Novel Strategy to Control Polymorph Nucleation of Gamma

Jul 30, 2018 - Pyrazinamide is usually nucleated from solution as a dimeric form; it has rarely been reported in the γ form (chain structure) crystal...
0 downloads 0 Views 977KB Size
Subscriber access provided by READING UNIV

Communication

A novel strategy to control polymorph nucleation of gamma pyrazinamide by preferred intermolecular interactions during heterogeneous nucleation Keke Zhang, Shijie Xu, Shiyuan Liu, Weiwei Tang, Xiaoyan Fu, and Junbo Gong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00943 • Publication Date (Web): 30 Jul 2018 Downloaded from http://pubs.acs.org on July 30, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

A novel strategy to control polymorph nucleation of gamma pyrazinamide by preferred intermolecular interactions during heterogeneous nucleation Keke Zhanga,b, Shijie Xu a,b, Shiyuan Liu a,b, Weiwei Tang a,b, Xiaoyan Fu a,b, Junbo Gong a,b* a

School of Chemical Engineering and Technology, State Key Laboratory of Chemical

Engineering, Tianjin University, Tianjin 300072, People’s Republic of China. b

The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin

University, Tianjin 300072, People’s Republic of China. Abstract: Pyrazinamide usually nucleated from solution as dimeric forms, it has rarely been reported γ form (chain structure) crystallized from solution, especially for aqueous solution. Here, we innovated a novel way to obtain γ form of pyrazinamide from aqueous solution. Specific templates were applied to disturb the intrinsic self-association of pyrazinamide molecules and prevent the formation of dimer structure. In this paper, the heterosynthon design method was applied in pyrazinamide heterogeneous nucleation, in which sulfonamides were chosen as the templates. In the presence of sulfonamides templates, hydrogen bonding between the carbonyl moiety of the amide group in pyrazinamide molecules and the sulfonamide moiety of sulfonamides templates molecules was formed, this preferred intermolecular interactions protected the carbonyl groups of PZA, facilitating PZA molecules assembling in chain via N-H···N’ and nucleating as γ form of PZA. This is the first time that the heterosynthon design method was applied to screen effective templates, which can control and select desired polymorph in heterogeneous nucleation. Polymorphism is a common phenomenon in nature, referring to the same compound has different molecular arrangements, which leads to distinct chemistry and physical properties.1 Polymorph research is particularly important for pharmaceuticals. Different crystal structures bring varied morphologies and thermodynamic properties, which play vital influences on drug performances, such as compressibility, solubility, bioavailability and so on.2 Therefore, polymorph control has been regarded as a decisive role in the pharmaceutical sector. In recent decades, numerous researchers have studied on selecting and designing hetero-surfaces to control crystallization outcomes. In heterogeneous nucleation, the activation energy barrier for the formation of nucleus decreases by reducing the interfacial area and surface tension.3 Surfaces are always regarded to act as catalysts for the nucleation of crystals. Different properties of hetero-surface can determine the crystallization outcome. Quite a few studies have been carried out to elaborate the effects of different hetero-surfaces on the morphology,4 polymorphism5-7 and nucleation kinetics8-10 of the newly forming crystal. Ward’s research group 11, 12 demonstrated that certain geometric matching (crystal lattice parameters) between hetero-surfaces and the crystal shows preference to specific polymorphism as epitaxial ordering can alter the orientation order of the nucleus molecule. The aggregates tend to grow in the surfaces whose structure resembles the

