New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and

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New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity Shanmukha Prasad Gopi, Manas Banik, and Gautam R. Desiraju Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01540 • Publication Date (Web): 23 Nov 2016 Downloaded from http://pubs.acs.org on November 30, 2016

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Crystal Growth & Design

New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity Shanmukha Prasad Gopi, Manas Banik, and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India

Abstract: Hydrochlorothiazide (HCT), is a diuretic drug with poor solubility and permeability. Physicochemical properties of HCT have been modified by cocrystallization with piperazine (PPZ), tetramethylpyrazine (TMPZ), picolinamide (PCM), isoniazid (INZ), malonamide (MAM), and isonicotinic acid (INIC) using mechanochemical grinding (liquid assisted and neat). The solids obtained were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), FTIR spectroscopy and DSC and subjected to solubility and membrane permeability studies. SCXRD showed that the N−H⋅⋅⋅O sulfonamide catemer synthons found in the stable polymorph of pure HCT, have been replaced by drug-coformer heterosynthons in the cocrystals. HCT–PPZ and HCT–PCM cocrystals showed improvement in solubility and membrane permeability/diffusion compared to the parent API. The improved solubility and diffusion rates are due to the drug-coformer interactions in the new solid forms. A structure-property relationship is examined to evaluate the solubility and diffusion rates of the new solid forms. The cocrystal with INIC, which could not be prepared previously by conventional methods, was obtained by prolonged grinding for six days.

Introduction: Solid state reactions, induced by mechanical energy, liquid-assisted grinding (LAG) and ball milling, have become established methods for the preparation of pharmaceutical cocrystals.1,2 Examination of the mechanochemical reaction pathways reveal the existence of different intermediate phases of variable crystallinity. Poor physicochemical properties (solubility and permeability) of active pharmaceutical ingredients (API) are a serious concern in clinical development.3 Cocrystals and salts of APIs often have advantageous physicochemical properties, improved over the parent drugs, without change in therapeutic efficiency.4 Recently, the importance of cocrystals has been acknowledged by the FDA as revealed in their recent

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guidelines for the classification of various solid forms.5 The main advantages of cocrystals are that they are relatively stable and less prone to phase transformations.6 Selection of multiple coformers makes it possible to explore several cocrystals for the same API.7 Solubility enhancement may be achieved with the use of highly soluble coformers.8,9 Sanphui et al. have reported the solubility advantage and pharmacokinetic activities of cocrystals of the poorly soluble drug sildenafil.10 A recent report by Lu et al. on the apixaban-oxalic acid cocrystal showed improved solubility and bioavailability relative to the parent API.11 High solubility and permeability are essential for good oral absorption of an active drug to ensure optimal delivery and bioavailability.12 However, the structural features for good solubility often run counter to the features required for good permeability. Accordingly, there are only a few reports available on cocrystals/salts in which solubility and permeability/diffusion are simultaneously improved.13-17 In the present work, Hydrochlorothiazide (HCT) was chosen and a number of cocrystals were examined with respect to simultaneous improvement of the solubility and permeability. HCT is a diuretic drug, which acts by inhibiting the ability of the kidney to retain water. It is one of the essential drugs listed by WHO. The reported aqueous solubility is 0.7 g /L, and logP –0.07.18 HCT is reported as a BCS class IV drug in a number of reports.19-23 However, according to the WHO essential medicine list, BCS is a class III drug.24 Sanphui et al. reported five cocrystals of HCT and their solubility and permeability properties were extensively studied.13 The authors also specified that drug-coformer interactions play a major role on the physicochemical properties of the cocrystal. In the present investigation, eight new HCT cocrystals have been made with EAFUS (Everything Added to Food in the United States) and model GRAS (Generally regarded as Safe) coformers such as piperazine (PPZ), tetramethylpyrazine (TMPZ), picolinamide (PCM), malonamide (MAM), isonicotinic acid (INIC) and with a TB drugs isoniazid (INZ). The previously reported results on HCT cocrystals show physicochemical property modification through synthon alteration and a trade-off between solubility and permeability. Here we chose soluble and hydrophobic coformers that can favorably affect both solubility and permeability. So, we selected PPZ which is highly soluble but also has hydrophobic –CH2 groups. The cocrystal with isonicotinic acid (INIC) was made using prolonged mechanochemical neat grinding. Other methods, such as conventional liquid assisted grinding, sublimation, slurring and ball milling failed to produce HCT–INIC cocrystal.


