Differential Cocrystallization Behavior of Isomeric Pyridine

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Differential Cocrystallization behavior of isomeric pyridine carboxamides toward anti-tubercular drug Pyrazinoic acid Tayur Narasingarao Guru Row Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg501642m • Publication Date (Web): 22 Dec 2014 Downloaded from http://pubs.acs.org on January 8, 2015

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Differential Cocrystallization behavior of isomeric pyridine carboxamides toward anti-tubercular drug Pyrazinoic acid

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Crystal Growth & Design cg-2014-01642m.R1 Article 18-Dec-2014 Karothu, Durga; Indian Institute of Science, SSCU Cherukuvada, Suryanarayan; Indian Institute of Science, Solid State and Structural Chemistry Unit Ganduri, Ramesh; Indian Institute of Science, SSCU Stephen, Lazor; Gandhigram Rural University, Chemistry Perumalla, Sravankumar; Indian Institute of Science, IPC Guru Row, Tayur; Indian Institute of Science, Solid State and structural Chemistry Unit

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Differential Cocrystallization behavior of isomeric carboxamides toward anti-tubercular drug Pyrazinoic acid

pyridine

Karothu Durga Prasad,a Suryanarayan Cherukuvada,a Ramesh Ganduri,a L. Devaraj Stephen,b Sravankumar Perumalla,c and Tayur N. Guru Rowa* a

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India b Department of Chemistry, SRM Valliammai Engineering College, Chennai 603203, India c Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bengaluru 560012, India * Email: [email protected] ABSTRACT: Pyrazinoic acid, the active form of the anti-tubercular pro-drug Pyrazinamide, is an amphiprotic molecule containing carboxylic acid and pyridine groups and therefore can form both salts and cocrystals with relevant partner molecules. Cocrystallization of pyrazinoic acid with isomeric pyridine carboxamide series resulted in a dimorphic mixed-ionic complex with isonicotinamide and in eutectics with nicotinamide and picolinamide respectively. It is observed that with alteration of carboxamide position, steric and electrostatic compatibility issues between molecules of the combination emerge and affect intermolecular interactions and supramolecular growth, thus leading to either cocrystal or eutectic for different pyrazinoic acid-pyridine carboxamide combinations. Intermolecular interaction energy calculations have been performed to understand the role of underlying energetics on the formation of cocrystal/eutectic in different combinations. On the other hand, two molecular salts with piperazine and cytosine and a gallic acid cocrystal of the drug were obtained and their Xray crystal structures were also determined in this work. INTRODUCTION Pyrazinoic acid (also called Pyrazinecarboxylic acid or Pyrazinic acid; abbreviated as POA; Figure 1) is the active form of the pro-drug Pyrazinamide which is one of the frontline drugs used in the treatment of tuberculosis.1 POA is an amphiprotic molecule and therefore can exist both in ionized and unionized forms. The two known polymorphs of it manifest in an unionized state2 leaving a possibility for a zwitterionic polymorph3 upon solid form screening. Investigations on various supramolecular solid forms have become important for organic compounds in general and drugs in specific from both fundamental and application aspects.4 New polymorphs, amorphous forms, salts, cocrystals, eutectics etc. are of particular interest to modulate the physico-chemical properties of the compound of interest and achieve desired properties.4,5 An ionizable molecule can combine with different partners to form a salt/molecular salt, cocrystal or even salt cocrystal.5f,6 Further, based on the pKa difference between the molecules, a salt-cocrystal continuum6b,d,7 can manifest which is an interesting topic to understand the role of functional groups in affecting the nature of hydrogen bond. This is important because the nature of hydrogen bond can dictate the functional properties of a material4a,c,5e,g,6c,7a,8 and therefore the study of salts and cocrystals of a compound is necessary towards property 1 ACS Paragon Plus Environment


