Pharmaceutical Salts of Haloperidol with Some Carboxylic Acids and

Article pubs.acs.org/crystal

Pharmaceutical Salts of Haloperidol with Some Carboxylic Acids and Artificial Sweeteners: Hydrate Formation, Polymorphism, and Physicochemical Properties Srinivasulu Aitipamula,*,† Annie B. H. Wong,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †

Crystallization and Particle Science, Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore, 627833 ‡ Department of Chemical & Biomolecular Engineering, National University of Singapore, 4, Engineering Drive 4, Singapore 117576 S Supporting Information *

ABSTRACT: We report novel pharmaceutical salts of an important neuroleptic drug haloperidol (HAL) with some carboxylic acids and artificial sweeteners. The pKa difference between HAL and the selected carboxylic acids and sweeteners suggests salt formation. All the salts were obtained from conventional solvent evaporative crystallization experiments at ambient conditions. Except formic acid, all the carboxylic acids form salt hydrates. Crystal structure analysis revealed an isostructural crystal packing in succinate, fumarate, and acetate salt hydrates. This study reports a stable polymorph of the known HAL-saccharinate, and two polymorphs of a novel salt with acesulfame. Both polymorphic sets feature significant differences in hydrogen bonding and conformations of HAL. Stability of the polymorphs was deduced by thermal analysis, comparison of the calculated density, and slurry experiments in the case of the HAL-acesulfame salt. The reported salts with artificial sweeteners could offer advantages in terms of masking the bitter taste of the parent HAL base. All the salts showed higher solubility and intrinsic dissolution rate in 10% EtOH−water medium compared to HAL. These salts provide a means of increasing the number of solid forms for HAL that facilitate selection of a suitable salt form for development of fast-dissolving HAL formulations.

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INTRODUCTION Screening for a potential solid form is an essential step in the development of a drug to optimize the properties of the final formulation.1 In this regard various solid forms are considered for development. Most common of these include, salts, amorphous forms, polymorphs, hydrates, solvates, and recently cocrystals.2 Whereas salt formation is one of the widely used method for improving stability, solubility and often bioavailability of a poorly soluble ionizable active pharmaceutical ingredient (API),3 cocrystal formation has become an attractive alternative for nonionizable drugs.4 Pharmaceutical salts are generally defined as chemical compounds comprising an API that is molecular, cationic, or anionic, and a counterion that might be molecular or monatomic (e.g., a halide anion).5 Salt formation has a dramatic effect on the solubility. For example, a 2000-fold increment in solubility has been observed for the anti-HIV drug delavirdine by forming a mesylate salt.6 Therefore, finding a salt with an appropriate counterion has a huge impact on the performance of the drug. Haloperidol (HAL, Figure 1) is a conventional butyrophenone antipsychotic drug synthesized in 1958.7 It is also a widely used tranquilizer for treatments related to psychiatry, obstetrics, and anesthesiology, and its pharmacology has been extensively reported.8 The neuroleptic action of HAL is related to © 2014 American Chemical Society

antidopaminergic effects toward dopamine subtype receptors in the mesocortex and limbic systems of the brain.9 HAL is mainly metabolized by the liver, where it undergoes cytochrome P450catalyzed oxidative cleavage of hydrocarbon chain, forming inactive fluorophenyl and piperidine metabolites.10 HAL belongs to the Class II drugs according to the Biopharmaceutics Classification System (BCS), which has poor aqueous solubility.11 The calculated pKa of HAL is 8.30, which makes it amenable to salt formation,11 and chloride, bromide, lactate, mesylate, phosphate, picrate, and saccharinate salts of HAL are known in the literature.12 Marketed oral dosage forms of HAL contain the active ingredient in its native base form and are marketed under the trade name of HALDOL.13 Decanoic acid ester of HAL (decanoate) has been developed in sesame oil in sterile form for intramuscular injection (trade name: HALDOL decanoate).14 Our main objective of this study was to explore salts or cocrystals of HAL. Our crystallization experiments involving HAL in the presence of compounds of pharmaceutical acceptance selected from the generally regarded as safe (GRAS) chemicals15 resulted in salts with carboxylic acids such as formic acid (FA), acetic acid (AA), oxalic acid (OA), succinic acid Received: February 18, 2014 Published: April 4, 2014 2542

dx.doi.org/10.1021/cg500245e | Cryst. Growth Des. 2014, 14, 2542−2556

Crystal Growth & Design

Article

Figure 1. Molecular structure of HAL, carboxylic acids, and artificial sweeteners that formed salts reported in this paper.

cocrystals.17 The technique has also been found to be effective in preparation of salts.17b In the case of HAL, cogrinding of HAL base and the corresponding salt formers resulted in the observed salts only in the case of FUA, SUA, and all the artificial sweeteners (see Supporting Information, Figures S1−S6). Physical mixture of the corresponding starting compounds was observed with all other salt formers. Crystal Structures. Cambridge Structural Database contains crystal structures of HAL base (REFCODE: HALDOL) and its chloride (BIDFUQ), bromide (HALOPB), saccharinate (YANMUW), and picrate (CUCYUV) salts.18 In all the reported salts, salt formation is evident by the proton transfer from the acid component to the piperidine N of the HAL. Salts with Carboxylic Acids. HAL-H+-OA− (2:1) Dihydrate. The salt hydrate was prepared by crystallization from methanol. Attempts to prepare the salt in bulk quantity by solid-state grinding resulted only in the physical mixture of both the components. Crystal structure analysis proved that the salt belongs to the triclinic, P1̅ space group with two molecules each of HAL-H+ and water, and two half molecules of OA− in the asymmetric unit (Table 2). This results in the overall stoichiometry of the salt to HAL-H+-OA−/water as 2:1:2. In the crystal structure, proton transfer from the symmetry independent OA to the piperidine N of the symmetry independent molecules of HAL can be easily recognized. In the crystal structure, bifurcated N+−H···O− hydrogen bond involving the hydrogen on the piperidinium N and the O atoms of the oxalate ion is found involving each pair of symmetry independent molecules of HAL-H+ and OA− (Figure 2, Table 3). An O−H···O− hydrogen bond involving the hydroxyl group of the HAL-H+ and carboxylate O of the oxalate ion results in an extended hydrogen bonded chain. The symmetry independent water molecules connect the hydrogen bonded chains via O−H···O− hydrogen bonds and O−H···F interaction. HAL-H+-OA− (2:1) Acetonitrile Solvate. Crystallization of HAL and OA in a 1:0.5 molar ratio from acetonitrile gave an acetonitrile solvate of HAL-H+-oxalate salt. The crystal structure belongs to monoclinic, P21/n space group with two molecules of HAL-H+, two half molecules of oxalate ions, and one acetonitrile molecule in the asymmetric unit. In the crystal structure, each pair of symmetry independent HAL-H+ and oxalate ions hydrogen bond in the same way as in the crystal structure of HAL-H+-oxalate hydrate, such that the piperidinium

(SUA), and fumaric acid (FUA). In addition, salts with artificial sweeteners such as acesulfame (ACE-H), saccharin (SAC), and N-cyclohexylsulfamic acid (or cyclamic acid, CSA) were also obtained. Interestingly, except for the formate salt which exists as FA solvate, all other salts with carboxylic acids were obtained in hydrate form, and salts with SAC and ACE-H were found to exist in polymorphic forms. An acetonitrile solvate of the oxalate salt was also identified. All the novel solid phases were characterized by thermal, spectroscopic, and X-ray diffraction techniques. Solubility and dissolution experiments were conducted in 10% EtOH−water medium to gauge the effect of different counterions on the solubility and dissolution rate of the HAL.