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Scheme 1. Hydrochlorothiazide (HCT) and coformers in the present study

Experimental: HCT was obtained from Yarrow Chem Products, Mumbai, India and used as such. Melting points were measured on a Büchi melting point apparatus. Water filtered through a double distilled water purification system (Siemens, Ultra Clear, Germany) was used in all experiments. Fourier Transform infrared (FTIR) spectra were recorded using an ATR accessory on a Perkin Elmer (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 40º and step size 0.027º. X'Pert HighScore Plus was used to compare the experimental PXRD pattern with the calculated lines from the crystal structure. The calculated PXRD patterns were generated using Mercury 3.7. Preparation of HCT cocrystals: (a) LAG method HCT–PPZ (1:1) 0.33 mmol of HCT and 0.33 mmol of PPZ were ground in a mortar and pestle with a few drops of nitromethane and acetone. Yellow blocks were obtained from MeNO2 after 10-12 days; m.p. 156 ºC.



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HCT–TMPZ–H2O (2:1:1) 0.66 mmol of HCT and 0.33 mmol of TMPZ were ground together in a mortar and pestle with a few drops of MeOH and dissolved in a variety of solvents. Colorless block-shaped crystals were harvested from MeOH after 2-3 days. HCT–PCM (1:1) 0.33 mmol of HCT and 0.33 mmol of PCM were ground together in a mortar and pestle for 30 min dissolved in a variety of solvents. Formation of new solid phase was confirmed by PXRD after grinding 30 min. Colorless blocks appeared from MeOH solvent mixture after 4-5 days; m.p. 186 ºC. HCT–INZ–H2O (1:1:1) 0.33 mmol of HCT and 0.33 mmol of TMPZ were ground together in a mortar and pestle with a few drops of MeOH (or CH3CN) and dissolved in a variety of solvents. Colorless needles were harvested from MeOH/EtOH solvent mixture after 4-5 days; m.p. 129 ºC. HCT–MAM (2:1) 0.66 mmol of HCT and 0.33 mmol of MAM were ground together in a mortar and pestle for 1015 min with a few drops of MeOH and dissolved in a variety of solvents. Colorless needle-like crystals were obtained from acetone after 2-3 days. m.p. 163 ºC. (b) Prolonged grinding method: HCT–INIC (1:1) 0.33 mmol (100 mg) of HCT and 0.33 mmol (41 mg) of INIC were ground together with mortar and pestle for six days (10 minutes grinding approximately at one hour intervals, roughly one hour per day overall). Formation of new solid phase was confirmed by PXRD after grinding for four days. However, complete conversion had not taken place even after six hours of grinding. The ground mixture was kept for crystallization in MeOH and EtOH. Colorless block-like crystals were harvested after 4-5 days; m.p. 262 ºC. Bulk samples and batches of cocrystals were prepared following the above mentioned procedures by solvent drop grinding. Phase purity of these samples was confirmed by comparison of experimental powder pattern with the calculated powder pattern from single crystal X-ray structure. The HCT–PPZ cocrystal PXRD is reproduced and matched with the PXRD pattern of the reported CA2513746 A1 patent.25 Recrystallization was performed in the


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cases of slightly impure samples. HCT–INIC bulk sample could not be prepared because of incomplete conversion. Solubility measurements: The absorption coefficient of each solid phase was measured from the slope of the absorbance versus concentration curve of more than five known concentrated solutions in pH 7.4 buffer phosphate medium, and measured at 317 nm in a Perkin Elmer UV-vis spectrometer. The apparent solubility of each solid was measured at 4h using the shake-flask method26 at room temperature (27±2 °C). The experiments were repeated twice or thrice. The pH values of the slurried solutions were also measured after the experiments and are given in table S2. Dissolution: Intrinsic dissolution rate (IDR) and was measured in an Electrolab dissolution tester. A 200 mg portion of the solid (sieved) was taken in the intrinsic attachment and compressed to a 0.5 cm2 pellet using a hydraulic press at a pressure of 3 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±0.5 °C with the disk rotating at 130 rpm. Aliquots of 5 mL samples were withdrawn at predetermined time intervals of 5, 10, 15, 20, 25, 30, and 60 min substituting the same with an equal quantity of fresh dissolution medium. For HCT–MAM, a regular intervals of 30 min was used for 6h. Samples were filtered through nylon filters and spectrophotometrically assayed for drug content at 317 nm on a Thermo scientific EV201 UV– 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. Dissolution measurements were repeated thrice. Diffusion measurements: Diffusion studies of HCT and its cocrystals/salts were carried out according to the literature using a modified Franz diffusion cell apparatus through a cellulose nitrate membrane (0.45 µm, 11306, Sartorius, Germany). The effective surface area of the dialysis membrane was 4.5 cm2. 50 mg finely powdered sample (average particle size ~2-10 µm, measured by Field Emission Scanning Electron Microscope instrument) 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 317 nm. The concentrations of cocrystals and API were measured, in pH 7.4 buffer at room temperature (27±2 °C), at one hour intervals till eight hours of the



