5 Conclusion 38
5.2 Future Work
A curva de calibração do BZN (Figura 36) em água foi realizada com preparo das soluções em triplicatas e medidas em espectrofotômetro UV a 321 nm. Comprimento de absorção máxima e também, indicado na monografia do BZN na Farmacopéia Brasileira. Figura 35 – Acompanhamento da estabilidade dos cocristais BZNSAL à 40 oC e 75% de U.R
Otimizar a solubilidade do BZN através da engenharia de cristais foi o principal motivador para este trabalho. Para isso foi verificada a solubilidade no tempo do BZN, do cocristal BZNSAL solvatado e do polimorfo gama do cocristal BZNSAL. Para todas as amostras foi preparado uma solução-mãe em água e nos tempos 5, 10, 15, 30, 45, 60, 90 e 120 minutos foram retiradas alíquotas, em triplicata, que diluídas em etanol:água e lidas por varredura de 200 a 400 nm em espectofotômetro. Os resultados das medidas foram plotados em gráfico e feito análise estatística, conforme apresentado na Figura 37.
A solubilidade do cocristal solvato é praticamente o dobro da solubilidade do BZN puro, o BZNSAL polimorfo gama tem uma resposta inicial melhor e um perfil sem grandes variações de solubilidade, o que também pode ser favorável a um IFA. Durante a primeira hora, os cocristais se apresentam como uma melhor opção, de fato é necessário estudar as consequências farmacológicas desse resultado. Os sólidos resultantes da solução- mãe foram filtrados e medidos em PDRX para confirmar que o material retido após 120 min ainda era o material de partida, conforme visualizado na Figura 38.
Figura 38 – Comparação do padrão de BZN com a amostra encontrada na solução-mãe após ensaio de solubilidade x tempo.
8.
CONCLUSÃO
A formação de solvatos, hidratos e polimorfos é um fenômeno comum para IFAs e representa um desafio para a Indústria Farmacêutica, pois pode aparecer durante a produção e armazenamento. Com a engenharia de cristais percebe-se um interesse crescente na avaliação de síntons supramoleculares, o reconhecimento molecular e a interação de cristais com solvente e água e nas suas diferentes propriedades comparadas aos produtos de origem. Nesse estudo dois polimorfos da forma anidra de SNZ foram identificados e caracterizados, alertando quanto ao controle de qualidade do SNZ para monitorar o surgimento de polimorfos. O comportamento térmico do SNZ for descrito com detalhes. Quanto ao BZN foram elucidados por difração de monocristal sete estruturas cristalinas inéditas por difração de monocristal e uma por difração de pó. São elas, três solvatos isomórficos do cocristal BZNSAL, os solventes hospedeiros foram acetonitrila, diclobenzeno e água:metanol (1:2); três polimorfos do cocristal BZNμSAL (α, e ), um cocristal hidratado de BZNPHE e observou-se que o ácido oxálico gera nova estrutura cristalina não elucidada. O processo de solvatação e dessolvatação entre os cocristal BZNSAL foram estudados. Foi acompanhado a estabilidade acelerada do cocristal BZNSAL solvatado por um mês e do polimorfo do cocristal BZNSAL por 2 mês, e os resultados são satisfatórios. Ambos os cocristais BZNSAL aumentam a solubilidade do BZN puro, chegando a atingir o dobro. Estudos biodisponibilidade de devem ser considerados.
REFERÊNCIAS
Aitipamula, S., Banerjee, R., Bansal, A. K., Biradha, K., Cheney, M. L., Choudhury, A. R., . . . Zaworotko, M. J. (β01β). Polymorphs, Salts, and Cocrystalsμ What’s in a Name? Crystal Growth & Design, 12(5), 2147-2152. doi: 10.1021/cg3002948
Aitipamula, S., Chow, P. S., & Tan, R. B. H. (2010). Conformational and enantiotropic polymorphism of a 1 μ 1 cocrystal involving ethenzamide and ethylmalonic acid. CrystEngComm, 12(11), 3691. doi: 10.1039/c004491a
Aitipamula, S., Chow, P. S., & Tan, R. B. H. (2014). Polymorphism in cocrystals: a review and assessment of its significance. CrystEngComm, 16(17), 3451. doi:
10.1039/c3ce42008f
Allen, F. H. (2002). The Cambridge Structural Database_: a quarter of a million crystal structures ans rising. Acta Crystallographica B, 58.
