How to use the Lasentec FBRM probe on manufacturing scale

Article pubs.acs.org/OPRD

How To Use the Lasentec FBRM Probe on Manufacturing Scale Neil K. Adlington,*,† Simon N. Black,§ and David L. Adshead† †

Chemical Sciences, Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, United Kingdom § Physical Sciences, Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, United Kingdom ABSTRACT: A Lasentec FBRM probe was installed in a 450-L production unit and deployed to monitor the final three stages of the manufacturing process. Each step features a different type of crystallization: reactive, pH switch and cooling. In total over 100 batches were monitored. The probe detected ‘oiling out’ and seeding with agitation but did not detect ‘bearding’ or seeding without agitation. There was remarkable consistency from batch to batch, except for the first batches in some campaigns, which more closely resembled laboratory experiments. The challenge of interpreting Lasentec FBRM data in a production environment is addressed and compared with the alternative, in process control (IPC).

1. INTRODUCTION Process Analytical Technology (PAT) tools are now widely applied during process development in the pharmaceutical industry, and this includes the development of crystallization processes.1 Lasentec focused beam reflectance measurement (FBRM) has been used primarily as a tool for the development of crystallization processes.2 In particular it can allow rapid assessment of when crystallization has started and when it finishes. There have been relatively few publications describing the application of this technology outside of the laboratory. A brief search of Org. Process Res. Dev. using the keyword ‘Lasentec’ identified 51 articles. The earliest,3 in 1999, describes a correlation between mean chord length and filtration times. Forty-five other articles describe studies at scales of up to 2 L. Applications include general crystallization studies,2,4 cooling crystallizations,5,6 impurity effects,7 polymorphic transformations,8,9 hydrate formations,10−12 secondary nucleation,13,14 temperature cycling,15,16 and ‘oiling out’.17,18 A common theme in these studies is generation of process understanding that is then applied to develop scalable processes. One study at the 10L scale19 investigated particle suspension, and another20 compared different in-line technologies at the 20-L scale. Sistare et al.21 describes the use of Lasentec FBRM installed in a dip pipe in a 5000-gal reactor to detect that a ‘granulation’ step at the end of a crystallization at plant scale was unnecessary. More recently, Barrios Sosa et al.22 used the Lasentec FBRM probe ‘in a plant setting’ to track the crystallization of an unwanted isomer at two different process concentrations. Lo et al.23 sited the Lasentec probe in series with a high shear mixer within a circulation loop attached to a 2000 L crystallizer in a pilot plant. We are not aware of a published analysis of in-line data covering several batches and multiple campaigns of the same process in a production environment. This also brings new challenges and opportunities in the installation and operation of the probe, in interpreting the data from the probe, and in deciding when and how to react to these data. Anastrozole is the active ingredient in ‘Arimidex’, an aromatase inhibitor in the treatment of breast cancer. The © 2013 American Chemical Society

production process was developed well before the availability of PAT tools such as the Lasentec FBRM probe. Production started at Macclesfield, UK, in 1993 following establishment and validation campaigns. In 1999 production was transferred to a smaller unit which included a 100-gal (∼450 L) crystallizer. Production continued until 2009, when annual sales peaked at $1.9 billion. The final three process steps, known as ‘anastrozole quaternary salt (AQS)’, ‘crude’, and ‘pures’ were operated in this unit. Soon after the transfer of the process to the new unit in 1999, problems occurred with the Crude process with four lowyielding batches caused by incomplete crystallization. A preliminary investigation confirmed that the chemical reaction was complete, but that on adjusting the pH with ammonia, the product had a tendency to ‘oil out’. This phenomenon is very common in industry, although infrequently investigated in the scientific literature.17,18,24 The ‘oil’, a dispersed liquid phase, passes through the filter so it is essential that conversion to crystals is complete before filtration. However, it proved difficult to distinguish between a suspended oil phase and suspended crystals by visual inspection of the reactor. Initially, the in process control (IPC) was changed to sample the batch to verify crystallization, but this has inherent problems as the sample could crash crystallize when sampling. The crystallization was reinvestigated in the laboratory using a Lasentec FBRM probe. In the laboratory the onset of crystallization was detected by a rapid decrease in the total counts by the probe as the many small ‘oil’ droplets dissolved at expense of fewer, larger crystals. This detection of the onset of crystallization justified the installation of a Lasentec FBRM probe in the production unit in 2004. As the same vessel was also used for the preceding AQS stage (reactive crystallization), and the subsequent pures stage (cooling crystallization), data were collected on all three stages. Special Issue: Polymorphism and Crystallization 2013 Received: November 9, 2012 Published: February 4, 2013 557

