Salts and Salt Cocrystals of the Antibacterial Drug Pefloxacin - Crystal

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Salts and Salt-Cocrystals of the Anti-bacterial Drug Pefloxacin Ashwini Nangia, anilkumar gunnam, and Suresh Kuthuru Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01600 • Publication Date (Web): 26 Mar 2018 Downloaded from http://pubs.acs.org on March 26, 2018

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Crystal Growth & Design

Salts and Salt-Cocrystals of the Anti-bacterial Drug Pefloxacin Anilkumar Gunnam,a Kuthuru Suresh,a and Ashwini Nangia*,a,b a

School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad 500 046, India b CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India E-mail: [email protected], [email protected] Abstract: Pefloxacin (PEF) is an amphoteric, antibacterial drug which exists as a neutral molecule in the crystal structure stabilized by C–H···O and C–H···F interactions. The design of multicomponent solids using crystal engineering was undertaken in a cocrystal / salt screen of PEF with GRAS dicarboxylic acids to improve the solubility and phase stability of the drug. Ten multicomponent forms, namely five salts, two salt hydrates, and three salt-cocrystals were crystallized by liquidassisted grinding followed by crystallization. In some cases, salt and salt-cocrystals were obtained concomitantly during solution evaporative crystallization. Single crystal X-ray diffraction showed that the structures are stabilized by N+–H···O–, O–H···O, C–H···O, C–H···F and π- π stacking interactions. The bulk phase purity of multicomponent forms was characterized by powder X-ray diffraction, spectroscopy and thermal techniques. The salt /salt-cocrystal forms exhibit faster dissolution rate and higher solubility compared to pure PEF in pH 1.2 (acidic, like gastric environment) and pH 7 phosphate buffer media (neutral, like intestinal passage). Specifically PEF+-SA– salt showed remarkably high solubility, dissolution rate and stability compared to the other multicomponent forms and PEF neutral form. The drug formulation compatible pefloxacin succinate is a promising soluble and stable PEF salt. Introduction Crystal engineering and supramolecular synthons are essential tools for the design and synthesis of multicomponent crystalline forms, such as molecular cocrystals and salts.1-5 These materials have enormous impact in controlling the physicochemical and mechanical behavior of pharmaceutical solids. Pharmaceutical cocrystals have expanded the role of crystal engineering in active pharmaceutical ingredients (APIs) to modify solubility, dissolution rate, physical and chemical stability, tabletability, flowability, and bioavailability of drugs.6-10 Crystal engineering offers an approach to alter the properties of a molecule through intermolecular interactions and packing in the crystal structure.11,12 A large proportion of oral drugs on the market suffer from poor aqueous solubility, formulation stability, and limited bioavailability leading to lower therapeutic efficacy.13 The Class II and IV quadrants of Biopharmaceutics Classification System (BCS) representing low solubility APIs14-16 can be improved by the design of molecular cocrystals and salts with GRAS (generally recognized as safe) coformers.17 The selection of GRAS coformer for a given API is guided by the ∆pKa rule.18-23 We report newly synthesized salts and salt-cocrystals of the antibiotic drug pefloxacin (PEF) with improved physicochemical properties of high solubility and good stability. Pefloxacin (PEF) is a fluoroquinolone antibiotic active against both gram positive and negative bacteria by inhibiting the DNA gyrase and topoisomerase enzymes.24 It is an amphoteric molecule with a zwitterion hexahydrate crystal structure.25 The crystal structures of mesylate26 1 ACS Paragon Plus Environment

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and picrate salts,27 as well as silver,28 manganese,29 cobalt,30 copper,31 zinc,32 bismuth,33 and platinum34 complexes of PEF have been reported in the Cambridge Structural Database.35 Crystalline forms of PEF were characterized by powder X-ray diffraction and thermal techniques.36 However, there is no report of the anhydrous crystal structure of PEF (neutral form) and its cocrystals. PEF is marketed as the mesylate dihydrate salt, PEF+-MES–-HYD (400 mg oral dose), which is freely soluble in water but sparingly soluble in alcoholic solvents. In continuation of our recent study with sparfloxacin,37 we report X-ray crystal structures of pefloxacin anhydrous form and salt and salt-cocrystals with GRAS alkane and alkene dicarboxylic acids. The solubility, dissolution rate and stability of products were measured in phosphate buffer (pH 7) and gastric buffer media (pH 1.2 HCl). Results and Discussion Pefloxacin (PEF) is an amphoteric molecule with acid and base functionalities and it can form cocrystal or salt with acidic/ basic coformers depending on the pKa difference. According to the ∆pKa rule,38 salt formation requires a difference of at least three pKa units between the conjugate acid of the base and the acid, i.e. ∆pKa > 3. When ∆pKa < 0 then the result is a cocrystal and for intermediate ∆pKa range of 0 < ∆pKa > 3, the result may be a cocrystal-salt continuum of mixed states. The dicarboxylic acids used in the present study gave cocrystal/ salt depending on the ∆pKa values39,40 (Scheme 1 and Table 1). The salts and salt-cocrystals were prepared by solventdrop grinding followed by solution crystallization (see Experimental Section). PEF formed salts with oxalic acid (OA), malonic acid (MLA), succinic acid (SA), maleic acid (MA), glutaric acid (GLA), adipic acid (ADP), and suberic acid (SBA) to provide oxalate (PEF+-OA– 1:1), malonate hydrate (PEF+-MLA–-HYD, 1:1:2), succinate (PEF+-SA–, 1:1), maleate (PEF+-MA–, 1:1), glutarate (PEF+-GLA–, 1:1), adipate hydrate (PEF+-ADA–-HYD, 1:1:2), and suberate (PEF+SBA–, 1:1) salts. PEF also formed salt-cocrystal with oxalic acid (OA), fumaric acid (FA), and glutaric acid (GLA) to give oxalate-oxalic acid (PEF+-OA–-OA,1:0.5:0.5), fumarate-fumaric acid (PEF+-FA–-FA,1:0.5:0.5), and glutarate-glutaric acid (PEF+-GLA–-GLA,1:1:1). The structures of these crystalline multicomponent forms including PEF anhydrous form were determined by single crystal X-ray diffraction (SC-XRD) and FT-IR spectroscopy. The bulk phase purity was confirmed by powder X-ray diffraction (PXRD) and thermal techniques (DSC and TGA). Furthermore solubility and stability of novel PEF forms are described. Table 1 Coformers resulting in salts and salt-cocrystals with PEF and their ∆pKa values.a,b PEF OA MLA SA FA MA

pKa in water (COOH) 5.66 (piperazine N) 6.47 1.23 2.83 4.19 3.03 1.93

∆pKa 0.81

Molecular structure neutral and zwitterionic

5.24 3.64 2.28 3.44 4.54

1:1 salt and 1:0.5:0.5 salt-cocrystal 1:1:2 salt hydrate 1:1 salt 1:0.5:0.5 salt-cocrystal 1:1 salt 2

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GLA ADP SBA a

4.34 4.42 4.52

2.13 2.05 1.95

1:1 salt and 1:1:1 salt-cocrystal 1:0.5:1 salt hydrate 1:1 salt

pKa’s were calculated using Marvin 5.10.1, 2017, ChemAxon, http://www.chemaxon.com (ref.

