Design of an integrated fermentation-crystallization process applied to the production of DOIP

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CPD nr. 3312

Conceptual Process Design

Process Systems Engineering

DelftChemTech - Faculty of Applied Sciences

Delft University of Technology

Appendix

Design of an integrated

fermentation-crystallization process

applied to the production of DOIP

Authors

Study nr. Telephone nr.

Sjoerd Blokker

Marcel Dabkowski

Willem Groendijk

Dirk Renckens

Jeroen de Rond

1013807

1013882

9279761

9686621

1014099

06 – 18812808

06 – 27106515

06 – 11340028

06 – 24897042

06 – 18086546

Keywords

Fermentation, crystallization, ISPR, in situ product removal,

Levodione production, (6R)-dihydro-oxoisophorone, DOIP

Assignment issued: 21-09-2004

Report issued:

20-12-2004

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Appendix 1 Extra designed unit operations

Appendix 1.1

Adsorber

The adsorber unit described for the Base case patent EP1074630 [10], uses sepabeads SP-850, a hydrophobic adsorption resin, which is made from

styrene-divinylbenzene polymer by Mitsubishi Chemical Company. The chemical structure1_of

the polymer can be seen in Figure A1.1.

Figure A1.1: schematic drawing of Sepabead SP-850 structure3_.

This resin has good adsorption and desorption (up to 100%) characteristics as some

researchers have reported1_.

Below some characteristics of the adsorber resin are given. Table A1.1: Characteristics of adsorber resin Sepabead SP-850

Parameter Value

Density2₆₇₀_kg/m3

Specific surface area2 _{1000 m}2_/g

Pore volume2 _{1.2 mL/g}

Swelling tendency3 _1.3

Mean particle diameter2_0.5_mm

Pore radius4 _{38 * 10}-10_m

The costs of an adsorber would consist of a column and the resin itself. The adsorber, described in the patent, would have a price of around 6,5 k€:

From [1, p 23] the price for the smallest column (V= 3.8 m3_{) was around 20 k€. A}

cylindrical tank of 0.8 m3_{was around 5 k€. The latter has been taken as the base}

price for a column of 200 L.

The price for the resin is typically 12,5 k€/m3_{[5], thus 0.15 m}3_{of resin, as is}

described in the patent, would cost around 1.5 k€.

1_{http://www.iwaponline.com/ws/00401/ws004010119.htm} 2 http://www.mitsubishichemical.com/Sepabeads_Main/Sepabeads_Main_R_E.htm 3_{http://www.ixresin.com/tech/data20.html} 4_{http://www.mitsubishichemical.com/Sepabeads_Tables/Sepabeads_Table_R_E.htm}

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Appendix 1.2

Dialysis

In this chapter the dialysis option will be evaluated to separate the DOIP from the fermentor stream in the ISPR case. The area of the dialysis unit will be the determining factor for the feasibility of the dialysis unit.

The area of the dialysis unit is calculated with

(A1.1)

with being the flow through the membrane, the overall mass-transfer

coeffienct a    DOIP DOIP lm DOIP DOIP n A K c n K , , ,

nd the log mean driving force.

can be calculated with:

1 1 1 _(A1.2)

where both are mass transf     lm DOIP m DOIP i f M i i p i c K l K k P k

k er coefficients for the feed side and the permeate side

boundary layer and is the wet thickness (thickness of membrane if wetted).lm

PM,i is the solute permeability and is equal to the effective internal diffusion (De,i),

which can be calculated with [22, p 728]:

, , (A1.3)

with the porosity of the membrane, the ordinary molecular diffusion coefficient of solute      i  e i r i i D D K D , 4 ,

in the solution, the tortuosity and the restrictive factor:

1 (A1.4)

with the molecul

           r i m r i p m i K d K d

d ar diameter and the pore diameter.dp

Equation A1.4 of the restrictive factor can only be used if dm/dp exceeds 0.01.

The molecular diameter is determined with Chemsketch to be 10*10-10_m.

For the other items of the formulas above the following assumptions have been made, all reasonable values when cellophane is used [22, p 748]:

- Porosity = 0.35

- Tortuosity = 4

- Pore diameter = 40*10-10 m

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Table A1.2: Calculation of lm/Pm,i Quantity value dm/dp 0.25 Kr 0.316 m/s De,i 3.4*10-11 m2/s. lm/Pm,i 1.8*106 s/m

The mass transfer coefficients for both the feed side and the permeate side are assumed to be equal and can be estimated with the empirical film-model correlation [22, p 745]: 0.33 Re (A1.5)        _{  }   d b i h h i k d d Sh a Sc D L

with Sh the Sherwood number, dh the hydraulic diameter of the membrane, Re the

Reynolds number, Sc the Schmidt number and L the length of the channel of the membrane. The expressions of Re en Sc are given below.

                  10 2 and Re

where is the viscosity of the solute.

With the solute being water, 0.001 and 1000 kg/h and

the diffusivity of DOIP in water 8.5 10 m / , this gives Sc = 1176

h i i v d Sc D Pa s D s

The ki’s have been calculated for 2 regimes, turbulent (Re = 10000) and laminar (Re

= 200) flow in the tube. This has been done to see if these mass transfer coefficient have an influence on the diffusivity.

Typical values for hollow fibre membranes are L = 1 m and dh=0.005 m [22, p 722].

For the different regimes the values of a, b and d differ. With all the values given

above and the values of a, b and d from [22, p 746], the ki is calculated for circular

tubes and given in the table below.

Table A1.3: values for constants a, b, d and ki

Flow regime Re a b d ki (m/s) 1/ki (s/m)

Turbulent 10000 0.023 0.8 0 6.4*10-5 _1.6*104

Laminar 200 1.86 0.33 0.33 3.3*10-6 _3.0*105

As can be seen in Table A1.3 the values for 1/ki are much smaller than the obtained

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Table A1.2), so in both regimes they can be neglected in the calculation of the

overall mass transfer coefficient, KDOIP, which then becomes 5.6*10-7 m/s.

With the resistance over the membrane now known the flow (nDOIP) and driving force

(∆clm) have to be estimated.

To have a production of 2000 kg a flow over the dialysis unit should be 1.8 mmol/s according to:

W,DOIP

Total DOIP Production _(A1.6)

M Total Production Time

2000 kg 1000 0.0018 / 154.19 2000 h 3600 sec/h DOIP DOIP n n mol s       

The driving force over the unit can be described by the log mean driving force:



 











               , , , , , , , , ln f in c out f out c in lm f in c out f out c in C C C C c C C C C

The concentration of DOIP (Cf, in) from the fermentor into the dialysis unit is the

maximal solubility of DOIP in water at 30 o_{C, 57 mmol/l. The concentration of DOIP}

Cc,in coming from the crystallizer is the maximal solubility of DOIP in water at 5 oC,

25 mmol/l. With the assumption that the minimal concentration difference over the membrane is 5 mmol/s, this gives a concentration of DOIP going out of the dialysis

unit at the crystallizer side (Cc,out) out 50 mmol/l.

With Cf,out having a guessed value of 40 mmol/l, this gives

clm  9.1 mmol/s

With all these numbers a total membrane area of 353 m2_{is obtained. The membrane}

area would be smaller if a solvent on the crystallizer side would be used, because of the higher solubility of DOIP in a solvent. This has however a significant backlash of removing also OIP from the fermentor, which would make it impossible to operate the system.

