固体核磁技术在药物多晶型研究中的应用
|
摘要
长期的研究表明,药物的多晶型现象直接影响药品的质量、药品安全和药品的临床药效。固体核磁共振参数,例如各向同性(isotropic)和各向异性(anisotropic)化学位移对自旋核周围电子分布的细微变化极其敏感,使其在研究自旋核的局部和短程电子环境方面成为不可取代的工具之一,因而特别适合于药物多晶型的结构、性质研究。2007年美国联邦食品和药物管理局(Food and Drug Administration, FDA)将固体核磁共振技术列为简化新药申请(Abbreviated New Drug Application, ANDA)中多晶型研究表征的推荐技术方法。这一举措一方面说明固体核磁共振技术日益显著的重要性,另一方面必将为推动固体核磁共振技术在药物多晶型研究领域中的应用,起到积极作用。作为药物分子晶型研究的模型化合物,人们对药物吡罗昔康(piroxicam)的晶型用各种技术进行了广泛的研究,但鉴于其结构的复杂性,有些结构细节特别是多晶型固体中的氢键连接方式至今没有定论。我们采用固体核磁技术对其多个晶型进行了细致的研究,从而对三种药物分子晶型的固体核磁谱峰做了全面指认。通过理论计算和实验结果相结合的办法证明了中性分子向两性分子转化的方式,对水合分子PM(Piroxicam Monohydrate)的结构提出了新的模型并辅以有力的证据。
在研究过程中,我们还提出一种固体核磁脉冲程序(DD-SUPER)以获得季碳信号化学位移张量(Chemical Shift Tensors, CST),结合常规SUPER实验,在拟合中减少变量数,使其能够更为精确的得到重叠碳信号中非季碳的化学位移各向异性(Chemical Shift Anisotropy, CSA)信息。尤其是在吡罗昔康晶型Ⅱ(PⅡ)实例中,该方法很好的解决了多组重叠谱峰的CST提取问题,并通过理论计算的方法证明了该脉冲程序的可靠性。
这一系列工作为研究药物分子晶型结构提供了一整套方法,目前也正在对更多有重要研究意义的药物分子做进一步的探索。
It is well known that X-ray single crystal or powder diffraction (XRD) is probably the most powerful tool to study structure of crystalline solids. With the aid of other techniques, such as Raman spectroscopy, thermo-analytical method (DSC) and infrared spectroscopy (IR), one, in principle, can resolve the accurate structure of pure crystals. But in a system with structural defects or with polymorphous forms, the abovementioned techniques are limited, to certain extent. Because it is extremely sensitive to the local electronic environment, solid state NMR spectroscopy (SSNMR) has been widely used to investigate molecular structures of crystalline and amorphous solids. It is well documented that the vast majority of commercial solid pharmaceutical products consist of multiple polymorphs. For amorphous pharmaceutical material, the role of XRD may be limited, because important structural features are often lost due to broadening lines for such samples. The SSNMR, however, often can be utilized to analyze these systems effectively. The characterization of a drug compound using SSNMR methods has been recommended by the FDA in 2007, indicating its ever-increasing importance in the study of pharmaceutical products.
One can obtain the isotropic chemical shift by employing the magic angle spinning (MAS) method, to produce NMR spectra in which the resonances of the diluted spin 1/2 nuclei such as 13C and 15N are resolved because of the inherent narrowing. The isotropic chemical shift, an average of three principal values of the chemical shift tensor, is—by far—the most sensitive NMR parameter related to molecular structure in solids. Its value provides a global representation of the local electronic structure. However, the principal values of the chemical shift tensor provide information on the geometry of the electronic distribution about the nuclear center, something that cannot often be directly determined from a simple MAS experiment. To gain a more complete picture of solid structure in polymorphous material, it is critical to determine the principal values of the NMR chemical shift tensor. In principle, analysis of static powder patterns gives the information on these principal values directly, but in system with multiple sites, it becomes difficult to resolve overlapping powder patterns from even a few sites.
To obtain detailed geometric information on the electronic structure, a pulse sequence named SUPER is employed and modified to extract a static powder pattern of each nuclear site. With a proper data processing, principal values of each chemical shift tensor can be directly read out from the spectrum, giving a more specific delineation of electronic environment information in the vicinity of nucleus.
