Communication pubs.acs.org/crystal
Harvesting Potential Dissolution Advantages of Soluble Cocrystals by Depressing Precipitation Using the Common Coformer Effect Hiroyuki Yamashita†,‡ and Changquan Calvin Sun*,‡ †
Analytical Research Laboratories, Technology, Astellas Pharma Inc., Tsukuba-shi, Ibaraki 305-8585, Japan Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
‡
S Supporting Information *
ABSTRACT: A highly soluble cocrystal of a poorly soluble drug has the potential to improve the dissolution rate and bioavailability. Reaping the potential dissolution advantage of soluble cocrystals is challenged by the precipitation of the parent drug during dissolution. Using the carbamazepine−nicotinamide cocrystal, we show that the use of excess coformer can be an effective strategy for eliminating precipitation during dissolution by taking advantage of the “common coformer effect”. When excess coformer is present, the solubility of the cocrystal is depressed, which leads to a lower degree of supersaturation. At an appropriate level, precipitation can be prevented and improved dissolution is realized.
T
CBZ dihydrate rapidly forms in the diffusion layer, and the precipitated CBZ dihydrate coats the cocrystal so that no improvement in dissolution rate was observed.15 We hypothesized that maintaining an elevated concentration of coformer in the diffusion layer depresses the degree of supersaturation and hence lowers the precipitation propensity of the cocrystal. This is because the theoretical solubility of a cocrystal, S, in a medium containing the coformer with a concentration, C, can be expressed using eq 1.16
he use of a highly soluble solid form, such as cocrystal, is a common strategy to improve dissolution and bioavailability of a poorly soluble active pharmaceutical ingredient (API).1−5 Two notable examples of successfully marketed cocrystal products are Suglat and Entresto.6,7 A main challenge that hinders the realization of the potential dissolution advantage of a soluble cocrystal is the tendency for rapid precipitation of the poorly soluble API during dissolution. This will negate the solubility advantage of the soluble cocrystal, especially when the precipitate covers the surface of the soluble cocrystal.8,9 As such, a soluble cocrystal may not necessarily improve dissolution and bioavailability. This phenomenon is analogous to the precipitation of a soluble salt under certain unfavorable pH conditions.10 The main difference is that the risk of uncontrolled precipitation of salts is lower, because of the self-buffering effect in the diffusion layer, which mitigates the risk of precipitation.11,12 When precipitation does occur, the addition of counterion can be used to address the challenge by the common ion effect.13 Here, the presence of a higher concentration of the counterion in diffusion layer reduces the concentration of the drug ion in solution and the degree of supersaturation. Consequently, the tendency of precipitation is lowered. In this study, we have considered a “common coformer” strategy for modulating precipitation behavior of a highly soluble cocrystal during dissolution using carbamazepine− nicotinamide cocrystal (CBZ-NCT) as a model system. The solubilities of CBZ-NCT and CBZ dihydrate are 70 mM and 0.46 mM, respectively.14 Thus, the degree of supersaturation at the surface of CBZ-NCT is more than 140 relative to CBZ dihydrate. Driven by such a high degree of supersaturation, © XXXX American Chemical Society
S=
−C +
C 2 + 4KSP 2
(1)
where Ksp is the solubility product of the cocrystal, which is assumed to be constant at a fixed temperature and in the same dissolution medium. Thus, the common coformer effect reduces the equilibrium solubility of CBZ-NCT in a manner dependent on the concentration of NCT, where the solubility of CBZ-NCT is lower at higher concentrations of NCT. The reported Ksp of CBZ-NCT is 4.9 × 10−3 M2.14 With this value, the theoretical solubility curve of CBZ-NCT as a function of NCT concentration can be calculated using eq 1. At a critical concentration of NCT in the diffusion layer, the CBZ concentration is sufficiently depressed so that immediate precipitation on the surface of the cocrystal can be avoided. Precipitation in the bulk solution is also unlikely, because the CBZ concentration is much lower due to the dilution effect. Received: September 28, 2016 Revised: October 15, 2016 Published: October 24, 2016 A
DOI: 10.1021/acs.cgd.6b01434 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Communication
The intrinsic dissolution rates (IDR) measured using pure CBZ-NCT pellets at 37 °C in the presence of various concentrations of NCT in a pH 6.8 phosphate buffer are shown in Figure 1. At lower NCT concentrations (less than 0.1
Figure 2. X-ray diffraction patterns of pellets after IDR tests.
The data suggest the potential benefit of enhancing IDR of the soluble cocrystal by the common coformer approach. Therefore, it should be possible to maintain a high dissolution rate of a soluble cocrystal through supersaturation suppression by mixing coformer with the cocrystal in a formulation. To test the feasibility of such a formulation strategy, physical mixtures of CBZ-NCT and NCT at 3:1, 1:1, and 1:3 (w/w) ratios were prepared, and the IDRs were determined in a pH 6.8 phosphate buffer at 37 °C (Figure 3). IDRs of pure CBZ-
Figure 1. IDR of CBZ-NCT (blue solid line) in comparison to the theoretical solubility of CBZ-NCT (red broken line) in phosphate buffer containing different concentrations of NCT.