Cf, out

Cc, in Cc, out

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Appendix 2 Process, Options and Selection

Appendix 2.1

Process flow sheets Base case

Here simplified flow sheets of the Base case production process are given. First the flow sheet of the process as described in a patent is shown and shortly explained. Afterwards our designed process is shown. All flows except the airflow are non-continuous.

Figure A2.1: Simplified Block Scheme of DOIP production process as mentioned in patent EP1074630 [10] OIP 2.6 t/a (1.24 t/t) Glucose 7.9 t/a (3.8 t/t) Water 421.6 t/a (200.8 (t/t) Air 59.4 t/a (28.3 t/t) Solvent 38.7 t/a (18.4 t/t) Reactor T = 30o_C P = 1 bar pH = 4.5 Yield = 80% Extractor T = 20o_C P = 1 bar Yield = 98% Crystallizer T = 5o_C P = 0.03 - 1 bar Yield = 94%

Reaction Separation Product recovery

Solvent 65.3 t/a Air 59.4 t/a (28.3 t/t) 69.5 t/a To waste To waste 3.9 t/a (0.19 t/t) DOIP crystals 2.1 t/a (1.0 t/t) 432.1 t/a 466.6 t/a (222.2 t/t) Filter T = 20o_C P = 1 bar Yield = 0.999% 16.8 t/a Filtrate 12.6 t/a Washing water 1.8 t/a (0.86 t/t)

Purification

Total in 532 t/a Total out 532 t/a

OIP 2.6 t/a (1.24 t/t) Glucose 7.9 t/a (3.8 t/t) Water 421.6 t/a (200.8 (t/t) Air 59.4 t/a (28.3 t/t) Solvent 38.7 t/a (18.4 t/t) Reactor T = 30o_C P = 1 bar pH = 4.5 Yield = 80% Extractor T = 20o_C P = 1 bar Yield = 98% Crystallizer T = 5o_C P = 0.03 - 1 bar Yield = 94%

Reaction Separation Product recovery

Solvent 65.3 t/a Air 59.4 t/a (28.3 t/t) 69.5 t/a To waste To waste 3.9 t/a (0.19 t/t) DOIP crystals 2.1 t/a (1.0 t/t) 432.1 t/a 466.6 t/a (222.2 t/t) Filter T = 20o_C P = 1 bar Yield = 0.999% 16.8 t/a Filtrate 12.6 t/a Washing water 1.8 t/a (0.86 t/t)

Purification

Total in 532 t/a Total out 532 t/a

Figure A2.2: Simplified Block Scheme of Base case DOIP production process

The thicker lines show the flow of product. The numbers shown in this figure are flows per annum, where in this case an annum is 2000 hours. The downstream of the patented production process is not used in the further design, so no mass streams are given in the particular block scheme.

Reactor T = 30o_C P= 1 bar pH= 4.5 Reactor T = 30o_C P= 1 bar pH= 4.5 T = 70o_C P = 1 bar T = 5-70o_C P < 1.1 bar

Reaction

Separation

Purification

OIP Glucose water air air methanol methanol methanol DOIP crystals air Water to waste OIP Glucose water air Reactor T = 30o_C P= 1 bar pH= 4.5 Reactor T = 30o_C P= 1 bar pH= 4.5 T = 70o_C P = 1 bar T = 5-70o_C P < 1.1 bar

Reaction

Separation

Purification

OIP Glucose water air air methanol methanol methanol DOIP crystals air Water to waste OIP Glucose water air

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Appendix 3 Basis of Design

Appendix 3.1

List of Pure components

APART INVOEREN EXCEL SHEET Table A3.1: List of pure components

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Appendix 3.2

Battery limit

In this appendix the materials entering and leaving the battery limit are presented in tables with their additional information.

Table A3.2: Ingoing baker’s yeast

Name: Ingoing baker’s yeast (Saccharomyces cerevisiae)

Comp. Units Specification Case: ISPR

Available Design Notes Additional Information

Baker’s yeast %wt 97.5 97.5 (1) (1) The baker’s yeast has to be

handled aseptically in order

Water 2.5 2.5 to prevent contamination

with harmful organisms for the

fermentation.

Total 100.0 (2) This price is an indication given by

Process Conditions and Price DSM Bakery Ingredients.

Temp. N/A5 _ambient _{Acquisition of larger amounts}

might reduce the price per kg.

Press. Bara 1

Phase V/L/S S

Price €/kg 1.40 (2)

Table A3.3: Ingoing immobilized biomass

Name: Ingoing immobilized biomass (Saccharomyces rouxii)

Comp. Units Specification Case: Base

Ionized water %wt 41.6 41.6 (1) (1) See Table A3.23

Modified yeast cells 2.2 2.2

Resin 55.5 55.5

Calcium alginate 0.4 0.4

2-hydroxy-2-methylpropiophenone 0.1 0.1

Total 100.0

Process Conditions and Price

Temp. N/A ambient

Press. Bara 1

Phase V/L/S S

Price €/kg 15.45 (1)

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Table A3.4: Ingoing OIP

Name: Ingoing OIP

Comp. Units Specification Case: Base, ISPR

OIP %wt >98 >98 (1) (1) The OIP will be provided by Fluka

Impurities <2 <2 Chemie AG. For now, there is

insufficient information present

about the impurities.

(2) OIP is supposed to be liquid

Total 100.0

Process Conditions and Price (3) This price is an indication given

Temp. o_C ₃₀ ₍₂₎ _{by the market price for OIP}

Press. Bara 1 (5kg, purity of ≥98 %wt)

Phase V/L/S L divided by factor 36

Price €/kg 100 (3)

Table A3.5: Ingoing glucose

Name: Ingoing glucose (aq)

Glucose %wt 80 80.0 (1) (1) The glucose is dissolved in

Water 20 20.0 water and added to the

Total 100.0 fermentation as the C-source for

the biomass.

Process Conditions and Price (2) Taken from [12, p 340]

Temp. N/A ambient

Press. Bara 1

Phase V/L/S L

Price €/kg 0.3 (2)

Table A3.6: Ingoing filtered air

Name: Ingoing filtered air

Nitrogen %vol 78.1 78.1 (1) Price indication is obtained

from [23, p 263].

Oxygen 21.0 21.0

Other 0.9 0.9

Total 100.0

Temp. N/A ambient

Press. Bara 2

Phase V/L/S V

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Table A3.7: Ingoing sterilised process water

Name: Ingoing sterilised process water

Water %wt 100 100 (1) (1) Sterilised process water is used

for the fermentation and other purposes in the design.

Total 100.0

Temp. N/A ambient

Press. Bara 1 (2) Price is twice the price for

process water from [23, p 263].

Phase V/L/S L

Price €/t 0.34 (2)

Table A3.8: Ingoing activation liquid (buffer)

Name: Ingoing activation liquid (buffer)

NaxHyPO4 %wt 0.52 (1) (1) The buffer is used for the

activation of the biomass and as fermentor liquid in ISPR.

MgSO4 0.06

Water 99.42

Total 100.00 (2) The price is taken from the

market price of sodium phosphate and magnesium sulphate from [12, p 340]. The price of water is taken from [23, p 263].

