Organic Process Research & Development
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 Improve-
ments 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.
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′-Tetramethyl-
5-(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 <20 °C to destroy excess nitrous acid. The slurry is filtered to
remove carbon/harbolite with a line wash of water (77 L) and
acetonitrile (10 kg) to the crystallizer. The solution is adjusted
to >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.
1H 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
■
(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.
Corresponding Author
Notes
(17) Deneau, E.; Steele, G. An In-Line Study of Oiling Out and
Crystallization. Org. Process Res. Dev. 2005, 9, 943−950.
The authors declare no competing financial interest.
̀
(18) Lafferrere, L.; Hoff, C.; Veesler, S. In Situ Monitoring of the
ACKNOWLEDGMENTS
Impact of Liquid−Liquid Phase Separation on Drug Crystallization by
Seeding. Cryst. Growth Des. 2004, 4, 1175−1180.
■
We acknowledge the assistance of Lyn Powell, Fiona Kenley,
Dave Laffan, and Bernd Schmidt (anastrozole process develop-
ment), 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).
(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.
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
dx.doi.org/10.1021/op300326b | Org. Process Res. Dev. 2013, 17, 557−567