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

nucleus. Besides, the heterosurface’s structure was found to influence crystallization outcomes in some other studies. Not only the size of imprinted nanopore13-15, the shape of pores16-18 can also affect selection of specific polymorphism. In addition to the geometry, heterosurface’s functionalities19, 20 are of great importance for controlling crystallization of polymorphism. The functional groups on heterosurfaces can be involved into intermolecular interactions, forming specific interactions with the molecule of solute. By taking advantage of this, polymorph control can be achieved. Heterogeneous nucleation is a complex process. In some cases, the combined analysis of the contributions from the intermolecular interactions and geometric matching12, 21-23 need to be included to interpret the relationship between polymorph control and heteronucleation. However, research about polymer-induced heteronucleation24, 25 have proved that geometric matching is not a very necessary factor in crystalline polymorph. Besides that, heteronuleation studies which the substrates are organic /inorganic crystals,4, 5, 26 self-assembled monolayers (SAMs)27, 28 demonstrated that chemical interaction contribute more to heterogeneous nucleation. Pyrazinamide (PZA) is one of the first-line drugs against Mycobacterium tuberculosis, which can shorten the therapy from previously 9-12 months to 6 months.29, 30 Despite its importance for tuberculosis treatment, PZA can act as an inhibitor of ethylene biosynthesis which help to decrease postharvest loss.31 PZA polymorphic forms have been thoroughly studied by Castro32 and Cherukuvada,33 α form is most stable at ambient condition and used commercially. However, its fine needle shape is undesirable for the process of filtration and drying. Many studies34-36 has been conducted to prepare the alternative polymorphs such as δ form and γ form, which are relatively stable at ambient condition and with superior crystal morphology. While most of them employed unconventional crystallization method like spry drying, 34, 35 it has barely reported to gain γ form of PZA via solution crystallization. In this study, PZA with γ form is successfully prepared in the guidance of heterosynthon design method by controlling the heterogeneous nucleation. To the authors’ knowledge, this is the first time to achieve polymorph control by designing heterosynthon during heterogeneous nucleation.

ACS Paragon Plus Environment

Page 2 of 11

Page 3 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Figure 1. Pyrazinamide polymorphic forms: four packing polymorphisms. Pyrazinamide has been reported to have four packing polymorphisms (Figure 1).The molecules of pyrazinamide contain several H-bond acceptor/donor groups, providing possibilities of forming different hydrogen bonds. Hydrogen bonds are more flexible than covalent bonds. Besides that, the property of being rather directional also favors hydrogen bonds adjusting and controlling the self-assembly of molecules. Based on this specific characteristic, adding templates which can manipulate the hydrogen bonds networks of PZA aims to directionally select and control polymorph of pyrazinamide. Instead of having carboxamide dimer as the main building blocks in α, β and δ polymorphs, the γ form is prominently different with molecules assembling in chain by N-H···N’ hydrogen bonds. Therefore, we attempt to choose templates with specific functional groups to hamper the self-association of carboxamide dimer, by forming hydrogen bonding with the –C=O groups of PZA directionally to compel the PZA molecules arranging in chain. Instead of tentatively screening the effective template, the synthon design approach was considered. As mentioned above, molecular associations of PZA play a determining effect on nucleated polymorph. The decisive step is to find a template which can form a supramolecular synthon with the –C=O groups of PZA. The reported co-crystals of pyrazinamide have been searched in Cambridge Structural Database (CSD), and all the heterosynthons were analyzed. Then we found co-crystals of PZA with hydrochlorothiazide,37 hydrogen bonding between PZA molecule and hydrochlorothiazide molecule was observed between the carbonyl moiety of the amide group in pyrazinamide molecules and the sulfonamide moiety of HCT molecules. The synthon is shown in Fig. S1. As the Fig. S1 shows, the hydrogen bonding between the carbonyl moiety of the amide group and the sulfonamide moiety compelled the PZA molecules arranging in chain. Obviously, the sulfonamide moiety plays a vital part in the formation of H-bonds. Therefore, a series compounds containing sulfonamide moiety were selected as the templates in the present work. The heterosynthons diagram is shown in Figure 2. As expected, the pure γ form crystals of PZA were successfully obtained with these templates in a series of heterogeneous nucleation experiments.

