Salts and Cocrystals of the Antidiabetic Drugs Gliclazide, Tolbutamide

Apr 3, 2017 - According to the WHO model list of essential medicines, GCZ is one of the most remarkable medications needed in the basic health system...
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Salts and Cocrystals of Antidiabetic Drugs, Gliclazide, Tolbutamide and Glipizide: Solubility Enhancements through Drug-Coformer Interactions Ali Samie, Gautam R. Desiraju, and Manas Banik Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01804 • Publication Date (Web): 03 Apr 2017 Downloaded from http://pubs.acs.org on April 4, 2017

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Crystal Growth & Design

Salts and Cocrystals of Antidiabetic Drugs, Gliclazide, Tolbutamide and Glipizide: Solubility Enhancements through Drug−Coformer Interactions Ali Samie†,‡, Gautam R. Desiraju*,† and Manas Banik† †

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012,

India. ‡

Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 917751436, I.R., Iran.

Abstract Gliclazide (GCZ), tolbutamide (TOL) and glipizide (GPZ) are BCS class II antidiabetic drugs with poor aqueous solubility. Multicomponent solid forms, salts, and cocrystals of GCZ were obtained upon liquid assisted grinding with coformers of catechol (CAT), resorcinol (RES), p-toluenesulfonic acid (PTSA) and piperazine (PPZ). The solubility of TOL was also modified by salt formation with PPZ. The multicomponent solids were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) and further subjected to solubility studies. The cocrystals/salts, in all cases, showed improvements in the solubility and dissolution rates compared to the parent APIs. GCZ−PPZ and TOL−PPZ(I) showed 6.6 and 80 and fold enhancements respectively in the solubility. The reasons for the improved solubility of the cocrystals/salts in terms of drug-coformer interactions are discussed.

Introduction Pharmaceutical cocrystals are well-investigated compounds in which properties of active pharmaceutical ingredients (APIs)1,2 are improved and optimized.3-6 While specific definitions of the word "cocrystal" might not be uniform in all respects, there is a general consensus that they “are crystalline single phase materials composed of two or more different molecular and/or ionic compounds, generally in a stoichiometric ratio, which are neither solvates nor simple salts.”7-10 When the cocrystal is formed through hydrogen bonding, movement of the proton across the hydrogen bond constitutes a structural continuum, the other extreme of which is a salt, where the proton transfer across the hydrogen bond is complete.10 The reasons for cocrystal/salt preparation from APIs with coformers are by now well-established. In the pharmaceutical industry, drug molecules are categorized into four different classes based on the solubility and membrane permeability: 1 ACS Paragon Plus Environment

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class I (high solubility, high permeability), class II (low solubility, high permeability), class III (high solubility, low permeability), and class IV (low solubility, low permeability). This classification is known as the Biopharmaceutics Classification System (BCS). Alteration in physical properties such as solubility11-15 for poorly soluble drugs, which belong to BCS class II or IV, is one of the operational targets. Nowadays, a large number of the APIs in the market face the serious problem of poor aqueous solubility.16 Cocrystals and salts of APIs often have an advantage in physicochemical properties and have been improved over the parent drugs without a change in therapeutic efficiency.17 While salt formation can enhance solubility by 100–1000 times, cocrystal formation can increase it typically 4–160 fold.18,19 On occasions, cocrystal formation is beneficial in reducing an adverse property in the parent material.20 Salts and cocrystals are also prepared sometimes to lower the solubility of the parent API.21 In this study, three different sulfonylurea antidiabetic drugs were used to prepare six multi-component crystals. All drugs have been recognized as belonging to the BCS class-II because of their low solubility and high permeability. Gliclazide (GCZ) and Tolbutamide (TOL) are oral hypoglycemic antidiabetic drugs. Glipizide (GPZ) is an oral rapid-acting and short-acting antidiabetic medication. Among these drugs, TOL and GPZ belong to the first and second generation of antidiabetic sulfonylurea drugs22. But, the GCZ classification is ambiguous, in the sense that the literature categorizes it both as a first-generation23 and a second-generation24 sulfonylurea. According to the WHO model list of essential medicines, GCZ is one of the most remarkable medications needed in the basic health system.25 Use of high soluble coformers can heighten solubility.18,26 Piperazine is distinctive as a coformer for cocrystallization or salt formation.27 Phenolic coformers play a ubiquitous role in authenticating solubility advantages.28 There is no report for either TOL or GPZ salts/cocrystals nor even a report for the crystal structure determination of pure GPZ. There are only a few reports describing cocrystals of GCZ with succinic acid and malic acid. In these cases, obtaining single crystals was arduous and so the structures were solved from powder diffraction data.29 Recently, two more papers have been published of GCZ multicomponent crystals.30,31 In light of these observations, the present study aims to obtain cocrystal/salt/solvates with improved solubility. In this investigation, two new GCZ cocrystals have been made with catechol (CAT) and resorcinol (RES); one new GCZ salt also has been made with piperazine (PPZ). In addition, a multicomponent solid of GCZ with p-toluenesulfonic acid (PTSA) has been prepared but a suitable single crystal could not be grown. In this case with FTIR study, proton transfer is distinguishable which concludes salt formation. Two salts have been obtained with 2 ACS Paragon Plus Environment

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Crystal Growth & Design

Tolbutamide TOL−PPZ in 1:1(I) and 2:1(II) ratio. Scheme 1 indicates all APIs and coformers with the pKa value of principal acidic site of the API molecule. The new solid forms are characterized by FTIR, DSC, TGA, powder and single crystal X-ray diffraction.

Scheme 1. GCZ, TOL, GPZ (with pKa values) and coformers RES, CAT, PPZ, PTSA.

