Professional Documents
Culture Documents
Manufacturing of CPG
Manufacturing of CPG
Project Engineers:
Milana Trifkovic
306-916 Wonderland Rd.S.
London, ON N6K 2V8
519.471.2675
milanat@gmail.com
250174208
Sandra Cardoso
19 Cherish Court
London ON N6K 4H2
519.472.3061
sandra.cardoso@gmail.com
250114116
Table of Contents
1 Abstract..........................................................................................................6
2 Acknowledgments.........................................................................................7
3 Introduction....................................................................................................8
4 Need Analysis..............................................................................................10
6 Selected Process.........................................................................................15
17
7.3 Resolution..............................................................................................25
7.5 Methylation.............................................................................................29
8.2 Scheduling..............................................................................................36
2
9 Process Economics....................................................................................40
10 Conclusion...................................................................................................47
11 References.................................................................................................49
12 Appendix........................................................................................................50
3
List of Figures
Figure 2. Results of CAPRIE Study (Harker, Boissel, Pilgrim & Gent, 1996).......11
4
List of Tables
5
1 Abstract
Bisulfate (an anti-platelet drug) was successfully designed and simulated using
SuperPro Designer (SPD) software package. The plant was designed based on
pressure were designed to reduce the production and maintenance costs. The
performance of each unit as well as the overall process were evaluated by the
software which facilitated diagnosis and solution of the problems. The software
was extremely useful not only in design and simulation but also in economical
analysis. The simulation was the authors enhancement of the fourth year design
6
2 Acknowledgments
The project engineers would like to thank their advising professors, Dr. Shazhad
Barghi, Dr. Sohrab Rohani as well the invaluable help of Mehdi Sheikhzadeh,
from The University of Western Ontario. We would also like to thank the
(Academic Site Edition) v. 6.0. for this project after the authors request. The
help provided by Dr. David Stradiotto of Apotex Pharmachem has also been
invaluable and the project engineers would also like to express their thanks to
him as well.
7
3 Introduction
A brief history and background of the process as well as current trends in this
necessary to express the full anti-aggregating activity of the drug. Six different
polymorphs have been identified so far, but only Form I and Form II are used in
(S)--(o-chlorophenyl)-6,7-dihydrothiento[3,2-c]pyridine-5(4H)-acetate), in 2D
8
3.2 Current Trends and Future Directions
2002, more than any other disease (W1, 2005). Heart disease is one of the
leading causes of death for men and women in Canada today. The exact number
that one in four Canadians have some form of heart disease, disease of the
blood vessels or is at risk for stroke (W1, 2005). If this estimate is accurate,
The economic burden worldwide in treating patients who have suffered and
these costs that the move to prevent thrombotic events in patients at risk through
Aspirin and Plavix were studied in patients at risk of stroke. Overall, it was
found that those treated with any anti-platelet drug had an 8.9 % reduction in
stroke versus those treated with no drugs. It was also reported that patients
This report summarizes the design simulation and economical analysis of the
9
4 Need Analysis
The section below summarizes the various aspects of a full needs analysis
including a market study, possible environmental issues and finally economic and
The patent for Plavix expires in 2007, and many generic pharmaceutical
clopidogrel bisulfate. Interest in the production of this drug comes from the fact
that sales of anti-thrombotic drugs have more than doubled in the past few years
(W2, 2005).
As of March 2004, the anti-thrombotic market reached annual sales of $13 billion
(USD) and has shown constant growth since 1999 (W2, 2005). Plavix is
currently the market leader with sales reaching nearly $4 billion in 2004 (W2,
2005).
study was a double blind trial which compared the effect of Plavix (75 mg daily)
10
approximately 19, 000 patients with recent histories of myocardial infarction 1
(within 35 days) and recent histories of ischemic stroke 2(within 6 months) for an
average of 1.6 years. Figure 2 below summarizes the results of this study.
Months of follow up
Figure 2. Results of CAPRIE Study (Harker, Boissel, Pilgrim & Gent, 1996)
It can be seen from this graph that patients using Plavix experienced less fatal
and non-fatal vascular events compared to the patients treated with Aspirin.
