Crystallization process

Introduction

Crystallization is the formation of a solid structure, known as a crystal, from a liquid or gas. This
happens when the concentration of a chemical in a solution or melt rises above normal, resulting
in the formation of organized structures. Typically, the procedure begins with a solution or melt
containing the desired material. By varying parameters such as temperature or pressure, the
solution becomes supersaturated, which means it holds more dissolved material than it should.
This causes the development of nuclei, which are tiny solid particles that evolve into larger
crystals. Conditions are carefully manipulated to control growth. Once the crystals have reached
the proper size and quality, they are generally separated from the remaining liquid by filtration. To
produce the final product, the gathered crystals may go through additional stages such as washing
to eliminate contaminants and drying. Crystallization is a critical process in many sectors for
producing pure compounds with certain qualities, and its effectiveness is dependent on variables
such as temperature, pressure, and the pace of cooling or evaporation.

The crystallization stage of penicillin synthesis is critical because it converts the extracted penicillin
solution into a refined and powerful form. After being reextracted stage, the penicillin solution
goes through a process to concentrate and improve its composition. Controlled dehydration at 30
°C and 5 kP reduces the water content by 80%. Following the addition of potassium acetate and
cooling to 2 °C gradually, the critical crystallization of penicillin as potassium penicillin salt begins.
This step is critical in getting the appropriate antibiotic purity and quality.

Fig: The block flow diagram of crystallization process

x1 = mass of penicillin in extracted solvent solution

x2 = mass of penicillin after dehydration
x3 = mass of penicillin potassium in crystals
x4 = mass of remain penicillin in solution after crystallization
y1 = mass of water in extracted solvent solution
y2 = mass of water after dehydration
y3 = mass of water in crystals
y4 = mass of remain water in solution after crystallization
w = mass of water vapor
z1 = mass of impurities in extracted solvent solution
z2 = mass of impurities after dehydration
z3 = mass of impurities crystals
z4 = mass of remain impurities in solution after crystallization
k1 = mass of potassium acetate added
k2 = mass of potassium acetate remaining

Dehydration process
Introduction

In this stage, basically excess water solvent is removed from the solution and concentrates the
penicillin molecules and saturated the penicillin in the solution. Dehydration process is basically
done in 3 methods. They are,

 Evaporation at high temperature

Increased the temperature of the solution and reach boiling point.
 Evaporation at low temperature
Applying a vacuum lowers the boiling point of the solvent, allowing dehydration at lower
temperatures, protecting sensitive molecules.
 Freeze drying
Freezes the solution, then sublimates the frozen solvent directly into vapor under vacuum.

By dehydration process, efficiency of crystallization process is increased and resource friendly

because concentrated solutions require less overall volume to handle and it helps to achieve
desired crystal quality and yield.

Mass Balance for Dehydration process

Assumptions and Justifications

  Assumed dehydration is done by evaporation at low temperature technique.
Penicillin in the aqueous phase has a stable temperature range of 10 – 40 °C (Heilig, 1994).
Preventing degradation of penicillin, the solution should be concentrated by aqueous
evaporation. Therefore, among the dehydration methods, low temperature evaporation
should be chosen. For that reduce the pressure of solution about to 5kPa
(www.engineeringtoolbox.com, n.d.) and maintain temperature at 30 °C.

 Assumed that penicillin is not removed with water vapor molecules.

Melting point of Penicillin G = 214 – 217 °C @ room temperature (PubChem, n.d.).
According to literature, there is no evidence to remove penicillin with water vapor in
dehydration process, therefore loss of penicillin in dehydration process has a less
probability.

 Assumed that impurities are not removed with water vapor molecules.
According to literature, there is no evidence to remove impurities with water vapor in
dehydration process, therefore loss of impurities in dehydration process has a less
probability.

 Assumed that water evaporates 80% (w/w) from water amount in solution.

Process Conditions

Temperature : 30°C
Pressure : 5kPa
Operating time duration : 1hour

Prediction of Physical properties

Table Error! Use the Home tab to apply 0 to the text that you want to appear here.-1 Prediction of physical properties of energy
balance of dehydration

Component Value Reference

Molar weight of Penicillin 334.4 g/mol (PubChem, n.d.)

Mass Balance Calculations

Table Error! Use the Home tab to apply 0 to the text that you want to appear here.-2 BFD for mass balance

Basis : per day

Mass¿ + Mass generated =Massout + Massloss + Mass accumulation + Massconsumption

0 0 0 0

Assumed that there is no any mass loss, mass generation or mass accumulation throughout the
extraction process.

