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A drug-drug salt hydrate of norfloxacin and sulfathiazole: Enhancement of in vitro biological properties via improved physicochemical properties Shanmukha Prasad Gopi, Somnath Ganguly, and Gautam R. Desiraju Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00320 • Publication Date (Web): 31 Aug 2016 Downloaded from http://pubs.acs.org on September 1, 2016

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Molecular Pharmaceutics

A drug-drug salt hydrate of norfloxacin and sulfathiazole: Enhancement of in vitro biological properties via improved physicochemical properties Shanmukha Prasad Gopi, Somnath Ganguly and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India

Abstract A new multi-component solid consisting of an antibacterial (norfloxacin) and an antimicrobial (sulfathiazole) was made and characterised with single crystal X-ray diffraction, PXRD, FTIR and DSC. The title salt shows enhanced solubility in different pH buffers and improved diffusion as well as release and inhibition of bacterial and fungal species relative to the parent drugs. The enhanced in vitro biological properties of the drug-drug salt hydrate may be attributed to the higher extent of its supersaturation with respect to the individual components, which leads to higher diffusion rates.

Key words: solid form, solubility, permeability, antibacterial, antimicrobial, crystal engineering.

Physicochemical profiles of lead compounds depend on basic structural principles of medicinal chemistry.1,2 Improvement of in vitro activity is generally achieved by incorporating lipophilic groups. Inevitably a number of leads have poor solubility.3,4 To increase the solubility of lipophilic compounds various formulation techniques are employed.5 Pharmaceutical salts and cocrystals, made with coformers, have also become important.6-8 These multi-component solids show enhanced solubility, release and bioavailability relative to the parent drugs. A natural and practical extension of such a strategy would be to substitute the coformer with another drug in the same therapeutic area9-11 (combination therapy) to obtain a synergism of the physicochemical properties. Bacteria are the cause of some of the most deadly diseases and widespread epidemics in human civilization. Bacterial infections, with complications of drug resistance from increased antibiotic use, have increased dramatically in recent times.12 Drug resistant strains, such as vancomycin-resistant enterococci (VRE) and multidrug1 ACS Paragon Plus Environment


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resistant staphylococcus aureus (MRSA), are capable of surviving the effects of most, if not all, currently used antibiotics.13,14 So, attention has shifted to developing new antimicrobial drug combinations.15,16 The fluoroquinolones17,18 are a family of broad−spectrum systemic antibacterial agents that have been used in respiratory and urinary tract infections and are active against a wide range of aerobic gram-positive and gram-negative organisms. Norfloxacin is a nalidixic acid analogue and one of the most potent DNA gyrase inhibitors. Generally, it is taken with antimicrobials like sulfonamides to treat mixed infections and to reduce resistance.19,20 These mixed drug systems are usually marketed as physical mixtures formulated by the use of binders. However, the components of such mixtures could well have very different physicochemical properties that could result in inferior biological activity.21 Cocrystals and salts of fluoroquinolones22,23 and sulfonamides24 might be an answer to compromised physicochemical and biological properties of these marketed physical mixtures. Although pharmaceutical cocrystals and salts have been studied extensively,25-27 only limited work has been done in the area of crystal engineered multidrug systems with regard to their physicochemical properties. In this communication, we use the concepts of pharmaceutical crystal engineering to design a new dual drug system, namely the antibacterial/antimicrobial salt combination of norfloxacin28 (BCS class IV) and sulfathiazole29 (BCS class II), hereafter NF and ST, and have studied its physicochemical properties. Biological property evaluation of the salt with respect to inhibition behavior of bacterial as well as fungal species is reported. It must be noted here that enhancement of properties (solubility, dissolution kinetics, bioavailability, pharmaceutical activity) is a reality in several salts and cocrystals as compared to the native drugs.7,8 Efficacy as a drug depends on events that take place in solution or at solution-membrane interfaces. To summarize, there cannot be a black and white distinction between the crystal and the solution, for if this were the case, cocrystals would have exactly the same pharmaceutical effects as mixtures of the relevant compounds—and this is clearly not the case in many situations, such as the one described in this communication. The title salt hydrate was prepared by taking 100 mg NF (0.31 m mol) and 79.14 mg ST (0.31 m mol) in a mortar and pestle and performing liquid assisted grinding with 5

