Computers and Chemical Engineering 34 (2010) 10301035

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Computers and Chemical Engineering

journal homepage: www.elsevier.com/locate/compchemeng

Process modeling and optimization of batch fractional distillation to increase throughput and yield in manufacture of active pharmaceutical ingredient (API)
Yubo Yang , Rosalin Tjia
Abbott Laboratories, Manufacturing Science and Technology, Building R-13, Department 045B, 1401 Sheridan Road, North Chicago, IL 60064, United States

a r t i c l e

i n f o

a b s t r a c t
An active pharmaceutical ingredient (API) is puried by fractional batch distillation to achieve a high purity drug substance. This work is to improve the process throughput and to increase the yield using batch distillation modeling and engineering principles to better understand the process so high quality product can be produced consistently. A batch of the drug substance was produced in about 7 days by batch distillation using a packed column with approximately 32 theoretical plates. Process improvements were required to decrease the cycle time. Based on process modeling and other engineering principles, four process improvements have been made to increase the manufacture throughput. After improvements the average cycle time has been reduced to 2.5 days from an average of 7 days process originally. Furthermore, the yield is also increased. This was achieved with the original equipment. Since the changes are within the regulatory lings for the process, they are implemented quickly in commercial production. 2010 Elsevier Ltd. All rights reserved.

Article history: Received 18 August 2009 Received in revised form 9 February 2010 Accepted 31 March 2010 Available online 10 April 2010 Keywords: Fractional batch distillation Process modeling Pharmaceutical API purication

1. Introduction An active pharmaceutical ingredient (API) is puried at the nal step by fractional batch distillation to achieve a high purity for an injectable formulation. The purpose of this work is to improve the process throughput and to increase the yield using process modeling tools and other engineering principles to fundamentally understand the process so a high quality product can be produced consistently in commercial production. The API was separated by a fractional batch distillation column with 32 theoretical plates, which was validated and led with regulatory agencies over 15 years ago. Approximately 7 days of cycle time were required to manufacture a batch of drug substance in the original process. Fundamental engineering understanding of the batch distillation process was limited in the original development led by chemists. To meet the increased commercial demand of this drug substance using the existing equipment, better fundamental understanding of the process and improvements were required to decrease the cycle time for throughput improvement. The batch distillation process generates three fractions:

(1) low-boiling fraction, consisting of product and low-boiling impurities, (2) product fraction, and (3) high-boiling tail fraction, collected after the product fraction. The low-boiling fraction typically contains more than 95% of product and the product fraction consists of >99.5% of API. In commercial production the distillation column is held at total reux under vacuum to reach vaporliquid equilibrium. The system is then switched to front-cut distillation to separate the low-boiling impurities. The distillate is sampled, tested, and collected in the product receiver once the fresh distillate (collected from the condensate line without mixing with the content in the front-cut receiver) contains not less than 99.4% of API by gas chromatography (GC) analysis. The distillate is collected in the product receiver until the purity of fresh distillate drops to <99.4%. The decision to switch the distillate to product receiver is based on the In-Process (IP) GC analysis. Batch distillation is utilized extensively in production of high value-added, low-volume pharmaceuticals and ne chemicals (Perry & Green, 1997). The exibility of batch distillation, combined with its unsteady nature of the process, poses challenging design, operation and optimization problems for engineers (Diwekar, 1995). A rigorous model for the batch distillation involves solving stiff ordinary differential equations. The development of accurate models for batch distillation processes is a difcult task. The objectives for this work are to model the batch distillation using the rigorous model BatchFracTM from Aspen Technology (Aspen Tech

Corresponding author at: Manufacturing Science and Technology, Abbott Laboratories, Building R-13, Department 045B, North Chicago, IL 60064, United States. Tel.: +1 847 937 2316. E-mail address: Yubo.Yang@abbott.com (Y. Yang). 0098-1354/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.compchemeng.2010.03.019

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Fig. 1. Flow diagram of the batch distillation process.

