A Device to Crystallize Organic Solids: Structure of Ciprofloxacin

Mar 21, 2010 - A Device to Crystallize Organic Solids: Structure of Ciprofloxacin, Midazolam, and Ofloxacin as Targets. Sudarshan Mahapatra, K. N. Ven...
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DOI: 10.1021/cg901565q

A Device to Crystallize Organic Solids: Structure of Ciprofloxacin, Midazolam, and Ofloxacin as Targets

2010, Vol. 10 1866–1870

Sudarshan Mahapatra, K. N. Venugopala, and Tayur N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560 012, India Received December 12, 2009; Revised Manuscript Received February 22, 2010

ABSTRACT: The crystal structure determination of the anhydrous form of any organic compound has been a challenge because of solvent incorporation during crystallization. A device to grow anhydrous forms of low melting organic solids based on vaporization and condensation by a gradient cooling technique has been designed. Its utility has been evaluated by growing anhydrous forms of ciprofloxacin, midazolam, and ofloxacin. Ciprofloxacin crystallizes in triclinic P1, midazolam in monoclinic P21/n, and ofloxacin in the C2/c space group. Comparative studies on the conformational features with solvated structure show no significant variation in the aromatic moieties.

Introduction The crystal structure determination of organic compounds has become essential to understand structure-property correlation and is of specific importance in the pharmaceutical industry. In particular, the structure determination is unambiguously carried out using data obtained from a single crystal. One of the essentials for a successful structure determination is the requirement of a good quality single crystal or a single phase polycrystalline sample of the given material. Often crystals are formed with the incorporation of the solvent in the lattice during crystallization. This generally occurs either through randomly absorbed solvent molecules or through the capture of fluid inclusions of solvent. The last mechanism is the most dangerous for the crystal quality and is mainly due to kinetic reasons. As a matter of fact, it is well-known that when the normal growth rate of a given crystal face exceeds a critical value, macro steps form and run on the face surface, and their overhanging generates the privileged locations for the capture of nano- or microscopic fluid inclusions. Water of crystallization is invariably preferred in the crystal of many small biomolecules, large proteins, and enzymes. In order to obtain crystal structures of anhydrous compounds, a novel approach is required where intervention of solvent can be entirely eliminated. There are a large number of methods to synthesize single crystals of a required compound like for example slow evaporation, vapor diffusion, solvent diffusion, sublimation, convection, and zonemelting.1-8 Out of these techniques, slow evaporation from a solution is frequently adopted to grow single crystals of organics, and frequently this process leads to the incorporation of the solvent in the crystal structure. For example, adenine always crystallizes with the incorporation of three water molecules during crystallization. Recently, we have reported a methodology to crystallize anhydrous adenine based on its sublimation characteristics.3,8 Ciprofloxacin (patented in 1987) is a widely used broadspectrum antibiotic, which is active against both Grampositive9 and Gram-negative10 bacteria. An analysis of the Cambridge structure database (CSD 5.3, Updates May 2009) shows 52 hits for ciprofloxacin, which contain both organic *Author for correspondence. Tel: þ91-80-2292796. Fax: þ91-80-3601310. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 03/21/2010

