Pharmaceutical Cocrystal and Salts of Norfloxacin - Crystal Growth

CRYSTAL GROWTH & DESIGN

Pharmaceutical Cocrystal and Salts of Norfloxacin Srinivas Basavoju,† Dan Bostro¨m,‡ and Sitaram P. Velaga*,† Department of Health Science, Luleå UniVersity of Technology, Luleå S-971 87, Sweden, and Energy Technology and Thermal Process Chemistry, Umeå UniVersity, Umeå S-90187, Sweden

2006 VOL. 6, NO. 12 2699-2708

ReceiVed June 2, 2006; ReVised Manuscript ReceiVed August 14, 2006

ABSTRACT: The aim of this study was to investigate the structural and pharmaceutical properties of norfloxacin (a poorly soluble antibacterial drug), its cocrystal, and salts. Norfloxacin in the anhydrous form (form A, 1) was crystallized. It was cocrystallized with isonicotinamide (2), and organic salts were prepared with succinic acid, malonic acid, and maleic acid (3-5, respectively). These phases were characterized by differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, and powder X-ray diffraction (PXRD). Single-crystal X-ray diffraction data were obtained, and crystal structures were solved. The apparent solubility of these phases was determined. Robust O-H‚‚‚O, O-H‚‚‚O-, O-H‚‚‚N, N-H‚‚‚O, N+-H‚‚‚O-, and N-H‚‚‚N interactions were present in all these structures. Quinolone moieties in these structures stack with π‚‚‚π interactions and form channels to include CHCl3 or H2O. Herein we report a new cocrystal and salts of norfloxacin with improved aqueous solubility. 1. Introduction Crystal engineering has emerged into the pharmaceutical field with its importance in the pharmaceutical cocrystallization of active pharmaceutical ingredients (APIs).1 The term crystal engineering is defined as “the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties”.2 Subsequently, crystal engineering has grown into a prototype for the design or supramolecular synthesis of new compounds based on the synthon approach.3 Recently, this strategy was effectively explored by Zaworotko to design pharmaceutical cocrystals.4 A pharmaceutical cocrystal is defined as a cocrystal that is formed between an API (neutral or in the ionic form) and a cocrystal former that is a solid under ambient conditions.5,6 Furthermore, a cocrystal comprising two or more solid components under ambient conditions and a liquid is called a cocrystal solvate. For APIs with solubility-limited bioavailability, a challenging task in the product development is to improve their solubility without compromising the stability and other performance characteristics. These properties can be manipulated by a change in the crystal form (polymorphs, hydrates, etc.), formation of an amorphous phase, salt formation, and complexation or encapsulation of an API.7 Indeed, a widely accepted approach to overcome poor solubility and/or inadequate material properties of an API is the preparation of its salt forms.8 Pharmaceutical cocrystallization is an alternative and potentially reliable method to amend physical and technical properties such as solubility, dissolution, moisture sorption, compressibility, etc. of API molecules.4,6 The idea of crystal engineering extends to these issues without altering the pharmacological behavior of the drug. The presence of many functional groups in APIs, which may form robust supramolecular synthons such as acid‚‚‚acid, acid‚‚‚pyridine, acid‚‚‚amide, amide‚‚‚amide, amide‚‚‚pyridine N-oxide, OH‚‚‚O, O-H‚‚‚N, N-H‚‚‚O, and N-H‚‚‚N, offers a great opportunity to design pharmaceutical cocrystals.9 An early work * Author to whom correspondence should be addressed. E-mail: [email protected]. Tel: +46-920-493924. Fax: +46-920-493850. † Luleå University of Technology. ‡ Umeå University.

by Zaworotko et al. on the cocrystals of carbamazepine has drawn the attention of many pharmaceutical scientists and crystal engineers and has led to the pipeline of very interesting publications on the topic.10 A recent review on the topic conveys the potential of cocrystallization technology in addition to presenting various practical and important issues in the design of pharmaceutical cocrystals.11 Norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid) is a widely used fluoroquinolone antibacterial compound.12 In aqueous solution, norfloxacin essentially exists in a zwitterionic form, owing to the acid/base interaction between the basic nitrogen of the piperazine and the carboxylic acid group (Scheme 1). Therefore, the aqueous solubility of norfloxacin at a pH close to 7 (isoelectric point of the molecule) is low (0.28-0.40 mg/mL).13 This poses significant challenges in the formulation of conventional dosage forms, e.g. tablets, and impedes the design of liquid dosage forms, such as parenteral and ophthalmic solutions. Therefore, improving the aqueous solubility of norfloxacin through the preparation of cocrystals and new salt forms of the compound is of interest for the design of dosage forms. In addition to the discovery and identification of new polymorphs of a drug substance, obtaining structural information is important to better elucidate their pharmaceutical properties such as bioavailability, stability, and processability. Norfloxacin is claimed to exist in two polymorphic forms (enantiotropic forms A and B) and hydrates.14,18a However, except for norfloxacin dihydrate,15 there is no structural evidence for any other crystal forms or salts of norfloxacin. Hence, in this contribution, we present the structural analysis of norfloxacin anhydrate (form A), its cocrystal with isonicotinamide, and its salts with succinic acid, malonic acid, and maleic acid. Among these salts, succinic acid is the FDA-approved GRAS (generally recognized as safe) compound. We employed solid-state material characterization techniques such as DSC, IR, Raman, and PXRD to characterize these new phases. Crystal structures of these compounds were obtained from single-crystal X-ray diffraction studies. Finally, the solubility of the new phases was determined. 2. Materials and Methods All chemicals (purity >99.8%) were obtained from Sigma Aldrich, Stockholm, Sweden. Solvents (purity >99%) were purchased from