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diffusion experiment. No significant change of pH was noticed in the receptor compartment solution after diffusion experiments. All diffusion measurements were repeated twice. Thermal Analysis: DSC (Differential scanning calorimetry) measurements were carried out using Mettler Toledo DSC instrument equipped with a nitrogen purge gas. 5−10 mg of sample was typically used for analysis. The heating rate was 10°/min over a range of 30−330 °C. 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 data were processed with the Rigaku Crystal clear software.27 Structure solution and refinements were executed using SHELX-9728 using the WinGX29 suite of programs. Refinement of coordinates and anisotropic thermal parameters of non-hydrogen atoms were performed with the full-matrix least-squares method. The H atom positions were located from difference Fourier maps or calculated using a riding model. The PLATON30,31software was used to prepare material for publication, and Mercury 3.7 was utilized for molecular representations and packing diagrams. Crystallographic cif files (CCDC Nos. 1510699–1510706) are available at www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Information (SI).

Results and Discussion All cocrystals of HCT were characterized by SCXRD, PXRD, FTIR and DSC; further, the solubility and membrane permeability/diffusion of these solid forms were examined. The HCT–MAM structures is isomorphous to earlier reported HCT–SAM (succinamide) cocrystal.32 The crystallographic parameters and normalized hydrogen bonds for the crystal data are summarized in Table 1 and Table S1 in the SI. While HCT can form cocrystals with pyridine derivatives like nicotinic acid (NIC), picolinic acid (PIC)23, pyrazinamide (PZM),22 nicotinamide (NCT), picolinamide (PCM) and isonicotinamide (INCT),33 the HCT–INIC cocrystal is so far not reported. Sanphui et al. attempted to make this cocrystal but did not succeed.32 In the present work, we were successfully able to make the INIC cocrystal with prolonged grinding after several days and single crystals were obtained from solution crystallization. There seems to be a long induction period before cocrystal formation can be observed but once it begins it proceeds rapidly to partial conversion. Complete conversion was not observed (Figure 1).


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Figure 1. PXRD pattern of HCT–INIC cocrystal at different time intervals. New peaks are highlighted.

Table 1. Crystallographic parameters of Hydrochlorothiazide cocrystals Compound Emp. Formula Formula wt. Crystal system Space group T/K a/Å b/Å c/Å α /° β/° γ/°

HCT–PPZ C11H18ClN5O4S2 383.87 Triclinic 1 150 6.431 9.496 13.457 71.6400 86.0600 82.2300

HCT–TMPZ–H2O C22H30Cl2N8O9S4 749.68 Orthorhombic Pna21 150 23.479(5) 7.5212(16) 17.587(4) 90 90 90


HCT–PCM C13H14ClN5O5S2 419.86 Monoclinic P21/n 150 10.406(12) 13.659(14) 12.636(14) 90 105.414(10) 90


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Volume/Å3 Z Dcalcd(g cm–3) µ (mm-1) F(000) Total ref. Unique ref. Observed ref. (I > 2σ(I)) Rint R1 (I> 2 σ(I)), wR2

772.510 2 1.650 0.546 400 32522 3374

3105.7(12) 4 1.603 0.542 1552 27614 6105

1731(3) 4 1.611 0.499 864 15932 3396

3245

6063

3097

0.033 0.0266

0.055 0.0300

0.095 0.0504

0.0724

0.0957

0.1666

Goodness-of-fit 2θ range CCDC No.

