Production of a Synthetic Pharmaceutical Intermediate

This example analyzes the production of a synthetic pharmaceutical intermediate which is formed by condensation of
quinaldine and hydroquinone. Several reaction and separation steps are required to synthesize and purify the product.
The generation of the flowsheet was based on information available in the patent and technical literature. The
objective is to demonstrate how SuperPro can be used as a tool to assist with scaling up the available pilot plant
process into a large-scale process, and maximize capacity using the available equipment at the lowest possible cost.

The following SuperPro flowsheet files have been included with this example. A more detailed description of the files
and their features will follow in a later section:

1) SynPharma_v10a: This file represents an existing pilot plant process, which will act as the starting point for
the scale up process. The equipment sizes reflect a pilot plant environment. Four pieces of equipment are
used to carry out the process: Two reactors (1,200 L each), a Nutsche filter (1 m 2 filter area) and a tray dryer
(3 m2 tray area). For information related to specifying equipment sharing and visualizing equipment
utilization through the Equipment Occupancy Chart, refer to section 1.

2) SynPharma_v10b: In this file, large-scale equipment is used while the process is still at the pilot plant scale
(section 3.1).

3) SynPharma_v10c: This file is based on the previous one. The process is scaled up to the maximum batch
size based on the limit imposed by NFD-101 in P-3 (the depth of the filter cake). For information related to
scaling up a process, refer to section 3.2 of this document.

Once the process is scaled up, several strategies are evaluated on how to increase the process throughput. The
following SuperPro files analyze the strategies implemented in this case and demonstrate to the user how to access
the pertinent SuperPro features in order to perform a similar exercise.

4) SynPharma_v10d: This file demonstrates how to eliminate an equipment size bottleneck (which limits the
batch size of the process) by increasing its time utilization. In this case, NFD-101 is the size bottleneck
(imposed by the depth of its cake) but it is underutilized in time. By increasing the number of cycles per
batch from one to two for P-3 (which utilizes NFD-101), the size bottleneck shifts to R-102 in P-10. R-102
is the scheduling bottleneck as well. This can be noted by viewing the equipment occupancy chart. For
information on how to specify multiple cycles per batch for a given procedure, and consequently increase the
batch size, refer to section 3.3 in this document.

5) SynPharma_v10e: It was mentioned above that in file SynPharma_v10d, the time bottleneck is R-102. In
the SynPharma_v10e file an extra reactor is added in order to eliminate that bottleneck. As a consequence,
the number of batches performed annually is increased and the scheduling bottleneck shifts to NFD-101. The
above can be easily viewed with the help of the equipment occupancy chart (section 3.4)

6) SynPharma_v10f: To eliminate the new scheduling bottleneck, a filter is added (just as an extra reactor was
added previously to eliminate an earlier bottleneck). As a result, the annual number of batches is increased
(section 3.5).

7) SynPharma_v10g: This case is not as straightforward as the previous ones. It can be noted by selecting
Charts \ Throughput Analysis \ Utilization Factors for the SynPharma_v10f case that P-10 in R-103 is the
size bottleneck while all the other vessels in the other procedures have modest size utilizations. In this case
the batch is split into two halves starting with P-10. That enables us to increase the batch size, but the
number of batches per year drops. Nevertheless, the increase in batch size more than compensates for the
reduction in the number of batches. For more details on this strategy and the appropriate way to schedule
such a scenario, refer to section 3.6 in this document.
1. PROCESS DESCRIPTION
This section describes the process in detail. There is some variation between the files related to the names and sizes of
the equipment used. Nevertheless, the main processing steps are identical. The names of the equipment and the
procedures below relate to file SynPharma_v10a.

Chlorination Reaction and Salt Formation Steps (P-1 in R-101)

The first reaction step involves the chlorination of quinaldine. Quinaldine is dissolved in carbon tetrachloride (CCl 4)
and reacts with gaseous Cl2. The yield of the reaction is around 98%. The generated HCl is neutralized using
Na2CO3. The stoichiometry and yield data of the three reactions follow:

Quinaldine + Cl2 Chloroquinaldine + HCl Yield = 98 %

Na2CO3 + HCl NaHCO3 + NaCl Yield = 100 %
NaHCO3 + HCl NaCl + H2O + CO2 Yield = 100 %

Small amounts of unreacted Cl2, generated CO2, and gaseous CCl4 are vented. The above three reactions occur
sequentially in P-1 (R-101).

The second reaction in the same procedure (P-1) involves the formation of Chloroquinaldine.HCl. The added HCl
first neutralizes the remaining NaHCO 3 and then reacts with chloroquinaldine to form its salt. The stoichiometry and
yield of the two reactions follows:

NaHCO3 + HCl NaCl + H2 O + CO2 Yield = 100 %

Chloroquinaldine + HCl Chloroquinaldine.HCl Yield = 100 %

Small amounts of generated CO2 and gaseous CCl4 are vented. The presence of water (added with HCl as
hydrochloric acid solution) and CCl4 leads to the formation of two liquid phases. The small amounts of unreacted
quinaldine and chloroquinaldine remain in the organic phase while the salts Chloroquinaldine.HCl and NaCl move to
the aqueous phase. After the reaction the contents are allowed to settle, and the aqueous phase is transferred to R-102
for further processing. The organic phase is then discharged as waste. Approximately 11.3 hours are required for the
chlorination and salt formation reactions above, along with all associated charges and transfers. (Note – the times
given for other procedures below also include associated material transfers, etc.)

