Pharmaceutical salts of ciprofloxacin with dicarboxylic

European Journal of Pharmaceutical Sciences 77 (2015) 112–121

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Pharmaceutical salts of ciprofloxacin with dicarboxylic acids Artem O. Surov a, Alex N. Manin a, Alexander P. Voronin a, Ksenia V. Drozd a, Anna A. Simagina a, Andrei V. Churakov b, German L. Perlovich a,⇑ a b

Institution of Russian Academy of Sciences, G.A. Krestov Institute of Solution Chemistry RAS, 153045 Ivanovo, Russia Institute of General and Inorganic Chemistry RAS, Leninskii Prosp. 31, 119991 Moscow, Russia

a r t i c l e

i n f o

Article history: Received 27 April 2015 Received in revised form 20 May 2015 Accepted 8 June 2015 Available online 9 June 2015 Keywords: Ciprofloxacin Dicarboxylic acids Pharmaceutical salts Single crystal X-ray Solubility Intrinsic dissolution rate

a b s t r a c t New salts of antibiotic drug ciprofloxacin (CIP) with pharmaceutically acceptable maleic (Mlt), fumaric (Fum) and adipic (Adp) acids were obtained and their crystal structures were determined. The crystal lattices of the fumarate and adipate salts were found to accommodate the water molecules, while the maleate salt was anhydrous. The dehydration and melting processes were analyzed by means of differential scanning calorimetry and thermogravimetric analysis. Solubility and intrinsic dissolution rates of the salts were measured in pharmaceutically relevant buffer solutions with pH 1.2 and pH 6.8. Under acidic conditions, the salts were found to be less soluble than the parent form of drug, while the [CIP + Fum + H2O] and [CIP + Mlt] solids showed enhanced dissolution rate when compared to a commercially available ciprofloxacin hydrochloride hydrate. In the pH 6.8 solution, all the salts demonstrated solubility improvement and faster dissolution rate with respect to pure CIP. Ó 2015 Published by Elsevier B.V.

1. Introduction Ciprofloxacin (CIP) belongs to a family of broad-spectrum oral antibiotics called fluoroquinolones, drugs that are widely prescribed worldwide for treatment of several types of bacterial infections. As for most of fluoroquinolones, the aqueous solubility of ciprofloxacin is strongly pH-dependent, due to the proton transfer from the carboxylic acid to the basic piperazin ring to form zwitterionic species. As a result, CIP shows low solubility at neutral pH (Ross and Riley, 1990), limiting the bioavailability of the compound. Moreover, CIP has poor permeability across biological membranes (Breda et al., 2009), which makes it a class IV drug of the Biopharmaceutics Classification System (BCS) (Takagi et al., 2006). This is by far the most challenging case for the drug development as well as their formulation design. It is widely accepted, however, that formulation approaches similar to those for BCS class II drugs (improvement of the solubility and the dissolution behavior) could be practically applied to BCS class IV drugs, even though the absorption could be limited by the poor permeability after dissolving (Kawabata et al., 2011). One of the common procedures to improve the aqueous solubility of a drug is salt formation using a suitable counter ion. This strategy has been employed for many fluoroquinolones, including CIP, to form hydrochlorides (Turel and Golobic, 2003). However, hydrochloride salts often ⇑ Corresponding author. E-mail address: [email protected] (G.L. Perlovich). http://dx.doi.org/10.1016/j.ejps.2015.06.004 0928-0987/Ó 2015 Published by Elsevier B.V.

suffer from a decreased solubility in the stomach due to a common ion effect (Li et al., 2005). An alternative way to enhancement of the dissolution performance is to develop CIP salts with different organic counter ions. For example, preparation and solubility profiles of CIP salts with carboxylic acids such as citric, tartaric, and malonic acids have previously been reported by Reddy et al. (2011). Saccharinate of ciprofloxacin is found to be polymorphic, with two forms currently established (Romanuk et al., 2009, 2010; Garro Linck et al., 2011). It has also been shown that salt formation between dicarboxylic acids and CIP often leads to crystallization with multiple stoichiometries and hydration levels (Paluch et al., 2013). In addition, the so-called drug–drug salt forms of CIP with non-steroidal anti-inflammatory drugs, diflunisal and indoprofen, have recently been obtained and characterized (Bag et al., 2014). While, Vitorino et al. (2013) were able to isolate a multicomponent molecular complex comprising ciprofloxacin and norfloxacin ions in the solid state. It has recently been reported that new ciprofloxacin salts enhance the aqueous solubility and simultaneously influence the octanol–water partition coefficient of the drug, which allows the tuning of relevant pharmacological properties by the counter ion alteration (Florindo et al., 2014). In this paper, we extend the range of ciprofloxacin crystal forms through salt formation with well-known dicarboxylic acids: maleic acid (Mlt), fumaric acid (Fum) and adipic acid (Adp) (Fig. 1). The salts were characterized by single-crystal X-ray diffraction, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Aqueous solubility and intrinsic dissolution rate

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isotropically. Crystallographic data (excluding structure factors) for the structures [CIP + Mlt], [CIP + Fum + H2O] and [CIP + Adp + 2H2O] have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-1061664, 1061665 and 1061666, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: + 44 1223 336 033; e-mail: [email protected]]. X-ray powder diffraction data of the bulk materials were recorded under ambient conditions in Bragg– Brentano geometry with Bruker D8 Advance diffractometer with Cu Ka1 radiation (k = 1.5406 Å). The experimental powder pattern was compared with that simulated from crystal structures to confirm bulk phase purity (see Supplementary Fig. S2).

