Crystal and Molecular Structure and Stability of Isoniazid Cocrystals

Jan 29, 2013 - ABSTRACT: Reaction of isoniazid with benzoic acid, sebacic acid, suberic acid, and cinnamic acid results in formation of cocrystals...
0 downloads 0 Views 1MB Size
Download PDF
Article pubs.acs.org/crystal

Crystal and Molecular Structure and Stability of Isoniazid Cocrystals with Selected Carboxylic Acids Inese Sarcevica,†,‡ Liana Orola,† Mikelis V .Veidis,† Anton Podjava,† and Sergey Belyakov*,‡ †

University of Latvia, Faculty of Chemistry, Kr. Valdemara 48, Riga, LV-1013, Latvia Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia

‡

S Supporting Information *

ABSTRACT: Reaction of isoniazid with benzoic acid, sebacic acid, suberic acid, and cinnamic acid results in formation of cocrystals. Two polymorphs of isoniazid−suberic acid and two polymorphs of isoniazid−cinnamic acid cocrystals were isolated. Crystal structure analysis shows the presence of a pyridine−carboxylic acid synthon in the studied cocrystals. The hydrazide group of isoniazid participates in N−H···O and N−H···N hydrogen bond formation, producing different supramolecular synthons. The stability study of isoniazid cocrystals has been performed over a 22 week period. A comparison of melting points of isoniazid−dicarboxylic acid 2:1 cocrystals shows the decrease of melting point with an increasing length of the acid. Solubility of isoniazid−carboxylic acid cocrystals tends to increase with increasing solubility of the acid.

■

INTRODUCTION

pound, with carboxylic acids is expected to give O−H···N hydrogen bonded cocrystals.23−25 Pyridine and hydrazide groups of isoniazid allow formation of a variety of hydrogen-bonding motifs in isoniazid crystal structures. Carboxylic−pyridine synthons containing isoniazid cocrystals with 4-aminosalicylic acid and 26 hydroxybenzoic and dicarboxylic acids27−30 have been reported. In addition to carboxylic−pyridine hydrogen bonds, hydrazide−hydrazide hydrogen bonds form in crystal structures of isoniazid cocrystals with 2,2′-dithiodibenzoic acid,31 dicarboxylic acids (malonic, succinic, glutaric, adipic, and pimelic acid,28 terephthalic acid27), and hydroxybenzoic acids (4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid,28 2-hydroxybenzoic acid,30 and 4-aminosalicylic acid26). Moreover, hydrazide− hydrazide hydrogen bonds are also present in the isoniazid crystal structure and some of its organometallic complexes with copper (catena-[(μ3-iodo)-(isonicotinazide)-copper(i)]32 and catena-((μ2-cyano)-(μ2-isonicotinohydrazide-N′,N″)-copper(i)33). Other isoniazid organometallic complexes, namely, hydrated coordination compounds with zinc perchlorate,34 copper hydrochloride,35 manganese trichloride,36 and samarium nitrate,37 have been described. A pyridine−hydrazide hydrogen bond has been observed in the monohydrate of isoniazid 3-carboxy-4-hydroxybenzenesulfonate.38 Crystal structures of isoniazid salts with inorganic anions, such as phosphate,39 dihydrochloride,40 and hexafluorosilicate,41 are known.

Crystal engineering is applied in the pharmaceutical industry to improve the quality of pharmaceutical substances1 and resolve patent issues.2,3 This can be achieved by designing multicompound cocrystals with the API. A recent discussion on nomenclature of crystalline structures of pharmaceutical substances defines cocrystals as “solids that 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”.4 Cocrystals can have higher stability5,6 and solubility7,8 than their pharmaceutical ingredients and improved mechanical properties of tablet forms.9 Although the connection between crystal structure and physicochemical properties of cocrystals has been studied,10−13 it still is not fully understood. For example, the difficulty in predicting a cocrystal melting point has been noted,13,14 and a reliable general explanation for the observed melting point of a cocrystal is not available due to the complexity of the problem. The melting point of a crystalline form is influenced by the hydrogen bonding and other intermolecular interactions, molecular conformations, packing, and entropy factors.14−16 On the basis of possible hydrogen bonds between functional groups of the compounds, the formation of cocrystals can be expected.17−19 Van der Waals forces and π−π interactions can also affect the structure of the cocrystal.20 Analysis of the Cambridge Structural Database (CSD)21 data shows a 91% probability of hydrogen bond formation between compounds containing the pyridyl ring and a carboxylic acid.22 Therefore, cocrystallization of the antituberculosis drug isoniazid (isonicotinic acid hydrazide), a pyridyl group containing com© XXXX American Chemical Society