Experimental section All APIs (GCZ, TOL, and GPZ) were purchased from Yarrow Chem Products, Mumbai, India. In order to measure melting points, a Büchi melting point apparatus (SigmaAldrich, Bangalore, India) was used. Differential Scanning Calorimetry (DSC) was recorded on a Mettler Toledo DSC 823e instrument within a range of 25 to 300 °C with a step size of 10 °C/min. Thermal Gravimetric Analysis (TGA) was performed with Mettler Toledo TGA/SDTA 851e within a temperature range of 25 to 400 °C. Water filtered through a double distilled water purification system (Siemens, Ultra Clear, Germany) was used in all experiments. Fourier Transform Infrared Spectroscopy (FTIR) spectra were recorded using an ATR accessory on a PerkinElmer (Frontier) spectrophotometer (4000–600 cm−1). Powder X-Ray Diffraction (PXRD) data were recorded using a PANalytical X-ray powder diffractometer equipped with a X’cellerator detector at room temperature in the scan range 2θ 3 ACS Paragon Plus Environment

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= 5 to 35 °C with a step size of 0.026 °C. X’Pert HighScore Plus was used to compare the experimental PXRD pattern with the calculated lines from the crystal structure.

Table 1. Crystallographic Parameters of GCZ, TOL, GPZ Salts and Cocrystals. GCZ−CAT Emp.

GCZ−RES

GCZ−PPZ

TOL−PPZ(II) GPZ

C21H27N3O5S C21H27N3O5S C19H31N5O3S C28H46N6O6S2

C21H27N5O4S

433.51

433.51

409.55

626.83

445.54

Triclinic

Monoclinic

Monoclinic

Orthorhombic

Triclinic

Space group

P

P21/n

Cc

Pba2

P

T/K

293(2)

293(2)

100(2)

293(2)

100(2)

a/Å

10.657(9)

10.343(11)

9.8913(7)

16.92(2)

5.1578(3)

b/Å

10.743(7)

16.358(16)

8.1638(7)

18.28(2)

8.9760(5)

c/Å

11.615(11)

13.785(14)

24.7811(19)

10.354(13)

23.9704(13)

α/°

75.87(3)

90

90

90

83.247(2)

β/°

89.15(4)

106.560(12)

90.060(3)

90

85.543(2)

γ/°

60.80(2)

90

90

90

78.987(2)

Volume/Å3

1117.1(16)

2236(4)

2001.1(3)

3202.47

1080.01(11)

Z

2

4

4

4

2

Dcalcd(g.cm−3)

1.289

1.288

1.359

1.300

1.370

μ (mm−1)

0.181

0.181

0.193

0.216

0.189

F(000)

460.0

920.0

880.0

472.0

616.0

Total ref.

4797

4858

3510

6889

4698

Unique ref.

3780

4090

3358

5238

3486

10868

30888

36374

30470

38929

Rint

0.1298

0.0904

0.0625

0.1157

0.0776

R1 (I > 2σ(I))

0.0719

0.0695

0.0401

0.0855

0.0541

wR2

0.2064

0.1734

0.0889

0.2454

0.1119

98.2

99.6

99.9

98.5

99.6

1.070

1.106

1.087

1.060

1.127

Formula Formula wt. Crystal system

Observed ref. (I > 2σ(I))

Completeness (%) Goodness-of-

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Crystal Growth & Design

fit 2θ range

2.486-26.998 3.155-26.998 3.236-24.944 3.110-26.997

3.030-26.997

MP(K)

395

390

430

377

481

CCDC No.

1516969

1516970

1516971

1516973

1516974

Solubility Measurements: The absorption coefficient of each solid phase was measured by the slope of the absorbance versus concentration curve of at least five known concentrated solutions in pH 7.4 phosphate buffer medium and measured at different λmax in a PerkinElmer UV-Vis spectrometer. For GCZ−CAT, GCZ−RES, GCZ−PTSA, GCZ−PPZ, GCZ, TOL−PPZ(I), TOL−PPZ(II), TOL, and GPZ; λmax was determined at 223, 222, 222, 222, 225, 227, 226, 227, and 275nm, respectively. The solubility of each solid was measured after 1 h and 24 h using the shake-flask method at room temperature (27±2°C). The experiments were iterated thrice.

Intrinsic Dissolution Rate (IDR) 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 107148 kg/m (3 ton/inch) 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 phosphate buffer medium at 37 °C with the disk rotating at 150 rpm. At regular intervals of specified time (3, 6, 9, 12, 15, 18, 21, 24 min for all of the compounds), 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 different λmax on a Thermo scientific EV201 UV-Vis spectrometer. The amount of drug dissolved in each time interval was calculated using a calibration curve. Diffusion measurements were repeated thrice, for each sample. Buffer Preparation: 50 mL of 0.2 M KH2PO4 were 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 (SCXRD): Single crystal X-ray data were collected on either a Rigaku Mercury 375/M CCD (XtaLAB mini) or a Bruker SMART APEX CCD diffractometer. The diffraction data of GCZ−CAT, GCZ−RES, TOL−PPZ(I) and TOL−PPZ(II) were collected on a Rigaku Mercury 375/M CCD (XtaLAB mini) 5 ACS Paragon Plus Environment

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diffractometer using graphite monochromatic Mo(Kα) radiation. The data were processed with the Rigaku Crystal Clear 2.0 software.32 Structure solution and refinements were executed using SHELX-9733 and the WinGX34 suite of programs. Refinement of coordinates and anisotropic thermal parameters of non-hydrogen atoms were performed with the fullmatrix 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 PLATON35,36 software was used to prepare material for publication, and Mercury 3.8 was utilized for molecular representations and packing diagrams. The diffraction data of GCZ−PPZ, GPZ−PPZ and GPZ were collected on a Bruker SMART APEX CCD diffractometer utilizing the SMART/SAINT software.37 Intensity data were collected using graphite-monochromatic Mo(Kα) radiation (0.7107 Å) at 100(2) and 293(2) K. The structures were solved by direct methods employing the SHELX-201338 contained in WinGX.34,39−41 Empirical absorption corrections were applied with SADABS. Crystallographic data and refinement parameters are depicted in Table 1, and the important bond lengths and angles are presented in Table S2 in supporting information (SI). All crystallographic

cif

files

(CCDC

Nos.

1516969−1516975)

are

available

atwww.ccdc.cam.ac.uk/data_request/cif.