40). b

These values are closely matching with pKa values compiled by R. Williams (ref. 39).

Scheme 1 Molecular structures of PEF and its coformers. Crystal structure analysis PEF: The X-ray crystal structure of PEF guest free form (anhydrous) was solved and refined in the triclinic space group P-1 and molecule exists in the neutral state. Adjacent PEF molecules are connected via C–H···O (C11–H11A···O3, 2.40 Å, 166º and C9–H9···O3, 2.68 Å, 148º) hydrogen bond interactions in a R44(12) and R22(10) ring motif, and such motifs extend in a 1D tape through C–H···O (C12–H12B···O2, 2.64 Å, 141º) interaction (Figure 1a). Such 1D tapes are connected into 2D sheets via C–H···F (C13–H13A···F1, 2.57 Å, 129º) interactions (Figure 1b). Because the molecule is locked in an intramolecular O–H···O hydrogen bond (COOH···O=C), the intermolecular interactions in the structure are weak C–H···O/F interactions. Sparfloxacin also exists in the neutral molecule state in the crystal structure (CSD37 Refcode JEKMOB) and due to intramolecular strong H bonds, its crystal structures are stabilized by weaker C–H···O/F interactions. In the salt /salt-cocrystal structures of PEF, the weak hydrogen bonds are replaced by stronger ionic carboxylate···piperizinium and carboxylic acid···piperizinium synthons along with C–H···O interactions and π-π stacking. Surprising, OA and GLA coformers produced salt and saltcocrystal structures concomitantly during evaporative solution crystallization. However in both cases we did not obtain the bulk phase material PEF+-GLA– (1:1) salt and PEF+-OA–-OA (1:0.5:0.5) salt-cocrystal to perform a full characterization and property measurements.

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(a) (b) Figure 1 Inversion related PEF molecules are connected by C–H···O hydrogen bonds in the 1D tape (a) and these extend to 2D sheets via C–H···F interactions (b). PEF+-OA– (1:1) salt: A 1:1 stoichiometry PEF+-OA– (oxalate) salt was solved and refined in the orthorhombic space group Pbca. Pefloxonium (PEF+) cation and oxalate (OA–) anion are connected via two point N–H···O (N3–H3A···O4, 1.93 Å, 148º and N3–H3A···O7, 2.34 Å, 129º) interactions in a R12(5) ring motif. Such units extend in zigzag chain through O–H···O (O7–H7A···O5, 1.52 Å, 173º) H bonds along the b-axis (Figure 2). Additional C–H···O interactions stabilize the salt molecule in the crystal structure.

(b)

(a)

Figure 2 (a) PEF+-OA– associated through N–H···O interaction in a R12(5) ring motif. (b) PEF+OA– salt with screw axis related molecules in a zigzag through O–H···O hydrogen bonds along the b-axis. PEF+-OA–-OA (1:0.5:0.5) salt-cocrystal: The X-ray crystal structure of oxalate salt-cocrystal was solved and refined in the triclinic space group P-1 with 1:0.5:0.5 (PEF+-OA–-OA) stoichiometry. Inversion related PEF+ cation and oxalate anion OA– are bonded via the strong, ionic piperazinium···carboxylate N+–H···O– (N3–H3A···O4, 1.88 Å, 151º) H bond and extend in a 1D tape through C–H···O dimer (C9–H9···O3, 2.67 Å, 136º) R22(10) ring motif. Such 1D tape structures are connected by OA molecule O–H···O (O6–H6A···O5, 1.51 Å, 175º) connections (Figure 2). The oxygen atoms of keto-acid reside at O···O distance of 3.00 Å in the 2D sheet structure (Figure 3).


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Figure 3 PEF+-OA–-OA salt-cocrystal connected by neutral OA molecule. PEF+-MLA–-HYD (1:1:2) salt: This molecular salt hydrate crystallized in triclinic space group P-1 with one PEF+ cation, malonate (MLA–) anion and two water (1:1:2) molecules. The PEF+ cation and MLA– anion are connected by ionic piperazinium···carboxylate N+–H···O– (N3– H3A···O4, 1.73 Å, 160º) H bond. Adjacent salt molecules of the tape are connected via C–H···O (C13–H13A···O9, 2.62 Å, 142º) interactions and as 2D sheet through R22(8) ring motifs (C19– H19A···O4, 2.62 Å, 170º). The water molecules are connected with PEF through C–H···O and O–H···O bonds (H atoms of water could not be located in difference density maps). The water molecule O showed disorder and the hydrogen atoms could not be fixed (Figure 4).

Figure 4 Inversion related PEF+-MLA–-HYD salt hydrate molecules/ ions are connected via O– H···O hydrogen bonds. PEF+-SA– (1:1) salt: The 1:1 stoichiometry salt PEF+-SA– was solved and refined in P-1 space group. PEF+ cation and SA– anion associate via strong ionic piperazinium···carboxylate N+– H···O– (N3–H3A···O4, 1.80 Å, 166º) H bond and extend in a 1D chain through the carboxylic acid···carboxylate O–H···O synthon (O6–H6A···O4, 1.71 Å, 167º) (Figure 5a). The chains are cross linked by C–H···O (C14–H14B···O3, 2.51 Å, 147º) interactions to form ladder arrangement with π- π stacking along the c-axis (Figure 5b).



(a) (b) Figure 5 (a) PEF -SA salt ions extend via O–H···O bonds. (b) The H bonded chains stack through by π-π interactions. +

–

PEF+-FA–-FA (1:0.5:0.5) salt-cocrystal: PEF+-FA–-FA salt cocrystal of 1:0.5:0.5 stoichiometry in P-1 space group contains FA– anion reside about the inversion center between two PEF+ cations and connected via N+–H···O– hydrogen bonds (N3–H3A···O4, 1.78 Å, 163º). Such salt molecules in lD chain are connected by FA neutral molecule via O–H···O hydrogen bond (O6– H6A···O4, 1.58 Å, 169º) along with C–H···O interaction (C9–H9A···O5, 2.46 Å, 154º) (Figure 6).