Inc., 2004) that has been validated by other researchers in literature for batch distillation simulation (Cook, Engel, Zehnder, Landis, & Tedeschi, 2004; Jimenez, Basualdo, Gomez, Toselli, & Rosa, 2002), to determine the key parameters affecting the separation efciency and yield, and to develop strategies to reduce the low-boiling fraction to achieve a better yield. 2. Process description The schematic of process ow diagram for the batch distillation is illustrated in Fig. 1. The key points for the manufacturing process that was led with regulatory agencies are: 1. Charge approximately 150 kg of the crude starting material (feed) to reboiler under nitrogen. 2. Obtain 16 mbar vacuum, and maintain the vacuum for 1 h before heating. 3. Heat the reboiler to 60 5 C, then ramp up at 510 C/h until the still pot (reboiler) temperature stabilizes. The system is equilibrated for 12 h at total reux before starting of distillation. 4. Set the front-cut reux ratio at about 45:1 and start the front-cut distillation until the fresh distillate purity reaches 99.4% by GC analysis. 5. Set the product-cut reux ratio at about 10:1 and start the product-cut distillation until the distillate purity decreases to 99.4% by GC analysis. 6. Collect the tail-cut if necessary at a reux ratio of 3:1 until distillation completes. 7. Product-cut material is ltered, tested, and packaged. 8. Column residue is drained to reboiler and reboiler residue is disposed of as waste. The main challenge for the distillation process is that the frontcut took very long time (up to 50 h) to achieve the required 99.4% purity since this product was introduced to, mainly due to one impurity (Impurity A). Nevertheless, the existing batch distillation column had been able to produce a high quality product for many years, and there were no urgent requirements to improve the process. However, due to an increased commercial demand, more capacity in the existing plant is needed. After cycle time anal-

ysis of each operating steps, it was realized that the cycle time in the front-cut was too long. If the separation efciency for key lowboiling impurities can be improved, the cycle time for the front-cut could be signicantly shortened that would lead to an increased throughput to meet the increased demand. This led the study to generate ideas for improvement, quantify the benets, validate the feasibility and implement the solution. 3. Modeling of the batch distillation to improve efciency The vaporliquid equilibrium (VLE) is the key parameter to determine the separation for a given mixture. The liquid and vapor phases consist of same components but in different compositions. The more volatile (low-boiling or light) components tend to be enriched in the vapor phase while the less volatile components (high boiling or heavy) tend to stay in the liquid phase. As the mixture moves up along distillation column, vapor phase becomes richer and richer in the volatile components while liquid phase contains more and more heavy components as it cascades down the column. The VLE data are typically determined by experiments under a xed pressure or vacuum at total reux or estimated by modeling. The VLE curve for the major low boiling Impurity A and product is shown in Fig. 2. The symbols are the experimental data obtained under vacuum of approximately 16 mbar. The pink curve is the calculated VLE using UNIFAC and group contribution method in the built-in property estimator of AspenPlus (Aspen Tech, 2004). The required parameters for UNIFAC (boiling point, heat of formation and Gibbs energy) on the two components are calculated using the build-in chemical property calculation of ChemDraw (ChemDraw, 2003). Normal boiling points are calculated using the Joback fragmentation method modied by S.E. Stein; heat of formation and Gibbs energy is calculated using the Joback fragmentation method. The Txy diagram of product and Impurity A is shown in Fig. 3 at 16 mbar vacuum, which is calculated using the UNIFAC and group contribution method with the build-in property estimator of AspenPlus (Aspen Tech, 2004). The measured boiling temperature of pure product is approximately 118.6 C at 16 mbar, very similar to the calculated value of 119 C. The good agreement between the calculated values by UNIFAC and measured data is not surprising since the molecular structures of product and Impurity A are very similar.

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Fig. 4. Dimensionless time to reach equilibrium as a function of relative volatility.

Fig. 2. Vaporliquor equilibrium diagram of Impurity A and product at 16 mbar.

The mean relative volatility of Impurity A and product is calculated to be = 1.13 according to the following equation from the VLE curve in Fig. 2: = yi /xi yj /xj

where is the relative volatility of the more volatile component i to the less volatile component j; yi and yj is the vaporliquid equilibrium concentration of component i and j in the vapor phase, respectively, and xi and xj is the vaporliquid equilibrium concentration of component i and j in the liquid phase, respectively. Relative volatility is a measure comparing the vapor pressures of the components in a liquid mixture that is widely used in design of distillation processes. The closer the relative volatility to 1, the more difcult it is to separate the two components by distillation. It is also determined experimentally that other low-boiling impurities are more volatile than Impurity A and can be easily separated into the front-cut. For modeling purpose, it is assumed that the entire low-boiling components are Impurity A since it dominates the amount of low-boiling impurities and it has the lowest relative volatility, which represents the worst case situation. The model simulation, based on such an assumption, would be slightly

different from that by considering the exact composition of the low-boiling components. In the original manufacturing procedure the distillation column was held at total reux for 12 h after the temperature in the reboiler reached the boiling temperature under vacuum. Since the relative volatility of Impurity A and product is very small, the temperature at top of the distillation column is nearly constant after 2 h of total reux. However, close examination of the temperature charts along the column revealed that the column did not reach complete equilibrium after 2 h of total reux. Due to the low relative volatility of Impurity A, it is very difcult to separate it from the product. Additionally, the specication for this impurity in the product is low (0.1% in the product). Theoretical calculation indicated that at least 45 h of total reux is required for the column to reach 99% of equilibrium after the reboiler has reached the boiling temperature. Only after the equilibrium for the distillation column is reached, will the separation of the low-boiling components from the product become efcient. The time required for a distillation column to reach equilibrium can be calculated by the following equation (Robinson & Gilliland, 1950): tequi = nh

vvap

Fig. 3. Txy diagram of Impurity A and product at 16 mbar vacuum as calculated by AspenPlus .