The complete 13C NMR chemical shift tensors (CST) for the carbon sites of the three polymorphic forms (PI, PII, and PM) of the analgesic drug, piroxicam, are reported. The NMR parameters (isotropic chemical shifts, chemical-shielding anisotropies and asymmetries, and dipolar couplings), X-ray powder diffraction, and density-functional calculations to predict NMR parameters are analyzed in terms of hydrogen bonding and structure in these solids. The integration of all the data gives an improved model of the local solid-state structures of the polymorphs. In particular, the solid-state NMR spectra demonstrate that the asymmetric unit of the monohydrate, PM, contains two zwitterionic piroxicam molecules.
With the increased complicity in molecular structure, overlap of spectral resonances is inevitable. A modified 2D-SUPER technique is proposed here to allow independent measurement of the principal values of the chemical-shift tensors of overlapping protonated and unprotonated carbons. The insertion of a dipolar-dephasing period into the sequence causes loss of signal from protonated carbons. The spectrum obtained with this modification allows one to determine the principal values of the unprotonated carbons with high precision. Subsequent fitting of the usual 2D-SUPER spectrum, with the chemical-shift parameters of the unprotonated carbons fixed, gives the parameters of the overlapped resonances of the protonated carbons. As an example, we report the determination of the 3C chemical-shift parameters of the carbons of formⅡof piroxicam. The experimental results are compared with those obtained from calculations using the DFT/GIAO method. Potential applications of this method are also discussed.
The results of this research provide a systematic method for investigating polymorphism of solid organic compound. Adding this SSNMR technique to other well-established techniques should help resolve or confirm structures in these more complicated systems, as exemplified by the polymorphic states of piroxicam.
在研究过程中,我们还提出一种固体核磁脉冲程序(DD-SUPER)以获得季碳信号化学位移张量(Chemical Shift Tensors, CST),结合常规SUPER实验,在拟合中减少变量数,使其能够更为精确的得到重叠碳信号中非季碳的化学位移各向异性(Chemical Shift Anisotropy, CSA)信息。尤其是在吡罗昔康晶型Ⅱ(PⅡ)实例中,该方法很好的解决了多组重叠谱峰的CST提取问题,并通过理论计算的方法证明了该脉冲程序的可靠性。
这一系列工作为研究药物分子晶型结构提供了一整套方法,目前也正在对更多有重要研究意义的药物分子做进一步的探索。
It is well known that X-ray single crystal or powder diffraction (XRD) is probably the most powerful tool to study structure of crystalline solids. With the aid of other techniques, such as Raman spectroscopy, thermo-analytical method (DSC) and infrared spectroscopy (IR), one, in principle, can resolve the accurate structure of pure crystals. But in a system with structural defects or with polymorphous forms, the abovementioned techniques are limited, to certain extent. Because it is extremely sensitive to the local electronic environment, solid state NMR spectroscopy (SSNMR) has been widely used to investigate molecular structures of crystalline and amorphous solids. It is well documented that the vast majority of commercial solid pharmaceutical products consist of multiple polymorphs. For amorphous pharmaceutical material, the role of XRD may be limited, because important structural features are often lost due to broadening lines for such samples. The SSNMR, however, often can be utilized to analyze these systems effectively. The characterization of a drug compound using SSNMR methods has been recommended by the FDA in 2007, indicating its ever-increasing importance in the study of pharmaceutical products.
One can obtain the isotropic chemical shift by employing the magic angle spinning (MAS) method, to produce NMR spectra in which the resonances of the diluted spin 1/2 nuclei such as 13C and 15N are resolved because of the inherent narrowing. The isotropic chemical shift, an average of three principal values of the chemical shift tensor, is—by far—the most sensitive NMR parameter related to molecular structure in solids. Its value provides a global representation of the local electronic structure. However, the principal values of the chemical shift tensor provide information on the geometry of the electronic distribution about the nuclear center, something that cannot often be directly determined from a simple MAS experiment. To gain a more complete picture of solid structure in polymorphous material, it is critical to determine the principal values of the NMR chemical shift tensor. In principle, analysis of static powder patterns gives the information on these principal values directly, but in system with multiple sites, it becomes difficult to resolve overlapping powder patterns from even a few sites.
To obtain detailed geometric information on the electronic structure, a pulse sequence named SUPER is employed and modified to extract a static powder pattern of each nuclear site. With a proper data processing, principal values of each chemical shift tensor can be directly read out from the spectrum, giving a more specific delineation of electronic environment information in the vicinity of nucleus.
