Drug-Bridge-Drug Ternary Cocrystallization Strategy for

266003 , PR China. Cryst. Growth Des. , 2018, 18 (3), pp 1283–1286. DOI: 10.1021/acs.cgd.7b01738. Publication Date (Web): January 23, 2018. Copy...
0 downloads 10 Views 464KB Size
Subscriber access provided by TEXAS STATE UNIVERSITY

Communication

Drug-bridge-drug ternary cocrystallization strategy for anti-tuberculosis drugs combination Fang Liu, Yu Song, Ya-Nan Liu, Yan-Tuan Li, Zhi-Yong Wu, and Cui-Wei Yan Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01738 • Publication Date (Web): 23 Jan 2018 Downloaded from http://pubs.acs.org on January 28, 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 free 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 accessible to all readers and 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.

Crystal Growth & Design 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 6 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

Drug-bridge-drug ternary cocrystallization strategy for antituberculosis drugs combination Fang Liu,a Yu Song,a Ya-Nan Liu,a Yan-Tuan Li,∗a,b Zhi-Yong Wu∗a and Cui-Wei Yan∗c a. School of Medicine and Pharmacy, Ocean University of China, 266003, PR China. E-mail: [email protected] b. Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, 266003, PR China. c. College of Marine Life Science, Ocean University of China, 266003, PR China. ABSTRACT: Realizing combination drugs at a molecular level via drug-drug cocrystallization opens a new pathway for effective therapeutic hybrids. A “drug-bridge-drug” strategy is developed to cocrystallize two first-line antitubercular drugs isoniazid and pyrazinamide using fumaric acid as the bridge, overcoming the issue of hardly cocrystallizing two different drugs. The first example of ternary cocrystal with combination drugs exhibits optimized formulation capacity and in vitro/vivo synergistic effects, which provides a new insight into antituberculosis combination drugs. Tuberculosis (TB) is a worldwide pandemic caused by the Mycobacterium tuberculosis (MTB). Owing to MTB serious intractability and drug resistant, TB has been a scourge of mankind for thousands of years, and remains a huge number of new cases every year.1 In order to overcome the drug resistance in MTB and ensure effective treatment of the patients, combination drugs, or fixed dose combinations (FDCs), have become necessary.2 Among these FDCs, isoniazid (INH) and pyrazinamide (PZA), as illustrated in Scheme 1a, are two of the first-line anti-tubercular drugs used clinically recommended by world health organization.3 In spite of these traditional FDCs playing important roles in treating TB, they might occur many potential issues. It is mainly because they are usually marketed as physical mixtures formulated, and the parent drugs have markedly different properties, such as solubility, stability, resulting in the pharmacokinetic defects and poor compatibility, limiting clinical appli-cation.4,5 Therefore, it is significant to find new multidrug solid formations to replace these mixture systems.6-7 In this context, structural modification through crystal engineering techniques offers a route to optimize in vitro release and pharmacokinetic properties of active pharma-ceutical ingredients (APIs) without altering the chemical structures and inherent bioactivities of the APIs of interest.8–11 Especially, drug-drug cocrystallization, which could realize combination drugs at a molecular level, presents an alternative method to settle the problems associated with the traditional FDCs.7,12 The new technology has garnered wide attention from both industry and academia, and the first drug-drug cocrystal product has been approved by USFDA in 2015.11 These facts inspired researchers to explore the cocrystallization of INH and PZA for the development of more preponderant antitubercular drugs.13 Since INH and PZA possess similar therapeutic efficacies and the targets in close proximity,2 cocrystallizing them together by crystal engineering techniques might not only diminish the difference in the physico-chemical properties by playing their complementary advantages but also greatly increase the synergetic bactericidal efficacy when they move toward their

targets together. However, unfortunately, cocrystallizing the two drugs into a single crystal directly has so far not been successful.14,15 To gain new insights into antituberculosis combination drugs, we have been engaged in cocrystallizing the two firstline anti-TB drugs by inventive crystal engineering technologies. From the structural point of view, PZA and INH possess multiple sites which have potential hydrogen bonding capacities. The N-containing electron-rich aromatic heterocycle as common features of INH and PZA is one of the best hydrogen-bonding acceptors.16 Moreover, both the amide group of PZA and the hydrazide group of INH also have the abilities to form a variety of hydrogen-bonding motifs in crystals.17,18 With these facts in mind, we attempted to explore a ternary cocrystallization strategy in which a bridge was induced to connect two different APIs into the same crystal lattice in the absence of direct contact between the two APIs. The inserted third component (bridge) should possess two or more hydrogen-bonding sites which are adaptive matched with the APIs to form robust supramolecular synthons, respectively. For that, an intriguing "drug-bridge-drug" ternary cocrystallization strategy was proposed. Indeed, as opposed to binary cocrystals, the design and preparation of ternary cocrystals are a challenging subject.19,20 Thus, the choice of the bridge is the key aspect of this strategy. Since the advantages in structure and drugability, the series of pharmaceutically acceptable aliphatic dicarboxylic acids are the perfect candidates of the bridge to link INH and PZA. Firstly, the