Figure 6 2D layered structure of PEF+-FA– salt is stabilized by O–H···O and C–H···O hydrogen bonds. PEF+-MA– (1:1) Salt: PEF+-MA– (1:1) salt structure in P-1 space group contains PEF+ cation bonded to MA– anion via N–H···O (N3–H3A···O4, 1.85 Å, 162 º). Furthermore, C–H···O interactions (C11–H11A···O7, 2.40 Å, 141º; C16–H16A···O7, 2.54 Å, 139 º; C11–H11B···O4, 2.62 Å, 161º) are present in the layer structure (Figure 7).


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Figure 7 2D sheet structure of PEF+-MA– salt sustained through C–H···O interactions in the crystal structure. PEF+-GLA– (1:1) salt: PEF+-GLA– (1:1) crystal structure was solved and refined in P-1 space group. PEF+ and GLA– ions are connected ionic N+–H···O– (N3–H3A···O4, 1.77 Å, 152º) hydrogen bond and extend as 1D chain through carboxylic acid···carboxylate O–H···O (O7– H7A···O5, 1.60 Å, 175º) (Figure 8). The crystal structure is isostructural to PEF+-SA– analyzed by the unit cell similarity index (Π=0.0055, close to zero)41 and the internal molecular arrangement was compared using the XPac method.42 The two structures are related by a 3D supramolecular construct with dissimilarity index of 7.6 (Figure S1a-b, SI), which means that the glutarate and succinate salts of PEF are reasonably similar with change of homolog acids.

Figure 8 (a) PEF+-GLA– salt ions extend in a chain via O–H···O bonds. (b) Inversion chains stack through by π- π interactions. PEF+-GLA–-GLA (1:1:1) salt-cocrystal: PEF+-GLA–-GLA crystallized in 1:1:1 stoichiometry in P-1. PEF+ cations and GLA– anions are associated through N+–H···O– bonds (N3–H3A···O5, 1.78 Å, 176º). Adjacent molecules/ ions are connected via O–H···O (O7–H7A···O5, 1.63 Å, 173º) bonds in a R22 (16) ring motif, which are in turn bridged by neutral GLA molecules



through O–H···O bonds (O9–H9A···O4, 1.79 Å, 158º and O11–H11C···O3, 1.88 Å, 160º) (Figure 9).

Figure 9 R22 (16) dimer ring motif of PEF+-GLA– ions connected via GLA molecule in the crystal structure. PEF+-ADP–-HYD (1:0.5:1) salt: PEF+-ADP–-HYD salt crystallized in 1:0.5:1 stoichiometry in P-1 space group. ADP– anion lies about the inversion center (two protons of ADP are transferred to two PEF molecules) between PEF+ cations and associate via N+–H···O– hydrogen bonds (N3– H3A···O4, 1.64 Å, 171º). Such inversion center related molecules are bridged by two water molecules which connect them via O–H···O (O6–H6A···O5, 1.88 Å, 165º and O6–H6B···O4, 2.38 Å, 164º) bonds in a R44(12) tetramer and extend in 1D chain along the b-axis (Figure 10).

Figure 10 Inversion related PEF+-ADP– ions are connected via water molecules hydrogen bonded in a R44(12) tetramer motif (inset figure) and extend as 1D chains. PEF+-SBA– (1:1) salt: The X-ray crystal structure of 1:1 stoichiometry PEF+-SBA– salt in P21/n space group contains PEF+ cation bonded to SBA– anon via N+–H···O– (N3–H3A···O4, 1.77 Å, 157º). The ions extend in a screw axis related chain through carboxylate –carboxylic acid O– H···O bonds (O6–H6A···O5, 1.64 Å, 166º). A 2D sheet is sustained by C–H···O interactions (C12–H12C···O6, 2.69 Å, 151º and C15–H15A···O7, 2.56 Å, 110º) (Figure 11). 8 ACS Paragon Plus Environment

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Figure 11 PEF+-SBA– molecular salt contains chains connected through O–H···O hydrogen bonds in a 2D layer extending through C–H···O interactions.

Table 2 Crystallographic parameters of PEF cocrystals and salts. PEF C17H20FN3O3 Emp. form. Form. wt. Cryst. syst. Sp. gr. T (K) a (Å) b (Å ) c (Å ) α (º) β (º) γ (º) Z V (Å3) Rflns. Collect Unique rflns. Obsd. rflns Parameters R1 wR2 GOF Diffractometer

333.36 Triclinic P-1 298(2) 4.2908(4) 9.1445(8) 20.0754(16) 88.440(5) 89.545(5) 86.977(5) 2 786.30(12) 2764 2759 1889 223 0.0539 0.1550 1.055 Bruker

PEF+-OA– (1:1) C17H21FN3O3, C2HO4

PEF+-OA–-OA (1:0.5:0.5) C17H20FN3O3, C2O4, C2H2O4

PEF+-MLA–HYD (1:1:2)

423.40 Orthorhombic Pbca 298(2) 11.1095(6) 16.4746(8) 20.7562(10) 90 90 90 8 3798.9(3) 3386 3372 1942 279 0.0699 0.1704 1.148 Bruker APEX-

423.40 Triclinic P-1 298(2) 9.0121(13) 10.3013(15) 11.1131(16) 81.101(8) 66.613(8) 85.964(8) 2 935.5(2) 3307 3300 2263 283 0.0470 0.1296 1.032 Bruker APEX-



C17H20FN3O3 , C3H3O4, 2O

PEF+-SA– (1:1) C17H20FN3 O3, C2H5O4

PEF+-FA–-FA (1:0.5:0.5) C17H20FN3O3, C4H2O4, C4H2O4


449.43 Triclinic P-1 298(2) 7.167(9) 12.674(16) 12.685(16) 111.34(11) 99.11(6) 97.76(4) 2 1036(2) 3658 3654 2539 299 0.0573 0.1276 1.096 Bruker APEX-II


APEX-II CCD detector

Emp. form Form. wt. Cryst. syst. Sp. gr. T (K) a (Å) b (Å ) c (Å ) α (º) β (º) γ (º) Z V (Å3) Rflns. collect Unique rflns Obsd rflns Parameters R1 wR2 GOF Diffractometer