ANVISA. (2009). Resolução - RDC Nº 57, DE 17 de Novembro de 2009, Dispõe sobre o registro de insumos farmacêuticos ativos (IFA) e dá outras providências.
ANVISA. (2017a). LISTA DE MEDICAMENTOS DE REFERÊNCIA. Retrieved 07/07, 2017, from http://portal.anvisa.gov.br/registros-e-
autorizacoes/medicamentos/produtos/medicamentos-de-referencia/lista
ANVISA. (2017b). Nota Técnica n° 02/2017 - Registro de medicamentos novos, genéricos e similares contendo solvatos e cocristais como insumo farmacêutico ativo.
Armas, H. N., Hernández, R. G., & Rivera, A. B. (1999). Crystal pseudopolymorphism of secnidazole bulk drug, C7H11N3O3. Powder diffraction, 14(2), 136-141.
Arunan, E., Desiraju, G. R., Klein, R. A., Sadlej, J., Scheiner, S., Alkorta, I., . . . Nesbitt, D. J. (2011). Definition of the hydrogen bond (IUPAC Recommendations 2011). Pure and Applied Chemistry, 83(8). doi: 10.1351/pac-rec-10-01-02
Aufderheide, A. C., Salo, W., Madden, M., Streitz, J., Buikstra, J., Guhl, F., . . . Allison, M. (2004). A 9,000-year record of Chagas' disease. Proc Natl Acad Sci U S A, 101(7), 2034-2039. doi: 10.1073/pnas.0307312101
Ayala, A. P. (2007). Polymorphism in drugs investigated by low wavenumber Raman scattering. Vibrational Spectroscopy, 45(2), 112-116. doi:
10.1016/j.vibspec.2007.06.004
Ayala, A. P., Siesler, H. W., Boese, R., Hoffmann, G. G., Polla, G. I., & Vega, D. R. (2006). Solid state characterization of olanzapine polymorphs using vibrational spectroscopy. International journal of pharmaceutics, 326(1-2), 69-79. doi:
10.1016/j.ijpharm.2006.07.023
Bakshi, M., & Singh, S. (2004). ICH guidance in practice: establishment of inherent stability of secnidazole and development of a validated stability-indicating high-performance liquid chromatographic assay method. J Pharm Biomed Anal, 36(4), 769-775. doi: 10.1016/j.jpba.2004.08.008
Bern, C. (2015). Chagas' Disease. N Engl J Med, 373(5), 456-466. doi: 10.1056/NEJMra1410150
Bezerra, B. P., Fonseca, J. C., de Oliveira, Y. S., de Santana, M. S. A., Silva, K. F., Araújo, B. S., & Ayala, A. P. (2016). Phase transitions in secnidazole: Thermal stability and polymorphism studied by X-ray powder diffraction, thermal analysis and vibrational spectroscopy. Vibrational Spectroscopy, 86, 90-96. doi: 10.1016/j.vibspec.2016.06.007 Bolla, G., Mittapalli, S., & Nangia, A. (2014). Celecoxib cocrystal polymorphs with cyclic
amides: synthons of a sulfonamide drug with carboxamide coformers. CrystEngComm, 16(1), 24-27. doi: 10.1039/c3ce41885e
Bolla, G., Sanphui, P., & Nangia, A. (2013). Solubility Advantage of Tenoxicam Phenolic Cocrystals Compared to Salts. Crystal Growth & Design, 13(5), 1988-2003. doi: 10.1021/cg4000457
Bruker. (2012). SAINT (Version version V8.34A). Madison, Wisconsin, USA. .