ACS Paragon Plus Environment

Crystal Growth & Design

200 FA INH PZA

180 160

180.1

139.6

140 120

115.9

100 38.4

80

35.1

60

29.3 27.7

22.5

25.0

21.6

40

17.7

7.3 I C NH oc ry sta l PZ A

0

(pH = 6.8)

Scheme 1. (a) Molecular structures of INH, PZA and FA.

(b)

Crystal structure of INH-FA-PZA ternary cocrystal.

carboxylic acid groups of dicarboxylic acids tended to form strong heteromolecular interactions with the two APIs. The interactions, such as acid···pyridine, acid···amide and acid···hydrazine, are verified more competitive and have high occurrence frequency in the Cambridge Structural Database.18 Secondly, the linear structure of aliphatic chain with an absence of steric hindrance groups could effectively avoid the decrease of H−H contact and longer hydrogen bonding contact.21 Thirdly, from the pharma-ceutical viewpoint, screening in the Everything Added to Food in the United States (EAFUS) or Generally Regarded as Safe (GRAS) substances was required to reduce or eliminate the additional risk of negative side effects.9 Along this line, a novel ternary cocrystal formed by INH and PZA with fumaric acid (FA, a model GRAS compound) as the bridge has been identified and presented in Scheme 1b, which is the first example of ternary dual-API cocrystal with combination drugs. The ternary cocrystal reported here was obtained from solvent evaporative crystallization experiments. Structural analysis revealed the cocrystal crystallized in a chiral P21 space group with the asymmetric unit consisting of one molecule of INH, one PZA and two FA molecules (Table S1 and Figure S1). One fumaric acid named tFA has two protons arranged in transoid conformation, but the other one, cFA, has cisoid arrangement protons. As presented in Scheme 1b, the bridge molecule tFA links INH and PZA via robust carboxylic acid-pyridine supramolecular heterosynthon (N6···O5(H5A), 2.603(6) Å; N3···O3(H3A), 2.743(5) Å). And the other bridge, cFA, contributes to a very strong hydrogen bonding heterotrimer by the two carboxylic acid groups connecting with the hydrazide group of INH molecule and the amide group of PZA to form an R22(7), and an R22(8) hydrogen-bonding systems, respectively. Consequentially, these molecules, INH, cFA, PZA and tFA, are arranged alternately to form a one-dimensional zigzag chain

17.3 9.6

8.3

(pH = 4.0)

I C NH oc ry sta l PZ A

20

C INH ocr ys ta l PZ A

Concentration (mg/mL)

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

Page 2 of 6

(pH = 1.2)

Figure 1. Solubility comparisons of PZA, INH and cocrystal in pH buffers 1.2, 4.0 and 6.8.

extending along [3ത 0 1] direction. Furthermore, these zigzag chains connect each other as anti-parallel through the hydrogenbonding (O6···N4(H4A), 2.969(6) Å) connections between INH and tFA molecules, giving rise to a two-dimensional grid parallel to (3 0 1) crystal plane (Scheme 1b). Between the layers, there are left-handed helixes as expected extending along b axis formed by alternate molecules of PZA and tFA (Figure S2), by which, the layers are wavied to a threedimensional network. Interestingly, the whole cocrystal is composed of such two interpenetrating networks (Figure S3), linked with the N-H···O (O2···N4(H4B), 3.178(6) Å) interactions between the hydrazide groups of INH molecules (Table S2). It is noteworthy that, compared with the previously reported ternary cocrystal among equimolar INH, FA and nicotinamide (NA, strongly related to PZA),13 the stoichiometric ratio of the present ternary cocrystal (INH: FA:PZA) is 1:2:1, in which FA molecules played a bridging role as predesigned in the two ways with no hydrogen bond being observed between INH and PZA. The solubilities of the ternary cocrystal were studied in pH buffers 1.2, 4.0 and 6.8 with pure INH and PZA as controls, using the shake-flask method by slurrying the excess amounts of solids in the buffers.22 The solubility data were obtained from HPLC, and the remaining solids were analyzed by PXRD. Figure 1 shows the solubility comparisons of PZA, INH and the cocrystal in the three different pH buffers. As viewed from Figure 1, the solubilities of INH and PZA were observed to increase with decreasing pH. In contrast, the solubility of ternary cocrystal increases with increasing pH values, and reaches a maximum value (91.1 mg/mL) at pH 6.8. This belongs to the pH range of small intestine where most absorption of drugs occurs, providing a basis for favourable bioavail-ability. 23 The overall solubility of the ternary cocrystal was seen as a function of pH, but the constitution proportion of the solubility values of the two APIs from the t e r n a r y Table 1. IDR comparisons of PZA, INH, and cocrystal in pH buffers 1.2, 4.0 and 6.8. Solubility medium