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RESULTS AND DISCUSSION Estimated pKa difference between the HAL base and salt formers used in the present study suggested salt formation based on the Rule of Three.16 The rule postulates that when the ΔpKa (pKa of conjugate acid of base-pKa of acid) is less than 0 then a cocrystal is expected; on the other hand, when the ΔpKa is greater than 3 an ionic salt is expected to result. In the range of 0 < ΔpKa < 3, the resulting molecular complex will have an intermediate character, and there exists a cocrystal−salt continuum.16b The ΔpKa values for the HAL and salt former combinations in this study are all greater than 3 (Table 1), from Table 1. pKa Value of HAL (pKa = 8.30), Carboxylic Acids, and Artificial Sweeteners Used in This Study carboxylic acid

pKa

ΔpKa

artificial sweetener

pKa

ΔpKa

FA AA OAa SUAa FUAa

3.77 4.76 1.23 4.19 3.03

4.53 3.54 7.07 4.11 5.27

ACE-H SAC CSA

3.02 2.20 1.90

5.28 6.10 6.40

a

First ionization constant for diacids.

which we conclude that the crystallization of HAL in the presence of these salt formers results in the formation of the corresponding ionic salt. Indeed, crystallization of the HAL base together with the corresponding salt former from common organic solvents readily gave the salts. Solid-state grinding has been evolved as an effective technique for preparation of 2543


chemical formula formula mass crystal system a/Å b/Å c/Å α/° β/° γ/° V/Å3 T/K space group Z no. of reflections measured no. of independent reflections Rint R1 (I > 2σ(I)) wR2 (all) GOF

compound reference

9840

10 070

0.0487 0.0850 0.2114 1.233

882.80 monoclinic 13.125(3) 11.996(2) 26.810(5) 90.00 90.06(3) 90.00 4221.3(15) 110(2) P21/n 4 33 321

877.78 triclinic 11.961(2) 12.954(3) 14.825(3) 114.00(3) 99.25(3) 90.72(3) 2063.4(9) 110(2) P1̅ 2 29 670

0.0149 0.0383 0.0972 1.073

C46H51Cl2F2N3O8

HAL-H+−OA− acetonitrile

C44H52Cl2F2N2O10

HAL-H+−OA− dihydrate

0.0222 0.0494 0.1234 1.124

5448

469.92 triclinic 8.7151(17) 10.152(2) 14.454(3) 97.42(3) 98.87(3) 114.92(3) 1118.6(4) 110(2) P1̅ 2 15 849

C23H29ClFNO6

HAL-H+−FUA− dihydrate

Table 2. Crystallographic Parameters of HAL Salts

0.0509 0.0587 0.1650 1.122

5520

470.93 triclinic 8.6026(17) 10.585(2) 13.862(3) 108.39(3) 101.96(3) 99.31(3) 1136.2(4) 110(2) P1̅ 2 15 621

C23H30ClFNO6

HAL-H+−SUA− dihydrate

0.0145 0.0379 0.1059 1.084

5746

471.94 triclinic 8.7476(17) 10.374(2) 13.837(3) 105.57(3) 100.04(3) 96.10(3) 1175.5(4) 118(2) P1̅ 2 16 886

C23H31ClFNO6

HAL-H+−AA− dihydrate

0.0267 0.0481 0.1272 1.081

5524

467.91 monoclinic 8.4958(17) 10.032(2) 26.324(5) 90.00 94.46(3) 90.00 2236.9(8) 110(2) P21/c 4 16 994

C23H27ClFNO6

HAL-H+−FA− FA

0.0317 0.0575 0.1503 1.154

6310

559.03 monoclinic 11.189(2) 19.890(4) 12.562(3) 90.00 114.22(3) 90.00 2549.6(11) 110(2) P21/c 4 19 286

C28H28ClFN2O5S

HAL-H+−SAC− Form II

0.0288 0.0704 0.1829 1.185

6765

555.09 triclinic 8.4571(17) 9.768(2) 17.989(4) 87.28(3) 86.32(3) 68.48(3) 1379.1(5) 110(2) P1̅ 2 19 286

C27H36ClFN2O5S

HAL-H+−CSA−

0.0348 0.0668 0.1580 1.239

6185

539.00 monoclinic 26.571(5) 9.925(2) 21.954(4) 90.00 120.59(3) 90.00 4983.9(17) 110(2) C2/c 8 34 027

C25H28ClFN2O6S

HAL-H+−ACE− Form I

0.0194 0.0465 0.1099 1.112

6129

539.00 triclinic 9.5340(19) 10.120(2) 14.360(3) 88.15(3) 83.73(3) 65.69(3) 1254.9(4) 110(2) P1̅ 2 17 330

C25H28ClFN2O6S

HAL-H+−ACE− Form II

Crystal Growth & Design Article

2544



Article

Figure 2. A part of the crystal structure of HAL-H+-OA− (2:1) dihydrate showing the hydrogen bonding involving one of the symmetry independent molecules of OA−. Water and OA− molecules are shown in ball and stick model.

N+−H is involved in a bifurcated hydrogen bond with oxalate ions to result in three-component hydrogen bonded units (Figure 3). These units are self-assembled in the crystal structure via O−H···O− hydrogen bonds and form a layered network in the crystallographic ab-plane. The acetonitrile molecules are located in the interstitial sites and stabilized within via several C−H···N and C−H···O interactions. HAL-H+-FUA− (1:0.5) Dihydrate. The crystal structure of the HAL-H+-FUA− dihydrate belongs to triclinic, P1̅ space group. The asymmetric unit contains one molecule of HAL-H+, half a molecule of FUA−, and two molecules of water. In the crystal structure, two molecules of water are hydrogen bonded to carboxylate O on either side of the fumarate ion via O−H···O− hydrogen bonds. The resulting five-component supramolecular unit is enclosed by four molecules of HAL-H+ via N+−H···O− hydrogen bonds involving the piperidium N + −H and carboxylate O (Figure 4). The units further self-assemble in the crystal structure via O−H (HAL-H+)···O (water), and O− H···O− (FUA−) hydrogen bonds, and C−H···F, and Cl···O (water) interactions. HAL-H+-SUA− (1:0.5) Dihydrate. The crystal structure of the HAL-H+-SUA− dihydrate belongs to triclinic, P1̅ space group. Asymmetric unit contains one molecule of HAL-H+, half a molecule of SUA−, and two molecules of water. The crystal structure is isostructural to the crystal structure of HAL-H+fumarate dihydrate in which the fumarate ion is now replaced with a succinate ion (Figure 4). The crystal structure features a five-component supramolecular unit composed of one succinate ion and four water molecules. The self-assembly of the five-component supramolecular units is identical to the fumarate salt. HAL-H+-AA− (1:1) Dihydrate. Crystallization of HAL from aqueous AA gave HAL-H+-acetate in dihydrate form. The crystal structure of the HAL-H+-acetate dihydrate belongs to triclinic, P1̅ space group. The asymmetric unit contains one molecule each of HAL-H+ and acetate ion and two molecules of water. Interestingly, the crystal structure is isostructural to the crystal structures of HAL-H+-fumarate dihydrate and HAL-H+succinate dihydrate. The only difference here is that the fumarate and succinate counterions are now replaced with two acetate ions (Figure 4). The crystal structure features six-component