Bruno, I. J., Cole, J. C., Edgington, P. R., Kessler, M., Macrae, C. F., McCabe, P., . . . Taylor, R. (2002). New software for searching the Cambridige Structural Database and visualizing crystals structure. Acta Crystallographica Section B, 58, 389-397. Bugay, D. E. (2001). Characterization of the solid-state: spectroscopic techniques. Advanced
Drug Delivery Reviews, 48, 43-65.
Buschini, A., Giordani, F., de Albuquerque, C. N., Pellacani, C., Pelosi, G., Rossi, C., . . . Poli, P. (2007). Trypanocidal nitroimidazole derivatives: relationships among chemical structure and genotoxic activity. Biochem Pharmacol, 73(10), 1537-1547. doi: 10.1016/j.bcp.2007.01.024
Cosar, C., & Julou, L. The activity of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (R. P. 8823) against experimental Trichomonas vaginalis infections. [Activite de l'(hydroxy- 2'ethyl)-1 methyl-2 nitro-5 imidazole (8.823 R. P.) vis-a-vis des infections
experimentales a Trichomonas vaginalis.]. (0020-2444 (Print)). doi: D - CLML: 5936:1370:271:543 OTO - NLM
Coura, J. R., & Castro, S. L. (2002). A critical review on Chagas Disease chemotherapy. Mem Inst Oswaldo Cruz, 97(1), 3-24.
Cruz-Cabeza, A. J., Reutzel-Edensb, S. M., & Bernstein, J. (2015). Facts and fictions about polymorphism. Chem.Soc.Rev., 44(23), 8619-8635. doi: 10.1039/C5CS00227C Datta, S., & Grant, D. J. (2004). Crystal structures of drugs: advances in determination,
prediction and engineering. Nat Rev Drug Discov, 3(1), 42-57. doi: 10.1038/nrd1280 de Andrade, A. L. S. S., Zicker, F., de Oliveira, R. M., Almeida e Silva, S., Luquetti, A.,
Travassos, L. R., . . . Martelli, C. M. T. (1996). Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. The Lancet, 348(9039), 1407-1413. doi: 10.1016/s0140-6736(96)04128-1
de Lima, A. A. N., Soares Sobrinho, J. L., da Silva, J. L., Corrêa Júnior, R. A. C., Lyra, M. A. M., & Rolim Neto, P. J. (2009). Development Of Dissolution Method For
Benznidazole Tablets. Quim. Nova, 32(8), 2196-2199.
de Toranzo, E. G. D., Castro, J. A., de Cazzulo, B. M. F., & Cazzulo, J. J. (1988). Interaction of benznidazole reactive metabolites with nuclear and kinetoplastic DNA, proteins and lipids from Trypanosoma cruzi. Experientia, 44, 880-881.
Delaney, S. P., Witko, E. M., Smith, T. M., & Korter, T. M. (2012). Investigating tautomeric polymorphism in crystalline anthranilic acid using terahertz spectroscopy and solid- state density functional theory. J Phys Chem A, 116(30), 8051-8057. doi:
10.1021/jp303961w
Desiraju, G. R. (1995). Supramolecular Synthons in Crystal Engineering-A New Organic Synthesis. Angew. Chem Int Ed. Engl., 34(2311-2327).
Desiraju, G. R. (2002). Hydrogen bridges in Crystal Engineering: Interactions without borders. Acc. Chem. Res., 35(7), 565-573.
Desiraju, G. R. (2013). Crystal engineering: from molecule to crystal. J Am Chem Soc, 135(27), 9952-9967. doi: 10.1021/ja403264c
Dias, J. C., Ramos, A. N., Jr., Gontijo, E. D., Luquetti, A., Shikanai-Yasuda, M. A., Coura, J. R., . . . Alves, R. V. (2016). Brazilian Consensus on Chagas Disease, 2015. Epidemiol Serv Saude, 25(spe), 7-86. doi: 10.5123/S1679-49742016000500002
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K., & H., P. (2009). OLEX2 : a complete structure solution, refinement and analysis program. . Journal of Applied Crystallography., 42(2), 339-341.