M), the apparent IDR was constant at approximately 60 μg· cm−2 min−1, which is the same as the IDR of CBZ dihydrate. This suggests that the precipitated CBZ dihydrate covered the surface of CBZ-NCT. However, the IDR of the cocrystal in a 0.1 M solution of NCT was much greater, suggesting successful retardation of the precipitation of CBZ dihydrate. With further increases in NCT concentration, the IDR gradually decreased. The shape of the IDR profile at NCT concentration >0.1 M closely tracked that of the theoretical solubility of CBZ-NCT (Figure 1). This is reasonable, since the IDR is proportional to the solubility according to Nernst-Brunner diffusion layer model as shown in eq 217,18 J=
DA (Cs − C) h
(2)
where J is the dissolution rate, A is surface area, Cs is the saturation solubility of the solid in the dissolution medium, C is the concentration of drug in the bulk solution, D is diffusion coefficient, and h is the thickness of the diffusion layer. When Cs ≫ C, the IDR (= J/A) is proportional to Cs since D and h are constant for the same molecule under constant hydrodynamic conditions. At the NCT concentration of 0.11 M, which corresponds to the peak IDR value, the theoretical solubility of the cocrystal is 34.4 mM. At this point, the degree of supersaturation is more than 70. At higher degrees of supersaturation (lower NCT concentrations), CBZ dihydrate formed during the dissolution and a low IDR was observed (Figure 1). X-ray diffraction (XRD) patterns of the pellets recovered from the IDR tests (Figure 2) showed transformation from CBZ-NCT into CBZ dihydrate when no NCT was used in the dissolution medium. The diffraction peaks corresponding to those of CBZ dihydrate were intense, suggesting that a relatively thick layer of CBZ dihydrate coated the pellet. When the dissolution medium was 0.35 M NCT, only a very small amount of CBZ dihydrate could be observed by XRD, which does not fully cover the surface of the cocrystal pellet. At 0.65 M NCT, CBZ dihydrate peaks were absent, which indicates elimination of the precipitation of CBZ dihydrate.
Figure 3. IDR tests in phosphate buffer including no NCT (mean ± SD, n = 3).
NCT were comparable to that of CBZ dihydrate, because of the immediate transformation to CBZ dihydrate on the surface of CBZ-NCT. The 3:1 or 1:1 CBZ-NCT/NCT mixtures did not have any significant improvement in IDR. However, the IDR of the 1:3 CBZ-NCT/NCT was 3-fold higher. Thus, this ratio was effective in reducing the precipitation of CBZ dihydrate during dissolution. As a comparison, we attempted to prevent precipitation of CBZ dihydrate by using a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS), which is an efficient crystallization inhibitor for CBZ molecules.19 At 1:1 (w/w) CBZ-NCT to polymer ratio, the IDR was 533.6 μg·cm−2·min−1. This is 2.8 times greater than that of the 1:3 CBZ-NCT to NCT mixture. The higher efficiency of HPMCAS is likely because of its dual role in preventing the crystallization of CBZ dihydrate; that is, it acts as both a nucleation inhibitor and a crystal growth retardant. If a drug is solubilized by the presence B
DOI: 10.1021/acs.cgd.6b01434 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Communication
coformers and their characterization by thermoanalytical, spectroscopic and X-ray diffraction methods. CrystEngComm 2011, 13, 6271− 6284. (5) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J. Am. Chem. Soc. 2004, 126, 13335−13342. (6) Tahara, A.; Kurosaki, E.; Yokono, M.; Yamajuku, D.; Kihara, R.; Hayashizaki, Y.; Takasu, T.; Imamura, M.; Qun, L.; Tomiyama, H.; Kobayashi, Y.; Noda, A.; Sasamata, M.; Shibasaki, M. Antidiabetic Effects of SGLT2-Selective Inhibitor Ipragliflozin in StreptozotocinNicotinamide-Induced Mildly Diabetic Mice. J. Pharmacol. Sci. 2012, 120, 36−44. (7) Feng, L. L.; Karpinski, P. H.; Sutton, P.; Liu, Y. G.; Hook, D. F.; Hu, B.; Blacklock, T. J.; Fanwick, P. E.; Prashad, M.; Godtfredsen, S.; Ziltener, C. LCZ696: a dual-acting sodium supramolecular complex. Tetrahedron Lett. 2012, 53, 275−276. (8) Cherukuvada, S.; Babu, N. J.; Nangia, A. Nitrofurantoin-pAminobenzoic Acid Cocrystal: Hydration Stability and Dissolution Rate Studies. J. Pharm. Sci. 2011, 100, 3233−3244. (9) Remenar, J. F.; Peterson, M. L.; Stephens, P. W.; Zhang, Z.; Zimenkov, Y.; Hickey, M. B. Celecoxib: Nicotinamide dissociation: Using excipients to capture the cocrystal’s potential. Mol. Pharmaceutics 2007, 4, 386−400. (10) Terebetski, J. L.; Michniak-Kohn, B. Combining ibuprofen sodium with cellulosic polymers: A deep dive into mechanisms of prolonged supersaturation. Int. J. Pharm. 