and organometallic derivatives. There are only five structures [ref code- UJAGUH,11 JIRYAL,12 IDARUA,13 SESZEW,14 and COVPIN15] which represent salts with ciprofloxacin. Midazolam (patented in 2001), which is a benzodiazepine derivative drug has a wide variety of properties such as amnestic,16 hypnotic,17 anxiolytic,18 and sedative,17 and the database contains only one salt structure of midazolam with saccharinate.19 Ofloxacin was first patented in 1982 as a broader spectrum analogue of norfloxacine, the first fluoroquinolone antibiotic. Database analysis of ofloxacin gives seven hits out of which four are organometallic complexes, two are hydrated forms, and one is a perchloric acid salt. These observations suggest that crystallization of such drugs without the incorporation of solvent and/or hydration due to incorporation of water of crystallization is not an easily reachable target. In this article, we report the design of an apparatus to crystallize such compounds and in fact any organic solid (including sublimating organics) in its anhydrous form. The crystal structures of the anhydrous form of ciprofloxacin, midazolam, and ofloxacin are reported. Experimental Section Materials. Ciprofloxacin, midazolam, and ofloxacin were synthesized following U.S. Patent Nos. 4670444, 4280957, and 4777253, respectively. The compounds were then used in the crystallization experiments carried out with the new device. Crystallization Set Up. A device was constructed to grow the crystals of low melting organics which essentially involves melting of the starting material initially followed by vaporization. The vapor is then allowed to pass through a variable temperature gradient. The schematic diagram of the apparatus is shown in Figure 1. All the necessary information associated with the compound, particularly in terms of its thermal history, is verified using differential scanning calorimetry and thermogravimetric analysis measurements and also to ensure that the material agrees with the reported thermal characterization. Since the process of crystallization involves vaporizing the sample so the purity of the starting material is not of much concern. The apparatus consists of a quartz furnace with a PID temperature controller, a vacuum pump (30-650 mm/Hg), an oil bath, and a specially designed gradient cooling system (Figure 1). The gradient cooling apparatus is an assembly of six crystallization zones, each made up of coaxial glass tubes of length 15 cm having an inner tube diameter of 10 mm and wall thickness of 1.5 mm. The outer tube of these coaxial glass tubes has a diameter of 30 mm and a wall thickness of 1.5 mm. Each of these coaxial tubes r 2010 American Chemical Society

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Figure 1. Schematic diagram of the set up used for crystallization. Table 1. Crystal Data and Structural Refinement Parameters of Anhydrous Ciprofloxacin, Midazolam, and Ofloxacin

Figure 2. ORTEP diagram of anhydrous ciprofloxacin with ellipsoids drawn at 50% probability. has 19/23 ground joint at the two ends for extension. Each crystallization zone is divided into two compartments having an inlet and an outlet for the circulation of the hot oil around the inner tube. For example, the first zone has two compartments A and B with an inlet Ai and outlet Ao for A and inlet Bi and outlet Bo for B (Figure 1). The remaining five crystallization zones similarly have two compartments each (C D, E F, G H, I J, and K L) with an inlet and an outlet. Silicone oil is used in the oil bath whose temperature can be programmed such that the initial temperature at the oil bath is beyond the melting point of the compound to be crystallized. On vaporization, the compound goes through the inner tube with each compartment providing a temperature gradient. It is to be noted that the temperature gradient can be controlled by hot oil circulation through the outer tube. The hot oil enters the outer tube through Ai and gets out through Ao and passes through a coil whose temperature can be varied by using an external heating or a cooling device (a hot zone or an ice bath) before entering Bi. Thus, it is possible to predetermine a temperature gradient which ensures the formation of the crystals in the inner tube of any one of the compartment. Further, the rate of flow can be controlled by the vacuum pump attachment through the pressure gauge (Figure 1). The sample holder is made up of a 19/23 ground joint which can be easily connected and disconnected to the gradient cooling part. The inner tube allows the vaporized sample to pass through the compartments only after entering through a fine nozzle at the main entry point which ensures cooling by the Joule-Thompson effect and also provides an aspirator effect on the sample. Crystallization. Crystallization of anhydrous ciprofloxacin, midazolam, and ofloxacin resulted from the use of the device. Depending on the melting point of each drug, the oil temperature was maintained at 270, 165, and 275 C, respectively. During the experiment, a vacuum is maintained at 650 mm. Because of gradient cooling, crystals were grown at the inner wall of the crystallization

details

ciprofloxacin

midazolam

ofloxacin

molecular formula crystal size (mm) formula weight crystal system space group a (A˚) b (A˚) c (A˚) R () β () γ () volume (A˚3) Z density calc (g/cm3) temperature (K) μ (mm-1) F(000) hmin,max kmin,max lmin,max θ range () no. of measured reflections Rint no. of unique reflections no. of parameters R [I > 2σ(I)] wR [I > 2σ(I)] GOF max/min ΔF (e/A˚3)

