Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion

Jul 21, 2016 - E-mail: [email protected]. ... Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid...
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Cocrystal and Salt Forms of Furosemide: Solubility and Diffusion Variations Manas Banik, Shanmukha Prasad Gopi, Somnath Ganguly, and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *

ABSTRACT: Multicomponent solid forms of the BCS class IV drug furosemide (FSM) were obtained upon liquid assisted grinding with coformers anthranilamide (ANT), 4-toluamide (TOL), 2-picolinamide (PCM), piperazine (PPZ), 2,3,5,6tetramethylpyrazine (TMPZ), pyrazine (PYZ), 2-picolinic acid (PIC), isoniazid (INZ), and theophylline (THP), and identified with powder X-ray diffraction. Solid forms FSM−TMPZ (2:1), FSM−ANT (1:1), FSM−PPZ (1:1), and FSM−TOL ethanol solvate (1:1:1) were further characterized with single crystal Xray diffraction and differential scanning calorimetry; a sesquihydrate structure for FSM−PCM (1:1:1.5) was additionally confirmed with thermogravimetric analysis. The thermodynamically stable form I of FSM contains O−H···O acid···acid and N−H···O sulfonamide dimer synthons and chains. These synthons are modified in the cocrystals/salts sometimes leading to changes in physicochemical properties. The FSM−PPZ (1:1) salt converted to a thermodynamically more stable form FSM−PPZ (2:1) within 1 h. The apparent solubility of FSM−PPZ (1:1) salt is ∼3 times higher than the equilibrium solubility of the thermodynamically stable FSM−PPZ (2:1) salt. The solubilities of FSM−TMPZ and FSM−ANT are comparable to FSM, and this could be linked to coformer solubility. The metastable FSM−PCM sesquihydrate exhibited unusually high FSM concentration in solution as a function of time and as monitored in a slurry experiment. This prolonged presence of FSM in solution is rationalized by a synthon-extended-spring-andparachute model. Our rationale starts with Nangia’s explanation of the apparently high solubility of pharmaceutical cocrystals based on the simple spring-and-parachute model of Guzman et al. and later detailed by Brouwers et al. We go on to suggest that certain heteromolecular aggregates might well persist in soluble amorphous forms leading to a higher persistence of the drug in solution. Cocrystals/salts with higher solubility show higher values of initial diffusion/flux. A few bases when used as coformers render stable salt/cocrystals that resulted in low solubility/diffusion. In the new solid forms of FSM studied here, solubility and flux are seen to go hand in handan observation of import in drug absorption.

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INTRODUCTION A significant number of pharmaceutical leads being synthesized today tend to have high lipophilicity, and this reduces drug absorption leading to a high rate of failure.1−3 To increase solubility of such compounds, formulations have been used, but these show a drop in membrane permeability.4,5 Permeability through the GI tract is an important parameter in absorption, and low permeability causes poor absorption.6 Modification of the physical properties of pharmaceutical substances has been a subject of considerable interest, and the design of new solid forms using suitable and accepted modifiers known as coformers is an active area of research.7 The solubility and release rates of these solid forms have been studied extensively.8−15 However, only a few of these have been studied for permeability/diffusion behavior.11,16,17 Sanphui et al. reported simultaneous enhancements in both solubility and permeability for a few cocrystals of BCS class IV hydrochlorothiazide.11 These authors indicated that the physical properties of the coformers and drug−coformer interactions of the cocrystal have an important bearing on the solubility and permeability/diffusion of the cocrystal. © 2016 American Chemical Society

To investigate this further, another BCS class IV drug furosemide (FSM) was chosen for the present study.18,19 FSM is a loop diuretic and acts on the ascending loop of Henle in the kidney inhibiting the reabsorption of NaCl.20,21 Oral formulations of FSM are commonly used in the treatment of edema, congestive heart failure, renal failure, and hypertension.22 It exhibits poor solubility (7.31 mg/L) and permeability (Caco2 permeability = −6.5).21,23 FSM is a conformationally flexible molecule with −SO2NH2 groups and a dangling furan moiety and also has three hydrogen bond donating groups: −COOH, −SO2NH2, and −NH−. Lack of hydration/solvation potential arising from strong intra- and intermolecular H-bonding interactions and the presence of furan rings causes poor solubility. Nangia et al. used cocrystallization methods to improve solubility and dissolution of FSM relative to the parent FSM (10% ethanol−water) but encountered stability problems in the cocrystals.24 FSM has Received: June 14, 2016 Revised: July 19, 2016 Published: July 21, 2016 5418