dx.doi.org/10.1021/op300326b | Org. Process Res. Dev. 2013, 17, 557−567

Organic Process Research & Development

Article

From a crystallization perspective, the three steps are very different. The ‘quaternary salt’ step involves five major components, and supersaturation is created by a chemical reaction. The ‘crude’ stage involves four major components, and supersaturation is created by a change of pH. There are only three components in the ‘pures’ stagethe product and two solventsand supersaturation is created by cooling. These three different conditions provided an unusual opportunity to compare crystallization behaviors, as monitored by the Lasentec FBRM probe, at laboratory and production-plant scales.

A review of the data collected on all three stages between 2004 and 2009 set out to address the following questions: (1) Could the probe detect both the onset and end of crystallization for all three crystallization types? (2) How consistent were the nucleation and crystallization times, from batch to batch and campaign to campaign? (3) How would the probe respond to the addition of seed in the pures step? (4) Would the probe detect any other features of these processes, and would this be useful? (5) How would the staff running the production unit work with the probe and use the data? The manufacturing process involves three stages; anastrozole quaternary salt 3, crude 4, and pure 5, starting from the outsourced starting material anastrozole pentamethyl 1 as shown in Scheme 1;

2. RESULTS AND DISCUSSION For each step, a brief description of the chemistry and general operating experience is followed by a review of the Lasentec FBRM data. 2.1. Reactive Crystallization: Anastrozole Quaternary Salt. The formation of quaternary salt involves the bromination of pentamethyl using N-bromosuccinimide as the brominating agent to form the intermediate monobromo 2 in the presence of acetic acid. The resulting monobromo solution is transferred to the crystallizer containing 4-aminotriazole at ambient and heated to reflux to generate quaternary salt which crystallizes at reflux as a cream crystalline solid. The quaternary salt is isolated at ambient, washed with acetonitrile and partly dried to minimize dust formation upon discharge from the pressure filter. The quality of isolated quaternary salt is excellent with the major impurity being unreacted pentamethyl, typically at levels ∼0.4% w/w. There is no 4-N isomer formed using this procedure as the alkylation is regioselective.25,26 In early development the monobromo (2) process was a separate stage before it was telescoped to yield the quaternary salt in one step. This not only increased the overall yield but also avoided exposure to the lachrymator monobromo species. The bromination uses an undercharge of N-bromosuccinimide to minimize the overbromination to form the dibromopentamethyl [dibromo] impurity. This impurity although unreactive with 4-aminotriazole, is difficult to remove downstream and is controlled at this stage. It is important to heat the bromination mixture to reflux to consume the residual N-bromosuccinimide and bromine. This minimizes the bromination of quaternary salt, and the violent reaction between N-bromosuccinimide and 4-aminotriazole. Development work demonstrated two important aspects of the crystallization of quaternary salt. First the quality of isolated quaternary salt is dependent upon the precise temperature of nucleation and crystallization of the batch. Crystallization of quaternary salt leads to occlusion of unreacted pentamethyl, monobromo, and dibromo species present in solution. The level of these species occluded depends upon when crystallization of quaternary salt occurs and three possible impurity profiles maybe observed in the isolated product. If crystallization occurs before reflux is attained, higher than normal levels of impurities (in particular monobromo) are observed. Crystallization at reflux gives low levels of impurities. Crystallization during the cool down after the hold at reflux will normally give low levels of impurities provided a profile cooling is adopted. In early manufacture when no cooling profile was in place crystallization post reflux led to higher levels of pentamethyl due to crash crystallization. The second important factor is that the batch must be heated to reflux within 90 min to ensure nucleation of quaternary salt occurs at reflux. This heatup time is a critical attribute of the process, as failure will lead to specification failure due to the

Scheme 1. Anastrozole manufacturing processa

a

Reagents and conditions: a) N-bromosuccinimide/acetonitrile/acetic acid/AIBN/reflux; b) 4-amino-1,2,4-triazole/reflux; c) NaNO2/HCl/ H2O/acetonitrile/carbon/harbolite/15−20 °C; d) NH2SO3H/H2O; e) NH3; f) MTBE/carbon/reflux; g) pure seed.

