PRODUCTION OF L-PHENYLACETYLCARBINOL

Integrated Project Presentation Group KB1

NAME MATRIC NO.

CHUNG KEN VUI A 98753LIM KAH HUAY A132816TEE ZHAO KANG A 132597SONIA DILIP PATEL A133115WONG MEI FANG A132213

CONTENTS

Literature Review Usage of L-PAC Economy Analysis: Production & Demand Process Description with PFD Calculation of material and energy balance in the

fermentor Pressure Vessel Design Heat Utility Design and Heat Integration Control Dynamic and Process Pollution Control and Cleaner Production

Literature ReviewGlucose

Benzaldehyde

Saccharomyces cerevisiae

L-PAC

Other products:Ephedrine,

pseudoephedrine

Pyruvic acid

Acetaldehyde Ephedra sinica

Standard microbes for the fermentation where ethanol-producers are

preferred (Hagel et al. 2012) and gives significant yields

(Kumar et al. 2006)

Biotransformation route remains the preferred method for the industry

(Shukla & Kulkarni 2000)

Traditional process to produce ephedrine that is no longer preferred due to

tedious and expensive downstream processes

(Khan et al. 2012)

L-PAC: Applications and Usages

Methamphetamine

D-pseudoephedrine

L-ephedrine

Used as the precursor for the production of these drugs that are known for the nasal decongestant properties (Oliver et al. 1997,

Shukla & Kulkarni 2000)

Economy Analysis

Global demand and supply for L-PAC from 2006 to 2013 (reproduced on MATLAB®)

Source: Nanjing Pharmaceutical Company 2006, China Chemical Industry News 2012

2006 2007 2008 2009 2010 2011 2012 2013800

1000

1200

1400

1600

1800

2000

2200

2400Global Demand and Supply for L-PAC from 2006 to 2013

Year

Am

ount

of

L-P

AC

(in

103 k

g or

ton

nes)

Demand

Supply

PROPOSED PRODUCTION

Mode of operation: Fed-batch fermentation

Total demand for L-PAC in Malaysia in 2013 = 21,000 kg (Globinmed 2010)

Proposed annual Production:[L-PAC] = 25% of total demand

= 5,250 kg

Production rate:[L-PAC] = 5,250kg/150 cycles

= 35 kg per cycle

Bulk price for L-PAC is around RM312.30 per kg (Balantes Pharma 2012)

Process ProductionProcess Production

Cultivation of baker’s

yeast

Fermentation of pyruvic

avid

Fermentation of L-PAC

Centrifugation and holding Cold

adduction by precipitation

Rotary filtration

Dissolution of Adduct

Ethanol extraction

Distillation and recovery

of ethanol

Spray Drying

Mass Balance

Stoichiometric equation: (Shuler & Kargi 2002)Calculations are shown for F-102 and F-103 as examples:

Stream In OutFeed Gas Total Product Gas-off Total

Glucose 72.00 0 72.00 0.66 0 0.66C7H6O 3.03 0 3.03 0 0 0

NH3 0.50 0 0.50 0 0 0

Biomass 0.36 0 0.36 3.87 0 3.87L-PAC 0 0 0 35 0 35N2 0 1620.87 1620.87 0 1620.87 1620.87

CO2 0 0 0 0 14.53 14.53

H2O 458.71 0 458.71 480.54 0 480.54

Ethanol 5.40 0 5.40 5.40 0 5.40Total 540.00 1620.87 2160.87 525.47 1635.40 2160.87

Comparison with SuperPro® DesignerSuperPro® 533.47 1627.39 2160.86Error(%) -1.52 0.49 0.00

Mass balance involving F-102 and F-103:

Energy Balance

Unit Metabolism

Heat

(kJ)

Agitation

Heat

(kJ)

Sensible Heat Heat of

reaction

(kJ)

Energy In

(kJ)

Energy Out

(kJ)

F-102 75789.55 19639.53 8420.09 8587.11 - 95587.10

F-103 3697.05 18613.42 8606.01 8717.42 -23447.99

E-101 - - 60227.89 10037.98 50189.91

The heat balance inside the fermentor (O’Shea 1998):

iCON simulation is also used to calculate the energy balance in distillation column, COL-102.