C17H18FN3O3 0.30, 0.20, 0.20 331.34 triclinic P1 8.062(1) 9.730(2) 10.321(1) 99.927(17) 104.541(17) 98.073(17) 757.5(3) 2 1.453 298 0.109 348 -9, 9 -11, 11 -12, 12 3.09-25.50 19153

C18H13ClFN3 0.3, 0.1, 0.02 325.76 monoclinic P21/n 7.5588(3) 13.6840(5) 15.1242(8) 90 92.497(5) 90 1562.88(12) 4 1.385 298 0.257 672 -9, 9 -16, 16 -18, 18 2.98-26.00 16196

C18H20FN3O4 0.2, 0.18, 0.1 361.37 monoclinic C2/c 30.322(4) 6.8607(8) 16.9199(16) 90 105.271(11) 90 3395.6(7) 8 1.414 298 0.108 1520 -41, 41 -9, 9 -23, 22 3.05-29.46 19418

0.2845 2818

0.0880 3073

0.3075 4135

218 0.072 13.25 0.780 0.266/-0.234

208 0.0453 0.0902 0.811 0.281/-0.243

237 0.0552 0.0752 0.681 0.188/-0.179

zone and subsequently taken out for single crystal X-ray diffraction. The crystal morphology for ciprofloxacin was “block type”, while for both midazolam and ofloxacin the crystals were “platelike”. Single Crystal X-ray Diffraction. The single crystal X-ray diffraction data for all compounds were collected on a Oxford diffractometer (Microsource (MOVA), detector: Eos) and solved using direct methods.20-22 Of the three samples (ciprofloxacin, midazolam, and ofloxacin) only the crystals of ciprofloxacin were sealed in a Lindemann capillary to ensure that the sample is not affected by its highly hygroscopic character when exposed to air. X-ray Powder Diffraction. Powder patterns of all compounds were recorded on a Philips X’pert Pro diffractometer in a range of 2θ = 3-60 with a 0.02 step size and 500 s per step.

Result and Discussion Crystal Structure of Anhydrous Ciprofloxacin. The ORTEP diagram of anhydrous ciprofloxacin is shown in Figure 2, and

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crystallographic details are listed in Table 1. The characteristic (O-H 3 3 3 O) intramolecular hydrogen bond found in all the structures reported in the literature11-15 remains unaltered even in the anhydrous form. However, a unique N-H 3 3 3 N intermolecular interaction (Figure 3) across the center of inversion brings an altogether different packing motif in the anhydrous form. The intra- and intermolecular interactions for anhydrous ciprofloxacin are listed in Table 2. Additional C-H 3 3 3 O

Figure 3. The 3D packing diagram of anhydrous ciprofloxacin showing intramolecular O-H 3 3 3 O and intermolecular C-H 3 3 3 O and N-H 3 3 3 N interaction.

