Article pubs.acs.org/crystal
Bentazon: Effect of Additives on the Crystallization of Pure and Mixed Polymorphic Forms of a Commercial Herbicide Published as part of the Crystal Growth & Design virtual special issue IYCr 2014 - Celebrating the International Year of Crystallography Dario Braga,† Fabrizia Grepioni,*,† Laura Chelazzi,† Saverio Nanna,† Katia Rubini,† Marco Curzi,‡ Stefano L. Giaffreda,‡ Heidi E. Saxell,§ Matthias Bratz,∥ and Tiziana Chiodo*,⊥ †
Università di Bologna, Dipartimento di Chimica G. Ciamician, Via F. Selmi 2, Bologna, Italy PolyCrystalLine, Via F. S. Fabri, 127/1, 40059 Medicina (BO), Italy § Stora Enso Oyj, Wollfintie 5, 55800 Imatra, Finland ∥ BASF, 67117 Limburgerhof, Germany ⊥ BASF, 67056 Ludwigshafen, Germany ‡
S Supporting Information *
ABSTRACT: The structure−properties relationships of two new polymorphic forms of the herbicide bentazon were investigated by X-ray diffraction, hot stage microscopy, and differential scanning calorimetry; the relative thermal stability of all forms was explored, together with the effect of additives on the crystallization of one or a mixture of the three polymorphs.
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INTRODUCTION Polymorphism, the ability of a compound to crystallize in different crystal forms, is a challenge not only for scientists but also for the pharmaceutical industry.1 Studies of polymorphism blossomed in the last decades under the effort to obtain new crystal forms of known active pharmaceutical ingredients (APIs) with useful physicochemical properties.1 The discovery of a polymorph at a later stage of the drug development by a pharmaceutical company could indeed be a problem, not only in terms of production but it could influence the properties of the API changing the efficacy of the drug.2 Nowadays polymorphism studies on pharmaceutical compounds are very common, while in the agrochemical field the number of papers in which solid state properties are investigated is still limited.3 Scientific collaborations between academy and industry open new perspectives in this area, in particular concerning control improvements on crystallization processes. In order to investigate the solid state, it is fundamental to manage to control parameters that act during the steps of production, such as temperature, humidity, mechanical stress, concentration, and solvents. The large number of variables one has to take into account when dealing with polymorphism represents a challenge but also an opportunity to produce new forms with improved physicochemical properties. © XXXX American Chemical Society
Bentazon (IUPAC name: 3-isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide; see Scheme 1) is a selective herbicide belonging to the thiadiazine group of chemicals. It is manufactured by BASF chemicals, and its production process is described in the literature.4 Scheme 1. Bentazon
The commercial form of Bentazon is a mixture of two polymorphs; to date, the crystal structure of only one form has been published (CSD refcode FAXVAB).5 Herein we report on the preparation and characterization of two new polymorphs produced through crystallization techniques in solution and directly in the solid state. The two solids were characterized by Received: July 2, 2014 Revised: September 4, 2014
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dx.doi.org/10.1021/cg500980j | Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
single crystal X-ray diffraction. All polymorphs were also investigated by solid-state techniques such as variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM).
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Table 1. Details of X-ray Data Measurements and Refinements formula Mr temp/K λ/Å crystal system space group a/Å b/Å c/Å α/deg β/deg γ/deg V/Å3 Z Dc/Mg m−3 μ/mm−1 F(000) 2θ range/deg reflns collected indep reflns Rint refined params R1(obs) wR2(all)
EXPERIMENTAL SECTION
Bentazon was provided by BASF SE; all other reagents were purchased from Sigma-Aldrich and used without further purification. Crystallization from Solution. Bentazon (50 mg, 0.21 mmol) was dissolved in 4 mL of different solvents or solvent mixtures (ethanol, ethanol/water, methanol/water, and water); the solutions were heated to 50 °C and left to evaporate at room temperature, yielding single crystals of different polymorphs of bentazon (see Table 3). A second experiment concerned crystallization at room temperature with the addition of inorganic salts (LiCl, 8 mg, 0.21 mmol, NaCl, 12 mg, 0.21 mmol, KCl, 15 mg, 0.21 mmol, CaCl2, 11 mg, 0.1 mmol, MgCl2, 9 mg, 0.1 mmol, Na2HPO4, 15 mg, 0.1 mmol) to the bentazon solutions, with the intent of obtaining ionic co-crystals6 (see Tables 4 and 5). Co-crystallization at room temperature with amino acids (L-tryptophan, 42 mg, 0.21 mmol, L-proline, 23 mg, 0.21 mmol) was also tried (see Table 6). Slurry Experiments. For the slurry experiments, commercial bentazon (mixture of Forms I and II, 200 mg, 0.83 mmol) was suspended in water, ethanol, or chloroform in closed vessels, and stirred at room temperature or 50 °C for 3 weeks (see Table 10). A second experiment concerned a slurry of commercial bentazon (mixture of Forms I and II) in the presence of L-tryptophan (170 mg, 0.83 mmol). Slurry experiments on Form III (200 mg, 0.83 mmol) were carried out in a closed vessel at room temperature for 3 weeks (see Table 10). Solid State Experiments. Kneading (with a catalytic amount of water) and grinding experiments in an agate mortar for 20 min were performed on commercial bentazon (mixture of Forms I and II, 100 mg, 0.42 mmol). Ball milling (using a Retsch MM200 grinder mill operated at a frequency of 20 Hz) and kneading of commercial bentazon (100 mg, 0.42 mmol) in the presence of L-tryptophan (84 mg, 0.42 mmol) was carried out for 30 min with a few drops of water. Kneading (with a few drops of water and ethanol) experiments of commercial bentazon (100 mg, 0.42 mmol) with the addition of Na2HPO4 (30 mg, 0.21 mmol) were also carried out (see Table 7); kneading (with a catalytic amount of ethanol) and grinding experiments on Form III (100 mg, 0.42 mmol) with and without the presence of Na2HPO4 (30 mg, 0.21 mmol) were performed (see Table 8). X-ray Single Crystal Diffraction. X-ray data for Forms II and III were collected at room temperature on an Oxford Diffraction X’Calibur diffractometer [MoKα (λ = 0.71073 Å) radiation and graphite monochromator] equipped with a CCD detector (see Table 1). SHELX977 was used for structure solution and refinement based on F2. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were added in calculated positions. Mercury 2.38 and CyLView9 were used for the graphical representation of the results. X-ray Powder Diffraction. X-ray powder diffractograms in the 5− 50° 2θ range (step size 0.01°, time/step 50 s, VxA 40 × 40) were collected on a Panalytical X’Pert PRO automated diffractometer equipped with an X’Celerator detector. Data were collected in Bragg− Brentano geometry, using Cu−Kα radiation without a monochromator. An Anton Paar TTK 450 system was used for measurements at controlled temperature (variable temperature X-ray diffraction) in the 3−50° 2θ range. Differential Scanning Calorimetry (DSC). DSC measurements were performed with a PerkinElmer Diamond. Samples (3−5 mg) were placed in a sealed aluminum pans. Heating was carried out at 5 °C min−1 for all samples. Thermogravimetric Analysis (TGA). TGA measurements were performed with a PerkinElmer TGA7 in the temperature range 40− 350 °C under an N2 gas flow, at a heating rate of 5 °C min−1.
a
Form Ia
Form II
Form III
C10H12N2O3S 240.28 173
C10H12N2O3S 240.28 293 0.71073 Monoclinic P21/c 8.773(3) 9.582(2) 13.599(3) 90 97.27(2) 90 1134.0(5) 4 1.407 0.279 504.0 2