The complete 13C NMR chemical shift tensors (CST) for the carbon sites of the three polymorphic forms (PI, PII, and PM) of the analgesic drug, piroxicam, are reported. The NMR parameters (isotropic chemical shifts, chemical-shielding anisotropies and asymmetries, and dipolar couplings), X-ray powder diffraction, and density-functional calculations to predict NMR parameters are analyzed in terms of hydrogen bonding and structure in these solids. The integration of all the data gives an improved model of the local solid-state structures of the polymorphs. In particular, the solid-state NMR spectra demonstrate that the asymmetric unit of the monohydrate, PM, contains two zwitterionic piroxicam molecules.
With the increased complicity in molecular structure, overlap of spectral resonances is inevitable. A modified 2D-SUPER technique is proposed here to allow independent measurement of the principal values of the chemical-shift tensors of overlapping protonated and unprotonated carbons. The insertion of a dipolar-dephasing period into the sequence causes loss of signal from protonated carbons. The spectrum obtained with this modification allows one to determine the principal values of the unprotonated carbons with high precision. Subsequent fitting of the usual 2D-SUPER spectrum, with the chemical-shift parameters of the unprotonated carbons fixed, gives the parameters of the overlapped resonances of the protonated carbons. As an example, we report the determination of the 3C chemical-shift parameters of the carbons of formⅡof piroxicam. The experimental results are compared with those obtained from calculations using the DFT/GIAO method. Potential applications of this method are also discussed.
The results of this research provide a systematic method for investigating polymorphism of solid organic compound. Adding this SSNMR technique to other well-established techniques should help resolve or confirm structures in these more complicated systems, as exemplified by the polymorphic states of piroxicam.
引文
(1)Brittain, H. G.; Grant, D. J. W. Effect of polymorphism and solid-state solvation on solubility and dissolution rate; Marcel Dekker, Inc.:New York,1999.
(2)吕杨、杜冠华 晶型药物；人民卫生出版社：北京,2009.
(3)Bugay, D. E. Advanced Drug Delivery Reviews 2001,48,43-65.
(4)Stephenson, G. A.; Forbes, R. A.; Reutzel-Edens, S. M. Advanced Drug Delivery Reviews 2001,48,67-69.
(5)Shah, B.; Kakumanu, V. K.; Bansal, A. K. Journal of Pharmaceutical Sciences 2006,95.
(6)Geppi, M.; Mollica, G.; Borsacchi, S.; Veracini, C. A. Applied Spectroscopy Reviews 2008,43,202-302.
(7)Dybowski, C. D.; Bai, S. Analytical Chemistry 2008,80,4295-4300.
(8)Geppi, M.; Borsacchi, S.; Mollica, G.; Veracini, C. A. Applied Spectroscopy Reviews 2009,44,1-89.
(9)Harper, J. K.; Doebbler, J. A.; Jacques, E.; Grant, D. M.; Von Dreele, R. B. Journal of the American Chemical Society,132,2928-2937.
(10)Harper, J. K.; Grant, D. M.; Zhang, Y.; Lee, P. L.; Von Dreele, R. Journal of the American Chemical Society 2006,128,1547-1552.
(11)Heider, E. M.; Harper, J. K.; Grant, D. M. Physical Chemistry Chemical Physics 2007,9, 6083-6097.
(12)Olejniczak, S.; Potzebowski, M. J. Org. Biomol. Chem.2004,2,1.
(13)Olejniczak, S.; Mikula-Pacholczyk, J.; Hughes, C. E.; Potrzebowski, M. J. Journal of Physical Chemistry B 2008,112,1586-1593.
(14)Smith, J.; MacNamara, E.; Raftery, D.; Borchardt, T.; Byrn, S. Journal of American Chemical Society 1998,120,11710-11713.
(15)Smith, J. R.; Xu, W.; Raftery, D. Journal of Physical Chemistry B 2006,110,7766-7776.
(16)Bai, S.; Wang, W.; Dybowski, C. Analytical Chemistry 2010,82,4917-4924.
(17)Berendt, R. T.; Sperger, D. M.; Munson, E. J.; Isbester, P. K. TrAC-Trends in Analytical Chemistry 2006,25,977-984.
(18)Guidance for Industry ANDAs:Pharmceutical Solid Polymorphsim, Chemistry, Manufacturing, and Controls Infromation 2007, U. S. Department of Health and Human Services; Food and Drug Administration.
(19)Duer,M.J.2004.
(20)Andrew, E. R. B., A.; Eades, R. G. Nature 1958,182,1659-1659.
(21)Pines, A. G., M. G.; Waugh, J. S.J. Chem. Phys.1973,59,569-590.