PEF+-MA– (1:1) C17H20FN3O3, C3H3O4 449.43 Triclinic P-1 298(2) 6.9478(9) 12.3427(16) 12.7207(16) 93.442(7) 104.579(7) 94.604(7) 2 1048.7(2) 3706 3703 2493 299 0.0597 0.1672 1.120 Bruker APEXII CCD detector

II CCD detector

II CCD detector

PEF+-GLA– (1:1) C17H20FN3O3, C5H7O4 465.47 Triclinic P-1 298(2) 7.3036(4) 12.0619(8) 12.5318(8) 94.162(2) 93.100(2) 98.664(2) 2 1086.15(12) 3845 3843 2251 313 0.0630 0.1494 1.037 Bruker APEX-II CCD detector

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CCD detector

PEF+-GLA–-GLA (1:1:1) C17H20FN3O3, C5H7O4, C5H8O4 597.59 Triclinic P-1 298(2) 7.5930(4) 10.5016(5 19.3769(10) 77.041(2) 80.669(3) 71.726(2) 2 1422.74(13) 5894 5856 4915 393 0.0453 0.1249 1.025

PEF+-ADP–HYD (1:0.5:1) C17H20FN3O3, C6H8O4, H2O 424.45 Triclinic P-1 298(2) 9.1887(6) 9.3793(6) 12.7275(9) 106.818(4) 97.551(4) 96.967(4) 2 1026.11(12) 3625 3619 2298 281 0.0755 0.2037 1.106

PEF+-SBA– (1:1) C17H20FN3O3, C8H13O4 506.54 Monoclinic P21/n 298(2) 15.8131(13) 7.4628(6) 22.4843(17) 90 108.661(5) 90 4 2513.9(4) 5222 5198 2938 329 0.0588 0.1532 1.011

Bruker APEX-II CCD detector

Bruker APEX-II CCD detector

Bruker APEXII CCD detector

Table 3 Hydrogen bonds in PEF cocrystals and salts. D−H···A

D···A (Å)

O2−H2A···O1 C9−H9···O3 C11−H11A···O3 C13−H13A···F1

2.5211(2) 3.512(4) 3.356(4) 3.283(3)

O2−H2A...O1 N3−H3A…O4

2.508(4) 2.743(4)

H···A (Å) D−H···A (°) PEF 1.65 147 2.68 148 2.41 166 2.576 130 + – PEF -OA (1:1) 1.55 160 1.87 147 10

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Symmetry code ---a -x+2,-y+2,-z+1 -x+2,-y+2,-z+1 x+1,+y,+z ---a ---b

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N3−H3A...O7 O7−H7A...O5 C2−H2...O3 C11−H11A...O3 C13−H13A...O3 C15−H15A...O5 C16−H16B...F1

2.995(4) 2.469(4) 3.442 (5) 3.262(5) 3.174(5) 3.310(4) 2.833(5)

O2−H2A···O1 N3−H3A···O5 N3−H3A···O4 O6−H6A···O5 C11−H11B···O2 C13−H13A···F1 C14−H14B···O6 C15−H15B···O1 C16−H16A···O7

2.523(4) 2.9868(4) 2.7392(4) 2.500(2) 3.222(3) 2.8232(4) 3.2632(5) 3.1065(5) 3.4398(5)

O2−H2A···O1 N3−H3···O4 O6−H6A···O5 C12−H12B···O8 C13−H13B···O9 C14−H14B···O3 C15−H15A···O4 C15−H15B···O2 C17−H17C···O9 C19−H19A···O4

2.524(4) 2.680(4) 2.479(5) 3.307(14) 3.453(25) 3.275(5) 3.344(4) 3.256(5) 2.979(23) 3.587(6)

O2−H2A···O1 N3−H3A···O4 N3−H3A···O5 O6−H6A···O4 C13−H13A···F1 C13−H13B···F1 C14−H14B···O2 C14−H14B···O3 C16−H16A···O5 C16−H16B···O7 C17−H17A···O5

2.505(2) 2.759(2) 3.312(2) 2.651(3) 2.825(2) 3.352(2) 3.455(2) 3.361(2) 3.322(2) 3.253(3) 3.303(3)

2.30 1.52 2.55 2.54 2.40 2.46 2.15 PEF+-OA–-OA (1:0.5:0.5) 1.69 2.34 1.88 1.51 2.47 2.15 2.39 2.42 2.60 PEF+-MLA–-HYD (1:1:2) 1.73 1.74 1.69 2.52 2.53 2.46 2.46 2.36 2.05 2.63 PEF+-SA– (1:1) 1.65 1.80 2.55 1.71 2.11 2.49 2.56 2.51 2.60 2.56 2.60

127 173 162 131 137 146 126

---b x+1/2,+y,-z+1/2+1 -x+1/2+1,+y-1/2,+z -x+1/2+1,+y-1/2,+z -x+1/2+1,+y-1/2,+z -x+1/2,+y+1/2,+z ---a

157 126 151 175 134 125 150 127 146

---a -x+2,-y+1,-z+1 ---b ---b x+1,+y,+z ---a ---b 1+x,y,z 1-x,1-y,-z

152 161 161 139 160 142 151 153 162 170

---a x,+y,+z+1 ---a x,+y-1,+z -x+1,-y+1,-z+1 x,+y,+z+1 -x+2,-y,-z+1 -x+2,-y+1,-z+1 x+1,+y,+z+1 -x+1,-y,-z

160 166 135 168 130 148 154 147 131 128 131

---a ---b ---b x-1,+y,+z ---a -x+1,-y+1,-z+1 -x+2,-y+1,-z+2 -x+2,-y+1,-z+2 ---b -x,-y,-z+1 -x+1,-y,-z+1

156 162 123 167 154

---a x,+y+1,+z x,+y+1,+z x,+y+1,+z+1 ---b

PEF+-FA–-FA (1:0.5:0.5) O2−H2A···O1 N3−H3A···O4 N3−H3A···O5 O6−H6A···O4 C9−H9···O5

2.519(3) 2.730(4) 3.192(4) 2.568(4) 3.319(6)

1.58 1.78 2.55 1.57 2.46 11 ACS Paragon Plus Environment


C11−H11A···O5 C13−H13B···F1 C14−H14B···O3 C15−H15B···O2 C16−H16B···O7

3.248(5) 2.867(5) 3.199(6) 3.256(5) 3.167(5)

O2−H2A···O1 N3−H3A···O4 N3−H3A···O5 O6−H6A···O5 C11−H11A···O7 C13−H13B···F1 C14−H14A···O2 C14−H14A···O3 C14−H14B···O3 C16−H16A···O7 C17−H17C···O6 O2−H2A···O1