Temp. N/A Ambient

Press. Bara 1

Phase V/L/S L

Price €/kg 0.008 (2)

Table A3.9: Ingoing acid N.N.F.

Name: Ingoing sulfuric acid (H2SO4)

H2SO4 (aq) %wt 95-98 96 (1) (1) This acid is the cheapest

Water 2-5 4 option and is technically pure,

which is sufficient for its purpose.

Total 100.0

Temp. N/A ambient by the market price7_for

Press. Bara 1 H2SO4 (aq) for laboratory

Phase V/L/S L purposes divided by factor 10.

Price €/L 0.14 (2)

7_{http://www.fd.tudelft.nl/pics/PDF/Cataloguscmcjan2003.pdf, visited in November}

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Table A3.10: Ingoing base

Name: Ingoing sodium hydroxide (NaOH)

NaOH (aq) %wt 33 33 (1) (1) This base is the cheapest

Water 67 67 option and is technically pure,

which is sufficient enough for

Total 100.0 its purpose.

Temp. N/A ambient by the market price8_for

Press. Bara 1 NaOH (aq) for laboratory

Phase V/L/S L purposes divided by factor 10.

Price €/kg 0.07 (2)

Table A3.11: Ingoing nitrogen

Name: Ingoing nitrogen

Nitrogen %vol N/A N/A (1) (1) Nitrogen is needed for drying of

the crystals as is common practice in the industry.

Oxygen N/A N/A

Other N/A N/A

Total 100.0

Process Conditions and Price (2) Price indication is obtained from

FD, TU Delft and is dived by 5 for industrial use

Temp. N/A ambient

Press. Bara 2

Phase V/L/S V

Price €/kg 0.4 (2)

Table A3.12: Ingoing anti-foaming agent

Name: Ingoing anti foaming agent

Struktol

solution J-673 %wt 100 100

Total 100.0 (1) This price is an indication9_.

Process Conditions and Price The price is based on pure anti-

Temp. N/A ambient foaming agent. For its application

Press. Bara 1 it should be dissolved in water.

Phase V/L/S L

Price €/kg 4.00 (1)

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Table A3.13: Ingoing solvent

Name: Ingoing solvent

Ethyl acetate %wt 100.0  100 (1) (1) The ethyl acetate is chemically

pure, which is sufficient for its

Total 100.0 purpose.

Process Conditions and Price (2) The price is obtained from

Temp. o_C _ambient _{SuperPro Designer}®_v5.1

Press. Bara 1

Phase V/L/S L

Price €/L 1.19 (2)

Table A3.14: Outgoing spent biomass

Name: Outgoing spent baker’s yeast

Comp. Units Specification Case: ISPR

Bakers’ yeast %wt N/A 80 (1) (1) For now it is assumed that this

Water N/A 20 will be the composition of

spent biomass. Further investigation of required

Total 100.0 specifications for discarding

Process Conditions and Price biomass should be done.

Temp. N/A ambient

Press. Bara 1

Phase V/L/S S

Price €/kg N/A

Table A3.15: Outgoing spent biomass

Name: Outgoing spent immobilized biomass

Ionized water %wt 41.6 41.6 (1) (1) For now it is assumed that this

will be the composition of spent biomass. Further investigation of required specifications for

discarding biomass should be done. Modified yeast cells 2.2 2.2 Resin 55.5 55.5 Calcium alginate 0.4 0.4 2-hydroxy-2-methylpropiophen one 0.1 0.1 Total 100.0

Process Conditions and Price (2) Estimated price for treatment,

with the help of [12].

Temp. N/A ambient

Press. Bara 1

Phase V/L/S S

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Table A3.16: Outgoing DOIP

Name: Outgoing DOIP

DOIP %wt N/A 99.5 (1) (1) Values taken in consultation

OIP N/A <0.5 with the principal.

ACT N/A <0.5 (2) Calculated with at ratio DOIP/OIP

of 4.

Total 100.0

Temp. N/A ambient

Press. Bara 1

Phase V/L/S S

Price €/kg 400 (2)

Table A3.17: Outgoing spent air

Name: Outgoing spent air

Nitrogen %vol N/A 78.1 (1) No water is present since the gas

Oxygen N/A <21.0 exit passes a condenser.

CO2 N/A >0

Water N/A <<1 (1)

OIP N/A <<0.1

DOIP N/A <<0.1

Total 100.0

Temp. N/A ambient

Press. Bara 1

Phase V/L/S V

Price €/kg N/A

Table A3.18: Outgoing spent process water

Name: Outgoing spent process water

Water %wt N/A N/A (1) (1) The fermentation water may

Contaminations N/A N/A contain DOIP, OIP, ACT,

fermentation chemicals and in the Base Case also ethyl acetate.

Total 100.0

Temp. N/A ambient (2) Cost for treatment in waste water

facility from [12, p 341]

Press. Bara 1

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Table A3.19: Outgoing spent solvent

Name: Outgoing spent solvent

Ethyl acetate %wt N/A <100 (1) (1) When solvent is used for

DOIP/OIP/ACT >0 extraction of product or

Total 100.0 crystallization there will also

Process Conditions and Price move OIP and ACT into the

Temp. o_C ₅ _{solvent. An amount DOIP will also}

Press. Bara 1 remain in the solvent.

Phase V/L/S L

Price €/kg 4.00 (2) (2) Estimated price for treatment

[12, p 341]

Table A3.20: Cooling medium (T=-10o_C)

Name: Cooling medium (T=-10o_C)

Heat transfer oil %wt 100  100 (1) (1) Heat transfer oil available at the

MPP will be desired as an utility for cooling the crystallizer, condensers and heat exchangers. For the design the properties of

Total 100.0 Brine were taken into account.

Process Conditions and Price (2) This is the inlet temperature of

Temp. o_C _-10 ₍₂₎ _{Brine according to Super Pro}

Press. Bara 1 Designer®_v5.1.

Phase V/L/S L (3) Price based on database Super

Price €/kWh 0.021 (3) Pro Designer®_v5.1.

Table A3.21: Cooling medium (T=20o_C)

Name: Cooling medium (T=20o_C)

Water %wt 100 100 (1) (1) It is assumed that cooling water

will be desired as an utility for cooling the fermentor.

Total 100.0 (2) This is the inlet temperature

Process Conditions and Price according to Super Pro

Temp. o_C ₂₀ ₍₂₎ _Designer®_v5.1.

Press. Bara 1 (3) Price based on database Super

Phase V/L/S L Pro Designer®_v5.1.

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Table A3.22: Heating medium (T=50o_C)

Name: Heating medium (T=50o_C)

Heat transfer oil %wt 100 100 (1) (1) Heat transfer oil from the MPP is

used for heating the fermentation solution. For the design of this

Total 100.0 heat exchanger the properties of

Process Conditions and Price water were taken into account.

Temp. o_C ₅₀

Press. Bara 1 (2) Price based on database Super

Phase V/L/S L Pro Designer®_v5.1.

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Appendix 3.3

Costs of immobilization

The costs of immobilization have been calculated by multiplying the raw material costs by a production factor. After consultation with several people from the biotechnology department of TU Delft this factor has been set to 3. Below an overview of the raw material costs can be found.