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 2. The heterosynthons diagram of the carbonyl moiety of the amide group and the sulfonamide moiety. In this study, seven sulfonamide compounds (hydrochlorothiazide, sulfadiazine, sulfathiazole, benzenesulfonamide, p-toluenesulfonamide, saccharin and sulfanilamide) were chosen as the templates in PZA cooling crystallization (Figure 3). The crystallization experiments were conducted with the concentration of PZA in water of 35.9 mg/mL (saturated solution at 45 °C). 5 g solution was filtrated into preheated 15 mL vials via a polytetrafluoroethylene (PTFE) filter with 0.2 µm pores, and a certain amount of templates (mtemplate/mpyrazinamide: hydrochlorothiazide = 5%, sulfadiazine = 10%, sulfathiazole = 10%, benzenesulfonamide = 10%, p-toluenesulfonamide = 10%, saccharin = 10% and sulfanilamide = 10%) was added to the vial respectively. The capped vials were placed on a temperature controller, the solution was cooled from 45 °C to 10 °C with a cooling rate of 0.58 °C/min. A blank experiment was conducted without templates at the same condition. Noting that during the cooling crystallization, the samples remained undisturbed. The obtained crystals from cooling crystallization of water were analyzed by X-ray Powder Diffraction (XRPD) and Infrared Spectroscopy (FTIR), respectively. Comparing with simulated XRPD, crystals grown in the absence of templates were all α form, while crystals obtained in the presence of templates were all γ form (Figure 4). The microscope images (Fig. S2) of obtained PZA crystals clearly illustrate the change of crystal habits of different polymorphs, the needlelike α form (aspect ratio > 20) crystalized without templates and the long flaky γ form (aspect ratio < 10) obtained with templates. By further studying the XRPD pattern in Figure 4, it was found that the crystal shows preferred orientation. In all cases of PZA with seven templates, XRPD analysis revealed three significant reflections occurring at 17.3° (2 0 0), 18.3° (2 0 -1) and 33.5° (4 0 -1).

Figure 3. Sulfonamide compounds, (a) hydrochlorothiazide, (b) sulfadiazine, (c) sulfathiazole, (d)

ACS Paragon Plus Environment

Page 4 of 11

Page 5 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

sulfanilamide, (e) benzenesulfonamide, (f) saccharin and (g) p-toluenesulfonamide.

Figure 4. Powder X-ray diffraction patterns of obtained PZA crystals with a: benzenesulfonamide, b: p-toluenesulfonamide, c: sulfanilamide, d: sulfadiazine, e: sulfathiazole, f: saccharin, g: hydrochlorothiazide as templates and h: without templates, along with the simulated PXRD pattern of α form and γ form of PZA. It is believed that infrared spectra are quite sensitive to the change of hydrogen bond network. Thus Infrared Spectroscopy (FTIR) was employed in this study to confirm the crystal form of PZA crystals, which were obtained in the presence of sulfonamides templates (see S3). By further analyzing the infrared spectra, an interesting phenomenon was found. For the crystals grown with hydrochlorothiazide as template, the –C=O stretching region in Figure 6 shows a shift relative to that of pure γ form of PZA. The occurrence of this shift can be attributed to formation of hydrogen-bonding with the –C=O groups of PZA and hydrochlorothiazide. Also, comparing with the infrared spectrum of pure γ form (Figure 5: blue line b), there appeared an additional peak at 3368cm-1 in red line d. As the particle size of hydrochlorothiazide is relatively large, it is unavoidable that there still existed some hydrochlorothiazide crystals mixing with the PZA after washing and filtration. Hence we further analyzed the infrared spectrum of hydrochlorothiazide and the physical mixture of hydrochlorothiazide and PZA. As Figure 5 shows, the infrared spectrum of hydrochlorothiazide has a peak at 3357cm-1 which is the NH2 stretching vibrations. This indicates that the NH2 stretching region of hydrochlorothiazide experienced a shift after interacted with PZA. Occurrence of the shift of –C=O stretching region of PZA combined with the NH2 stretching vibrations of hydrochlorothiazide’s shift, the formation of hydrogen bonds between PZA –C=O groups and hydrochlorothiazide NH2 groups is rationally confirmed. The supramolecular synthon between the carbonyl moiety of the amide group in pyrazinamide molecules and the sulfonamide moiety of HCT molecules is exited.

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 5. Infrared spectra of the NH2 stretching vibrations and the CO stretching vibrations of hydrochlorothiazide and PZA. (a) Pure hydrochlorothiazide. (b) Pure γ form of PZA. (c) The physical mixture of hydrochlorothiazide: PZA=1:20. (d) The obtained PZA crystals with hydrochlorothiazide as a template. To further explore the intermolecular interactions between PZA and templates, the preferred facets (2 0 0), (2 0 -1) and (4 0 -1) of PZA were analyzed. Figure 6 shows the (2 0 0), (2 0 -1) and (4 0 -1) faces with the –C=O groups of PZA pointing towards the surfaces. The shift of the –C=O stretching region of PZA and the –C=O groups exposed of the preferred orientation faces reinforce our assumption. The –NH2 groups of sulfonamides molecules form hydrogen-bonding with the – C=O groups of PZA, resulting to the occurrence of intermolecular interactions. These preferred intermolecular interactions protect the carbonyl groups of PZA, facilitating PZA molecules assembling in chain via N-H···N’. Equally, these preferred interactions accounted for the preferred orientation of PZA crystals in Figure 4 and long flake crystals shape in Fig. S2.