Preparation of Salt/Cocrystals. Many of these crystals were obtained after several months from the respective mother liquors. Obtaining these crystals was, in almost all the cases, far from straightforward. It should be noted that when crystallization is attempted from solution, crystals may be obtained quickly or slowly, and these crystals maybe of good quality or poor quality.42 In general, these choices (slow/fast; good/bad) are not correlated. In the present study, all crystals of salts were obtained slowly, after many months and were of indifferent quality. The slow appearance of crystals is typical for molecules that contain many rotatable bonds, and the reason for the delayed appearance of crystals is an entropic one: it is a matter of statistics that a critically large number of molecules have the same or similar conformation, to enable them to enter the crystal without problem. This is certainly true of GCZ, TOL, and GPZ. All of them contain many flexible, rotatable bonds, five for GCZ,43 seven for TOL44 and ten for GPZ45, (Scheme 1). Two of the six salts/cocrystals in this study also have multiple molecules in the asymmetric unit. Whether or not this observation is related to the entropic considerations mentioned above is, at present, a matter only of speculation. All of PXRD pattern for parent drug and products are given in Figure S1. 6 ACS Paragon Plus Environment

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Crystal Growth & Design

GCZ−CAT (1:1): An equimolecular mixture (0.5mmol:0.5mmol) of GCZ and CAT was ground in a mortar with a pestle for about three hours with dropwise addition of MeOH and THF. Colorless prism shaped crystals were obtained from toluene at 5 °C after a couple of months. GCZ−RES (1:1): An equimolecular mixture (0.5mmol:0.5mmol) of GCZ and RES was ground in a mortar with a pestle for about three hours with dropwise addition of MeOH and THF. Colorless prism shaped crystals were obtained from 1:1:1 MeOH, EtOH, and MeCN mixture at 5 °C after two months. GCZ−PTSA (1:1): Liquid assisted grinding was performed on a 1:1 (0.5mmol:0.5mmol) mixture of the precursor compounds for 20 min with MeOH and THF as solvents. The slurry was further ground for 10 min with acetone for drying. We could not obtain single crystals irrespective of the solvent choice. GCZ−PPZ (1:1): Liquid assisted grinding was performed on a 1:1 (0.5mmol:0.5mmol) mixture of the precursor compounds for 20 min with MeOH as a solvent. Prism shaped crystals, suitable for single crystal X-ray diffraction (SCXRD), were obtained after six months through slow evaporation from DMSO solution at ambient temperature in a stable, dark closet with a very small hole on the cap of the vial. The crystals apparently were of proper shape but there were twinning problems which were solved with the twinning matrix. The data was collected five times at both room temperature and low temperature. With the twinning matrix, the R-factor improved from 16.8 to 4.01. TOL−PPZ (1:1): An equimolecular mixture of TOL and PPZ (0.5mmol:0.5mmol) was ground together with a few drops of MeCN for 30 min and dissolved in a variety of solvents. Colorless prism-like crystals were harvested from MeNO2:MeCN (1:1) after three months at 5 °C. However, the data quality is not good enough to model the side chain disorder properly (Ref CCDC No. 1516972). TOL−PPZ (2:1): 1 mmol of TOL and 0.5 mmol of PPZ were ground together with a few drops of MeCN for 30 min. The ground powder was dissolved in different solvents and was kept at 5 °C for slow evaporation. After three months, diffraction quality crystals were acquired from MeNO2. GPZ−PPZ: 0.5 mmol of TOL and 0.25 mmol of PPZ were ground together with a few drops of MeOH for 30 min and dissolved in a variety of solvents. Colorless needle-like poor quality crystals were noticed in isobutanol (IBA) at 5 °C after six months. Poor but diffraction quality crystals are acquired after numerous trials. However, the data quality is not good enough to model disorder properly (Ref. CCDC No. 1516975). 7 ACS Paragon Plus Environment

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GPZ: GPZ was crystallized from IBA:MeCN (1:1) mixture using slow evaporation method at 5 °C. After four months, colorless plate-like diffraction quality single crystals were achieved.

Structural Studies GCZ−CAT: The substance crystallizes in the P space group (Z=2) with one molecule each of CAT and GCZ in the asymmetric unit. The GCZ and CAT molecules are attached to each other through O16−H16···O1 and N2−H2N···O17 hydrogen bond interactions, which lead to tetramer synthon formation (Fig. 1a). API and conformer form inversion symmetry related homodimers through N1−H1N···O3 and O17−H17···O16 hydrogen bond interactions respectively (Fig. 1a and 1b). The tetrameric synthons form a 1D chain along the ac-diagonal direction (Fig. 1c). Finally, the structure is stabilized through weak C−H···O hydrogen bond interactions.

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Crystal Growth & Design

Figure 1. Crystal structure of GCZ−CAT: (a) Tetramer synthon formed between GCZ and CAT (b) GCZ homodimer synthon (c) 1D chain of GCZ and CAT running along the acdiagonal direction.

GCZ−RES: The cocrystal takes the P21/n space group (Z=4) with one molecule each of GCZ and RES in the asymmetric unit. The API and coformer molecules are connected through O18−H18B···O1 and N2−H2N···O16 classical hydrogen bonds along with two non-classical C19−H19···O2 and C21−H21···O2 hydrogen bonds (Fig. 2a). Similar to GCZ−CAT, sulfonamide···sulfonamide homodimer synthons through N1−H1N···O3 interactions are seen here as well (Fig. 2b). However, the RES molecules form a 1D chain through O16−H16···O18 9 ACS Paragon Plus Environment

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hydrogen bonds running perpendicular to the (102) plane (Fig. 2c). The 1D chain is then converted to a 2D layer through O18−H18B···O1 and N2−H2N···O16 hydrogen bond interactions along the (10 ) plane (Fig. 2d). Finally, the structure is propagated along the third direction through weak bifurcated C19−H19···O2 and C21−H21···O2 hydrogen bond interactions.

Figure 2. Crystal structure of GCZ−RES: (a) Classical and non-classical hydrogen bond interactions between GCZ and RES (b) sulphonamide homodimer connecting 1D RES chain (c) 1D chain formed between RES molecules (d) 2D layer formed between GCZ and RES along the (10 ) plane.