10.1021/cg060327x CCC: $33.50 © 2006 American Chemical Society Published on Web 10/13/2006

2700 Crystal Growth & Design, Vol. 6, No. 12, 2006 Scheme 1.

Basavoju et al.

Zwitterionic Form of Norfloxacin (a) and Norfloxacin Protonated by Dicarboxylic Acids (b)

Table 1. Solvents of Crystallization, Crystal Morphology, and Melting Points of Compounds 1-5 compd 1 2 isonicotinamide 3 succinic acid 4 malonic acid 5 maleic acid a

solvent of crystallizn

morphology of the cryst

mp (°C)

lit. mp (°C)a

DMF CHCl3 -

needles irreg blocks -

221 180-185 -

220-221 155-157

H2O H2O H2O -

rectangular blocks rectangular blocks needles -

226-230 216-218 207-210 -

184-186 132-135 137-140

Obtained from Merck Index and Sigma Aldrich catalog.

VWR International, Stockholm, Sweden, and were used without further purification. Distilled water was used. Crystallization of Norfloxacin Anhydrate (1). We crystallized norfloxacin in several organic solvents, including MeOH, CHCl3, acetone, THF, and DMF. Preparation of Norfloxacin-Isonicotinamide-CHCl3 Cocrystal Solvate (2). A 1:1 mixture of norfloxacin (31.9 mg, 0.1 mmol) and isonicotinamide (11.2 mg, 0.1 mmol) was dissolved in 8 mL of CHCl3 in a 25 mL conical flask. The CHCl3 was evaporated at room temperature in a fume hood. Preparation of Salts and Crystallization. Norfloxacin and the dicarboxylic acids in the specified ratios were hand-ground using a mortar and pestle for 15-20 min. One or two drops of distilled water were added, and the mixture was again ground for 10 min. The mixture was transferred into a 25 mL conical flask, and 5-6 mL of distilled water was added and this mixture heated to dissolve the contents completely. The solution was then allowed to slowly evaporate in a controlled fume hood (temperature 22 °C, air flow 0.54 m/s) for crystallization. Diffraction-quality crystals were obtained within 3-5 days. Each sample was scaled up to 250 mg for the solubility determination. In a separate experiment, ground material after addition

of two drops of water was dried and PXRD patterns were collected to check if salt formation had taken place. However, the PXRD patterns indicated only partial conversion. Norfloxacin 0.5(Succinate) Hydrate (3). A 1:1 mixture of norfloxacin (63.8 mg, 0.2 mmol) and succinic acid (23.6 mg, 0.2 mmol) was used for the crystallization. However, the salt was formed in a 2:1 ratio. Norfloxacin Malonate Dihydrate (4). A 1:1 mixture of norfloxacin (63.8 mg, 0.2 mmol) and malonic acid (20.8 mg, 0.2 mmol) was used for the crystallization. Norfloxacin Maleate Hydrate (5). A 1:1 mixture of norfloxacin (63.8 mg, 0.2 mmol) and maleic acid (23.2 mg, 0.2 mmol) was used for the crystallization. The melting points of 1-5 were observed using an Electro Thermal 1A9000 series digital melting point apparatus. Optical micrographs of all crystals were taken under the Leica MZ6 polarization microscope. IR Spectroscopy. A Perkin-Elmer 2000 FT-IR spectrophotometer was used in the KBr diffuse-reflectance mode (sample concentration 2 mg in 20 mg of KBr) for collecting the IR spectra of the samples. It was equipped with an MCT detector. The spectra were measured over the range of 4000-400 cm-1. Data were analyzed using Spectrum software (version 1.5, Feb 24, 1997). Raman Spectroscopy. The Raman spectra were recorded on a Perkin-Elmer near-IR FT-Raman 1700X spectrometer equipped with an indium gallium arsenide (InGaAs) detector. An excitation wavelength of 1064 nm of Nd:YAG laser radiation was used. A total of 50 scans was collected from 4000 to 400 cm-1 for each sample. Differential Scanning Calorimetry (DSC). Thermal analyses of these samples were performed on a Mettler Toledo DSC 822e module equipped with liquid nitrogen cooling. The crystals (3-5 mg) were placed in aluminum crucibles (30 µL) and were scanned at 10 °C/min in the range 25-300 °C under a dry nitrogen atmosphere (flow rate 80 mL/min). The data were managed by STAR software. Powder X-ray Diffraction (PXRD). PXRD patterns were collected on a Siemens DIFFRACplus 5000 powder diffractometer with a Cu KR radiation (1.540 56 Å). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for the illumination on the 20 mm sample