Table A3.23: Raw material costs immobilized biomass as described in [10, p 6] Component of immobilized

yeast particle %wt Weight (kg) Price (€/kg)

Total costs/kg immobilized biomass (€) Costs per kg biomass cell (€) Ionized water 41.6 0.416 0.00017 0.00 0.00

Modified yeast cells 2.2 0.022 54 1.20 54.00

Resin 55.5 0.555 7 3.89 175.00

Calcium alginate 0.4 0.004 9.86 0.04 1.77

2-hydroxy-2-methylpropiophenone 0.1 0.001 30 0.03 1.35

Total Raw Materials 5.15 232.12

Total Production 15.45

The resin is a combination of polyethylene glycol (PEG, molecular weight 3500) and polypropylene glycol (PPG, molecular weight 4000). The costs of the resin, calcium alginate and the 2-hydroxy-2-methylpropiophenone are taken as 1/10 of the price

given by Fluka. The price for the Saccharomyces rouxii cells is taken from Deutsche

Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ)10_{. Finally the price}

for ionized water has been taken to be the same as for sterilized water.

As can be seen in Table A3.23 the cost of producing 1 kg of immobilized biomass is 15.45 €, mostly due to the costs for the resin with 55% of the total mass. If costs here can be reduced, this will affect the price for immobilizing a lot.

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Appendix 3.4

Economic Margin

The economic margin is calculated by subtracting the costs of the raw materials and waste streams from the revenues of the products. The amounts are taken from the calculations in the process streams and the prices are taken from Appendix 3.2. The results can be found in the two tables below. For the revenues two options for DOIP pricing have been used. The produced ACT and the spent biomass and ethyl acetate are assumed to have zero value here. In fact in the end they need to be processed in some wastewater treatment plant facility (WWTP).

For calculation of the costs of waste treatment the following assumption are made:

- 1 kg of COD costs €0.3011

- The cost of the outgoing air is considered to be zero.

Table A3.24: Total costs and revenues Base case for 2000 hours price/unit

[€/unit] Unit Quantity [kg] Costs [€]

Costs

Raw materials

OIP 100.00 kg 2600 260,000

Glucose solution 0.30 kg 9875 2,963

Immobilised Biomass 15.45 kg 345 5,300

Sterilised process water 0.34 ton 216 73

Fermentation buffer 8.30 ton 204 1,693

Ethyl acetate 1.19 kg 39750 47,303

NaOH 0.07 kg 2112 148

Filtered air 4.31 ton 72 309

Subtotal Raw materials (A) 317,789

Waste Water/COD 0.30 kg 76800 23,040 Ethyl acetate 4.00 kg 2200 8,800 Immobilised biomass 8.00 kg 345 2,760 Air - m3₅₁₀₀₀ -Subtotal waste (B) 34,600

Total Costs (A+B) 352,389

Revenues

DOIP 400.00 kg 2074 829,600

Total Revenues (C) 829,600

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With the NCF, the maximum investment can be calculated, also called the Net Present Value. (NPV).

The discounted cash-flow rate of return (DCFRR, r’) is a measure of the maximum rate that the project could pay and still break even by the end of the project life. The DCFRR is also known as Internal Rate of Return or Earning Power.

The maximum allowed investment can be calculated by taking the DCFRR as the interest rate for calculating the total Net Present Value for the plant

The actual Net Present Value (NPV) of year n is calculated with:





, A3.1 1 ' Year n Now year n n NFV NPV r  

with r’ the DCFRR and NFV the expected income of year n.

The NPV is the present value of all income of future years taking into consideration the interest rate.

The total NPV then is





1 A3.2 1 ' n t Year n Now n n NFV NPV r    



With a total economic life of 15 years and a given r’ of 10%, the total NPV can be calculated. One example is given below, for the DOIP pricing of 400€/kg for the base case. The NCF is considered to be constant.

Table A3.25: Total Net Present Value Base case End of year NCF (€) 1/(1+r’)^n sum(1/(1+r’)^n) NPV (€) 1 1,440,000 0.9091 0.9091 1,309,091 2 1,440,000 0.8264 1.7355 1,190,083 3 1,440,000 0.7513 2.4869 1,081,893 4 1,440,000 0.6830 3.1699 983,539 5 1,440,000 0.6209 3.7908 894,127 6 1,440,000 0.5645 4.3553 812,842 7 1,440,000 0.5132 4.8684 738,948 8 1,440,000 0.4665 5.3349 671,771 9 1,440,000 0.4241 5.7590 610,701 10 1,440,000 0.3855 6.1446 555,182 11 1,440,000 0.3505 6.4951 504,711 12 1,440,000 0.3186 6.8137 458,828 13 1,440,000 0.2897 7.1034 417,117 14 1,440,000 0.2633 7.3667 379,197 15 1,440,000 0.2394 7.6061 344,725 Total 10,952,754

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The same procedure has been done for the ISPR case, generating: Table A3.26: Total costs and revenues ISPR for 2000 hours

price/unit

[€/unit] Unit Quantity [kg] Costs [€]

Costs

Raw materials

OIP 100.00 kg 2300 230,000

Glucose solution 0.30 kg 11398 3,419

Biomass 1.4 kg 677 947

Fermentation buffer 8.30 ton 21 172

NaOH 0.07 kg 5584 391

Filtered air 4.31 ton 115 494

Nitrogen 0.40 kg 3000 1,200

Subtotal Raw materials (A) 236,623

Waste

Water/COD 0.30 kg 1200 360

Air/Nitrogen - ton 118

-Subtotal waste (B) 360

Total Costs (A+B) 236,983

Revenues

DOIP 400.00 kg 2131 852,400

Total Revenues (C) 852,400

Net Cash Flow (C - A - B) 615,417

The revenues for the ISPR are the same as for the Base case since the same amount of DOIP is produced. With these figures an NPV of 14,000,000 € is obtained.

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Appendix 4 Thermodynamic Properties

Appendix 4.1

Method of Anderson, Beyer and Watson

In the method of Anderson, Beyer and Watson a compound is considered to be composed of a base group, which is modified by the substitution of other groups. These base groups are, for example, methane, cyclopentane, cyclohexane, benzene and methylamine. The first substitution of a methyl group on the base group is termed a primary methyl substitution. Except in the case of the base groups benzene, naphthalene and cyclopentane, any further substitution of methyl groups in the base group is called a secondary substitution. The increment in this case depends upon the type of adjacent carbon atoms. The letter A designates the carbon atom where the substitution is made and the letter B the highest type number carbon adjacent to A. The type numbers are reported in Table A4.1. The values for the different starting groups and contributions can be found in [21, p 267-270]. When these are added up an estimate for the enthalpy and entropy is found.

Table A4.1: Type numbers of carbon atoms

Type 1 2 3 4 5

CH3 CH2 CH C C*

C* is on a benzene or naphthalene ring

Table A4.2: Enthalpy and entropy of formation of OIP

Contribution ∆Hf (kcal/mol) ∆Sf (cal/(mol.K))

Base = cyclohexane -29.43 71.28 Primary CH3 substitution -7.56 10.78 A B Secondary CH3 substitution (1) -7.00 3 2 -7.00 3.87 Secondary CH3 substitution (2) -7.00 2 4 -3.83 7.46 Secondary CH3 substitution (3) -7.00 2 3 -5.25 6.53 Secondary CH3 substitution (4) -7.00 2 2 -6.33 7.15

Substitution CH3 for O (ketone) -13.2 -2.40

C1 C2

Double bond 2 3 26.72 -0.28

Total -73.8812_104.39

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Appendix 4.2

Lydersen’s method

The relations used in Lydersen’s method are as follows:

2 1 2 [0.567 ( ) ] A4.1 (0.34 ) A4.2 40 c b T T c W P c V T T P M V             



A4.3

The units are Kelvin, atmospheres13_{and cubic centimetres per gram mole. The ∆}

quantities are evaluated by summing the contributions of various atoms or groups of

atoms. Only the normal boiling point (K) and molecular weight MW (g/mole) are

needed. In Table A4.3 the ∆ quantities for OIP are given. The C-atom dealt with is represented in the first column; all single bonds with other C-atoms are left out. So, for example, the first atom given in the table has four single bonds to other C-atoms.