supramolecular unit composed of two acetate ions and four water molecules. Self-assembly of the six-component supramolecular units is identical to the fumarate and succinate salts. HAL-H+-FA− (1:1) FA Solvate. Crystallization of HAL from aqueous FA gave HAL-H+-formate in FA solvate form. Crystal structure analysis revealed that it belongs to the monoclinic P21/c space group, and the asymmetric unit contains one molecule each of HAL-H+, formate ion, and FA. The crystal structure features zero-dimensional hydrogen bonded units composed of each two molecules of HAL-H+, FA and formate ion and connected via N+−H···O and O−H···O− hydrogen bonds (Figure 5). The resulting six-component supramolecular units self-assemble in the crystal structure via several C−H···O interactions. Salts with Artificial Sweeteners. Many pharmaceutical compounds, including HAL, taste bitter, and the bitter taste is known to trigger stereotypical behavioral outputs leading to low patient compliance.19 As oral route is one of the preferred routes for HAL administration,20 it is worthy to explore methods that can mask the bitter taste of HAL base. Therefore, artificial sweeteners such as SAC, ACE-H, and CSA were chosen as salt formers in this study that have been previously used to mask the unpleasant taste of several other active ingredients.12f,21 HAL-H+-SAC− (1:1) Form II. SAC is a GRAS compound and potent sweetener. Crystallization of HAL base and SAC in a 1:1 molar ratio from methanol gave block-shaped crystals within a few hours. Crystal structure analysis revealed that it belongs to a new polymorph (Form II) of the reported HAL-H+-SAC− (1:1) salt (Form I).12f All our attempts to prepare the previously reported polymorph were not successful. The crystal structure of the new polymorph belongs to monoclinic, P21/c space group with one molecule each of HAL-H+ and SAC− ions in the asymmetric unit. The crystal structure is composed of infinite hydrogen bonded chains involving HAL-H+ and SAC− ions via N+−H (HAL-H+)···N− (SAC−) and O−H (HAL-H+)··· O (CO of SAC−) hydrogen bonds (Figure 6). Hydrogen bonding in the reported Form I is significantly different from Form II.12f The piperidinium N+−H forms N+−H (HAL-H+)···N− (SAC−) hydrogen bond in Form II, whereas it forms an N+−H 2545



Article

Table 3. Neutron Normalized Intermolecular Interactions in the Crystal Structures of HAL Salts crystal forms −

HAL-H −OA dihydrate +

HAL-H+−OA− acetonitrile

HAL-H+−FUA− dihydrate

HAL-H+−SUA− dihydrate

D−H···Aa

H···A/Å

D···A/Å

D−H···A/°

O1−H1A···O6 N1−H2···O7 N1−H2···O8 O3−H3···O7 N2−H4···O6 N2−H4···O5 O9−H5···F2 O9−H6···O8 O10−H7···O4 O10−H8···O9 C8−H8A···O7 C8−H8B···O5 C25−H25A···O5 C25−H25B···F2 C27−H27A···O6 C27−H27A···F1 C27−H27B···O8 C41−H41···Cl1 O1−H1···O3 N1−H2···O7 N1−H2···O8 O5−H3···O8 N2−H4···O3 N2−H4···O4 C4−H4A···O7 C5−H5A···O7 C5−H5B···F1 C8−H8A···O4 C8−H8B···O8 C9−H9A···O4 C12−H12···N3 C24−H24A···O3 C26−H26A···F2 C27−H27A···F2 C28−H28A···O7 C28−H28B···O3 C42−H42···Cl1 C43−H43···N3 C46−H46···Cl2 O1−H1···O6 N1−H2···O4 O5−H3···O2 O5−H4···O4 O6−H5···O5 O6−H6···O3 C3−H3A···O6 C3−H3B···O2 C4−H4A···F1 C4−H4B···O1 C6−H6A···O5 C6−H6B···O3 C9−H9A···O3 C14−H14···Cl1 C15−H15···O3 C22−H22···F1 O1−H1···O5 N1−H2···O4 O5−H3···O3 O5−H4···O6 O6−H5···O2 O6−H6···O4

1.85 2.01 2.13 1.80 1.90 2.18 2.27 1.74 1.98 1.87 2.22 2.51 2.55 2.45 2.54 2.59 2.43 2.85 1.84 2.14 1.91 1.77 2.00 2.05 2.51 2.57 2.57 2.47 2.31 2.56 2.59 2.47 2.44 2.54 2.28 2.48 2.79 2.59 2.86 1.75 1.66 1.98 1.76 1.80 1.80 2.62 2.45 2.60 2.48 2.49 2.55 2.40 2.80 2.23 2.37 1.74 1.69 1.76 1.80 2.14 1.79

2.829(2) 2.929(2) 2.859(2) 2.782(2) 2.834(1) 2.867(2) 3.189(2) 2.710(2) 2.949(2) 2.842(2) 3.071(2) 3.244(2) 3.128(2) 3.413(2) 3.318(2) 3.459(2) 3.447(2) 3.667(2) 2.820(3) 2.866(3) 2.822(3) 2.746(3) 2.922(3) 2.770(3) 3.150(3) 3.085(3) 3.594(3) 3.208(3) 3.131(3) 3.086(3) 3.382(3) 3.355(4) 3.409(3) 3.503(3) 3.325(3) 3.281(3) 3.621(4) 3.541(4) 3.916(4) 2.727(2) 2.659(2) 2.919(2) 2.733(2) 2.774(2) 2.759(2) 3.446(2) 2.839(2) 3.152(3) 3.321(2) 3.543(2) 3.517(2) 3.399(2) 3.859(2) 3.303(2) 3.339(2) 2.715(2) 2.661(2) 2.735(2) 2.783(2) 3.104(2) 2.742(2)

173 151 127 175 153 124 155 170 167 169 134 124 113 148 128 137 156 133 173 127 150 173 151 126 116 108 157 124 131 109 129 138 148 147 162 130 133 146 166 173 168 160 170 172 165 133 100 111 134 165 148 153 165 171 148 171 160 174 175 165 163

2546

symmetry code

1 − x, 2 − y, 1 − z 1 + x, y, z 1 − x, 1 − y, 1 − z 2 −x, 1 − y, 1 − z 1 − x, 1 − y, 1 − z −1 + x, y, −1 + z x, 1 + y, z

1 − x, 1 − y, 1 − z −1 + x, y, z 1 + x, y, z 1 − x, 1 − y, −z 2 − x, 2 − y, 2 − z 1 + x, y, z 1 − x, 1 − y, 1 1 − x, 1 − y, 1 x, −1 + y, z 1 − x, 1 − y, 1 1 + x, y, z 1 + x, y, z 3/2 − x, 1/2 +