ACS Paragon Plus Environment

Page 6 of 11

Page 7 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Figure 6. View of the (2 0 0), (2 0 -1) and (4 0 -1) faces of γ form of PZA (view along b axis). While the infrared spectra of crystals obtained in the presence of other six templates shown no apparent shift. We speculated that the interactions between the PZA molecules and these templates molecules are relatively weak, so the stretching vibrations of corresponding functional groups were not affected. The adding amount of hydrochlorothiazide which was smaller than those of other six templates also corroborate this explanation. Usually dimeric forms of PZA are preferentially nucleated from solution, the reproducibility of γ form (chain structure) from solution crystallization remains a challenge, especially for aqueous solution. In our study, the pure γ form was stably obtained by innovatively employing a heteronucleation method aided with the sulfonamide compounds as templates. We found the presence of sulfonamide moiety in templates is decisive in adjusting intermolecular interactions and influencing molecular self-association of PZA molecules, and finally induce the construction of chain structure existed in γ form. The supramolecular synthon design was demonstrated to be a crucial step in the formation of hydrogen bonding and polymorph control. Even though many studies using chemical interactions to direct polymorphic nucleation, to the best of our knowledge, no studies have been reported on applying synthon design approach to obtain target polymorph in heterogeneous nucleation. In this study, γ form of PZA was first obtained in aqueous solution crystallization. Our results indicated that for packing polymorphism, proper templates, through synthon design, one can change the hydrogen networks and further guide the nucleation outcomes, is a prominent way to control the polymorph. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Additional data and figures (PDF).

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

AUTHOR INFORMATION Corresponding Author *Tel.: 86-22-27405754. Fax: 86-22-27314971. E-mail: [email protected]. ORCID Junbo Gong: 0000-0002-3376-3296 Notes The authors declare no competing financial interest. ACKNOWLEGEMENT The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 21676179), Tianjin Science and Technology Project (15JCZDJC33200 and KJXH2015-01). REFERENCES (1) Dutton, D., Physics and Chemistry of the Organic Solid State. J. Am. Chem. Soc. 1967, 86, (8), 1654-1654. (2) Brittain, H. G., Polymorphism in pharmaceutical solids. J. Controlled Release 2001, 71, (3), 354-355. (3) Vekilov, P. G., The two-step mechanism of nucleation of crystals in solution. Nanoscale 2010, 2, (11), 2346-57. (4) Kensuke Naka, Y. C., Control of Crystal Nucleation and Growth of Calcium Carbonate by Synthetic Substrates. Chem. Mater. 2001, 13, (10), 3245-3259. (5) Caridi, A.; Kulkarni, S. A.; Di Profio, G.; Curcio, E.; ter Horst, J. H., Template-Induced Nucleation of Isonicotinamide Polymorphs. Cryst. Growth Des. 2014, 14, (3), 1135-1141. (6) Kulkarni, S. A.; Weber, C. C.; Myerson, A. S.; ter Horst, J. H., Self-association during heterogeneous nucleation onto well-defined templates. Langmuir 2014, 30, (41), 12368-75. (7) Patel, M. A.; Kaplan, K.; Yuk, S. A.; Saboo, S.; Melkey, K.; Chadwick, K., Utilization of Surface Equilibria for Controlling Heterogeneous Nucleation: Making the “Disappeared” Polymorph of 3-Aminobenzensulfonic Acid “Reappear”. Cryst. Growth Des. 2016, 16, (12), 6933-6940. (8) Curcio, E.; López-Mejías, V.; Di Profio, G.; Fontananova, E.; Drioli, E.; Trout, B. L.; Myerson, A. S., Regulating Nucleation Kinetics through Molecular Interactions at the Polymer–Solute Interface. Cryst. Growth Des. 2014, 14, (2), 678-686. (9) Frank, D. S.; Matzger, A. J., Influence of Chemical Functionality on the Rate of Polymer-Induced Heteronucleation. Cryst. Growth Des. 2017, 17, (8), 4056-4059. (10) Patel, M. A.; Nguyen, B.; Chadwick, K., Predicting the Nucleation Induction Time Based on Preferred Intermolecular Interactions. Cryst. Growth Des. 2017, 17, (9), 4613-4621. (11) Christine A. Mitchell, L. Y., Michael D. Ward, Selective Nucleation and Discovery of Organic Polymorphs through Epitaxy with Single Crystal Substrates. J. Am. Chem. Soc. 2001, 123, 10830-10839. (12) Olmsted, B. K.; Ward, M. D., The role of chemical interactions and epitaxy during nucleation of organic crystals on crystalline substrates. CrystEngComm 2011, 13, (4), 1070-1073. (13) Jeong-Myeong Ha, J. H. W., Marc A. Hillmyer, Michael D. Ward, Polymorph Selectivity under Nanoscopic Confinement. J. Am. Chem. Soc. 2004, 126, 3382-3383. (14) Benjamin D. Hamilton, M. A. H., Michael D. Ward, Glycine polymorphism in nanoscale