DOI: 10.1021/acs.cgd.6b00902 Cryst. Growth Des. 2016, 16, 5418−5428

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FSM−ANT (1:1). 0.30 mmol of FSM and 0.30 mmol of ANT were ground together with a few drops of MeOH and dissolved in a variety of solvents. Colorless plate-like crystals were harvested from MeOH/ MeCN solvent mixture after 3−4 days. FSM−TOL Solvate (1:1:1). 0.30 mmol of FSM and 0.30 mmol of TOL were ground with a few drops of MeOH. Colorless needle crystals of 1:1:1 MeOH, EtOH, and MeNO2 solvates of FSM-TOL were obtained from MeOH, EtOH, and MeNO2 respectively after 3−5 days. Bulk FSM−TOL−EtOH was also synthesized from both slurry crystallization and liquid assisted grinding with EtOH. FSM-toluene solvate single crystals were obtained when the above powder cocrystal was crystallized from a MeOH/toluene solvent mixture. FSM−PCM Sesquihydrate (1:1:1.5). 0.30 mmol of FSM and 0.30 mmol of PCM were ground together with a few drops of acetone and dissolved in a variety of solvents. Colorless needle-like crystals were harvested from acetone after 2−3 days. FSM−PPZ (1:1). 0.30 mmol of FSM and 0.30 mmol of PPZ were ground together with a few drops of MeOH (or acetone) and dissolved in a variety of solvents. Yellow block-shaped crystals were harvested from MeOH/EtOH solvent mixture after 4−5 days. FSM−PPZ (2:1). FSM-PPZ (II) was prepared stirring 200 mg of FSM−PPZ (1:1) in 5−6 mL of pH 7.4 buffer; the residue was filtered, dried, and dissolved in a variety of solvents. Alternatively 0.30 mmol of FSM and 0.15 mmol of PPZ were ground together with a few drops of MeOH and dissolved in a variety of solvents. White needle-shaped crystals were harvested from MeOH after 2−3 days. FSM−THP (1:1). 0.30 mmol of FSM and 0.30 mmol of THP were ground for 2 min in the presence of a few drops of acetone then 15 min in presence MeCN. No single crystals could be grown. Formation of a new solid phase was confirmed by PXRD. FSM−PIC. 0.30 mmol of FSM and 0.30 mmol of PIC were ground together with a few drops of MeOH (or acetone). Formations of new solid phases were confirmed by PXRD. FSM−PYZ. 0.30 mmol of FSM and 0.30 mmol of PYZ were ground together with a few drops of MeOH. Formation of a new solid phase was confirmed by PXRD. FSM−INZ. 0.30 mmol of FSM and 0.30 mmol of INZ were ground together with a few drops of MeOH (or acetone). Formations of new solid phases were confirmed by PXRD. Bulk samples and batches were prepared following the abovementioned procedures (solvent drop grinding). Phase purity of these samples was confirmed by comparison of experimental powder pattern with the calculated powder pattern from the single crystal X-ray structure. Recrystallization was performed in the case of slightly impure samples. Solubility Measurements. The absorption coefficient of each solid phase was measured from the slope of the absorbance vs concentration curve of more than five known concentrated solutions in pH 7.4 buffer phosphate medium and measured at 330 nm in a PerkinElmer UV−vis spectrometer (for ANT, the 277 nm peak was chosen as both API and coformer show UV peaks at ∼330 nm). The solubility of each solid was measured at an interval of 1 h, 4 h, and 24 h using the shake-flask method at room temperature (27 ± 2 °C).34 The experiments were repeated twice or thrice. Diffusion Measurements. Diffusion studies of FSM and its cocrystals/salts were carried out according to the literature using the modified Franz diffusion cell apparatus through a cellulose nitrate membrane (0.45 μm, 11306, Sartorius, Germany).11 The effective surface area of the dialysis membrane was 4.5 cm2. A 100 mg finely powdered sample (average particle size ∼2−10 μm, measured using FESEM) was taken in the donor compartment in all experiments. The receptor compartment was filled with 20 mL of phosphate buffer (pH 7.4) and stirred at 60 ± 5 rpm. The diffusion samples were analyzed in a UV−visible spectrophotometer at a λmax of 330 nm (for FSM−ANT 277 nm) after suitable dilution. The concentrations of cocrystals and API were measured, in pH 7.4 buffer at room temperature (27 ± 2 °C), at 1 h intervals until 8 h of the diffusion experiment. No significant change of pH was noticed in the receptor compartment solution after diffusion experiments. All diffusion measurements were repeated twice.

been investigated heavily in the context of solid forms, and a number of reports on salts, cocrystals and solvates of FSM have appeared recently.25−30 However, none of these papers throw much light on flux/diffusion behavior. In our search for new solid forms of FSM, the acid···amide and acid···Nheterocyclic supramolecular synthons were targeted using crystal engineering with coformers containing basic nitrogen and −CONH2 groups, which would be complementary to the −COOH group of FSM.31−33 New solid forms of FSM were found with the coformers piperazine (PPZ), 2,3,5,6tetramethylpyrazine (TMPZ), 2-picolinamide (PCM), anthranilamide (ANT), 4-toluamide (TOL), theophylline (THP), pyrazine (PYZ), 2-picolinic acid (PIC), and isoniazid (INZ). These solids were characterized using single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differental scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, and thermogravimetric analysis (TGA); then the solubility (pH 7.4 buffer) and diffusion behavior were studied. An interpretation of the physicochemical properties was finally attempted through an analysis of structural and thermal data. Scheme 1. Furosemide (FSM) and Coformers in the Present Study

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EXPERIMENTAL SECTION

FSM was obtained from Yarrow Chem Products, Mumbai, India and used as such. Melting points were measured on a Büchi melting point apparatus (Sigma-Aldrich, Bangalore, India). Water filtered through a double distilled water purification system (Siemens, Ultra Clear, Germany) was used in all experiments. FTIR spectra were recorded using an ATR accessory on a PerkinElmer (Frontier) spectrophotometer (4000−600 cm−1). PXRD data were recorded using a PANalytical X-ray powder diffractometer equipped with a X’cellerator detector at room temperature with the scan range 2θ = 5 to 35° and step size 0.026°. X’Pert HighScore Plus were used to compare the experimental PXRD pattern with the calculated lines from the crystal structure. Solid state grinding, solution crystallization, and slurry methods in polar solvents such MeOH, EtOH, acetone, and MeCN were used to obtain the cocrystals. Preparation of Furosemide Salt/Cocrystals. FSM−TMPZ (2:1). 0.30 mmol of FSM and 0.15 mmol of TMPZ were ground together with a few drops of MeOH and dissolved in a variety of solvents. Colorless needle-like crystals were harvested from MeOH after 3−4 days. 5419

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Table 1. Crystallographic Parameters of FSM Salt, Solvate, and Cocrystals compound emp formula formula wt crystal system space group T/K a/Å b/Å c/Å α/° β/° γ/° volume/Å3 Z Dcalcd (g cm−3) μ (mm−1) F(000) total ref unique ref observed ref (I > 2σ(I)) Rint R1 (I > 2σ(I)) wR2 completeness (%) goodness-of-fit 2θ range CCDC No. compound emp formula formula wt crystal system space group T/K a/Å b/Å c/Å α/° β/° γ/° volume/Å3 Z Dcalcd (g cm−3) μ (mm−1) F(000) total ref unique ref observed ref (I > 2σ(I)) Rint R1 (I > 2σ(I)) wR2 completeness (%) goodness-of-fit 2θ range CCDC No.