Table 2. Salient Crystallographic Data and Structure Refinement Parameters

empirical formula formula wt cryst syst space group (No.) T (K) a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) Z V (Å3) Dcalcd (g/cm3) µ (mm-1) no. of rflns collected no. of unique rflns no. of obsd rflns no. of params R1 wR2 GOF CCDC No.

1

2

3

4

5

C16H18FN3O3 319.33 triclinic P1h (2) 295(2) 4.3240(10) 9.6350(10) 18.0890(10) 78.514(10) 87.121(10) 80.574(10) 2 728.43(19) 1.456 0.111 3469 3469 1247 209 0.1050 0.1791 1.047 617104

C23H25Cl3FN5O4 560.83 monoclinic C2/c (15) 150(2) 18.8749(7) 14.6353(6) 18.4094(4) 90 98.432(2) 90 8 5030.4(3) 1.481 0.412 13 809 7545 4435 341 0.1020 0.2582 1.032 617105

C18H23FN3O6 396.39 triclinic P1h (2) 150(2) 6.8086(2) 9.3743(3) 15.5127(4) 93.690(2) 93.262(2) 110.885(2) 2 919.75(5) 1.431 0.115 5555 5555 4268 273 0.0596 0.1267 1.067 617106

C19H26FN3O9 459.43 triclinic P1h (2) 150(2) 8.2170(1) 9.1380(2) 13.8830(2) 90.3920(10) 91.0800(10) 96.7710(10) 2 1034.93(3) 1.474 0.123 11 273 6218 5558 321 0.0405 0.1072 1.020 617107

C20H24FN3O8 453.42 triclinic P1h (2) 150(2) 7.0890(2) 9.8742(3) 14.5854(3) 96.457(2) 92.300(2) 102.937(2) 2 986.47(3) 1.526 0.125 10 413 5931 4562 313 0.0492 0.1217 1.077 617108

Pharmaceutical Cocrystal and Salts of Norfloxacin size. Each sample was scanned between 5 and 50° in 2θ with a step size of 0.02°. The instrument was previously calibrated using a silicon standard. The experimental PXRD patterns and simulated PXRD spectra from single-crystal structures were Rietveld refined using TOPAS R (version 2.1, 2003) and Powdcell (version 2.4, 2000) and were compared to confirm the composition of the materials 1-5. Single-Crystal X-ray Diffraction. The single-crystal X-ray diffraction data of the crystals were collected on a Bruker Nonius Kappa CCD. The data set for compound 1 was collected at room temperature (295 K), while the remaining data sets were collected at 150 K. All of the data sets were collected using Mo KR radiation (λ ) 0.710 73 Å), and crystal structures were solved by direct methods using SHELXS-97 and refined by full-matrix least-squares refinement on F2 with anisotropic displacement parameters for non-H atoms using SHELXL-97.16 N-H and O-H hydrogens were refined from difference Fourier maps (except for compound 1, where these hydrogens were fixed), whereas aromatic and aliphatic C-H hydrogens were generated by the riding model in idealized geometries. Table 2 gives the pertinent crystallographic data, and Table 3 gives the hydrogen-bond parameters. Solubility Studies. The solubility studies for various powders (15) were performed according to Higuchi and Connor’s method with some variations.17 Excess amounts (∼21 mg) of the samples were suspended in 2.5 mL of water in screw-capped glass vials. These vials were kept in a laboratory oven (Memmert, Germany) maintained at 25 °C ((1) and were stirred at 300 rpm using a magnetic stirrer. After 72 h, the suspensions were filtered through a paper filter (0.8 µm) and solid filtrates were collected for PXRD analysis. The resulting solution was again filtered through a 0.2 µm syringe filter. The filtered aliquots were sufficiently diluted, the absorbances were measured at 276 nm in triplicate, and the values were normalized for norfloxacin. Finally, the concentration of norfloxacin after 72 h (apparent aqueous solubility) in each sample was determined from the previously made standard graph. A standard graph was made by measuring the absorbance of varied concentrations of norfloxacin in water using a UV spectrophotometer (Perkin-Elmer Lambda 2S UV/vis spectrometer) at λmax 276 nm.

