Technical Note pubs.acs.org/OPRD
Crystallization Engineering in Aza-Steroid: Application in the Development of Finasteride⊥ Apurba Bhattacharya,‡ Kushal S. Manudhane,† Srinivasula Reddy Maddula,† B. R. Sreekanth,§ Sridhar Thota,† and Rakeshwar Bandichhor*,† Center of Excellence, Research and Development, †Integrated Product Development, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54 Bachupally, Qutubullapur, Ranga Reddy District 500072, Andhra Pradesh, India ‡ Department of Chemistry, Texas A&M University, Kingsville, Texas 78363, United States Department of Analytical Research, §Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500049, Andhra Pradesh, India S Supporting Information *
ABSTRACT: Novel and robust crystallization approach based on solid solution formation was developed for the purification of finasteride. This is an unprecedented approach that describes the use of pure finasteride 1 to purify different lots of finasteride 1 (impure) contaminated with dihydrofinasteride 2.
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INTRODUCTION
Finasteride, 1, is a 5α-reductase inhibitor and is employed in the treatment of benign prostatic hyperplasia (BPH) in males. It is a novel, potent, mechanism-based inhibitor of the human prostate (type 2) isozyme.6 The synthesis of finasteride involves a crucial silicon-mediated quinone oxidation to introduce the Δ1 double bond in the A ring of the aza-steroid as depicted in Figure 1.7 We were perplexed by the phenomenon that, during
In recent years significant advances in crystal engineering have inspired research in the systematic design of pharmaceutical material by directing molecular assembly of different components in the crystal lattice. The bioavailability including pharmacokinetic as well as the pharmacodynamic properties of drug substances can be manipulated via formation of cocrystals or crystalline molecular complex formation with pharmacologically acceptable and structurally related congeners.1 Seminal work from Professor Blackmond’s group served as a milestone in this area that led chemists to think systematically about incorporation of small molecules in the crystal lattice of racemic material leading to manipulation of the phase behavior resulting in strong asymmetric amplification.2 Crystallization plays pivotal role in industry mainly in the realm of resolution and purification3 and we were intrigued by the paucity of similar crystallization engineering applications in the area of pharmaceutical process development especially in the area of supramolecular synthesis, invoking self-assembly of existing molecules to generate a wide range of new solid API forms without the need to break or form covalent bonds. The scope of purification via crystallization of an API, especially in a linear nonconvergent sequence where the changes in molecular composition are more incremental in nature, is often encumbered due to the preferential cocrystallization of structurally similar unwanted congener(s).4 Such preferential cocrystallization can often be attributed to a “solid solution” whereby the crystalline lattice can partially accommodate structurally related components. Solid solution is a state where one component gets dissolved into the other, contributing significantly to the resulting crystallite.5 As a part of our ongoing efforts directed to the development of finasteride, 1, we encountered such an intriguing preferential cocrystallization phenomenon in the purification of the final drug substance. © 2012 American Chemical Society
Figure 1. Precedented synthesis of finasteride 1.