Stream 47 48 51 In – Out

Energy (W) -11379.47 -3243.51 -5854.92 -2281.04

Utility Condenser Reboiler Change

Energy (W) 264819.45 267100.60 -2281.15

Pressure Vessel Design: Internal Pressure

Fermentor, F-102

Specifications and dimensions:Material = SS 316 or ASME SA-240

Radius of vessel = 0.3545 mDiameter of vessel = 0.709 mHeight = 1.996 m

Cylindrical shellHeight = 1.418 m

Torispherical heads (Top and Bottom)Knuckle radius = 0.0425 mCrown radius = 0.363 mHeight = 0.289 m

Calculated that:Design pressure = 69.12 psi = 477 kPaToverall = 0.14’’Tmin= 3 mmDesign thickness = 5 mmMAWP vessel = 98.94 psi

Specifications and dimensions:Material = SS 316 or ASME SA-240

Radius of vessel = 0.25 mDiameter of vessel = 0.50 mHeight = 3.77 m

Cylindrical shellHeight = 3.52 m

Ellipsoidal heads (Top and Bottom)Height = 0.125 m

Calculated that:Design pressure = 20.36psiToverall = 5.65mmTmin= 3.65mmDesign thickness = 6.35 mmMAWP vessel = 15psi (Atmospheric pressure)

Pressure Vessel Design: External Pressure

Distillation column, COL-102

Properties F-102 C0L-102Design Pressure, PD (psi) 69.12 20.36

Minimum wall thickness, tmin (mm) 3.00 3.65

Design thickness, tD (mm) 5.00 6.35

MAWP vessel (psi) 98.94 15Circumferential stress, σ1 (N/mm2) 33.78 3.99

Total longitudinal stress, σ2 (N/mm2) 16.26 - 1.36

Maximum stress intensity, (Δσ)max

(N/mm2)

17.52 5.34

Design stress, S (N/mm2) 108.8 132.32Critical buckling stress,σc (N/mm2) 139.08 247.71

σcompressive (N/mm2) 0.629 4.0345

Skirt thickness, ts (mm) - 10

Design skirt thickness, tD(mm) - 12

Bolt root diameter, (mm) - 10.41Impeller diameter, Di (m)

Impeller spacing, Hi (m)

Impeller blade length, Li (m)

Impeller blade height, Wi (m)

Location of gas sparger, Hb (m)

0.2340.4680.0590.0470.117

-----

Pressure Vessel Design: Summary

Heat Utility Design

Jacketed Vessel into F-

102

Cooler E-101

Jacketed Vessel into F-

103

Condensor E-102

Reboiler E-103

Kettle Reboiler3.2 mm o.d., 1.9 mm i.d., L = 4.8 m, plain U-tubes

Total Condensor3.2 mm o.d., 1.9 mm i.d., L = 0.508 m, admiralty brass

Dimple JacketSS 316, pattern type 1 (100/100) 11 mm, base length = 63.5 mm

U-tube exchanger6.35 mm o.d., 2.465 mm i.d., L = 6.10 m, cupro-nickel

Jacket with spiral baffleStainless steel 316, channel 15 x 200 mm, 6 spirals

Heat Utility Design: Types

Figure 6.7 Heat Cascade

18.67

0

-23.97

0

-261

18.67

0

-23.97

0

-261

Start with 0 kW

Start with 18.67 kW

107.6

97.05

72

25

20

-5

∆Tmin = 20°C

-18.67

-18.67

5.3

5.3

266.3

0

0

42.64

42.64

303.64

QHmin = 18.67 kW

1

2

3

4

5

QCmin = 303.64 kW

Heat Utility Design: Heat Integration

Before After

Total energy required 303.64kW 303.64kW

Total energy recovery 0%

Table 6.10 Total energy requirement

Figure 6.8 Grid Representative

20

48

55

30°C

82°C

97.6°C

35°C

Cp

pinch

1.77

0.51

10.44

∆Habove pinch (kW)