Table A4.3: ∆ quantities for OIP

C-atom ∆T ∆P ∆V C -0.007 0.154 31.0 CH3 0.020 0.227 55.0 CH3 0.020 0.227 55.0 C=O (ring) 0.033 0.200 50.0 CH2 0.020 0.227 55.0 =C 0.011 0.154 36.0 =CH 0.011 0.154 37.0 C=O (ring) 0.033 0.200 50.0 CH2 0.013 0.184 44.5 Total 0.154 1.727 413.5

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Appendix 4.3 Critical compressibility factor and acentric factor

The critical compressibility factor is calculated with the following equation [21, p 17]:

3

A4.4 in which

critical compressibility factor critical pressure (Pa)

critical volume (m /mo

c c c c c c c P V Z RT Z P V     le) critical temperature (K) gasconstant (8.3145 J/(mol.K)) c T R  

The acentric factor (omega) is calculated with equation A4.5 [21, p 20]. 3 log 1 A4.5 7 1 in which acentric factor boiling temperature (K) critical temperature (K) critical pressure (at

Pc Tb Tc Pc             m)

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Appendix 4.4

Yen and Woods correlation

The correlation uses the critical density, temperature and compressibility factor for the calculation of the saturated molar liquid density [21, p 62]. The correlation used is the following: 4 ₃ 1 (1 ) A4.6 1 2 3 17.4425 214.578 989.625 1522.06 A4.7 1 3.28257 1 2 j l _K _Tr j j c where K Z_c Z_c Z_c K              3.6377 107.4844 2 384.211 3 if 0.26 A4.8 2 3 60.2091 402.063 501.0 641.0 if 0.26 A4.9 2 0 3 Z_c Z_c Z_c Z_c K Z_c Z_c Z_c Z_c K          A4.10 0.93 A4.11 4 2 in which liquid density (g/l) critical density (g K K l c       /l) reduced temperature (-) critical temperature (K)

critical compressibility factor

T Tr Tc Tc Zc    

When this correlation is plotted over a small temperature range it is approximately linear. In Figure A4.1 this is done for OIP and it is subsequently approximated with the following equation:

( / ) . ( ) A4.12 in which liquid density (g/l) temperature (K) l l g l A B T K T      

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Liquid density of OIP vs. temperature

y = -0.6849x + 1181.5 R2 = 0.9998 950 960 970 980 990 1000 1010 1020 250 270 290 310 330 Temperature (K) Liquid density (g/l)

Figure A4.1: Liquid density of OIP against temperature

As seen in Figure A4.1 A is 1181.5 and B is –0.6849; looking at R2_{, which is a}

measure of the ‘goodness of fit’, shows that over a small temperature range a linear approximation is justified.

Appendix 4.5

Method of Chueh and Swanson

The molar liquid heat capacity is estimated with the help of the method of Chueh and Swanson as reported [21, p 151]. In Table A4.4 the results of the different contributions for OIP are given. As with Lydersen’s method (see Appendix 4.1) the single bonds of the C-atoms to other C-atoms are not shown in this table.

Table A4.4: Liquid molar heat capacity of OIP at 20 0_C

Contribution Value CH3 8.8 CH3 8.8 C (ring) 2.9 C=O 12.7 =C (ring) 2.9 CH3 8.8 =CH (ring) 5.3 C=O 12.7 CH2 6.2 Cp (cal/(mol.K)) 69.1 Cp (J/(mol.K)) 289.9

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Appendix 4.6

Method of Rihani and Doraiswamy

The method of Rihani and Doraiswamy [21, p 234] is used. The relation given is the following:

0 2 3

0

A4.13 in which

ideal-gas heat capacity (cal/(mol.K)) temperature (K) p i i i i i i i i i i i i p C n a n bT n c T n d T C T      



The constants A, B, C and D are calculated as shown Table A4.5. Again the single bonds of the C-atoms to other C-atoms are not shown in the table.

Table A4.5: Constants for the calculation of the ideal-gas heat capacity of OIP

Contribution A B (x10^2) C (x10^4) D (x10^6) CH3 0.609 2.143 -0.085 0.00114 CH3 0.609 2.143 -0.085 0.00114 C -5.831 4.454 -0.421 0.01263 C=0 1.002 2.076 -0.164 0.00449 C=CH -1.471 3.384 -0.237 0.00606 CH3 0.609 2.143 -0.085 0.00114 C=O 1.002 2.076 -0.164 0.00449 CH2 0.395 2.136 -0.120 0.00260

Hexane ring formation -13.392 2.139 -0.043 -0.00187

Cp0 (cal/(mol.K)) -16.468 22.694 -1.404 0.03182

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Appendix 4.7

Vapour pressure relation

To determine the constants in the Antoine equation the critical point, boiling point at

normal pressure and the saturated vapour pressure at 25 o_{C are used. These three}

points are fitted to the Antoine equation in Mathcad®_{in the file}

Vapour_pressure_calculations.mcd. In Figure A4.2 the three points and the Antoine equation, with the calculated constants, are plotted to verify the constants.

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Log(Pressure (mm Hg)) vs. Temperature

-4

-3

-2

-1

0

1

2

3

4

5

250

350

450

550

650

Temperature (K) Log(P (mm Hg)) Vapour pressure (T = 25 degrees C) Boiling point Critical temperature Antoine equation

Figure A4.3: Plot of the Antoine equation and the three points used for the determination of the constants for OIP

Appendix 4.8

Solubility experiments of DOIP

Goal:

Determination of solubility of DOIP in certain solvents Solvents needed:

The solubilities in the following solvents are measured.

 _{Methanol (mentioned in patent EP 1074630, [10])}

 _{Ethyl acetate (Leuenberger, [17])}

 _{1-Octanol (because K}

wvalue is known)

The first two solvents are chosen, because they are mentioned in literature as suitable solvents for the purification of DOIP. The solubility in 1-octanol is also measured. This is done because the equilibrium constants between water and 1-octanol are given in literature, so it will give a good reference value.

Experiments:

T= 9o_C

1. Fill the Eppendorff with the desired amount of DOIP. 2. Add 1 ml of the solvent to the Eppendorff.

3. Close the Eppendorff.

4. Put the Eppendorff in the refrigerator.

5. Repeat this sequence with the various amounts of DOIP needed. 6. Shake the Eppendorff every once and a while.

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T= 30 o_C/50o_C

1. Set the water bath to 30o_C/50o_C

2. Fill the Eppendorff with the desired amount of DOIP. 3. Add 1 ml of the solvent to the Eppendorff.

4. Close the Eppendorff.

5. Put the Eppendorff in the refrigerator.

6. Repeat this sequence with the various amounts of DOIP needed. 7. Shake the Eppendorff every once and a while.

8. Wait 20-30 minutes to get equilibrium. 9. Judge by eye if it is dissolved or not. Results and discussion:

The experimental data are given on the CD-ROM14_{. From the experiments}

approximate values for the maximum solubilities were determined. These are shown in Table A4.6 and Table A4.7.