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modulation in desired lines. In the present case, the pro-drug Pyrazinamide, being the marketed drug form, was well explored7c,9 but the active Pyrazinoic acid did not receive proper attention in terms of supramolecular solid form diversity. POA, of its carboxylic acid and pyridine groups, is amenable to both salt and cocrystal formation. Further, it makes a good model system to study the formation of cocrystal and eutectic as the two alternatives of a cocrystallization experiment.5h In continuation of recent efforts from our group to comprehend the cocrystallization phenomenon and reliably make cocrystals and eutectics,10 POA was subjected to cocrystallization with isomeric pyridine carboxamides (Figure 1) in this study. Our notion is that with variation in the position of carboxamide functionality in different combinations, intermolecular interactions and packing between the molecules should vary and lead to differential supramolecular growth to give rise to either a cocrystal or a eutectic. When there is steric fit and energetic advantage for heteromolecular interactions in a particular combination, supramolecular growth can happen as a cocrystal or as a eutectic in case of steric misfit in heteromolecular interactions and packing.5h,10 POA formed a dimorphic cocrystal with isonicotinamide and eutectics with nicotinamide and picolinamide respectively. Intermolecular interaction energy computations were performed to rationalize the formation of cocrystal/eutectic for the combinations. Our solid form screening experiments on POA also resulted in its molecular salt hydrates with piperazine and cytosine and in a hydrated cocrystal with gallic acid. X-ray crystal structures of new cocrystals and salts and eutectic compositions of POA-nicotinamide and POA-picolinamide systems are reported in this article.

Figure 1 Molecular structures and acronyms of the compounds studied in this work. RESULTS AND DISCUSSION All selected coformers have complementary basic or acidic groups (Figure 1) which can form either a salt or a cocrystal or even a eutectic with amphiprotic POA. In practice, the ∆pKa rule is used as a guide to assess the formation of salt or cocrystal for an acid-base 2 ACS Paragon Plus Environment

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combination (here carboxylic acid-pyridine/amine, Figure 1) according to which a salt forms when ∆pKa >3 and a cocrystal when ∆pKa homotetramers; Table 3, see Supporting Information for motifs), only POA–INAM combination formed cocrystal and POA–PAM and POA–NAM combinations formed eutectics. This shows that the energetic advantage of a combination over parent compounds is not sufficient to establish/conclude cocrystal formation. On the other hand, stabilization energy values of POA–NAM are greater than that of POA–INAM and not significantly lower for POA– PAM (Table 3) such that the non-formation of cocrystals in these cases is justified. It is interesting to note that the tetrameric motif composed of acid–pyridine dimers (Scheme 1a,c,e) has less stabilization energy as compared to the motif composed of acid–amide dimers (Scheme 1b,d,f) in all combinations (acid–pyridine 75-90 kJ/mol < acid–amide; Table 3), yet has manifested in POA–INAM polymorphs. This is in contrast to the domination of acid–pyridine synthon over the acid–amide one.9b,10a,25 It appears that even though the tetrameric acid–amide motif is low in energy, the unavailability of anti NH group for propagation renders the motif finite such that it cannot make cocrystal growth units. For this reason, both POA–INAM polymorphs should have organized with tetrameric acid–pyridine units having anti NH available for propagation (Scheme 1e) and not with tetrameric acid–amide units having anti NH locked (Scheme 1f). In POA–PAM and POA–NAM systems, the anti NH in both acid–amide and acid–pyridine tetramers is locked (Scheme 1), thus leading to non-formation of cocrystals. To sum up, the obtained energy values does not validate the formation/non-formation of cocrystal in POApyridine carboxamide series. We surmise that reliable computational methodologies to predict or validate the formation of a cocrystal need to be developed. Table 3 Stabilization energy values of dimeric and tetrameric motifs in kJ/mol. Parent Homodimer Homotetramer Combination Heterodimer compound POA

–50.53

–158.51

PAM

–59.87

–160.22

NAM

–53.38

–162.57

INAM

–64.68

–146.49

Heterotetramer Heterotetramer (acid–pyridine (acid–amide dimers) dimers)