2.4. Differential scanning calorimetry (DSC) Thermal analysis was carried out using a Perkin Elmer DSC 4000 differential scanning calorimeter with a refrigerated cooling system (USA). The sample was heated in sealed aluminum sample holders at the rate of 10 °C min1 in a nitrogen atmosphere. The unit was calibrated with indium and zinc standards. The accuracy of the weighing procedure was ±0.01 mg. Fig. 1. Molecular structures of ciprofloxacin and dicarboxylic acids used in this work. Flexible torsion angles in the ciprofloxacin molecule are numbered and indicated by s1 and s2.

2.5. Thermogravimetric analysis (TGA)

2. Material and methods

TGA was performed on a TG 209 F1 Iris thermomicrobalance (Netzsch, Germany). Approximately 10 mg of the sample was added to a platinum crucible. The samples were heated at a constant heating rate of 10 °C min1. The samples were purged with a stream of flowing dry Ar at 30 ml min1 throughout the experiment.

2.1. Compounds and solvents

2.6. Aqueous solubility and intrinsic dissolution rate experiments

Ciprofloxacin (C17H18FN3O3, anhydrous, 98%), maleic acid (C4H4O4, 99%), fumaric acid (C4H4O4, 99%) and adipic acid (C6H10O4, 99%) were purchased from Acros Organics. The X-ray powder diffraction patterns of ciprofloxacin starting material were found to be in good agreements with the diffractogram of the zwitterionic form of the drug (see Supplementary Fig. S1). All the solvents were available commercially and used as received without further purification.

Dissolution measurements were carried out by the shake-flask method in the hydrochloric buffer with pH 1.2 and the phosphate buffer with pH 6.8 at 28 ± 0.1 °C. The media at pH 1.2 was prepared with 0.1 N aqueous hydrochloric acid solution and potassium chloride. For the phosphate buffer, 0.05 M solution of Na2HPO4 was adjusted to pH 6.8 with sodium hydroxide. The excess amount of each sample was suspended in the respective buffer solution in Pyrex glass tubes. The amount of the drug dissolved was measured by taking aliquots of the respective media. The solid phase was removed by isothermal filtration (RotilaboÒ syringe filter, PTFE, 0.2 lm), and the concentration was determined with suitable dilution by Cary 50 UV–vis spectrophotometer (Varian, Australia) at the reference wavelength (277 nm in pH 1.2 and 272 nm in pH 6.8). The results are stated as the average of at least three replicated experiments. Concentrations were calculated according to an established calibration curve. Intrinsic dissolution rate (IDR) measurements were carried on a USP-certified Electrolab EDT-08LX dissolution tester by the disk intrinsic dissolution method. For IDR experiments, approximately 120 mg of pure drug or salt were compressed by a hydraulic press for 5 min to form a nonporous compact of 8 mm diameter. The intrinsic attachment with the sample was rotated at 150 rpm in 500 ml of the respective buffer media preheated to 37.0 °C. The cumulative amount dissolved per unit surface area was determined by taking aliquots of 2 ml at specific time intervals with volume replacement and concentration measured spectrophotometrically. The slope of the plot of mass dissolved per unit surface area vs. time gives the intrinsic dissolution rate in appropriate units, e.g. mg min1 cm2.

experiments were performed under the conditions similar to those for the previously reported salts in order to compare the dissolution behavior of different CIP solid forms in a systematic manner.

2.2. Crystallization procedure Ciprofloxacin (50 mg, 0.15 mM) was dissolved with maleic, fumaric and adipic acids in the 1:1 M ratio in 10 ml of a methanol–water mixture (1:1 v:v) and stirred at 50–60 °C until a clear solution was obtained. The solution was slowly cooled and kept in a fume hood at room temperature. Diffraction quality crystals of the ciprofloxacin salts were grown over a period of 1–2 days. Crystals obtained from the crystallization batches were air dried before being subjected to further analysis. 2.3. X-ray diffraction experiments Single-crystal X-ray diffraction data were collected on a Bruker SMART APEX II diffractometer using graphite-monochromated MoKa radiation (k = 0.71073 Å). The structures were solved by direct methods and refined by full matrix least-squares on F2 with anisotropic thermal parameters for all non-hydrogen atoms (Sheldrick, 2007). Absorption corrections based on measurements of equivalent reflections were applied (Sheldrick, 1997). All hydrogen atoms were found from difference Fourier map and refined