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intermolecular interactions (Figure 3) provide further stability to the packing motif. In all the salts of ciprofloxacin studied earlier, there is no N-H 3 3 3 N hydrogen bond holding the ciprofloxacin molecule together; instead, the hydrogen bonding involves the solvate.13 Even though the quality of the crystal was not so good [Rint(0.28)], a reasonable single crystal data set was collected on a capillary mounted tiny crystal. In open mounting, it is found that the single crystal becomes polycrystalline after a few minutes of data collection. The hygroscopic nature of anhydrous ciprofloxacin has been analyzed by taking the “as prepared” polycrystalline powder and heating the sample to 50-250 C. The X-ray powder diffraction (XRPD) pattern shown in Figure 4 indicates that two prominent peaks at 2θ = 6.46 and 6.95 disappear gradually with increasing temperature. At 250 C, the XRPD pattern matches that of the simulated single crystal XRD patterns of the anhydrous ciprofloxacin. It is of interest to note that the hydration is reversible (Figure S1, Supporting Information) when the heated sample is exposed to air for over 1 h. Crystal Structure of Anhydrous Midazolam. The ORTEP diagram with 50% probability for anhydrous midazolam is shown in Figure 5, and the crystallographic details are given in Table1. The structure of anhydrous midazolam presents unique packing characteristics with a type I23 Cl 3 3 3 Cl interaction holding the molecule together (Figure 6 and Table 2). Additional C-H 3 3 3 π and π 3 3 3 π interactions provide further stability to the packing. The only other derivative of midazolam is a saccharinate,19 and the intermolecular interactions are significantly different with the saccharinate forming a dimer through well-defined C-H 3 3 3 O intermolecular interactions. Crystal Structure of Anhydrous Ofloxacin. The ORTEP diagram with 50% probability for anhydrous ofloxacin is shown in Figure 7, and the crystallographic details are given in Table 1. Once again, the single crystal data quality for anhydrous midazolam is poor [Rint = 0.3075]. However, the

Table 2. Hydrogen Bonding Geometry and Weak Interactions for Anhydrous Ciprofloxacin, Midazolam, and Ofloxacin D-X 3 3 3 A *O2-H2AA 3 3 3 O3 N3-H3AA 3 3 3 N3 *C14-H14A 3 3 3 F1 C14-H14B 3 3 3 O1 C16-H16A 3 3 3 O1 C17-H17B 3 3 3 O2 Cg(2) 3 3 3 Cg(2) Cg(4) 3 3 3 Cg(4) Cg(2) 3 3 3 Cg(4)

C4-H4 3 3 3 N3 Cl1 3 3 3 Cl1 C4-H4 3 3 3 Cg(1) C16-Cl1 3 3 3 Cg(3) C2-F1 3 3 3 Cg(2)

*O3-H1 3 3 3 O2 C3-H3 3 3 3 O4 C5-H4 3 3 3 O4 C2-H6 3 3 3 O2 C16-H16B 3 3 3 O3 Cg(3) 3 3 3 Cg(3) C7-O2 3 3 3 Cg(3)

symmetry

r (D-X) (A˚)r (X 3 3 3 A) (A˚)

r (D 3 3 3 A) (A˚)

— D-X 3 3 3 A ()

Hydrogen bonding geometry and weak interactions in anhydrous ciprofloxacin x, y, z 0.82 1.79 2.548(7) 154 2 - x, 1 - y, 1 - z 0.86 2.29 3.076(9) 153 x, y, z 0.97 2.15 2.842(8) 127 1 - x, -y, 2 - z 0.97 2.56 3.252(10) 128 1 - x, -1 - y, 2 - z 0.97 2.52 3.486(9) 175 x, y, -1 þ z 0.97 2.48 3.451(9) 175 1 - x, -y, 2 - z 3.516(5) where Cg is the centroid of cyclic ring containing atoms 2 - x, -y, 2 - z 3.556(5) Cg(2) = N1/C2/C1/C6/C3/C10 Cg(4) = C1/C2/C8/C4/C7C5 1 - x, -y, 2 - z 3.833(5) Hydrogen bonding geometry and weak interactions in anhydrous midazolam No classical hydrogen bond found for midazolam 1 - x, -y, 1 - z 0.93 2.725 3.639(5) 168 -x, 1 - y, 1 - z 3.282(2) 148 1 - x, -y, 1 - z 0.93 2.77 3.562(3) 144 3.609(2) where Cg is the centroid of cyclic ring containing atoms 1 - x, 1 - y, 1 - z 1 - x, -y, 1 - z 3.309(2) Cg(1)=N2/C9/C10/N3/C11 Cg(2) =C1/C2/C3/C4/C5/C6 Cg(3)= C13/C14/C15/C16/C17/C18 Hydrogen bonding geometry and weak interactions in anhydrous ofloxacin x, y, z 0.82 1.75 2.5171 154 -x, y, -1/2 - z 0.98 2.55 3.2726 130 -x, y, -1/2 - z 0.93 2.48 3.3148 150 -x, -y, -z 0.97 2.51 3.4159 156 -x, -y, -z 0.97 2.51 3.4291 158 3.7114 where Cg is the centroid of cyclic ring containing atoms -x, -y, -z -x, 1 - y, -z 3.2887 Cg(3) = N4/C5/C6/C7/C13/C12