(22)Hartmann, S. R. H., E. L. Phys. Rev.1962,128,2042.
(23)Othman, A.; Evans, J. S. O.; Radosavljevic Evans, I.; Harris, R. K.; Hodgkinson, P. Journal of Pharmaceutical Sciences 2007,96,1380-1391.
(24)Wolniak, M.; Tomczyk, M.; Gudej, J.; Wawer, I. Journal of Molecular Structure 2006, 825,26-31.
(25)Van Rossum, B. J.; Forster, H.; De Groot, H. J. M. Journal of Magnetic Resonance 1997, 124,516-519.
(26)Antzukin, O. N.; Lee, Y. K.; Levitt, M. H. Journal of Magnetic Resonance 1998,135, 144-155.
(27)Lee, M.; Goldburg, W. I. Physical Review 1965,140, A1261-A1271.
(28)Antzukin, O. N.; Shekar, S. C.; Levitt, M. H. Journal of Magnetic Resonance 1995,115, 7-19.
(29)Suzanne R. Kiihne, A. F. L. C., Johan Lugtenburg, Huub J.M. de Groot Journal of Magnetic Resonance 2005,172,1-8.
(30)Heller, J.; Laws, D. D.; Thomaselli, M.; King, D. S.; Wemmer, D. E.; Pines, A.; Havlin, R. H.; Oldfield, E. Journal of American Chemical Society 1997,119,7827-7831.
(31)Le, H.; Pearson, J. G.; de Dios, A. C.; Oldfield, E. Journal of American Chemical Society 1995,117,3800-3807.
(32)Facelli, J. C.; Grant, D. M. Nature 1993,365(6444),325-327.
(33)Harper, J. K.; Barich, D. H.; Hu, J. Z.; Strobel, G. A.; Grant, D. M. Journal of Organic Chemistry 2003,68,4609-4614.
(34)Harper, J. K.; Mulgrew, A. E.; Li, J. Y.; Barich, D. H.; Strobel, G. A.; Grant, D. M. Journal of American Chemical Society 2001,123,9837-9842.
(35)Jaroni, C. P.; MacPhee, C. E.; Bajaj, V. S.; McMahon, M. T.; Dobson, C. M.; Griffin, R. G. Proceedings of the National Academy of Sciences 2003,101,711-716.
(36)Rienstra, C. M.; Tucker-Kellogg, L.; Jaroniec, C. P.; Hohwy, M.; Reif, B.; McMahon, M. T.; Tidor, B.; Lozano-Perez, T.; Griffin, R. G. Proceedings of the National Academy of Sciences 2002,99(16),10260-10265.
(37)Harris, R. K.; Joyce, S. A.; Pickard, C. J.; Cadars, S.; Emsley, L. Physical Chemistry Chemical Physics 2006,8,137-143.
(38)Harris, R. K. Journal of Pharmacy and Pharmacology 2007,59,225-239.
(39)Sheth, A. R.; Lubach, J. W.; Munson, E. J.; Muller, F. X.; Grant, D. J. W. Journal of the American Chemical Society 2005,127,6641-6651.
(40)Harper, J. K.; Facelli, J. C.; Barich, D. H.; McGeorge, G; Mulgrew, A. E.; Grant, D. M. Journal of American Chemical Society 2002,124,10589-10595.
(41)Antzutkin, O. N.; Lee, Y. K.; Levitt, M. H. Journal of Magnetic Resonance 1998,135, 144-155.
(42)Portieri, A.; Harris, R. K.; Fletton, R. A.; Lancaster, R. W.; Threlfall, T. L. Magnetic Resonance in Chemistry 2004,42,313-320.
(43)Elena, E.; Lesage, A.; Steuernagel, S.; Bo¨ckmann, A.; Emsley, L. Journal of American Chemical Society 2005,127,17296-17302.
(44)Mollica, G.; Geppi, M.; Pignatello, R.; Veracini, C. A. Pharmaceutical Research 2006, 25,2129-2140.
(45)Sheth, A. R.; Zhou, D.; Muller, F. X.; Grant, D. J. W. Journal of Pharmaceutical Sciences 2004,93,3013-3026.
(46)Alderman, D. W.; Mc George, G.; Hu, J. Z.; Pugmire, R. J.; Grant, D. M. Molecular Physics 1998,95.
(47)Liu, S. F.; Mao, J. D.; Schmidt-Rohr, K. Journal of Magnetic Resonance 2002,155, 15-28.