2.515(3) 2.800(3) 3.129(3) 2.435(3) 3.216(4) 2.810(3) 3.511(4) 3.347(3) 3.121(4) 3.330(4) 3.377(5) 2.515(3)

O2−H2A···O1 N3−H3A···O4 O7−H7A···O5 C11−H11B···O5 C13−H13A···F1 C14−H14A···O3 C14−H14B···O3 C16−H16A···O4 C17−H17A···O4 C21−H21A···O5

2.516(4) 2.657(4) 2.524(4) 3.281(5) 2.829(4) 3.341(5) 3.478(5) 3.201(4) 3.469(5) 3.127(5)

O2−H2A···O1 N3−H3A···O4 N3−H3A···O5 O11−H11C···O3 O9−H6A···O4 O7−H7A···O5 C5−H5···O1 C11−H11A···O10 C13−H13B···F001 C15−H15A···O8 C15−H15B···O2 C17−H17A···O8 C17−H17B···O4 C17−H17C···O11 C26−H26B···O6

2.485(1) 3.10(2) 2.715(2) 2.699(2) 2.617(2) 2.575(2) 3.347(2) 3.337(2) 2.904(2) 3.385(2) 3.268(2) 3.217(3) 3.136(2) 3.465(3) 3.333(3)

2.38 2.18 2.37 2.36 2.45 PEF+-MA– (1:1) 1.62 1.85 2.46 1.41 2.40 2.13 2.58 2.57 2.44 2.54 2.52 1.62 PEF+-GLA– (1:1) 1.56 1.77 1.61 2.35 2.10 2.60 2.51 2.55 2.60 2.54 PEF+-GLA–-GLA (1:1:1) 1.48 2.51 1.77 1.88 1.80 1.64 2.43 2.55 2.25 2.59 2.41 2.38 2.55 2.55 2.43 + PEF -ADP–-HYD (1:1:2) 12 ACS Paragon Plus Environment

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149 127 143 152 130

---b ---b x,+y+1,+z -x+1,-y+1,-z+1 x,+y,+z-1

155 162 125 178 141 126 160 137 127 139 148 155

---a ---b ---b ---b -x,-y+1,-z ---b -x+2,-y+2,-z+1 -x+2,-y+2,-z+1 x,+y-1,+z -x,-y+1,-z -x+1,-y+1,-z ---a

166 151 175 159 131 133 175 124 151 119

---a ---b x-1,+y,+z x,+y,+z-1 ---a x,+y,+z+1 -x+2,-y+1,-z ---b -x+2,-y+2,-z+1 ---a

158 121 176 160 159 173 171 138 124 139 147 146 119 159 155

---a x,+y,+z-1 x,+y,+z-1 x-1,+y+2,+z ---b -x+2,-y,-z+2 -x 3,-y,-z+1 -x+1,-y+1,-z+1 ---a -x+1,-y+1,-z+1 -x+2,-y,-z+1 -x+2,-y,-z+1 x,+y,+z-1 -x+1,-y+2,-z+1 x,+y+1,+z

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a

O2−H2A···O1 N3−H3A···O4 O6−H6A···O5 O6−H6B···O4 C9−H9···O3 C11−H11A···O6 C13−H13B···F1 C13−H13B···F1 C15−H15A···O4

2.513(2) 2.611(3) 2.747(4) 3.140(5) 3.094(5) 3.419(6) 2.868(4) 3.208(3) 3.297(4)

O2−H2A···O1 N3−H3A···O4 N3−H3A···O5 O6−H6A···O5 C13−H13B···F1 C13−H13B···O3 C14−H14A···O3 C14−H14B···O3 C15−H15A···O7

2.510(2) 2.706(3) 3.201(3) 2.529(3) 2.801(3) 3.001(3) 3.258(3) 3.204(3) 3.034(3)

1.75 1.64 1.88 2.39 2.38 2.55 2.21 2.51 2.41 PEF+-SBA– (1:1) 1.58 1.77 2.39 1.65 2.07 2.52 2.29 2.59 2.56

155 171 165 164 134 149 124 129 152

---a ---b x,+y+1,+z -x+1,-y+1,-z+2 -x+2,-y+2,-z+1 ---b ---a -x+1,-y,-z+1 -x+1,-y+1,-z+2

157 158 140 166 130 110 174 122 110

---a ---b ---b x+1/2,-y+1/2+1,+z+1/2 ---a x+1/2,-y+1/2,+z+1/2 -x+1,-y,-z x+1/2,-y+1/2,+z+1/2 -x+1,-y+1,-z+1

intramolecular hydrogen bond

PXRD analysis PXRD is a reliable technique to characterize the bulk phase purity and homogeneity by the unique diffraction lines of the novel crystalline form. It is a fast and reliable method to distinguish between the multicomponent solid product from its starting materials.43,44 The PXRD of novel crystalline multicomponent forms prepared in this work was confirmed by the bulk phase purity and homogeneity of the crystalline phase by an overlay of the experimental powder pattern with the calculated lines from the X-ray crystal structure (Figure 12). We were unable to obtain PEF+-OA–-OA (1:0.5:0.5) and PEF+-GLA– (1:1) in sufficient quantity for PXRD overlay comparison and further characterization of these products is not presented in this work.



Figure 12 Overlay of experimental PXRD line pattern of PEF salts and cocrystals (black trace) shows excellent match with the calculated line profile from the X-ray crystal structure (red trace), indicating bulk purity and phase homogeneity. Thermal analysis Differential Scanning Calorimetry (DSC) is a prime technique45-47 to validate the purity of a material and understand phase transformations. DSC of PEF cocrystals/ salts (Figure 13, Table 4) shows that the melting point of products is above 140 ºC except PEF+-ADP–-HYD (whose melting endotherm occurs at 90 ºC). There is a lowering of melting point with increase in chain length of dicarboxylic acid compared to neutral PEF (272-274 °C). Surprisingly all the salts and salt cocrystals exhibit lower melting endotherm than PEF neutral form. This may be due to the charge-assisted N−H···O hydrogen bonding along with other C−H···O interactions in the multicomponent forms being weaker than those in pure PEF structure. PEF+-OA- (1:1) salt exhibited two endotherms due to phase transitions (which need to be studied separately). In controlled heating experiments, salt turned black at that temperature (Figure S2a) due to decomposition. The stoichiometric composition of salt-cocrystal hydrates was estimated by weight loss during TGA measurements and dehydration experiments (Table S1 and Figure S2be, Supporting Information).