Received: September 16, 2012 Revised: January 18, 2013

A

dx.doi.org/10.1021/cg301356h | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

cinnamic acid from hot (70 °C) ethanol/acetonitrile (2:1 mixture) gave two polymorphic forms of 1:1 isoniazid−cinnamic acid cocrystals. Form I crystallizes as blocks, and form II crystallizes as thin plates. Polymorphs were separated manually according to their crystal morphologies. Liquid-Assisted Grinding (LAG). The LAG of isoniazid cocrystals was performed by milling in a Retsch MM301 ball mill with solvent addition. Starting compounds were milled in 1.5 mL grinding jars with two 5 mm stainless steel balls. The stoichiometry of starting compounds was the same as that for crystallization from solvent. Co-grinding was carried out for 25, 50, and 75 min at 25 Hz. Ethanol and acetonitrile were used as solvents for the LAG of each cocrystal. Before milling, 0.02 mL of the solvent was added to each sample. The grinding products were analyzed by PXRD, and the resulting patterns are available in the Supporting Information (Figures S1−S8 in Supporting Information). Cocrystals of isoniazid with malonic, succinic, glutaric, adipic, and pimelic acids were prepared by LAG using previously described stoichiometries.28 Single-Crystal X-ray Diffraction. X-ray diffraction data were measured with a Nonius Kappa CCD diffractometer (Bruker AXS GmbH, Germany) with Mo Kα radiation (0.71073 Å). The Oxford Cryosystems Cryostream Plus equipment was used to ensure a temperature of 173 K. Data reduction was performed with the DENZO/SCALEPACK.48 Crystal structures of 1, 2, 3a, 4a, and 4b were solved by direct methods with Shelxs97;49 refinement was performed by Shelxl97.49 Cell parameters were determined for 3b from a single crystal analysis, but the poor quality of the crystal did not allow structure determination. Hydrogen bond distances for the investigated isoniazid cocrystals were determined by PLATON.50 The Mercury 3.0 software51 was used for the preparation of crystal structure images and simulation of X-ray powder patterns based on single crystal structure data. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Advance powder diffractometer (Bruker AXS GmbH, Germany) equipped with a LynxEye position sensitive detector and Cu Kα radiation (λ = 1.5418 Å), 40 kV, 40 mA. Data were collected at ambient temperature with a step of 0.02° and scan speed of 0.1 s/step. Thermal Analysis. Differential thermal analysis (DTA) was performed using Seiko Exstar6000 TG/DTA6300 (Seiko Instruments Inc., Japan) equipment. The samples (4−10 mg) were heated in open aluminum pans at a rate of 10 °C/min in air. Differential scanning calorimetry (DSC) experiments were performed with STA 6000 (Perkin-Elmer) equipment. The samples (15−20 mg) were heated in open aluminum pans at a rate of 10 °C/ min in nitrogen (flow of 20.0 mL/min). High-Performance Liquid Chromatography Coupled to Photodiode Array and Mass Spectrometry Detectors (HPLCPDA-MS). HPLC-PDA-MS analyses were performed using a Waters Alliance 2690 Separation Module with a Waters 991 photodiode detector and a Waters Micromass Quattro micro API triple quadrupole mass spectrometer equipped with an electrospray ionization source (Z-spray). Separations were performed using a reversed-phase chromatographic column (Agilent Zorbax SB C-18, 4.6 × 250 mm, 5 μm) at a flow rate of 1.5 mL/min at 30 °C. Data acquisition was carried out using both positive and negative ionization electrospray modes and UV detection at 220−400 nm. The mobile phase consisted of 0.2% formic acid aqueous solution and 0.2% formic acid solution in methanol. All the data were treated using MassLynx 4.1 software. UV/vis Spectrometry (UV/vis). The concentrations of cocrystal aqueous solutions were determined by UV/vis spectrometry using a Lambda 25 (Perkin-Elmer) equipped with 1.0 cm quartz cuvettes. UV/vis absorption spectra in the 200−600 nm range were recorded for all samples. The absorption maxima for all cocrystal solutions correspond to 270 nm, and the concentration measurements were performed at this wavelength. A separate linear calibration curve was plotted for each cocrystal.