−z −z −z

y, 3/2 − z

1 − x, 1 − y, 1 − z 1 − x, 2 − y, 1 − z x, −1 + y, z x, 1 + y, z x, 1 + y, z 1 − x, 1 − y, 1 − z x, −1 + y, z 3/2 − x, −3/2 + y, 1/2 − z 1/2 + x, 1/2 − y, −1/2 + z −1 + x, y, z 1 − x, 1 − y, 1 − z 2 − x, 1 − y, 1 − z −1 + x, y, z 1 − x, 1 − y, 1 − z

x, −1 + y, z 1 − x, −y, −z 1 − x, −y, 1 − z 1 − x, 1 − y, 1 − z 2 − x, 1 − y, 1 − z x, −1 + y, z 3 − x, 1 − y, 2 − z 2 − x, 1 − y, 1 − z x, 1 + y, 1 + z x, y, −1 + z 1 + x, y, z x, y, 1 + z 1 − x, −y, 1 − z 1 + x, y, z



Article

Table 3. continued crystal forms

HAL-H+−AA− dihydrate

HAL-H+−FA− FA

HAL-H+−SAC− Form II

HAL-H+−CSA−

HAL-H+−ACE− Form I

D−H···Aa

H···A/Å

D···A/Å

D−H···A/°

C4−H4A···O2 C4−H4A···F1 C4−H4B···O1 C5−H5A···O3 C14−H14···Cl1 C15−H15···O3 O1−H1···O5 N1−H2···O3 O5−H3···O6 O5−H4···O4 O6−H5···O2 O6−H6···O3 C4−H4A···O1 C4−H4B···O2 C4−H4B···F1 C5−H5B···O4 C6−H6B···O4 C11−H11···O4 C12−H12···Cl1 C23−H23A···F1 O1−H1···O4 N1−H2···O3 NX1−H2···O5 O6−H3···O3 C4−H4A···O3 C4−H4B···O1 C8−H8B···O6 C9−H9B···O3 C11−H11···O1 C15−H15···O6 C20−H20···O2 C23−H24···F1 O1−H1···O3 N1−H2···N2 C3−H3A···O4 C3−H3B···N2 C5−H5A···Cl1 C5−H5B···O4 C6−H6B···O4 C9−H9A···O1 C11−H11···O1 C11−H11···N2 C26−H26···F1 O1−H1···O4 N1−H2···O3 N2−H3···O5 C4−H4A···O2 C4−H4B···O1 C5−H5A···O5 C5−H5B···O3 C6−H6A···N2 C6−H6B···O3 C12−H12···F1 C20−H20···Cl1 C25−H25B···Cl1 C26−H26B···F1 O1−H1···O6 N1−H2···O4 N1−H2···N2 C2−H2A···O1 C5−H5B···F1

2.53 2.46 2.35 2.39 2.82 2.33 1.73 1.68 1.84 1.76 2.14 1.79 2.36 2.49 2.43 2.25 2.45 2.25 2.84 2.36 1.73 2.47 1.87 1.46 2.56 2.33 2.45 2.51 2.35 2.42 2.43 2.65 1.83 1.90 2.51 2.72 2.93 2.31 2.41 2.34 2.42 2.28 2.28 1.88 1.69 2.01 2.43 2.32 2.34 2.41 2.46 2.58 2.59 2.84 2.79 2.48 1.92 1.74 2.55 2.51 2.38

3.131(2) 3.268(2) 3.385(2) 3.102(2) 3.848(2) 3.399(2) 2.708(2) 2.662(2) 2.821(2) 2.735(2) 3.088(2) 2.761(2) 3.394(2) 3.109(2) 3.230(2) 3.104(2) 3.441(2) 3.315(2) 3.865(2) 3.151(2) 2.715(2) 2.991(2) 2.809(2) 2.444(2) 3.131(2) 3.362(2) 3.535(2) 3.176(2) 2.753(2) 3.453(2) 3.249(2) 3.299(2) 2.804(2) 2.879(3) 3.423(3) 3.525(3) 3.999(2) 3.372(3) 3.399(3) 3.377(2) 2.810(3) 3.221(3) 3.291(2) 2.816(2) 2.694(2) 3.016(2) 3.031(3) 3.350(3) 3.260(3) 3.473(3) 3.407(3) 3.327(3) 3.496(4) 3.852(3) 3.856(3) 3.531(4) 2.898(3) 2.733(3) 3.319(3) 3.481(3) 3.192(3)

114 131 160 122 159 167 171 164 172 172 162 169 159 115 130 134 151 167 158 129 175 111 153 176 112 160 179 119 100 159 132 118 169 164 141 131 169 167 151 160 100 145 155 159 173 173 114 158 141 166 146 125 141 155 168 165 174 166 133 149 131

2547

symmetry code 1 1 1 2 1

− x, 1 − y, 1 − z − x, 1 − y, −z − x, 1 − y, −z − x, −y, −1 − z + x, y, z

−1 + x, y, z 1 − x, 1 − y, 1 − z

−1 + x, y, z 1 − x, −y, 1 − z 1 − x, −y, −z 1 − x, −y, 1 − z −1 + x, y, z −1 + x, y, z −x, 1 − y, 2 − z 1 − x, −y, −z 1 − x, 1/2 + y, 1/2 − z −1 + x, 1/2 − y, 1/2 + z x, 1/2 − y, 1/2 + z −1 + x, y, z −1 + x,1/2 − y, 1/2 + z 1 − x, 1 − y, 1 − z −x, −1/2 + y, 1/2 − z −1 + x, 1/2 − y, 1/2 + z −x, −1/2 + y, 1/2 − z 1 − x, 1/2 + y, 3/2 − z 1 − x, 1 − y, 1 − z 1 + x, 1/2 − y, 1/2 + z 1 + x, y, z 1 − x, 1 − y, 1 − z 1 + x, y, z −1 + x, 1/2 − y, −1/2 + z 1 − x, 1 − y, 1 − z 1 + x, y, z x, 1/2 − y, −1/2 + z 1 + x, 1/2 − y, 1/2 + z x, y, 1 + z 1 + x, 1 + y, z x, 1 + y, z −x, −y, 1 − z 2 − x, 1 − y, 1 − z 1 + x, 1 + y, z 1 − x, 1 − y, 1 − z 1 + x, 1 + y, z x, 1 + y, z 1 + x, y, −1 + z 1 − x, 1 − y, 1 − z 1 − x, 1 − y, −z x, −1 + y, −1 + z x, −1 + y, z x, −1 + y, z 1/2 − x, 1/2 − y, 1 − z 1/2− x, 1/2 + y, 3/2 − z



Article

Table 3. continued crystal forms

HAL-H+−ACE− Form II

a

D−H···Aa

H···A/Å

D···A/Å

D−H···A/°

C6−H6B···O4 C9−H9A···O5 C11−H11···O1 C14−H14···Cl1 C20−H20···Cl1 O1−H1···O6 N1−H2···O4 C4−H4A···O2 C5−H5A···O6 C5−H5B···O4 C8−H8A···N2 C9−H9A···N2 C9−H9B···O6 C14−H14···Cl1 C15−H15···O5 C17−H17···O3