FSM−TMPZ

FSM−ANT

FSM−PPZ

FSM−PCM hydrate

C16H17ClN3O5S C19H19ClN4O6S C16H21ClN4O5S 398.84 466.89 416.88 monoclinic monoclinic monoclinic P21/c C2/c P21/n 150 150 150 13.624(3) 10.3022(14) 13.339(6) 5.4540(13) 15.721(2) 8.792(4) 24.623(6) 26.101(5) 16.202(7) 90 90 90 98.232(7) 91.402(9) 98.941(6) 90 90 90 1810.8(7) 4226.1(11) 1877.0(14) 4 8 4 1.463 1.468 1.475 0.359 0.324 0.351 828 1936 872 13460 19189 16556 3560 4151 3686 2067 3426 3464 0.102 0.072 0.133 0.0699 0.0555 0.0520 0.1951 0.1834 0.1579 99.9 99.8 99.9 1.03 1.17 1.15 3.02−26 1.56−26 1.84−25.99 1470973 1470970 1470971 FSM−TOL−EtOH FSM−TOL−MeOH FSM−TOL−MeNO2 FSM−toluene C22H26ClN3O7S 511.97 monoclinic P21/c 150 11.2753(17) 9.3387(10) 22.881(4) 90 101.364(6) 90 2362.1(6) 4 1.440 0.299 1072 20795 4629 4192 0.055 0.0435 0.1531 99.9 1.12 1.82−26 1470974

C21H24ClN3O7S 497.94 monoclinic P21/c 150 11.0827(16) 9.0114(11) 23.460(4) 90 99.520(6) 90 2310.7(6) 4 1.431 0.303 1040 20951 4533 4171 0.093 0.0454 0.1485 99.9 1.14 1.76−26 1470976

Dissolution. Intrinsic dissolution rate (IDR) and was measured in an Electrolab dissolution tester. A 200 mg portion of the solid was taken in the intrinsic attachment and compressed to a 0.5 cm2 pellet using a hydraulic press at a pressure of 2.5 ton/in for 3 min. The pellet was compressed to provide a flat surface on one side, and the other side was sealed. Then the pellet was dipped into 500 mL of pH 7.4 buffer medium at 37 °C with the disk rotating at 150 rpm. At regular

C21H23ClN4O8S 526.94 monoclinic P21/c 150 11.673(3) 8.8845(19) 23.058(5) 90 99.784(7) 90 2356.5(9) 4 1.485 0.306 1096 20134 4617 2414 0.154 0.0732 0.1771 99.8 1.00 1.76−26 1470975

C31H29Cl2N4O10S2 752.63 triclinic P1̅ 150 8.133(8) 10.449(9) 10.926(9) 63.91(4) 78.79(4) 80.82(4) 815.1(13) 1 1.533 0.392 389 7567 3189 2612 0.117 0.0597 0.1918 99.9 1.13 2.10−25.99 1470977

C18H15ClN4O7.68S 477.73 triclinic P1̅ 150 5.117(2) 14.475(6) 14.859(6) 76.363(7) 82.502(8) 87.226(8) 1440.0(2) 2 1.497 0.331 491 8489 4103 1614 0.163 0.1077 0.2694 98.0 1.00 3.48−25.99 1470972 FSM−PPZ (2:1) C14H16ClN3O5S 373.81 monoclinic P21/n 293 6.4623(9) 19.983(3) 13.1428(17) 90 98.376(7) 90 1679.1(4) 4 1.479 0.382 776 15435 3284 2496 0.044 0.0473 0.1176 99.8 1.07 3.1−26 1483447

intervals of specified time (30 min for FSM, FSM−ANT, FSM−PPZ (2:1), 3 min for FSM−PCM sesquihydrate, FSM−TOL−EtOH, FSM−THP and 5 min for FSM−PPZ (1:1)), 5 mL of the dissolution medium was withdrawn and replaced by an equal volume of fresh medium to maintain a constant volume. Samples were filtered through nylon filters and spectrophotometrically assayed for drug content at 330 nm (for FSM−ANT 277 nm) on a Thermo scientific EV201 UV− 5420

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Figure 1. Crystal structure of FSM−TMPZ: (a) 2D corrugated layer view along the b-axis (b) 1D catemer-like chain via N−H···O hydrogen bonds along the b-axis.

Figure 2. Crystal structure of FSM−ANT: (a) acid···amide heterodimer synthons form 1D chain via N−H···O hydrogen bonds along the b-axis (b) 1D stacked chains: view along the b-axis.