NOTE: The vapor-liquid split calculations for streams and operations are by default performed based on the normal
boiling point of components. Since the reactions in procedure P-1 are carried out at 50 oC, the added HCl (part of the
hydrochloric acid solution) will appear to be in the vapor phase, resulting in emissions of HCl. However, under the
conditions of this process, HCl is dissolved in water and practically no HCl is present in the vapor phase. To set up
this scenario correctly, select Edit \ Process Options \ Default Shortcut V/L Split Options. In the table that
appears, notice that for the HCl line the V/L Split Method is “Pure Liquid/Solid”. This will ensure the incoming HCl
doesn’t bypass the vessel contents and simply exit as emissions. Note that if you wish to limit the scope of the “VL
Split Method” for a component, you may specify the V/L split on a procedure-by-procedure basis by right-clicking on
the procedure(s) of interest and selecting “Procedure State Properties”. This would allow you to specify that HCl
stays in the liquid phase in a given procedure, but it could enter the vapor phase in a later procedure. This option is
also available in the context of streams (through the Physical State tab of a stream’s dialog).

Condensation Reaction Step (P-2 in R-102)

The second unit procedure (P-2 in R-102) involves the condensation of chloroquinaldine and hydroquinone. First, the
salt chloroquinaldine.HCl is converted back to chloroquinaldine using NaOH. Then, hydroquinone reacts with NaOH
and yields hydroquinone.Na. Finally, chloroquinaldine and hydroquinone.Na react and yield the desired intermediate
product. Along with product formation, a small amount of chloroquinaldine dimerizes and forms an undesirable by-
product (Impurity) that needs to be removed from the product. The stoichiometry and yield of the four reactions
follows:

Chloroquinaldine.HCl + NaOH  NaCl +H 2O + Chloroquinaldine Yield = 100%

2Chloroquinaldine + Hydroquinaldine + 2NaOH  Impurity + 2NaCl + Yield = 2%
2H2O
Hydroquinone + NaOH  H 2O + Hydroquinone.Na Yield = 100%
Chloroquinaldine + Hydroquinone.Na  Product + NaCl Yield = 100%

This step takes a total of 11 h.

Filtration Step #1 (P-3 in NFD-101)

Both the product and impurity molecules formed during the condensation reaction precipitate out of solution and are
recovered using a nutsche filter (P-3 in NFD-101). The product recovery yield is 90%. The wash volume per cake
volume ratio is 2.The total filtration and cake discharge time is 4.9 h assuming an average filtrate flux of 200 L/m2-h.

Solubilization Reaction Step (P-4 in R-101)

The Product/Impurity cake recovered by filtration is added into a NaOH solution. The Product molecules react with
NaOH to form Product.Na which is soluble in water. The Impurity molecules remain in the solid phase. The
stoichiometry and yield of the solubilization reaction follows:

Product + NaOH H 2O + Product.Na Yield = 100 %

This step takes a total of 6.9 h and it is performed in R-101. In other words, step P-4 utilizes the same reactor vessel
as P-1 but at a later time.

Filtration Step #2 (P-5 in NFD-101)

Next the Impurity is removed using another filtration step (P-5 in NFD-101). The total filtration, cake wash and cake
discharge time is 3.2 h assuming an average filtrate flux of 200 L/m2-h.

Precipitation Reaction Step (P-6 in R-102)

The excess NaOH is neutralized using HCl and then Product.Na is converted back to Product. The stoichiometry and
yield of the two reactions follows:

HCl + NaOH H2O + NaCl Yield = 100 %

HCl + Product .Na NaCl + Product Yield = 100 %

The Product, which is insoluble in water, precipitates out of solution. This step takes around 9.2 h.

Filtration Step #3 (P-7 in NFD-101)

Next the Product is recovered using another filtration step. The Product cake is washed with water to remove
impurities. The product recovery yield is 90%. The filtration and cake discharge time is 4.4 h assuming an average
filtrate flux of 200 L/m2-h.

Charcoal Treatment (P-8 in R-101)

The recovered Product cake is dissolved in isopropanol and treated with charcoal for removal of colorants. This step
takes a total of 13.5 h.
Filtration Step #4 (P-9 in NFD-101)

After charcoal treatment, the carbon particles are removed using another filtration step. The filtration and cake
discharge time is around 4 h assuming an average filtrate flux of 200 L/m2-h.

Crystallization Step (P-10 in R-102)

In this step, the product solution is concentrated threefold by vaporizing isopropanol. During vaporization the
maximum working volume ratio is set to 70% (which also determines the size of the equipment). The reason behind
this is the volume expansion that needs to be accounted for due to the vapor formation. Vaporization operations
generally require a lower working to vessel volume ratio than reaction operations. The 70% working to vessel volume
is set for all the SuperPro files of this example.