Duggirala, N. K., Perry, M. L., Almarssonb, O., & Zaworotko, M. J. (2016). Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun, 52, 640-655. doi: 10.1039/C5CC08216A
10.1039/c5cc08216a
Duggirala, N. K., Wood, G. P. F., Fischer, A., Wojtas, Ł., Perry, M. L., & Zaworotko, M. J. (2015). Hydrogen Bond Hierarchy: Persistent Phenol···Chloride Hydrogen Bonds in the Presence of Carboxylic Acid Moieties. Crystal Growth & Design, 15(9), 4341- 4354. doi: 10.1021/acs.cgd.5b00628
Eddleston, M. D., Sivachelvam, S., & Jones, W. (2013). Screening for polymorphs of cocrystals: a case study. CrystEngComm, 15(1), 175-181. doi: 10.1039/c2ce26496j Edwards, D. I. (1993a). Nitroimidazole drugs - action and resistance mechanisms I.
Mechanisms of action. Journal of Antimicrobial Chemotherapy, 31, 9-20. Edwards, D. I. (1993b). Nitroimidazole drugs - action and resistance mechanisms I. Mechanisms of action. Journal of Antimicrobial Chemotherapy, 31, 9-20. doi:
https://doi.org/10.1093/jac/31.1.9
Escobedo, A. A., & Cimerman, S. (2007). Giardiasis: a pharmacotherapy review. Expert Opin Pharmacother., 8(12), 1885-1902. doi: 10.1517/14656566.8.12.1885
Farrugia, L. (1997). ORTEP-3 for Windows - a version of ORTEP-III with a Graphical User Interface (GUI). J. AppL CrysL, 30, 568. doi: 10.1107/S0021889897006638
Figueiredo, C. B. M., Nadvorny, D., de Medeiros Vieira, A. C. Q., Soares Sobrinho, J. L., Rolim Neto, P. J., Lee, P. I., & de La Roca Soares, M. F. (2017). Enhancement of dissolution rate through eutectic mixture and solid solution of posaconazole and benznidazole. Int J Pharm, 525(1), 32-42. doi: 10.1016/j.ijpharm.2017.04.021 Fischer, F., Scholz, G., Batzdorf, L., Wilkeab, M., & Emmerling, F. (2015). Synthesis,
structure determination, and formation of a theobromine: oxalic acid 2: 1 cocrystal. CrystEngComm,, 17, 824. doi: 10.1039/c4ce02066a
Fraxedas, J. (2008). Molecular Organic Materials From Molecules to Crystalline Solids [Press release]
Gabbott, P., & Bottom, R. (2008). Principles and Applications of Themal Analysis (Vol. 1). Oxford, UK: Blackwell Publishing Ltd
Giarolla, J., & Ferreira, E. I. (2015). Drug Design for Neglected Disease in Brazil. Mini- Reviews in Medicinal Chemistry, 15, 220-242.
Gillis, J. C., & Wiseman, L. R. (1996). Secnidazole
A Review of its Antimicrobial Activity, Pharmacokinetic Properties and Therapeutic Use in the Management of Protozoal Infections and Bacterial Vaginosis. DRUG
EVALUATION, 51(4), 621-638.
Giron, D. (2002). Applications of Thermal Analysis and Coupled Techniques in
Pharmaceutical Industry. Journal of Thermal Analysis and Calorimetry, 68, 335-357. Goud, N. R., & Nangia, A. (2013). Synthon polymorphs of sulfacetamide–acetamide cocrystal
based on N–H⋯O=S and N–H⋯O=C hydrogen bonding. CrystEngComm, 15(37), 7456. doi: 10.1039/c3ce41179f
Haleblian, J., & McCrone, W. (1969). Pharmaceutical Applications of Polymorphism. J Pharm Sci, 58(8), 911-929.