Figure 3. Crystal structure of FSM−PPZ: (a) PPZ···PPZ 1D zigzag chain extending along the b-axis (b) FSM tetramer 1D chain extending along the b-axis (c) 2D layer view along the b-axis. data were processed with the Rigaku Crystal clear software.35 Structure solution and refinements were executed using SHELX-9736 using the WinGX37 suite of programs. Refinement of coordinates and anisotropic thermal parameters of non-hydrogen atoms were performed with the full-matrix least-squares method. The differing treatment of H atoms in D−H in any structure depends on data quality. The H atom positions were located from difference Fourier maps or calculated using a riding model. The PLATON38,39 software was used to prepare material for publication, and Mercury 3.7 was utilized for molecular representations and packing diagrams. Crystallo-

vis spectrometer. The amount of drug dissolved in each time interval was calculated using a calibration curve. The linear region of the dissolution profile was used to determine the intrinsic dissolution rate (IDR) of the compound. Diffusion measurements were repeated twice. Buffer Preparation. 50 mL of 0.2 M KH2PO4 was taken into a 200 mL volumetric flask followed by 39.1 mL of 0.2 M NaOH; water was then added to fill the volume. Single Crystal X-ray Diffraction. Single crystal X-ray data were collected on a Rigaku Mercury 375/M CCD (XtaLAB mini) diffractometer using graphite monochromated Mo Kα radiation. The 5421

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Figure 4. Crystal structure of FSM−TOL−EtOH: (a) acid···amide heterodimer synthons give 1D chain via N−H···N hydrogen bonds along the baxis (b) FSM−ethanol 1D tape along the b-axis. graphic cif files (CCDC Nos. 1470970−1470977 and 1483447) are available at www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Information (SI).

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RESULTS AND DISCUSSION FSM−TMPZ (2:1), FSM−ANT (1:1), FSM−PPZ (1:1), FSM−TOL−EtOH (1:1:1), and FSM−PCM sesquihydrate

Figure 5. Crystal structure of FSM−PCM sesquihydrate: amide··· pyridine homodimer synthons and sulfonamide···water interactions along the a-axis.

Figure 7. Simple spring-and-parachute model for cocrystals (according to Nangia).

were characterized by DSC and single crystal X-ray diffraction; in addition, the stoichiometry of the FSM−PCM sesquihydrate (1:1:1.5) was confirmed with TGA. Isomorphous FSM−TOL cocrystal solvates of EtOH, MeOH, and MeNO2 were obtained from the respective solvents. FSM−toluene solvate was obtained serendipitously when a FSM−TOL mixture was crystallized from an MeOH/toluene solvent mixture (Figure S1). FSM−PPZ (1:1) transformed to FSM−PPZ (2:1) salt when stirred in buffer. FSM−THP complex formation was confirmed only with PXRD and DSC as no suitable single crystal was obtained for SCXRD. For the rest of the compounds, multiple endotherms were seen for an equimo-

lecular ground powder. Solution crystallization of these forms led to disintegration, which can be attributed to a mismatch of solubility between the FSM and coformers. The crystallographic parameters and normalized hydrogen bonds for the crystal data are summarized in Table 1 and Table S1 in the SI. Structural Studies. FSM−TMPZ (2:1). FSM−TMPZ cocrystal crystallizes in the P21/c space group with Z = 4. The TMPZ molecule lies on the inversion center. The cocrystal adopts a 2D corrugated layer structure through the acid··· pyridine (d: 1.869 Å; θ: 160.28°) synthons which connect FSM catemer-like 1D chains forming from SO2HN−H···OS (d: 2.131 Å; θ: 152.85°) hydrogen bonds between neighboring

Figure 6. Crystal structure of FSM−PPZ (2:1): (a) FSM···PPZ 1D zigzag chain extending along the a-axis (b) extended supramolecular structure along the bc-plane. 5422

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Figure 8. Proposed mechanism of synthon-extended-spring-and-parachute model.

Table 2. Solubility and Stability Profiles of FSM in pH 7.4 Buffer compounds

first hour (mg/mL)

fourth hour (mg/mL)

24th hour (mg/mL)

FSM FSM−CAF FSM−CYT FSM−ADE FSM−TMPZ FSM−ANT FSM−PPZ (1:1) salt FSM−PPZ (2:1) salt FSM−THP FSM−TOL−EtOH FSM−PCM sesquihydrate

6.81 3.03 3.01 5.80 7.78 6.02 15.07 7.12 7.80 8.83 11.28

7.38 3.29 3.15 5.98 8.16 6.31

7.28 2.70 2.35 4.96 7.31

7.15

7.61

FSM FSM−PPZ (2:1) salt FSM−PPZ (1:1) salt FSM−ANT FSM−PCM sesquihydrate FSM−TOL−EtOH FSM−THP

IDR (mg cm−2 min−1)

apparent solubility (mg/mL)

1.003 0.807 2.425 0.882 1.416

7.28 7.61 22.86 6.40 10.28

1.200 1.074

8.71 7.80

FSM FSM−CAF FSM−CYT FSM−ADN FSM−TMPZ FSM−ANT FSM−PPZ (2:1) FSM−PPZ (2:1) FSM, THP hydrate FSM, TOL FSM

residue (fourth hour)

residue (24th hour)

FSM FSM−CAF FSM−CYT FSM−ADN FSM−TMPZ FSM−ANT

FSM FSM−CAF FSM−CYT FSM−ADN FSM−TMPZ FSM−ANT, FSM

FSM−PPZ (2:1)