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ml EtOH for about 15 minutes followed by crystallization from the same solvent at ambient temperature. Well-formed block shaped crystals (P1, Z=2) of the 1:1:1 NF⋅ST⋅H2O salt monohydrate appeared after a few days. MeOH and MeCN solvates of NF−ST are reported in the SI (Figure S1, S2, Table S1, Supporting Information). The asymmetric unit contains one molecule each of the drugs NF and ST along with a disordered water molecule. A heterodimer is formed between ST and NF through proton transfer from the N−H group of the sulfonamide groupST to the piperazinyl group of NF (Figure 1). Such dimers form chains via N−H⋅⋅⋅O hydrogen bonds (aniline of ST to carboxyl group of NF), which make a sheet-like structure through auxiliary interactions involving N−H⋅⋅⋅O, C–H⋅⋅⋅F and C−H⋅⋅⋅O bonds. Successive sheets make channels for disordered water molecules (sustained by O−H⋅⋅⋅O and C−H⋅⋅⋅O interactions) along the baxis. Water molecule(s) are disordered about inversion centers and bind with the carbonyl group of NF. (Figure S3 SI).

Figure1. Structure of the NF−ST salt hydrate: (a) interactions/chains of NF and ST; (b) packing diagram to show water channels. Differential scanning calorimetry (DSC) of the salt shows a sharp melting endotherm at 176−178 °C (Figure S4 SI) indicating a single homogeneous phase of the drug-drug salt. Generally, desolvation takes place before or at the boiling point of the



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solvent, well before melting of the solvate. Nevertheless, a hydrate/solvate exhibiting desolvation at the melting point is not unusual.30-32 The melting point shows a shift downwards from the melting points of the parent drugs; the lower melting point of salt may be due to weaker electrostatic, hydrogen bonding and other interactions. Thermogravimetric analysis (TGA) indicates a monohydrate NF−ST salt and shows water loss at the same temperature as the DSC melting endotherm (Figure S4 SI). The FTIR spectrum (Figure S5 SI) of the salt hydrate shows bands at 1450 cm-1 (ω, strong), 745 cm1

(r, medium) and the characteristic stretching band at 3600 cm-1 due to the NH2+ ion of

the salt.33 Solubility is an important pre-formulation property that has a direct impact on the absorption of orally administered drugs. There are numerous methods used to improve the solubility of poorly soluble drugs and among these, salt formation is the most common in industry because of the high solubility and purity of salts. It is also known that solubility varies as a function of pH.34 In our solubility studies, we conducted extensive experiments using the traditional shake-flask method35 to understand the effect of pH on the solubility behaviour of the parent drugs NF, ST and the NF−ST salt. These studies were carried out in pH buffers 1.2, 4.0 and 7.4 in addition to a cosolvent system (ethanol−buffer) (Figure 2).


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Figure 2. Solubility comparisons of NF, ST and NF−ST salt hydrate in (a) pH 7.4 buffer (b) pH 4.0 buffer (c) pH 1.2 buffer and (d) Cosolvent medium (10% EtOH−pH 7.4 buffer). NF (green), ST (purple) and water (orange) are plotted according to their molar equivalents in NF−ST−H2O (54:43:3). At pH 7.4 the salt hydrate showed a large enhancement in the overall solubility (1362 mg/L) with molar equivalent solubility enhancement being 4x for NF (736 mg/L vs. 178 mg/L of pure NF). A marginal decrease was seen for ST (586 mg/L) compared to its original solubility value (703 mg/L, Figure 2a). At pH 4.0, the overall solubility of the salt is 1198 mg/L, which is slightly lower than at pH 7.4 (Figure 2b). However, in this case, both NF and ST show comparable solubilities, namely NF 3x (647 mg/L vs. 221 mg/L) and ST 1.7x ST (515 mg/L vs. 316 mg/L). At acidic pH 1.2, which corresponds to a fasting state of the stomach (Figure 2c) both components are highly soluble as might be expected and the values are presented in Table S3 of the SI. However, whether a drug is acidic or basic, most of its absorption occurs in the small intestine36 (pH 6−8), and hence the solubility at pH 7.4 is more relevant. In summary, the enhancement of solubility is due to salt formation between the two drugs as typically seen for pharmaceuticals,37,38 5 ACS Paragon Plus Environment