The first stage involves brominating pentamethyl 1 using Nbromosuccinimide to yield the intermediate monobromo 2 in acetonitrile. Quaternary salt 3 is formed by regioselective alkylation of the intermediate monobromo 2 solution with 4aminotriazole, followed by isolation as a solid. Treatment of 3 with nitrous acid, formed by hydrochloric acid and sodium nitrite, generates anastrozole crude 4, as a salt, which is isolated as the free base by pH adjustment with ammonia. Finally anastrozole crude 4 is purified from carbon treatment in methyl tert-butyl ether to yield anastrozole pure 5 as a brilliant white solid. The crystallization conditions for all three process stages are shown in Table 1; Table 1. Crystallization conditions of the anastrozole process stage

product

type

conditions

seed

quaternary salt crude

3 4

reactive pH adjustment

pures

5

cooling

reflux initial 12−15 °C modified 12−27 °C 30−20 °C

N N N Y 558



Article

it, observed by a spiky distribution curve. However, in the majority of the batches the distribution curve became smooth again indicating that the solid was removed from the probe by the slurry. It was shown in the lab that further crystallization of the batch occurs upon cooling to 20 °C, and the fact that the plant ‘total counts’ increase during the profile cool confirms that this is the same on-plant. In addition, a shoulder on the distribution curve at low chord length was observed prior to transfer to the filter, indicating the formation of smaller particles. Both attrition of crystals and growth of smaller crystals during the cool down to 20 °C had occurred. Traces from both laboratory and plant show a sharp increase in ‘total counts’, indicating the nucleation; hence, the probe could be used to verify crystallization on-plant if required. Figure 2 shows the nucleation and crystallization times for the manufacturing batches. The nucleation time is from the start of heating of the batch (point B) to the observation of rapid increase in counts on the Lasentec trace (point C). The times show little variation over the data collected, and nucleation always occurred at reflux, demonstrating the process is consistent from campaign to campaign. Most of the slight variability of nucleation of the batches is due to the heatup to reflux which typically varied between 33 and 66 min. The crystallization time for each batch is the time taken from the initial increase in counts to the peak (points C to D). Although slightly subjective, as the counts tail off towards the end of the crystallization period, this does give a reasonable reflection of the crystallization time, and the timings are consistent from campaign to campaign. There are differences between laboratory and plant data when considering both the nucleation and crystallization times. Table 2 shows the mean nucleation and crystallization data for both laboratory and plant. The laboratory timings are considerably longer and this has been ascribed to the clean vessels as the equipment is cleaned prior to each experiment. However, on-plant there is no inter batch clean of the crystallizer so a small amount of quaternary salt from the previous batch could be present and could ‘seed’ the following batch. This observation also explains the shorter crystallization times for the plant compared to the laboratory as the presence of this material is actively seeding the process. As a result both nucleation and crystallization events are faster on-plant compared to the laboratory. Table 2 also shows the nucleation times after reflux for the first batch of the campaigns and shows that the first batch of the campaign nucleates longer after reaching reflux. The nucleation times for the remainder of the batches in the same campaign are shorter. In the first batch the crystallizer is clean and nucleation occurs later into the reflux period as would be expected from primary nucleation. This is an example of a ‘first batch effect‘: the first batch of any campaign behaves in a similar manner to the laboratory. Hence in this process for the second batch onwards the laboratory nucleation time is not a guide to the anticipated nucleation times on-plant as there are two different nucleation processes i.e. primary and secondary. The Lasentec probe was able to detect both primary and secondary nucleation and crystallization events in the process. The process is robust and consistently crystallizes at reflux leading to material of suitable quality in the campaigns monitored. The first batch of any campaign behaves in a similar manner as the laboratory. Although not implemented the Lasentec probe could be used by production staff to