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2.7. Computational procedure Geometric optimization of the protonated ciprofloxacin molecule was carried out using the GAUSSIAN03 program at the B3LYP/6-311++G(d,p) level of theory (Frisch et al., 2003). Since no imaginary frequency was found, the optimized structure was characterized as minima. 3. Results and discussion It was established in the literature that the reaction of an acid with a base will be expected to form a salt if the difference in DpKa = pK(base) —pK(acid) is greater than 3, and it is most widely a a known as a ‘‘rule of three’’ (Huang et al., 1997; Stahl and Wermuth, 2002; Bhogala et al., 2005; Childs et al., 2007). This states that salt formation generally requires a difference of at least three pKa units between a base and a acid. Cruz-Cabeza, 2012 has conducted a study on the relationship between the proton transfer probability and the DpKa value of 6465 acid-base crystalline complexes taken from CSD. It has been shown that components with DpKa < 1 form mostly cocrystals, while systems with DpKa > 4 tend to form exclusively salts. This ‘‘rule’’ has been also adjusted to various drug/coformer pairs (Kathalikkattil et al., 2011; da Silva et al., 2013; Sanphui et al., 2013; Elacqua et al., 2013; Thomas et al., 2014), despite the fact that DpKa range between 0 and 3 remains hardly predictable. For ciprofloxacin (pKa = 8.74 for the piperazine fragment (Ross and Riley, 1990)) and coformers of interest, however, the DpKa values are considerably greater than 3 units, which strongly suggests proton transfer and salt formation to occur. Indeed, the difference between pKa of ciprofloxacin (piperazine fragment) and first ionization constants of maleic acid (pKa,1 = 1.90; pKa,2 = 6.07), fumaric acid (pKa,1 = 3.03; pKa,2 = 4.44) and adipic acid (pKa,1 = 4.43; pKa,2 = 5.41) is equal to 6.84, 5.71 and 4.31, respectively. The relatively strong acids (maleic and fumaric) form 1:1 salts with ciprofloxacin. Crystallization of the drug with adipic acid, however, resulted in the formation of the 2:1 salt, despite the fact that it is the weaker acid. It should also be noted the pKa of the carboxylic group in ciprofloxacin (pKa = 6.09) is at least two orders less acidic than the organic acids used, and hence zwitterionic form of the drug is not expected. 3.1. Crystal structures Crystallographic data are summarized in Table 1, and the packing arrangements of the salts are shown in Figs. 2–4 (asymmetric units of the CIP salt with displacement ellipsoids are presented in Fig. S3). The single crystal X-ray diffraction data confirmed protonation of the piperazine ring of CIP by acid groups of the salt formers, as evidenced by the proton location and bond length analysis. The [CIP + Mlt] salt is an anhydrate. It crystallizes in the monoclinic P21/n space group with one ciprofloxacin cation and one maleate anion in the asymmetric unit. Two charge assisted N+– H O hydrogen bonds connect CIP and Mlt ions to form a closed-ring tetrameric unit across a crystallographic inversion center that can be described in graph set notation as R24 ð8Þ (Etter, 1990; Bernstein et al., 1995) (Fig. 2a). The neighboring units, in turn, interact to each other only by weak van der Waals forces. The quinolone moieties of ciprofloxacin molecules stack with p– p interactions along the a-axis (3.514 Å) (Fig. 2b). The asymmetric unit of [CIP + Fum + H2O] contains ciprofloxacin cation, fumarate anion and one water molecule. Each CIP ion forms N+–H O and N+–H O hydrogen bonds with two distinct molecules of Fum (Fig. 3a). Whereas fumarate anions are linked through the water molecules acting as bridges to form C(9)