FSM−PPZ (2:1)

interactions between alkyl C−H groups and Cl-atoms of neighboring FSM molecules. FSM−PPZ (1:1). The FSM−PPZ salt crystallizes in the P21/n space group with Z = 4. The electron density map showed that the acidic H atom of the FSM carboxyl group is transferred to one of the basic N atoms of PPZ resulting in an N+−H···O− (d: 1.793 Å; θ: 166.61°) ionic interaction. Protonated PPZ molecules are linked through N−H···N (d: 1.842; θ: 163.54°) hydrogen bonds to give PPZ···PPZ zigzag chains along the b-axis (Figure 3a). FSM molecules are connected with SO2HN−H···O (d: 2.004 Å, 2.195 Å; θ: 171.65°, 136.63°) hydrogen bonds forming a tetramer synthon chain also along the b-axis (Figure 3b). These adjacent FSM-tetramer chains and PPZ chains are connected to each other through ionic interactions to form a 2D layer structure (Figure 3c). Finally, sulfonamide oxygens of neighboring layers form bifurcated C− H···O hydrogen bonds with furan ring hydrogens and alkyl hydrogens (d: 2.632 Å, 2.503 Å; θ: 129.34°, 151.09°). FSM−TOL−EtOH (1:1:1). The cocrystal solvate takes the P21/c space group with Z = 4. FSM forms robust acid···amide (d: 1.585 Å, 2.406 Å; θ: 171.50°, 162.06°) heterodimer synthon with TOL. These heterodimer aggregates form 1D chain via N−H···N (d: 2.386 Å; θ: 151.16°) hydrogen bonds along the caxis (Figure 4a). Sulfonamide groups of FSM molecules are assembled together with EtOH and form tapes along the b-axis

Table 3. IDR and Apparent Solubility in pH 7.4 Buffer compound

residue (first hour)

FSM molecules (Figure 1). Finally, weak C−H···Ofuran (d: 2.747 Å; θ: 139.78°) hydrogen bonds connect these layers to form the 3D structure. FSM−ANT (1:1). The FSM−ANT cocrystal takes the C2/c space group with Z = 8. FSM forms the robust acid···amide (d: 1.443 Å, 2.237 Å; θ: 164.44°, 166.46°) heterodimer synthon with ANT. These heterodimers make 1D chains via HN−H··· OS (d: 2.221 Å; θ: 141.48°) hydrogen bonds (Figure 2a). Such chains are stacked through SO2HN−H···NH2 (d: 2.222 Å, θ: 172.95°), >N−H···OS (d: 2.449 Å, θ: 129.34°) hydrogen bonds, slip-stacked π···π (closest C···C distance: 3.385 Å) interactions and weak N−H···πfuran (closest C···H distance: 2.788 Å) interactions to give the 2D structure (Figure 2b). The structure is additionally stabilized by weak C−H···Cl (2.958 Å) 5423

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Figure 9. Intrinsic dissolution curves of (a) FSM−PPZ (1:1), (b) FSM−PCM sesquihydrate, FSM−TOL−EtOH, FSM−THP, (c) FSM, FSM− ANT, and FSM−PPZ (2:1) in pH 7.4 buffer at 37 °C.

Figure 10. (a) Cumulative amounts of salts/cocrystals diffused vs time. (b) Flux/permeability of salts/cocrystals vs time.

FSM forms a robust acid···amide heterodimer synthon (d: 1.452 Å, 2.075 Å; θ: 172.30°, 153.55°) with PCM. The −SONH2 group was also found to be disordered, and no sulfonamide H atoms could be obtained from the difference map. FSM molecules form 1D chain pairs along the a-axis via sulfonamide···sulfonamide interactions. The structure is stabilized with amide···pyridine (d: 2.309 Å, θ: 149.69°) homodimer synthons and sulfonamide···water interactions (Figure 5). The water molecules are found in a continuous chain; whether or

(Figure 4b). The structure is additionally stabilized by weak C− H···πfuran (closest C···H distance: 2.719 Å) interactions. FSM−PCM Sesquihydrate (1:1:1.5). The cocrystal hydrate takes the P1̅ space group with one FSM molecule, one PCM molecule, and disordered water molecule(s) in the asymmetric unit. The ratio of components (1:1:1.5) of the molecular complex was confirmed with TGA and the calculated PXRD pattern was found to be in good agreement with the experimental microcrystalline sample (Figures S2 and S3). 5424

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corresponding to loss of crystalline water molecules, followed by melting at 120 °C. Multiple endotherms were observed for FSM−TOL−EtOH and a broad endotherm was seen in the range 115−135 °C corresponding to loss of lattice solvent. Multiple endotherms were also seen for FSM−PIC, FSM− PYZ, and FSM−INZ. TGA confirms the presence of crystalline solvate/hydrate molecules in the cocrystals (Figure S3). Solubility and Stability Studies. Solubility is a preformulation property that has immense impact on the bioavailability of an active pharmaceutical ingredient (API). FSM is a weak acid and its solubility increases with increase with pH.22,40 The solubility value obtained for FSM at pH 7.4 is 7.3 mg/mL, and this is in good agreement with the reported solubility of 6.9 mg/mL at pH 7.5.22 Solubility experiments of the new solid forms were carried out in pH 7.4 phosphate buffer, and their phase stability was studied at intervals of 1, 4 and 24 h by checking the PXRD of the residues (Figure S2). The pH values of the slurried solutions were also measured after the experiments and are given in Table S3. The pH variations are around ±1 and so the solubility values in the different experiments may be meaningfully compared, especially because the pH decreases upon slurrying in all cases excepting FSM−PPZ (1:1) where a small increase of 0.8 pH units was observed. The solubility of multicomponent systems like cocrystals and salts depends on a number of factors such as drug···coformer interactions, and the individual concentrations of the coformer and the un-ionized drug in solvent.12,41 The thermodynamically stable solid form I of FSM contains O−H···O acid···acid and N−H···O sulfonamide dimer synthons and chains; these are modified in the cocrystals and salts.42 The spring-and-parachute model of Guzman et al. seeks to explain the enhanced (kinetic) solubility of selected solid forms of an API relative to a pure drug compound.43 These authors proposed that the existence of high energy crystal forms (spring) transiently increases the solubility in water relative to the pure API. Excipients that function as precipitation inhibitors (parachute) provide enhanced dissolution and increased bioavailability. Brouwers et al. continued with the idea of API supersaturation through high energy solid forms and specifically mentioned amorphous forms and cocrystals as solid forms that could show enhanced solubility.44 They noted that that “the term ‘apparent solubility’ describes the apparent equilibrium between drug in solution and a solid whose structure is not in the most stable state”. The breakthrough paper in the application of the spring-andparachute model to pharmaceutical cocrystals is, however, the 2011 review of Nangia, where the connection between a cocrystal and an amorphous form was clearly stated.45 A more recent review from Nangia further expands the point.46 This model is schematically illustrated in Figure 7, and its essence is that when the solubility of the coformer is in excess of that of the API, it is leached out of the solid cocrystal by the solvent leaving an “amorphous” API structure, which being amorphous, may be temporarily held in solution. This manifests itself as an apparent increase in (kinetic) solubility. This amorphous form is the spring (high energy form), and it leads to enhanced solubility. The amorphous assembly may then transform either to a metastable crystalline form, the parachute, which gradually converts into the low solubility thermodynamic form, or it may collapse quickly to the thermodynamic form (dotted line in scheme) showing just a spike in the solubility of the API. However, the parachute effect is not clearly explained in the literature. Guzman et al. ascribe it to excipients. Brouwers et al.