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Crystal Growth & Design

GCZ−PPZ: The salt crystallizes in the Cc space group (Z= 4) with one molecule each of GCZ and PPZ in the asymmetric unit. The electron density map showed that both the acidic H-atoms of the GCZ sulfonylurea group are transferred to the basic N-atoms of PPZ resulting in a pair of N+−H···N− ionic interactions (Fig 3a). The molecule adopts a 2D layer structure along the ab-plane (Fig. 3b and 3c) through N+−H···N− ionic interactions along with bifurcated N4−H4B···O1, N5−H5B···O1 hydrogen bond interactions where carbonyl group of GCZ acts as bifurcated acceptor (Fig. 3a). In addition, there are several strong N−H···O, weak C−H···O hydrogen bond interactions exist in the molecule. The structure is additionally stabilized in the third dimension by weak C−H···π (closet C···H = 2.682 Å) interactions.

Figure 3. Crystal structure of GCZ−PPZ: (a) Bifurcated hydrogen bond interactions between PPZ and GCZ (b) Perspective side view of a 2D layer of GCZ−PPZ perpendicular to the (110) plane (c) Perspective side view of the 2D layer of GCZ−PPZ along the ab-diagonal direction.

TOL−PPZ(II): TOL−PPZ(II) crystallizes in the Pba2 (Z=4) space group with two molecules of TOL and two half molecule of PPZ in the asymmetric unit. The electron density map showed that the acidic hydrogen atoms (sulfonamide NH) of both the TOL are transferred to the basic N-atoms of PPZ resulting in a salt formation. Each PPZ molecule is connected to four neighboring TOL molecules through several N−H···O, N−H···N hydrogen bonds. All the hydrogen atoms of both NH2+ group act as bifurcated donor connect four neighboring TOL 11 ACS Paragon Plus Environment

Crystal Growth & Design

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molecules through N6−H6B···O3, N6−H6B···N1, N6−H6A···O4, N6−H6A···O5, N5−H5A···O1, N5−H5A···O2, N5−H5B···N3 and N5−H5B···O6 (Fig. 4a) thereby form a 2D layer along the abplane (Fig. 4b). In addition, there are several other secondary interactions that are prevalent in the layers. Finally, the structure is stabilized through dispersion interactions. Packing diagram shows the molecule posses hydrophobic channel along the a and b-axis (Fig. 4c).

Figure 4. Crystal structure of TOL−PPZ(II); (a) bifurcated hydrogen bond interactions of NH2+ groups of PPZ with TOL (b) 2D layer formed between the TOL and PPZ along the abplane (c) perspective packing view of TOL-PPZ(II) along the a-axis.

Crystal structure of GPZ (P , Z = 2) was obtained previously by Burley, using structure determination from powder (SDPD) method.45 Here we could get crystals (from 1:1 IBA: MeCN mixture) which are suitable for SCXRD experiments and refinement of the X-ray data (R=5.4) shows overlapping with the earlier SDPD determined structure. Crystallographic parameters are given in table S6.

Results and Discussion DSC and TGA studies:

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Crystal Growth & Design

DSC is a trustworthy method to ascertain solid form purity for cocrystals, solvates, and salts. The presence of a single sharp peak in DSC is a good indicator for bulk purity and homogeneity. This peak obviously should be different from those of the starting materials. All the GCZ compounds are phase pure and show single melting endotherms from 117 to 178 o

C region, which are less than that of the GCZ melting point (Table S3, Fig. S2). The melting

points of GCZ salts/cocrystals are GCZ−CAT (122 oC), GCZ−RES (117 oC), GCZ−PTSA (178 oC) and GCZ−PPZ (157 oC). The melting temperature of GPZ−PPZ is 178 oC. A wide peak is seen at 60 °C, which could be due to the loss of crystalline MeOH molecule(s) from the sample since GPZ and PPZ were ground with MeOH (Figure S2).

Figure 5. Time-dependent DSC of TOL− PPZ(I) (a) after 3 min of grinding with MeCN (b) after 15 min of grinding with MeCN (c) after 30 min of grinding with MeCN. Melting points of TOL salts follow the order of TOL (129oC) > TOL−PPZ(I) (113oC) > TOL−PPZ(II) (104oC). While recording DSC profile, we noticed that TOL−PPZ(I) showed two almost equally sharp peaks at 111 and 113 oC (similar to Fig. 5b), which neither belong 13 ACS Paragon Plus Environment

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to TOL nor PPZ. To investigate such a phenomenon, we carried out time-dependent DSC measurements of an equimolecular mixture of MeCN ground sample of TOL and PPZ. The DSC curve of a 3 min ground sample showed a sharp melting peak at 111 ºC (Fig. 5a). On further grinding, we observed that the mixture gave a sharp split-peak having melting temperature 111 ºC and 113 ºC (Fig. 5b). After, 30 min of rigorous grinding, it was noticed that the 111 ºC peak was completely converted to a single melting peak of 113 ºC (Fig. 5c). Such a result can possibly be explained in terms of polymorphous nature of TOL. TOL reportedly has four polymorphs with stability order: Form I > Form III > Form II > Form IV.44 In addition, several other polymorphs are also reported.46,47 In order to analyze such behavior, we have ground the commercially purchased TOL (Form I) with a few drops of MeCN for 30 minutes and recorded PXRD at 3 min intervals (Figure 6). It has been observed that the form I has partially converted to form II after 30 minutes. Therefore form I is susceptible to phase transition upon liquid assisted grinding. Similar phase transition has also been noticed when commercially purchased TOL was co-ground with PPZ with a few drops of MeCN (Figure 7a). The peak at 2θ = ~ 8.8 is an indicative of new phase observed after 3 min of grinding; with prolong grinding it was shifted to 2θ = ~ 7.9 (Figure 7b), which is indicative of the another form corresponding to TOL−PPZ(I).

Figure 6. Time-dependent PXRD pattern of MeCN ground commercially purchased TOL sample.

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Figure 7. (a) Time-dependent PXRD pattern of MeCN ground 1:1 TOL and PPZ mixture (b) Expanded region of 2θ = 6–10.