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Figure 13 Stacking of DSC thermograms for salts and cocrystals. Table 4 Melting point of PEF salts and cocrystals. Cocrystal/Salt m.p. (°C) 1 PEF 272-274 + – 2 PEF -OA (1:1) 273-275 + – 3 PEF -MLA -HYD (1:1:2) 271-274 + – 4 PEF -SA (1:1) 202-205 + – 5 PEF -FA -FA (1:0.5:0.5) 261-265 + – 6 PEF -MA (1:1) 228-237 + – 7 PEF -GLA -GLA (1:1:1) 146-151 + – 8 PEF -ADP -HYD (1:0.5:1) 112-117 + – 9 PEF -SBA (1:1) 139-143

coformer

m.p. (°C)

OA MLA SA FA MA GLA ADP SBA

189-191 135-137 183-186 286-289 134-137 95-98 151-154 141-144



Solubility and phase stability studies Solubility is “how much” of the API is soluble in the medium while dissolution rate is “how fast” the API reaches that equilibrium value. The first is a thermodynamic quantity while the latter is influenced by kinetic factors. Dissolution gives an idea of the peak concentration and amount of drug dissolved in a short time. Solubility and dissolution are controlled by coformer solubility, melting point, hydrogen bonding, particle size and crystal packing effects. Equilibrium solubility measurements were carried out in the gastric pH 1.2 (0.1 N HCl) and phosphate buffer (pH 7) media. IDR measurements were performed for 1 h by the rotating disk intrinsic dissolution rate (DIDR) method48 at 37° C in phosphate buffer (pH 7) medium. Both solubility and IDR concentrations were measured by UV spectroscopy and undissolved materials characterized by PXRD to confirm the phase stability during measurements in slurry conditions. All PEF multicomponent forms exhibited enhanced solubility in both gastric and phosphate buffer media compared to the reference drug (Table 5). However, solubility in the gastric medium was higher than that in buffer conditions. Except for PEF+-MLA–-HYD and PEF+-FA–FA (which transformed to new phase based on PXRD), all other forms were stable in pH 1.2 medium for 24 h slurry (Figure S4, SI). In phosphate buffer solubility measurements, PEF+-OA–, PEF+-MLA–-HYD and PEF+-ADP–-HYD were unstable and transformed to a new phases/ starting materials (salt disproportionation of PEF+-ADP–-HYD and new phase for PEF+-OA– and PEF+-MLA–-HYD) (Figure S5a-c, SI). The remaining five forms displayed high solubility and stability (Figure S5d-i, SI). PEF+-SA– (1:1) salt displayed higher solubility (about 46 fold in phosphate buffer and 838 fold in gastric medium) compared to neutral drug PEF. IDR measurements showed enhanced dissolution rates than PEF and the salts/ cocrystals were stable (except PEF+-OA–) as confirmed by PXRD (Figure S6a-i, SI). The reference salt on the market PEF+-MES–-HYD has intermediate stability in that there is partial conversion to neutral PEF in the dissolution experiment after 1 h, and complete conversion to neutral PEF in the equilibrium solubility experiment over 24 h in neutral pH 7.0 medium (Figure S7a-c, SI). Even though PEF+MLA–-HYD– exhibited the highest IDR, it has stability problem after longer exposure in solubility experiments. The marketed drug PEF-+MES--HYD has the drawback of dissociation/ disproportionation during solubility and also the dissolution curve is at the 40% drug dissolved value at 1 h compared to 70% for PEF+-SA– salt. The best salt therefore appears to be PEF+-SA– which has excellent solubility along with improved stability and the second highest IDR rate among the salts studied. In addition, according to the Orange book database published by USFDA, succinic acid (SA) as a counter ion is present in about 1.7% of oral dosage forms and 0.5% for injectable dosage forms in the market. Hence PEF+-SA– (1:1) is a better choice for an alternative oral formulation of PEF.


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Figure14 Dissolution rate curves of PEF salts: 1 = PEF, 2 = PEF+-OA–, 3 = PEF+-SA–, 4 = PEF+-MLA–-HYD, 5 = PEF+-FA–-FA, 6 = PEF+-ADP–-HYD, 7 = PEF+-MA–, 8 = PEF+-GLA–GLA, 9 = PEF+-SBA–, 10 = PEF+-MES–-HYD. Table 5 Equilibrium solubility and IDR comparison of PEF and its solid forms. Compound

Coformer Equilibrium solubility solubility In pH7.0 buffer (mg/mL) (mg/mL)

Equilibrium solubility in pH 1.2 (0.1N HCl) (mg/mL)

IDR

0.043 0.52 (x 12.09) 14.58 (x 339.06) 12.61 (x 293.5) 2.69 (x 62.55) 3.65 (x 84.88) 4.23 (x 98.37) 1.50 (x 34.88) 5.48 (x 127.44) 5.62 (x 130.69)

PEF PEF+-OAPEF+-MLA--HYD

220 763

0.29 -

36.79 138.39 (x 3.76) -

PEF+-SAPEF+-FA--FA PEF+-MAPEF+-GLA--GLA PEF+-ADP--HYD PEF+-SBAPEF+-MES–-HYD

820 7 441 1600 30 12 2000

243.08 (x 838.20) 2.51 (x 8.65) 2.62 (x 9.03) 108.74 (x 374.96) 106.37 (x 366.79) -

1693.43 (x 46.02) 31.46 (x 0.87) 262.91 (x 7.14) 639.88 (x 17.39) 349.85 (x 9.50) 1865 (x 50.69)

Conclusions The crystalline salt and salt-cocrystals multicomponent forms of Pefloxacin were synthesized by solvent drop grinding and isothermal solvent evaporative crystallization. The crystal structures were satisfactorily analyzed by single X-ray diffraction techniques. The crystal structures are stabilized by N+–H···O–/ N–H···O, O–H···O, C–H···O, C–H···F and π–π stacking interactions. Two coformers OA and GLA resulted in salt and salt-cocrystal products concomitantly during crystallization. The structural analysis of these multi-component salt-cocrystals at a molecular level provides further direction towards ternary systems/ solid solutions. All the products were 17 ACS Paragon Plus Environment