Compared with aspirin, clopidogrel reduced the combined risk of ischemic stroke,
1
Heart attack. Damage to the heart muscle due to insufficient coronary artery blood supply
(www3.uta.edu/sswtech/sapvc/information/teens13_15/Teens_(ages13-15)_Glossary.htm)
2
The most common kind of stroke; caused by an interruption in the flow of blood to the brain
(wordnet.princeton.edu/perl/webwn)
3
Unstable angina occurs at rest and usually means that a coronary artery has narrowed to such a
critical degree that the heart is not receiving enough oxygen even at rest
(www.med.miami.edu/glossary/art.asp).
11
randomized to receive Plavix (75 mg daily) and Aspirin (75 325 mg daily)
or placebo and Aspirin (75 325 mg daily) and were treated for up to one year
Figure 3 depicts the results from the CURE trials and is shown below.
From this graph, it is clear that Plavix combined with Aspirin is more effective
Overall, there was a 20 % relative risk reduction (95% CI of 10%-28%) for the
From both the CAPRIE and CURE studies it is clear that Plavix is effective at
12
4.2 Economic and Cost Factors
Currently the cost of one Plavix tablet is $2.50 (CAD) which is very costly for a
patient that requires to take one tablet/day. Recent sales forecasts made by IMS
Using the SuperPro Design software package, a full economic and cost analysis
of the process in terms of cost of equipment, raw material, utilities is shown later
on in the report.
The proposed plant capacity for the manufacturing of CPG is 91.25 million tablets
per year, although there will also be production of other active pharmaceutical
13
The process is related to a patented procedure therefore alternative processes, if
they exist at all, are not available. However, after reviewing the procedure
described in the patent and developing the process described in this report, the
The entire drug synthesis could be performed using one reactor, but the choice of
two reactors in parallel was made according to the length of the batch process.
Although the initial investment will be greater, the main advantage of two reactors
simultaneously.
One other alternative for the reactor set up that was considered was the
possibility of an adjustable size reactor. That is, being able to attach different
sized bottoms to the reactor as dictated by the capacity required for a given
reaction. This option is advantageous since it would allow the plant to be adapted
for different processes with a smaller initial investment. However, the chances of
contamination would be high and could pose a problem in the quality of the final
product.
One main advantage with both of these alternatives is the shortening of the batch
6 Selected Process
The selected process is a modified version of the method found in the Sanofi-
Synthelab patent (US patent: 6858734). Figure 4 below depicts a very simplified
14
representation of the main units required for manufacturing of Clopidogrel
Bisulfate.
There are six chemical reactions involved in producing Clopidogrel Bisulfate from
the raw materials. Figure 5 summarizes these steps, including the operating
15
Figure 5. Summary of Reaction Scheme
The sample Process Flow Diagram for the Step 1 with is shown in Appendix.
16
7 Process Description and Model Development with SuperPro
Software
The following section describes the process and simulation with SuperPro
software. SuperPro is an advanced simulation and data management tool for the
2002).