(48)Antzutkin, O. N.; Shekar, S. C.; Levitt, M. H. Journal of Magnetic Resonance, Series A 1995,115,7-19.
(49)Chan, J. C. C.; Tycko, R. Journal of chemical physics 2003,118,8378-8398.
(50)Bennett, A. E.; Rienstra, C. M.; Auger, M.; Lakshmi, K. V.; Griffin, R. G. The Journal of Chemical Physics 1995,103,6951-6958.
(51)Opella, S. J.; Frey, M. H. Journal of the American Chemical Society 1979,101, 5854-5856.
(52)Bielecki, A.; Kolbert, A. C.; Levitt, M. H. Chemical Physics Letters 1989,155,341-346.
(53)Dixon, W. T. The Journal of Chemical Physics 1982,77,1800-1809.
(54)Liu, W.; Wang, W. D.; Wang, W.; Bai, S.; Dybowski, C. Journal of Magnetic Resonance 2010,206,177-181.
(55)Vrecer, F.; Vrbinc, M.; Meden, A. International Journal of Pharmaceutics 2003,256, 3-15.
(56)Kojic-Prodic, B.; Ruzic-Toros, Z. Acta Cryst.1982, B38,2948-2951.
(57)Reck, G.; Dietz, G.; Laban, G.; Gunther, W.; Bammier, G.; Hohne, E. Pharmazie 1988, 45,477-481.
(58)Baerends, E. J.; Autschbach, A.; Berces, A.; Bickelhaupt, F. M.; Bo, C.; Boerrigter, P. M.; Cavallo, L.; Chong, D. P.; Deng, L.; Dickson, R. M.; Ellis, D. E.; Van Faassen, M.; Fan, L.; Fischer, T. H.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.; Groeneveld, J. A.; Gritsenko, O. V.; Gruning, M.; Harris, F. E.; Van Den Hoek, P.; Jacob, C. R.; Jacobsen, H.; Jensen, L.; Van Kessel, G.; Kootstra, F.; Van Lenthe, E.; McCormack, D. A.; Michalak, A.; Neugebauer, J.; Osinga, V. P.; Patchkovskii, S.; Philipsen, P. H. T,; Post, D.; Pye, C. C.; Ravenek, W.; Ros, P. S.; T, P. R.; Schreckenbach, G.; Snijders, J. G.; Sola, M.; Swart, M.; Swerhone, D.; Te Velde, G.; Vernooijs, P.; Versluis, L.; Visscher, L.; Visser, O.; Wang, F.; Wesolowski, T. A.; Van Wezenbeek, E.; Wiesenekker, G. ADF2009.01, SCM, Theoretical Chemistry; Vrije Universiteit; Amsterdam. The Netherlands. URL http://www.scm.com
(59)Schreckenbach, G.; Ziegler, T. Journal of Physical Chemistry 1995,99,606-611.
(60)Krykunov, M.; Ziegler, T.; Van Lenthe, E. International Journal of Quantum Chemistry 2009,109,1676-1683.
(61)Wolff, S. K.; Ziegler, T. Journal of Chemical Physics 1998,109,895-905.
(62)Wolff, S.; Ziegler, T.; van Lenthe, E.; Baerends, E. Journal of chemical physics 1999, 110,7689.
(63)Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J.; Vreven, J. A. T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc.Wallingford, CT 2004.
(64)Kehlet, S.; Bjerring, R.; Khaneja, G.; Nielsen, N. C. Journal of American Chemical Society 2004,126,10202-10203.
(65)Bak, M.; Rasmussen, J. T.; Nielse, N. C. Journal of Magnetic Resonance 2000,147, 296-330.
(66)Hohenberg, P.; Kohn, W. Physics Review 1964,136, B864.
(67)Kohn, W.; Sham, L. J. Physics Review 1965,140, A1133.
(68)Ditchfield, R. Molecular Physics 1974,27,789.
(69)Childs, S. L.; Hardcastle, K. I. Crystal Growth and Design 2007,7,1291-1304.
(70)Bates, S.; Zografi, G.; Engers, D.; Morris, K.; Crowley, K.; Newman, A. Pharmaceutical Research 2006,23,2333-2349.
(71)Bertoluzza, A.; Rossi, M.; Taddei, P.; Redenti, E.; Zanol, M.; Ventura, P. Journal of Molecular Structure 1999,480-481,535-539.
(72)Taddei, P.; Torreggiani, A.; Simoni, R. Biopolymers-Biospectroscopy Section 2001,62, 68-78.