hydrogen bonded chains along the b-axis. The water molecules are also responsible for formation of the ring motives (R44 ð12Þ), which unite two neighboring chains to each other (Fig. 3b). The ciprofloxacin molecules are arranged into infinite columnar stacks along the b-axis held by p–p interactions with an interplanar distance of 3.37 Å. So the overall structure consists of alternating layers containing the p-stacks of the drug and the hydrogen bonded fumaric acid and water molecules (Fig. 3c). The asymmetric unit of [CIP + Adp + 2H2O] contains one molecule of ciprofloxacin with two water molecules and an adipate ion occupying a special position in the inversion centre. In contrast to the previously described salts, where only one carboxylic group per a salt former molecule is deprotonated, the carboxylic groups of adipic acid in [CIP + Adp + 2H2O] are found to be fully deprotonated, despite the fact that it is the weaker acid. In the crystal, the adipate ion accepts charge assisted N+–H O hydrogen bonds from two CIP molecules (Fig. 4a). Meanwhile, two water molecules form H-bonds with the adipate ions as well as with each other constructing complex three-dimension R66 ð16Þ hydrogen bonded rings (Fig. 4b). The water molecules are also linked by H-bonds with the piperazinium fragment and the carboxylic group of ciprofloxacin expanding the hydrogen bond network between the salt constituents. The packing arrangement of the CIP molecules in the salt is similar to that in [CIP + Fum + H2O]. The infinite columnar p-stacks (3.372 Å) of the drug extended along the a-axis define the border between the layers which contain either ciprofloxacin or salt former and water molecules (Fig. 4c). It should be noted that alternation of layers containing columnar p-stacks and hydrogen bonds is a recurring supramolecular motive in the crystal structures of most of the ciprofloxacin salts with carboxylic acids. This packing arrangement can be observed in the salts with malonic acid (ORUZAD), tartaric acid (ORUYOQ), citric acid (ORUYIK), lactic acid (IDARUA), succinic acid (Paluch et al., 2013) as well as described here [CIP + Fum + H2O] and [CIP + Adp + 2H2O]. In the case of [CIP + Mlt] structure, however, no infinite columnar stacks of the CIP molecules were found. Instead, two maleate ions occupy the space between the pairs of the p-stacked CIP molecules which prevents conventional columnar packing to be formed (Fig. 2b). The conformation of the ciprofloxacin molecule can be defined in terms of at least two torsion angles, one defining the orientation of the piperazinium ring (s1) and the other corresponding to the conformation of the cyclopropyl group (s2) (Fig. 1). The values of the selected torsion angles for the ciprofloxacin molecules in various salts are given in Table 2. It is evident that the ciprofloxacin conformations in the salts are similar. In the case of [CIP + indoprofen + H2O], [CIP + malonate + 2H2O], [CIP + succinate + 4H2O] mol A and [CIP + Adp + 2H2O], the piperazinium ring is rotated around the C11–N2 bond, so that the s1 angle values have a positive sign. For most of the salts, however, the s1 torsion angle deviates by no more than ±20° from the value corresponding to the calculated minimum conformational energy of the ciprofloxacin ion (Table 2). The values of the s2 torsion angle are located in the narrow region (±10°), which indicates a high conformational energy penalty for rotation of the cyclopropyl group. 3.2. Thermal analysis The DSC and TG traces for the salts and ciprofloxacin are shown in Fig. 5, and the thermal data are given in Table 3. For [CIP + Fum + H2O] and [CIP + Adp + 2H2O], the first endothermic event in the DSC curves corresponds to a dehydration process, which is followed by melting of an unhydrated product. It is found that the number of water molecules observed in the crystal

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A.O. Surov et al. / European Journal of Pharmaceutical Sciences 77 (2015) 112–121 Table 1 Crystallographic data for the ciprofloxacin salts. Compound reference

[CIP + Mlt] (1:1)

[CIP + Fum + H2O] (1:1:1)

[CIP + Adp + 2H2O] (1:0.5:2)

Chemical formula Formula mass Crystal system a (Å) b (Å) c (Å) a (°) b (°) c (°) Unit cell volume (Å3) Temperature (K) Space group Z Absorption coefficient, l (mm1) No. of reflections measured No. of independent reflections Rint Final R1 values (I > 2r(I)) Final wR(F2) values (I > 2r(I)) Final R1 values (all data) Final wR(F2) values (all data) Goodness of fit on F2 Largest diff. peak & hole (e Å3) CCDC No.

C17H19FN3O3C4H3O4 447.42 Monoclinic 9.1709(3) 16.1160(5) 14.0148(5) 90.00 106.4203(4) 90.00 1986.88(11) 150(2) P21/n 4 0.119 20,279 4792 0.0185 0.0331 0.0924 0.0363 0.0953 1.028 0.384/0.217 1061664

C17H19FN3O3C4H3O4H2O 465.43 Triclinic 9.5317(4) 9.7507(4) 11.5108(5) 79.3599(6) 89.0894(6) 78.8004(6) 1031.18(8) 150(2) P1 2 0.122 10,711 4969 0.0158 0.0352 0.0981 0.0401 0.1018 1.054 0.389/0.181 1061665

(C17H19FN3O3)0.5C6H8O42(H2O) 440.44 Triclinic 7.2777(6) 11.4105(10) 12.6082(11) 87.1858(11) 73.9132(11) 87.0372(12) 1004.01(15) 150(2) P1 2 0.116 11,186 5309 0.0166 0.0352 0.1000 0.0393 0.1038 1.039 0.438/0.224 1061666

Fig. 2. (a) Hydrogen bonded supramolecular tetrameric unit in the crystal structure of [CIP + Mlt] and (b) molecular packing projections for [CIP + Mlt].

structure analysis is in agreement with the results of TG analyses within experimental uncertainty. In the case of [CIP + Mlt], the DSC thermogram shows only one endotherm, indicating the melting process of the salt. For all the salts, melting is immediately followed by decomposition.As Table 3 shows, the dehydration onset temperature for [CIP + Fum + H2O] is found to be ca. 141.0 °C, while for [CIP + Adp + 2H2O], water starts to release at ca. 84.0 °C. It

Fig. 3. (a) Interaction between CIP and Fum molecules in the crystal via N+–H O and N+–H O hydrogen bonds; (b) hydrogen bonded ring motives R44 ð12Þ between fumarate ions and water molecules in the crystal; (c) molecular packing projections for [CIP + Fum + H2O].