POA–PAM

–65.64

–182.29

–258.78

POA–NAM

–70.25

–199.66

–285.24

POA–INAM

–63.28

–190.49

–273.02

On the other hand, we suspect the role of pKa on the differential cocrystallization behavior of pyridine carboxamides with POA. There is a gradual decrease in ∆pKa values in POA-pyridine carboxamide series (POA–INAM 0.77 > POA–NAM 0.4 > POA–PAM 10 ACS Paragon Plus Environment

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–1.73; Table 1) which indicates diminishment of electrostatic interactions from cocrystalforming combination to eutectic-forming combination. It is not out of place to draw such a relationship between electrostatic interactions (dictated by pKa here) and cocrystal/eutectic formation in the light of role of electrostatic force compatibility (dictated by inductive strength) of hydrogen bonding functional groups in their formation (interaction of high –I group with high +I group resulted in cocrystals and that with weak +I group in eutectics).10b However, this observation needs to be substantiated by relevant investigations. It is worthy to study a series with ∆pKa >3, i.e. having the potential for salt formation, and establish the role of electrostatic and steric factors in salt vs. eutectic formation. These studies are currently in progress in our laboratory. Binary phase diagrams of POA–NAM and POA–PAM combinations exhibit ‘V’type pattern characteristic of a eutectic system10,20d,24c (Figure 7). The eutectic compositions of the combinations are found to be 1:4 and 1:5 respectively.

(a)

(b)

Figure 7 Binary phase diagrams of (a) POA–NAM and (b) POA–PAM eutectic systems. Solidus points are shown as filled circles and liquidus points as open squares. CONCLUSIONS Cocrystallization of pyrazinoic acid with isomeric pyridine carboxamides was performed to probe and establish the role of position of hydrogen bonding functionality (carboxamide here) on the formation of cocrystal vs. eutectic as the two alternatives of a cocrystallization experiment. As such, both cocrystals and eutectics have formed in different combinations and the first case of polymorphism in a mixed-ionic complex was noted in this study. The higher ∆pKa value and steric comfort in POA–PPZ and multiple hydrogen bond sites offered by CYT and GA in POA–CYT and POA–GA systems were responsible for strengthening and sustenance of heteromolecular interactions to result in their respective salts and cocrystal. The variation in steric compatibility and electrostatic complementarity at supramolecular level, stemming from the differences in functional group position (carboxamide) and pKa (pyridine) among isomeric pyridine carboxamides, were found to influence supramolecular growth and packing and thus dictate the formation of cocrystal/eutectic for POA–pyridine carboxamide series. All in all, this 11 ACS Paragon Plus Environment