ACS Paragon Plus Environment

IDR (mg⋅min-1) PZA INH

Cocrystal

5.85 5.21 4.88

cocrystal at different pH remains almost constant (pHindependent), and closes to 1:1. Interestingly, the proportion is substantially equal to the stoichiometric ratio of the two APIs in the cocrystal. It indicates that the ternary cocrystal can remain stable in the solutions, further demonstrating by the fact that no phase transformation was monitored by PXRD (Figure S6). More interestingly, it is worthwhile to mention that there is a huge difference of the solubility between pure INH and PZA, suggesting potential issues of compatibility between the two APIs. However, after formation of ternary cocrystal, the solubility of highly water-soluble INH reduces along with the increase of comparatively poorly soluble PZA. Thus, the ternary cocrystal formation diminishes the difference in the solubility of the two APIs, which favours the integrality and synergy of the two APIs. With the purpose of evaluating the kinetic changes in the solubility for the ternary cocrystal, intrinsic dissolu-tion rate (IDR) measurements were further performed in pH buffers 1.2, 4.0, and 6.8 by the rotating disk IDR method at 37 ℃.24 The dissolution profiles are given in Figure S7, and the calculated IDR values at the three pH are listed in Table 1. It can be seen from this table that the IDR values of the cocrystal increase with increasing pH values, and to be contrary in the cases of pure INH and PZA, which is consistent with the thermodynamic changes of their solubility. Notably, although the dissolution rates varied with pH, the IDR values of the cocrystal always located in between pure PZA and INH at all the pH values, and more closed to the pure INH. Particularly, in pH 6.8, the IDR values of the cocrystal improved ca. 7.0-fold over pure PZA, and became comparable to the dissolution rate of pure INH which is recognized as a very highly soluble drug molecular.25 The excellent solubility of both from kinetic and thermodynamic results for the ternary cocrystal may be explained by the fact that INH forms a soluble layer of molecules in the surface of the cocrystal, makes the overall dissolution properties of the ternary cocrystal significantly be improved.26 In addition, the crystal lattice energy and solvation energy may also affect the dissolution rate and solubility.27 These factors lead to the cocrystal releasing quickly. As the high permeability is essential for absorption and delivery of orally administered drugs, the permeability of the cocrystal and the two individual APIs, as well as a physical mixture of equimolar INH and PZA were studied to understand their difference in permeation diffusion behavior, using a Franz diffusion cell in pH 6.8 buffer.28 The plots of flux for the ternary cocrystal and the two individual APIs, together with the cumulative diffused amounts obtained by HPLC at 10 h, are shown in Figures

Figure 2. (a) Plots of flux of PZA, INH, and ternary cocrystal with respect to time in pH 6.8 buffer. (b) Cumulative amount of PZA, INH, mixture and cocrystal diffused at 10 h. 3.0

a

PZA INH FA

PZA Cocrystal INH

2.5

b

10

Cumulative diffused ( mg cm-2)

6.10 6.51 7.39

8

2.0

6 1.5

4 1.0

2

0.5

0.0

0

0

2

4

Time (h)

6

8

10

IN H PZ Co A cr ys t a M l ix tu re

0.84 1.13 1.33

-1

pH 6.8 buffer pH 4.0 buffer pH 1.2 buffer

-

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

Flux diffused (mg cm 2 h )