3. Results and Discussion Solvents of crystallization together with information on the shapes of the crystals of various phases and their melting points are presented in Table 1. The difference in melting points of these phases compared to those of either of the materials present strongly indicates the formation of new phases. Morphologies of these crystals are shown in Figure 1. IR and Raman Analysis. It has been reported that the norfloxacin anhydrate exists as a neutral molecule and shows an IR absorption frequency for the carboxylic acid CdO group at 1732 cm-1.18 Once the water molecule is incorporated (i.e. hydrated form), it converts to a zwitterion and shows a lower IR absorption frequency, 1584 cm-1 (Scheme 1a). The absorption frequency for CdO in 1 was 1730.8 cm-1, which indicates that the -COOH group is stable and norfloxacin exists as an anhydrate. However, in cocrystal 2, a shift in the CdO stretching frequency from 1732 cm-1 to 1572 cm-1 (i.e. a characteristic peak for the norfloxacin zwitterion) suggests that norfloxacin exists as a zwitterion. Further, in compound 2, the broad IR absorption peak at 2501.8 cm-1 indicates the protonation of the piperazinyl ring N atom (NH2+), while the corresponding peak is clearly absent in norfloxacin anhydrate. This suggests that the intramolecular proton transfer occurs (resulting as zwitterion) in the case of 2. The IR absorption frequencies (1701.3-1719.8 cm-1) for the carboxylic acid CdO group in salts 3-5 were observed in a range similar to that of compound 1. This suggests that the -COOH group of norfloxacin moiety in 3-5 is stable and does not participate in the formation of a zwitterion. However, the broad IR absorption frequencies 2501.8-2509.2 cm-1 for compounds 3-5 indicate the protonation of the piperazinyl ring N atom (NH2+) and this proton is evidently transferred from the dicarboxylic acids (salt formers) (Scheme

Crystal Growth & Design, Vol. 6, No. 12, 2006 2701 Table 3. Geometrical Parameters of Hydrogen Bonds in Compounds 1-5 D-H‚‚‚Aa

D‚‚‚A (Å)

H‚‚‚A (Å)

D-H‚‚‚A (deg)

N3-H18‚‚‚N3 intra O2-H17‚‚‚O3 intra C11-H5‚‚‚F4 C1-H1‚‚‚O1 C15-H12‚‚‚O1 C16-H16‚‚‚O2 C15-H16‚‚‚O1 C15-H16‚‚‚O2

Compound 1 3.638(7) 2.527(6) 2.898(7) 3.440(7) 3.455(7) 3.547(7) 3.594(7) 3.705(8)

2.66 1.68 2.17 2.44 2.41 2.65 2.63 2.73

163 142 122 154 161 140 147 149

N3-H17‚‚‚O3 N3-H18‚‚‚O2 N5-H23‚‚‚O1 N5-H24‚‚‚O4 C1-H1‚‚‚N4 intra C11-H4‚‚‚F1 C13-H9‚‚‚O1 C15-H12‚‚‚O2 C18-H20‚‚‚O1 C23-H25‚‚‚O3

Compound 2 2.668(12) 2.657(12) 2.929(13) 2.889(13) 3.466(15) 2.813(13) 3.277(14) 3.654(16) 3.475(15) 3.221(15)

1.73 1.66 1.96 1.89 2.41 2.12 2.44 2.70 2.47 2.48

152 170 161 170 166 120 133 147 153 124

N3-H17‚‚‚O5 intra O2-H18‚‚‚O3 N3-H19‚‚‚O4 O6-H22‚‚‚O4 O6-H23‚‚‚O5 C6-H2‚‚‚F1 C9-H3‚‚‚O6 intra C11-H4‚‚‚F1 C11-H4‚‚‚O1 C12-H7‚‚‚O6 C13-H8‚‚‚O5 C14-H11‚‚‚O2 C15-H12‚‚‚O6 C15-H13‚‚‚O1

Compound 3 2.7260(18) 2.5135(17) 2.7522(18) 2.8540(19) 2.9288(19) 3.2331(16) 3.610(2) 2.8735(17) 3.475(2) 3.639(2) 3.3936(19) 3.3526(19) 3.324(2) 3.2529(19)

1.74 1.58 1.76 1.89 1.96 2.34 2.53 2.23 2.55 2.63 2.43 2.45 2.58 2.50

165 156 167 166 167 139 176 116 143 155 147 140 125 125

N3-H17‚‚‚O6 intra O2-H18‚‚‚O3 N3-H19‚‚‚O8 Intra O5-H22‚‚‚O7 O8-H23‚‚‚O1 O8-H24‚‚‚O9 O9-H25‚‚‚O7 O9-H26‚‚‚O4 C1-H1‚‚‚O4 C11-H4‚‚‚O1 Intra C11-H5‚‚‚F1 C13-H8‚‚‚O2 C16-H15‚‚‚O4 C16-H16‚‚‚O5 C17-H20‚‚‚O1

Compound 4 2.7038(11) 2.4814(11) 2.7078(16) 2.4740(10) 2.7910(15) 2.7250(16) 2.7557(12) 2.8239(13) 3.5907(13) 3.5241(14) 2.8430(12) 3.3684(14) 3.3136(13) 3.4543(12) 3.3133(14)