Mass¿ =Massout
for penicillin:

x1 = x2

for water:

y1 = y2+w

for impurities:

z1= z2

Assumed that water evaporates 80% (w/w) from water amount in solution

w = 0.8 y1

Results

Inputs Outputs(Vapor) Outputs

Penicillin x1 - x2

water y1 w y2

impurities z1 - z2

Inputs(kg) Outputs (Vapor)(kg) Outputs(kg)

Penicillin 679.55 - 679.55

water 8857.95 7086.36 1771.59

impurities 8.87 - 8.87

7086.36 2460.01
Total 9546.37 9546.37

Energy Balance for dehydration process

Assumptions and Justifications

 It assumed that process is operated under steady state condition.

 No heat loss or grain
Heat losses or gains to the surroundings are assumed to be negligible. This assumes that
the crystallizer is well-insulated, and the energy input is precisely balanced with the energy
requirements.
 It is assumed that the heat required for solution heating of impurities in solution is
neglected.
 Assumed that MP steam is used to heat the solution 10 °C to 30°C.

When hot water is used, required high mass of hot water for heating process. Therefore,
MP steam is used to heat the solution.
Temperature of steam – 250 °C
MP steam pressure range : 3 – 30 bar
MP steam temperature range : 200-300 °C
(Quora, 2019)

 Assumed that Cp value of penicillin is not vary with temperature range 2-30 °C because of
data availability.

Data/prediction of Physical Properties

Physical Properties Value Unit Reference

Specific heat capacity of the penicillin @10°C 133.14 (kJ/kg°C) (www.chegg.com, n.d.)
(Engineering ToolBox, 2004)
Specific heat capacity of the water @10°C 4.2 (kJ/kg°C)
Specific heat capacity of the penicillin @30°C 133.14 (kJ/kg°C) (www.chegg.com, n.d.)
Specific heat capacity of the water @30°C 4.18 (kJ/kg°C) (Engineering ToolBox, 2004)
Final temperature of solution after heating (T_final) 30 °C
Initial temperature of solution before heating (T_initial) 10 °C
Latent heat of vaporization of water at 30°C (L_vap:) 2429.8 kJ/kg (Engineering Toolbox, 2014)
Enthalpy of MP steam 2801.5 (kJ/kg) (Steam table)
Specific heat capacity of the water @40°C 4.18 (kJ/kg°C) (Engineering ToolBox, 2004)
Initial temperature of hot water assumed (Tw_initial) 95 °C
Assumed final temperature of hot water assumed (Tw_final) 35 °C

Calculations

Energy¿ + Energy generated =Energyout + Energy loss + Energyaccumulation + Energyconsumption

0 0 0 0

Initial temperature of solution before heating (T_initial) - 10 °C

Final temperature of solution after heating (T_final) - 30 °C

Energy out

Heat required for water evaporation:

∆Q_vap = mw × L_vap

= 17218436.77 kJ

Heat required for solution heating:

∆Q_heating = m_penicillin (C_p_penicillin@30°C × T_final - C_p_penicillin@10°C × T_initial ) +

m_water ( C_p_water@30°C × T_final - C_p_water@30°C × T_final)
 = 2548248.66 kJ

Energy in

Required heat supply from heating coil:

Q_heating = ∆Q_heating + ∆Q_vap

= 19766.69 MJ

Calculate the required mass of hot stream:

When using the hot water for that purpose;

 Assumed that initial temperature of hot water(Tw_initial) - 95 °C

 Assumed that final temperature of hot water(Tw_final) - 35 °C

Q_heating = m_water (C_p_water@35°C× Tw_final - C_p_water@95°C× Tw_initial)

m_water = Q_heating / (C_p_water@35°C× Tw_final - C_p_water@95°C× Tw_initial)

= 77928.978 kg/hr

This value is too high. Therefore, MP steam is used.

When using MP steam for heat supplied;

Temperature of steam = 250 °C

Required steam quantity heating feed = Q_heating / Enthalpy of MP steam

= 7055.752 kg

Assumed that 10% of the heat loss through the jacket,

Required steam quantity for steam jacket = 7055.752*10%

= 7761.328 kg
Results

Inputs(MJ) Outputs(MJ)

heat supply from heating jacket 19766.69

heat for solution heating 2548.25

heat for water evaporation 17218.44

Total 19766.69 19766.69

Crystallization process
Introduction

After dehydration, potassium acetate is added to the concentrated solution. When added potassium
acetate, it increases the ionic strength of the solution and reduces solubility of penicillin G in the solution.
As the solubility of penicillin G decreases, it becomes less stable in the solution and starts to precipitate out
as crystals. As well as, temperature of solution should be cooled down gradually to the temperature range
between 0-5 °C using agitator.