Figure 11. Solubility (mg/mL) and initial flux (mg cm−2 h−1) values for FSM solid forms.

not the term “channel hydrate” can be applied is a matter of discussion because there is hydrogen bonding between the water and the sulfonamide groups. FSM−PPZ (2:1). The FSM−PPZ salt crystallizes in the P21/n (Z = 4) with one molecule of FSM and half molecule of protonated PPZ in the asymmetric unit. Accordingly, the protonated PPZ ring lies on the inversion center. FSM ions are bridged by protonated PPZ ions via N+−H···O− (d: 1.879 Å, 1.812 Å; θ: 58.57, 167.80°) ionic interactions forming a 1D chain along the crystallographic a-axis (Figure 6a). These 1D chains are then extended along the bc-plane through SO2HN− H···O (d: 2.091 Å, θ: 148.80°) hydrogen bonds to form a 3D supramolecular structure (Figure 6b). The structure is additionally stabilized by two weak C−H···O (d: 2.594 Å, 2.371 Å) hydrogen bonds formed from two sulfonamide oxygen atoms with furan and piperazine fragments. Moreover, auxiliary interactions such as N−H···π and C−H···π (closest C···H distance: 2.579, 2.606 Å) also augment the packing. A molecular overlay diagram (Figure S5) shows that the molecular conformations in all these solids differ in the orientations of the furanylmethylamino fragments of FSM. This fragment is almost perpendicularly (C−N−C−C = 70.67°) oriented to the central benzene ring in FSM−ANT. However, in other cases smaller torsions (C−N−C−C = 163−178°) are observed; both PPZ salts possess similar FSM conformations with an angle of 19.7° between the furan planes. Formation of an equimolecular complex of FSM−THP was evident from PXRD (Figure S2), but crystallization from different solvents gave separate crystals of FSM and THP. IR spectra of the complex shows three carbonyl peaks at 1704 cm−1, 1669 and 1642 cm−1 (Figure S4). The PXRD pattern of FSM−THP neither matches with the FSM−CAF nor with the FSM−pentoxyphylline.24,29 The instability of the complex in different solvents could be indicative of cocrystal formation. Thermal Analysis. The thermal behavior of these compounds was investigated by DSC. FSM exhibits a small endothermic peak at 136 °C followed by a sharp exothermic peak at 213 °C (the melting endotherm was not clearly seen). FSM−PPZ shows a melting endotherm at 225 °C followed by decomposition, the higher melting point being due to the salt form. FSM−ANT and FSM−TMPZ cocrystals exhibit melting endotherms at 144 °C (sharp) and 150−170 °C (broad) respectively. FSM−THP shows a sharp melting endotherm differentiable from FSM and observed at 201 °C (lower than that of coformer as well as FSM). FSM−PCM sesquihydrate shows a broad endotherm in the range 95−105 °C, 5425