1.77 1.53 1.80 1.58 2.04 1.95 1.87 1.98 2.65 2.59 2.20 2.44 2.56 2.63 2.60

165 160 171 159 151 167 179 171 166 165 124 163 134 146 131

N3-H17‚‚‚O8 intra O2-H18‚‚‚O3 intra O5-H22‚‚‚O6 N3-H19‚‚‚O7 O8-H23‚‚‚O6 O8-H24‚‚‚O7 C1-H1‚‚‚O1 intra C11-H4‚‚‚F1 C11-H5‚‚‚O8 C11-H5‚‚‚O1 C12-H6‚‚‚O1 C13-H8‚‚‚O4 C13-H8‚‚‚O8 C13-H9‚‚‚O2 C16-H15‚‚‚O6 C18-H21‚‚‚O2

Compound 5 2.757(9) 2.522(8) 2.468(8) 2.772(9) 3.022(9) 2.733(8) 3.371(10) 2.843(9) 3.364(10) 3.488(11) 3.705(11) 3.479(11) 3.482(11) 3.407(10) 3.290(10) 3.564(11)

1.76 1.58 1.49 1.77 2.04 1.78 2.40 2.05 2.58 2.68 2.72 2.48 2.64 2.48 2.44 2.57

165 160 174 171 179 163 148 127 129 131 150 152 134 143 135 152

a All of the C-H, N-H, and O-H distances are neutron normalized to 1.083, 1.009, and 0.983 Å.

1b). Raman spectra show that the wavenumbers for the carboxylic acid group vibration (1712.4 cm-1 in 3, 1701.3 cm-1

2702 Crystal Growth & Design, Vol. 6, No. 12, 2006

Basavoju et al.

Figure 1. Optical micrographs of compounds 1-5.

Figure 2. IR and Raman spectra of compounds 1-5.

in 4, and 1719.8 cm-1 in 5) were comparable to that of norfloxacin anhydrate (1; 1719.5 cm-1) (Figure 2). This reiterates that the carboxylic acid group of norfloxacin is stable and is not involved in the formation of a zwitterion. The existence of norfloxacin as a neutral species and zwitterions in the crystal structures was later confirmed by the single-crystal X-ray diffraction study. DSC Analysis. DSC curves showing the thermal behavior of the compounds 1-5 in this study are shown in Figure 3.

The DSC thermogram for 1 showed an endothermic melting peak at 221 °C followed by an exothermic peak, possibly a melt degradation. The thermal behavior of 1 is similar to that of polymorphic form A, signifying that 1 is indeed norfloxacin anhydrate form A.14 In the DSC thermogram for 2, a small endothermic transition at around 120 °C, attributed to solvent loss followed by a two-step endothermic melting transition of the cocrystal, was observed. The endothermic transitions between 60 and 120 °C in the DSC thermograms for 3-5

Pharmaceutical Cocrystal and Salts of Norfloxacin

Figure 3. DSC thermograms of compounds 1-5.

Crystal Growth & Design, Vol. 6, No. 12, 2006 2703

indicate the loss of water molecules from the crystal structure. Later endothermic peaks between 137 and 225 °C indicate the phase transitions leading to the melting of the materials. The melt degradation, as evidenced by the exothermic peak after the melting, was also observed in the case of 3-5. PXRD Analysis. The PXRD pattern for 1 was identical with that of the starting material (anhydrous form) and with the reported PXRD pattern for polymorphic form A.14a This confirms that 1 is norfloxacin polymorph A. The distinct nature of PXRD patterns of 2-5 compared to that of 1 indicates the generation of new solid phases. Furthermore, the experimental and simulated PXRD patterns of compounds 1-5 were identical (Figure 4). Crystal Structure Analysis. (a) Norfloxacin Anhydrate (1; Form A). It is evident from the single-crystal X-ray diffraction study that an anhydrous form with a neutral molecule (no proton transfer from carboxylic acid to piperazinyl N atom) is present

Figure 4. Comparison of PXRD patterns: Rietveld refined simulated PXRD patterns (red) and experimental PXRD patterns (black) for compounds 1-5.

Figure 5. (a) ORTEP representation of norfloxacin (1). Thermal ellipsoids are drawn at the 50% probability level. (b) Molecular diagram showing interactions in the crystal.


Basavoju et al.

Figure 6. Layered structure of 1 in which norfloxacin molecules are connected by N-H‚‚‚N and C-H‚‚‚O hydrogen bonds. Note the intramolecular O-H‚‚‚O hydrogen bond.

