.15
8 0.42 3.27 4.90 0.09 0.02 0.01 0.04 - - - - Trace - - 8.75
9 13.42 105.85 - 2.92 0.66 0.35 1.18 - - - - - - - 124.40
10 13.42 105.85 - 2.92 0.66 0.35 1.18 - - - - - - - 124.40
11 - - - - 0.01 - - - - - - - - - 0.01
12 13.42 105.85 - 2.92 0.67 0.35 1.18 - - - - - - - 124.41
13 - - - - - - - 28.35 - - - - - - 28.35
Line number

14 1.34 105.85 - 2.92 0.67 0.35 1.18 - - - - - - - 112.32

15 12.08 - - - - - - 28.35 - - - - - - 40.44
16 - 15.75 - - - - - - - - - - - - 15.75
17 1.21 - - - - - - 28.35 - - - - - - 29.56
18 10.87 15.73 - - - - - - - - - - - - 26.61
19 - - - - - - - - 3.11 - - - - - 3.11
20 - 15.79 - - - - - - - 1.86 11.75 - 0.03 0.28 29.71
21 - 14.75 - - - - - - - 1.86 - - 0.04 0.38 17.04
22 - 1.05 - - - - - - - - 11.63 - - - 12.68
23 - 0.99 - - - - - - - - - - - - 0.99
24 - 0.06 - - - - - - - - 11.63 - - - 11.69
All values in kg/day

75
 10. List of References

Bloch, H. and Soare, C. 1998, Process Plant Machinery , Second Edition, pp. 631-651.

Boerio-Goates, J 1991 , ‘Heat-capacity measurements and thermodynamic functions of crystalline α-

D-glucose at temperatures from 10 K to 340 K’, The Journal of Chemical Thermodynamics , vol. 23,
no. 5 , pp. 403-409.

Candan, G, Taşkin, M. & Yazgan, H 2014, “Demand Forecasting in Pharmaceutical Industry”.,Journal

of Military and Information Science, pp. 41-49.

Carmody, O, Frost, R, Xi, Y & Kokot S 2006, ‘Adsorption of hydrocarbons on organo-clays—

Implications for oil spill remediation’, Journal of Colloid and Interface Science, vol. 305, pp. 17-24.

Chemical Engineering II. Calculation exam 20.12.2007. Available from :

< https://noppa.aalto.fi/.../KE-42_3200_2007-12-20.pdf> [21 April 2015].

Filorikyan, DF , Vylinkina, ES 1969 , Drying Pasty Streptomyain or Penicillin Preparations in the

fluidized state , pp. 45-49.

Gopalakrishnan, KK & Detchanamurthy S 2011, ‘Effect of Media Sterilization Time on Penicillin G

Production and Precursor Utilization in Batch Fermentation’ Bioprocessing & Biotechniques 1, no.3.

Haar, L & Gallagher, JS 1978, ‘ Thermodynamic Properties of Ammonia’ ‘J. Phys. Chem’, vol. 7, no. 3,
pp. 635-792.

Heinzle, E, Biwer, AP & Cooney, CL 2006, Development of Sustainable Bio Processes, Kohn Wiley and
Sons Ltd, Chichester.

Laurence, DR & Bennet PN 1980, Clinical Pharmacology, 5th edn, English Language Book Society,
Churchil Lavingstone.

Moyer, AJ 1945, Method for production of penicillin, US Patent 2,442,141.

Najafpour, GD 2007, Biochemical Engineering and Biotechnology, Elsavier, Amsterdam.

76
Perry, RL 1934, Perry’s Chemical Engineers’ Handbook, 7th edn, McGraw Hill, New York.

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Contribution by Team Members

E/09/151 Fermentation

E/10/006 Filtration, Cooling

E/10/103 Acidification, Re extraction, Precipitation

E/10/258 Stelilization, Cooling, Extraction

E/10/247 Basket Centrifugation

E/10/267 Fluid Bed Drying

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