Isoniazid is an antitubercular drug that has been widely used to treat the Mycobacterium tuberculosis bacterial infection. It exhibits synergistic activity with the t-cinnamic acid,42,43 a nontoxic natural compound with antimycobacterial activity. A combination of isoniazid and cinnamic acid, therefore, may enhance multidrug resistant tuberculosis treatment possibilities.42,43 Crystalline isoniazid is stable over long time periods,44 and at accelerated conditions,45 whereas isoniazid tablet formulations have been reported to undergo degradation.44−46 The degradation level of isoniazid depends on the conditions of storage and composition of the formulation. Accelerated climatic conditions (40 °C, 75% RH) increase the level of isoniazid degradation in fixed dose formulations with other antitubercular drugs.45 The exposure to light and the presence of other drug compounds (pyrazinamide, ethambutol) also increase the level of isoniazid degradation.46,47 Because combinations of antitubercular drugs are usually prescribed, it is important to develop stable formulations. In this study, isoniazid cocrystals with benzoic acid, sebacic acid, suberic acid, and cinnamic acid (structural formulas given in Scheme 1) have been prepared and characterized. Scheme 1. Structural Formulas of Cocrystal Components

■

EXPERIMENTAL SECTION

All chemicals were purchased from commercial suppliers and used without further purification. Solution Crystallization. Isoniazid−Benzoic Acid Cocrystal (1). Isoniazid (34.3 mg, 0.25 mmol) and benzoic acid (30.5 mg, 0.25 mmol) were dissolved in 5 mL of ethanol/acetonitrile (2:1 mixture) and heated at 70 °C for 30 min. Colorless thin plates were obtained upon slow evaporation of the solution. Isoniazid−Sebacic Acid Cocrystal (2). Crystallization of 68.6 mg (0.5 mmol) of isoniazid and 50.6 mg (0.25 mmol) of sebacic acid from hot (70 °C) ethanol/acetonitrile (2:1 mixture) resulted in a 2:1 isoniazid−sebacic acid cocrystal. Isoniazid−Suberic Acid Cocrystal (3a). Crystallization of starting compounds (68.6 mg, 0.5 mmol of isoniazid and 43.6 mg, 0.25 mmol of suberic acid) from a hot (70 °C) ethanol/acetonitrile 2:1 mixture produced colorless platelike crystals. Isoniazid−Suberic Acid Cocrystal (3b). Prismatic single crystals were obtained by crystallization of 68.6 mg, 0.5 mmol of isoniazid and 43.6 mg, 0.25 mmol of suberic acid from a hot (50 °C) acetonitrile/ methyl tert-butyl ether 1:1 mixture with seed addition (seed crystals were obtained from liquid-assisted grinding experiments). Isoniazid−Cinnamic Acid Cocrystal, 4a and 4b. Cocrystallization of 68.6 mg (0.5 mmol) of isoniazid and 74.1 mg (0.5 mmol) of B

dx.doi.org/10.1021/cg301356h | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 1. Crystallographic Data of Isoniazid Cocrystals cocrystal

1

2

3a

3b

4a

4b

chemical formula crystal system space group Mr a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z μ (mm−1) Dcalc (g cm−3) no. of parameters reflns collected reflns (I > 2σ) wR (all data) final R (I > 2σ) GOF

C6H7N3O·C7H6O2 monoclinic P21 259.26 25.815(1) 3.8880(6) 6.1323(6) 90 88.416(4) 90 615.27(12) 2 0.102 1.400 188 2080 1360 0.1329 0.0623 1.034