Mass Balance

Assumptions and Justifications

 Assumed that penicillin crystal purity is 85% (w/w)

Penicillin purity is taken as 85% because of above statement purity should not be less than 85%
(Heilig, 1994).

 Assumed that, yield is 98% (mol/mol)

In industry crystallization yield is approximately 99%. Therefore, assumed that yield of penicillin is
98 % (Misailidis and Petrides, 2020).

 Assumed that percentage of impurities in penicillin crystals is 1% (w/w)

 As an antibiotic, the amount of impurities in penicillin should be reduced. But the final product can
not be taken as zero impurities at all. Therefore, I assumed that the impurity contained 1% of final
penicillin salt crystals.

 Assumed that potassium acetate to penicillin ratio = 1.45

The selection of a potassium acetate to penicillin molar ratio of 1.45:1 in the butyl acetate phase is
supported by the available literature in penicillin production down process. While direct
information on the aqueous phase ratio may not be readily accessible, assumed that potassium
acetate to penicillin ratio in aqueous phase is equal to potassium acetate to penicillin ratio in butyl
acetate phase. (Guan, Zhu and Mei, 1996)

 It is assumed that the process is operated under steady-State condition.

Data/prediction of Physical Properties

 Intput (PenicillinG) formula is C16H18N2O4S

 Output (crystals) formula is C16H17KN2O4S

 Molar weight of Potassium acetate = 98.15 g/mol (www.vedantu.com, n.d.)

 Molar weight of Penicillin crystals = 372.5 g/mol (www.scbt.com, n.d.)

 Molar weight of potassium = 39.1 g/mol (Wikipedia Contributors, 2019)

 Molar weight of hydrogen = 1 g/mol (s.r.o, n.d.)

 Molar weight of acetic acid = 60.05 g/mol (PubChem, 2019)

Calculations

0 0 0 0
 Mass¿ =Massout

For penicillin:

x2 = x3+x4

For water:

y2 = y3+y4

For impurities:

z2 = z3+z4

assuming that yield is 98%,

x3 = 0.98*x1*Molar mass_pen.crystals/Molar mass_penicillin

assuming that impurities are 1% of pencillin crystals,

0.01 = ¿) 1

assuming that purity is 85%

x3
0.85 = ( ) 2
x 3+ y 3+ z 3

From 1 and 2 equations:

99
y3 = x3 ( −1 ¿
85

1
z3 = x3 ( )
85
For potassium acetate:

assuming that potassium acetate is added to the solution in a ratio of 1.45:1,

x2
k1 = ( ) M_potassium acetate*1.45
M penicillin

= 289.21 kg

k2 = ¿) *M_potassium acetate*0.45

= 89.75 kg

molar of penicillin output = ¿)

molar of penicillin output = ¿)

Results

Inputs Outputs(crystals) Outputs(remain solution)

Penicillin x2 x3 x4
water y2 y3 y4
Potassium Acetate k1 k2
Impurities z2 z3 z4

Inputs(kg) Outputs(crystals)(kg) Outputs(remain solution)(kg)

Penicillin 679.55 665.96 13.59
water 1771.59 122.28 1649.31
Potassium Acetate 289.21 89.75
Impurities 8.87 8.63 0.24
Acitic acid 123.59

Penicillin potassium salt 741.83

872.74 1876.48
Total 2749.22 2749.22

Energy Balance

Assumptions and Justifications

 Assumed that crystallization process is at 2 °C because crystallization is most efficiently performed

at 2 °C. (Bienkowski, Lee and Byers, 1988)
 Assumed that Cp value of penicillin is not vary with temperature range 2-30 °C because of
data availability.

 Assumed that crystallization enthalpy of NFT(nitrofurantoin) antibiotic and crystallization enthalpy

of Penicillin salt are equal.
Because of crystallization enthalpy of Penicillin salt is not available in literature, I assumed that
crystallization enthalpy of NFT(nitrofurantoin) antibiotic and crystallization enthalpy of Penicillin
salt are equal.

Fig: Structure of NFT and penicillin

 Assumed that used R134a temeperatures as follows,

 Initial temperature of R134a @ 84.3kPa(T_initial) - -30°C

 Final temperature of R134a (T_final) - 0°C

Boiling point of R134a at 100kPa is -26.1 °C (Product Information, n.d.). Therefore, initial and
final temperatures should be these range.
Data/prediction of Physical Properties
Physical property Value Unit References

enthalpy of O-H bond 467 kJ/mol (Song and Le, 2019)

(Standard Enthalpy of Formation

K ions(aq) -251.2 kJ/mol * for Various Compounds, n.d.)

(Standard Enthalpy of Formation

H ions(aq) 0 kJ/mol * for Various Compounds, n.d.)