Page 3 of 6

2a and 2b, respectively. It can be seen from Figure 2a that the plot of the flux displays an initial sharp rise in the absorption of the cocrystal within an hour, after which a high-level steady state relative to INH and PZA was observed. Furthermore, as indicated in Figure 2b, the overall cumulant of cocrystal at 10 h is 7.45 mg·cm-2, which is 2.7 times of INH (2.71 mg·cm-2) and 5.7 times of PZA (1.30 mg·cm-2). These observations indicate that the permeability of cocrystal was much higher than that of both individual INH and PZA. Interestingly, the perme-ability behavior of cocrystal is in sharp contrast with the trend of the solubility that always fell in between the two APIs. The findings of high diffusivity/flux suggest that the ternary cocrystal can stay intact as a whole in the solutions with excellent overall solubility, which generates higher concentration gradients across the membrane, thereby traversing through the membrane more quickly.29 Furthermore, attributing to the strong cyclic hydrogen bonding system of the heterotrimer (Scheme 1b), the strong polar carboxylic, amide and hydrazide groups, which is unfavourable to transit the membrane, are nullified each other. Therefore, the cocrystal entity exhibited a lower polarity relative to the two individual APIs, enhancing the nonpolar membrane permeability when the cocrystal traverses as the whole.28 The integrity of cocrystal entity permeating through the membrane is further confirmed by the fact that the equimolar INH and PZA were determined by HPLC in the receptor chamber. In contrast, the diffused amount of PZA is much lower than that of INH in the case of the physical mixture (Figure 2b). Thereby, it is the ternary cocrystal formation that results in higher concentration gradients and trans-membrane enhancements, increasing the diffusion/-permeability, which lays the foundation for improving the bioavailability of the tenary cocrystal. The pharmacokinetic (PK) properties were evaluated in order to examine the changes of in vivo performance of the ternary cocrystal in comparison with the physical mixture of INH with

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

PZA (equimolar ratio) by oral administration of cocrystal/mixture to Sprague Dawley rats.30 The serum concentration profile is given in Figure S11 and the PK parameters are illustrated in Table 2. It can

Table 2. PK parameters (SD for 5 readings in parentheses). TMAX (h) CMAX (μg⋅mL-1) AUC0-t (μg⋅h⋅mL-1) AUC0-inf (μg⋅h⋅mL-1) FREL T1/2 (h)

INH INH PZA (cocrystal) (in mixture) (cocrystal) 0.50 0.55(0.11) 0.50

PZA (in mixture) 0.95(0.11)

10.34(0.95) 7.31(0.45)

25.53(2.15)

45.10(3.57)

20.92(1.13) 14.14(0.61) 101.93(4.64) 55.21(2.80) 21.25(1.11) 14.74(0.52) 112.05(5.16) 56.76(3.38)

1.48 -/1.02(0.07) 1.03(0.08)

1.85 1.75(0.20)

-/1.02(0.20)

be found that the CMAX and AUC of INH in the ternary cocrystal are 1.41-fold and 1.48-fold higher than in the physical mixture, respectively. Similarly, for the case of PZA, the CMAX and the AUC are 1.77-fold higher and 1.85-fold higher in the cocrystal than in the mixture. In addition, it is noteworthy that, after the formation of cocrystal, the TMAX of PZA was advanced from 0.95 to 0.50 h, and the T1/2 was delayed from 1.02 to 1.75 h. These results illustrate that the cocrystallization accelerates the absorption, and slows the elimination of PZA, suggesting a faster onset time and a longer duration of PZA in the cocrystal. More importantly, due to the accelerated absorption of PZA through cocrystallization, the TMAX difference between PZA and INH (Table 2) was diminished, indicating that the cocrystallization can bring a better synergistic effect between INH and PZA. The simultaneous and high plasma concentration of the two APIs is vital to kill MTB and minimize resistance. Thus, the ternary cocrystal displayed an improved PK properties compared with the corresponding physical mixture, implying a promising advantage of clinical effects. In conclusion, a “drug-bridge-drug” strategy was developed to overcome the challenges of cocrystallizing two APIs being difficult to cocrystallize directly. As a result, INH and PZA were successfully connected into the same crystal lattice with the GRAS status FA as the bridge based on this strategy. It is the first example of ternary dual-API cocrystal with combination drugs, which was subjected to aqueous solubility/dissolution and mem-brane permeability as well as in vivo PK properties to predict the enabled clinical efficacy of the cocrystal drug. The results highlighted that the cocrystal drug exhibited optimized formulation capacity and in vitro/vivo synergistic effects. The present studies not only open new avenues of effective therapeutic hybrids for TB but also provide new insight into the design of some drug combination systems with similar therapeutic efficacies and/or with targets in close proximity.

ASSOCIATED CONTENT Supporting Information. Experimental, spectro scopic, and crystallographic details. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENT We thank the NSFC-Shandong Joint Fund for Marine Science Research Centers (grant no U1606403).