(73)Mehrens, S. M.; Kale, U. J.; Qu, X. Journal of Pharmaceutical Sciences 2005,94, 1354-1367.
(74)Drebushchak, V. A.; Shakhtshneider, T. P.; Apenina, S. A.; Drebushchak, T. N.; Medvedeva, A. S.; Safronova, L. P.; Boldyrev, V. V. Journal of Thermal Analysis and Calorimetry 2006,84,643-649.
(75)Vrecer, F.; Srcic, S.; Smid-Korbar, J. International Journal of Pharmaceutics 1991,68, 35-41.
(76)Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. J.; Pham, T. N.; Watson, S. A. Crystal Growth and Design 2009,9,921-937.
(77)Sheth, A. R.; Bates, S.; Muller, F. X.; Grant, D. J. W. Crystal Growth and Design 2004, 4,1091-1098.
(2)吕杨、杜冠华 晶型药物；人民卫生出版社：北京,2009.
(3)Bugay, D. E. Advanced Drug Delivery Reviews 2001,48,43-65.
(4)Stephenson, G. A.; Forbes, R. A.; Reutzel-Edens, S. M. Advanced Drug Delivery Reviews 2001,48,67-69.
(5)Shah, B.; Kakumanu, V. K.; Bansal, A. K. Journal of Pharmaceutical Sciences 2006,95.
(6)Geppi, M.; Mollica, G.; Borsacchi, S.; Veracini, C. A. Applied Spectroscopy Reviews 2008,43,202-302.
(7)Dybowski, C. D.; Bai, S. Analytical Chemistry 2008,80,4295-4300.
(8)Geppi, M.; Borsacchi, S.; Mollica, G.; Veracini, C. A. Applied Spectroscopy Reviews 2009,44,1-89.
(9)Harper, J. K.; Doebbler, J. A.; Jacques, E.; Grant, D. M.; Von Dreele, R. B. Journal of the American Chemical Society,132,2928-2937.
(10)Harper, J. K.; Grant, D. M.; Zhang, Y.; Lee, P. L.; Von Dreele, R. Journal of the American Chemical Society 2006,128,1547-1552.
(11)Heider, E. M.; Harper, J. K.; Grant, D. M. Physical Chemistry Chemical Physics 2007,9, 6083-6097.
(12)Olejniczak, S.; Potzebowski, M. J. Org. Biomol. Chem.2004,2,1.
(13)Olejniczak, S.; Mikula-Pacholczyk, J.; Hughes, C. E.; Potrzebowski, M. J. Journal of Physical Chemistry B 2008,112,1586-1593.
(14)Smith, J.; MacNamara, E.; Raftery, D.; Borchardt, T.; Byrn, S. Journal of American Chemical Society 1998,120,11710-11713.
(15)Smith, J. R.; Xu, W.; Raftery, D. Journal of Physical Chemistry B 2006,110,7766-7776.
(16)Bai, S.; Wang, W.; Dybowski, C. Analytical Chemistry 2010,82,4917-4924.
(17)Berendt, R. T.; Sperger, D. M.; Munson, E. J.; Isbester, P. K. TrAC-Trends in Analytical Chemistry 2006,25,977-984.
(18)Guidance for Industry ANDAs:Pharmceutical Solid Polymorphsim, Chemistry, Manufacturing, and Controls Infromation 2007, U. S. Department of Health and Human Services; Food and Drug Administration.
(19)Duer,M.J.2004.
(20)Andrew, E. R. B., A.; Eades, R. G. Nature 1958,182,1659-1659.
(21)Pines, A. G., M. G.; Waugh, J. S.J. Chem. Phys.1973,59,569-590.
(22)Hartmann, S. R. H., E. L. Phys. Rev.1962,128,2042.
(23)Othman, A.; Evans, J. S. O.; Radosavljevic Evans, I.; Harris, R. K.; Hodgkinson, P. Journal of Pharmaceutical Sciences 2007,96,1380-1391.
(24)Wolniak, M.; Tomczyk, M.; Gudej, J.; Wawer, I. Journal of Molecular Structure 2006, 825,26-31.
(25)Van Rossum, B. J.; Forster, H.; De Groot, H. J. M. Journal of Magnetic Resonance 1997, 124,516-519.
(26)Antzukin, O. N.; Lee, Y. K.; Levitt, M. H. Journal of Magnetic Resonance 1998,135, 144-155.
(27)Lee, M.; Goldburg, W. I. Physical Review 1965,140, A1261-A1271.