Although not covered in this report, the software is very useful for secondary
This report focuses on simulation of the primary process (the production of the
17
Manufacturing Process of Clopidogrel Bisulfate
S-301
P-7 / RV-103
Storage
S-303
S-207 P-5 / RV-101
P-6 / R-102 Mixer-Settler Extraction
S-306 P-8 / F-101
S-305 Vessel Procedure
Nutsche Filtration
S-405
Methylation Reaction
S-133
S-401 S-502 S-134
S-403 P-10 / RV-104
S-503
Storage S-504
S-402
S-404 S-137
P-12 / F-101
P-11 / R-101 S-506
P-9 / R-101
Nutsche Filtration
Vessel Procedure S-601
Vessel Procedure
CPG-BS
P-15 / DCDR-101 P-13 / R-102
S-606
Double Cone Drying Vessel Procedure
P-14 / F-101
Nutsche Filtration
18
7.1 Coupling Reaction (Strecker Synthesis)
O CN
T=40-50C
1.H2O N
NH H
+ NaCN +
S S Cl
Cl
6,7dihydro-4H-thieno[3,2-c]pyridine 2-chlorobenzaldehyde 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]
pyridin-5(4H)-yl)acetonitrile
Scheme 1. Reaction Mechanism for Strecker Synthesis (Step 1)
The raw materials are received and put under quarantine until they pass testing
criteria for purity. Sodium bisulfate (S-101) is mixed with purified water (S- 105) in
the reactor (R-101). The reactor is not pressurized (although is still equipped with
a pressure relief valve (PRV-101) as a safety precaution) and the addition of all
101.3 kPa) and room temperature (approximately 25 C). Once the sodium
pyridine (S- 103) is pumped into the reactor via (P-102) and sodium cyanide (S-
104) is also added to the reaction mixture. The reactor jacket temperature is
steam (S-112) and cold water (S-110) and maintained for 6 hours until the
reaction is quenched with water (S-105) via pump (P-103). The product of this
(S-107) is pumped (P-107) into the same receiving vessel and the mixture
19
back to the reactor while the aqueous layer is left in the receiving vessel (RV-
101). Here the aqueous layer is extracted a second time to maximize the
isolation of the product, which is then sent back to the reactor via a pump (P-
106). The aqueous layer (S-109) is sent to the waste treatment facility.
application. The first step in the simulation is registering all the ingredients
involved in the process. This can be done by retrieving the specific component
from SPD pure component library, or by entering the physical data manually in
user databank.
The user enters the process flowsheet by putting together unit procedures
selected from the SPD library. The equipment included for this step is:
shown below Table 1.The operation sequence was set according to the process
20
Charge (Sodium Bisulfate)
Heat
Agitate
Charge (Chlorobenzaldehyde )
Charge (6,7 dihydro-4H-pyridine)
Charge (NaCN)
Batch Stoich. Reaction
Charge (Water-Qenching)
Transfer Out
RV-101 Mixer Settler Extraction (Extract Intermediate I)
Each operation was initialized with the appropriate engineering data such are
duration was fixed (US patent: 6858734). Furthermore, the operations start was
specified either based on the beginning of the batch (charging the raw material),
or related to the end of another operation (i.e. reaction was started at the end of
stoichiometry, and the extraction operation required a separation yield for each
stream component. The reaction conversion was known from the patent data
(96%), and the separation was assumed to be perfect for the purpose of
The quenching operation was not available in the software, and thus water-
21
7.2 Efficient Hydration of Nitriles to Amides
CN CONH2
T=80-82C
N 1.KOH N
2.t-BuOH
S S Cl
Cl
(2-cholrphenyl)-(6,7-dihydro-4H-thieno 2-chloro-phenyl-(6,7-dihydro-4H-thieno
[3,2-c]pyrid-5-yl) acetonitrile [3,2-c] pyrid-5-yl) acetamide
into the receiving vessel (RV-102). The product of the first step remains in the
reactor where butyl alcohol (S-201) is pumped (P-201) and KOH (S-202) is
added. This mixture is stirred vigorously after which it is refluxed using the
condenser (C-101) for 3 hours at 80-82 C. The reactor jacket is then cooled (S-
reaction. The product is not soluble in water, thus, in this case, water behaves as
(RV-203) to 5-10 C, and added slowly to the reactor for 15 minutes. The reaction
acetate (S-206) is pumped (P-205) into the same receiving vessel where the
(P-206) back to the reactor while the aqueous layer (S-208) is sent for waste
treatment. The residual solvents vapors are removed from the reactor (R-102)
22
under vacuum by the condenser (C-101), which is sent to solvent recovery in the
The flowsheet was expanded by adding three additional unit procedures selected
The unit-operations in the sequence needed to simulate the Step 2 are shown in
Table 2.