related impurities. As the reaction mixture is heated up to reflux, the quaternary salt concentration increases until it is supersaturated, and nucleation of quaternary salt is initiated. Hence, provided that the quaternary salt concentration remains in the metastable region during the rapid heat up and nucleates at reflux, this will lead to good-quality material. However, if the heat up is >90 min, then quaternary salt moves into the supersaturated region prior to reaching reflux and nucleates, occluding a significant portion of monobromo, thus leading to specification failure. Data has shown that for crystallization of the batch at temperatures lower than reflux (60, 70, and 75 °C) the level of monobromo intermediate in the isolated quaternary salt ranged from 1.36% (60 °C) to 0.83% (75 °C). Attempts to obtain kinetic data were unsuccessful as no suitable wavelength by IR could be found, and sampling of the reaction solution at temperatures >70 °C caused premature crystallization. Typically in the laboratory nucleation of quaternary salt occurs an hour into the 3-h hold at reflux. Therefore, as earlier plant batches were known to crystallize after this reflux hold period, addition of seed was considered to ensure crystallization prior to cooling. Two potential modes of addition were investigated. The first involved adding the seed prior to the heatup to reflux. Unfortunately it was observed that the batch nucleated below reflux at ∼75 °C, leading to high levels of monobromo 1, and was not considered further. The second mode of addition was at reflux and led to consistent nucleation. This procedure was considered for operation on the plant, but problems of designing a port to add the seed at reflux meant this idea was not considered further. It was decided that if crystallization of the batch had not occurred after the 3-h hold, it would be cooled just off reflux to initiate crystallization. Lasentec data in the lab had shown that nucleation of the batch could be detected as a rapid increase in the counts. Therefore, the probe was used to verify the actual nucleation point in the process with reference to the reflux attainment.

Figure 1. Typical quaternary salt plant Lasentec trace. (A) Transfer of batch to crystallizer; (B) heating started; (C) nucleation of batch; (D) crystallization complete.

The Lasentec data were collected from 73 batches over 5 campaigns. A typical ‘total counts’ trace is shown in Figure 1. The batch is transferred to the crystallizer (at ∼12.15), and upon heating any solid stuck to the probe dissolves, leading to a clean baseline. At the point of nucleation (∼13.40) a rapid increase in counts is observed. This time of nucleation was consistent with the batch at or just after reaching reflux (∼82−3 °C) which leads to suitable-quality isolated quaternary salt. After crystallization is complete, there is a peak in the ‘total counts’, and the probe appears to be blinded by solid sticking to 559



Article

Figure 2. Quaternary salt nucleation (red) and crystallization (blue) Lasentec plant data.

which eventually crystallizes during the profile cool to 12 °C. However, observing the change from oil to solid is difficult due to the very similar visual appearance of both phases. As a result of this difficulty, two crude batches were filtered before crystallization was complete. The oil passed through the filter and crystallized in the waste receiver. Sampling of the batch after the hold at 12 °C was introduced to verify crystallization of the batch, but two further low-yielding batches occurred. Initially seeding the batch was considered as it was demonstrated that this gave consistent crystallization of the oil phase and occurred within a few minutes of the addition of the seed and the product quality was not affected. However, due to internal regulatory considerations this avenue was not pursued further. The oil droplets are dependent upon the concentration of acetonitrile in the system. In the crystallization liquor the acetonitrile content was found to vary slightly between 10.2 to 11.7% w/w (by NMR). This is lower than the input acetonitrile, theoretical 16.3% w/w, due to losses from the deamination part of the process where a nitrogen purge is applied to the vessel to remove nitrous oxide. Increasing the acetonitrile content regenerated the oil phase at lower temperatures until two distinct phases were observed when the acetonitrile content reached >18% w/w and no crystallization of anastrozole occurred. Reducing the acetonitrile content can cause crystallization of anastrozole salt in the acidic deamination mixture and during the pH adjustment. The Lasentec probe was investigated as an aid to the detection of crystallization in the process. Upon pH adjustment by ammonia the free base, as oil, is detected by the Lasentec as a sharp increase in counts. The resulting oil phase is held at 12 °C and a rapid reduction in counts indicates crystallization of the batch has occurred. Optical microscopy (Figure 3) shows clearly the difference between the oil droplets and the crystals

Table 2. Mean nucleation, crystallization, and first batch nucleation times for quaternary salt process time (min) campaign (batches)

nucleation

crystallization

first batch nucleation

laboratory 2004 (12) 2006 (7) 2006/07 (17) 2007 (13) 2008 (24)