Hickey, M. B., Peterson, M. L., Scoppettuolo, L. A., Morrisette, S. L., Vetter, A., Guzman, H., . . . Almarsson, O. (2007). Performance comparison of a co-crystal of
carbamazepine with marketed product. Eur J Pharm Biopharm, 67(1), 112-119. doi: 10.1016/j.ejpb.2006.12.016
Hilfiker, R., Blatter, F., & von Raumer, M. (2006). Polymorphism in the Pharmaceutical Industry. Weinheim, Germany.
Honorato, S. B. (2009). Polimorfismo Em Fármacos. Universidade Federal do Ceará. (A748p)
Honorato, S. B., Mendonca, J. S., Boechat, N., Oliveira, A. C., Mendes Filho, J., Ellena, J., & Ayala, A. P. (2014). Novel polymorphs of the anti-Trypanosoma cruzi drug
benznidazole. Spectrochim Acta A Mol Biomol Spectrosc, 118, 389-394. doi: 10.1016/j.saa.2013.08.096
Izutsu, K.-i., Koide, T., Takata, N., Ikeda, Y., Ono, M., Inoue, M., . . . Yonemochif, E. (2016). Characterization and Quality Control of Pharmaceutical Cocrystals. Chem. Pharm. Bull., 64(10), 1421-1430.
Jackson, Y., Pinto, A., & Pett, S. (2014). Chagas disease in Australia and New Zealand: risks and needs for public health interventions. Trop Med Int Health, 19(2), 212-218. doi: 10.1111/tmi.12235
Kasim, A. N., Whitehouse, M., Ramachandran, C., Bermejo, M., Lennern, H., Hussain, A. S., . . . Amidon, G. L. (2004). Molecular Properties of WHO Essential Drugs and Provisional Biopharmaceutical Classification. MOLECULAR PHARMACEUTICS, 1(1), 85-96. doi: 10.1021/mp034006h
Khan, S., Haseeb, M., Baig, M. H., Bagga, P. S., Siddiqui, H. H., Kamal, M. A., & Khan, M. S. (2015). Improved efficiency and stability of secnidazole - An ideal delivery system. Saudi J Biol Sci, 22(1), 42-49. doi: 10.1016/j.sjbs.2014.05.009
Kissinger, P. (2015). Trichomonas vaginalis: a review of epidemiologic, clinical and treatment issues. BMC Infect Dis, 15, 307. doi: 10.1186/s12879-015-1055-0
Lange, L., & Sadowski, G. (2016). Polymorphs, Hydrates, Cocrystals, and Cocrystal Hydrates: Thermodynamic Modeling of Theophylline Systems. Crystal Growth & Design, 16(8), 4439-4449. doi: 10.1021/acs.cgd.6b00554
M., S. G. (2008). A short history of SHELX. Acta Crystallogr Sect A, 64(1), 112-122. Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., . . .
Wood, P. A. (2008). Mercury CSD 2.0– new features for the visualization and
investigation of crystal structures. Journal of Applied Crystallography, 41(2), 466-470. doi: 10.1107/s0021889807067908
Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., . . . van de Streek, J. (2006). Mercury: visualization and analysis of crystal structures. . Journal of Applied Crystallography, 39(3), 453-457.
Maximiano, F. P., Costa, G. H. Y., & de Souza, J. (2010). Caracterização Físico-Química Do Fármaco Antichagásico Benznidazol. Quim. Nova, 33(8), 1714-1719.
Maya, J. D., Bollo, S., Nuñez-Vergara, L. J., Squella, J. A., Repetto, Y., Morello, A., . . . Chauvière, G. (2003). Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran derivatives. Biochem Pharmacol, 65(6), 999-1006. doi: 10.1016/s0006- 2952(02)01663-5
McCrone, W. (1965). Polymorphism. Physics and chemistry of the organic solid state, 2, 725- 767.