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study strengthens the role of steric factors and their consequent effect on cocrystallization and adds to the existing knowledge and understanding of the phenomenon. Experimental Section Materials Commercially available pyrazinoic acid and other compounds (Sigma-Aldrich, Bengaluru, India) were used without further purification. Solvents were of analytical or chromatographic grade and purchased from local suppliers. Methods Liquid-assisted grinding and characterization of adduct: Compounds in molar ratios combined on the 100 mg scale were manually ground with 1-2 mL of solvent (methanol and/or water) added using a mortar-pestle for 15 min. The ground materials were analyzed by powder X-ray diffraction (PXRD), IR spectroscopy and thermal techniques to ascertain the formation of the adduct. Cocrystal or molecular salt exhibited distinct PXRD pattern, IR spectrum and melting behavior but eutectics showed only a depression in melting point compared to the parent materials.5h,10 Evaporative crystallization POA–INAM: Ground mixture of POA (12 mg, 0.1 mmol) and INAM (12 mg, 0.1 mmol) was dissolved in 3 mL of hot 1,4-dioxane and left for slow evaporation at room temperature. Two different morphology crystals (plates of α polymorph and blocks of β polymorph, both of which are colorless) were obtained after a few days upon solvent evaporation. m.p. 180 °C. 2POA–PPZ–2H2O: Ground mixture of POA (24 mg, 0.2 mmol) and PPZ (4.5 mg, 0.1 mmol) was dissolved in 5 mL of hot methanol and left for slow evaporation at room temperature. Colorless plate crystals were obtained after a few days upon solvent evaporation. m.p. 230 °C. POA–CYT–H2O: Ground mixture of POA (12 mg, 0.1 mmol) and CYT (11 mg, 0.1 mmol) was dissolved in 3 mL of hot 1,4-dioxane and left for slow evaporation at room temperature. Colorless plate crystals were obtained after a few days upon solvent evaporation. m.p. 260 °C. POA–GA–H2O: Ground mixture of POA (12 mg, 0.1 mmol) and GA (18 mg, 0.1 mmol) was dissolved in 5 mL hot of isopropanol and left for slow evaporation at room temperature. Colorless plate crystals were obtained after a few days upon solvent evaporation. m.p. 215 °C. Single crystal X-ray diffraction X-ray reflections were collected on an Oxford Xcalibur Mova E diffractometer equipped with an EOS CCD detector and a microfocus sealed tube using Mo Kα radiation (λ= 0.7107 Å). Data collection and reduction was performed using CrysAlisPro (version 1.171.36.32)26 and OLEX2 (version 1.2)27 was used to solve and refine the crystal structures. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on heteroatoms were located from difference electron density maps and all C–H atoms were fixed geometrically. The WinGX package28 was used for final refinement and production of CIFs and crystallographic table. Powder X-ray diffraction PXRD were recorded on PANalytical diffractometer using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA. Diffraction patterns were collected over 2θ range of 512 ACS Paragon Plus Environment

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40° using a step size of 0.06° 2θ and time per step of 1 sec. X'Pert HighScore Plus (version 1.0d)29 was used to collect and plot the diffraction patterns. IR spectroscopy IR spectra were recorded using PerkinElmer Frontier FT-IR spectrometer on samples dispersed in potassium bromide pellets. Thermal analysis Melting behavior of the combinations was analyzed on a Labindia visual melting range apparatus (MR 13300710) equipped with a camera and a LCD monitor. Solidus-liquidus events of different compositions of eutectic-forming combinations were monitored and based on the merger of solidus and liquidus points the eutectic composition was determined. Packing diagrams X-Seed30 was used to prepare packing diagrams. Energy calculations The motifs present in crystal structures of polymorphs, which matched with commercial materials by PXRD (commercial forms are supposedly stable i.e. low energetic in nature), of respective parent compounds (CSD refcodes: Pyrazinoic acid – PYAZAC; Picolinamide – PICAMD02; Nicotinamide – NICOAM02; Isonicotinamide: EHOWIH) were taken for calculations. For combinations, various plausible motifs were considered and compared with that of present in the crystal structure of pyrazinoic acid– isonicotinamide mixed-ionic complex. All the geometries were optimized using M062x31/6-31++ (d, p) level of theory in Gaussian 09 package.32 The basis set superposition error (BSSE) in the energies of dimers and tetramers was corrected using counterpoise method.33 The stabilization energy of the adduct was calculated by subtracting the amount of the individual energies of fragments from the adduct energy. ASSOCIATED CONTENT Supporting Information PXRD patterns and IR spectra of compounds, energy calculations on dimeric and tetrameric motifs, and CIF files. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS KDP and RG thanks the CSIR and SP thanks the UGC for Research Fellowship. SC thanks the UGC for Dr. D. S. Kothari Postdoctoral Fellowship. LDS thanks the IAS for Summer Research Fellowship Program. TNG thanks the DST for J. C. Bose Fellowship. We thank the Institute for providing infrastructural facilities. REFERENCES

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TOC Graphical Abstract

Cocrystallization of pyrazinoic acid with isomeric pyridine carboxamides resulted in a dimorphic mixed-ionic complex with isonicotinamide and in eutectics with nicotinamide and picolinamide respectively depending on the relative differences in carboxamide position and ensuing supramolecular and electrostatic compatibility in the combinations.


Differential Cocrystallization Behavior of Isomeric Pyridine

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