the isolation/purification via crystallization, the unreacted starting material, namely the dihydrofinasteride 2 (present even in trace amounts), tends to preferentially cocrystallize in the isolated finasteride crystal lattice instead of getting digested in the solvent mother liquor, notwithstanding the fact that the concentration of 2 in the mother liquor was significantly below the saturation limit. Even more perplexing was the fact that, the same cocrystallization tendency exists irrespective of the functionality in the D-ring of the steroid; the dihydro-azasteroid ester and the amide behave in an analogous manner.a Indeed, any purification attempt via traditional crystallization techniques, irrespective of the solvent used, failed to purify the product finasteride 1 from dihydrofinasteride impurity 2 and repeated crystallizations only led to concurrent enrichment of dihydrofinasteride after each crystallization to an unacceptable Special Issue: Polymorphism and Crystallization 2013 Received: May 29, 2012 Published: October 31, 2012 599
dx.doi.org/10.1021/op300142a | Org. Process Res. Dev. 2013, 17, 599−602
Organic Process Research & Development
Technical Note
level in the final API. The only plausible solution to this problem was to carry out the oxidation to a very high level (>99.8% or higher), which rendered the process nontrivial and impractical. Logically, we reasoned that finasteride itself could potentially act as the best medium to purify itself from its dihydro analogue. Such rationale led to a novel, nontraditional approach that was utilized in removing dihydrofinasteride from finasteride by exploiting the strong attractive interaction that exists in the crystal lattice between the two stereoidal congeners. Herein we present the results of our studies directed towards an in-depth understanding of the exact nature of the finasteride−dihydrofinasteride interaction in the crystal lattice which led to a unique solution to the problem, resulting in a simple and efficient purification of finasteride 1 from its structurally similar cocrystallizable congeners. We reasoned that, if a saturated solution of finasteride (impure) contaminated with the dihydro analogue in ethyl acetate was passed through a short column (pad filtration) packed with finasteride 1, potentially the purity of the saturated solution of impure finasteride would be significantly enhanced in the eluent by this operation, exploiting in this case the solid solution formation between dihydrofinasteride 2 and pure finasteride 1. The purity enhancement of finasteride 1 would be a direct result arising out of the structurally similar steroidal framework of 1 and 2 and their irreversible crystallite formation. Irreversibility of this crytallite formation in the given conditions (disclosed in this work) is quite evident as we were able to purify 1 (contaminated with 1−3% of 2), and it was possible to access the solid solution as crystals. Such a concept although seemingly implausible was surmised by experiment that simply involves filtering a solution of 1 (containing 1−3% of 2) through a short column of 1 where 1 essentially acts as a molecular trap for 2 in an irreversible manner; the eluent was essentially free of the impurity 2 ( 2.0σ(I)], Rint = 0.041, R1_obs = 0.049, wR2_all = 0.076. Crystal data for solid solution of 1 and 2: Formula C23H37.33N2O2, M = 370.53, monoclinic, a = 10.129(6) Å, b = 7.686(4) Å, c = 28.564(17) Å, β = 94.255(7)°, V = 2217(2) Å3, T = 298 K, space group C2, Z = 4, ρcalc = 1.11 g cm−3, μ(Mo Kα) = 0.070 mm−1, 11992 reflections measured, 2455 unique reflections, 1468 observed reflections [I > 2.0σ(I)], Rint = 0.045, R1_obs = 0.056, wR2_all = 0.083. 4 It is understood that the pure finasteride column may conceptually be used until it gets enriched with 10−15% (This depends on concentration, length, width and flow rate; as the preliminary data indicate.). Since the yield and purity data were collected out of impure finasteride [contaminated with 3% dihydrofinasteride (input)] and pure finasteride [ICH grade (output)], we thus did not generate/include the meaningful data from repeated use of the pure finasteride column (until it becomes enriched with 10−15% of dihydrofinasteride). However, there is much direct evidence (see SI) that the solid solution can occur even with the 1:1 or 1:2 ratio of finasteride and dihydrofinasteride; thus, there may be a possibility of retaining even more than 15% of dihydrofinasteride on the pure coloumn of finasteride. Since the retention percentage may vary as it depends not only on finasteride and dihydrofinasteride equilibrium but also on several other factors such as concentration, length, width, and flow rate, it seems a ternary phase diagram may not help. Thus we do not include the related data. a
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EXPERIMENTAL SECTION Polymorphic form III of finasteride 1 was used in all the experiments. Solvents and regents were used for all the reactions as received. Solid-state 13C NMR was recorded at 300 MHz. Infrared (IR) spectra were recorded as thin films on a Mattson Galaxy series FTIR 3000 spectrometer referenced to polystyrene standard. X-ray powder diffraction was collected on the Rigaku D/Max-2200 model diffractometer equipped with a horizontal goniometer in θ/2θ geometry. Cu Kα (λ = 1.5418 Å) radiation was used, and the samples were scanned between 3 and 45° 2θ. Differential scaning calorimetric (DSC) analyses were carried out on Shimadzu DSC50. The ThermoGravimetric Analysis (TGA) was performed on Q500 of TA Instruments. The thermogram was recorded from 25 to 250 °C under the nitrogen gas purge at a flow of 40 mL/min for balance and 60 mL/min for a sample at a heating rate of 10 °C/ min.