McNamara, D. P., Childs, S. L., Giordano, J., Iarriccio, A., Cassidy, J., Shet, M. S., . . . Park, A. (2006). Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res, 23(8), 1888-1897. doi: 10.1007/s11095-006-9032-3 Meites, E. (2013). Trichomoniasis: the "neglected" sexually transmitted disease. Infect Dis
Clin North Am, 27(4), 755-764. doi: 10.1016/j.idc.2013.06.003
Menezes, C. B., Frasson, A. P., & Tasca, T. (2016). Trichomoniasis - are we giving the deserved attention to the most common non-viral sexually transmitted disease worldwide? Microb Cell, 3(9), 404-419. doi: 10.15698/mic2016.09.526
Mnguni, M. J. (2017). Polymorphism in Pharmaceutical Co-crystals. (Master of Science), University of the Witwatersrand, Johannesburg.
Mukherjee, A., & Desiraju, G. R. (2011). Synthon polymorphism and pseudopolymorphism in co-crystals. The 4,4'-bipyridine-4-hydroxybenzoic acid structural landscape. Chem Commun (Camb), 47(14), 4090-4092. doi: 10.1039/c0cc05857b
Nanubolu, J. B., & Ravikumar, K. (2017). Designing a new cocrystal of olanzapine drug and observation of concomitant polymorphism in a ternary cocrystal system.
CrystEngComm, 19(2), 355-366. doi: 10.1039/c6ce02227h
Newman, A. N., & Byrn, S. R. (2003). Solid-state analysis of the active pharmaceutical ingredient in drug products. Drug Discovery Today., 9(19), 898-905.
Olenik, B., Smolka, T., Boese, R., & Sustmann, R. (2003). Supramolecular Synthesis by Cocrystallization of Oxalic and Fumaric Acid with Diazanaphthalenes. Crystal Growth & Design, 3(2), 183-188.
Patterson, S., & Wyllie, S. (2014). Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. Trends Parasitol, 30(6), 289-298. doi:
10.1016/j.pt.2014.04.003
Pedrique, B., Strub-Wourgaft, N., Some, C., Olliaro, P., Trouiller, P., Ford, N., . . . Bradol, J.- H. (2013). The drug and vaccine landscape for neglected diseases (2000–11): a systematic assessment. The Lancet Global Health, 1(6), e371-e379. doi: 10.1016/s2214-109x(13)70078-0
Polak, A., & Richle, R. (1978). Mode of action of the 2-nitroimidazole derivative benznidazole. Annals of Tropical Medicine & Parasitology, 72(1), 45-54. doi: 10.1080/00034983.1978.11719278
Prohens, R., Barbas, R., Portell, A., Font-Bardia, M., Alcobé, X., & Puigjaner, C. (2016). Polymorphism of Cocrystals: The Promiscuous Behavior of Agomelatine. Crystal Growth & Design, 16(2), 1063-1070. doi: 10.1021/acs.cgd.5b01628
PubChem. (2017). National Center for Biotechnology Information. PubChem Compound Database; CID=31593, https://pubchem.ncbi.nlm.nih.gov/compound/31593 (accessed July 5, 2017). Retrieved 5 de Julho de 2017
Raether, W., & Hanel, H. (2003). Nitroheterocyclic drugs with broad spectrum activity. Parasitol Res, 90 Supp 1, S19-39. doi: 10.1007/s00436-002-0754-9
Rassi Junior, A., Rassi, A., & Marin-Neto, J. A. (2010). Chagas disease. Lancet, 375, 1388- 1402.
Rivera, A. B., Hernández, R. G., Armas, H. N., Elizástegi, D. M. C., & Losada, M. V. (2000). Physico-chemical and solid-state characterization of secnidazole. IL Farmaco, 55, 700-707.
Robertson, L. J., Devleesschauwer, B., Alarcon de Noya, B., Noya Gonzalez, O., & Torgerson, P. R. (2016). Trypanosoma cruzi: Time for International Recognition as a Foodborne Parasite. PLoS Negl Trop Dis, 10(6), e0004656. doi: 10.1371/journal.pntd.0004656 Rodriguez-Spong, B., Price, C. P., Jayasankar, A., Matzger, A. J., & Rodriguez-Hornedo, N.