23
The excess solvent from the first step had to be transferred to the receiving
vessel (RV-102) before the next reaction was initiated, for the purpose of
optimizing the reactor volume. This was simulated by using Batch Vaporization
the percentage of their removal. The reactor (R-101) was shared between the
procedures for Step 1 and Step 2, and this was specified in the reactor data, and
also taken into account when scheduling the various operations. The reaction
was scheduled after the reactor content was transferred to the receiving vessel
cleaning was also specified. As mentioned in the process description the reaction
mixture is refluxed by using condenser for three hours, and this is a quite
However, this operation was not available in the SPD library. The extraction was
simulated in the same way as in Step 1; the partition coefficients for several
components were selected. For the purpose of the simplicity of the calculation,
the total separation of the desired component was assumed, and the partition
24
7.3 Resolution
CONH2 CONH2
O
N N S
OH
O
S S Cl
Cl O
2-chloro-phenyl-(6,7-dihydro-4H- (+)-(S-(2-chlorophenyl)-(6,7-dihydro-4H-thieno-[3,2-c]pyrid-5-yl)
thieno[3,2-c] pyrid-5-yl) acetamide acetamide (1S-(+)-camphor-10-sulfonic acid ) salt
Scheme 3. Reaction Mechanism for Resolution (Step 3)
The excess of ethyl acetate that comes in the reactor with the Intermediate II is
first removed by vacuum into the receiving vessel (RV-103). Acetone (S-301) and
into the reactor (R-102) containing the product from the previous reaction. This
addition is done at 15-20 C over the course of 4 hours. After the reaction is
completed, the solvents are removed from the reaction mixture under reduced
gravity to a filter (F-101) where it is filtered and washed twice with acetone (S-
304). The filtrate (S-306) is sent to the waste treatment and the filter cake (S-
The Step 3 is simulated using the following unit procedures from the SPD library:
25
Nutsche Filter (F-101) in which the separation of the Intermediate III
occurs
The operations in the sequence needed to simulate the Step 3 are shown in
Table 3.
The Batch Vaporization was used twice in this step to simulate the removal of
specified, and the components to be removed were specified as well. The first
26
time, the excess of the solvent from the extractor was vaporized, and the second
time acetone was removed from the reaction mixture. The stoichiometric reaction
was simulated using the conversion of 60% of the Intermediate II, which was a
reference component. The product of Step 3 was filtered using Nutshce filter unit
procedure. The cake thickness as well as the cake dryness had to be specified in
order to simulate the procedure. The cake was also washed with acetone.
CONH2
CONH2
O
N
N S
OH
O S
S Cl
Cl O
(+)-(S-(2-chlorophenyl)-(6,7-dihydro-4H-thieno-[3,2-c]pyrid-5-yl) (+)-(S-(2-chloro-phenyl)-(6,7-dihydro-4H-
acetamide (1S-(+)-camphor-10-sulfonic acid ) salt thieno[3,2-c] pyrid-5-yl) acetamide
Once the solid product from Step 3 is transferred to the second reactor (R-102),
purified water (S-403) and sodium carbonate solution (S-401) are added using
pumps (P-401) and (P-402) respectively. This mixture is stirred for 2 hours and
after the reaction is completed, ethyl acetate (S-402) is pumped (P-103) into the
reactor for extraction of the product. The reaction occurs at 40 C. The aqueous
layer contains the undesired (R) - enantiomer and is removed from the bottom of
the reactor (S-404) where it may undergo further purification. The solvents from
the organic layer are removed by condenser (C-101) and sent to the receiving
27
vessel (RV-104) via (S-405). This process results in obtaining the solid product
(S-enantiomer).
The Step 4 is simulated using Stirred reactor (R-101) in which the Intermediate
component. The excess solvent is removed in this case using Batch Extraction /
Phase Split for the separation of the Intermediate IV. The percentage of
component removal was specified in the model and the undesired components
28
7.5 Methylation
CONH2 COOMe
N N
S S Cl
Cl
the solid product from the previous step and stirred. Once the product is
dissolved concentrated sulfuric acid (S-502) was added in portions via (P-502) to
the reaction mixture over a period of 1.5 hours. This reaction mixture is then
this information was taken from the patent, and those experiments have not been
optimized. It is also applicable to the lab scale, but it is most likely different in the
pilot plant. After the reaction is complete the residual solvents are removed under
into the reactor and mixed for 0.5 hours. This solution is filtered (F-101) and the
filtrate is sent back to the reactor using a pump (P-506) and the solid waste from
the cake (S-506) is sent to waste treatment. The aqueous layer is separated in
the reactor and sent to waste treatment via (S-508). The remaining solvents are
removed under vacuum using (C-101), and the oily product is obtained and sent
29
Process Simulation for Step 5
The unit-operations in the sequence needed to simulate the Step 2 are shown in
Table 5.