1.10 3.2-27.0 1510706

1.18 1.7-26.0 1510704

1.15 2.2-26.0 1510701

HCT–MAM C17H22Cl2N8O10S4 697.57 Monoclinic C2/c 150 17.741(15) 10.341(8) 14.385(12) 90 97.686(13) 90 2615(4) 4 1.772 0.639 1432 11870 2563

HCT–INZ–H2O C13H15ClN6O6S2 450.88 Triclinic 1 150 7.183(4) 11.247(6) 12.027(7) 92.708(6) 107.097(12) 102.106(5) 901.9(9) 2 1.660 0.491 464 12967 6509

HCT–INIC C13H13ClN4O6S2 420.84 Monoclinic Cc 150 8.861(7) 16.261(15) 11.884(11) 90 90.05(3) 90 1712(3) 4 1.633 0.508 864 7912 3353

2369

6006

2899

0.095

0.042

0.054

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


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R1 (I> 2 σ(I)), wR2 Goodness-of-fit 2θ range CCDC No.

0.0431

0.0398

0.0616

0.1414

0.1278

0.1677

1.13 2.3-26.0 1510700

1.10 1.8-33.7 1510699

1.05 2.5-26.0 1510705

Structural description of HCT cocrystals HCT–PPZ cocrystal (1:1): The crystal structure of HCT–PPZ (1 space group, Z=2) has in the asymmetric unit, one molecule of HCT, and two symmetry independent half molecules of PPZ. The HCT molecules form a 1D chain along the b-axis through N–H···N hydrogen bonds between the primary sulfonamide and secondary sulfonyl group (Figure 2a). The 1D chain is further assembled into a 2D layer in the ab-plane via C–Cl···O=S=O halogen bonds. Two such 2D HCT layers form a 2D bilayer via N–H···N hydrogen bonds between the secondary amine and primary sulfonyl group. These 2D bilayers then extended through N–H···N hydrogen bonds with the bridging PPZ molecules to form a 3D supramolecular structure (Figure 2b).

(b)

(a)

Figure 2. a) 2D HCT layer propagated along the ab-plane. b) Packing of HCT bilayers through PPZ bridging.

HCT–TMPZ cocrystal hydrate (2:1:1): The cocrystal hydrate takes the Pna21 space group with Z=4. The two symmetry independent HCT molecules are almost perpendicularly (73-80°) oriented and connected to each other via N–H···N intermolecular hydrogen bonds as shown in Figure 3a. HCT molecules form a 1D ribbon along the a-axis with water molecules (Figure 3a). The TMPZ molecules, oriented in a slip-stacked fashion (π···π= 3.770 and 3.867 Å) between the



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HCT ribbons, are bonded to HCT molecules via N–H···N hydrogen bonds between the primary sulfonamide and one of the pyridyl N-atoms. The other pyridyl N-atom is hydrogen bonded to the water molecule of the neighboring HCT ribbon, stabilizing the whole structure (Figure 3b).

(a)

(b)

Figure 3. a) HCT ribbon along the a-axis. b) HCT–TMPZ interactions: view along the c-axis.

HCT–PCM cocrystal (1:1): The HCT–PCM crystallizes in the P21/n space group with Z=2. The HCT and PCM molecules are connected to each other along the 21 screw axis through a pair of N–H···O intermolecular hydrogen bonds (Figure 4a). The amide oxygen of PCM molecule serves as a bifurcated acceptor, forming N–H···O hydrogen bonds with the primary sulfonamide and the secondary amine group of two neighboring HCT molecules, leading to tetramer formation. These tetramers are extended in the bc-plane through N–H···O intermolecular hydrogen bonds between the amide –NH group and the primary sulfonyl group (Figure 4b).