(2004). General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Adv Drug Deliv Rev, 56(3), 241-274. doi: 10.1016/j.addr.2003.10.005 Romanha, A. J., Murta, S. M. F., Alves, R. O., Silva, J. S., Ropert, C., & Gazzinelli, R. T.
(2002). Experimental chemotherapy against Trypanosoma cruzi Infection: Essential role of endogenous interferon-g in mediating parasitologic cure. The Journal of Infectious Diseases, 186, 823-828. doi: 0022-1899/2002/18606-0013
Romero, E. L., & Morilla, M. J. (2010). Nanotechnological approaches against Chagas disease. Adv Drug Deliv Rev, 62(4-5), 576-588. doi: 10.1016/j.addr.2009.11.025 Sanphui, P., Goud, N. R., Khandavilli, U. B. R., & Nangia, A. (2011). Fast Dissolving
Curcumin Cocrystals. Crystal Growth & Design, 11(9), 4135-4145. doi: 10.1021/cg200704s
Sildenafil with Dicarboxylic Acids: Solubility and Pharmacokinetic Advantage of the Glutarate Salt. MOLECULAR PHARMACEUTICS, 10, 46κ7−46λ7. doiμ
10.1021/mp400516b
Schultheiss, N., & Henck, J.-O. (2011). Chapter 6. Role of Co-crystals in the Pharmaceutical Development Continuum. In L. Q. Johan Wouters (Ed.), Pharmaceutical Salts and Co- crystals (pp. 110-127): The Royal Society of Chemistry.
Schultheiss, N., & Newman, A. (2009). Pharmaceutical Cocrystals and Their Physicochemical Properties. Crystal Growth & Design, 9(6), 2950-2967.
Secor, W. E., Meites, E., Starr, M. C., & Workowski, K. A. (2014). Neglected parasitic infections in the United States: trichomoniasis. Am J Trop Med Hyg, 90(5), 800-804. doi: 10.4269/ajtmh.13-0723
Sena, A. C., Bachmann, L. H., & Hobbs, M. M. (2014). Persistent and recurrent Trichomonas vaginalis infections: epidemiology, treatment and management considerations. Expert Rev Anti Infect Ther, 12(6), 673-685. doi: 10.1586/14787210.2014.887440
Shan, N., Toda, F., & Jones, W. (2002). Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem Commun (Camb)(20), 2372-2373. doi:
10.1039/b207369m
Sheldrick, G. M. (2015). Crystal structure refinement with SHELXL. . Acta Crystallographica Section C Structural Chemistry, 71(1).
Silveira, A. C., de Arjas, A. R., Segura, E., Guillén, G., Russomando, G., Shenone, H., . . . Salvatella, R. (2002). O controle da Doença de Chagas nos países do Cone Sul da Ámerica. História de uma iniciativa internacional. 1991/2001. Organização Pan- Americana da Saúde.
Soares-Sobrinho, J. L., de La Roca Soares, M. F., Lopes, P. Q., Correia, L. P., de Souza, F. S., Macedo, R. O., & Rolim-Neto, P. J. (2010). A preformulation study of a new medicine for Chagas disease treatment: physicochemical characterization, thermal stability, and compatibility of benznidazole. AAPS PharmSciTech, 11(3), 1391-1396. doi:
10.1208/s12249-010-9495-8
Sosa-Estani, S., Viotti, R., & Segura, E. L. (2009). Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina. Mem Inst Oswaldo Cruz, 104 (Suppl. I)(167), 167-180.
Sreekanth, B. R., Vishweshwar, P., & Vyas, K. (2007). Supramolecular synthon polymorphism in 2 : 1 co-crystal of 4-hydroxybenzoic acid and 2,3,5,6-tetramethylpyrazine. Chem Commun (Camb)(23), 2375. doi: 10.1039/b700082k
Stahly, G. P. (2007). Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals. Crystal Growth & Design, 7(6), 1007- 1026.