114 45 40.1 47.1 44.4 51.3

42 21 10.2 11.5 7.8 5.3

179 129 n/a 90 55 n/a

confirm that crystallization of the batch with respect to attainment of reflux has occurred. 2.2. Crystallization by pH Switch: Anastrozole Crude. The anastrozole crude process involves the removal of the amino function on the triazole group in quaternary salt. This deamination is carried out with nitrous acid formed from the addition of sodium nitrite to a slurry of quaternary salt, aqueous acetonitrile, hydrochloric acid, activated carbon and harbolite. Anastrozole crude is formed as a salt and excess nitrous acid destroyed by sulphamic acid before being screened to the crystallizer. The free base of anastrozole crude is generated by the addition of ammonia, isolated at 12 °C and washed with purified water then discharged as a water-wet paste. The crude is isolated in high strength, >99.3% w/w with related substances 40 °C followed by cooling regenerates the oil phase at temperatures ∼25−8 °C. This suggests that the liquid−liquid system is thermodynamically more stable than the solid−liquid system at T > 40 °C, but slightly less thermodynamically stable at lower temperatures. The oil droplets coalesce at 22−25 °C and settle on the bottom of the vessel. NMR analysis of this bulk oil phase found it contains anastrozole 45−50% w/w and acetonitrile 28−35% w/w, the residual presumed to be water. It is hypothesized that anastrozole in the oil droplets is transported to the growing crystal via the continuous liquid phase. This is supported by the fact that the isolated crude is not only of high HPLC strength, >99.3% w/w, but contains very little acetonitrile 2 h). This decrease in the nucleation time from the third batch onwards is probably due to some residual free base remaining in the crystallizer from the previous batches seeding the remaining batches. Although the probe only indicated when crystallization of the batch started but not when it was complete, the 12 h hold at 12 °C was sufficient to ensure it was complete prior to discharge to the filter. On a laboratory scale the addition time was rapid as better temperature control was achieved, whilst a longer plant addition time was required to maintain the temperature 40 °C. This gives a sufficient safety margin out of the solubility region and into the metastable region during seeding. The seed was taken from an unmcironised batch of anastrozole pure from the previous campaign. The presence of water is essential as anastrozole is insoluble in methyl tert-butyl ether. The water present in the crude waterwet paste is sufficient to aid dissolution. The anastrozole pure is typically isolated in 82% yield and results in very low levels of total related substances 2 h at 30 °C. Therefore, seed addition to the batch was implemented, and the addition temperature of 30 °C was chosen as the seed 563



Article

campaign. The quality derived from either the unagitated and agitated seed addition batches was similar. A more detailed study of this phenomenon will be reported separately. The crystallization times for the manufacturing batches are shown in Figure 10, and the mean times, in Table 3. The

The nucleation time was the time taken from addition of the seed to the sharp increase in counts (points A to B); the crystallization time was taken from the sharp increase in counts to the peak of counts (points B to C), (Figures 8 and 9, time

Figure 8. Typical Lasentec trace for anastrozole pures in unagitated crystallizer: (A) seed added, (B) nucleation of batch, (C) crystallization complete.

Figure 10. Anastrozole pures Lasentec crystallization times.

Table 3. Crystallization times of anastrozole pures process time (min) campaign (batches) lab 2005 2006 2007 2008 2009

(10) (4) (8) (4) (19)

mean

range

13 27.5 13.3 17.4 19 17

n/a 16−42 9−16 10−25 10−29 9−43

crystallization data (Figure 10) are very consistentthe slight variability may reflect a variable amount of suspended seed present in the batch. The mean crystallization times (Table 3) are remarkably similar from campaign to campaign except for the first. This reflects the lack of suspended seed in the first campaign when the agitator was switched off during seed addition. Another interesting observation was the nucleation and crystallization times for the final batch of the first campaign. The nucleation time was 2.5 h, whilst the crystallization time was 42 min. This crystallization time was considerably longer than those of the previous batches which varied between 16 and 33 min. This batch self-nucleated (primary nucleation) before seed could be added. This long nucleation time is operationally unsatisfactory for production process, as different nucleation times are likely to be encountered, leading to varying batch processing times. Hence, this demonstrated the advantages of adding seed on-plant. In the remaining campaigns the agitator was left on during seed addition; as a result, more nucleation points were present in the crystallizer, leading to shorter nucleation and crystallization times of the batches. On-plant the production staff could assess whether crystallization had occurred by observing the batch either through the sight glass or on the Lasentec computer trace. Once batch crystallization was assessed to have initiated, the 2 h hold at 30 °C was started. As the Lasentec plant crystallization time in the remaining batches was 98.5% w/w with related substances 40 °C, is heated to 65 °C over an hour. The solution is held for 4 h at 65 °C before being heated to reflux for 1.5 h. The solution is cooled to 20 °C before being transferred to the crystallizer containing 4-aminio1,2−4-triazole (19.3 kg, 229 mol). The solution is heated to reflux with a jacket temperature of 100 °C, and the contents are held for 3 h at reflux. The product crystallizes during the reflux hold period. The contents are profile cooled over 7 h to 20 °C