(28)Antzukin, O. N.; Shekar, S. C.; Levitt, M. H. Journal of Magnetic Resonance 1995,115, 7-19.
(29)Suzanne R. Kiihne, A. F. L. C., Johan Lugtenburg, Huub J.M. de Groot Journal of Magnetic Resonance 2005,172,1-8.
(30)Heller, J.; Laws, D. D.; Thomaselli, M.; King, D. S.; Wemmer, D. E.; Pines, A.; Havlin, R. H.; Oldfield, E. Journal of American Chemical Society 1997,119,7827-7831.
(31)Le, H.; Pearson, J. G.; de Dios, A. C.; Oldfield, E. Journal of American Chemical Society 1995,117,3800-3807.
(32)Facelli, J. C.; Grant, D. M. Nature 1993,365(6444),325-327.
(33)Harper, J. K.; Barich, D. H.; Hu, J. Z.; Strobel, G. A.; Grant, D. M. Journal of Organic Chemistry 2003,68,4609-4614.
(34)Harper, J. K.; Mulgrew, A. E.; Li, J. Y.; Barich, D. H.; Strobel, G. A.; Grant, D. M. Journal of American Chemical Society 2001,123,9837-9842.
(35)Jaroni, C. P.; MacPhee, C. E.; Bajaj, V. S.; McMahon, M. T.; Dobson, C. M.; Griffin, R. G. Proceedings of the National Academy of Sciences 2003,101,711-716.
(36)Rienstra, C. M.; Tucker-Kellogg, L.; Jaroniec, C. P.; Hohwy, M.; Reif, B.; McMahon, M. T.; Tidor, B.; Lozano-Perez, T.; Griffin, R. G. Proceedings of the National Academy of Sciences 2002,99(16),10260-10265.
(37)Harris, R. K.; Joyce, S. A.; Pickard, C. J.; Cadars, S.; Emsley, L. Physical Chemistry Chemical Physics 2006,8,137-143.
(38)Harris, R. K. Journal of Pharmacy and Pharmacology 2007,59,225-239.
(39)Sheth, A. R.; Lubach, J. W.; Munson, E. J.; Muller, F. X.; Grant, D. J. W. Journal of the American Chemical Society 2005,127,6641-6651.
(40)Harper, J. K.; Facelli, J. C.; Barich, D. H.; McGeorge, G; Mulgrew, A. E.; Grant, D. M. Journal of American Chemical Society 2002,124,10589-10595.
(41)Antzutkin, O. N.; Lee, Y. K.; Levitt, M. H. Journal of Magnetic Resonance 1998,135, 144-155.
(42)Portieri, A.; Harris, R. K.; Fletton, R. A.; Lancaster, R. W.; Threlfall, T. L. Magnetic Resonance in Chemistry 2004,42,313-320.
(43)Elena, E.; Lesage, A.; Steuernagel, S.; Bo¨ckmann, A.; Emsley, L. Journal of American Chemical Society 2005,127,17296-17302.
(44)Mollica, G.; Geppi, M.; Pignatello, R.; Veracini, C. A. Pharmaceutical Research 2006, 25,2129-2140.
(45)Sheth, A. R.; Zhou, D.; Muller, F. X.; Grant, D. J. W. Journal of Pharmaceutical Sciences 2004,93,3013-3026.
(46)Alderman, D. W.; Mc George, G.; Hu, J. Z.; Pugmire, R. J.; Grant, D. M. Molecular Physics 1998,95.
(47)Liu, S. F.; Mao, J. D.; Schmidt-Rohr, K. Journal of Magnetic Resonance 2002,155, 15-28.
(48)Antzutkin, O. N.; Shekar, S. C.; Levitt, M. H. Journal of Magnetic Resonance, Series A 1995,115,7-19.
(49)Chan, J. C. C.; Tycko, R. Journal of chemical physics 2003,118,8378-8398.
(50)Bennett, A. E.; Rienstra, C. M.; Auger, M.; Lakshmi, K. V.; Griffin, R. G. The Journal of Chemical Physics 1995,103,6951-6958.
(51)Opella, S. J.; Frey, M. H. Journal of the American Chemical Society 1979,101, 5854-5856.
(52)Bielecki, A.; Kolbert, A. C.; Levitt, M. H. Chemical Physics Letters 1989,155,341-346.
(53)Dixon, W. T. The Journal of Chemical Physics 1982,77,1800-1809.
(54)Liu, W.; Wang, W. D.; Wang, W.; Bai, S.; Dybowski, C. Journal of Magnetic Resonance 2010,206,177-181.