Storey, R. A., & Ymén, I. (2011). Solid State Characterization of Pharmaceuticals.
Strasen, J., Williams, T., Ertl, G., Zoller, T., Stich, A., & Ritter, O. (2014). Epidemiology of Chagas disease in Europe: many calculations, little knowledge. Clin Res Cardiol, 103(1), 1-10. doi: 10.1007/s00392-013-0613-y
Strauss, M. J. (1979). The Nitroaromatic Group in Drug Design. Pharmacology (for Nonpharmacologists). Ind. Eng. Chem. Prod. Res. Dev., 18(3), 158-166.
Sun, C. C., & Hou, H. (2008). Improving Mechanical Properties of Caffeine and Methyl Gallate Crystals by Cocrystallization. Crystal Growth & Design, 8(5), 1575-1579. Takata, N., Shiraki, K., Takano, R., Hayashi, Y., & Terada, K. (2008). Cocrystal Screening of
Stanolone and Mestanolone Using Slurry Crystallization. Crystal Growth & Design, 8(8), 3032-3037.
Thakuria, R., Delori, A., Jones, W., Lipert, M. P., Roy, L., & Rodriguez-Hornedo, N. (2013). Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm, 453(1), 101-125. doi:
10.1016/j.ijpharm.2012.10.043
Tillei, R. J. D. (2014). Cristalografia, cristais e estruturas cristalinas: Oficina de textos. Torreele, E., Bourdin Trunz, B., Tweats, D., Kaiser, M., Brun, R., Mazue, G., . . . Pecoul, B.
(2010). Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis, 4(12), e923. doi: 10.1371/journal.pntd.0000923
Tothadi, S., Bhogala, B. R., Gorantla, A. R., Thakur, T. S., Jetti, R. K., & Desiraju, G. R. (2012). Triclabendazole: an intriguing case of co-existence of conformational and tautomeric polymorphism. Chem Asian J, 7(2), 330-342. doi: 10.1002/asia.201100638 Tothadi, S., & Desiraju, G. R. (2012). Synthon Modularity in 4-Hydroxybenzamide–
Dicarboxylic Acid Cocrystals. Crystal Growth & Design, 12(12), 6188-6198. doi: 10.1021/cg3013766
Trouiller, P., Olliaro, P., Torreele, E., Orbinski, J., Laing, R., & Ford, N. (2002). Drug development for neglected diseases: a deficient market and a public-health policy failure. The Lancet, 359(9324), 2188-2194. doi: 10.1016/s0140-6736(02)09096-7 Vippagunta, S. R., Brittain, H. G., & Grant, D. J. W. (2001). Crystalline solids. Advanced
Drug Delivery Reviews, 48, 3-26.
Vishweshwar, P., McMahon, J. A., Bis, J. A., & Zaworotko, M. J. (2006). Pharmaceutical co- crystals. J Pharm Sci, 95(3), 499-516. doi: 10.1002/jps.20578
Weyna, D. R., Shattock, T., Vishweshwar, P., & Zaworotko, M. J. (2009). Synthesis and Structural Characterization of Cocrystals and Pharmaceutical Cocrystals:
Mechanochemistry vs Slow Evaporation from Solution. Crystal Growth & Design, 9(2), 1106-1123.
WHO. (2015). Investing to overcome the global impact of neglected tropical diseases: third WHO report on neglected diseases 2015.
WHO. (2017). WHO (World Health Organization). Neglected tropical diseases. . from http://www.who.int/neglected_diseases/diseases/en/
Wouters, J., & Quéré, L. (2012). Pharmaceutical Salts and Co-crystals (Vol. 16). Cambridge: The Royal Society of Chemistry.
Zhang, Q., Lu, L., Dai, W., & Mei, X. (2014). Polymorphism and isomorphism of Huperzine A solvates: structure, properties and form transformation. CrystEngComm, 16(10), 1919. doi: 10.1039/c3ce41965g