(b)

(a)

Figure 4. a) HCT and PCM hydrogen bond interactions along the 21 screw axis. b) Tetramer


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formation between HCT and PCM. HCT–INZ cocrystal hydrate (1:1:1): The cocrystal hydrate takes the 1 space group with Z=2. The water molecule in the asymmetric unit was found to be disordered and no H-atoms could be obtained from the difference map. The HCT and INZ molecules are bonded to each other through intermolecular N–H···N hydrogen bonds (Figure 5a). The –NHNH2 group of the INZ and the primary sulfonamide group of HCT form homodimer synthons involving N– H···N, N–H···O hydrogen bonds respectively. HCT dimers via C–Cl···O=S=O halogen bond form a 1D chain along the a-axis. The 1D chain is further assembled into a corrugated 2D layer in the ab-plane via N–H···N hydrogen bonds between the secondary amine and primary sulfonyl group (Figure 5b). Further, these corrugated HCT layers are extended along the c-axis via INZ dimers to form a 3D supramolecular structure (Figure 5c). Additionally, the structure is also stabilized by water molecules with N–H···O and O–H···O hydrogen bonds.

(b) (a)

(c) Figure 5. a) Homodimer synthons of HCT and INZ. b) 2D corrugated layer of HCT: view along the a-axis. c) 3D supramolecular structure of HCT–INZ–H2O.



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HCT–INIC cocrystal (1:1): The HCT–INIC cocrystal takes the Cc space group with Z=4. The HCT molecules are connected to INIC molecules in a slip-stacked fashion (π···π= 3.844Å) through N–H···O intermolecular hydrogen bonds between the primary sulfonamide and the –OH group of the carboxylic acid. Unlike PIC and NIC32 binary systems, INIC does not undergo zwitterion formation, yet form a 1D straight chain along the ac-diagonal direction through O–H···N hydrogen bond mediated acid···pyridine synthons (Figure 6a). Accordingly, HCT molecules also form a 1D chain with N–H···O hydrogen bonds between the secondary amine and primary sulfonyl group. The HCT–INIC chain pairs are then extended through N–H···O hydrogen bonds between the primary sulfonamide group and secondary sulfonyl group to form a 3D supramolecular structure (Figure 6b).

(a)

(b)

Figure 6. a) HCT–INIC chain pair propagating along the ac-plane. b) N–H···O hydrogen bonds connecting the HCT–INIC chain pairs.

HCT–MAM cocrystal (2:1): HCT–MAM crystallizes in the C2/c space group (Z=4) with one molecule of HCT and a half molecule of MAM in the asymmetric unit. The MAM molecule is found to lie on the crystallographic 2-axis rather than the inversion center. The carbonyl group of MAM molecule serves as a bifurcated acceptor, forming N–H···O intermolecular hydrogen bonds with the primary sulfonamide and the secondary amine of the HCT molecules (Figure 7a). The amide –NH of MAM molecule forms N–H···O hydrogen bond with the primary sulfonyl group of another HCT molecule. The primary sulfonamide of HCT participates in a centrosymmetric N–H···O hydrogen bonded homodimer synthon. Further, there is another dimer formed through N–H···O hydrogen bonds between the primary sulfonamide and secondary sulfonamide. These HCT dimers form a 2D layer along the ac-plane through N–H···O hydrogen bonds between the primary sulfonamide and the carbonyl group of the amide (Figure 7b).


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(b)

(a)

Figure 7. a) Interactions between the HCT and MAM molecules. b) 2D layer of HCT–MAM along the ac-diagonal direction.

Solubility studies: Solubility is one of the important preformulation properties that have a significant impact on the bioavailability of drugs. Drug solubility is dependent on properties such as temperature, pH, dielectric constant and melting point.34-36 For instance, a lower melting point for a compound reflects a decreased lattice energy, which would lead to a higher solubility. Several methods have been employed to improve the solubility of poorly aqueous soluble APIs; this includes nanoparticles, solid dispersions, cyclodextrin complexes, the inclusion of additives (excipients), amorphous phases, cocrystals and salts. However, pharmaceutical salts and cocrystals have gained a lot of attention due to their significance in industry to facilitate pre-formulations.



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Figure 8. Solubility comparisons of HCT and cocrystals (only API contributions are shown). Asterisk mark denotes 4h solubility.