The charge operations as well as the scheduling of the various operations were
performed in the similar manner as in the previous steps. The reaction extent
30
pressure of 50 KPa. The reactor (R-101) is shared between several steps, and
this was also specified when scheduling the operations in various sections. The
In Place Cleaning operation was scheduled after the reactor content was
transferred to the filter (F-101). Methanol was chosen as a cleaning agent, and
COOMe
COOMe
N
N
HSO4
S Cl
S Cl
(+) Methyl (2-chlorophenyl)-(6,7-dihydro-4H (+) Methyl (2-chlorophenyl)-(6,7-dihydro-4H
-thieno[3,2-c] pyrid-5-yl) acetate -thieno[3,2-c] pyrid-5-yl) acetatehydrogen sulfate salt
Scheme 6. Reaction Mechanism for Acid Addition (Step 6)
last step. Concentrated sulfuric acid (S-602) is also pumped and cooled by (P-
of the CPG bisulfate. Water by itself is not a sufficient coolant to obtain this
temperature inside the reactor, and thus the mixture of methanol and water will
be used as a coolant for this reaction step. The reaction mixture (S-605) is sent
to a filter (F-101) to separate the solid product and the filter cake is washed twice
with acetone (S-604). The solid is sent to a vacuum rotary cone dryer (D-101) at
31
25 C where it is dried by contact with the hot surface of the dryer walls. The
For this step the following unit procedures are needed to simulate the process
described above:
The unit-operations in the sequence needed to simulate the Step 6 are shown in
Table 6.
32
Table 6. Unit Operations for Step 6
The reactive crystallization occurs in Step 6, and this was still simulated by using
This was done in order to obtain the product first with the conversion of 100%,
and then to indicate the formation of solids. The crystal form component was
indicated, and the final temperature of 5 C. The cleaning of the reactor was
simulated using In Place Cleaning operation, so that the reactor is ready for the
next running the next batch. The excess of the solvent was vaporized under the
pressure of 50 KPa. The final product of was filtered using Nutshce filter unit
33
procedure. The cake thickness as well as the cake dryness had to be specified in
order to simulate this procedure. The cake was also washed with acetone.
Finally, the product was dried using Double Cone Dryer unit procedure. In the
real process the drying is performed under vacuum, but this unit procedure was
34
8 Simulation Results
The material and energy balance, the scheduling information, as well as the
economic analysis for the entire process are presented in this section.
The software package track material balances across the entire process. The
solution of material and energy balances involves the calculation of the flowrate,
the flowsheet. The composition of the intermediates and outlet process streams
is calculated assuming that the information about the feed streams were entered
and initialized for all the unit operations. The advantage of SPD over other batch
software packages used for this project was that material balance results are
This opens a window with the detail description of the composition, flowrate and
The generated report for material and stream balance contains the overall
material balance, the stream material balance, the material balance related to
The overall process data and the raw material requirements are shown below in
Tables 7 and 8.
35
Table 7. Overall Process Data
Table 8 depicts the raw material requirements for the entire process.
8.2 Scheduling
The SPD perform process scheduling and generates the Gantt chart which is
shown below in Figure 7. Note that in this Gantt chart, only the main procedures
were shown, but there is an option of showing each operation within the specific
procedure.
36
Figure 7. Gantt chart for Manufacturing Process of Clopidogrel Bisulfate
As seen from the Figure 6, the longest procedure is P-11 (Methylation Reaction)
in the reactor (R-101). This indicates that the main bottleneck of the entire
process is in this procedure, and that main optimization of the process should be
It can be also seen that there is an overlap between some of the steps. This is
due to the cleaning in place operation of one reactor, while the reaction for the
following step is carried out in the other reactor. Figure 8 depicts this occurrence
37
R-101 is being cleaned
while R-102 is in
operation
39
9 Process Economics
Designer which also allows for an extensive economic analysis. With the
successful compilation, the Total Capital Investment, Annual Operating Costs and
full Profitability Analysis were completed and shown below in more detail.