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DETAILS OF RECOVERY OF THE PURIFIED MATERIAL THAT WAS USED TO PACK THE COLUMN AND PURIFICATION OF IMPURE FINASTERIDE Ten grams of finasteride containing 3% DHF impurity was dissolved in 800 mL of ethyl acetate to prepare a saturated solution. This saturated solution obtained above was passed at a rate of 0.4 mL/min through the 15 g of pure finasteride powder (solid) packed in 1.1 cm × 10 cm glass column with 1−2 cm glass beads of 90−150 μ packed from both the ends of column. After completion of elution, either in continuous or batch mode, the impurity level of finasteride 1 dropped down to 0.20−0.25% from the initial 3%. After evaporating the solvent, dry powder was obtained in 97% yield (∼9.7 g), and the yield of the solid powder recovered from the column (continuous mode) or flask (batch mode) was about 102% (∼15.28 g).
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ASSOCIATED CONTENT
S Supporting Information *
This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Telephone: +91 8458 279 485. Fax: +91 8458 279 619. Email:
[email protected]. 601
dx.doi.org/10.1021/op300142a | Org. Process Res. Dev. 2013, 17, 599−602
Organic Process Research & Development
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Technical Note
REFERENCES
(1) (a) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. (b) Schulthesis, N.; Newmann, A. Cryst. Growth Des. 2009, 9, 2950−2967. (c) Meanwell, N. A. The Emerging Utility of Co-Crystals in Discovery and Development. In Annual Reports in Medicinal Chemistry; Macor, J. E.; Academic Press: New York, 2008; Chapter 22, Vol. 43, pp 373−404. (2) Klussmann, M.; Izumi, T.; White, A. J. P.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007, 129, 7657−7660. (3) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788−824. (b) McCague, R. Tetrahedron Lett. 2007, 48, 869−872. (4) The impurities generated via a final convergent assembly of molecules tend to be structurally less similar to the desired product and hence amenable to purification via crystallization. (5) Tamura, R.; Fujimoto, D.; Lepp, Z.; Misaki, K.; Miura, H.; Takahashi, H.; Ushio, T.; Nakai, T.; Hirotsu, K. J. Am. Chem. Soc. 2002, 124, 13139−13153. (6) (a) Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. J. Med. Chem. 1997, 40, 1293−1315. (b) Rittmaster, R. S. New Engl. J. Med. 1994, 330, 120−125. (c) Dallob, A. L.; Sadick, N. S.; Unger, W.; Lipert, S.; Geissler, L. A.; Gregoire, S. L.; Hguyen, H. H.; Moore, E. C.; Tanaka, W. K. J. Clin. Endocrinol. Metabol. 1994, 79, 703−706. (d) Walsh, D. S.; Dunn, C. L.; James, W. D. Arch. Dermatol. 1995, 131, 1373−1375. (e) Sudduth, S. L.; Koronkowski, M. J. Pharmacotherapy 1993, 13, 309−329. (7) (a) Bhattacharya, A.; DiMichele, L. M.; Dolling, U. H.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988, 110, 3318−3319. (b) Karrothu, S. B.; Kolla, N.; Lekkala, A. R.; Golla, C. M.; Anand, R. V.; Gandu, V.; Bhattacharya, A.; Padi, P. R.; Bandichhor, R. Org. Process Res. Dev. 2007, 11, 889−891. (8) Othman, A.; Evans, J. S. O.; Evans, I. R.; Harris, R. K.; Hodgkinson, P. J. Pharm. Sci. 2007, 96, 1380−1397 and references therein..
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