In the present work, we have studied solubility in pH 7.4 buffer for 1h and 4h and the solubility of HCT is 0.99 mg/mL (Figure 8). Among all the cocrystals, HCT–PCM and HCT–TMPZ are found to be stable after 4h slurry experiments. The stability table (Table S2) may be found in the supporting information. The solubility order of cocrystals is HCT–PPZ > HCT–PCM > HCT–INZ > HCT–MAM > HCT–TMPZ. It is well known that the solubility of multi-component systems is related to the solubility of coformers and the same trend is noticed here as well. As expected, the HCT–PPZ cocrystal exhibits highest, ~ 7-fold (6.6 mg/mL), enhancement in solubility because of very high solubility of PPZ. Cocrystals of HCT–TMPZ and HCT–MAM show less solubility compared to the parent API and HCT–INZ shows solubility similar to HCT. The low solubility of HCT– MAM and HCT–INZ can be explained in terms of drug···coformer interactions in the crystal structure. In both cocrystals, strong primary sulfonamide dimer synthons, as seen in the HCT polymorph, are retained in the structure resulting in poor solubility. Generally, cocrystals having longer alkyl chains are more hydrophobic and hence exhibit poor aqueous solubility. Accordingly, the solubility of HCT–MAM is expected to be low. The low solubility of TMPZ cocrystal could be due to its hydrophobic nature, as well as hydrate formation. An expected inverse correlation is noticed between the solubilities and melting points of the anhydrous cocrystals, except for HCT–MAM. The order of melting


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points, is as follows HCT–PCM (186 oC) > HCT–MAM (161 oC) > HCT–PPZ (157 oC). In summary, HCT–PPZ cocrystal shows the highest solubility among the new multicomponent systems of HCT in this study. We also checked the pH of the solution after each slurry experiment; however, no pH variations (±1) are noticed and hence the solubility results may be meaningfully compared.

Figure 9. Intrinsic dissolution curves of (a) HCT, HCT–TMPZ, HCT–INZ, HCT–PCM, (b) HCT–MAM, in pH 7.4 buffer at 37 °C.

Table 2. IDR and apparent solubility in pH 7.4 buffer. Compound HCT HCT–PCM HCT–TMPZ HCT–INZ HCT–MAM

IDR (mg cm-2 min-1) 0.18 1.04 0.28 0.25 0.05

Apparent solubility (mg/mL) 0.994 5.742 1.546 1.384 0.276

For metastable corystals, which undergo phase transformation during the slurry experiment, the intrinsic dissolution rate (IDR) is a relevant parameter. IDR is the rate at which the equilibrium solubility is reached. The rotating disk IDR order is as fellows, HCT–PCM > HCT–INZ > HCT–TMPZ > HCT > HCT–MAM. HCT–PPZ is a highly soluble compound which came out entirely within 15 minutes from the tablet chamber of the rotating disk, and so the IDR could not be measured. The order of the dissolution rate



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obeys their order of solubility. Apparent solubilities ware measured using the NoyesWhitney equation.37

Membrane diffusivity of cocrystals: Permeability depends on the absorption of the drugs on cell membranes. It is an essential parameter for an orally administered drug and when taken along with the solubility, one obtains a good idea about bioavailability.12,38 In general, permeability depends on the lipophilicity of the permeant. However, the flux of the drug across the membrane is proportional to the concentration gradient, and therefore a permeant with high solubility might be absorbed well.39 The diffusion behavior also depends upon the particle size. The diffusion behavior of the new solid forms of HCT was studied using a Franz diffusion cell, which measures relative permeation. The diffusion behavior of all cocrystals was measured in pH 7.4 buffer at 1 hour intervals for 8 hours (Figure 11). The diffusivity behavior of HCT has also been reported by Sanphui et al.13 They have tuned the API permeability by making cocrystals: improved permeability was noticed for moderately soluble cocrystals HCT–NIC and HCT–NCT whereas HCT–PABA cocrystal showed high solubility but moderate permeability.

Figure 10. (a) Cumulative amounts of cocrystals diffused vs time (b) Flux/permeability of cocrystals vs time. In the present study, we noticed that the cumulative amount of material diffusing through the membrane increases rapidly in the first hour and reaches a steady state after 3 h. The plots of