The calculations for fixed capital cost were done using SPD. The purchase cost
is first factor for cost estimation. This can be evaluated either by using built-in
known value for all equipments. In this study, the purchase costs of all major
40
Table 9. Purchase Costs (PC) of Major Units
The model was in the design mode, so the equipment was sized appropriately.
The purchase cost calculated by SuperPro Designer takes into account the
allocated a different factor which is multiplied by the base purchase cost. For
stainless steel (SS 316) the material factor is 1.0 and for a glass-lined vessel, like
Once the total purchase cost in calculated, the next step in the calculations
requires evaluating the Direct Costs (DC) associated with the purchase cost of
the unit. The Direct Costs (DC) are calculated as a percentage of the PC and
Indirect Costs (IC) included construction and engineering costs, and were a
percentage of the total Direct Costs (DC). Other Costs (OC) were made up of the
contractors fee and contingency fees and were a percentage of the sum of the
41
Direct and Indirect Costs. Each of these costs and their associated percentage
Once all of these costs were calculated the Direct Fixed Capital Costs (DFC) was
Direct Fixed Capital Costs = Direct Cost (DC) + Indirect Cost (IC) + Other Cost
(OC)
The total capital cost detail information for manufacturing CPG-BS project are
presented on Table 10. Once the software performed all above calculations, the
total capital investment for the proposed plant was found to be approximately $29
42
Table 10. Fixed Capital Estimate Summery
associated operating costs of the proposed facility. Some of the main factors for
3. Raw materials
43
4. Utilities: It includes all the costs for electricity and heat transfer agents
5. Facility Dependant Cost: Main factors for this item are maintenance,
6. Waste Treatment and disposal Cost: CPG-BS plant has organic and
aqueous wastes, solid disposals and emission and annual operating cost
Once this was done, the estimated operating costs for this plant was found to
44
9.3 Profitability Analysis
The final step in the economic analysis was to calculate the profitability of the
proposed plant. This was done using SuperPro Designer economic estimator
and simply took the total revenues generated by the product and subtracted the
and this cost was fixed for all process steps. The gross margin of the project was
calculated 72.59%, and the payback period for this plant was found to be a little
over 1.38 years. Table 12 depicts profitability analysis for this project.
45
SPD has very flexible and comprehensive cost analysis tool and also it has
updated library for cost information. There is this possibility to choose SPD
suggested variable for cost analysis or change them to other value or correlation.
SPD is generating detail reports for total capital investment, annual operating
cost and profitability which are very helpful for tracking results and detail
analysis. Table 13 shows the executive summery of cost analysis for
manufacturing CPG-BS project.
46
10 Conclusion
The SuperPro Designer software package was successfully applied for design
anti-platelet drug). The reactor was designed with a high degree of flexibility to
accommodate for all reactions and crystallization of final product. The design
also included a rotary vacuum dryer to avoid contamination and loss of the drug
the design and simulation of this process in different ways, some of which have
reactions with different residence time must have been carried out in the
process. This was especially useful for evaluating different options with
- The errors during the design and simulation were explicitly explained by
the software in a very simple way. (i.e. the specific stream has to be
47
Economic analysis is one of the strongest points of the SPD software package.
The software accounts for operational, equipment, and overhead cost. It also has
an option of incorporating R&D cost, which is an important part of capital cost in
pharmaceutical industry. The economic analysis yielded the period of 1.38 years
for the return on the investment.
48
11 References
2. Koradia, V., Chawla, G., & Bansal, A.K. Qualitative and quantitative analysis
3. Evers, S.M., Struijs, J,N. & Ament, A,J. International comparison of stroke
2001, 787-798
versus aspirin in patients at risk of ischemic events (CAPRIE). The Lancet 348
6. Gerschutz, G.P. & Deepak, B.L.. The CURE trial: Using clopidogrel in acute
49
12 Appendix
50
51
52