event on the Lasentec trace shows that this could be used to confirm that crystallization of the batch has started. The results show that crystallization of anastrozole pures onplant is consistent and behaves in a manner similar to that of the laboratory, demonstrating the robust nature of the process. The probe could be used to assist production staff to confirm that crystallization of the batch has occurred. As a monitoring tool it can observe the addition of the seed and suspension by the agitator in the crystallizer as a slight increase in counts, thus ensuring consistent operation on-plant. This study has also demonstrated the advantages of secondary nucleation by the addition of seed in production, rather than relying on variable primary nucleation.

3. CONCLUSION The Lasentec probe installed in the three anastrozole stages generated data on the crystallization characteristics of these processes. The probe was initially installed to monitor the crude crystallization to ensure the batch had crystallized prior to transfer to the filter, and this was extended to all three stages. The plant data showed that both nucleation and crystallization events could be observed in both the reactive and the cooling crystallizations. The nucleation and crystallization times in these two processes were consistent from campaign to campaign, showing robust processes. After the first batch the actual nucleation times on-plant for the reactive crystallization were different compared to those of the laboratory due to secondary nucleation of the remaining batches. The first batch behaved as expected according to the laboratory experiments, whilst the remaining batches contained residual quaternary salt from the previous batch acting as seed. Unfortunately the pH-switch crystallization, which the probe was specially installed to monitor, was found to be complicated due to the three-phase system and blinding of the probe during crystallization. Hence, it could only detect the onset of crystallization in this process. In the cooling crystallization, the probe could detect the addition of the seed in an agitated crystallizer by a small increase in the number of counts. This showed that the agitator is required to suspend the seed to initiate nucleation of the batch. The actual time of nucleation in the reactive crystallization could be used to ascertain whether the batch nucleated at reflux as this was a critical attribute of the process. This would ensure that material of suitable quality was isolated from the process. The production staff, process operators, and managers could use the plant data as IPC to verify whether crystallization events had occurred in the process as expected. In two-phase systems, such as quaternary salt and pures, sharp distinct events were observed, corresponding to nucleation/crystallization events. Unfortunately, in the crude three-phase system, oil−solid− liquid, interpretation of the Lasentec trace was difficult; as a result, the current in process control was retained. 4. EXPERIMENTAL SECTION 4.1. General. All the plant manufacturing processes described in this paper were carried out in a glass-lined reactor, nominal volume ∼100 gal (450 L) of diameter 88 cm, with an anchor agitator of 85 cm diameter with a clearance of ∼10 cm at the bottom under positive nitrogen pressure. The crystalliser was fitted with a D600R Lasentec FBRM probe. The probe, made from hastalloy, was installed on top of the crystalliser and 565