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cumulative drug diffused and flux against the per unit time indicate that HCT–PPZ and HCT– PCM cocrystals exhibit better diffusion behavior among all the cocrystals including the earlier reporting cocrystals.13 The diffusion behavior of other cocrystals (HCT–MAM and HCT–INZ) showed a marginal increase in the diffusion rate compared to the parent API. HCT–TMPZ cocrystal showed lower cumulative amount/flux than the HCT. Our findings of high diffusivity/flux may be attributed to the solubility of the donor formulations (cocrystals). A similar diffusion behavior trend was also noticed by some of us recently in furosemide cocrystals.16 Diffusivity dependence on solubility of a lipophilic compound is not trivial. Often, solubilizing agents or alternative vehicles such as ethanol-water mixture are used to solubilize less soluble lipophilic permeants. We believe that the higher concentration of the donor formulations (cocrystals) in solution leads to amorphous cocrystal formation in solution through moderate or weak hydrogen bonds; thereby the high solution concentration of API through coformers generate higher concentration gradients across the membrane and traverse through the membrane overcoming the lipophilicity and particle size effects. A similar solution hydrogen bonding was also observed for lidocaine-ibrufen deep eutectic liquid cocrystal by Rogers et al.40 In summary, we suggest that coformers that cause higher solubility in cocrystals lead to higher diffusion.

Conclusions: The present study is an attempt to explore a number of cocrystals of HCT and to

improve the physicochemical properties by cocrystallization method. Eight new cocrystals of Hydrochlorothiazide have been prepared and their structural aspects studied. The physicochemical properties of new multicomponent systems were extensively studied and compared with the parent drug. Enhanced molar contribution of API solubility and membrane permeability/diffusion rates are observed for few cocrystals compared to previously reported cocrystals. HCT–PPZ and HCT–PCM showed large enhancement in the solubility and diffusion rates compared to the parent API. The HCT–PPZ cocrystal shows best physicochemical behavior (solubility and diffusion) among all the cocrystals including the earlier reported cocrystals. This could be a promising candidate for further study. Modification of the sulfonamide synthon of HCT leads to improvements of physicochemical properties. The cocrystal with INIC is now obtained with prolonged grinding; this could not be obtained previously. This result further confirms that cocrystallization is condition and method dependent.



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Supporting Information Available Neutron normalized hydrogen bonding parameters, PXRD, DSC, and FTIR plots of the HCT cocrystals. This material is available free of charge via the Internet at http://pubs.acs.org

Author information Corresponding author Fax: +91 80 23602306. Tel.: +91 80 22933311. *Email: [email protected]

Acknowledgements S.P.G. and M.B. thank the UGC for a Dr. D. S. Kothari fellowship. G.R.D. thanks DST for a J. C. Bose fellowship. We thank Dr. S. Ganguly for helpful discussions.

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14. Yan, Y.; Chen, J. M.; Lu, T. B. CrystEngComm 2013, 15, 6457–6460. 15. Saikia, B.; Bora, P.; Khatioda, R.; Sarma, B. Cryst. Growth Des. 2015, 15, 5593–5603. 16. Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Cryst. Growth Des. 2016, 16, 5418−5428 17. Gopi S. P.; Ganguly, S.; Desiraju, G. R. Mol. Pharmaceutics 2016, 13, 3590-3594. 18. http://www.drugbank.ca/drugs/DB00999#properties. 19. Onnainty, R.; Schenfeld, E. M.; Petiti, J. P.; Longhi, M. R.; Torres, A.; Quevedo, M. A.; Granero, G. E. Mol. Pharmaceutics 2016, 13, 3736–3746. 20. Pires, M. A. S.; dos Santos, R. A. S.; Sinisterra, R. D. Molecules 2011, 16, 4482–4499. 21. Kavuru, P. Hierarchy of Supramolecular Synthons in the of Design Multi-Component Crystals. Ph. D. Dissertation, University of South Florida, 2012. 22. Wong, J. R.; Ye, C.; Mei, X. CrystEngComm 2014, 16, 6996–7003. 23. Chadha, R.; Bhandari, S.; Khullar, S.; Mandal, S. K.; Jain, V. S. Pharm. Res. 2014, 31, 2479–3489. 24. http://www.who.int/medicines/services/expertcommittees/pharmprep/QAS04_109Rev1_ Waive_invivo_bioequiv.pdf 25. Almarsson, O.; Bourghol, H. M.; Peterson, M.; Zaworotko, M. J.; Moulton, B.; Rodriguez-Hornedo, N. International publication No CA 2513746A1. 26. Glomme, A.; Marz, J.; Dressman, J. B. J. Pharm. Sci. 2005, 94, 1−16. 27. Rigaku Mercury 375R/M CCD. Crystal Clear-SM Expert 2.0 rc14; Rigaku Corporation: Tokyo, Japan, 2009. 28. Sheldrick, G. M. Acta Crystallogr. Sect. A: Found. Crystallogr. 2008, 64, 112−122. 29. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. 30. Spek, A. L. PLATON: A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherlands, 2002. 31. Spek, A. L. Single crystal structure validation with the program PLATON. J. Appl. Crystallogr. 2003, 36, 7−13. 32. Sanphui, P.; Rajput, L. Acta Crystallogr. 2014, B70, 81– 90. 33. Clarke, H. D.; Arora, K. K; Bass, H.; Kavuru, P.; Ong, T.T; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 2152–2167. 34. Gutsche, S.; Krause, M.; Kranz, H. Drug Dev. Ind Pharm. 2008, 34, 1277−1284. 35. Alhalaweh, A.; Roy, L.; Rodríguez-Hornedo, N.; Velaga, S. P. Mol.Pharmaceutics 2012, 4, 2605−2612. 36. Kuminek, G.; Rodríguez -Hornedo, N.; Siedler, N S.; Rocha, H. V. A.; Cuffinibdand, S. L.; Cardoso, S. G. Chem. Commun. 2016, 52, 5832−5835. 37. Otsuka, M.; Teraoka, R.; Matsuda, Y. Chem. Pharm. Bull. 1991, 39, 2667– 2671. 38. Waterbeemd, H.; Testa, B., Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability, second edition. 2009 39. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 2001, 46, 3–26. 40. Wang, H.; Gurau, G.; Shamshina, J.; Cojocaru, O. A.; Janikowski, J.; MacFarlane , D. R.; Davis Jr, J. H. D.; Rogers, R. D. Chem. Sci. 2014, 5, 3449–3456.