Table A4.6: Solubility in the solvents at different temperatures

Solvent Concentration

(g/l) at T = 9 0_C Concentration _{(g/l) at T = 32}0_C Concentration _{(g/l) at T = 52}0_C

Methanol 70 - 80 210 650 - 707

Ethyl acetate 147 - 159 250 - 258 609 - 652

1-Octanol 11 - 21 11 - 21 49 - 109

During the experiments a significant increase in volume in the Eppendorffs was seen,

especially in the experiments at 52 o_{C. This is due to the considerable amount of}

DOIP added to the solvent. To account for this increase in volume the concentrations are divided by the sum of the volume solvent added and the amount of DOIP added to the solvent. The density of DOIP is about 1000 g/l so the amount of DOIP added in grams is equal to millilitres.

E.g.: if 762 mg DOIP added = 762/1000 = 0.762 ml. Revised concentration = 762/(1+0.762)=432 g/l When this is done values in and Table A4.7 are found.

Table A4.7: Solubility in the solvents at different temperatures revised

Solvent Concentration

(g/l) at T = 9 0_C Concentration _{(g/l) at T = 32}0_C Concentration _{(g/l) at T = 52}0_C

Methanol 65 - 74 173 394 - 432

Ethyl acetate 128 - 137 200 - 205 378 - 395

1-Octanol 11 - 21 11 - 21 47 - 98

The solubility of 1-octanol is neglected in further calculations, because the experimental errors are large and it is of little interest. The solubilities (in g/l) for methanol and ethyl acetate are plotted against the reciprocal of the temperature (1/K). The results are shown in Figure A4.4 and Figure A4.5. For these plots the average values of the range given in Table A4.7 are taken.

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Solubility of DOIP in Ethyl acetate

y = 3.62E+05e

-2.25E+03x

R

2

= 9.61E-01

0 50 100 150 200 250 300 350 400 450 0.003 0.0031 0.0032 0.0033 0.0034 0.0035 0.0036 0.0037 1/Temperature (1/K) S o lubility (g/l)

Figure A4.4: Solubility of DOIP in ethyl acetate

Solubility of DOIP in methanol

y = 4E+07e

-3751x

R

2

= 0.9955

0 50 100 150 200 250 300 350 400 450 0.003 0.0031 0.0032 0.0033 0.0034 0.0035 0.0036 0.0037 1/Termperature (1/K) Solubility (g/l)

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Looking at the two graphs one can see that the trendline for methanol fits very well,

but the trendline for ethyl acetate fits much less. When the solubility at 9 0_{C is}

lowered to about 100 g/l the trendline fits much better as can be seen when looking

at the R2_{-value. This can be seen in Figure A4.6 The justification for this is found in}

the way the experiments were done. Tube EA3 was first kept at room temperature, at which all DOIP could dissolve, after which it was put in the refrigerator to cool it to

9 0_{C. At this temperature no DOIP crystallized, but the solution was probably}

supersaturated. Therefore, as concluded before, the maximum solubility is lower that the 150 g/l derived from the experiments.

Solubility of DOIP in Ethyl acetate

y = 3E+06e

-2871.6x

R

2

= 0.9969

0 50 100 150 200 250 300 350 400 450 0.003 0.0031 0.0032 0.0033 0.0034 0.0035 0.0036 0.0037 1/Temperature (1/K) Solubility (g/l)

Figure A4.6: Solubility of DOIP in ethyl acetate revised

Appendix 4.9

Solubility and melting enthalpy

Solubility

The relations that are found experimentally are showed below: Solubility of OIP in water:

13905 3

Solubility(mol) 27200 e RT A4.14

m



 

Solubility of DOIP in water: 22970 3

m



 

Solubility of ACT in water: 4710 3

m



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Melting enthalpy

The melting enthalpy of the components is determined by measurements of the solubility of DOIP in ethyl acetate. The Regular-Solution Theory, introduced by Scatchard and Hildebrand [21, p 326] describes the activity coefficients in binary mixtures of non-polar molecules as follows:

L 2 1 1 2 11 22 12 L 2 2 2 L L 1 1 2 2 i ii L i 1 / 2 12 11 22 12 RT ln( ) V (c c 2c ) A4.17 with : x V x V x V U c V c (c c ) (1 )              

This theory is combined with the theory for Solubilities of Solids in Liquids in order to estimate the enthalpy of fusion. This latter theory is described as follows:

i i m i i m H _T ln( x ) 1 A4.18 RT T       _  _  

Rearrangement of the equations resulted in the melting enthalpy of DOIP. A second theory of Dannenfalser and Yalkowsky [14] for melt enthalpy estimation is used of DOIP, OIP and ACT. The theory describes the total entropy change of melting, which subsequentially yields the melting enthalpy.

tot m S 50 R ln( ) R ln( ) A4.19 with : 2.345 SP3 SP2 0.5 RING 1               

Multiplication of the total melt entropy by the melting temperature resulted in the melt enthalpy of each particular component. The obtained values were in the same range, which is explained by the fact that the components have a more or less similar molecular structure. However, the result for the melt enthalpy of DOIP deviated from the estimated value from the solubility in ethyl acetate. The first result is considered to be more reliable, since it is calculated straightforward from the solubility of DOIP. For the melt enthalpy of OIP and ACT a proportional factor with respect to DOIP is determined from the theory of Dannenfalser and Yalkowsky. With these factors the melt enthalpy of these components is estimated from the obtained value for DOIP with the Regular-Solution theory and the theory for Solubilities of Solids in Liquids. An overview of the results is given below in Table A4.8. The

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Table A4.8: Estimation melt enthalpy

Method 1 Method 2 Estimation

Component Hmi (104 J/mol) Hmi (104 J/mol) Hmi (104 J/mol)

DOIP 2.717 1.831 2.717

OIP N/A 1.501 2.227

ACT N/A 1.591 2.361

Appendix 4.10

Distribution coefficients

In order to obtain distribution coefficients for the components over ethyl acetate and water, the activity coefficients of the components in these solvents need to be investigated.

Ethyl acetate

Rearrangement of equations A4.17 and A4.18 gives the activity coefficient at maximum solubility and the accompanying maximum dissolved fraction of the particular component. This fixed point is used to estimate the parameters of the Wilson equations, which describe the activity coefficients for binary mixtures [21, p 300] as follows: i 12 21 1 1 12 2 2 1 12 2 21 1 2 12 21 2 2 21 1 1 1 12 2 21 1 2 L j ij ii ij L i ij ji ii v ln( ) ln(x x ) x A4.20 x x x x ln( ) ln(x x ) x A4.21 x x x x with : V exp RT V ( H RT) 2_{for component 2 h} z           _  _                 _  _                            L 2 L 1

aving the smaller volume V

2 _{for component 1 having the larger volume}

z V

 

    

 

With these given parameters a relation is obtained for the activity coefficient of a solute as a function of its fraction in the solvent. The activity coefficient at half the solubility is chosen as a point of departure for the distribution coefficient calculation. The results of these mathematical operations are presented in Table A4.9.