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We are also able to rule out the possibility that the enhanced solubility of the sesquihydrate over a sustained time period is due to conversion of the cocrystal to amorphous FSM, which then shows enhanced solubility. Perusal of the literature shows that amorphous FSM exists only up to 20−30 min in solution, whereas in our case the high concentration of the susbstance in solution persists even after 24 h.50 Further, it is mentioned quite clearly that the solubility of crystalline and amorphous FSM is nearly the same (and moderate) at 25−27 °C, which is close enough to the ambient temperature of the experiment here. Therefore, the sustained presence in solution of FSM cannot arise from the contribution of amorphous FSM (even if the latter does exist in solution, for which there is no particular indication). Entropic considerations are also undoubtedly important in extending the lifetime of the API in solution. The presence of an amorphous cocrystal assembly surely decreases the entropy of transformation in each of the stages solid cocrystal → amorphous cocrystal in solution → amorphous API in solution → metastable API → stable API effectively increasing the (kinetic) solubility of the API. We emphasize that each of these transients serves to extend the lifespan of the API in solution, and the cumulative effect is that it is still held in significant amounts in solution after 24 h. This is surely long enough for the drug to be absorbed by the body, and therefore it suffices to render a cocrystal an effective solid form for drug absorption and delivery. The removal of solvent from the lattice in both cocrystal solvate and hydrate could be the cause of their instability in slurry conditions. Poorly soluble FSM and TOL precipitate out within 1 h. In the case of FSM−THP, the thermodynamically stable form 1 of FSM and the poorly soluble THP hydrate were detected after 1 h. It was also observed that FSM−PPZ (1:1) salt transformed to a thermodynamically more stable form FSM−PPZ (2:1) within 1 h. The concentration of FSM−PPZ (1:1) is more than twice that of FSM after 1 h and must be due to the ionic nature of the salt and the pH (8.2) of the medium.51 However, the solubility of FSM−PPZ (2:1) is reduced to 7.61 mg/mL, which could be explained from the crystal structures. In FSM−PPZ (2:1), the carboxylate group of FSM symmetrically interacts with two neighboring PPZ ions, which is reflected in C−O bond distances of 1.252 and 1.257 Å, leading to strong ionic interaction. In FSM−PPZ (1:1), the FSM carboxylate interacts unsymmetrically with the PPZ ion and a sulfonamide hydrogen with C−O bond distances 1.251 and 1.267 Å. Such a structural difference leads to a more stable structure for FSM−PPZ (2:1) with a ≈ 10° increase in melting point. The driving force in this transformation could be the charge distribution in the carboxylate moiety. Cocrystal FSM− ANT was found to be stable after a 4 h slurry experiment (solubility at 4 h is 6.31 mg/mL). However, thermodynamically stable forms of FSM and FSM−ANT were detected after a 24 h slurry experiment. The solubility of FSM−TMPZ at room temperature is 7.31 mg/mL after 24 h. The solubilities of FSM−TMPZ and FSM−ANT are not high enough compared to FSM, and this may be linked to coformer solubility. The stability difference of these two complexes could be attributed to the presence of strong −SO2HNN−H···OS interactions forming a 1D chain in FSM−TMPZ, absent in FSM−ANT. To understand the solubility dependence of cocrystals on coformer structure, three more stable solid forms of FSM were prepared with bases (studied earlier in 10% EtOH-water): furosemide−cytosine salt (FSM−CYT), furosemide−caffeine

identify the parachutes as precipitation inhibitors, which are possibly introduced in the formulation steps. Nangia equates the parachute with metastable polymorphs. The essence of Nangia’s model is that dissolution of a cocrystal can lead to an amorphous API structure in solution, while a slow dissolving crystalline metastable polymorph acts as the parachute. The results observed in the FSM−PCM sesquihydrate cocrystal system in this study suggest an elaboration of the Nangia model. The concentration of FSM−PCM sesquihydrate after 1 h is 11.28 mg/mL. We note that the solubility of pure FSM under similar conditions, namely, in pH 7.4 buffer, is 7.28 mg/mL; the effect of pH can be ignoredin both pure API and cocrystal, similar pH changes are observed upon dissolution. One needs, in effect, to account for the increase of 4.00 mg/mL of FSM concentration in solution. Further, the concentration of FSM−PCM sesquihydrate is well maintained even after 24 h in a supersaturated solution (it falls only to 9.47 mg/mL). We ascribe this retention of high solubility over prolonged duration to the formation of a loosely bound, amorphous cocrystal structure in solution through a supramolecular synthon effect. This is depicted in Figure 8. The origin of this extended kinetic solubility effect could be owing to the intermediate solubility of the PCM coformer. It is not so high that it is leached out rapidly as in the simple spring-andparachute model, and yet it is not so low that the cocrystal itself has poor solubility (TMPZ, ANT). A coformer of intermediate solubility gets leached out of the cocrystal by the solvent but only gradually, and there is time for a loosely associated amorphous cocrystal to form and be held in solution. The presence of such an aggregate effectively extends the lifetime of the API in solution. Whether it is a delayed action spring or the early beginnings of the parachute is a matter for further discussion. In summary, this uniquely bonded drug−coformer system in solution may be visualized as a disordered/ amorphous drug assembly obtained through the slow leaching out of the coformer. We believe that after rearrangement in saturated solution the FSM−PCM sesquihydrate system would resemble an amorphous cocrystal phase wherein the weak acid···amide synthon would sustain a drug−coformer bonding which in turn would cause the increase in concentration of FSM in solution. This situation resembles the model of Nangia in that we are proposing the existence of an amorphous aggregate in solution, but it differs in that we are suggesting that it is an amorphous cocrystal rather than an amorphous single phase material. Whether this goes to a metastable cocrystal or a metastable API polymorph (which collapses to the low solubility thermodynamic form of the API) is still a matter of conjecture. However, what seems to suggest itself is that the synthon structure is an effective precipitation inhibitor. We propose the term synthonextended-spring-and-parachute to describe our model for cocrystal solubility. Basically, our model proposes the existence of supramolecular synthons in solution. This is not new.47,48 Recently, we have provided NMR data in selected (nonpharmaceutical) systems that show the presence of discrete molecular aggregates in solution that are closely related to the synthons in the final crystal structure.49 The present work touches upon this idea in a different and interesting way: the presence of amorphous heteromolecular clusters in solution are the precipitation inhibitors of Guzman and Brouwers and constitute the parachute in the spring-and-parachute model of Nangia. 5426

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diffusion behavior as FSM, and this may be due to their similar solubility nature, but it shows higher diffusion behavior later, which likely is linked to the hydrophobic nature of the salt former. The salt and cocrystal of bases CYT and CAF exhibit the lowest flux and mass of drug diffused per unit time. This appears to be lower due to lesser amount of dissolved solids at the membrane. FSM−ADE has a higher flux than CYT and CAF cocrystals in line with its higher solubility. Overall, we suggest that coformers causing higher solubility of cocrystal/salt lead to higher diffusion. Solubility and flux/diffusion are seen to go hand in hand: higher solubilities give higher flux/diffusion (Figure 11). These results on salts and cocrystals of FSM are extremely positive for the improvement of physicochemical properties of poorly soluble and poorly permeable drug candidates.