Considering that there are two stable polymorphs in the mortar at the time of grinding, it is interesting that two different salts are formed. In effect, if there is a drug which has two or more stable (or unstable) polymorphs, grinding of each of these separately with the same coformer might also result in two different polymorphic cocrystals/salts. This observation is reminiscent of a recent study by Fischer et al. in which an API, having a single polymorph, when solvent ground with a coformer using different solvents, resulted in two different polymorphic cocrystals.48

In both these cases (Fischer et al. and the present study), the pathways to polymorphic cocrystals arise in the grinding step. In the Fischer et al. study48, the difference is set up by the solvent used for cogrinding; in the present study, the difference is set up initially, through 15 ACS Paragon Plus Environment

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the crystal structure of the starting material itself. The implications are interesting: cogrinding can affect the outcome of cocrystal/salt formation,49,50 and perhaps these results throw up a hint as to the solid state diffusion that must take place before "molecular level mixing" of the API and the coformer can occur. Obviously, the story would be different after slow recrystallization with slow evaporation because molecules have enough time to rearrange and they will mostly give a single product. Perhaps, this could be a reason why the number of reported API cocrystal polymorphs is not so large, crystallization having been attempted only from solution.51

FTIR study: The shift of the carbonyl stretching is often used to determine the salt/cocrystals especially when a single crystal is hard to obtain. The GCZ shows the carbonyl stretching frequency at 1709 cm-1. The cocrystals/salts show red-shift of carbonyl stretching frequencies at 1687, 1688.5 and 1595.5 cm-1 for GCZ−CAT, GCZ−RES, and GCZ−PPZ respectively. They are all noticeable hydrogen bonds.52 Red-shift in GCZ−PPZ is larger than the others because of its intermolecular interaction. On the other hand, the carbonyl stretching band at 1741 cm-1 for GCZ−PTSA shows a blue-shift. The carbonyl IR band is shifted from 1660 to 1588 and 1587 cm-1for TOL−PPZ(I) and TOL−PPZ(II). For GPZ−PPZ, there are two carbonyl IR bands which are shifted from 1688 to 1668 and from 1650 to 1579 cm-1, Figure S3. GCZ has two N−H stretching bands at 3273 cm-1 (medium, sharp) and 3112 cm-1 (weak, broad). These bands are shifted to 3245, 3457 cm-1 for GCZ−CAT and to 3233, 3414 cm-1 for GCZ−RES. The existence of N−H bands in the IR spectra of these binary systems denotes that no proton transfer takes place. In the case of GCZ−PPZ, one N−H band corresponding to the amine group of PPZ is retained at 3233 cm-1. TOL exhibits two amide bands at 3090 (sharp, medium) and 3325 (broad, weak) cm-1, (Figure 8). In TOL−PPZ(II) salt, the first N−H band belongs to TOL at 3090 cm-1 and vanishes but the second one shifted from 3325 to 3365 cm-1. It indicates that the band at 3090 cm-1 (broad and weak) belongs to the most acidic N−H in TOL, which has been deprotonated, as it lies in between the two electron withdrawing SO2 and C=O groups. Blue-shift of another set of a N−H band from 3325 to 3365 cm-1 is due to the charge distribution, which occurs after proton detachment. After salt formation, the secondary amine band of PPZ shifts from 3274 cm-1 to 2927 cm-1 for >NH and to 2870 cm-1 for

. IR spectrum of TOL−PPZ(I) shows a single N−H peak at 2951cm-1 corresponding

to the PPZ

as both the amide hydrogens of TOL have been transferred to PPZ,

(Figure 8). GPZ exhibits three bands at 2944, 3251 and 3325 cm-1 for amine groups, all of 16 ACS Paragon Plus Environment

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them have sharp and medium intensity. For GPZ−PPZ, only two bands are seen. The first band is shifted to 2995 cm-1, the third one is shifted to 3422 cm-1, but the second has vanished due to proton transfer. Blue-shift occurs for these bands because of charge distribution whilst the salt-former PPZ shows red-shift of the amine band from 3274 cm-1 to 2951 cm-1 (Figure S3).

Figure 8. IR spectra of GCZ and TOL salts and cocrystals.

Solubility and stability studies: Solubility is one of the most important pre-formulation properties and it has a noteworthy effect on drugs, especially on their bioavailability. Solubility of an API is often improved by making salts. In addition, solubility of an API, can also be altered by cocrystallization through drug···coformer interaction and the solubility of the cocrystals generally depends on the solubility of the coformers. Thus by incorporating highly soluble coformer, API solubility can be improved by cocrystal formulations.

Table 2. Solubility and Stability Profiles (after 1hour) of GCZ/TOL/GPZ compounds in pH 7.4 Buffer (only API contributions are measured). Solubility1 Solubility2 Solubility3 Compound

Average

standard

Residue

deviation

(after1 h)

(after 1h)

(after 1h)

(after 1h)

Solubility

(mg/L)

(mg/L)

(mg/L)

(mg/L

GCZ

1145

1180

1185

1170

21.8

GCZ

GCZ−CAT

7134

7114

7091

7113

21.5

GCZ

GCZ−RES

4110

4099

4130

4113

15.7

GCZ

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GCZ−PTSA

3137

3142

3108

3129

18.4

GCZ

GCZ−PPZ

7710

7753

7667

7710

50.5

GCZ−PPZ

TOL

4168

4170

4199

4179

17.4

TOL

TOL−PPZ(I)

331889

331809.6

331989.4

331896

90.1

TOL−PPZ(I)

TOL−PPZ(II)

9980

9991

9990

9987

6.1

TOL−PPZ(II)