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rather than some pH effect. We also have studied the effect of ethanol cosolvent on the solubilities of the salt and the parent compounds. Systems like ethanol−buffer are used to test the solubilities of poorly soluble compounds.39 The effect of ethanol cosolvent is to cause a large increase in the solubility of the salt (6166 mg/L) in which NF has 12x (3329 mg/L vs. 513 mg/L) and ST about 1.5x (2651 mg/L vs. 1715 mg/L) enhancements (Figure 2d). In vitro absorption of molecules is estimated with permeability measurements, in other words by passive diffusion through non-living systems. In this study, we used a Franz diffusion cell with 0.45 µ cellulose nitrate membranes to compare the diffusion of solutions of salt hydrate crystals vis-à-vis solutions of the parent drugs (Figure 3). The curve shows a single and steep diffusion curve for the binary salt. The cumulative amount of material diffusing through the membrane increases rapidly in the first hour after which it tapers off and after 5 hours another small increase is noticed. In contrast, the parent molecules show much lower diffusion. Diffusion curves for NF and ST are distinct for a solution of a physical mixture of the two compounds, indicating different rates of diffusion/permeation across the barrier. For the salt solution, however, NF and ST diffuse together (as observed by HPLC). In the case of the solution of the physical mixture, only ST diffuses for all practical purposes. No diffusion is seen for NF and this is observed at a gross level by the physical appearance of a light yellow powder (NF) in the donor chamber. The analyte too does not show any peak corresponding to NF. The enhanced solubility of the salt hydrate and the improved diffusion of the dissolved material is indicative of an easier passage through bacterial fluids and cells compared to the solution of the physical mixture. The higher solubility of the drug-drug salt is consistent with its lower melting point. Given the data in Figure 3, and the other data obtained (and depending on pH), one may say that the drug-drug salt clearly dissolves to give a solution has a higher concentration with respect to each compound, relative to the respective crystalline forms taken separately (or a physical mixture thereof). Hence, the solution formed upon dissolution of the drug-drug salt is supersaturated with respect to each of the crystal forms, since complexation seems to be ruled out by the lack of solubility increase in a physical mixture of crystalline forms. Supersaturated solutions are well known to have higher diffusion rates as compared to their saturated counterparts,40 and this would appear to rationalize our experimental observations. In summary,


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the enhanced flux may be explained by the formation of a solution that is supersaturated with respect to both species.

Figure 3. (a) Cumulative amount of NF, ST and the salt diffused vs time plot (b) Plots of flux of the salt with respect to time in pH 7.4 buffer

In order to test the potency of the salt hydrate, the compounds (physical mixture, represented hereafter as P.M. and salt) were assayed (using in vitro studies) on antibacterial and antifungal species of pathogenic bacteria Escherichia coli (ATCC 25922, hereafter E. coli), Staphylococcus aureus (ATCC 29213, hereafter S. aureus) and fungi (Aspergillus). Table S4 shows the pathogens/micro organism counts on an E. coli strain that was subjected to a solution containing a mixture of NF and ST and its salt at a concentration of 1 mg/ml. The inhibition of the salt and the P.M. on bacterial and fungal strains were compared. In the case of the P.M., broad growth of E. coli was noticed at 0.8 µg/ml, (MIC 1.6 µg/ml) whereas in the salt it was observed at 0.4 µg/ml (MIC 0.8 µg/ml, Table S4 SI). The MIC of the NF−ST P.M. matched with the reported MIC values of NF (0.3 – 0.12 µg/ml)41,42 which also indicates that ST in the mixture does not have any additional impact on inhibition of E. coli by NF (The IR spectra of P.M. in solution confirms the presence of both drugs and their quantitative amounts were evaluated using HPLC (Figure S5(f) S9 SI). This study was supplemented with the disc diffusion technique of inhibition zones of the P.M. and salt (Figure S7 SI). The radius of the zone