Table A4.9: Fraction and Activity coefficient solutes in ethyl acetate

Component Maximum solubility 50 % solubility

xmax (-) EAmax (-) x (-) EA (-)

DOIP 0.096 1.134 0.048 1.174

OIP 0.059 13.783 0.029 23.278

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Water

For the estimation of the activity coefficients of the solutes in water, the experimental solubility relations (see Appendix 4.9) are combined with equation A1.18. This resulted in the activity coefficients at maximum solubility in water of the particular components. Subsequentially this fixed point is used to calculate the parameters of the Wilson equations, which finally resulted in a relation of the activity coefficients as a function of the dissolved fraction. Also in this case, the activity coefficient at half the solubility is chosen as the point of departure for the distribution coefficient calculation. The results are presented below.

Table A4.10: Fraction and activity coefficient solutes in water

Maximum solubility 50 % solubility

Component xmax (-) Wmax (-) x (-) W (-)

DOIP 7.705 x 10-4 _140.614 _{3.853 x 10}-4 _146.511

OIP 1.638 x 10-3_493.415 _{8.189 x 10}-4 _765.467

ACT 5.656 x 10-3 _82.592 _{2.828 x 10}-3 _101.375

The distribution of a solute over water and ethyl acetate is described as follows:

i W i D EA i K   A4.22 

The distribution coefficient can also be described as a ratio of the solute fractions in both solvents, which can be rewritten into a distribution coefficient based on mass

(mDi). The results of the distribution coefficient calculations are given below:

Table A4.11: Distribution coefficients Component KDi (-) mDi (-)

DOIP 124.805 23.471

OIP 32.884 7.017

ACT 45.093 9.291

The calculations were performed with Mathcad®_{and can be reviewed in the file}

Calculation_distribution_coefficients.mcd on the CD-ROM.

Appendix 4.11

Diffusion coefficients in water

The infinite dilution diffusion coefficients of non-electrolytes in water can be estimated with the Hayduk-Laudie correlation [21]:

1.14 0.589 5 , 13.26 10 A4.23 i w m i D _ _  _  _V 

where w is the viscosity of water (cP) and Vm,i the molal volume of the substance at

normal boiling point (cm3_{/mol). Division of the molar weight by the density can}

obtain the molar volume. The viscosity of water at 30 o_{C is 0.80 cP [15, p 108]. The}

exact calculation of these values can be found in the Mathcad®_file

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Appendix 4.12

Base case reaction kinetics

In Table A4.12 a comparison is made between the productivity of baker’s yeast and Saccharomyces rouxii, both in immobilized form: the productivity of Saccharomyces

rouxii is a factor 7.07 higher than baker’s yeast. Therefore qDOIPmax is taken to be

7.07 *qDOIPmax (ISPR case) = 13.79 mmol/gdw/h. Subsequently KM,OIP is changed to

increase the goodness of fit of the predicted OIP concentration to the experimental values. In Table A4.12 the goodness of fit can be seen.

Table A4.12: Comparison of productivity [10]

Productivity (g/kg yeast cells/h)

Free-cell Immobilized

Baker’s yeast 8.8 0.69

Saccharomyces rouxii 25.7 4.88

Figure A4.7: Experimental data from [10] and the predicted concentrations from the kinetic model

When qDOIPmax and KM,OIP are known, k1 and k2 can be determined by trial and error.

The values for k1 and k2 are 0.0031 and 0.1 L2/mmol/gd/h respectively, the final

result can be seen in Figure A4.7. In Table A4.13 the kinetic parameter of both cases are compared. The difference in parameters cannot be explained theoretically.

Table A4.13: Comparison kinetics ISPR and Base case

Parameter ISPR Base case Unit

qDOIPmax 1.95 13.79 mmol/gdw/h

Km 860 86 mM

k1 3.1*10-6 0.0031 L2/mmol/gdw/h

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Appendix 5 Process Structure & Description

Appendix 5.1

Process Flow Schemes Base case

In this appendix the process flow schemes of the Base case are presented. In Appendix 5.1.1 the fermentation and the downstream section are presented. The succeeding smaller process flow schemes (see Appendix 5.1.2) represent the batch operations. Tabulated data in Appendix 6 is added as a support for these process flow schemes.

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Appendix 5.1.1

Main Process Flow Scheme Base case

Appendix 5.1.2

Batch Operations Base case

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Appendix 5.2

Batch Cycle Diagrams Base case

A general Batch Cycle Diagram for all the process steps in the Bas case is presented in Figure A5.1. In the succeeding figures detailed Batch Cycle Diagrams are given for each process step. Tabulated data in Appendix 6 is enclosed as a support for the detailed Batch Cycle Diagrams.

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Figure A5.2: Detailed Batch Cycle Diagram for fermentation Base case

Figure A5.3: Detailed Batch Cycle Diagram Transfer Aqueous Solution to downstream Base case

Detailed Batch Cycle Diagram Transfer Aqueous Solution To Downstream Base Case

0.5 1.5 2.5 3.5 4.5 5.5 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 time [hours]

BO 1.7: V102: Transfer aqueous solution to downstream section

BO 1.7: V204: Loading with filtrated aqueous solution BO 1.7: P104: Pumping aqueous

BO 1.7: S101: Filtering the aqueous solution while transferred

BO 1.7: E103: Cooling aqueous solution

Detailed Batch Cycle Diagram for fermentation base case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5 15.5 16.5 17.5 0 1 2 3 4 5 6 7 8 9 10 time [hours]

BO 1.1: R101: Filling with fermentation solution from T103 BO 1.2: R101: Fermentation in bubble column (and aeration) BO 1.3: R101: Emptying fermentor

BO 1.6: R101: Emptying fermentor

BO 1.4: R101: Filling with washing water for washing BO 1.5: R101: Washing with aeration

BO 1.1: P102: Pumping fermentation solution from T103 to R101 BO 1.4: P102: Pumping washing water from T104 to R101 BO 1.3: P103: Pumping finished fermentation liquid from R101 to V102 BO 1.6: P103: Pumping washing water from R101 to V102 BO 1.3: V102: Loading with finished fermentation liquid from R101 BO 1.6: V102: Loading with washing water

BO 1.2: E102: Heat exchanging with gas exit of bubble column during fermentation BO 1.1: E101: Heating fermentation solution

BO 1.2: P101: Pumping aqueous sodium hydroxide from T101 to R101

BO 1.4: E101: Heating washing water

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Figure A5.4: Detailed Batch Cycle Diagram Reactivation Base case Detailed Batch Cycle Diagram Extraction 1 Base Case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5 15.5 16.5 0 10 20 30 40 50 60 70 80 90 100 110 120 time [min]

BO 2.2: S201: Filling with aqueous solution from V204

BO 2.3: S201: Filling with EA make up from T201 BO 2.4: S201: Filling with EA medium from V201

BO 2.5: S201: Transfer raffinate 1 to V204 S201: Mixing of content

S201: Settling content

BO 2.3: P201: Pumping EA make up from T201 to S201 BO 2.4: P201: Pumping EA medium from V201 to S201 BO 2.5: P202: Pumping raffinate 1 from S201 to V204