(PROPERTIES OF ATOMS,
enthalpy of O-K bond 239 kJ/mol RADICALS, AND BONDS, 2004)

average enthalpy for bonding 23.2 kJ/mol

Specific heat capacity of the penicillin (www.chegg.com, n.d.)

@30°C(Cp_penicillin@30°C) 133.14 (kJ/kg°C)

Specific heat capacity of the water (Engineering ToolBox, 2004)

@30°C(Cp_water@30°C) 4.18 (kJ/kg°C)

Specific heat capacity of the potassium (Wikipedia, 2022)

acetate@30°C(Cp_PA@30°C) 109.38 (kJ/kg°C)

Specific heat capacity of the penicillin

@2°C(Cp_penicillin@2°C) 133.14 (kJ/kg°C)

crystallization enthalpy of penicillin potassium

salt @ 25 °C (delta_H_cry of PS) -146.5 kJ/mol

Specific heat capacity of the water (Engineering ToolBox, 2004)

@2°C(Cp_water@2°C) 4.22 (kJ/kg°C)

Assuming specific heat capacity of the potassium

acetate@2°C(Cp_PA@2°C) 109.38 (kJ/kg°C)

Initial temperature before cooling(T_initial) 30 °C

Final temperature after cooling(T_final) 2 °C

Enthalpy of PA solubility -15.3 kJ/mol (Manin et al., 2021)

Specific heat capacity of the R134a(liquid)@-30°C (Huber and Ely, 1992)

& 84.3kPa (C_p_R134a@-30°C) 1.26 (kJ/kg°C)

Specific heat capacity of the R134a(liquid) @- (Product Information, n.d.)

26.1°C & 100kPa ([email protected]°C) 1.268 (kJ/kg°C)

(Product Information, n.d.)

Specific heat capacity of the R134a(gas) @-
26.1°C & 100kPa ([email protected]°C) 0.7876 (kJ/kg°C)

Specific heat capacity of the R134a @0°C & (Product Information, n.d.)
100kPa (C_p_R134a@0°C) 0.8169 (kJ/kg°C)

Initial temperature of R134a @

Calculations

Energy¿ + Energy generated =Energyout + Energy loss + Energyaccumulation + Energyconsumption

0 0 0 0

Heat for mixture of solution

Q=(m 1C p 1+ m1 C p 2 +…+ mnC pn)× ΔT

 Initial temperature before cooling(T_initial) - 30 °C

 Final temperature after cooling(T_final) - 2 °C

Energy out

Energy for solution cool:

Q_solution = m_penicillin (C_p_penicillin@2°C * T_final - C_p_penicillin@30°C * T_initial ) +m_water

( C_p_water@2°C * T_final - C_p_water@30°C * T_final)+ m_potassium_acetate
( C_p_PA@2°C * T_final - C_p_PA@30°C * T_final)

= 1461584.995 kJ

energy for bond:

 average enthalpy for bonding - 23.2 kJ/mol
calculations:
O-H + K+ O-K + H+

ΔH_bond = ΔH_O-K + ΔH_H+ -( ΔH_O-H + K+)

= 239+0 – (-251.2 + 467)

=23.2 kJ/mol

Q_bond = ΔH_bond *Molar_penicillin

= 46202.63972 kJ

energy for crystallization of penicillin salt :

Q_crys = ΔH _cry of PS*penicillin_molar

= -291.7537379 kJ

energy of dissolution of potassium acetate (KC2H3O2) in water:

Q_diss = ΔH_PA solubility* potassium acetate molar

= -45.08316862 kJ

Comparing other output energies, heat of dissolution of potassium acetate (KC2H3O2) in water is small
value. Therefore, this energy is neglected.

Energy in

cooling refrigerant energy:

Q_refr = m_R134a ((cp_R134a@0°C *T_final - [email protected]°C *T_BP) + Latent heat +

([email protected]°C *T_BP - cp_R134a@-30°C *T_initial))

required mass of R134a = Q_refr / ((cp_R134a@0°C *T_final - [email protected]°C *T_BP) +

Latent heat + ([email protected]°C *T_BP - cp_R134a@-30°C *T_initial))

= 5015.181845 kg

Required mass rate of R134a = required mass of R134a / operating time

 = 5015.181845 / 3

= 1671.727282 kg/hr

Results

Inputs(MJ) Outputs(MJ)
1215.98881
R134a energy 4
heat of dissolution of potassium acetate in water -0.04508316862
solution heat change 1461.584995
Energy for bond 46.20263972
energy for crystallization -291.7537379
1215.98881
4 1215.988814

32.1863797
work done by motor_agitator 7

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