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DHS ¼ ðDHTdehyd 100=DmS Þ MS ; where DHTdehyd is the enthalpy of dehydration derived from the DSC data, DmS is the percent mass loss measured in TG experiment and MS is the molecular weight of the solvent. The resulting DHS values for [CIP + Fum + H2O], [CIP + Adp + 2H2O] as well as for some hydrated salts of CIP available in the literature are shown in Table 3. It is evident that water is the most tightly bound component in the [CIP + Fum + H2O] salt. The water content increase in the crystals of adipate and succinate salts predictably reduces the DHS value. An exception is observed for [CIP + Citrate + H2O]. The DHS values for [CIP + Fum + H2O] and [CIP + Adp + 2H2O] indicate 1.8 and 1.5 times stronger interactions of water molecules with the host structure than in the pure liquid. In the [CIP + succinate + 3H2O] and [CIP + succinate + 4H2O] salts this value is approximately equal to the enthalpy of vaporization of pure water. Apparently, large differences in the dehydration temperature are well correlated with the crystal structure features of the salts. In [CIP + Fum + H2O], the water molecules are embedded into the hydrogen bond network between CIP and Fum, which considerably reduces their mobility in the crystal. As a result, [CIP + Fum + H2O] melts soon after water release process takes place. The [CIP + Adp + 2H2O], [CIP + succinate + 3H2O] and [CIP + succinate + 4H2O] salts contain water–water hydrogen bonds, that are not sustainable at elevated temperatures. The dehydrated host structure of [CIP + Adp + 2H2O] remains thermally stable up to 243 °C. Similar behavior is also observed in the succinate salts of CIP. The anhydrous [CIP + Mlt] salt shows moderate thermal stability with the melting temperature of 216.3 °C. 3.3. Solubility and intrinsic dissolution rate (IDR) Fig. 4. (a) Charge assisted N+–H O hydrogen bonds between two CIP molecules and adipate ion in the crystal; (b) hydrogen bonded ring motives R66 ð16Þ between adipate ions and water molecules in the crystal; (c) molecular packing projections for [CIP + Adp + 2H2O].

suggests that the interaction energies between the water molecules and the host structure of the salts are different. The binding strength of water in [CIP + Fum + H2O] and [CIP + Adp + 2H2O] can be estimated by calculating the enthalpy of vaporization (DHS) of the salt-bound water using the following relationship (Caira et al., 2002):

It is known that solubility and dissolution rate in aqueous media are key parameters among other physicochemical properties for pharmaceutical salts and co-crystals, as they are effectively correlated with oral bioavailability of drugs (Hickey et al., 2007; Bak et al., 2008; Jung et al., 2010; Stanton et al., 2011; Smith et al., 2011; Weyna et al., 2012; Sanphui et al., 2013). As mentioned above, the aqueous solubility of ciprofloxacin is strongly pH-dependent due to its amphoteric nature. Hence, the solubility (at 28 °C) and the intrinsic dissolution rate (at 37 °C) of the salts were examined in the hydrochloric buffer with pH 1.2 and the phosphate buffer with pH 6.8. This set of conditions was used in

Table 2 Selected torsion angles of the CIP ions in different salts. Ref. code/reference [CIP + Mlt] [CIP + Fum + H2O] [CIP + Adp + 2H2O] [CIP + lactate + 1.5H2O] mol A [CIP + lactate + 1.5H2O] mol B [CIP + diflunisal] [CIP + indoprofen + H2O] [CIP + citrate + H2O] [CIP + tartarate] [CIP + malonate + 2H2O] [CIP + saccharinate] [CIP + HCl + H2O] [CIP + acesulfamate] [CIP + 4-hydroxybenzoic acidHCl] [CIP + succinate + 3H2O] [CIP + succinate + 4H2O] mol A [CIP + succinate + 4H2O] mol B

IDARUA IDARUA KOFFAO KOFFES ORUYIK ORUYOQ ORUZAD PEFZIL UJAGUH WEFLEA XOHVAT Paluch et al. (2013) Paluch et al. (2013) Paluch et al. (2013)

CIP protonated molecule after geometrical optimizationa a

Geometrical optimization was performed at B3LYP/6-311++G(d,p) level of theory.

s1 (C10–C11–N2–C16) (°)

s2 (C3–N1–C5–C6) (°)

167.7 165.7 174.9

50.0 41.3 47.1

154.8 169.1 154.4 167.0 167.1 173.9 176.4 164.9 159.5 163.0 166.1 165.9 168.8 156.7

40.7 50.6 42.7 49.7 45.7 44.7 41.8 38.7 42.1 36.0 43.8 43.6 33.0 45.3

157.2

42.5


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Fig. 5. DSC thermograms and TG analysis of (a) [CIP + Fum + H2O], (b) [CIP + Adp + 2H2O] and (c) [CIP + Mlt].

order to perform a comparative analysis of the dissolution data available for the known CIP salts. The results of the dissolution experiments for the pure CIP and its salts at different pH

values are summarized in Table 4. Fig. 6 shows the dissolution profiles and the IDR results for the salts and CIP in pH 1.2 media.