C10H18O4·(C6H7N3O)2 triclinic P1̅ 476.54 6.8942(6) 7.1004(6) 12.4475(1) 104.455(4) 92.400(3) 95.106(4) 586.40(9) 1 0.100 1.349 158 2710 1613 0.1600 0.0617 1.040

C8H14O4·(C6H7N3O)2 triclinic P1̅ 448.48 6.8989(2) 7.4686(3) 21.375(9) 84.096(1) 82.381(1) 89.843(2) 1085.77(7) 2 0.103 1.372 289 3747 2889 0.1296 0.0453 0.957

C8H14O4·(C6H7N3O)2 monoclinic P21/c 448.48 48.643(1) 10.111(1) 9.086(1) 90 90.25(1) 90 4468.7(7) 8

C9H8O2·C6H7N3O triclinic P1̅ 285.30 7.4573(3) 9.5154(4) 10.1737(3) 96.904(3) 103.264(2) 101.946(2) 676.70(5) 2 0.100 1.400 190 3561 2630 0.1436 0.0504 1.048

C9H8O2·C6H7N3O monoclinic P21/c 285.30 14.9124(8) 3.7468(2) 24.309(2) 90 96.975(2) 90 1348.18(1) 4 0.100 1.406 197 2395 1308 0.2012 0.0693 0.999

Stability Experiments. The stability of cocrystals 1, 2, and 3b was investigated over a 22 week period. Stability experiments for 4a and pure crystalline isoniazid were performed for 11 weeks and for its cocrystals with malonic, succinic, glutaric, adipic, and pimelic acids for 8 weeks. Sample holders containing approximately 100 mg of cocrystal powder were stored in glass chambers at 30 °C and 75% RH. The composition of samples was determined by PXRD (Figures S9−S18 in the Supporting Information) and purity by HPLC-PDA-MS (Figures S24−S35 in the Supporting Information). The relative stability of 3a and 3b was investigated by preparing a 1:1 (20 mg:20 mg) mixture of 3a and 3b. The mixture was treated with a few drops of ethanol to form a slurry. The experiment was conducted at ambient conditions (21 ± 1 °C, approximately 60% RH). After evaporation of the solvent, the sample was analyzed by PXRD. The treatment and evaporation process was repeated two times on the same sample. PXRD patterns were recorded after each processing step to determine changes in composition. Solubility Experiments. The cocrystal solubility was determined by suspending excess cocrystal in 5 mL of deionized water at room temperature (22 ± 1 °C). Suspensions were shaken for 4 and 16 h in closed beakers. The concentration of the cocrystal in the solution was determined by UV/vis spectrometry, and the composition of the solid phase was analyzed by PXRD. All UV/vis measurements were performed in triplicate.

■

Each isoniazid molecule is hydrogen-bonded to two isoniazid molecules through N−H···O homosynthons. These R22(10) graph sets extend along the b axis in a herringbone arrangement. The crystal structure of 1 is chiral, despite the achiral reactants. According to Matsuura and Koshima,54−56 the chiral crystal structure can be characterized by a rotation around the bonds, helical or propeller-type arrangement of molecules, and head-to-head stacking. In the crystal structure of 1, N−H···N bonds link hydrazide groups of isoniazid molecules to form a helix parallel to the 2-fold symmetry element (Figure 1). The angle between pyridyl rings of two N−H···N hydrogen-bonded isoniazid molecules is 54.8°. All helices have the same handedness. Isoniazid−Sebacic Acid Cocrystal (2). Cocrystal of 2 was crystallized from solution and by LAG. The isoniazid−sebacic acid cocrystal crystallizes in the triclinic space group P1̅ with one molecule of isoniazid and half a molecule of sebacic acid in the asymmetric unit. The acid molecule lies on an inversion center. Each sebacic acid molecule is attached to two symmetrically equivalent isoniazid molecules via O−H···N hydrogen bonds. The angle between the plane of the carboxylic acid group and the plane of the pyridyl ring is 2.8° (Figure 2). Isoniazid molecules are connected by two distinct homosynthons. One homosynthon results from hydrogen bonding between the terminal NH2 and the oxygen atom of the hydrazide side chain with a graph set R22(10). The second homosynthon forms by the hydrogen bond of the terminal NH2 and its adjacent NH with a graph set R22(6). These two homosynthons alternate to form acid connected isoniazid chains. Isoniazid−Suberic Acid Cocrystal (3a and 3b). Cocrystallization of isoniazid with suberic acid gives two polymorphs (3a and 3b). Form 3a was crystallized from ethanol and acetonitrile (2:1 mixture) solution. LAG of isoniazid with suberic acid produced 3b, as indicated by a powder diffraction pattern that was inconsistent with that of 3a. Single crystals of 3b could be obtained by crystallization with seed addition; however, the poor quality of crystals did not allow crystal structure determination.