Then the product is crystallized with a yield of 97%. Crystallization is represented by the following reaction:

Product Product-Cryst Yield = 97 %

In other words, a new component (Product-Cryst) is used to represent the crystalline form of product. This step is
performed in 10.9 h.

Filtration Step #5 (P-11 in NFD-101)

The crystalline product is recovered using another filtration step with a yield of 90%. The filtration and cake
discharge take place in 2.8 h, assuming an average filtrate flux of 200 L/m2-h.

Drying Step (P-12 in TDR-101)

The recovered product crystals are dried in a tray dryer. The drying is done in 14 h. Approximately 55.7 kg of dried
product is produced per batch.

Storage (P-13 in SB-101)

Finally the dried product is stored in a storage bin.

2. GENERAL FEATURES OF SUPERPRO

This section deals with general features of SuperPro that are pertinent to this example and provides information to
the user on how to access them. In a later section the way to apply these features in a process development exercise
will be demonstrated step by step. The file used for generating the material for this section is SynPharma_v10a.

2.1. Specifying and Editing Sections

A section in SuperPro is simply a set of unit procedures. The flowsheet of this example was divided into four
sections:

1) Product Synthesis (Green icons)

2) Isolation and Purification (Blue icons)

3) Final Purification (Purple icons)

4) Crystallization and Drying. (Black icons)

To edit section properties, such as specifying the color of its procedure icons or the parameters for
conversion/recovery yield calculations, select the desired section from the drop down menu on the left hand side of the
section toolbar and click on the Edit Section Properties button ( ). Through this same toolbar you can also adjust
the section capital cost parameters ( ) as well as the section operating costs parameters ( ). To create a new
section or delete an existing section, use and respectively.

Figure 1: The dialog box for editing the section properties.

2.2. Raw Material Requirements

SuperPro generates material balance and stream tables that can be viewed as part of the flowsheet or a report. To
view stream information in tabular format on the flowsheet, click on the button of the main toolbar. To change
the contents of this stream table, right click on it and choose Edit Contents. Stream information, material
summaries, etc can also be viewed from the Materials and Streams report by selecting Reports \ Materials and
Streams (SR). The following table was copied from the RTF version of the Materials and Streams report.
 BULK MATERIALS
Material kg/yr kg/batch kg/kg MP
Carb. TetraCh 25,120 160.000 2.871
Quinaldine 7,508 47.820 0.858
Water 182,923 1,165.115 20.909
Chlorine 4,522 28.800 0.517
Na2CO3 5,307 33.800 0.607
HCl (20% w/w) 18,055 115.000 2.064
NaOH (50% w/w) 10,331 65.800 1.181
Methanol 27,946 178.000 3.194
Hydroquinone 8,660 55.160 0.990
Sodium Hydroxid 3,746 23.860 0.428
HCl (37% w/w) 10,990 70.000 1.256
Isopropanol 112,749 718.146 12.888
charcoal 801 5.100 0.092
Nitrogen 56,092 357.275 6.412
TOTAL 474,748 3,023.875 54.265

This table provides information on raw material requirements for the entire process. The quantities are displayed in
kg/year, kg/batch, and kg/kg MP (MP stands for main product and it refers to the final dried crystals). Note that
around 54.3 kg of materials (solvents, reagents, etc) are used per kg of main product produced. Thus the product to
raw material ratio is only 2%, an indication that this process generates large amounts of waste.

The format of the reports is specified through the dialog that is displayed when you select “Reports \ Options”
(Figure 2). The contents of the various reports can be adjusted through this dialog as well. Charts can also be
included in the reports if the Include Charts checkbox is checked.
Figure 2: The Report Options dialog box

2.3. Process Scheduling

This pilot plant (SynPharma_v10a) operates around the clock for 330 days (7920 hours) per year. On an annual
basis, the plant processes 157 batches and produces approximately 8,749 kg of purified intermediate (55.7 kg/batch).
This information can be seen by choosing Tasks \ Recipe Scheduling Information.

SuperPro generates two types of charts for visualizing detailed scheduling information, the Equipment Occupancy
and Gantt charts. Figure 3 displays the Equipment Occupancy chart for consecutive batches of the pilot plant case.
The two different colors represent two different batches. To generate this chart, select Charts \ Equipment
Occupancy Chart \ Multiple Batches. To generate the Scheduling Summary dialog, right click on the chart in an
open area and select Scheduling Summary (also seen at the top right hand corner of Figure 3). To change the
number of displayed batches, right click on the chart and select Set No of Batches or Time Horizon. As can be seen,
the overall batch time (from start to finish of a single batch) is approximately 74 h. The time between consecutive
batches (also known as the recipe cycle time) is approximately 50 h and it is determined by equipment R-101, which
is the time bottleneck. Note that vessel R-101 is used for three unit procedures, P-1, P-4 and P-8. The three
procedures are displayed by the three different rectangles of the same color (on the line of R-101). R-102 and NFD-
101 also handle multiple processing steps (unit procedures) within each batch. It is important to understand that
when you model batch processes in SuperPro, the flowsheet is primarily a representation of processing steps (unit
procedures) and not a representation of equipment. This is the case because multiple unit procedures may share
(utilize) the same piece of equipment within a batch. In this example, for instance, the chlorination/salt formation,
product solubilization and charcoal treatment steps share reactor R-101. The condensation, precipitation, and
crystallization steps share reactor R-102. Finally, all five filtration steps utilize the same Nutsche filter (NFD-101).