(55)Vrecer, F.; Vrbinc, M.; Meden, A. International Journal of Pharmaceutics 2003,256, 3-15.
(56)Kojic-Prodic, B.; Ruzic-Toros, Z. Acta Cryst.1982, B38,2948-2951.
(57)Reck, G.; Dietz, G.; Laban, G.; Gunther, W.; Bammier, G.; Hohne, E. Pharmazie 1988, 45,477-481.
(58)Baerends, E. J.; Autschbach, A.; Berces, A.; Bickelhaupt, F. M.; Bo, C.; Boerrigter, P. M.; Cavallo, L.; Chong, D. P.; Deng, L.; Dickson, R. M.; Ellis, D. E.; Van Faassen, M.; Fan, L.; Fischer, T. H.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.; Groeneveld, J. A.; Gritsenko, O. V.; Gruning, M.; Harris, F. E.; Van Den Hoek, P.; Jacob, C. R.; Jacobsen, H.; Jensen, L.; Van Kessel, G.; Kootstra, F.; Van Lenthe, E.; McCormack, D. A.; Michalak, A.; Neugebauer, J.; Osinga, V. P.; Patchkovskii, S.; Philipsen, P. H. T,; Post, D.; Pye, C. C.; Ravenek, W.; Ros, P. S.; T, P. R.; Schreckenbach, G.; Snijders, J. G.; Sola, M.; Swart, M.; Swerhone, D.; Te Velde, G.; Vernooijs, P.; Versluis, L.; Visscher, L.; Visser, O.; Wang, F.; Wesolowski, T. A.; Van Wezenbeek, E.; Wiesenekker, G. ADF2009.01, SCM, Theoretical Chemistry; Vrije Universiteit; Amsterdam. The Netherlands. URL http://www.scm.com
(59)Schreckenbach, G.; Ziegler, T. Journal of Physical Chemistry 1995,99,606-611.
(60)Krykunov, M.; Ziegler, T.; Van Lenthe, E. International Journal of Quantum Chemistry 2009,109,1676-1683.
(61)Wolff, S. K.; Ziegler, T. Journal of Chemical Physics 1998,109,895-905.
(62)Wolff, S.; Ziegler, T.; van Lenthe, E.; Baerends, E. Journal of chemical physics 1999, 110,7689.
(63)Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J.; Vreven, J. A. T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc.Wallingford, CT 2004.
(64)Kehlet, S.; Bjerring, R.; Khaneja, G.; Nielsen, N. C. Journal of American Chemical Society 2004,126,10202-10203.
(65)Bak, M.; Rasmussen, J. T.; Nielse, N. C. Journal of Magnetic Resonance 2000,147, 296-330.
(66)Hohenberg, P.; Kohn, W. Physics Review 1964,136, B864.
(67)Kohn, W.; Sham, L. J. Physics Review 1965,140, A1133.
(68)Ditchfield, R. Molecular Physics 1974,27,789.
(69)Childs, S. L.; Hardcastle, K. I. Crystal Growth and Design 2007,7,1291-1304.
(70)Bates, S.; Zografi, G.; Engers, D.; Morris, K.; Crowley, K.; Newman, A. Pharmaceutical Research 2006,23,2333-2349.
(71)Bertoluzza, A.; Rossi, M.; Taddei, P.; Redenti, E.; Zanol, M.; Ventura, P. Journal of Molecular Structure 1999,480-481,535-539.
(72)Taddei, P.; Torreggiani, A.; Simoni, R. Biopolymers-Biospectroscopy Section 2001,62, 68-78.
(73)Mehrens, S. M.; Kale, U. J.; Qu, X. Journal of Pharmaceutical Sciences 2005,94, 1354-1367.
(74)Drebushchak, V. A.; Shakhtshneider, T. P.; Apenina, S. A.; Drebushchak, T. N.; Medvedeva, A. S.; Safronova, L. P.; Boldyrev, V. V. Journal of Thermal Analysis and Calorimetry 2006,84,643-649.
(75)Vrecer, F.; Srcic, S.; Smid-Korbar, J. International Journal of Pharmaceutics 1991,68, 35-41.
(76)Vogt, F. G.; Clawson, J. S.; Strohmeier, M.; Edwards, A. J.; Pham, T. N.; Watson, S. A. Crystal Growth and Design 2009,9,921-937.
(77)Sheth, A. R.; Bates, S.; Muller, F. X.; Grant, D. J. W. Crystal Growth and Design 2004, 4,1091-1098.