Article

(3) Ennis, D. S.; McManus, J.; Wood-Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A. Multikilogram-Scale Synthesis of a Biphenyl Carboxylic Acid Derivative Using a Pd/C-Mediated Suzuki Coupling Approach. Org. Process Res. Dev. 1999, 3 (4), 248−252. (4) Birch, M.; Fussell, S. J.; Higginson, P. D.; McDowall, N.; Marziano, I. Towards a PAT-Based Strategy for Crystallization Development. Org. Process Res. Dev. 2005, 9 (3), 360−364. (5) Black, S. N.; Quigley, K.; Parker, A. A Well-Behaved Crystallisation of a Pharmaceutical Compound. Org. Process Res. Dev. 2006, 10 (2), 241−244. (6) Liotta, V.; Sabesan, V. Monitoring and Feedback Control of Supersaturation using ATR-FTIR to produce an Active Pharmaceutical Ingredient of a Desired Crystal Size. Org. Process Res. Dev. 2004, 8, 488−494. (7) Scott, C.; Black, S. In-Line Analysis of Impurity Effects on Crystallisation. Org. Process Res. Dev. 2005, 9, 890−893. (8) O’Sullivan, B.; Barrett, P.; Hsiao, G.; Carr, A.; Glennon, B. In situ Monitoring of Polymorphic Phase Transitions. Org. Process Res. Dev. 2003, 7, 977−982. (9) Saranteas, K.; Bakale, R.; Hong, Y.; Luong, H.; Foroughi, R.; Wald, S. Process Design and Scale-Up Elements for Solvent-Mediated Polymorphic Controlled Tecastemizole Crystallization. Org. Process Res. Dev. 2005, 9, 911−922. (10) Black, S. N.; Phillips, A.; Scott, C. I. Crystallisation Design Space: Avoiding a Hydrate in a Water-Based Process. Org. Process Res. Dev. 2009, 13, 78−83, DOI: 10.1021/op800249r. (11) Wenju, Liu; Hongyuan, Wei; Simon, Black An Investigation of the Transformation of Carbamazepine from Anhydrate to Hydrate Using in Situ FBRM and PVM. Org. Process Rev. Dev. 2009, 13, 494− 500, DOI: 10.1021/op8002773. (12) Howard, K. S.; Nagy, Z. K.; Saha, B.; Robertson, A. L.; Steele, G. Combined PAT-Solid State Analytical Approach for the Detection and Study of Sodium Benzoate Hydrate. Org. Process Res. Dev. 2009, 13, 590−597. (13) Mousaw, P.; Saranteas, K.; Prytko, B. Crystallization Improvements of a Diastereomeric Kinetic Resolution through Understanding of Secondary Nucleation. Org. Process Res. Dev. 2008, 12, 243−248. (14) Kamahara, T.; Takasuga, M.; Tung, H. H.; Hanaki, K.; Fukunaka, T.; Izzo, B.; Nakada, J.; Yabuki, Y.; Kato, Y. Generation of Fine Pharmaceutical Particles via Controlled Secondary Nucleation under High Shear Environment during Crystallization: Process Development and Scale-up. Org. Process Res. Dev. 2007, 11, 699−703. (15) Abu Bakar, M. R.; Nagy, Z. K.; Reilly, C. D. Seeded Batch Cooling Crystallization with Temperature Cycling for the Control of Size Uniformity and Polymorphic Purity of Sulfathiazole Crystals. Org. Process Res. Dev. 2009, 13, 1343−1356. (16) Kim, J.-W.; Kim, J.-K.; Kim, H.-S.; Koo, K.-K. Application of Internal Seeding and Temperature Cycling for Reduction of Liquid Inclusion in the Crystallization of RDX. Org. Process Res. Dev. 2011, 15, 602−609. (17) Deneau, E.; Steele, G. An In-Line Study of Oiling Out and Crystallization. Org. Process Res. Dev. 2005, 9, 943−950. (18) Lafferrère, L.; Hoff, C.; Veesler, S. In Situ Monitoring of the Impact of Liquid−Liquid Phase Separation on Drug Crystallization by Seeding. Cryst. Growth Des. 2004, 4, 1175−1180. (19) Custers, J. P. A.; Hersmis, M. C.; Meuldijk, J.; Vekemans, J. A. J. M.; Hulshof, L. A. 3,4,5-Tri-dodecyloxybenzoic Acid: Combining Reaction Engineering and Chemistry in the Development of an Attractive Tool To Assist Scaling Up Solid−Liquid Reactions. Org. Process Res. Dev. 2002, 6, 645−651. (20) Li, R. F.; Penchev, R.; Ramachandran, V.; Roberts, K. J.; Wang, X. Z.; Tweedie, R. J.; Prior, A.; Gerritsen, J. W.; Hugen, F. M. Particle Shape Characterisation via Image Analysis: from Laboratory Studies to In-Process Measurements Using an in Situ Particle Viewer System. Org. Process Res. Dev. 2008, 12, 837−849. (21) Sistare, F.; St. Pierre Berry, L.; Mojica, C. Process Analytical Technology: An Investment in Process Knowledge. Org. Process Res. Dev. 2005, 9, 332−336.