RESULTS

Cocrystallization of isoniazid with benzoic, suberic, sebacic, and cinnamic acids results in cocrystals. These are characterized by single-crystal X-ray diffraction, PXRD, and thermal analysis (see the Supporting Information). The crystallographic information is given in Table 1, and hydrogen bonds are presented in Table 2. Isoniazid−Benzoic Acid Cocrystal (1). Cocrystal 1 was crystallized from solution and by LAG. Both methods gave the expected product. The isoniazid−benzoic acid cocrystal crystallizes in the P21 space group. The asymmetric unit contains one isoniazid molecule and one benzoic acid molecule. Benzoic acid is hydrogen-bonded to isoniazid pyridine N through O−H···N. The angle between the carboxyl group plane and the pyridyl ring plane is 7.1°. A weak pyridyl−benzoic acid C−H···O hydrogen bond52 results in a R22(7) ring motif.53 C

dx.doi.org/10.1021/cg301356h | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 2. Hydrogen Bond Distances in Isoniazid Cocrystals D−H (Å)

H···A (Å)

N9−H9···N10 N10−H101···O8 N10−H101···O8 N10−H102···O8 O11−H11···N1

1.09 1.02 1.02 0.93 1.07

1.85 2.36 2.37 2.04 1.65

N9−H9···N9 N9−H9···N10 O11−H11···N1 N10−H101···O8 N10−H102···O12 C6−H6···O12

0.93 0.93 1.00 0.85 0.96 0.93

2.57 2.06 1.64 2.27 2.29 2.35

N9−H9···N32 O11−H11···N1 O22−H22···N23 N31−H31···N9 N31−H31···N10 N10−H101···O13 N10−H102···O30 N32−H322···O8 N32−H322···O13 C6−H6···O13 C24−H24···O21

0.85 0.92 0.96 0.99 0.99 0.96 0.90 0.87 0.87 0.93 0.93

2.13 1.75 1.73 2.60 2.08 2.32 2.24 2.48 2.48 2.42 2.39

N9−H9···O12 O11−H11···N1 N10−H102···O12 C3−H3···O8 C5−H5···O12 C6−H6···O12 C14−H14···N10

0.94 1.00 0.95 0.93 0.93 0.93 1.02

2.05 1.62 2.34 2.51 2.39 2.54 2.52

N9−H9···O12 O11−H11···N1 C5−H5···O12 C6−H6···O12 C14−H14···N10

0.96 0.82 0.93 0.93 1.04

1.96 1.85 2.44 2.58 2.61

D···A (Å) cocrystal 1 2.910(4) 2.743(4) 2.987(4) 2.965(4) 2.684(4) cocrystal 2 3.165(3) 2.932(3) 2.643(3) 2.901(3) 3.169(3) 3.158(3) cocrystal 3a 2.913(2) 2.665(2) 2.679(2) 3.199(2) 2.990(2) 3.221(2) 2.965(2) 2.904(2) 3.247(3) 3.230(3) 3.202(3) cocrystal 4a 2.980(2) 2.616(2) 3.166(2) 3.277(2) 3.308(2) 3.212(2) 3.485(2) cocrystal 4b 2.919(4) 2.659(4) 3.309(5) 3.271(5) 3.546(6)