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For Table of Contents use only New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and Membrane Diffusivity Shanmukha Prasad Gopi, Manas Banik, and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India

Synopsis Hydrochlorothiazide is a diuretic drug, often used to treat high blood pressure and swelling due to fluid buildup. New solid forms of HCT were made using coformers. HCT–PPZ and HCT– PCM cocrystals showed improved solubility and membrane diffusivity than the parent API. The improved physicochemical properties are due to the drug-coformer interactions in the new solid forms.


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Scheme 1. Hydrochlorothiazide (HCT) and coformers in the present study 186x180mm (150 x 150 DPI)



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Figure 1. PXRD pattern of HCT–INIC cocrystal at different time intervals. New peaks are highlighted 197x168mm (150 x 150 DPI)


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Figure 2. a) 2D HCT layer propagated along the ab-plane. b) Packing of HCT bilayers through PPZ bridging. 255x95mm (150 x 150 DPI)



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Figure 3. a) HCT ribbon along the a-axis. b) HCT–TMPZ interactions: view along the c-axis. 255x85mm (150 x 150 DPI)


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Figure 4. a) HCT and PCM hydrogen bond interactions along the 21 screw axis. b) Tetramer formation between HCT and PCM. 204x108mm (150 x 150 DPI)



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Figure 5. a) Homodimer synthons of HCT and INZ. b) 2D corrugated layer of HCT: view along the a-axis. c) 3D supramolecular structure of HCT–INZ–H2O. 244x132mm (150 x 150 DPI)


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Figure 6. a) HCT–INIC chain pair propagating along the ac-plane. b) N–H•••O hydrogen bonds connecting the HCT–INIC chain pairs. 249x66mm (150 x 150 DPI)



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Figure 7. a) Interactions between the HCT and MAM molecules. b) 2D layer of HCT–MAM along the acdiagonal direction. 248x73mm (150 x 150 DPI)


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Figure 8. Solubility comparisons of HCT and cocrystals (only API contributions are shown). Asterisk mark denotes 4h solubility. 190x140mm (133 x 133 DPI)



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Figure 9. Intrinsic dissolution curves of (a) HCT, HCT–TMPZ, HCT–INZ, HCT–PCM, (b) HCT–MAM, in pH 7.4 buffer at 37 °C. 245x108mm (150 x 150 DPI)


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Figure 10. (a) Cumulative amounts of cocrystals diffused vs time (b) Flux/permeability of cocrystals vs time. 235x96mm (150 x 150 DPI)



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Table of Contents 89x35mm (150 x 150 DPI)


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New Cocrystals of Hydrochlorothiazide: Optimizing Solubility and

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