Figure 7. (a) ORTEP perspective of the cocrystal 2. Thermal ellipsoids are drawn at the 50% probability level. (b) Molecular diagram showing interactions in the cocrystal.

in the crystal structure (Figures 5 and 6). The norfloxacin anhydrate crystallizes in the triclinic P1h space group with one molecule in the asymmetric unit. The carboxylic acid group is coplanar with the quinolone moiety (torsion angle O2-C3C2-C1 ) 179.63°) and participates in intramolecular O-H‚‚ ‚O (O‚‚‚O ) 2.527(6), 1.68 Å, O-H‚‚‚O ) 142°) hydrogen bonding with the carbonyl oxygen atom of the quinolone moiety (Figure 5a). The C-O and CdO bond distances of the carboxylic acid group of norfloxacin molecule are 1.316 and 1.207 Å, respectively. The piperazinyl ring is in the usual chair conformation with a torsion angle of C11-N2-C8-C9 ) 123.45°. The investigation of the crystal structure reveals that the molecules form layers and these layers are parallel to (113) planes. The inversion-related molecules in the layers interact via N-H‚‚‚N (N‚‚‚N ) 3.638(7), 2.66 Å, N-H‚‚‚N ) 163°) and C-H‚‚‚O (C‚‚‚O ) 3.440(7), 2.44 Å, C-H‚‚‚O ) 154°) hydrogen-bonded dimers (Figure 6). These layers are stacked with π‚‚‚π (4.324 Å) interactions along the short axis (a-axis) and further stabilized by C-H‚‚‚O interlayer interactions.19 Intramolecular C-H‚‚‚F interactions are present in 1 as well as in other structures. (b) Norfloxacin-Isonicotinamide-CHCl3 Cocrystal Solvate (2). 2 crystallizes in the centrosymmetric C2/c space group with one molecule of norfloxacin, one molecule of isonicotinamide, and one molecule of CHCl3 in the asymmetric unit. Surprisingly, the norfloxacin exists in a zwitterionic form without any H2O molecules. This suggests that even the CHCl3 molecule can induce the formation of a zwitterion. The carboxylate group of norfloxacin is not coplanar with the quinolone moiety (torsion angle O2-C3-C2-C1 ) 146.96°), due to the repulsion of the carboxylate and quinolone oxygen atoms (O2,

Figure 8. (a) Amide dimer synthon formed by isonicotinamide molecules and the rectangular network formed by four molecules of norfloxacin in 2. The additional hydrogens of the amide dimer interact with the carboxylate group of the norfloxacin molecules. CHCl3 molecules are removed for clarity. (b) CHCl3 molecules lying in the channels of the host framework viewed down the c-axis.



Figure 9. (a) ORTEP diagram of the salt 3. Thermal ellipsoids are drawn at the 50% probability level. (b) Molecular diagram showing interactions in 3.

O3) (Figure 7a). The C-O and CdO bond lengths of the carboxylate group of norfloxacin molecule are 1.259 and 1.249 Å. The structural analysis reveals that the four norfloxacin molecules generate a rectangular host type network with N+H‚‚‚O (N+‚‚‚O ) 2.668(12), 1.73 Å, N+-H‚‚‚O ) 152°) and N+-H‚‚‚O- (N+‚‚‚O- ) 2.657(12), 1.66 Å, N+-H‚‚‚O- ) 170°) interactions. Two isonicotinamide molecules form a robust amide‚‚‚amide (N‚‚‚O ) 2.889(13), 1.89 Å, N-H‚‚‚O ) 170°) homodimer synthon, resulting in a supermolecule. This supermolecule fits into the rectangular grid by additional anti hydrogen atoms of the amide groups interacting with carboxylate oxygen atoms of 1 (N‚‚‚O- ) 2.929(13), 1.96 Å, N-H‚‚‚O) 161°), as shown in Figure 8a. The overall structure is corrugated layers, and these form voids to incorporate the CHCl3 molecules. The CHCl3 molecules lie in the channels by interacting with norfloxacin molecules via weak C-H‚‚‚O (C‚ ‚‚O ) 3.221(15), 2.48 Å, C-H‚‚‚O ) 124°) and C-H‚‚‚Cl interactions (Figure 8b). It can be explained from the thermal behavior of 2 that these interactions cause the delayed escape of CHCl3 from the host framework. Further, these corrugated layers are stacked by π‚‚‚π (4.519 Å) interactions. (c) Salts of Norfloxacin (3-5). The salts of norfloxacin 3-5 crystallize in the triclinic P1h space group. These salt structures form channels that extend along the crystallographic axis with π-stacks of norfloxacin moieties linked through H2O molecules. A similar structural feature with hydrophilic channels and π-stacked layers formed by quinolone moieties is also reported in case of ciprofloxacin lactate sesquihydrate.20 The crystal structure of norfloxacin 0.5(succinate) hydrate (3) has one norfloxacin cation, a half-molecule of succinate dianion, and one H2O molecule of crystallization in the asymmetric unit. The two carboxylic acid groups of succinic acid transfer two protons to the piperazinyl ring N atom of two norfloxacin molecules, thereby forming a succinate dianion and norfloxacin cations in the crystal structure (Figure 9a). The C-O and CdO bond distances of the carboxylate group of the succinate dianion are 1.257 and 1.256 Å, respectively. The carboxylic acid group of norfloxacin is involved in intramolecular hydrogen bonding with the quinolone oxygen atom (O‚‚‚O ) 2.5135(17), 1.58 Å, O-H‚‚‚O ) 156°). The two succinate anions and two norfloxacin cations form a cyclic tetramer synthon (N+‚‚‚O- ) 2.7260(18), 1.74 Å, N+-H‚‚‚O- ) 165°; N+‚‚‚O- ) 2.7522(18), 1.76 Å, N+-H‚‚‚O- ) 167°) and infinitely extends with H2O molecules through the channel (major diameter 8.864 Å, minor diameter 4.931 Å) generated by quinolone stacked layers (π‚‚‚π ) 4.041 Å) along the a-axis via O-H‚‚‚O- (O‚‚‚O- ) 2.9288(19), 1.96 Å, O-H‚‚‚O- )