2014, 475, 536−546. (11) Serajuddin, A. T. M.; Jarowski, C. I. Effect of Diffusion Layer Ph and Solubility on the Dissolution Rate of Pharmaceutical Acids and Their Sodium-Salts 0.2. Salicylic-Acid, Theophylline, and BenzoicAcid. J. Pharm. Sci. 1985, 74, 148−154. (12) Serajuddin, A. T. M.; Jarowski, C. I. Effect of Diffusion Layer Ph and Solubility on the Dissolution Rate of Pharmaceutical Bases and Their Hydrochloride Salts 0.1. Phenazopyridine. J. Pharm. Sci. 1985, 74, 142−147. (13) Hawley, M.; Morozowich, W. Modifying the Diffusion Layer of Soluble Salts of Poorly Soluble Basic Drugs To Improve Dissolution Performance. Mol. Pharmaceutics 2010, 7, 1441−1449. (14) Good, D. J.; Rodriguez-Hornedo, N. Solubility Advantage of Pharmaceutical Cocrystals. Cryst. Growth Des. 2009, 9, 2252−2264. (15) Qiao, N.; Wang, K.; Schlindwein, W.; Davies, A.; Li, M. Z. In situ monitoring of carbamazepine-nicotinamide cocrystal intrinsic dissolution behaviour. Eur. J. Pharm. Biopharm. 2013, 83, 415−426. (16) Nehm, S. J.; Rodriguez-Spong, B.; Rodriguez-Hornedo, N. Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation. Cryst. Growth Des. 2006, 6, 592− 600. (17) Nernst, W. Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen. Z. Phys. Chem. 1904, 47, 52−55. (18) Dokoumetzidis, A.; Macheras, P. A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System. Int. J. Pharm. 2006, 321, 1−11. (19) Ueda, K.; Higashi, K.; Yamamoto, K.; Moribe, K. Inhibitory Effect of Hydroxypropyl Methylcellu lose Acetate Succinate on Drug Recrystallization from a Supersaturated Solution Assessed Using Nuclear Magnetic Resonance Measurements. Mol. Pharmaceutics 2013, 10, 3801−3811. (20) Ullah, M.; Hussain, I.; Sun, C. C. The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance. Drug Dev. Ind. Pharm. 2016, 42, 969−976. (21) Qiu, S.; Lai, J. M.; Guo, M. S.; Wang, K.; Lai, X. J.; Desai, U.; Juma, N.; Li, M. Z. Role of polymers in solution and tablet-based carbamazepine cocrystal formulations. CrystEngComm 2016, 18, 2664−2678.
of a polymer in the dissolution medium, dissolution rates can also be enhanced. However, the effectiveness of polymeric inhibitors requires specific interactions between drug and polymer. Thus, a suitable polymer can be identified only after a screening study.20,21 In contrast, no screening study is required for employing the common coformer approach. An integration of the two strategies, using both polymeric inhibitor and excess coformer, may be more effective for achieving superior dissolution performance of soluble cocrystals. In conclusion, a soluble CBZ-NCT cocrystal did not exhibit high IDR because of the fast precipitation of poorly soluble CBZ dihydrate during dissolution. Apparent IDR could be modulated by controlling the concentration of the coformer, NCT, in the dissolution medium. At a critical NCT concentration, a high IDR could be obtained. However, cocrystal solubility and dissolution rate continue to decrease with increasing NCT concentration. Therefore, they can be lower than that of CBZ dihydrate when NCT concentration is sufficiently high (Figure 1). An ideal coformer concentration is when the solubility is moderately reduced so that precipitation can be avoided while drug concentration is still high for an improved IDR. The use of the common coformer formulation strategy for improving the IDR of CBZ-NCT was confirmed. This strategy is expected to be effective as long as the solubility of a soluble cocrystal can be depressed by excess coformer.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01434. Materials and methods and data on summaries of IDR tests (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for resources from The Characterization Facility in University of Minnesota. ABBREVIATIONS CBZ, carbamazepine; NCT, nicotinamide; CBZ-NCT, carbamazepine-nicotinamide cocrystal; IDR, intrinsic dissolution rate REFERENCES
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DOI: 10.1021/acs.cgd.6b01434 Cryst. Growth Des. XXXX, XXX, XXX−XXX