Equipment sharing between multiple procedures is specified through the Selection box on the Equipment tab of the
Equipment Data dialog for a given unit procedure (Figure 4). To view this dialog, simply right-click on a procedure
icon and select Equipment Data. Then, through the Select drop-down menu of the Selection box (upper left corner),
select a pre-existing compatible equipment item for this processing step. Please note that if the processing times of
two procedures that share the same equipment overlap in time, SuperPro will generate a warning. Also note that both
the Equipment Occupancy and Gantt charts generated by SuperPro are interactive. In other words, the user can edit
operation, procedure, and equipment data by right-clicking on the relevant bar and selecting the appropriate item
from the menu that appears.

Figure 3: The equipment occupancy chart for the pilot plant process.
Figure 4: The equipment data dialog through which the user can specify equipment sharing (red circle) or request a
new piece of equipment (green circle)

The figure below is part of the Gantt chart for a single batch. It displays the execution of the various procedures and
their operations in greater detail than the Equipment Occupancy Chart. This chart also can be exported to MS
Project. To generate the Gantt chart below select Charts \ Gantt Charts \ Operations GC.
Figure 5: Operations Gantt chart

2.4. Cost Analysis and Economic Evaluation

Since this is a pilot plant process, the economics will not be investigated at this point. A full economic
evaluation will be performed for the final file, which represents the large scale manufacturing process.
However, at the pilot plant stage a useful feature is the estimation and breakdown of the operating costs of the
pilot plant process. These are shown in the table below, which was copied from the Economic Evaluation
Report (EER) of file SynPharma_v10a. This report is generated by selecting Reports \ Economic Evaluation
(EER).

ANNUAL OPERATING COST (2013 prices)

Cost Item $ %
Raw Materials 562,000 14.98
Labor-Dependent 735,000 19.58
Facility-Dependent 2,112,000 56.27
Laboratory/QC/QA 110,000 2.94
Consumables 0 0.00
Waste Treatment/Disposal 234,000 6.24
Utilities 0 0.00
Transportation 0 0.00
Miscellaneous 0 0.00
Advertising/Selling 0 0.00
Running Royalties 0 0.00
Failed Product Disposal 0 0.00
TOTAL 3,754,000 100.00
A graphical representation of the above table is shown in Figure 6. Figure 6 was also copied from the Economic
Evaluation Report. To include such charts in the report, the user must check the Include Charts box in the report
options dialog (highlighted earlier in this document in Figure 2).

Figure 6: The annual operating cost breakdown in %

The raw material cost is an important part of the operating costs (16%). The raw material cost breakdown is shown
below:

MATERIALS COST
Unit Cost Annual Annual Cost
Bulk Material %
($) Amount ($)
Carb. TetraCh 0.800 25,120 kg 20,096 3.57
Quinaldine 32.000 7,508 kg 240,248 42.73
Water 0.100 182,923 kg 18,292 3.25
Chlorine 3.300 4,522 kg 14,921 2.65
Na2CO3 6.500 5,307 kg 34,493 6.14
HCl (20% w/w) 0.000 18,055 kg 0 0.00
NaOH (50% w/w) 0.150 10,331 kg 1,550 0.28
Methanol 0.240 27,946 kg 6,707 1.19
Hydroquinone 4.000 8,660 kg 34,640 6.16
Sodium Hydroxid 2.000 3,746 kg 7,492 1.33
HCl (37% w/w) 0.170 10,990 kg 1,868 0.33
Isopropanol 1.100 112,749 kg 124,024 22.06
charcoal 2.200 801 kg 1,762 0.31
Nitrogen 1.000 56,092 kg 56,092 9.98
TOTAL 562,185 100.00
2.5. Throughput Analysis and Debottlenecking
SuperPro generates two charts and a report that provide useful information for throughput analysis and
debottlenecking studies. The figure below displays the utilization chart for this process. This chart is generated by
selecting Charts \ Throughput Analysis \ Utilization Factors from the application’s main menu. The blue bars
represent size utilization for equipment with storage capacity or throughput utilization for pass-through types of
equipment. The cyan bars represent time utilization, and the magenta bars represent combined utilization (size
utilization x time utilization). Vessel R-102 is identified as the most likely throughput bottleneck because it has the
highest combined utilization. Please note that vessel R-102 handles three steps, P-2, P-6 and P-10. It has its highest
utilization (95%) in P-10.

Figure 7: The equipment throughput utilization chart for the pilot plant process.