167°; O‚‚‚O- ) 2.8540(19), 1.89 Å, O-H‚‚‚O- ) 166°) interactions (Figure 10).21 The 1:1 salt structure of norfloxacin malonate dihydrate (4) contains a norfloxacin cation, a malonate anion, and two H2O molecules in the asymmetric unit (Figure 11a). One of the carboxylic acid groups of malonic acid is involved in intramolecular hydrogen bonding (O‚‚‚O ) 2.4814(11), 1.53 Å, O-H‚‚‚O ) 160°), and the other is ionized by proton transfer to the norfloxacin molecule to form a N+-H‚‚‚O- (N+‚‚‚O) 2.7038(11), 1.77 Å, N+-H‚‚‚O- ) 165°) hydrogen bond. The C-O and CdO bond distances of the carboxylate moiety of the malonate anion are 1.273 and 1.244 Å, respectively. The C-O and CdO bond lengths of the carboxylic acid moiety of the malonate anion are 1.221 and 1.310 Å, respectively. The norfloxacin molecules form stacked layers in the crystal structure with π‚‚‚π interactions of 3.960 Å, thereby forming hydrophilic channels with major and minor diameters of 14.908 and 5.077 Å, respectively (Figure 12). The two H2O molecules connect the inversion-related salt structure in the channel via O-H‚‚‚O (O‚‚‚O ) 2.7910(15), 2.04 Å, O-H‚‚‚O ) 151°; O‚‚‚O ) 2.8239(13), 1.98 Å, O-H‚‚‚O ) 171°), O-H‚‚‚O- (O‚‚‚O- ) 2.7557(12), 1.87 Å, O-H‚‚‚O- ) 179°), and N+-H‚‚‚O (N+‚ ‚‚O ) 2.7078(16), 1.80 Å, N+-H‚‚‚O ) 171°) interactions to form a one-dimensional ladder structure. These ladders are further connected by weak C-H‚‚‚O interactions. The single-crystal X-ray structure of norfloxacin maleate hydrate (5) has one norfloxacin cation, one maleate anion, and one H2O molecule in the asymmetric unit. A proton transfer

Figure 10. H2O molecules in 3 lying in the channels formed by the quinolone stacked layers viewed along the a-axis. The succinate dianions are connected by O-H‚‚‚O- and N-H‚‚‚O- interactions.


Basavoju et al.

Figure 11. (a) ORTEP representation of the salt 4. Thermal ellipsoids are drawn at the 50% probability level. (b) Molecular diagram showing interactions in 4.

Figure 12. One-dimensional ladder type network formed in 4 with O-H‚‚‚O, O-H‚‚‚O-, N-H‚‚‚O, and N-H‚‚‚O- interactions. The stacked layers can also be seen. Note the intramolecular O-H‚‚‚O hydrogen bond in the malonate ion.

takes place from one of the carboxylic groups of the maleic acid to the norfloxacin molecule, forming a salt structure (Figure 13a). Another carboxylic acid group participates in the intramolecular (O‚‚‚O ) 2.522(8), 1.50 Å, O-H‚‚‚O ) 167°) hydrogen bonding. The C-O and CdO bond distances of the carboxylate moiety of the maleate anion are 1.263 and 1.246 Å, respectively. The C-O and CdO bond lengths of the carboxylic acid group of the maleate anion are 1.316 and 1.218 Å, respectively. A closer examination of the crystal structure shows that the norfloxacin ions form hydrogen bonds with the maleate ion via N+-H‚‚‚O- (N+‚‚‚O- ) 2.774(9), 1.77 Å, N+-H‚‚‚ O- ) 175°) interactions. The outward-projecting norfloxacin molecules form stacked layers along the a-axis (π‚‚‚π ) 3.659 Å), thereby forming channels with a major diameter of 9.321 Å