analyzed by PXRD and DSC for bulk phase purity and homogeneity, except for PEF+-OA–-OA (1:0.5:0.5) and PEF+-GLA– (1:1) which could be prepared in small quantity only. The novel salts-cocrystals exhibit improved solubility and intrinsic dissolution rate compared to the reference drug PEF. These solids exhibit unique thermal behavior and the alkane chain influences the melting behavior of these solids (with increasing chain length the melting point is lower). All the salts and salt-cocrystals displayed dramatic improvement in dissolution rate and solubility compared to pure PEF. Specifically, PEF+-SA– (1:1) salt has remarkably high solubility and stability compared to the PEF multicomponent forms including the marketed PEF+-MES–-HYD. The pharmaceutically acceptable succinate is a promising candidate of high solubility and stable PEF salt. Experimental Section Pelfoxacin mesylate (purity >99.8%) was purchased from Yarrow Chemical Products (Mumbai, India) and salts formers were purchased from Sigma-Aldrich (Hyderabad, India). All solvents (purity >99%) were purchased from Finar chemicals (Hyderabad, India). Extraction of neutral pefloxacin Neutral pefloxacin was extracted from pefloxacin mesylate hydrate by using aqueous KOH. Initially 10 g of Pefloxacin mesylate hydrate was dissolved in excess water and then 5M aqueous KOH was added drop wise with constant stirring till a white precipitate was formed. The precipitate was filtered and dried. The neutral product is confirmed by PXRD, DSC and SCXRD as pefloxacin. Preparation of salts The salts and salt-cocrystals were prepared by solvent-drop grinding (few drops of solvent added) for grinding followed by solution crystallization of the powder material. PEF Neutral: 333 mg (0.1 mmol) of PEF was dissolved in 10 mL of methanol and left for slow evaporation at room temperature. Good quality single crystals were harvested for SC-XRD analysis after 5 days. PEF+-OA– (1:1) and PEF+-OA–-OA (1:0.5:0.5): 333 mg (0.1 mmol) of PEF and 90 mg (0.1 mmol, 98% purity) of OA were ground using acetonitrile solvent for 30 min at room temperature and the salt formed was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in 5 mL 1:1 mixture of acetonitrile and acetone and left for slow evaporation at ambient conditions. Good quality single crystals of PEF+-OA– (1:1) and PEF+-OA–-OA (1:0.5:0.5) were obtained concomitantly after 3 days, which were handpicked for SC-XRD. The bulk phase purity was matched with PEF+-OA– (1:1). PEF+-OA–-OA (1:0.5:0.5) could not be isolated for bulk characterization studies. PEF+-MLA–-HYD (1:1:2): 333 mg (0.1 mmol) of PEF and 104 mg (0.1 mmol, 98% purity) of MLA were ground with a mixture of water and acetonitrile for 20 min at room temperature and salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in acetonitrile-chloroform (6 mL, v/v) and left for slow evaporation at room temperature. Good quality single crystals were obtained for SC-XRD after 4 days. PEF+-SA– (1:1): 333 mg (0.1 mmol) of PEF and 118 mg (0.1 mmol, 98% purity) of SA were ground in acetonitrile for 20 min at room temperature and salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved acetonitrile-toluene (6 mL, v/v) and 18 ACS Paragon Plus Environment

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left for slow evaporation at ambient conditions. Good quality single crystals were obtained for SC-XRD after 7 days. PEF+-FA--FA(1:0.5:0.5): 333 mg (0.1 mmol) of PEF and 116 mg (0.1 mmol, 98% purity) of FA were ground in acetonitrile for 20 min at room temperature and salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in methanol-THF (6 mL, v/v) and left for slow evaporation at ambient conditions. Good quality single crystals were obtained for SC-XRD after 5 days. PEF+-MA-(1:1): 333 mg (0.1 mmol) of PEF and 116 mg (0.1 mmol, 98% purity) of MA were ground using acetonitrile for 20 min at room temperature and salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in methanol-chloroform (6 mL, v/v) and left for slow evaporation at ambient conditions. Good quality single crystals were obtained for SC-XRD after 3 days. PEF+-GLA– (1:1) and PEF+-GLA–-GLA (1:1:1): 333 mg (0.1 mmol) of PEF and 131 mg (0.1 mmol, 98% purity) of GLA were ground using acetonitrile solvent for 20 min at room temperature and the resulting salt was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in mixture of acetonitrile and chloroform (6 mL, v/v) and left for slow evaporation at ambient conditions. Good quality single crystals of PEF+-GLA– (1:1) and PEF+GLA–-GLA (1:1:1) were obtained concomitantly for SC-XRD after 4 days. The bulk material of PEF+-GLA– (1:1) could not be crystallized to perform characterization studies. PEF+-ADP–-HYD (1:0.5:1): 333 mg (0.1 mmol) of PEF and 146 mg (0.1 mmol, 98% purity) of ADP were ground with a mixture of water and acetonitrile solvent for 20 min at room temperature and the salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in mixture of acetonitrile and toluene (6 mL, v/v) and left for slow evaporation at ambient conditions. Good quality single crystals were obtained for SC-XRD after 5 days. PEF+-SBA– (1:1): 333 mg (0.1 mmol) of PEF and 174 mg (0.1 mmol, 98% purity) of SBA were ground in acetonitrile solvent for 20 min at room temperature and salt formation was confirmed by PXRD, DSC and TGA. 30 mg of this material was dissolved in mixture of acetonitrile and nitromethane (6 mL, v/v) and left for slow evaporation at ambient conditions. Good quality single crystals were obtained for SC-XRD after 4 days. Powder X-ray diffraction Powder X-ray diffraction was recorded on Bruker D8 Advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Kα X-radiation (λ = 1.5406 Å) at 40 kV and 30 mA power. X-ray diffraction patterns were collected over the 2θ range 3–50° at a scan rate of 3.9°/min. Powder Cell 2.449 (Federal Institute of Materials Research and Testing, Berlin, Germany) was used for Rietveld refinement of experimental PXRD and calculated lines from the X-ray crystal structure. Vibrational spectroscopy Thermo-Nicolet 6700 FT-IR-NIR spectrometer with NXR FT-Raman module (Thermo Scientific, Waltham, MA) was used to record IR spectra. IR spectra were recorded on samples dispersed in KBr pellets. Data were analyzed using the Omnic software (Thermo Scientific, Waltham, MA).