where tequi is the equilibrium time, n is the number of plates, h is the liquid hold-up per plate, vvap is the boiling rate of vapor, and is the dimensionless time (a function of relative volatility and degree to equilibrium). Fig. 4 shows the dimensionless time to reach 95% and 99% of equilibrium as a function of relative volatility (Robinson & Gilliland, 1950). It indicates that it takes longer time to reach a high degree of equilibrium for components with a small relative volatility. Fig. 5 illustrates the total reux time required for the commercial column to reach 99% of equilibrium as a function of relative volatility (using the actual hold-up and boiling-up rate for the commercial column), which implies that it takes 46 h after total reux to reach 99% of equilibrium for Impurity Aproduct pair with a relative volatility of 1.13. The front-cut typically took 2 days with 12 h total reux prior to the front-cut in production. Since a longer total reux time yields better equilibrium, it will be benecial to increase the total reux time prior to the front-cut based on this analysis. To evaluate the benets of better equilibrium on the efciency of Impurity A separation, the batch distillation process is modeled with a rigorous distillation model.

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Fig. 5. Reux time required to reach 99% equilibrium for the production column.

Fig. 7. Comparison of model simulation and In-Process test results of Impurity A in distillate.

A rigorous model for batch distillation involves solving several stiff ordinary differential equations (Diwekar, 1995). For the modeling purpose, the commercial available software, BatchFracTM from AspenPlus , was chosen and used for this work due to its exibility and availability although other commercial software are available (such as CHEMCADTM BATCH and HYSYS.Plant ). BatchFracTM is a rigorous model for modeling batch distillation with multi-stages from AspenTech (Aspen Tech Inc., 2004) that has been veried and validated by researchers in literature (Cook et al., 2004; Jimenez et al., 2002). Thus, validation of the accuracy of batch distillation simulator is not subject of this work since it has been done elsewhere. BatchFracTM uses a robust and efcient algorithm to solve the unsteady-state heat and mass balance equations that describe the batch distillation processes. BatchFracTM is exible and can handle a wide variety of batch distillation problems. In addition, the property estimation/correlation of AspenPlus is integrated with BatchFracTM , simplifying the modeling task. In batch distillation modeling the equilibrium composition along the column has to be calculated rst. Equilibrium or steady state under the batch mode distillation at total reux can be very different from the continuous mode distillation, since liquid holdup and amount of low-boiling impurities in the hold-up needs to be considered, especially for a low level of low-boiling components in the feed. Impurity A concentration is about 0.230.25% in typical feed material. Impurity A along the column at equilibrium is calculated using BatchFrac and is illustrated in Fig. 6 for the column used in manufacturing (33 theoretical plates with a total 9.6 kg of liquid hold-up). Plate number 1 and 32 in the gure corresponds to

Fig. 6. Impurity A along column after reaching equilibrium.