and a minor diameter of 5.013 Å to include H2O molecules via O-H‚‚‚O- (O‚‚‚O- ) 3.023(9), 2.04 Å, O-H‚‚‚O- ) 179°) hydrogen bonds (Figure 14). These stacked layers are interconnected by C-H‚‚‚F interactions. CSD Analysis. A CSD (ConQuest version 5.27, Nov 2005, number of hits 355 064) search for C-O and CdO bond distances in carboxylic acids and carboxylate anions was performed. Good-quality carboxylic acid structures containing ordered, error-free, and nonpolymeric organic compounds with 3D coordinates and having R < 5% were chosen for the analysis.22 A total of 1974 carboxylic acid crystal structures revealed that C-O and CdO distances average 1.307 and 1.216 Å, respectively, while 1947 structures containing at least one carboxylate group show that the C-O distances average 1.252 Å. This implies that the C-O bond distances can distinguish the carboxylic acids of cocrystals or solvates from carboxylates of salts, even though the carboxylate moieties tend to be unsymmetrical. This analysis can also be implemented in this study to better understand the structural features of 1-5. The C-O and CdO bond lengths (1.316 and 1.207 Å) in 1 indicate the stable carboxylic acid group in 1. In the cocrystal 2, C-O and CdO distances (1.259 and 1.249 Å) show the presence of a chargeassisted carboxylate group in zwitterionic norfloxacin. The C-O and CdO distances of norfloxacin in 3-5 (averages 1.329 and 1.216 Å, respectively) indicate that the carboxylic acid group is stable. However, the salt formation in 3-5 can be evidenced from the C-O and CdO distances (averages 1.264 and 1.248 Å, respectively) of carboxylate groups of dicarboxylic acids. Solubility Data for 1-5. The apparent solubility data for 1-5 are presented in Table 4. The solubility of 1 was 0.21 mg/

Figure 13. (a) ORTEP diagram of the salt 5. Thermal ellipsoids are drawn at the 50% probability level. (b) Molecular diagram showing interactions in 5.



Figure 14. Norfloxacin N-H‚‚‚O and N-H‚‚‚O- interactions with the maleate ion in 5. The H2O molecules bind with maleate ions by O-H‚‚‚Ointeractions. Note the intramolecular O-H‚‚‚O- hydrogen bond in the maleate ion. Table 4. Solubility Data for Norfloxacin (Starting Material) and 1-5 compd

apparent solubilitya (mg/mL)

norfloxacinb

0.21 (0.01) 0.21 (0.01) 0.59 (0.01) 6.60 (0.01) 3.90 (0.00) 9.80 (0.01)

1 2 3 4 5

a Solubility measured after 72 h of equilibration. The standard deviation of the method is shown in parentheses. b Solubility of norfloxacin anhydrate, as cited in the Merck Index, is 0.28 mg/mL.

mL. This is in agreement with the reference value (0.28 mg/ mL) that indirectly validates our solubility method. The solubilities of 1 and the starting material are similar, which demonstrates that 1 is in fact norfloxacin form A. Further, the solubilities of 2-5 were improved from 3 times for a cocrystal to 20-45 times for salts. However, we were unable to confirm the solid state of the undissolved phase. It is very difficult to correlate solubility with crystal structures with the limited experimental/calculated data on enthalpy, crystal packing, etc. available for the new phases. However, it can be speculated that the solubility increase in the case of the cocrystal is a result of a change in the crystal energy (∆Hsolvation) and greater ionization potential in the case of salts. 4. Conclusions Norfloxacin anhydrate was crystallized, and the crystal structure was determined. A cocrystal with isonicotinamide and salts with succinic acid, malonic acid, and maleic acid were prepared, and their crystal structures were determined. Norfloxacin anhydrate forms a layered structure, and these layers are stacked with π‚‚‚π interactions. In the cocrystal, isonicotinamide forms an amide dimer synthon and additional hydrogens of the amide group interact with the carboxylate group of norfloxacin molecules. A channel network is formed in the cocrystal to include CHCl3 molecules. The crystal structures of salts form significant channels with π-stacked layers to accommodate H2O molecules. A common feature in norfloxacin and its salts is that the π-stacked layers are formed along the crystallographic a-axis. In the salt structures, the piperazinyl moieties of norfloxacin interact with the dicarboxylate ions. These dicarboxylate ions connect the H2O molecules alterna-

tively in the channels and propagate along the crystallographic a-axis. The norfloxacin cocrystal and salts show a 3-45× increase in the solubility as compared to that of the starting material. Acknowledgment. We acknowledge “Norbottensforskningsråd” for a grant (NoFo 05-011). We thank Prof. Allan Holmgren for the initial help with the handling of IR and Raman instrumentation. Supporting Information Available: CIF files giving crystal data for compounds 1-5. This material is available free of charge via the Internet at http://pubs.acs.org.

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Pharmaceutical Cocrystal and Salts of Norfloxacin - Crystal Growth

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