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of inhibition (ZOI) for E. coli was about 10±1 mm at 50 µg/ml and decreases at lower concentrations to 4±1 mm at 0.4 µg/ml (Figure S7 (c, d)). The radius of the ZOI for the P.M. was 2 mm at 0.8 µg/ml and for the salt it was 8 mm (Figure S7 (a-d)). Similarly, the compounds were tested against S. aureus gram-positive strain at a concentration of 1.8 µg/ml (Figure S7 (e-h)). A decreased MIC value was noticed for the salt compared to the P.M. (MIC for P.M. was 3.1 µg/ml and 1.6 µg/ml for the salt, Table S5 SI). The ZOI was about 5±1 mm at 1.6 µg/ml for the salt whereas there was no clear ZOI at this concentration for the P.M. (Figure S7 (e,f) SI). In vitro studies on gram-positive and gram-negative bacteria indicated that in the salt form MIC was observed on both bacteria at half the MIC of the P.M. This may arise from enhanced solubility and diffusion. The above results clearly indicate better inhibition effects from the salt compared to the P.M. Details are given in the SI. The increased inhibition might also have resulted from the faster release (intrinsic dissolution rate) of NF in the salt form compared to pure NF (Figure S8 SI). What is important is the simultaneous presence of both drugs at the site of action. This is unlikely in the P.M.s because the difference in solubilities of the individual components is very high. The effect of antimicrobial property of NF−ST salt was tested against an aspergillus strain using the disk diffusion method. Figure S7 (SI) depicts the disk of the antimicrobial activity of the salt and its P.M. against concentration of 2.2 mg/ml (a P.M. of 2.2 mg/ml contains NF and ST in equimolar ratio NF:ST as 1.2:1.0 mg same for the salt). Fungal growth was seen for the P.M. at the concentration of 20 µg/ml (ZOI 4±1 mm) but in the case of salt an inhibition zone was noticed even at 5 µg/ml (disk 2) with the ZOI at about 3±1 mm which increased to over 10±1 mm at higher concentrations (Figure S7 SI). In brief, antibacterial and antifungal studies showed a significant synergistic effect with inhibition by both NF and ST ions in the salt. The molar contribution solubility of both the drugs in salt form as well as the P.M. was determined with HPLC. The quantification of drugs (salt and P.M.) was carried out by comparing HPLC peak areas with that of the standards. The retention times of standard aqueous solutions of NF and ST were found to be 4.1 and 2.4 minutes respectively (Table S6 SI). It was found that both NF and ST contributed in nearly equimolar ratios (48:52) in the salt solution. However, only 44% of NF contribution to solubility was noticed in the 8 ACS Paragon Plus Environment

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P.M. solution due to its poor solubility compared to ST (the P.M. had to be stirred for about 24 h and slightly warmed to dissolve the components whereas the salt was freely soluble in 5−10 min at room temperature). In the P.M. a mild suspension/precipitate was noticed over time whereas no such suspension was seen in the salt solution. The P.M. sample was further quantified by HPLC and it was seen that the ratio of NF dropped to 36% (Table S6 SI). It is possible that the inhibition by NF will reduce with time in the P.M. or in the pure form. The respective HPLC spectra and method details are provided in the SI (Figure S9 SI).

That the initial solubilities of cocrystal/salt systems are higher than those of the individual components is an actively researched topic today and there are different models for the species which are held in the supersaturated solutions involved.43-46 In this context, the improved physicochemical properties of the NF-ST salt hydrate may be rationalized on the basis of higher supersaturation levels of the salt as compared to the individual components or a physical mixture thereof, at the pH of the experiment. The improved permeability of NF effectively leads to an enhancement of overall biological activity.

In summary, a novel salt hydrate of norfloxacin and sulfathiazole has been prepared using crystal engineering methods. The antibacterial/antimicrobial combination salt exhibits solubility enhancements in different pH buffers and also in a cosolvent system. A high single diffusion rate is seen for the salt compared to independent diffusion behaviour seen in a physical mixture of the two drugs. The salt shows enhanced inhibition of bacterial and fungal strains, which is a result of joint diffusion and increased solubility. Such new multidrug systems are expected to open up new directions in multidrug or combination therapeutics.

Supporting Information Available SCXRD, PXRD, DSC, TGA, FT-IR, HPLC, and in vitro inhibition data of the NF−ST salt hydrate, SCXRD data and experimental procedures of NF−ST salt solvates. This material is available free of charge via the Internet at http://pubs.acs.org 9 ACS Paragon Plus Environment


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Author information Corresponding author *Fax: +91 80 23602306. Tel.: +91 80 22933311. E-mail: [email protected] Acknowledgements S.P.G. thanks the University Grants Commission for a Dr. D. S. Kothari Fellowship. S.G. thanks IISc for a fellowship. G.R.D. thanks the Department of Science and Technology for a J. C. Bose Fellowship. The authors are grateful to Dr. S. G. Ramachandra, Ms. M. Shruthi Central Animal Facility, IISc and Dr. S. T. Girisha, Mr. V. Girish, Dept. of Microbiology & Biotechnology, Bangalore University for their help with biological studies.