ACS Paragon Plus Environment

Page 8 of 11

Page 9 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

crystallization chambers. Cryst. Growth Des. 2008, 8, (9), 3368-3375. (15) Ha, J.-M.; Hamilton, B. D.; Hillmyer, M. A.; Ward, M. D., Phase Behavior and Polymorphism of Organic Crystals Confined within Nanoscale Chambers. Cryst. Growth Des. 2009, 9, (11), 4766-4777. (16) Diao, Y.; Harada, T.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., The role of nanopore shape in surface-induced crystallization. Nat Mater 2011, 10, (11), 867-71. (17) Tan, L.; Davis, R. M.; Myerson, A. S.; Trout, B. L., Control of Heterogeneous Nucleation via Rationally Designed Biocompatible Polymer Surfaces with Nanoscale Features. Cryst. Growth Des. 2015, 15, (5), 2176-2186. (18) Stojaković, J.; Baftizadeh, F.; Bellucci, M. A.; Myerson, A. S.; Trout, B. L., Angle-Directed Nucleation of Paracetamol on Biocompatible Nanoimprinted Polymers. Cryst. Growth Des. 2017, 17, (6), 2955-2963. (19) Parambil, J. V.; Poornachary, S. K.; Hinder, S. J.; Tan, R. B. H.; Heng, J. Y. Y., Establishing template-induced polymorphic domains for API crystallisation: the case of carbamazepine. CrystEngComm 2015, 17, (33), 6384-6392. (20) Yang, H.; Song, C. L.; Lim, Y. X. S.; Chen, W.; Heng, J. Y. Y., Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties. CrystEngComm 2017, 19, (44), 6573-6578. (21) Delmas, T.; Shah, U. V.; Roberts, M. M.; Williams, D. R.; Heng, J. Y. Y., Crystallisation of the orthorhombic form of acetaminophen: Combined effect of surface topography and chemistry. Powder Technol. 2013, 236, 24-29. (22) Wijethunga, T. K.; Baftizadeh, F.; Stojaković, J.; Myerson, A. S.; Trout, B. L., Experimental and Mechanistic Study of the Heterogeneous Nucleation and Epitaxy of Acetaminophen with Biocompatible Crystalline Substrates. Cryst. Growth Des. 2017, 17, (7), 3783-3795. (23) Chadwick, K.; Chen, J.; Myerson, A. S.; Trout, B. L., Toward the Rational Design of Crystalline Surfaces for Heteroepitaxy: Role of Molecular Functionality. Cryst. Growth Des. 2012, 12, (3), 1159-1166. (24) Lopez-Mejias, V.; Knight, J. L.; Brooks, C. L., 3rd; Matzger, A. J., On the mechanism of crystalline polymorph selection by polymer heteronuclei. Langmuir 2011, 27, (12), 7575-9. (25) Grzesiak, A. L.; Matzger, A. J., New form discovery for the analgesics flurbiprofen and sulindac facilitated by polymer-induced heteronucleation. J Pharm Sci 2007, 96, (11), 2978-86. (26) Arribas Bueno, R.; Crowley, C. M.; Davern, P.; Hodnett, B. K.; Hudson, S., Heterogeneous Crystallization of Fenofibrate onto Pharmaceutical Excipients. Cryst. Growth Des. 2018, 18, (4), 2151-2164. (27) David H. Dressler, Y. M., Controlling Polymorphism by Crystallization on Self-Assembled Multilayers. Cryst. Growth Des. 2007, 7, (5), 847-850. (28) Capacci-Daniel, C.; Gaskell, K. J.; Swift, J. A., Nucleation and Growth of Metastable Polymorphs on Siloxane Monolayer Templates. Cryst. Growth Des. 2010, 10, (2), 952-962. (29) Rée H. Global Tuberculosis Programme: Treatment of Tuberculosis – Guidelines for National Programmes[J]. Transactions of the Royal Society of Tropical Medicine & Hygiene, 1999, 93(1):72-72. (30) Lemaitre, N.; Callebaut, I.; Frenois, F.; Jarlier, V.; Sougakoff, W., Study of the structure-activity relationships for the pyrazinamidase (PncA) from Mycobacterium tuberculosis. Biochem. J. 2001, 353, (3), 453-458. (31) Sun, X.; Li, Y.; He, W.; Ji, C.; Xia, P.; Wang, Y.; Du, S.; Li, H.; Raikhel, N.; Xiao, J.; Guo, H., Pyrazinamide and derivatives block ethylene biosynthesis by inhibiting ACC oxidase. Nat Commun