2.40 2.48 2.37 2.80 2.94 1.85 1.70 2.36 2.28 2.31 2.49 2.63 2.46 2.87 2.41 2.51

3.179(3) 3.094(3) 2.765(3) 3.758(2) 3.818(3) 2.811(2) 2.693(2) 2.947(2) 3.107(2) 3.297(2) 3.510(2) 3.359(2) 3.243(2) 3.935(2) 3.270(2) 3.401(2)

128 115 100 147 139 166 168 112 131 151 156 124 128 167 135 139

symmetry code x, −1 + y, z 1/2 − x, 1/2 − y, 1 − z −x, −y, −z 1/2 + x, −1/2 + y, 1 + z 1 + x, y, z

1 + x, y, z 1 − x, 1 − y, 1 − z 1 − x, −y, 1 − z 1 − x, −y, 1 − z 1 − x, −y, −z 1 − x, 1 − y, 1 − z

D = donor, A = acceptor.

Figure 3. Crystal structure of the HAL-H+-OA− acetonitrile solvate. Oxalate ion is shown in ball and stick model and acetonitrile molecules in the interstitial sites of the crystal structure (right) are shown in space filling model.

(HAL-H+)···O (carbonyl of SAC−) in Form I. Similarly, Form I features O−H (HAL-H+)···O (CO of SAC−) hydrogen bond, but Form II contains an O−H (HAL-H+)···O (SO of SAC−) hydrogen bond. The differences in hydrogen bonding motifs in Form I and II make them synthon polymorphs.22 In addition, conformation of HAL-H+ in both the polymorphs is also different (Figure 7), and thus these polymorphs can be classified as conformational and synthon polymorphs. HAL-H+-ACE− (1:1) Form I and Form II. ACE-H is a caloriefree sweetener, and its potassium salt is 200 times sweeter than sucrose and widely used in food products and pharmaceutical formulations.23 Pharmaceutical applications of ACE-H as a taste masker have been highlighted in the patent literature.21a We have recently used ACE-H as a cocrystal former for an antifungal drug, griseofulvin, that significantly improved the solubility and dissolution rate of griseofulvin.24 Crystallization of HAL base and ACE-H from methanol gave morphologically different (needle and block) shaped crystals from two different crystallization batches under identical conditions. Both the crystals correspond to a 1:1 salt of HAL-H+ and ACE−, and thus are polymorphs. Form I (needle crystals) belongs to monoclinic, C2/c space group. Asymmetric unit contains one molecule each of HAL-H+ and ACE− ions. In the crystal structure, HAL-H+ and ACE− ions form hydrogen bonded chains along the

crystallographic b-axis via N+−H···O (CO of ACE−) and O−H···O (SO of ACE−) hydrogen bonds (Figure 8). These hydrogen bonded chains are interconnected via C−H···Cl interactions. Crystal structure also features several C−H···O and C−H···F interactions. Form II belongs to triclinic, P1̅ space group with an asymmetric unit that contains one molecule each of HAL-H+ and ACE− ions. Form II also features a hydrogen bonded chain similar to Form I that involves HAL-H+ and ACE− ions and is connected through N+−H···O (CO of ACE−) and O−H···O (SO of ACE−) hydrogen bonds (Figure 9). However, the hydrogen bonded chains are now interconnected via a short Cl···O interaction instead of a C−H···Cl interaction in Form I (Figure 9). C−H···O, C−H···N−, and C−H···π interactions further stabilize the hydrogen bonded chains in the crystal structure. Notably, both the HAL-H+ and ACE− ions adopt different conformations in the crystal structures. As shown in Figure 10, the conformational change in the HAL-H+ ion is due to free rotation of the alkyl chain at the carbonyl bridge, whereas in the ACE−, the sulfoxide group adopts a strained conformation in Form II than in Form I. The polymorphs of HAL-H+-ACE− salt can be classified as conformational polymorphs due to the conformational variation in their polymorphs. 2548



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sweeteners in food, beverage, and pharmaceutical formulations.21b Crystallization of HAL base together with CSA in methanol gave platelike crystals that belong to triclinic, P1̅ space group. Asymmetric unit contains one molecule each of HAL-H+ and CSA− ions. In the crystal structure, CSA− ions form a dimer via N−H···O (sulfonyl O) hydrogen bonds. Two HAL-H+ ions connect translation related dimeric motifs of CSA− via O−H (HAL-H+)···O (sulfonyl of CSA−) and N+−H (HAL-H+)···O− (sulfonyl of CSA−), resulting in an infinite hydrogen bonded ladder network in the crystallographic a-axis (Figure 11). These ladders feature alternate HAL-H+ and CSA− dimers. Self-assembly of the hydrogen bonded ladders via several C−H···O, C−H···F, and C−H···Cl makes the complete crystal structure. In light of the significance of polymorphism in drug development,25 it is to be highlighted that the crystallization attempts to prepare salts of HAL with SAC and ACE-H resulted in polymorphs. In both cases, HAL-H+ adopts different conformations in the polymorphs suggesting that the conformational flexibility of HAL-H+ could be main cause for the polymorphism in these salts. From a recent exhaustive review of the polymorphic cocrystals, we have found that the conformational flexibility of the cocrystal components greatly contributes to the polymorphism in cocrystals.22a Whether or not such a rationale is valid for salts can only be realized by a systematic analysis of the polymorphic salts. On the other note, a recent database analysis revealed that salts are less frequently found in polymorphic forms than nonsalts (39% compared to 55%) but are more prone to form hydrates (38% compared to 30% of nonsalts), due to the greater propensity of water to bind to ionic sites.26 Spectroscopic Analysis of Salts. Formation of multicomponent crystals can be determined by Fourier transform infrared (FT-IR) spectroscopy. The changes in vibrational frequencies can be directly correlated with changes in hydrogen bonding due to formation of multicomponent crystals. In the case of salt formation involving acids and bases, the formation of carboxylate from the carboxylic acid can be easily realized by FT-IR. Generally, CO of the free COOH absorbs at 1720− 1700 cm−1 and COO− absorbs at 1650−1550 cm−1 (asymmetric) and a weaker symmetrical stretching band near 1400 cm−1. In all the salts with carboxylic acids as salt formers, there is a bathochromic shift due to salt formation (Table 4, see Supporting Information Figures S7−S15). Salt formation and hydrogen

Figure 4. Crystal structures of the isostructural salt hydrates of HAL with FUA, SUA, and AA. Acid counterions and water molecules are shown in ball and stick model.

HAL-H+-CSA− (1:1). CSA is a sulfonic acid derivative of cyclohexane. It is about 30 times sweeter than sucrose and sodium and calcium salts of CSA are commonly used as low-calorie

Figure 5. A zero-dimensional hydrogen bonded unit in the crystal structure of the HAL-H+-FA− (1:1) FA solvate. Formate ion and FA molecules are shown in ball and stick model. 2549



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Figure 6. A hydrogen bonded chain in the crystal structure of HAL-H+-SAC− salt mediated by N+−H (HAL-H+)···N− (SAC−) and O−H (HAL-H+)··· O (CO of SAC−) hydrogen bonds. SAC− ions are shown in ball and stick model.