References (1) Lionta, E.; Spyrou G.; Vassilatis D. K.; Cournia, Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem. 2014, 14, 1923−1938. (2) Cumming, J. G.; Davis, A. M.; Muresan, S.; Haeberlei, M.; Chen, H. Chemical predictive modelling to improve compound quality. Nat. Rev. Drug Discov. 2013, 12, 948−962. (3) Avdeef, A. Absorption and drug development: solubility, permeability, and charge state, John Wiley & Sons, Inc., 2nd Edition, 2012. (4) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46, 3−26. (5) Leuner, C.; Dressman, Improving drug solubility for oral delivery using solid dispersions. J. Eur. J. Pharm. Biopharm. 2000, 50, 47−60. (6) Stahl, P. H.; Wermuth, C. G. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Wiley-VCH: New York, 2002. (7) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju, G. R. Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt. Mol. Pharmaceutics 2013, 10, 4687−4697.


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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


(8) Rajput, L.; Sanphui, P.; Desiraju, G. R. New solid forms of the anti-HIV drug etravirine: salts, cocrystals, and solubility. Cryst. Growth Des. 2013, 13, 3681−3690. (9) Bhatt, P. M.; Azim, Y.; Thakur, T. S.; Desiraju, G. R. Co-crystals of the anti-HIV drugs lamivudine and zidovudine. Cryst. Growth Des. 2009, 9, 951−957. (10) Grobelny, P.; Mukherjee, A.; Desiraju, G. R. Drug-drug co-crystals: temperature-dependent proton mobility in the molecular complex of isoniazid with 4-aminosalicylic acid. CrystEngComm 2011, 13, 4358−4364. (11) Thorat, S. H.; Sahu, S. K.; Patwadkar M. V.; Badiger, M.; Gonnade, R. G. Drug-drug molecular salt hydrate of an anticancer drug gefitinib and a loop diuretic drug furosemide: an alternative for multidrug treatment. J. Pharm. Sci. 2015, 104, 4207−4216 (12) Fair, R. J.; tor, Y. antibiotics and bacterial resistance in the 21st century. Perspect Medicin Chem. 2014, 6, 25−64. (13) Carlet, J.; Jarlier, V.; Harbarth, S.; Voss, A.; Goossens, H.; Pittet, D. Ready for a world without antibiotics? the pensières antibiotic resistance call to action. Antimicrob. Resist. Infect. Control 2012, 11, 1−13. (14) Alekshun, M. N.; Levy, S. B. Molecular mechanisms of antibacterial multidrug resistance. Cell 2007, 128, 1037−1050. (15) Tamma, P. D.; Cosgrove, S. E.; Maragakis, L. L. Combination therapy for treatment of infections with gram-negative bacteria. Clin. Microbiol. Rev. 2016, 29, 450−470. (16) Cottarel, G.; Wierzbowski, J. Combination drugs, an emerging option for antibacterial therapy. Trends Biotechnol. 2007, 25, 547−555. (17) Andriole, V. T. The Quinolones, Academic Press, 1989. (18) Andersson, M. I.; MacGowan, A. P. Development of the quinolones. J. Antimicrob. Chemother. 2003, 51, 1−11. (19) Alangaden, G. J.; Bone, S. A. The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. Clin. Infect Dis. 1997, 25, 1213−1221. (20) Parenteral composition comprising a fluoroquinolone compound and a nitroimidazole compound. WO 2010146478 A1, Ranbaxy Laboratories Limited, May 8, 2010. (21) Frantz, S. The trouble with making combination drugs. Nat. Rev. Drug Discov. 2006, 5, 881−882.



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

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(22) Basavoju, S.; Bostrom, D.; Velaga, S. P. Pharmaceutical cocrystal and salts of norfloxacin.