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2017, 8, 15758. (32) Castro, R. A. E.; Maria, T. M. R.; Évora, A. n. O. L.; Feiteira, J. C.; Silva, M. R.; Beja, A. M.; Canotilho, J. o.; Eusébio, M. E. S., A New Insight into Pyrazinamide Polymorphic Forms and their Thermodynamic Relationships. Cryst. Growth Des. 2010, 10, (1), 274-282. (33) Cherukuvada, S.; Thakuria, R.; Nangia, A., Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy. Cryst. Growth Des. 2010, 10, (9), 3931-3941. (34) Pham, D. D.; Fattal, E.; Ghermani, N.; Guiblin, N.; Tsapis, N., Formulation of pyrazinamide-loaded large porous particles for the pulmonary route: avoiding crystal growth using excipients. Int J Pharm 2013, 454, (2), 668-77. (35) Baaklini, G.; Dupray, V.; Coquerel, G., Inhibition of the spontaneous polymorphic transition of pyrazinamide gamma form at room temperature by co-spray drying with 1,3-dimethylurea. Int J Pharm 2015, 479, (1), 163-70. (36) Hermanto, M. W.; Yeoh, A.; Soh, B.; Chow, P. S.; Tan, R. B. H., Robust Crystallization Process Development for the Metastable δ-form of Pyrazinamide. Org. Process Res. Dev. 2015, 19, (12), 1987-1996. (37) Wang, J.-R.; Ye, C.; Mei, X., Structural and physicochemical aspects of hydrochlorothiazide co-crystals. CrystEngComm 2014, 16, (30), 6996-7003.

ACS Paragon Plus Environment

Page 10 of 11

Page 11 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

For Table of Contents Use Only

A novel strategy to control polymorph nucleation of gamma pyrazinamide by preferred intermolecular interactions during heterogeneous nucleation Keke Zhanga,b, Shijie Xu a,b, Shiyuan Liu a,b, Weiwei Tang a,b, Xiaoyan Fu a,b, Junbo Gong a,b* a

School of Chemical Engineering and Technology, State Key Laboratory of Chemical

Engineering, Tianjin University, Tianjin 300072, People’s Republic of China. b

The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin

University, Tianjin 300072, People’s Republic of China.

Synopsis The selected templates with sulfamido groups can form hydrogen bonds with pyrazinamide molecules, which interrupted the intrinsic self-association of pyrazinamide in solution and compelled pyrazinamide molecules arranging in chain (γ form).

ACS Paragon Plus Environment