0

0

18.67

5°C

87.05°C

107.5°C

107.5°C

∆Hbelow pinch (kW)

261

23.97

0

Heat Utility Design: Heat Integration

Properties Jacketed Vessel F-102

Cooler E-101

Jacketed VesselF-103

Condensor E-102

Reboiler E-103

Heat load, Q (kW) 1.106 14.21 0.271 0.0444 2.71

Uestimate (W/m2 720 550 550 650 850

Area required (m2) 9.30 0.0014 0.1909

Area of channel (m2) 3 x 10-3 1.86 x 10-3

hj (W/m2°C) 1661.41 - 967.6 - -

hff,v (W/m2°C) 3785 - 3785 - -

hff,j (W/m2°C) 4000 - 5000 - -

∆wall (m) 0.003 - 0.003 - -

hv (W/m2°C) 13203.13 - 10562.73 - -

hnb (W/m2°C) - - - - 2528.69

hc (W/m2°C) - - - 1000 -

ut (m/s) - 0.57 - 2.68 -

hi (W/m2°C) - 3557.38 - 16243.92 -

us (m/s) - 0.18 - 50.35 2.08

hs (W/m2°C) - 3715.34 - - -

Ucalculated (W/m2°C) 726.81 473.47 562.93 649.99 863.56

∆Ps (kPa) - 36.66 - 52.29 2.09

∆Pt (kPa) 0.805 30.14 0.178 50.05 -

Heat Utility Design: Summary

Process Dynamic & Control: ModelingFermentor, F-

103

The mathematical models that are used for F-103:1. (Rate of accumulation) = (Rate in) + (Rate of formation)2. For component balance – cell:

3. For component balance – product:

4. For component balance – substrate:

SKS

XdtdX

s max

XYdtdP

XP /

dt

SSd

YX f

SP

/

PD&C: Degree of FreedomDegree of Freedom analysis

Number of variables = 10

Number of equation = 4 (as in previous slide)

Degree of freedom:

Variables to be controlled:

Revised degree of freedom:

Hence, 3 control loops are to be designed- Level, flow rate into the fermentor, antifoam

PXSSFYYVKN fSXXPSV ,,,,,,,,, //max

6410

F

EVF

N

NNN

SKV ,, max

336 FN

LT

LC

Sensor – Differential pressure

Signal type – Pneumatic

Valve – Diaphragm Source: Smith & Corripio 2006

Level sensor detects difference in pressure caused

by hydrostatic head

Sends pneumatic

signal to the transmitter

Transmitter directs the

signal to the level controller

Controller calculates the

necessary correction needed

Controller sends signal to the

diaphragm valve located at the

output of F-103

Diaphragm valve moves the

diaphragm to open or close the

area of flow

PD&C: Level Control Loop

• Based on the Environment Quality (Amendment) Act 2012:

1. Environmental Quality (Clean Air) (Amendment) Regulations 2000

2. Environmental Quality (Industrial Effluent) Regulations 2009

3. Environmental Quality (Scheduled Wastes) (Amendment) Regulations 2007

4. Environmental Quality (Sewage) Regulations 2009

(Source: DOE 2013)

Pollution Control and Cleaner Production

  (1)Unit

(2)Standard A

(3)Standard B

Chemical Oxygen Demand mg/L 80 200Temperature 0C 40 40pH value - 6.0-9.0 5.5-9.0BOD5 at 200C mg/L 20 50

Suspended solid mg/L 50 100Phenol mg/L 0.001 1.0Ammoniacal Nitrogen mg/L 10 20FormaldehydeColour

mg/LADMI*

1.0100

2.0200

Discharge Limit according EQ(IE)R 2009(Source: Taken and Modified from Department of Environment 2013)

PC&CP: Wastewater Treatment Plant

Overall Diagram for Modified WWTP

Stream Q Q + Qr Q - Qw Qu Qr Qw

Flow rate (m3/d) 13.15 14.77 9.37 5.40 1.62 3.78S, BOD(mg/L) 14062.86 18 18 - - -X, SS (mg/L) 0 9410.0