REFERENCES (1) Dye, C. The Lancet 2006, 367, 938-940. (2) Blomberg, B.; Spinaci, S.; Fourie, B.; Laing, R. Bull. World Health Organ. 2001, 79, 61-68. (3) Cavalcante, S. World Health Organ. Geneva 2010. (4)Bangalore, S.; Kamalakkannan, G.; Parkar, S.; Messerli, F. H. Am. J. Med. 2007, 120, 713-719. (5) Sica, D. A. Drugs 2002, 62, 443-462. (6) Simon, F. Nat. Rev. Drug Discov. 2006, 5, 881-883. (7) Wang, J.-R.; Yu, Q.; Dai, W.; Mei, X. Chem. Commun. 2016, 52, 3572-3575. (8) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335-13342. (9) Bolla, G.; Nangia, A. Chem. Commun. 2016, 52, 8342-8360. (10) Ross, S. A.; Lamprou, D. A.; Douroumis, D. Chem. Commun. 2016, 52, 8772-8786. (11)K. Duggirala, N.; L. Perry, M.; Almarsson, Ö.; J. Zaworotko, M. Chem. Commun. 2016, 52, 640-655. (12)Thipparaboina, R.; Kumar, D.; Chavan, R. B.; Shastri, N. R. Drug Discov. Today 2016, 21, 481-490. (13)Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2013, 15, 5877-5887. (14)Cherukuvada, S.; Nangia, A. CrystEngComm 2012, 14, 2579-2588. (15)Wang, J.-R.; Bao, J.; Fan, X.; Dai, W.; Mei, X. Chem. Commun. 2016, 52, 13452-13455. (16)Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem. Int. Ed. 2001, 40, 3240-3242. (17) Sarcevica, I.; Orola, L.; Veidis, M. V.; Podjava, A.; Belyakov, S. Cryst. Growth Des. 2013, 13, 1082-1090. (18) Wang, J.-R.; Ye, C.; Zhu, B.; Zhou, C.; Mei, X. CrystEngComm 2015, 17, 747-752. (19) Tothadi, S.; Desiraju, G. R. Chem. Commun. 2013, 49, 7791-7793. (20) Bolla, G.; Nangia, A. Chem. Commun. 2015, 51, 15578-15581. (21) Luo, Y.-H.; Sun, B.-W. Cryst. Growth Des. 2013, 13, 2098-2106. (22) Glomme, A.; März, J.; Dressman, J. B. J. Pharm. Sci. 2005, 94, 1-16. (23)Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Mol. Pharm. 2016, 13, 3590-3594. (24) Lawrence, X. Y.; Carlin, A. S.; Amidon, G. L.; Hussain, A. S. Int. J. Pharm. 2004, 270, 221-227. (25) Becker, C.; Dressman, J. B.; Junginger, H. E.; Kopp, S.; Midha, K. K.; Shah, V. P.; Stavchansky, S.; Barends, D. M. J. Pharm. Sci. 2009, 98, 2252-2267. (26) Almansa, C.; Mercè, R.; Tesson, N.; Farran, J.; Tomàs, J.; Plata-Salamán, C. R. Cryst. Growth Des. 2017, 17, 1884-1892. (27) Yang, Q.; Ren, T.; Yang, S.; Li, X.; Chi, Y.; Yang, Y.; Gu, J.; Hu, C. Cryst. Growth Des. 2016, 16 (10), 60606068. (28) Sanphui, P.; Devi, V. K.; Clara, D.; Malviya, N.; Ganguly, S.; Desiraju, G. R. Mol. Pharm. 2015, 12, 16151622.

ACS Paragon Plus Environment

Page 4 of 6

Page 5 of 6 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

(29) Moser, K.; Kriwet, K.; Froehlich, C.; Naik, A.; Kalia, Y. N.; Guy, R. H. J. Pharm. Sci. 2001, 90, 607-616. (30) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharm. 2011, 8, 1867-1876.

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

Page 6 of 6

For Table of Contents Use Only

Drug-bridge-drug ternary cocrystallization strategy for anti-tuberculosis drugs combination Fang Liu,a Yu Song,a Ya-Nan Liu,a Yan-Tuan Li,∗ab Zhi-Yong Wu∗a and Cui-Wei Yan∗c a.

School of Medicine and Pharmacy, Ocean University of China, 266003, PR China. E-mail: [email protected] Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, 266003, PR China. c. College of Marine Life Science, Ocean University of China, Qingdao, 266003, PR China. b.

TOC Graphic

Synopsis A “drug-bridge-drug” strategy was developed to overcome the issue of hardly cocrystallizing two different drugs. As a result, two antituberculotics isoniazid and pyrazinamide were successfully connected into the same crystal lattice with the GRAS status fumaric acid as the bridge based on this strategy. This ternary dual-drug cocrystal exhibited optimized formulation capacity and in vitro/vivo synergistic effects.

ACS Paragon Plus Environment

6