The figure below displays the batch throughput potential for each piece of equipment. This chart is generated by
selecting Charts \ Throughput Analysis \ Batch Size Potential from the application’s main menu. The batch
throughput potential is expressed in terms of equivalent final product. The bars of this chart represent available batch
throughput capacity. Tall bars represent plenty of available capacity and low likelihood of becoming a bottleneck.
Short bars represent limited capacity and increased likelihood of becoming a bottleneck.

The blue bars of this chart represent a conservative estimate of batch throughput potential, the cyan bars represents a
“realistic” estimate of batch throughput, and the magenta bars represents the theoretical maximum throughput. In the
Conservative case, the Equipment Uptime is kept the same as its current uptime, in the Realistic case, the Equipment
Uptime is set to correspond to the highest number of complete cycles that can be performed in that piece of
equipment within the time window of the recipe cycle time and in the Theoretical case, the Equipment Uptime is
assumed to be at 100%. This would require mixing of partial lots of product, which may not be an option in many
processes. R-102 is the most likely throughput bottleneck based on all approaches. For more information on the
definitions and theory behind throughput analysis, please refer to the user’s manual.
Note that the filter (NFD-101) has been excluded from the Batch Size Potential chart below. This was done because
in certain procedures (e.g., P-5 and P-9) the filter is used to remove very small amounts of solids. Therefore, the
theoretical batch size based on these steps is enormous, which results in a skewed scale on the chart. As a result, the
filter was excluded from the throughput calculations by right-clicking the filter, selecting Equipment Data, clicking
the Throughput tab, and clicking Omit from Throughput Analysis in the upper right corner of the dialog.

Figure 8: The equipment throughput potential chart for the pilot plant process.

3. SCENARIO ANALYSIS
The features described above will be used in this section to demonstrate how a pilot plant process can be scaled up in
order to design an efficient commercial scale production process. Once the process is finalized, a full economic
evaluation will be performed to assess the profitability.

3.1. Large Scale Equipment but Pilot Scale Process Quantities

(SynPharma_v10b)
The equipment in this model has been set to its production-scale sizes in preparation for the scale up of the process.
To specify the size of a piece of equipment, visit the equipment data dialog box by right clicking on a unit procedure
which takes place within that piece of equipment and selecting Equipment Data (Figure 4). The following sizes have
been specified for the equipment in this model:

 Volume of 3,780 L (1,000 gal) for reactors R-101 and R-102.

 Area of 2.5 m2 for the Nutsche filter NFD-101.

  Area of 10 m2 for the tray dryer TDR-101.

The material balance information for this model is the same as the pilot plant process model (SynPharma_v10a).
However, the scheduling has changed slightly. The overall batch time is now 63.56 h. The cycle time is
approximately 40.79 h and it is determined again by equipment R-101, which is the time bottleneck (Figure 9).
Assuming that the process operates around the clock for 330 days per year, the plant processes 193 batches and
produces approximately 10,754 kg of purified intermediate (55.7 kg/batch).

Figure 9: The equipment occupancy chart and scheduling summary for SynPharma_v10b

What has changed substantially in this case is the equipment throughput utilization chart shown in Figure 10. By
comparing the two charts (Figure 7 and Figure 10) it can be noted that the time utilization is similar for the
equipment in both cases. The capacity utilization, on the other hand, is considerably lower for all equipment. This
allows the user to increase the batch size (see next section) to the maximum possible size allowed by the current size
bottleneck. As noted above, the scheduling bottleneck is currently R-101. However, NFD-101 is the current size
bottleneck because it has the highest size utilization (tallest blue bar) in P-3 and thus it determines the maximum
possible batch size (see following section).
Figure 10: The equipment throughput utilization chat for SynPharma_v10b

3.2. Scaling up to Max Batch Size (SynPharma_v10c)

In this case the process is scaled up to a maximum batch size of 173.2 kg. This batch size limit is imposed by the
filter (NDF-101) in the “Product Isolation” operation of P-3. Note that the user can specify a scale up factor or a
target batch size, and SuperPro will perform the mass and energy balance calculations for all streams and operations
at the new scale. If the equipment sizes are not able to accommodate the new scale, the program will generate a
warning. The user can get information on possible batch sizes and specify the desired batch size by selecting Tasks \
Adjust Process Throughput (Figure 11). The area highlighted in this figure displays information on batch sizes that
can be accommodated by the available equipment. The Conservative max batch size is the relevant value in this case.
It corresponds to the case where we operate the size bottleneck equipment at 100% size utilization but without
making any changes in its number of cycles per batch.