Figure 7. Overlay of conformers of HAL-H+ (left) and SAC− (right) ions, red: Form I and blue: Form II.

Thermal Analysis and Stability of the Polymorphic Salts. All the salts reported herein were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC and TGA plots are shown in Figure 12−14. Thermal data are tabulated in Table 5. On the basis of the TGA and DSC curves, water release from the oxalate salt hydrate was observed between 110 and 135 °C; on the other hand, the acetonitrile release from the solvate was observed in a broad temperature range of 75−135 °C. Water release from the fumarate and succinate salt hydrates was observed between 75 and 130 °C. In the case of acetate hydrate and formate FA solvate, water and FA release was observed before 80 °C. The absence of melting peak in some of the thermograms is due to concomitant water/solvent release and melting. This could be because these molecules play an important role in the salt formation and removal of these molecules lead to complete collapse of the crystal lattice. Due to the pharmaceutical significance of polymorphism in the HAL-H+-SAC− salt and HAL-H+-ACE− salt, stability of the polymorphs reported herein was evaluated. The reported melting point for Form I of HAL-H+-SAC− salt is 139.6 °C.12f Interestingly, the new polymorph (Form II), melts at a significantly higher temperature (174.3 °C, Figure 14). The absence of endothermic transformation before melting and a flat baseline in the DSC thermogram of Form II suggest that it could be the most stable polymorph of the HAL-H+-SAC− salt. To further assess the stability of the polymorphs, lattice energy (Form I: −122.32; Form II: −123.85 kcal mol−1) of the polymorphs is compared. These values suggest that Form II is the most stable polymorph and agrees with the stability order deduced from the thermal analysis. Solubility data at different temperatures and

Figure 8. A part of the crystal structure of Form I of HAL-H+-ACE− showing the hydrogen bonded chains interconnected via C−H···Cl interactions. ACE− ions are shown in ball and stick model.

bonding involving SO2 group of artificial sweeteners and O−H group of HAL led to changes in the corresponding vibrational frequencies. Notably, similar hydrogen bonding in the polymorphs of HAL-H+-ACE− salt can also be justified based on the similar vibrational frequencies of the functional groups involved in the hydrogen bonds. 2550



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Figure 9. A part of the crystal structure of Form II of HAL-H+-ACE− salt showing the hydrogen bonded chains interconnected via Cl···O interaction. ACE− ions are shown in ball and stick model.

Figure 10. Overlay of conformers of HAL-H+ (left) and ACE− (right) ions, red: Form I and blue: Form II.

Figure 11. A hydrogen bonded ladder network in the crystal structure of the HAL-H+-CSA− salt. CSA− ions are shown in ball and stick model.

hand, Form II shows an initial endotherm at around 140 °C, which then immediately followed by an exotherm and then a second endotherm at around 165 °C (Figure 14, black curve). These triplet endotherm−exotherm−endotherm peaks was consistently observed in DSC thermograms of Form II (see Supporting Information, Figure S16). We hypothesized that these thermal events could be ascribed to melting of Form II at

slurry experiments provide a better understanding of the stability of the polymorphs; however, Form I was found to be elusive in our attempts and could be one of the cases of disappearing polymorphs.27 In the case of HAL-H+-ACE− salt polymorphs, the DSC thermogram of Form I (Figure 14, red curve) shows a single endotherm at 160 °C, which was ascribed to melting. On the other 2551



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Table 4. FT-IR Stretching Frequencies (νs, cm−1) of HAL Salts vibrational frequencies with carboxylic acids solid form

carboxylate (asym)

HAL-H+−OA− dihydrate HAL-H+−OA− acetonitrile HAL-H+−FUA− dihydrate HAL-H+−SUA− dihydrate HAL-H+−AA− dihydrate HAL-H+−FA− FA

1612.5 1597.8 1587.0 1585.8 1595.9 1595.4

SAC CSA ACE-H HAL-H+−SAC− Form II HAL-H+−CSA− HAL-H+−ACE− Form I HAL-H+−ACE− Form II

carboxylate (sym)

salt former (CO stretching)

1404.2 1415.7 1408.0 1409.7 1415.8 1406.1 with artificial sweeteners

1697.4 1697.4 1674.0 1693.4 1714.7 1770.2

SO2 stretching (sym)

SO2 stretching (asym)

O−H stretching (HAL free base: 3126.9 cm−1)

1177.1 1076.3 1197.6 1145.7 1032.1 1161.6 1161.9

1255.7 1275.7 1334.7 1277.1 1220.7 1313.9 1314.2

3263.9 3343.4 3429.6 3430.9

Figure 12. DSC thermograms of the salts with carboxylic acid salt formers, (a) HAL-H+-OA− dihydrate, (b) HAL-H+-OA− acetonitrile, (c) HAL-H+-SUA− dihydrate, (d) HAL-H+-FUA− dihydrate, (e) HALH+-AA− dihydrate, (f) HAL-H+-FA−-FA.

Figure 14. DSC thermograms of the HAL salts with artificial sweeteners.

Table 5. Thermal Data (DSC and TGA) for Some of the HAL Salts Reported in This Paper

salt form HAL-H+−OA− dihydrate HAL-H+−OA− acetonitrile HAL-H+−FUA− dihydrate HAL-H+−SUA− dihydrate HAL-H+−AA− dihydrate HAL-H+−FA−-FA

calculated weight loss (%)

observed weight loss (%)

solvent/water loss temperature in DSC (°C)

ΔH for guest loss (J g−1)

4.10

4.08

110−135

34.79

8.87

9.24

75−135

40.46

7.66

7.68

60−115

13.60

7.64

7.57

80−130

129.03

7.62

6.87

45−80

76.97

19.66

17.39

60−85

78.22

140 °C, followed by recrystallization leading to an unknown crystal form which melts at 165 °C. This interpretation of the thermal events was confirmed by hot-stage microscopy (HSM) (Figure 15). Microscopic observation on HSM revealed