Thermal analysis DSC was performed on a Mettler Toledo DSC 822e module and TGA on a Mettler Toledo TGA/SDTA 851e module. The typical sample size is 3-5 mg for DSC and 5-12 mg for TGA. Samples were placed in sealed pin-pricked aluminum pans for DSC experiments and alumina pans for TGA experiments. A heating rate of 10 °C min–1 in the temperature range 30-300 °C was applied. Samples were purged by a stream of dry nitrogen flowing at 80 mL min–1 for DSC and 50 mL min–1 for TGA. X-ray crystallography X-ray reflections were collected on Bruker D8 QUEST, CCD diffractometer equipped with a graphite mono chromator and Mo-Kα fine-focus sealed tube (λ = 0.71073 Å) and reduction was performed using APEX-II Software.50 Intensities were corrected for absorption using SADABS and the structure was solved and refined using SHELX97.51 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on hetero atoms were located from difference electrondensity maps and all C—H H atoms were fixed geometrically. Hydrogen-bond geometries were determined in PLATON.52,53 Crystal parameters (Table 2) and hydrogen bond distances shown in Table 3 which are much closer to neutron normalized true D–H distances (O–H 0.983 Å, N–H 1.009 Å, and C–H 1.083 Å). X-Seed (Barbour, 1999) was used to prepare packing diagrams.54,55 Crystallographic cif files (CCDC Nos. 1586074-1586084) are available at www.ccdc.cam.ac.uk/data or as part of the Supporting Information. Solubility measurements The solubility of PEF and its multicomponent forms was measured using the Higuchi and Connor method56 in gastric (pH 1.2 HCl) and phosphate buffer (pH 7) media at 30 °C. First, the absorbance of a known concentration of the PEF and its salts was measured at the given λmax (PEF 272 nm) in purified pH 7 phosphate buffer and pH 1.2 HCl media on Thermo Scientific Evolution 300 UV-vis spectrometer (Thermo Scientific, Waltham, MA) respectively. These absorbance values were plotted against several known concentrations to prepare the concentration vs. intensity calibration curve. From the slope of the calibration curves, molar extinction coefficients for PEF and its salts were calculated. Intrinsic dissolution rate (IDR) of PEF and its multicomponent forms were carried out on a USP certified Electrolab TDT-08L Dissolution Tester (Electrolab, Mumbai, MH, India). In intrinsic attachment unit 400mg sample (PEF/salts) is compressed between the smooth surface under the pressure of2.5 ton/inch2 for 4 minin an area of 0.5 cm2. Then the pelletes were dipped into 500 mL of pH7.0 phosphate buffer medium at 37 °C at rotating paddlee of 100 rpm.A 5 mL of dissolution medium was collected at an interval of 5 min by replacing each with same amount of fresh pH7.0 phosphate buffer. The absorbance is plotted againest time for samples collected at regular intervals for PEF and salts were calculated. An excess amount of the sample (PEF/ multicomponent forms) was added to 3 mL of purified pH 7 phosphate buffer medium and pH 1.2 HCl medium. The supersaturated solution was stirred at 800 rpm using a magnetic stirrer at 30 °C. After 24 h, the suspension was filtered through Whatmann 0.45µm syringe filter. Then equilibrium solubility is calculated as per procedure and remaining residues of PEF and its salts were characterized by PXRD. Associated Content


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Supporting Information contains TGA calculations, plots, and corresponding controlled heating experiments images (Table S1 and Figure S1). IR spectra (Table S2 and Figure S2), PXRD comparison of PEF salts and salt-cocrystals at the end of equilibrium solubility/IDR experiment (24 h and 1 h) with the calculated line pattern (Figure S3-S5), PXRD of PEF-MES-HYD (Figure S6), and crystallographic information (.cif files). This material is available free of charge via the Internet at http://pubs.acs.org. Author information Corresponding Author * E-mail: [email protected], [email protected] Notes The authors declare no competing financial interest. Acknowledgements: Financial and infrastructure support from the University Grants Commission, New Delhi (through the UPE and CAS programs) and the Department of Science and Technology, New Delhi (through the PURSE and FIST programs), JC Bose Fellowship (SR/S2/JCB-06/2009), CSIR project on Pharmaceutical cocrystals (02(0223)/15/EMR-II), and SERB scheme on Multi-component cocrystals (EMR/2015/002075) are gratefully acknowledged. AG thanks CSIR and KS thanks UGC for research fellowships. References 1. Desiraju, G. R. Crystal Engineering. The Design of Organic Solids, Elsevier, 1989. 2. Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering. A Textbook, World Scientific Publishing, Singapore, 2011. 3. Etter, M. C.; MacDonald, J. C.; Bernstein, J. Graph-set Analysis of Hydrogen-bond Patterns in Organic Crystals. Acta Crystallogr. 1990, B46, 256–262. 4. Etter, M. C.; Reutzel, S. M. Hydrogen Bond Directed Cocrystallization and Molecular Recognition Properties of Acyclic Imides. J. Am. Chem. Soc. 1991, 113, 2586–2598. 5. Desiraju, G. R. Crystal Engineering: From Molecule to Crystal. J. Am. Chem. Soc. 2013, 135, 9952–9967. 6. Wermuth, G.C.; and Stahl, P.H. Eds.; Pharmaceutical Salts: Properties, Selection, and Use / International Union of Pure and Applied Chemistry (IUPAC), Strasbourg and Freiburg, 2002. 7. Elder, D.P.; Holm, R., Diego, H.L.D.Use of Pharmaceutical Salts and Cocrystals to Address the Issue of Poor Solubility. Int. J. Pharm. 2013, 453, 88–100. 8. Serajuddin, A.T.M. Salt Formation to Improve Drug Solubility. Adv. Drug Deliv. Rev. 2007, 59, 603–616. 9. Berry, D. J.; Steed, J. W. Pharmaceutical Cocrystals, Salts and Multicomponent Systems: Intermolecular Interactions and Property Based Design. Adv. Drug Deliv. Rev. 2017, 117, 3–24. 10. Duggirala, N.K.; Perry, M.L.; Almarsson, Ö.; Zaworotko, M. J. Pharmaceutical Cocrystals: Along the Path to Improved Medicines. Chem. Commun. 2016, 52, 640–655. 11. Suresh, K.; Mannava, M. K. C.; Nangia, A. Cocrystals and Alloys of Nitazoxanide: Enhanced Pharmacokinetics. Chem. Commun. 2016, 52, 4223–4226. 21 ACS Paragon Plus Environment


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TOC

Synopsis: Ten multicomponent forms, namely five salts, two salt hydrates, and three saltcocrystals of Pefloxacin were crystallized by liquid-assisted grinding followed by solution evaporative crystallization. PEF+-SA– salt showed remarkably high solubility, dissolution rate and stability compared to the other adducts and PEF neutral form. The drug formulation compatible pefloxacin succinate is a promising soluble and stable PEF salt.


Salts and Salt Cocrystals of the Antibacterial Drug Pefloxacin - Crystal

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