NOTE: In order for the dialog of Figure 11 to be displayed, the user must first specify which stream on the flowsheet
is the main product by selecting Tasks \ Stream Classification and choosing an appropriate Main Product/Revenue
stream in the lower right corner of the dialog. In this case, the stream named Final Product has been selected as the
Main Product Rate stream.
Figure 11: The adjust process throughput dialog box

The scheduling for this process has also changed (compared to SynPharma_v10b) due to the different volumes
processed in the two files. The new batch time is approximately 92 h and the cycle time is 62 h, which allows the
processing of 126 batches per year (assuming 24/7 operation for 330 days per year). The annual production is
21,823 kg. The total number of batches per year has been reduced relative to the previous case, but this is more than
compensated for by the batch size increase. The scheduling bottleneck has also shifted from R-101 to R-102, as can
be seen in Figure 12.
Figure 12: The equipment occupancy chart and scheduling summary for the first scaled up model (SynPharma_v10c)

Note that NFD-101 in P-3 is the size bottleneck in this case, since it is the tallest blue bar in Figure 13. However,
both Figure 12 and indicate that the Nutsche filter has low time utilization (note the relatively low cyan bar in Figure
13 for P-3). Therefore, since we have spare time in NFD-101, we could potentially increase the number of cycles per
batch in P-3 from one to two. This would increase the time utilization of NFD-101, but it would also increase the
effective capacity of NFD-101 during this procedure because only half the material would need to be filtered during
each cycle. This may give us the opportunity to increase the recipe batch size. This idea is analyzed in the next
scenario.
Figure 13: The throughput utilization chart for the first scaled up process model (SynPharma_v10c)

3.3. Shifting the Size Bottleneck (SynPharma_v10d)

As was noted in section 3.2, NFD-101 in P-3 is the current size bottleneck (i.e., it has the highest size utilization) in
SynPharma_v10c. If the batch is processed in two cycles in P-3, we can reduce the size utilization of that step by
50% and create an opportunity to increase the recipe batch size. To specify the number of cycles for a certain
procedure, right click on the icon of that unit procedure and select Procedure Data (see Figure 14).
Figure 14: The procedure data dialog box

Figure 15 displays the Throughput Analysis chart for the case of 2 cycles per batch for P-3. It is obvious that NFD-
101 in P-3 in no longer the size bottleneck. Instead, R-102 in P-10 has become the new size bottleneck and its size
utilization is around 94%.
Figure 15: The throughput analysis utilization chart for SPhr8_5d (before increasing the batch size)

Figure 16 corresponds to the case where the recipe batch size is increased up to the capacity limit imposed by R-102
in P-10. The new batch size is 184.7 kg. R-102 is the new size as well as time bottleneck (see Figures 15 and 16).

The scheduling has also changed slightly (see Figure 17). The new batch time is approximately 95.3 h and the recipe
cycle time is 65 h, which allows the processing of 121 batches per year (assuming 24/7 operation for 330 days per
year). The annual production is 22,348 kg. The total number of batches per year is reduced a bit but this is more than
compensated for by the batch size increase. This is the highest capacity that can be achieved with the available
equipment. Therefore, for a further increase in throughput, new pieces of equipment need to be added. More
specifically, a new reactor is needed in order to reduce the current recipe cycle time. This is demonstrated in the
following section.

NOTE: The max allowable working to vessel volume for the vaporization reaction is low (70%) compared to other
vessel operations that have a max ratio of 90%. That’s because during vaporization there is volume expansion due to
bubble formation. The 70% working to vessel volume ratio is set for all the files associated with this example. To
view or edit the above ratio, right click on P-10 and select Operation Data \ VAPORIZE-1 (operation in question)
and switch to the Volumes tab.
Figure 16: The throughput analysis utilization chart for SynPharma_v10d (after increasing the batch size)

Figure 17: The equipment occupancy chart and scheduling summary for SynPharma_v10d
3.4. Addition of an Extra Reactor Vessel (SynPharma_v10e)
After the batch size increase in the previous case, R-102 became the size as well as the time bottleneck and therefore
it is clearly the overall process throughput bottleneck. The only way to increase throughput further is by eliminating
the current throughput bottleneck through installation of extra equipment. This strategy is the focus of this scenario.
A new reactor (R-103, identical in size to the existing ones) is added to handle procedures P-4 (Product
solubilization) and P-10 (Vaporization-Crystallization).
To specify a new piece of equipment for P-4, visit its Equipment Data dialog (Figure 4) by right clicking on the P-4
procedure icon. Then select Request New in the Selection box (upper left corner) and specify its name (R-103).
Next visit the Equipment Data dialog of P-10 and select R-103 through the Select drop-down menu of the Selection
box. The effect this has on scheduling is shown in Figure 18; the scheduling bottleneck has shifted from R-102 to the
Nutsche filter NFD-101 (see highlighted region). The batch size (184.7 kg) and time (95.3 h) are the same since the
process has not been altered. What has been reduced is the Cycle time, which determines the number of batches that
can be processed per year. The new cycle time is 57.8 h, which translates into 136 batches per year or 25,118 kg per
year. This estimation is based on the assumption that the plant will operate around the clock for 330 days a year.

Figure 18: The equipment occupancy chart and scheduling summary once a new reactor has been added to the process
(SynPharma_v10e)
3.5. Addition of an Extra Nutsche Filter (SynPharma_v10f)
Following the same strategy whereby a bottleneck is identified and removed, a new Nutsche filter (NFD-102 identical
to NFD-101) is added and is assigned to P-9 and P-11 (Figure 19). As a result, the scheduling bottleneck is shifted to
R-103. The batch time (95.3 h) and size (184.7 kg) are the same. The cycle time, however, is reduced to 52.6 h,
which results in 149 batches and a total of 27,519 kg of product per year.