GPZ

178

169.5

170

172.5

4.8

GPZ

In the present study, pH 7.4 phosphate buffer was used for all the solubility and dissolution experiments. The phase stability of buffer slurry was checked at the intervals of 1 h and 24 h by PXRD (Table 2 and S8). Stability profiles (residual results) of GCZ/TOL/GPZ compounds in pH 7.4 buffer are given in Table 2. GCZ−CAT, GCZ−RES, and GCZ−PTSA were found to be disintegrated into the API and coformers within 1h of slurry experiments. However, GCZ−PPZ, TOL−PPZ(I) and TOL−PPZ(II) were stable even after a 24 h slurry experiment (Figure S1). Thenceforth, the stability check was continued. Surprisingly, we noticed that TOL−PPZ(I) was stable even after 1 week. As expected, all the PPZ salts are stable. The GCZ shows solubility of 1170 mg/L after 1 h. The solubility (or the concentration of drug dissolved in solution) order of cocrystals/salts are GCZ−PPZ (6.6 fold) > GCZ−CAT (6.0 fold) > GCZ−RES (3.5 fold) > GCZ−PTSA (2.6 fold) > GCZ, (Figure 9). As anticipated, GCZ−PPZ presents the highest enhancement of solubility among all the systems, and this is due to the high solubility of PPZ, as well as salt formation. Both the cocrystals (RES, CAT) also show considerable improvement of drug concentration in solution after 1 h slurry experiment. Despite being metastable, GCZ−CAT, GCZ−RES, and GCZ−PTSA show high concentrations of GCZ in solution compare to the parent API after 1 h, which could be due to the production of transient amorphous API resulting from the leaching out of coformers.53 Another possible reason could be the formation of amorphous cocrystal due to weak drug···coformer and solvent···solute interactions in solution.54 The higher concentration of GCZ−CAT over GCZ−RES can be understood along the same lines. The “memory” of tetrameric synthon (O−H···O, N−H···O), as seen in figure 1a, could possibly hold the drug and coformer in the solution thereby increasing the amount of drug in solution.15,54 Paucity of such synthons in the GCZ−RES could be the cause of the lower amount of dissolved drug compared to GCZ−CAT. GCZ−PTSA shows smaller concentration of dissolved drug compared to other salts/cocrystals. Perhaps the instability (due to weak interaction) of the

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solid tends to fast saturation of drug in solution thereby causing a lowering of drug concentration.

Figure 9. The solubility/concentration comparisons of GCZ and its cocrystal/salts after 1 hour. The solubility order of TOL salts are as follows: TOL −PPZ(I) > TOL−PPZ(II) > TOL(API). TOL shows buffer solubility 4179 mg/L, which is improved up to 3.4 times in TOL −PPZ(II) salt, whereas the solubility of TOL−PPZ(I) is 80-fold compared to parent API, Figure 10a.

Figure 10. (a) The solubility comparisons of TOL and its salts after 1 hour (b) crystal structure of TOL−PPZ(I) (top) and TOL−PPZ(II) (bottom) in space fill mode; blue molecules are TOLs and red molecules are PPZ. The high solubility of 1:1 TOL −PPZ compare to 2:1 TOL−PPZ could be due to higher contribution of highly soluble PPZ in the crystal lattice. Crystal structure analysis of the two salts also reveals that in the case of 2:1 TOL −PPZ, the highly soluble PPZ cof ormer is surrounded by the less soluble API, thus the contacts of PPZ molecules to the solvent molecules are less compare to 1:1 TOL−PPZ and hence shows low solubility. The schematic diagram is shown in the Figure 10b. The phenomenon is also clearly evident in some other 19 ACS Paragon Plus Environment

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studies.54,55 Moreover, the crystal structure of TOL−PPZ(II) shows that the molecule possesses hydrophobic channels (Fig. 4c) which possibly repel the incoming water molecule thereby reduces solvent···solute interactions. It is to be noted that the pH variations after each experiment were between ±1 (Table S5), and hence the solubility results can be meaningfully compared. All the buffer solubilities are juxtaposed with water solubilities in Table S4.

Dissolution Studies: The intrinsic dissolution rate (IDR) and apparent solubility are two of the most important parameters for metastable cocrystals. IDR is the rate at which the equilibrium solubility is reached. Dissolution experiments were carried out for all the cocrystals/salts in pH 7.4 phosphate buffer and their dissolution profiles are compared with the parent APIs. The apparent solubility was measured using the Noyes −Whitney equation, C

m=Cs(Jm/Js),

where Cm is the apparent solubility of the metastable solid, Cs is the solubility of the thermodynamically stable form, and Jm and Js are the dissolution rates of metastable and stable solids.56,57 The apparent solubility of cocrystals follows grossly their coformer solubility behavior. The cumulative dissolution profiles for GCZ and TOL salts/cocrystals are shown in Figure 11. It is assumed that the solid state interactions in the poorly soluble API are strong and therefore it is difficult to disrupt them with solvent through solvent···solute interactions. However, the cocrystalization method can conjure modification of interactions in the crystal lattice by forming drug···conformer interactions. In general, when coformers are highly/moderately soluble (although not necessarily), solvent molecules can disrupt interactions of salt/cocrystal by solvent···solute interactions thereby leading to enhancement of dissolution.

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Figure 11. Dissolution profiles of (a) GCZ (b) TOL salts and cocrystals.

Table 3 shows the IDR of all the salts/cocrystals. IDR is measured from the slope of the initial linear region of the dissolution curve. The IDR order is as follows for GCZ cocrystals/salts GCZ−PPZ (1.058) > GCZ−PTSA (0.713) > GCZ−CAT (0.658) > GCZ−RES (0.608) > GCZ (0.200) mg.cm-2min-1. It is evident that highly soluble coformer causes enhancement in dissolution of GCZ. Unlike solubility result, GCZ−PTSA shows higher dissolution compared to the other two cocrystals. The quick leaching out of weakly bound highly soluble PTSA might be the reason for its fast dissolution. In the case of TOL salts, TOL−PPZ(I) (16.765) showed far better dissolution rate than TOL−PPZ(II) (1.383 mg.cm2

min-1).

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

IDR (mg.cm-2min-1)

Apparent solubility (mg/L)

GCZ

0.200

1316

GCZ−CAT

0.658

4330

GCZ−RES

0.608

4001

GCZ−PTSA

0.713

4691

GCZ−PPZ

1.058

-

TOL

0.808

-

TOL−PPZ(I)

16.765

-

TOL−PPZ(II)

1.383

-

The 24h solubility of GCZ is 1316 mg/L in pH 7.4 Buffer (see table S8).