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Table 3 Thermophysical data and water content for the ciprofloxacin salts. Tdehyd (°C) (onset) [CIP + Fum + H2O] [CIP + Adp + 2H2O] [CIP + Mlt] CIP [CIP + succinate + 3H2O]c(1:1) [CIP + succinate + 4H2O]c(2:1) [CIP + Citrate + H2O]d

141.0 ± 0.5 84.0 ± 0.7 n/a n/a n/a n/a 101.5

DHTdehyd (J g1) 156.5 ± 4.0 272.6 ± 5.0 n/a n/a 282.5 ± 4.4 181.0 ± 9.4 44.9

DmS (%) a

3.84 (3.87) 8.81 (8.18)a n/a n/a 12.6 8.8 3.3

Tfus (°C) (onset)

DHTfus (J g1)

DHS (kJ mol1b)

203.8 ± 0.7 243.5 ± 0.8 216.3 ± 1.0 270.7 ± 0.2 214.8 ± 0.6 228.1 ± 1.3 210.8

216.7 ± 5.0 161.4 ± 5.0 212.0 ± 6.0 164.9 ± 2.0 n/a n/a 397.7

72.8 55.8 n/a n/a 40.4 37.1 24.3

n/a – not available. a Values in the brackets indicate calculated TG mass loss. b Vaporization enthalpy of pure water is 40 kJ mol1. c Data taken from Paluch et al. (2013). d Data taken from Reddy et al. (2011).

Table 4 Intrinsic dissolution rates at 37 °C and solubilities at 28 °C for the CIP salts and pure CIP in pH 1.2 and pH 6.8 media.

a b c

Intrinsic dissolution rate (mg min1 cm2)

Solid phase recovered after IDR experimenta

Solubility (mg ml1)

Solid phase recovered after solubility experimenta

pH 1.2 CIP [CIP + Mlt] [CIP + Fum + H2O] [CIP + Adp + 2H2O] [CIP + malonate + 2H2O]b [CIP + tartarate]b [CIP + citrate + H2O]b [CIP + HCl + 1.34H2O]c

6.6 ± 0.1 1.89 ± 0.03 3.16 ± 0.07 5.50 ± 0.07 2.49 1.35 4.48 2.59 ± 0.12

CIP Salt Salt Salt – – – –

25.1 ± 1.5 10.0 ± 0.2 15.5 ± 0.5 18.7 ± 0.5 12.22 4.61 21.03 37.6 ± 3.3

CIP 3.7 hydrate Salt Salt Salt – – – –

pH 6.8 CIP [CIP + Mlt] [CIP + Fum + H2O] [CIP + Adp + 2H2O] [CIP + malonate + 2H2O]b [CIP + tartarate]b [CIP + citrate + H2O]b

0.019 ± 0.002 0.14 0.22 0.03 0.55 0.09 0.22

CIP 3.7 hydrate Salt + CIP 3.7 hydrate Salt + CIP 3.7 hydrate Salt + CIP 3.7 hydrate – – –

0.09 ± 0.01 1.8 ± 0.1 3.0 ± 0.3 0.63 ± 0.05 8.47 0.72 1.36

CIP 3.7 hydrate Salt Salt Salt + CIP 3.7 hydrate – – –

The residual materials were identified by DSC and XRPD analyses (see supporting information). Data taken from Reddy et al. (2011). Data taken from Martínez-Alejo et al. (2014). Solubility and IDR were measured in pH1.2 solution at 37 °C.

The dissolution profile for the pure CIP indicates a solution-mediated transformation of the bottom phase during the experiment. A gradual decline of the CIP concentration can be explained by formation of a ciprofloxacin hydrate, which is thermodynamically more stable than the parent drug under the current conditions. DSC analysis of the residual material recovered after the experiment confirmed this assumption (Fig. S4b). A weight loss of the sample in the temperature range of 25–120 °C was found to be 16.0%, which corresponds to the 1:3.7 hydrate of the drug (Mafra et al., 2012). This form was also indentified by XRPD analysis (Fig. S4a). Ciprofloxacin was expected to form the hydrochloride salt during the solubility experiment in the pH 1.2 solution, while it was not seen to occur. Probably, this process demands a considerable period of time to be completed. It should be noted that similar behavior of CIP at pH 1.2 was observed by Reddy et al., 2011. As Table 4 shows, the CIP salts with the organic counter ions are less soluble compared to hydrochloride salt in acidic conditions. Solubility of the salts decreases in the following order, CIP (CIP 3.7 hydrate) > [CIP + citrate + H2O] > [CIP + Adp + 2H2O] > [CIP + Fum + H 2 O] > [CIP + malonate + 2H 2 O] > [CIP + Mlt] > [CIP + tartarate]. Congruent solubility was confirmed by the DSC and XRPD analyses of the solid phase recovered after the experiment (Figs. S5–S7). The solubility of CIP in the pH 6.8 buffer solution was low, reaching 0.09 ± 0.01 mg ml1 (Table 4 and Fig. 7a), which is in good agreement with the previously reported solubility data in water