Figure 19: The equipment occupancy chart and scheduling summary after the addition of a new Nutsche filter (NFD-
102) (SynPharma_v10f).

The last two sections described a typical debottlenecking strategy. Following the same approach, we could add
another reactor to reduce the current cycle time and increase plant throughput. Let’s pause, however, and have a
closer look at R-103, our current size and time bottleneck. Figure 20 displays the current utilization chart. R-103 is
the current size bottleneck because of its high utilization in P-10 (the procedure that includes the vaporization
operation that requires a 70% working to vessel volume ratio). If there is a way to get around the size bottleneck of
R-103 in P-10, then there will be an opportunity for a significant capacity increase before hitting the next limit. The
next section deals with such a solution.
Figure 20: The throughput analysis utilization chart for SynPharma_v10f

3.6. Splitting the Batch in two Halves after P-8 (SynPharma_v10g)

For this case, half of the material coming out of P-8 is processed in the same manner as before while the other half is
stored in a new storage tank (T-101 in P-8b). Furthermore, the second half is filtered by NFD-102 instead of NFD-
101. The filtrate for both halves eventually ends up in R-103, but the filtrates for the two halves are processed at
different times (the second half can only be processed once the material from the first half has been transferred out
from R-103). In other words, the filtrate from the first half is processed in R-103 (P-10), then the contents of R-103
are transferred out to NFD-101 (P-11), then the second half of the batch is filtered through NFD-102 (P-13),
processed in R-103 (P-14), and transferred out to NFD-102 (P-15). This sequence of events is accomplished by
scheduling the Transfer Out in P-8b to start at the end of the Transfer Out in P-10 (Figure 21). Similarly, the
transfer out of the filter cake from P-15/NFD-102 is also delayed until the dryer TDR-101 has completed processing
the previous material.
Figure 21: The scheduling tab of the Transfer out operation in P-8b.

The new schedule for this process is shown in Figure 22. The idle time (white gaps) in T-101 indicate the waiting
time required for the subsequent equipment to be freed (the same applies for NFD-102). The new scheduling
bottleneck is the Nutsche filter NFD-101.
Figure 22: The equipment occupancy chart and scheduling summary once the batch has been split in two halves after
P-8 in R-102 (SynPharma_v10g)

Figure 23 displays the utilization chart for the current situation. R-102 in P-8 has the highest size utilization of
around 75%. Using the method described in section 3.2 (Figure 11) the batch size is increased to 246 kg (the limit
imposed by R-102 in P-8) and the new throughput analysis utilization chart is shown in Figure 24.

In terms of scheduling, the new batch time is 114.2 h and the cycle time is 59.3 h, which allows the processing of 132
batches per year. In other words, the number of batches per year drops compared to the previous case
(SynPharma_v10f, 149 batches per year) but the batch size increase translates to an annual production of 32,472 kg
as opposed to 27,519 kg in the previous case.
At this point the process is finalized. In the next section a full economic evaluation will be performed using the
finalized process (SynPharma_v10g).
Figure 23: The throughput analysis utilization chart after splitting the batch and prior to increasing the batch size
(SynPharma_v10g)
Figure 24: The throughput analysis utilization chart after the batch size has been increased to 246 kg
(SynPharma_v10g)
3.7. Economic Evaluation (SynPharma_v10g)
The key economic evaluation figures for a plant dedicated to the synthesis of 32,472 kg of the API that was analyzed
in this example are displayed in the table below. This table was extracted from the RTF version of the Economic
Evaluation Report (select Reports \ Economic Evaluation to generate this report). This analysis assumes that a new
facility will be built for this process, and the plant lifetime is 15 years. The revenues are based on a selling price of
$500/kg of the final dried material.

EXECUTIVE SUMMARY (2010 prices)

Total Capital Investment 20,827,000 $
Capital Investment Charged to This Project 20,827,000 $
Operating Cost 8,026,000 $/yr
Revenues 16,236,000 $/yr
Cost Basis Annual Rate 32,472 kg MP/yr
Unit Production Cost 247.15 $/kg MP
Net Unit Production Cost 247.15 $/kg MP
Unit Production Revenue 500.00 $/kg MP
Gross Margin 50.57 %
Return On Investment 32.53 %
Payback Time 3.07 years
IRR (After Taxes) 24.30 %
NPV (at 7.0% Interest) 27,320,000 $
MP = Total Flow of Stream 'Final Product'

The figure below shows the annual operating cost breakdown. This chart is automatically generated with the
Economic Evaluation report. To view charts such as this in the reports, visit Reports \ Options and select “Include
Charts” in the lower right corner of the dialog. The facility-dependent cost is the most important item for this process.
It mainly accounts for the depreciation and maintenance of the facility.