Conclusions: Six new cocrystal/salts of three antidiabetic drugs (GCZ, TOL, and GPZ) have been prepared and their structural aspects have been studied. The solubility and dissolution of the new multicomponent systems were extensively studied and compared with the parent API molecules. Salts obtained from PPZ have shown remarkable improvement in solubility. It is to be noted that the solution crystallization of these drugs is tedious and often results in poor crystals that were obtained slowly, after many months. This could be due to the entropic reason arising from the molecular flexibility which prolongs the crystallization process. In the case of 1:1 TOL and PPZ cogrinding, the DSC melting peak is split into two peaks. We 21 ACS Paragon Plus Environment

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conclude that this observation is due the presence of two TOL polymorphs in the mortar which lead to two different polymorphic salts when ground with PPZ.

Supporting Information Available Neutron normalized hydrogen bonding parameters, PXRD, DSC, TGA, IDR and FTIR plots are available in supporting information (SI). In addition, the results of MP, pH variations, buffer/water solubility, are presented in SI. These materials are 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: A.S. thanks to the Ministry of Science and Technology of Iran, and Iran Science Elites Federation. G.R.D. thanks the Department of Science and Technology for a J. C. Bose Fellowship. M.B. thanks University Grant Commission for DS Kothari fellowship. The authors are grateful to Dr. Shanmukha Prasad Gopi for helpful discussions.

References: 1) Stahly, G. P. Cryst. Growth Des. 2009, 9, 4212−4229. 2) Childs, S. L.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 4208−4211. 3) Grothe, E.; Meekes, H.; Vleig, E.; ter Horst, J. H.; de Gelder, R. Cryst. Growth Des. 2016, 16, 3237−3243. 4) Zegarac, M. CrystEngComm 2014, 16, 32−35. 5) Fayos, J. Cryst. Growth Des. 2009, 9, 3142−3153. 6) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri,V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper, R. K.; Thomas, S. P.; Tothadi,

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S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Cryst. Growth Des. 2012, 12, 2147−2152. 7) Shan, N.; and Michael J. Zaworotko, M. J. Drug Discovery Today 2008, 13, 440−446. 8) Bond, A. D. CrystEngComm 2007, 9, 833−834. 9) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. 10) Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering: A Textbook, World Scientific, 2011, 148–149. 11) Portell, A.; Barbas, R.; Font-Bardia, M.; Dalmases, P.; Prohens, R.; Puigjaner, C. CrystEngComm 2009, 11, 791−795. 12) Rajput, L.; Sanphui, P.; R. Desiraju G. R. Cryst. Growth Des. 2013, 13, 3681−3690. 13) Sanphui, P.; Tothadi, S.; Ganguly, S.; Desiraju G. R. Mol. Pharmaceutics 2013, 10, 4687−4697. 14) Gopi, S. P.; S.; Desiraju, G. R. Mol. Pharmaceutics 2016, 13, 3590−3594. 15) Gopi, S. P.; Banik, M.; Desiraju G. R. Cryst. Growth Des. 2017, 17, 308−316. 16) Prohotsky, D. L.; Zhao, F. J. Pharm. Sci. 2012, 101, 1−6. 17) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950−2967. 18) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252−2264. 19) Aitipamula, S.; Wong, A. B. H.; Chowa, P. S.; Tan, R. B. H. CrystEngComm 2012, 14, 8515−8524. 20) Puschner, B.; Poppenga, R. H.; Lowenstine, L. J.; Filigenzi, M. S.; Pesavento, P. A. J Vet Diagn Invest. 2007, 19, 616−624. 21) Aakeroy, C. B.; Forbes, J.; Desper, J. J. Am. Chem. Soc. 2009, 131, 17048−17049. 22) Seino, S. Diabetologia. 2012, 55, 2096−2108. 23) Ballagi-Pordany, G.; Koszeghy, A.; Koltai, M. Z.; Aranyi, Z.; Pogatsa, G. Diabetes Research and Clinical Practice. 1990, 8, 109−114. 24) Shimoyama, T.; Yamaguchi, S.; Takahashi, K.; Katsuta, H.; Ito, E.; Seki, H.; Ushikawa, K.; Katahira, H. Metabolism. 2006, 55, 722−730. 25) "19th WHO Model List of Essential Medicines (April 2015)"(PDF). WHO. April 2015. Retrieved May 10, 2015. 26) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888−1897. 27) Wang, L.; Xue, R.F.; Xu, L.Y.; Lu, X.F.; Chen, R.X.; Tao, X. T. Sci. China Chem. 2012, 55, 1228−1235. 23 ACS Paragon Plus Environment

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28) Bolla, G.; Sanphui, P.; Nangia, A. Cryst. Growth Des. 2013, 13, 1988−2003. 29) R. Chadha, R.; Rani, D.; Goyal, P. CrystEngComm 2016, 18, 2275−2283. 30) Putra, O. D.; Yonemochi, E.; Uekusa, H. Cryst. Growth Des. 2016, 16, 6568−6573. 31) Putra, O. D.; Furuishi, T.; Yonemochi, E.; Terada, K.; Uekusa, H. Cryst. Growth Des. 2016, 16, 3577-3581. 32) Rigaku Mercury 375R/M CCD. Crystal Clear-SM Expert 2.0 rc14; Rigaku Corporation: Tokyo, Japan, 2009. 33) Sheldrick, G. M. Acta Crystallogr. Sect. A: Found. Crystallogr. 2008, 64, 112−122. 34) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. 35) Spek, A. L. PLATON: A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherlands, 2002. 36) Spek, A. L. Single crystal structure validation with the program PLATON. J. Appl. Crystallogr. 2003, 36, 7−13. 37) SMART/SAINT; Bruker AXS, Inc.: Madison, WI, 2004. 38) Sheldrick, G. M. SHELX-97, Program for the Solution and Refinement of Crystal Structures; University of Gottingen: Gottingen, Germany, 1998. 39) Farrugia, L. J. WinGX: An Integrated System of Windows Programs for the Solution, Refinement and Analysis for Single Crystal Xray Diffraction Data, version 1.65.04; Department of Chemistry, University of Glasgow, 2003. 40) Sheldrick, G. M. SADABS, Bruker Nonius Area Detector Scaling and Absorption Correction, version 2.05; University of Gottingen: Gottingen, Germany, 1999. 41) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565. 42) Hursthouse, M. B.; Huth, L. S.;Threlfall, T. L. Org. Process Res. Dev. 2009, 13, 1231−1240. 43) Parvez, M.; Arayne, M. S.; Zaman, M. K.; Sultana, N. Acta Crystallogr. Sect. CCryst. Struct. Commun. 1999, 55, 74.75. 44) Thirunahari, S.; Aitipamula, S.; Chow, P. S.; Tan, R. B. H. J. Pharm. Sci. 2010, 99, 2975−2989. 45) Burley, J. C. Acta Cryst. 2005, B61, 710−716. 46) Rowe, E. L.; Anderson, B. D. J. Pharm. Sci.1984, 73, 1673−1675. 47) Nath, N. K.; Nangia, A. CrystEngComm 2011, 13, 47−51. 48) Fischer, F.; Heidrich, A.; Greiser, S.; Benemann, Rademann, K. Cryst. Growth Des. 2016, 16, 1701−1707. 49) Rastogi, R.P.; Singh, N. B. J. Phys. Chem. 1966, 70, 3315−3324. 24 ACS Paragon Plus Environment