645 9365.0

69365.0

69365.0

6

Mass Balance for Modified WWTP

Equation used (Michael & David 2011):

X = 9410.06 mg/L V = 56.46m3 θc = 14.83 days O2 = 4471.20 kg/day

References1. Bukhari, A. A. 2012. Part I: Treatment of Pharmaceutical Wastewater. Pharmaceutical Waste Treatment and Disposal Practices. KFUPM2. Cheresources. 2010. Jacketed vessel design forum. http://www.cheresources.com/content/articles/heat-transfer/jacketed-

vessel-design [29 April 2013].3. China Chemical Industry News. 2012. Synthetic Ephederine from Zhejiang Achievements Conversion Award.

http://www.39kf.com/my/tag_1_32032a-24892a-24901/ [16 March 2013].4. Department of Environment Malaysia. 2011. Legistration, acts, regulation & order.

http://www.doe.gov.my/portal/legislation-actsregulation-order/ [3 April 2013]5. Geankoplis, C.J. 2003. Transport Processes and Separation Process Principles: Includes Unit Operations. Fourth Edition. New

Jersey: Prentice Hall.6. Globinmed. 2010. Ephedrine and its salt. Price range by year from 2000 to 2007. http://www.globinmed.com/index.php?

option=com_content&view=article&id=81286:ephedrine-a-its-salts--price-values-by-year-from-2000-to-200&catid=45&Itemid=137

7. Hagel, J.M., Krizevski, R., Marsolais, F., Lewinsohn, E. & Facchini, P.J. 2012. Biosynthesis of amphetamine analogs in plants. Trends in Plant Science 17(7): 404-412.

8. Khan, M. A., Ul-Haq, I., Javed, M. M., Qadeer, M.A., Akhtar, N. & Bokhari, S.A.I. 2012. Studies on the Production of L-Phenylacetylcarbinol by Candida Utilis in Shake Flask. Pak J. Bot. 44: 361-364.

9. Kostraby, M.M. 1999. The yeast mediated synthesis of the L-ephedrine precursor, L-phenylacetylcarbinol, in an organic solvent. Thesis Doctor of Philosophy, School of Life Sciences and Technology, Victoria University of Technology.

10.Kumar, M.R., Chari, M.A. & Narasu, M.L. 2006. Production of L-phenylacetylcarbinol (L-PAC) by different novel strains of yeasts in molasses and sugar cane juice as production medium. Research Journal of Microbiology 1(5): 433 – 437.

11.McKetta, J.J.. 1991. Heat Transfer Design Methods. New York: Marcel Dekker, Inc.12.Mohamad Sulong, Astimar A. Aziz & AB Gapor Md. Top 2008 Bio-Fertiliser from palm Oil Biomass and POME Solids by Mobile

Composter. MPOB Information Series. ISSN 1511-787113.Nanjing Pharmaceutical Company. 2006. Ephederine and Mongolia Shengle Pharmaceutical Research Report.

http://wenku.baidu.com/view/dfcea5254b35eefdc8d3331a.html [16 March 2013].14.Oliver, A.L., Roddick, F.A., & Anderson, B.N. 1997. Cleaner production of phenylacetylcarbinol by yeast through productivity

improvements and waste minimisation. Pure & Applied Chemistry 69(11): 2371-2385.15.Shukla, V.B. & Kulkarni, P.R. 2000. L-phenylacetylcarbinol (L-PAC) biosynthesis and industrial applications. World Journal of

Microbiology and Biotechnology 16(7): 499-506.16.Smith, C.A. & Corripio, A.B. 2006. Principles andPractice of Automatic Process Control. Third edition. New Jersey: John Wiley

& Sons.17.Towler, G. & Sinnott, R. 2013. Chemical Engineering Design: Principles, Practice and Economics of Plant and Process

Design. Second edition. London: Butterworth-Heinemann.18.Tripathi, C.M., Agarwal, S.C. & Basu, S.K. 1997. Production of L-Phenylacetylcarbinol by fermentation. Journal of

Fermentation and Bioengineering 84: 487-492.

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