Figure 13. TGA thermograms of the salts with carboxylic acid salt formers. 2552



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To further understand this thermal behavior, TGA and HSM experiments were performed on a crystal of HAL-H+-CSA− salt. HSM images revealed that the crystal partially melts between 185 and 194 °C and recrystallizes thereafter (see Supporting Information, Figure S17). In addition, crystal color changes from colorless to red between 185 and 250 °C. TGA showed a 30% weight loss in this temperature range (see Supporting Information, Figure S18). All these observations suggest that the endotherm and exotherm between 185 and 200 °C in the DSC corresponds to the partial melting of the crystal and recrystallization of part of the solid, respectively. The fact that the crystal changes color and TGA shows a significant weight loss also suggests decomposition of the components of the salt. Solubility and Intrinsic Dissolution Rate (IDR). Solubility and dissolution rate are important parameters that can often determine the bioavailability of the pharmaceuticals. Salt formation can result in an increase or decrease of solubility relative to the parent API. While the highly soluble salts are useful for development of immediate release formulations, less water-soluble salts are more suitable for extended release formulations. HAL base is a BCS class II drug. Improved solubility of the reported salts places the HAL in BCS class I.12 Li et al. recently showed that the solubility and dissolution rate of HAL base and salts are pH dependent.12a It was found that the HAL free base exhibits superior dissolution rate compared to its salts at a low pH, but the dissolution rate of the HAL free base is lower than the dissolution rate of its salts at high pH. In the present study, all our attempts to measure the solubility and dissolution rate of HAL base in water, buffer, or acidic solutions did not give consistent results. Poor solubility of HAL base in these media often resulted in undetectable absorbance. This prompted us to use 10% EtOH−water as a medium to compare solubility and dissolution rate of HAL salts with HAL free base. Solubility and dissolution rate of the acetonitrile solvate of HAL-H+-OA−, HAL-H+-AA− dihydrate, and HAL-H+FA− FA solvate were not measured. In the case of polymorphic salts with artificial sweeteners, solubility and dissolution rate of only the stable polymorphs (Form I of HAL-H+-ACE− salt and Form II of HAL-H+-SAC− salt) were measured. Calculated solubility of HAL free base and the salts are tabulated in Table 6. All the salts show higher solubility than the HAL free base, with HAL-H+-SUA− dihydrate salt showing as much as more than 500 times the solubility of the HAL free base. The solubility follows the trend: HAL-H+-SUA− dihydrate> HAL-H+-ACE− > HAL-H+-OA− dihydrate > HAL-H+-CSA− > HAL-H+-SAC− > HAL-H+-FUA− dihydrate > HAL free base. Figure 17 shows the IDR profiles of the HAL free base and salts. HAL base shows a very poor dissolution compared to all other salts. Comparison of the calculated IDR values suggests that the HAL-H+ACE− shows the highest dissolution rate, which is ∼400 times the dissolution rate of HAL free base. The IDR follows the trend: HAL-H+-ACE− > HAL-H+-OA− dihydrate > HAL-H+SAC− > HAL-H+-CSA− > HAL-H+-SUA− dihydrate > HALH+-FUA− dihydrate > HAL free base. Higher solubility and dissolution rate of the salts with SUA, OA and ACE-H are due to their higher solubility in water compared to the other salt formers. Analysis of the samples remained after solubility and dissolution experiments by PXRD confirmed that the solids remained the same, suggesting that there was no dissociation of the salts to HAL under slurry and dissolution conditions (see Supporting Information Figures S19−S30). The observed solubility and dissolution trend in the 10% EtOH-water

Figure 15. Photomicrographs of Form I and II crystals of HAL-H+ACE− salt at various stages in the HSM experiment.

concomitant events of partial melting of the Form II crystal and recrystallization of the unknown form in the temperature range of 140−145 °C. Subsequent melting of the crystal was observed in the temperature range of 162−165 °C. Stability of HAL-H+-ACE− salt polymorphs was evaluated by performing slurry experiments under ambient conditions. Excess solids of the powdered Form I and II were stirred in deionized water for 24 h. Analysis of the filtered and air-dried samples by powder X-ray diffraction (PXRD) revealed that it complies well with PXRD of Form I (Figure 16). This suggests

Figure 16. Comparison of the PXRD patterns of HAL-H+-ACE− salt polymorphs and HAL base with the powder obtained from slurry experiment on a physical mixture of Form I and II. Notice that Form II converts to Form I in the slurry conditions.

that Form II converts to Form I under slurry conditions, and Form I should be the thermodynamic form at ambient conditions. That the Form I is more stable than Form II was also confirmed by lattice energy calculations, which places Form I at 12.88 kcal mol−1 lower in energy than the Form II. All our attempts to prepare the unknown polymorph of the HAL-H+ACE− salt were not yet successful. DSC thermogram of HAL-H+-CSA− salt shows endotherm− exotherm peaks first (185−200 °C) followed by a series of exoand endotherms in the temperature range of 200 to 250 °C. 2553



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Table 6. Solubility and Dissolution Rate of HAL Salts in 10% EtOH−Water Mediuma

a

salt form

absorption coefficient (mM−1 cm−1)

HAL HAL-H+−OA− dihydrate HAL-H+−FUA− dihydrate HAL-H+−SUA− dihydrate HAL-H+−SAC− (Form II) HAL-H+−CSA− HAL-H+−ACE− (Form I)

35.935 71.740 71.508 28.916 29.099 54.996 34.707

solubility after 24 h slurry (mg mL−1) 0.0036 1.1257 0.3468 2.0629 0.5116 0.5316 1.2077

(×313) (×96) (×573) (×142) (×148) (×335)

IDR (×10−4, mg cm−2 min−1) 0.03 10.85 (×362) 2.43 (×81) 4.23 (×141) 6.45 (×215) 4.25 (×142) 12.73 (×424)

Numbers in parentheses indicate improvement in the solubility and dissolution rate compared to HAL free base.

the reported salts provide additional options to develop fast dissolving HAL formulations.

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EXPERIMENTAL SECTION

HAL and all other salt formers were purchased from Alfa-Aesar, Singapore. ACE-H was prepared according to the reported procedure from commercial Acesulfame-Na.28 Analytical grade solvents were used for the crystallization experiments. Solution Based Cocrystallization. Pure crystalline salt samples were prepapred by solvent-evaporative crystallization experiments under ambient conditions. HAL-H+-OA− Dihydrate. HAL (200 mg, 0.53 mmol) and OA (23.9 mg, 0.26 mmol) were dissolved in 5 mL of methanol at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-OA− (2:1) hydrate were obtained as colorless blocks after 3 days. HAL-H+-OA− Acetonitrile Solvate. HAL (200 mg, 0.53 mmol) and OA (23.9 mg, 0.26 mmol) were dissolved in 5 mL of acetonitrile at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-OA− (2:1) acetonitrile were obtained as colorless needles in 5 days. HAL-H+-FUA− (2:1) Dihydrate. HAL (200 mg, 0.53 mmol) and OA (30.9 mg, 0.26 mmol) were dissolved in 5 mL of methanol at 45 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-FUA− (2:1) hydrate were obtained as colorless blocks in 5 days. HAL-H+-SUA− (2:1) Dihydrate. HAL (200 mg, 0.53 mmol) and OA (31.4 mg, 0.26 mmol) were dissolved in 5 mL of methanol at 45 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-SUA− (2:1) hydrate were obtained as colorless blocks in 5 days. HAL-H+-AA− (2:1) Dihydrate. HAL (200 mg, 0.53 mmol) was dissolved in 10 mL of aqueous AA at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-AA− (2:1) hydrate were obtained as colorless needles in 10 days. HAL-H+-FA− (1:1) FA Solvate. HAL (200 mg, 0.53 mmol) was dissolved in 10 mL of FA at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-FA− (1:1) FA solvate obtained as colorless plates in 10 days. HAL-H+-SAC− (1:1). HAL (200 mg, 0.53 mmol) and SAC (97.5 mg, 0.53 mmol) were dissolved in 10 mL of methanol at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-SAC− (1:1) were obtained as colorless blocks in 5 days. This corresponds to a new polymorph (Form II) of the reported HAL-H+SAC− salt (Form I). HAL-H+-CSA− (1:1). HAL (200 mg, 0.53 mmol) and CSA (95.4 mg, 0.53 mmol) were dissolved in 10 mL of methanol at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-CSA− (1:1) were obtained as colorless blocks in 5 days. HAL-H+-ACE− (1:1) Form I and Form II. HAL (200 mg, 0.53 mmol) and ACE (95.4 mg, 0.53 mmol) were dissolved in 10 mL of methanol at 50 °C and left for evaporation of the solvent at ambient conditions. Single crystals of the HAL-H+-ACE− (1:1) Form I were obtained as colorless needle in 5 days. Under identical experimental conditions, Form II crystals were obtained as blocks in one of the crystallization batches.