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50) Rastogi, R.P.; Singh, N. B. J. Phys. Chem. 1968, 72, 4446−4449. 51) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Chem. Commun. 2016, 52, 640−655. 52) Arunan, E.; Desiraju, G. R.; Klein, A. R.; Sadlej, J.; Scheiner, S.; Alkorta, I.; Clary, D. D.; Robert H. Crabtree, R. H.; Dannenberg, J. J.; Hobza, P.; Kjaergaard, H. G.; Legon, A. C.; Mennucci, B.; Nesbitt D. J. Pure Appl. Chem. 2011, 83, 1637−1641. 53) Babu, N. J.; Nangia, A. Growth Des. 2011, 11, 2662−2679. 54) Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju G. R. Cryst. Growth Des. 2016, 16, 5418−5428. 55) Sanphui, P.; Bolla, G.; Nangia, A.; Cryst. Growth Des. 2012, 12, 2023−2036. 56) Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R.; Nangia, A. Cryst. Growth Des. 2011, 11, 4135−4145. 57) Otsuka, M.; Teraoka, R.; Matsuda, Y. Chem. Pharm. Bull. 1991, 39, 2667−2671.

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For Table of Contents use only

Salts and Cocrystals of Antidiabetic Drugs, Gliclazide, Tolbutamide and Glipizide: Solubility Enhancements through Drug−Coformer Interactions Ali Samie†,‡, Gautam R. Desiraju*,† and Manas Banik† †

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012,

India. ‡

Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 917751436, I.R., Iran.

Synopsis Gliclazide (GCZ), tolbutamide (TOL) and glipizide (GPZ) are BCS class II antidiabetic drugs with poor aqueous solubility. New solid forms of these drugs were prepared using resorcinol, catechol, and piperazine coformers. GCZ–PPZ and TOL–PPZ showed improved solubility and dissolution compared to the parent API. The improved physicochemical properties are ascribed to drug-coformer interactions in the new solid forms.

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Scheme 1. GCZ, TOL, GPZ (with pKa values) and coformers RES, CAT, PPZ, PTSA. 547x850mm (96 x 96 DPI)

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Crystal Growth & Design

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Figure 1. Crystal structure of GCZ−CAT: (a) Tetramer synthon formed between GCZ and CAT (b) GCZ homodimer synthon (c) 1D chain of GCZ and CAT running along the ac-diagonal direction. 184x188mm (150 x 150 DPI)

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Crystal Growth & Design

Figure 2. Crystal structure of GCZ−RES: (a) Classical and non-classical hydrogen bond interactions between GCZ and RES (b) sulphonamide homodimer connecting 1D RES chain (c) 1D chain formed between RES molecules (d) 2D layer formed between GCZ and RES along the (101 ̅) plane. 217x228mm (150 x 150 DPI)

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Crystal Growth & Design

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Figure 3. Crystal structure of GCZ−PPZ: (a) Bifurcated hydrogen bond interactions between PPZ and GCZ (b) Perspective side view of a 2D layer of GCZ−PPZ perpendicular to the (110) plane (c) Perspective side view of the 2D layer of GCZ−PPZ along the ab-diagonal direction. 243x140mm (150 x 150 DPI)

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Crystal Growth & Design

Figure 4. Crystal structure of TOL−PPZ(II); (a) bifurcated hydrogen bond interactions of NH2+ groups of PPZ with TOL (b) 2D layer formed between the TOL and PPZ along the ab-plane (c) perspective packing view of TOL-PPZ(II) along the a-axis. 198x141mm (150 x 150 DPI)

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Crystal Growth & Design

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Figure 5. Time-dependent DSC of TOL−PPZ(I) (a) after 3 min of grinding with MeCN (b) after 15 min of grinding with MeCN (c) after 30 min of grinding with MeCN. 235x190mm (150 x 150 DPI)

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Crystal Growth & Design

Figure 6. Time-dependent PXRD pattern of MeCN ground commercially purchased TOL sample. 300x131mm (96 x 96 DPI)

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Crystal Growth & Design

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Figure 7. (a) Time-dependent PXRD pattern of MeCN ground 1:1 TOL and PPZ mixture (b) Expanded region of 2θ = 6–10. 314x275mm (96 x 96 DPI)

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Crystal Growth & Design

Figure 8. IR spectra of GCZ and TOL salts and cocrystals. 330x149mm (96 x 96 DPI)

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Crystal Growth & Design

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Figure 9. The solubility/concentration comparisons of GCZ and its cocrystal/salts after 1 hour. 276x174mm (96 x 96 DPI)

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Crystal Growth & Design

Figure 10. (a) The solubility comparisons of TOL and its salts after 1 hour (b) crystal structure of TOL−PPZ(I) (top) and TOL−PPZ(II) (bottom) in space fill mode; blue molecules are TOLs and red molecules are PPZ. 388x164mm (96 x 96 DPI)

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Crystal Growth & Design

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Figure 11. Dissolution profiles of (a) GCZ (b) TOL salts and cocrystals. 246x110mm (96 x 96 DPI)

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Crystal Growth & Design

For Table of Contents use only 116x79mm (96 x 96 DPI)

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