top and bottom of the distillation column, respectively, and plate 33 corresponds to the still pot. It is evident from this gure that liquid hold-up in the column has a dramatic effect on the impurity prole along the column. Impurity A along the column at equilibrium with 50% of the nominal hold-up (4.8 kg) and 200% of the nominal hold-up (19.6 kg) in Fig. 6 indicates that the larger the hold-up is, the less efcient the separation is for the low-boiling component due to lower Impurity A concentration at top of the column. After the low-boiling component moves to the top of the column in the equilibrium process, its concentration in the still pot starts to decrease that affects the level of low-boiling impurity on all the plates above the still pot. The model simulation indicates that if a better equilibrium is reached, Impurity A at top of the column could be enriched from 0.23% in the feed to approximately 8% at the top of the column. Thus, better equilibrium in principle would signicantly increase the separation efciency. Simulation result of Impurity A concentration (weight/weight percentage) as a function of distillation time in fresh distillate is illustrated in Fig. 7 (solid curve) using the actual reux ratio of 40:1 for the front-cut, 8:1 for the product-cut, boiling-up rate of 41 kg/h and total column hold-up of 9.6 kg for the distillation column. The deection point at 16 h of distillation is due to the change of reux ratio from 40:1 to 8:1, resulting in less efcient separation of Impurity A that reduces its concentration in fresh distillate after reducing the reux ratio to 8:1. The model simulation indicates that the front-cut distillation should be completed in 1214 h using the production column with a typical 0.23% of Impurity A in the feed, starting from which the fresh distillate should meet the In-Process specication of 0.6% of low-boiling impurities as measured by GC analysis. This is far less than the typical 48 h of front-cut distillation observed in production with 12 h of total reux prior to the front-cut. Based on the model simulation and engineering understanding, the total reux time for the production column was increased to approximately 5 h prior to the front-cut. For a commercial run with a typical 0.23% of Impurity A in the feed, fresh distillate samples from the condenser line were taken and tested by GC analysis every 2 h from beginning of the front-cut distillation. The In-Process GC testing results of Impurity A (square symbols in Fig. 7) show a good agreement with the model prediction for both the front-cut and the product-cut distillations. This demonstrates that the efciency of Impurity A separation from product can be signicantly enhanced with an increased in total reux time to about 5 h, which results in over 60% of cycle time reduction for the frontcut distillation. It has been shown in the commercial column that further increase in total reux time to more than 56 h has a minimum effect on the enrichment of Impurity A at top of the distillation

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Fig. 10. Front-cut cycle time before and after increasing equilibrium time. Fig. 8. Effect of reux ratio in front-cut on Impurity A removal with 0.23% of Impurity A in the feed.

column since an equilibrium has been reached, thus dismissing the return of even longer total reux time on the efciency of Impurity A removal. After the distillation model has been veried by the plant data, it is of interest to utilize the modeling tool to understand the effect of reux ratio in the front-cut on Impurity A removal and the effect of Impurity A level in the feed on the cycle time of front-cut distillation. Fig. 8 shows the effect of reux ratio in the front-cut on Impurity A removal with a typical 0.23% of Impurity A in the feed as a function of percentage of feed distillated. As the reux ratio is reduced from 40:1 to 20:1 in the front-cut, the percentage of feed to be distilled is actually reduced from 7.7% to 5.2% for the fresh distillate to meet the specication of 0.6% impurities due to a less degree of purication for the low volatility Impurity A at a low reux ratio. However, the overall percentage of Impurity A removed at end of the front-cut is reduced from 65.6% to 55.3% with a reduced reux ratio from 40:1 to 20:1. Fig. 9 illustrates the effect of reux ratio in the front-cut on Impurity A removal with a doubled amount of Impurity A in the feed (0.46%) as a function of percentage of feed distillated. For this elevated level of Impurity A, the percentage of feed to be distilled is almost the same at approximately 17% for 20:1, 40:1 and 60:1 reux ratios to meet the specication of 0.6% impurities in the fresh distillate. However, the overall percentage of Impurity A removed at end of the frontcut is reduced from 88.4% for 60:1 reux ratio to 84.2% for 40:1

reux ratio and 73.7% for 20:1 reux ratio with the corresponding front-cut cycle time of 38 h, 26 h and 13 h, respectively. It should be noted also that 73.7% removal of Impurity A in the front-cut with 20:1 reux ratio may not be sufcient to meet the specication of 0.1% of Impurity A in product. To balance the overall Impurity A removal and cycle time in the front-cut, 40:1 reux ratio in the front-cut is appropriate even with Impurity A doubled in the feed. The enrichment of low-boiling impurities (mainly Impurity A) in the front-cut with a longer total reux time (about 5 h) can be further explained in Fig. 10 by comparing the low boiling concentration in the fresh distillate with 12 h total reux (original process) and those with approximately 5 h total reux prior to the font cut (after process improvement). The total low-boiling impurities in the feed material for these ve production runs were very similar. Distillate samples were taken every 5 h (if the previous samples contains 1% of low-boiling impurities) and every 2 h (if the previous sample consists of <1% of low-boiling impurities) to test for low-boiling impurities by GC analysis after starting the front-cut distillation, until the low-boiling impurities are 0.6% in the fresh distillate. In the original process, the rst sample after 5 h of frontcut distillation normally contains 56% of low-boiling impurities in distillate and the impurities gradually decreased with a very long tail due to insufcient equilibrium prior to the front-cut distillation (three production lots with dotted lines grouped as original process in Fig. 10). After process improvement with about 5 h of total reux, low-boiling impurities are much enriched in the top portion of the distillation column due to better equilibrium. This results in a much higher concentration of the low-boiling components at the start of the front-cut distillation (solids curves in Fig. 10 with additional samples taken at 0 h after total reux), yielding a much shorter distillation time to achieve the In-Process specication of 0.6% of low-boiling impurities for switching to product-cut. It should be noted that the areas under the low-boiling impurity curves prior to and after the process improvement are essentially the same, representing that the total amount of low-boiling impurities removed are similar for these ve production runs. This process improvement not only reduces the cycle time of front-cut distillation, but also results in a lesser amount of front-cut material collected as waste, thus, increases the yield. 4. Other improvements to reduce cycle time 4.1. Increase of jacket temperature for faster boiling-up rate The jacket temperature during distillation was originally set at 130 C in production. Since the boiling temperature of the crude mixture under the given vacuum is about 118 C, the temperature