BO 2.2: P203: Pumping aqueous solution from V204 to S201 BO 2.4: V201: Transfer medium EA to S201

BO 2.6: V205: Loading with extract 1

BO 2.2: V204: Transfer aqueous solution to S201 BO 2.6: S201: Transfer extract 1 to V205

BO 2.6: P202: Pumping extract 1 from S201 to V205

BO 2.5: V204: Loading with raffinate 1

Each 8th fermentor batch the raffinate is stored in V204 and the 1st extract remains in S201. At this the content of V205 is transferred to S201 and the evaporative crystallization starts. After the crystallization the stored raffinate of the 8th fermentor batch undergoes the 2nd and 3rd extraction (see General Batch Cycle Diagram of Base Case). Detailed Batch Cycle Diagram Activation base case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 time [hours]

BO 1.8: R101: Filling fermentor with reactivation solution

BO 1.9: P101: Pump aqueous sodium hydroxide to R101 during reactivation BO 1.9: R101: Reactivation with aeration

BO 1.10: Emptying fermentor after reactivation

BO 1.8: P102: Pump reactivation solution from T105 to R101

BO 1.10: P103: Pump off reactivation solution to WWTP

BO 1.8: E101: Heating reactivation solution

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Figure A5.6: Detailed Batch Cycle Diagram Extraction 2 Base case

Figure A5.7: Detailed Batch Cycle Diagram Extraction 3 Base case Detailed Batch Cycle Diagram Extraction 2 Base Case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5 0 10 20 30 40 50 60 70 80 90 100 110 120 time [min]

BO 2.7: S201: Filling with raffinate 1 from V204

BO 2.8: S201: Filling with EA low from V202

BO 2.9: S201: Transfer raffinate 2 to V204 S201: Mixing of content

BO 2.8: P201: Pumping EA low from V202 to S201 BO 2.9: P202: Pumping raffinate 2 from S201 to V204

BO 2.7: P203: Pumping raffinate 1 from V204

t S201

BO 2.10: V201: Loading with extract 2 from S201

BO 2.9: V204: Loading with raffinate 1 BO 2.8: V202: Transfer EA low BO 2.10: S201: Transfer extract 2 to V201

BO 2.7: V204: Transfer raffinate 1 to S201

Detailed Batch Cycle Diagram Extraction 3 Base Case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 0 10 20 30 40 50 60 70 80 90 100 110 120 time [min]

BO 2.11: S201: Filling with raffinate 2 from V204

BO 2.12: S201: Filling with EA clean from V203

BO 2.13: S201: Transfer raffinate 3 to WWTP S201: Mixing of content

BO 2.12: P201: Pumping EA clean from V203 to S201

BO 2.13: P202: Pumping raffinate 3 from S201 to WWTP

BO 2.11: P203: Pumping raffinate 2 from V204 to S201 BO 2.14: V202: Loading with extract 3 from S201

BO 2.12: V203: Transfer EA clean to S201 BO 2.14: S201: Transfer extract 3 to V202

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Figure A5.8: Detailed Batch Cycle Diagram evaporative crystallization Base case Detailed Batch Cycle Diagram Crystallization Base Case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 time [hours]

BO 2.15: S201: Filling with loaded EA from V205 BO 2.16: S201: Evaporation of EA

BO 2.15: V205: Transfer loaded EA to S201 S201: Further crystallization

BO 2.15: P204: Pumping loaded EA from V205 to S201

BO 2.16: V203: Loading with recoverd EA from V206 BO 2.16: P205: Pumping recoverd EA from V206 to V203

BO 2.16: K201: Operating vacuumpump

BO 2.16: V206: Operating condensor

BO 2.16: E201: Operating condensor

BO 2.17: S201: Transfer crystal slurry from S201 to S202

BO 2.17: S202: Loading with crystal slurry

BO 2.17: P202: Pumping crystal slurry from S201 to S202

Detailed Batch Cycle Diagram Solid Handling Base Case

0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 0 1 2 3 4 5 6 7 8 9 10 11 time [hours]

BO 2.18: S202: Filter crystal suspension

BO 2.18: P206: Pumping filtrate to V205 and purge BO 2.19: S202: Wash crystals

BO 2.20: S202: Drying

BO 2.21: S202: Recovery crystals and packaging

BO 2.18: V205: Loading of V205 with filtrate BO 2.19: P206: Pumping spent wash water

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Appendix 5.3

Process Stream Summary Base case

APART UITPRINTEN en invoegen

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Appendix 5.4

Utilities Base case

APART UITPRINTEN

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Appendix 5.5

Process Flow Scheme ISPR

In this appendix the process flow schemes of the ISPR case are presented. The first scheme (see Appendix 5.5.1) presents the overall set up of the design. The following small schemes in Appendix 5.5.2 represent the successive batch operations.

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Appendix 5.5.1

Main Process Flow Scheme ISPR case

Appendix 5.5.2

Batch Operations ISPR case

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Appendix 5.6

Batch Cycle Diagrams ISPR

Below a general Batch Cycle Diagram of the ISPR case is presented for one year of production. In Figure A5.11 a Batch Cycle Diagram is given in which each procedure is presented in more detail.

Figure A5.10: Batch process cycle diagram ISPR one year of production

0

0 168 336 504 672 840 1008 1176 1344 1512 1680 1848 2016

time [weeks (hours)]

1. BO1/BO2 Filling of fermentor and start of aeration and glucose feeding, start using R101

2. BO3/BO4 Period of feeding of OIP to ISPR, start using S101 and S102

3. BO5 Closedown period, feeding of OIP stopped

4. BO11 Cleaning of ISPR system

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Appendix 5.7

Process Stream Summary ISPR

APART UITPRINTEN

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Appendix 5.8

Utilities Base ISPR

APART UITPRINTEN

Design of an integrated fermentation-crystallization process applied to the production of DOIP

CPD nr. 3312

Conceptual Process Design

Process Systems Engineering

DelftChemTech - Faculty of Applied Sciences

Delft University of Technology

Appendix

Design of an integrated

fermentation-crystallization process

applied to the production of DOIP

Authors

Study nr. Telephone nr.

Sjoerd Blokker

Marcel Dabkowski

Willem Groendijk

Dirk Renckens

Jeroen de Rond

1013807

1013882

9279761

9686621

1014099

06 – 18812808

06 – 27106515

06 – 11340028

06 – 24897042

06 – 18086546

Keywords

Fermentation, crystallization, ISPR, in situ product removal,

Levodione production, (6R)-dihydro-oxoisophorone, DOIP

Assignment issued: 21-09-2004

Report issued:

20-12-2004

Table of contents

Appendix 1 Extra designed unit operations

Appendix 1.1

Adsorber

Appendix 1.2

Dialysis



 











Appendix 2 Process, Options and Selection

Appendix 2.1

Process flow sheets Base case

Reaction

Separation

Purification

Reaction

Separation

Purification

Appendix 3 Basis of Design

Appendix 3.1

List of Pure components

Appendix 3.2

Battery limit

Appendix 3.3

Costs of immobilization

Appendix 3.4

Economic Margin

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







Appendix 4 Thermodynamic Properties

Appendix 4.1

Method of Anderson, Beyer and Watson

Appendix 4.2

Lydersen’s method

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





Appendix 4.3 Critical compressibility factor and acentric factor

Appendix 4.4