(0.067–0.14 mg ml1) (Ross and Riley, 1990; Yu et al., 1994; Caco et al., 2008; Reddy et al., 2011; Florindo et al., 2014). DSC and XRPD analyses of the solid phase recovered after the experiment reveals transformation of CIP to its 3.7 hydrated form (Fig. S3). All the salts, however, were not seen to undergo a solutionmediated transformation during the solubility study (Figs. S4– S6). However, partial transformation of [CIP + Adp + 2H2O] to the CIP 3.7 hydrate was detected by XRPD (Fig. S6a). As expected, the CIP salts show a considerable enhancement of solubility in comparison to the parent drug under the current conditions. For example, the [CIP + Fum + H2O] salt is approximately 33 times more soluble than pure CIP. For [CIP + Mlt], the solubility increases by a factor of 20, while [CIP + Adp + 2H2O] demonstrates the modest 7-fold improvement. It should be noted that [CIP + Fum + H2O] and [CIP + Mlt] are less soluble in the pH 6.8 solution than the previously reported malonate salt, nevertheless, their solubility level exceeds that of the citrate and tartarate salts (Table 4). Therefore, the solubility values of the CIP salts decrease according to the following sequence: [CIP + malonate + 2H2O] > [CIP + Fum + H2O] > [CIP + Mlt] > [CIP + citrate + H2O] > [CIP + tartarate] > [CIP + Adp + 2H2O] > CIP (CIP 3.7 hydrate). Apparently, there is no correlation between the solubility sets of the salts and of the corresponding salt formers (dicarboxylic acids). It was noticed, however, that the solubility of the salts is inversely related to their melting points, i.e. the solubility decreases as the melting temperature grows. This fact indicates that solubility difference in the pH 6.8


Fig. 6. Dissolution profiles at 28 °C (a) and intrinsic dissolution rates at 37 °C (b) for the salts and pure CIP in pH 1.2.

solution may be attributed to a variation in the crystal lattice energy of the salts. A similar relationship between melting temperature and solubility has been reported by Anderson and Conradi (1985) for a number of amine salts of flurbiprofen. The intrinsic dissolution rates were measured for 30 min because of fast dissolution of the salts at pH 1.2 (Fig. 6b). The IDR values of the salts diminish in the same manner as that for solubility. All the residual solid phases after the IDR study were identified as the starting material, including ciprofloxacin. It was found that during the IDR experiment ciprofloxacin did not seem to undergo a transformation to its hydrated form on account of rapid dissolution of the drug. This fact is consistent with the dissolution behavior of the pure CIP, which suggests that a solution-mediated formation process of the hydrate requires at least 500 min to be completed (Fig. 6a). In addition, Table 4 shows that the IDR value of the CIP base is found to be 2.5 times greater than that for a ciprofloxacin hydrochloride hydrate ([CIP + HCl + 1.34H2O]) measured in similar conditions (pH 1.2, 37 °C) (Martínez-Alejo et al., 2014). Moreover, the [CIP + Fum + H2O], [CIP + Adp + 2H2O] and [CIP + citrate + H2O] salts are also superior to the hydrochloride salt in terms of the dissolution rate (Table 4). Since ciprofloxacin is predominantly absorbed in the gastrointestinal tract (Harder et al., 1990), better dissolution rate of the CIP salts compared to the commercially available form (CIP hydrochloride hydrate) may be a useful advantage in terms of drug formulation. Unfortunately, the intrinsic dissolution rates of the CIP salts in the buffer with pH 6.8 cannot be accurately calculated due to a dramatic change of the IDR slope during the measurement period.

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Fig. 7. Dissolution profiles at 28 °C (a) and intrinsic dissolution rates at 37 °C (b) for the salts and pure CIP in pH 6.8.

Similar behavior under this condition is also observed in the [CIP + malonate + 2H2O], [CIP + tartarate] and [CIP + citrate + H2O] salts reported by Reddy et al. (2011). DSC analysis of the upper layer of the sample tablet (i.e. layer that was exposed to the solvent) collected after the study reveals partial conversion of the salts to a ciprofloxacin hydrate (Fig. S8). For the bulk samples, however, no evidence of transformation was detected. Therefore, it can be assumed that this layer of the poor soluble CIP on the tablet surface prevents further release of the bulk salts, which leads to a considerable decrease in the dissolution rate. In fact, the intrinsic dissolution behavior of salts (including systems studied by Reddy et al. (2011)) for the initial 20–30 min is different, but the slopes become comparable to that of pure CIP when they are considered over the period of 180 min. It should be noted that a similar phenomenon in the IDR experiment has been observed for a tetrahydrate form of diclofenac sodium, neutralization of which in the upper layer causes formation of a poorly soluble diclofenac acidum form that seals the underneath saline layer (Bartolomei et al., 2006).