and held for 2 h to complete crystallization. The solid is isolated on the pressure filter, washed twice with acetonitrile (63 kg), and dried in a stream of nitrogen. Typical yield: 60.7 kg at 100% w/w (74.6% theory based on NBS input). 4.3. 1,3-Benzenediacetonitrile, α,α,α′,α′-Tetramethyl5-(1H-1,2,4-triazol-1-ylmethyl) (Anastrozole Crude) (4). To a slurry of 3 (45 kg, 116 mol), 35% hydrochloric acid (13.6 kg, 133 mol), water (110 L), acetonitrile (45 kg), harbolite (1.8 kg), and carbon Norit SX+ (2.0 kg) is added a solution of sodium nitrite (9 kg, 130 mol) in water (68 L) over an hour between 15 and 20 °C. The slurry is held for 3 h at 22 °C to complete the deamination. A solution of sulphamic acid (11.2 kg, 115 mol) in water (90 L) is added to the slurry over 30 min at 27 °C before 33% ammonia solution (31 kg) is added over 10 min. The resulting oil slurry is profile cooled to 12 °C and held for 12 h. The precipitated solid is isolated on the pressure filter, washed three times with purified water (51 L), and partially dried under a stream of nitrogen. Typical yield 31.5 kg at 100% w/w (92.9% theory) 4.4. Anastrozole Pure (5). A slurry of 4 as a water-wet paste (77 kg at 100% w/w strength), methyl tert-butyl ether (234 kg), carbon Norit SX+ (3.9 kg), and purified water (if required) is heated to reflux for an hour. The contents are adjusted to 50 °C and then screened to remove carbon to the crystallizer with a line wash of methyl tert-butyl ether (59 kg) and water (2.2 L). The solution in the crystallizer is heated to reflux for 30 min and then profile cooled over 2 h to 30 °C. Anastrozole pure unmicronised seed (240 g) is added to initiate crystallization of the batch. The resulting slurry is held for 2 h at 30 °C, then profile cooled over 2 h to 20 °C, and held for a further 2 h to complete crystallization. The solid is isolated on the pressure filter, washed twice with methyl tert-butyl ether (68 kg), and dried in a stream of hot nitrogen. Typical yield: 63.5 kg (82% recovery) as a brilliant white, crystalline solid. 1 H NMR data (400 MHz, 300 K, DMSO) δ 1.70 (12 H, s), δ 5.51 (2 H, s), δ 7.46 (2 H, s), δ 7.58 (1 H, s), δ 8.03 (1 H, s), δ 8.72 (2 H, s). 13C NMR (100 MHz, 300 K, DMSO) δ 28.2, 36.8, 51.7, 121.5, 124.2, 124.4, 142.7, 144.2, 151.9.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge the assistance of Lyn Powell, Fiona Kenley, Dave Laffan, and Bernd Schmidt (anastrozole process development), Claire Scott (demonstration of oiling out in the laboratory), Martin Coleman (probe installation on-plant), and Anne Kane and Ian Jarvis (operation of probe in the plant).

■

REFERENCES

(1) Yu, L. X.; Leonberger, R. A.; Raw, A. S.; D’Costa, R.; Wu, H.; Hussain, A. S. Application of Process Analytical Technology to Crystallization Processes. Adv. Drug Delivery Rev. 2004, 56, 349−369. (2) Barrett, P.; Glennon, B. Characterizing the Metastable Zone Width and Solubility Curve Using the Lasentec FBRM and PVM. Chem. Eng. Res. Des. 2002, 80 (A7), 799−805. 566



Article

(22) Barrios Sosa, A. C.; Conway, R.; Williamson, R. T.; Suchy, J. P.; Edwards, W.; Cleary, T. Application of PAT Tools for the Safe and Reliable Production of a Dihydro-1H-imidazole. Org. Process Res. Dev. 2011, 15, 1458−1463. (23) Lo, E.; Mattas, E.; Wei, C.; Kacsur, D.; Chen, C.-K. Simultaneous API Particle Size Reduction and Polymorph Transformation Using High Shear. Org. Process Res. Dev. 2012, 16, 102−108. (24) Bonnett, P. E.; Carpenter, K. J.; Dawson, S.; Davey, R. J. Solution Crystallization via a Submerged Liquid-Liquid Phase Boundary: Oiling Out. Chem. Commun. 2003, 698−699. (25) Raeymaekers, A.; Freyne, E.; Van Gelder, J.; Venet, M. Eur. Pat. B-O 293,978, 1987 (26) Astleford, B. A.; Goe, G. L.; Keay, J. G. J. Org. Chem. 1989, 54, 731−732. (27) Kline, B. J.; Saenz, J.; Stankovic, N.; Mitchell, M. B. Polymorphs and Particles Size Control of PPAR Compounds PF00787585 and AG035029. Org. Process Res. Dev. 2006, 10, 203−211.

567


How to use the Lasentec FBRM probe on manufacturing scale

Recommend Documents