Figure 25: Annual operating cost breakdown (SynPharma_v10g)

The table below contains the operating cost breakdown per section for the SynPharma_v10g case. The table
was copied from the itemized cost report that can be generated by visiting Reports \ Itemized Cost (ICR).

SUMMARY PER SECTION

Section $/kg MP $/batch $/year %
Product Synthesis 88.550 21,784 2,875,423 33.59
Isolation and Purification 32.208 7,923 1,045,878 12.22
Final Purification 67.638 16,639 2,196,344 25.66
Crystallization and Drying 75.220 18,504 2,442,574 28.53
TOTAL 263.617 64,850 8,560,219 100.00

The tables below provide a breakdown of the raw material costs (the 2 nd most important contribution to operating
costs) and waste treatment costs. These tables were both extracted from the Economic Evaluation Report generated
by SuperPro.

MATERIALS COST - PROCESS SUMMARY

Unit Cost Annual Annual Cost
Bulk Material %
($) Amount ($)
Carb. TetraCh 0.800 93,237 kg 74,590 3.57
Quinaldine 32.000 27,866 kg 891,722 42.73
Water 0.100 678,950 kg 67,895 3.25
Chlorine 3.300 16,783 kg 55,383 2.65
Na2CO3 6.500 19,696 kg 128,027 6.14
HCl (20% w/w) 0.000 67,014 kg 0 0.00
NaOH (50% w/w) 0.150 38,344 kg 5,752 0.28
Methanol 0.240 103,727 kg 24,894 1.19
Hydroquinone 4.000 32,144 kg 128,574 6.16
Sodium Hydroxid 2.000 13,904 kg 27,808 1.33
HCl (37% w/w) 0.170 40,791 kg 6,935 0.33
Isopropanol 1.100 418,487 kg 460,336 22.06
charcoal 2.200 2,972 kg 6,538 0.31
Nitrogen 1.000 208,194 kg 208,194 9.98
TOTAL 2,086,647 100.00
 WASTE TREATMENT/DISPOSAL COST (2010 prices) –
PROCESS SUMMARY
Unit Cost Annual Annual Cost
Waste Category %
($) Amount ($)
Solid Waste 14,999 1.73
Impurity 5.000 1,043 kg 5,217 0.60
Charcoal Out 2.000 2,446 kg 4,891 0.56
S-117 2.000 2,446 kg 4,891 0.56
Aqueous Liquid 360,734 41.50
Waste-3 1.000 86,181 kg 86,181 9.91
Organic Phase 2.000 94,187 kg 188,373 21.67
S-112 1.000 86,180 kg 86,180 9.91
Organic Liquid 0 0.00
Emissions 493,471 56.77
Emissions 4.000 8,861 kg 35,444 4.08
Vapors 2.000 114,507 kg 229,013 26.35
S-120 2.000 114,507 kg 229,013 26.35
TOTAL 869,205 100.00

Finally, Figure 26 shows the cost distribution per section per item. It can be found in the ICR. To view such charts in
the report, visit Reports \ Options and select “Include Charts” in the lower right corner of the dialog.

Figure 26: Cost distribution per section (SynPharma_v10g)

3.8. Summary of all Scenarios
The table below summarizes the key process and economic evaluation parameters of all the scenarios investigated:

File name Batch Batch Cycle time Number of Annual Production cost ROI
size time (h) Batches per production ($/kg) %
(kg) (h) year (kg)
SPh9_5a 55.7 74.0 50.5 157 8,749 429 12.0

SPh9_5b 55.7 63.6 40.8 193 10,755 394 13.8

SPh9_5c 173.2 92.2 62.2 126 21,823 250 31.2

SPh9_5d 184.7 95.3 65.0 121 22,347 249 31.7

SPh9_5e 184.7 95.3 57.8 136 25,118 278 25.2

SPh9_5f 184.7 95.3 52.6 149 27,519 275 25.8

SPh9_5g 246 114.2 59.3 132 32,472 264 28.2

In the table above, notice that even though the annual production was increased for each successive iteration of the
model, the production cost (per kg of product) was actually the lowest and the ROI was highest for case SPh9_5d.
This is because the subsequent model iterations involved the addition (i.e., purchase) of new equipment, such as the
third reactor in file SPh9_5e, the second Nutsche filter in file SPh9_5f, and the new storage tank in file SPh9_5g.
Furthermore, splitting the batch into two halves in file SPh9_5g resulted in additional labor requirements (and
associated costs). This highlights the importance of considering the costs of process changes as you proceed with
debottlenecking. If the goal of this project is to maximize ROI, file SPh9_5d would actually be the “optimal”
solution. However, if the goal is to maximize annual production, file SPh9_5g is a better choice. Furthermore, if the
goal is to maximize NPV or net profit, SPh9_5g is still the best choice. SPh9_5g provides an NPV (at 7% interest)
of $23,972,000 and an annual net profit of $6,732,000, whereas file SPh9_5d only provides an NPV (at 7% interest)
of $18,459,000, and an annual net profit of $4,667,000. (The values for NPV and net profit can be found in the
Economic Evaluation Report).