Fig. 9. Effect of reux ratio in front-cut on Impurity A removal with 0.46% of Impurity A in the feed.

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difference in the reboiler was only 12 C. Stability studies indicated that the jacket temperature could be increased to 150 C without impacting the product quality. Since it is desired to reduce the cycle time, the jacket temperature was gradually increased to 140 C during distillation. The differential pressure along the distillation column only increased slightly from 1.6 kPa to 2.2 kPa when the jacket temperature was increased to 140 C, indicating a good column performance with an increased boiling-up/distillation rate. The product-cut distillation normally took 34 days (7296 h) in the original process with the jacket temperature at 130 C. After the jacket temperature is increased to 140 C, the average time for the product-cut has been reduced to 3653 h. 4.2. Decrease in condenser temperature The condenser temperature was set at 28 C during the productcut in the original process, resulting in loss of some product to the vacuum. When the condenser temperature was set to 22 C, the condenser was frozen with solids. Investigation on the issues revealed that the frozen material(s) was due to low-boiling impurities. The condenser temperature is then gradually decreased to 24 C for the front-cut and 22 C during the product-cut. It is measured that the loss of product to the vacuum is decreased by about 3% due to the lower condenser temperature. 4.3. Better vacuum The calculated VLE using UNIFAC and group contribution method in the built-in property estimator of AspenPlus (Aspen Tech, 2004) indicates that the relative volatility of Impurity A and product slight increases at a higher vacuum (low pressure). Because of the slight increase in separation efciency, the vacuum at the top of the column is reduced to less than 0.66 mbar from 2.63 mbar. This has resulted in smoother and lower temperatures at top of the column, made the separation more efcient, and slightly increased the boiling-up rate. Due to better vacuum the distillation rate is increased and the cycle time is slightly shortened. 4.4. Better control of reux ratio Careful evaluation of the reux ratio in the front-cut indicated that with a reux ratio setting at 135:3 s (45:1 ratio), the splitter valve actually closed and opened for 138.83 s and 3.50 s, respectively, resulting in an effective reux ratio of approximately 40:1 (due to the limit of control system and the physical movement of the valve). Lower reux ratio would reduce the separation efciency of low-boiling impurities in the front-cut. This is modied and compensated by changing the splitter setting from 135:3 s to 180:4 s in the front-cut. This produces a better reux ratio close to the setting that slightly increases the separation efciency. After these process improvements and optimization, the overall cycle time per batch has been gradually decreased from approximately 7 days to about 2.5 days as illustrated in Fig. 11, and the yield has been increased from original 82% to an average of 88% while still producing the same high quality of product. These improvements are achieved with the original equipment and with a minimal cost. Since these changes are within the regulatory lings for the process, they are implemented quickly in commercial production to improve the throughput.

Fig. 11. Reduction of process cycle time after process optimization.

5. Summary Process understanding and improvements were required to decrease the cycle time for a batch distillation process. Based on process understanding and modeling of the batch distillation, four process improvements have been made to reduce the cycle time and to increase the manufacturing throughput: (1) increasing the equilibrium time prior to the front-cut to achieve better equilibrium for a more efcient separation of low-boiling impurities, (2) increasing the jacket temperature of reboiler for faster boilingup/distillation rate, (3) reducing the condenser temperature to minimize the product loss to vacuum, and (4) optimizing the vacuum and splitter system. Through the process modeling and improvements, the average cycle time was dramatically decreased to 4.2 days rst and then to an average of 2.5 days, which represents 64% reduction in cycle time from an average of 7 days process originally, or increases the throughput by a factor of 2.8. Furthermore, the yield is also increased and the strict specications are met. This is achieved with the original equipment and without capital investment. These changes have been implemented in commercial production to manufacture the increased demands on the drug substance. In conclusion, fundamental understanding and process modeling of the batch distillation process allow us to quickly improve the existing commercial process to increase the throughput by a factor of 2.8 using the approach of quality by design (QbD), and to produce the quality product consistently. References
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