Cryst. Growth Des. 2006, 6, 2699–2708. (23) Huang, X. F.; Zhang, Z. H.; Zhang, Q. Q.; Wang, L. Z.; He, M. Y.; Chen, Q.; Song, G. Q.; Wei, L.; Wang, F.; Du, M. Norfloxacin salts with benzenedicarboxylic acids: chargeassisted hydrogen-bonding recognition and solubility regulation. CrystEngComm 2013, 15, 6090–6100. (24) Caira, M. R. Sulfa drugs as model cocrystal formers. Mol Pharmaceutics 2007, 4, 310−316. (25) Wouters, J.; Quéré, L. Pharmaceutical salts and co-crystals. RSC Drug Discovery Series No. 16, 2012. (26) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640−655. (27) Good, D. J.; Rodrigez-Hornedo, N. Solubility advantage of pharmaceutical cocrystals. Cryst. Growth Des. 2009, 9, 2252−2264. (28) Breda, S. A.; Jimenez-Kairuz, A. F.; Manzo, R. H.; Olivera, M.E.; Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives. J. Pharm. Sci. 2009, 371,106–113. (29) Chiou, W. L.; Chen, S. J.; Athanikar, N. Enhancement of dissolution rates of poorly watersoluble drugs by crystallization in aqueous surfactant solutions I: sulfathiazole, prednisone, and chloramphenicol. J. Pharm. Sci. 1976, 65, 1702–1704. (30) Campeta, A.M.; Chekal, B. P.; Abramov, Y. A.; Meenan, P. A.; Henson, M. J.; Shi, B.; Singer, R. A.; Horspool, K. R. Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API. J. Pharm. Sci. 2010, 99, 3874−3886. (31) Clarke, H. D.; Arora, K. K.; Bass, H.; Kavuru, P.; Ong, T. T.; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Structure−stability relationships in cocrystal hydrates: does the promiscuity of water make crystalline hydrates the nemesis of crystal engineering?. Cryst. Growth Des. 2010, 10, 2152–2167. (32) Cherukuvada, S.; Babu, S. N.; Nangia, A. Nitrofurantoin–p-aminobenzoic acid cocrystal: hydration stability and dissolution rate studies. J. Pharm. Sci. 2011, 100, 3233–3244. (33) Zeegers-Huyskens, T.; Bator, G. Fourier-transform infrared and fourier-transform raman investigation of alkylammonium hexachloroantimonates. Vib. Spectrosc. 1996, 13, 41−49.


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(34) Avdeef, A. Solubility of sparingly-soluble ionizable drugs. Adv Drug Deliv Rev. 2007, 9, 568–590. (35) Glomme, A.; Marz, J.; Dressman, J. B. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities. J. Pharm. Sci. 2005, 94, 1−16. (36) Washington, N.; Washington, C.; Wilson, C. Physiological pharmaceutics: Barriers to drug absorption, 2nd ed. CRC Press, 2001, p. 82. (37) Corrigan, O. I. Salt Forms: pharmaceutical aspects. In encyclopedia of pharmaceutical technology, 2nd ed.; Swarbrick, J.; Boylan, J. C. Eds.; Marcel Dekker: New York, 2002 (38) Serajuddin, A. T. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007, 59, 603−616. (39) Fagerberg, J. H.; Al-Tikriti, Y.; Ragnarsson, G.; Bergström, C. A. S. ethanol effects on apparent solubility of poorly soluble drugs in simulated intestinal fluid. Mol. Pharmaceutics 2012, 9, 1942−1952. (40) Moser, K.; Kriwet, K.; Froehlich, C.; Naik, A.; Kalia, Y. N.; Guy, R. H. Permeation enhancement of a highly lipophilic drug using supersaturated systems, J. Pharm.Sci. 2001, 90, 607−616. (41) Tenney, J. H.; Maack, R. W.; Chippendale, G. R. Rapid selection of organisms with increasing resistance on subinhibitory concentrations of norfloxacin in agar. Antimicrob. Agents Chemother. 1983, 23, 188−190. (42) Andrews, J. M. Determination of minimum inhibitory concentrations. Antimicrob. Agents Chemother. 2001, 48, 5−16. (43) Guzman, H. R.; Tawa, M.; Zhang, Z.; Ratanabanangkoon, P.; Shaw, P.; Gardner, C. L.; Chen, H.; Moreau, J.-P.; Almarsson, Ö.; Remenar, J. F. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J. Pharm. Sci. 2007, 96, 2686−2702. (44) Brouwers, J.; Brewster, M. E.; Augustijns, P. Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability? J. Pharm. Sci. 2009, 98, 2549−2572. (45) Babu, N. J.; Nangia, A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst. Growth Des. 2011, 11, 2662−2679.



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(46) Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Cocrystal and salt forms of furosemide: solubility and diffusion variations. Cryst. Growth Des. 2016, ASAP.

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A drug-drug salt hydrate of norfloxacin and sulfathiazole: Enhancement of in vitro biological properties via improved physicochemical properties Shanmukha Prasad Gopi, Somnath Ganguly and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India


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TOC 89x35mm (150 x 150 DPI)

ACS Paragon Plus Environment


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A DrugâDrug Salt Hydrate of Norfloxacin and ... - ACS Publications

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