Figure 17. IDR profiles of HAL base and some selected salts reported in this paper.

medium shows the ability of different salt formers to modify the physicochemical properties of HAL free base.

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CONCLUSIONS Pharmaceutical salts of HAL with some pharmaceutically acceptable carboxylic acids and artificial sweeteners were prepared by conventional crystallization techniques. Some of the salts can be prepared by solid-state grinding of HAL and the corresponding salt former. Interestingly, most of the carboxylic acid salt formers resulted in salt hydrates. Our attempts to reproduce the known HAL-saccharinate resulted in a novel polymorph. HAL-H+-ACE− salt exists in two polymorphic forms, and we categorized these polymorphs as conformational polymorphs based on the significant conformational differences in HAL-H+ and ACE−. Thermal analysis helped to assess the stability of the reported salts. Due to the presence of volatile solvents (water/solvent) in the crystal lattice, all the salts with carboxylic acids undergo thermal degradation upon heating. Salts with sweeteners showed higher thermal stability. Form I of HAL-H+-ACE− salt was confirmed as the thermodynamic form by thermal analysis, slurry experiments, and lattice energy calculations. The new polymorph of the HAL- SAC− is more stable than the reported polymorph based on the higher melting point and lower lattice energy. Solubility and IDR measurements in 10% EtOH−water medium confirmed that all the salts show higher solubility than the parent HAL free base. The solid forms reported herein provide a better understanding of the structural landscape of HAL. Salts with artificial sweeteners provide an alternative way of masking the bitter taste of HAL. In addition, the higher solubility and dissolution rate of 2554



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Grinding Experiments. Grinding was performed using a Retsch Mixer Mill model MM301 with 10 mL stainless steel grinding jars with one 7 mm stainless steel grinding ball at a rate of 20 Hz for 30 min. Experiments were carried out with 200 mg (0.53 mmol) of HAL free base and the corresponding amount of salt former. SDG experiments were conducted by adding 2 drops of water or methanol prior to the grinding. Single Crystal X-ray Diffraction. A good quality single crystal grown from solution crystallization was chosen under a Leica microscope and placed on a fiber needle, which was then mounted on to the goniometer of the X-ray diffractometer. X-ray reflections were collected on a Rigaku Saturn CCD area detector with graphite monochromated Mo Kα radiation (λ = 0.71073 Å). Data were collected and processed using CrystalClear (Rigaku) software. Structure was solved by direct methods and SHELX-TL29 was used for structure solution and leastsquares refinement. The non-hydrogen atoms were refined anisotropically. H atoms bonded to N and O atoms were located in the difference electron density map and allowed to ride on their parent atoms in the refinement cycles. All other H atoms were positioned geometrically and refined using a riding model. All O−H, N−H, and C−H distances are neutron normalized to 0.983, 1.009, and 1.083 Å, respectively. X-Seed was used to prepare the packing diagrams. CCDC 975499−975508 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac. uk/conts/retrieving.html and are deposited as Supporting Information. Powder X-ray Diffraction (PXRD). The powder materials were identified by D8 Advance powder X-ray diffractometer (Bruker AXS GmbH, Germany) with Cu Kα radiation (λ = 1.54056 Å). The voltage and current applied were 35 kV and 40 mA, respectively. Samples were placed on the sample holder which has 1 mm thickness and 1.5 cm diameter. The sample was scanned within the scan range of 2θ = 5° to 50° continuous scan, with a scan rate of 2 deg min−1. The PXRD patterns were plotted using OriginPro 7.5. Thermal Analysis. DSC was performed with a PerkinElmer Diamond DSC with an Autosampler. Crystals taken from the mother liquor were blotted dry with a filter paper and manually ground. The samples were placed in crimped but vented aluminum sample pans. The sample size was 2−5 mg, and the heating rate was 10 °C min−1. The samples were purged with a stream of flowing nitrogen (20 mL min−1). The instrument was calibrated using indium as the reference material. TGA was performed on a TA Instruments TGA Q500 thermogravimetric analyzer. Approximately 15 mg of the sample was added to an alumina crucible. The samples were heated over the temperature range of 25−300 °C at a constant heating rate of 10 °C min−1. The samples were purged with a stream of flowing nitrogen throughout the experiment at 40 mL min−1. Solubility and Dissolution Experiments. HAL concentration from the solutions obtained in solubility and dissolution experiments was measured using UV spectroscopy on a Varian Cary 50 UV−visible spectrophotometer after appropriate dilution. Prior to the measurements, UV−vis spectra of all the salt formers and HAL free base were measured and found that HAL shows two absorbance maxima at 197 and 249 nm. On the other hand, all the coformers show absorbance maxima in the range of 196−230 nm. Therefore, the absorbance at ∼249 nm has no interference from salt formers, and hence it was considered for calculating the HAL concentration. Prior to the solubility and dissolution experiments, the calibration plot for HAL and salts was constructed with R2 of 0.99 (n = 3). Equilibrium solubility values were determined using the shake-flask method by stirring an excess amount of each of the sample in 5 mL of 10% EtOH−water medium at 37 °C for 24 h. The solutions were filtered through 0.2 μm syringe filter and assayed for drug content spectrophotometrically at 249 nm. IDR experiments were conducted using a Varian VK7010 dissolution apparatus equipped with a VK750D heater/circulator. In each experiment, approximately 500 mg of sample was compressed to a 0.5 cm2 disk in a rotating disk intrinsic dissolution die using a hydraulic press at a pressure of 1 ton for 1 min. Only one side of the disk is exposed to the dissolution medium, and the surface of the disk is constant throughout the experiment. The intrinsic

attachment was placed in a jar of 900 mL of 10% EtOH−water preheated at 37 °C and stirring at 100 rpm. At regular time intervals, samples were withdrawn and automatically assayed for drug concentration using UV−vis spectrophotometer from the respective calibration plots.

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ASSOCIATED CONTENT

S Supporting Information *

PXRD plots of the samples obtained in grinding, solubility and dissolution experiments, FT-IR spectra, DSC thermogram of Form II samples of HAL-H+-ACE− salt, HSM images of HALH+-CSA− salt, and TGA thermograms of HAL salts with artificial sweeteners, and ORTEP plots. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*(S.A.) E-mail: [email protected]. *(R.B.H.T.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We greatly acknowledge Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research) for providing financial support for this work.

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REFERENCES

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Pharmaceutical Salts of Haloperidol with Some Carboxylic Acids and

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