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Figure 4. Comparison of powder X-ray diffraction pattern of ciprofloxacin raw base heated at a different temperature with that of simulated single crystal diffraction pattern of anhydrous ciprofloxacin.

Figure 5. ORTEP diagram of anhydrous midazolam with ellipsoids drawn at 50% probability.

structure has been refined to a reasonable residual factor (Table 1). It is noteworthy that ofloxacin does not possess strong complementary hydrogen bond functionality; indeed, only C-H 3 3 3 O interactions across the 2-fold axis result in the packing of the molecules in the crystal (Figure 8). The perchlorate salt structure of ofloxacin (SOYBEN CSD 5.3, Updates May 2009) is also stabilized by the similar intermolecular C-H 3 3 3 O interactions. However, the protonated nitrogen forms a strong N-H 3 3 3 O interaction with the solvated water molecule rather than with perchlorate. Conformational Analysis. The conformation of all three anhydrous compounds as compared to their salts and solvated forms show no major difference as far as the aromatic motifs are concerned. Indeed, the variation comes in the regions of bonds involving a free rotation, dictated essentially by the nature of the intermolecular interaction. For example, ciprofloxacin derivatives show variations in the torsional angle associated with C4-N2 bond, which links the piperazin ring with the aeromatic moiety and also across

Figure 6. The 3D packing diagram of anhydrous midazolam showing type-1 Cl-Cl interaction.

Figure 7. ORTEP diagram of anhydrous ofloxacin with ellipsoids drawn at 50% probability.

the N1-C12 bond linking the cyclopropane (Figure 9a). The structure of midazolam shows very little variation in the overall conformation compared to saccharinate salt

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Conclusion

Figure 8. The 3D packing diagram of anhydrous ofloxacin showing the C-H 3 3 3 O dimer around the 2-fold axis.

The structure determination of anhydrous compounds and the variation observed in the crystal packing clearly bring out the importance of growing the anhydrous form of any given drug. The understanding of structural features certainly enhances the potential for engineering newer drug complexes since they offer variability in hydrogen bonding character. It is to be noted that although the incorporation of solvent does provide additional stability through well-defined hydrogen bonds, it appears that analysis of the structural features of anhydrous compounds would also provide inputs for the design of cocrystal involving drug molecules. Acknowledgment. We thank FIST program for data collection on the CCD and powder XRD facility at SSCU, IISc, Bangalore. We acknowledge funding from DST, India, and financial support. S.M. thanks CSIR, India, for providing the research associateship. Supporting Information Available: Figure S1 X-ray powder diffraction pattern showing hygroscopic nature of ciprofloxacin. All crystallographic information (CIF) files for CCDC Nos. 757817, 738865, and 757816 are available free of charge via the Internet at http://pubs.acs.org.

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Figure 9. Molecular overlap of (a) anhydrous ciprofloxacin with (1) ciprofloxacin HCl, (2) ciprofloxacin phosphate, (3) ciprofloxacin 3 6H2O, (4) ciprofloxacin lactate, (5) ciprofloxacin methanol solvate. (b) Anhydrous midazolam with reported saccharinate salt. (c) Anhydrous ofloxacin with reported perchlorate salt.

(Figure 9b). The conformation of ofloxacin again shows significant rotational variation in torsion across the C10-N bond (Figure 9c).

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