4. Conclusions Three new salts of the well-known antibiotic ciprofloxacin with aliphatic dicarboxylic acids (maleic, fumaric and adipic acids) were obtained and analyzed by various physicochemical techniques (X-ray, DSC, TGA). Crystal structures of the fumarate and adipate salts contain one and two water molecules, respectively, while

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the maleate salt is found to be anhydrous. Thermal analysis of the CIP salts showed that water is the most tightly bound component in the structure of [CIP + Fum + H2O] on account of complex network of hydrogen bonds. On the contrary, the [CIP + Adp + 2H2O] salt easily released the solvent at elevated temperatures to form a dehydrated structure which was thermally stable up to 243 °C. Solubility and intrinsic dissolution rates of the salts were measured in pharmaceutically relevant buffer solutions with pHs 1.2 and 6.8. It was found that the salts solubility in the acidic media was less than that of the parent drug. However, the [CIP + Fum + H2O] and [CIP + Mlt] solids showed enhanced dissolution rate when compared to the ciprofloxacin hydrochloride hydrate, which is the main constituent of the drug formulations available in the market. In the pH 6.8 solution, the [CIP + Fum + H2O], [CIP + Mlt] and [CIP + Adp + 2H2O] demonstrated 33-, 20- and 7-fold solubility improvement with respect to pure CIP. In conclusion, the range of the ciprofloxacin salts with organic counter ions has been extended. However, further biopharmaceutical studies are required to investigate and to compare the behavior of the salts in vivo. Acknowledgements This work was supported by the Russian Scientific Foundation (No. 14-13-00640). We thank ‘‘the Upper Volga Region Centre of Physicochemical Research’’ for technical assistance with TG and XRPD experiments. The authors would like to thank Prof. Lyudmila G. Kuzmina for carrying out X-Ray diffraction experiment for [CIP + Fum + H2O]. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ejps.2015.06.004. References Anderson, Conradi, 1985. Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug. J. Pharm. Sci. 74, 815–820. Bag, P.P., Ghosh, S., Khan, H., Devarapalli, R., Reddy, C.M., 2014. Drug–drug salt forms of ciprofloxacin with diflunisal and indoprofen. CrystEngComm 16, 7393– 7396. Bak, A., Gore, A., Yanez, E., Stanton, M., Tufekcic, S., Syed, R., Akrami, A., Rose, M., Surapaneni, S., Bostick, T., King, A., Neervannan, S., Ostovic, D., Koparkar, A., 2008. The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid cocrystal characterization and pharmacokinetics. J. Pharm. Sci. 97, 3942–3956. Bartolomei, M., Bertocchi, P., Antoniella, E., Rodomonte, A., 2006. Physico-chemical characterisation and intrinsic dissolution studies of a new hydrate form of diclofenac sodium: comparison with anhydrous form. J. Pharm. Biomed. Anal. 40, 1105–1113. Bernstein, J., Davis, R.E., Shimoni, L., Chang, N.-L., 1995. Patterns in hydrogen bonding: functionality and graph set analysis in crystals. Angew. Chem. Int. Ed. Engl. 34, 1555–1573. Bhogala, B.R., Basavoju, S., Nangia, A., 2005. Tape and layer structures in cocrystals of some di- and tricarboxylic acids with 4,40 -bipyridines and isonicotinamide. From binary to ternary cocrystals. CrystEngComm 7, 551–562. Breda, S.A., Jimenez Kairuz, A.F., Manzo, R.H., Olivera, M.E., 2009. Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives. Int. J. Pharm. 371, 106–113. Caco, A.I., Varanda, F., Pratas de Melo, M.J., Dias, A.M.A., Dohrn, R., Marrucho, I.M., 2008. Solubility of antibiotics in different solvents. Part II. Non-hydrochloride forms of tetracycline and ciprofloxacin. Ind. Eng. Chem. Res. 47, 8083–8089. Caira, M.R., Bettinetti, G., Sorrenti, M., 2002. Structural relationships, thermal properties, and physicochemical characterization of anhydrous and solvated crystalline forms of tetroxoprim. J. Pharm. Sci. 91, 467–481. Childs, S.L., Stahly, G.P., Park, A., 2007. The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol. Pharm. 4, 323–338. Cruz-Cabeza, A.J., 2012. CrystEngComm 14, 6362–6365. da Silva, C.C.P., de Oliveira, R., Tenorio, J.C., Honorato, S.B., Ayala, A.P., Ellena, J., 2013. The continuum in 5-fluorocytosine. Toward salt formation. Cryst. Growth Des. 13, 4315–4322. Elacqua, E., Bucˇar, D.-K., Henry, R.F., Zhang, G.G.Z., MacGillivray, L.R., 2013. Supramolecular complexes of sulfadiazine and pyridines: reconfigurable

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