cocrystal (FSM-CAF) and furosemide−adenine cocrystal (FSM−ADE).24 The FSM−CYT salt showed lower solubility in pH 7.4 buffer and the reasons could be 2-fold: (a) low solubility of CYT; (b) a robust two-point carboxylate··· aminopyridine synthon. The higher solubility of FSM−ADE compared to FSM−CAF and FSM−CYT may be linked to lower lattice energy. Dissolution Studies. Intrinsic dissolution rate (IDR) is a kinetic parameter, the rate at which the equilibrium solubility is reached. For metastable drugs, which undergo phase transformation during slurry experiments, the IDR and apparent solubility are the relevant parameters. Kanke et al. derived the equation of apparent solubility, Cm = Cs(Jm/Js), applying the Noyes−Whitney equation,52,53 where Cm is the apparent solubility of the metastable solid, Cs is the solubility of the thermodynamically stable form, while Jm and Js are the dissolution rates of metastable and stable solids. Dissolution rate measurements at 30 min intervals over 4 h were carried out for FSM, FSM−ANT, and FSM−PPZ (2:1). However, for FSM−PPZ (1:1) the measurement was carried out for 40 min (5 min interval), and dissolution rate measurements of FSM− PCM sesquihydrate, FSM−TOF−EtOH, and FSM−THP were carried out for 21 min (3 min interval). The apparent solubility of FSM−PPZ (1:1) salt is ∼3 times higher as compared to the thermodynamically stable FSM−PPZ (2:1) salt (Table 3). Generally, the apparent solubility of cocrystals follows their coformer solubility behavior. Diffusion/Flux of Salts and Cocrystals. Drug absorption is dependent on solubility and membrane permeability. The diffusion behavior of the solid forms of FSM was studied using a simple Franz diffusion cell which gives a relative idea of permeation behavior when solids of the same series are studied. Any compound applied to either tissue or an artificial membrane will have a lag time, the time it takes to permeate through the membrane and diffuse into the receptor fluid and then finally to reach a steady state of diffusion. The lag time is also the period during which the rate of permeation across the membrane is increasing. A steady state is reached when there is a consistent, unchanging movement of the permeant through the membrane. During the lag period there is rapid diffusion/ flux which is reflected by a sharp peak which drops off when the steady state is attained. Diffusion of all the solids was measured in buffer pH 7.4 at 1 h intervals over 8 h (Figure 10). No significant change of pH was noticed in the receptor compartment solution after diffusion experiments. The plots of cumulative drug diffused and flux indicate that except for FSM−CYT and FSM−CAF all the cocrystals/salt exhibit better diffusion behavior compared to FSM; this may be explained by structural interactions. None of these salts/cocrystals contain the O−H···O acid···acid and N−H···O sulfonamide dimer synthons and chains which are seen in form I of FSM.41 FSM− TMPZ and FSM−ANT exhibit similar diffusion behavior with an initial rise in cumulative drug, which levels off after 3 h. FSM−PPZ (2:1) salt also exhibits initial slow increase in diffusion, which reaches a steady state after 6 h. The rest of the compounds show a steady increase in diffusion with time. The higher initial diffusion/flux of FSM−TMPZ and FSM−ANT compared to FSM could be due to the higher concentration gradient across the membrane resulting from higher dissolved solids.3 In addition to solubility of FSM−TMPZ, the hydrophobic nature of the TMPZ could be a reason for its higher diffusion behavior when compared with the FSM−ANT cocrystal. FSM−PPZ (2:1) salt shows similar first hour flux/

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CONCLUSIONS The thermodynamically stable form I of FSM contains O−H··· O acid···acid and N−H···O sulfonamide dimer synthons and chains which are modified in the cocrystals/salts. Two salts, one solvate and six cocrystals (including cocrystal solvates) were obtained and characterized by single crystal X-ray diffraction. Studies conducted on cocrystals/salts indicate a general dependence of kinetic solubilities on intrinsic coformer solubilities. FSM−PPZ (1:1) salt shows the highest drug concentration in saturated solution but transformed to a less soluble and more stable FSM−PPZ (2:1) salt form within an hour, and the driving force of the transformation is symmetric charge distribution in the carboxylate moiety. FSM−PCM sesquihydrate shows a higher concentration of FSM in solution with time. Such a result is interpreted with a synthon-extendedspring-and-parachute model, wherein it is suggested that the acid···amide synthon prolongs the drug concentration in solution via an amorphous cocrystal. It would need to be seen in the future whether such effects are seen in cocrystals that are not solvated/hydrated. We have also observed that the initial flux/diffusion and the solubility of these FSM solid forms go hand-in-hand. Drug···coformer and cocrystal/salt···solvent interactions are seen to play an important role in solubilitydiffusivity/flux variations in FSM cocrystals/salts. It is anticipated that our studies here of salts/cocrystals of FSM will be useful for the further development of physicochemical properties of poorly soluble and permeable drug candidates.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00902. Neutron normalized hydrogen bonding parameters, PXRD, DSC, TGA, and FT-IR plots of the furosemide solvate, salt and cocrystals (PDF) Accession Codes

CCDC 1470970−1470977 and 1483447 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 5427

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AUTHOR INFORMATION

Corresponding Author

*Fax: +91 80 23602306. Tel.: +91 80 22933311. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

M.B. and S.P.G. thank the UGC for a Dr. D. S. Kothari fellowship. S.G. thanks IISc for a fellowship. G.R.D. thanks DST for a J. C. Bose fellowship. We thank S. Chakraborty and S. Saha for their assistance in the crystal structure analysis.

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