WO2019158408A1 - Crystalline forms of broflanilide - Google Patents

Crystalline forms of broflanilide Download PDF

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Publication number
WO2019158408A1
WO2019158408A1 PCT/EP2019/052834 EP2019052834W WO2019158408A1 WO 2019158408 A1 WO2019158408 A1 WO 2019158408A1 EP 2019052834 W EP2019052834 W EP 2019052834W WO 2019158408 A1 WO2019158408 A1 WO 2019158408A1
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crystalline form
vol
solvent
broflanilide
water
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PCT/EP2019/052834
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French (fr)
Inventor
Tatjana Sikuljak
Tiziana CHIODO
Martin Viertelhaus
Wen Xu
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Basf Agrochemical Products B.V.
Mitsui Chemicals Agro, Inc.
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Publication of WO2019158408A1 publication Critical patent/WO2019158408A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to crystalline forms of the insecticide broflanilide, in particular to a crystalline form B, and to different processes for converting said crystalline form B into a crystal- line form A or vice versa.
  • the compound broflanilide [3-(benzoylmethylamino)-N-[2-bromo-4-[1 ,2,2,2-tetrafluoro- 1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide] belongs to the class of carboxamide insecticides.
  • the compound is depicted below, and will be referred to as broflani- lide or compound I in the following.
  • Compound I is described in W02010/018714. Preparation of compound I can be accomplished according to standard methods of organic chemistry, e.g. by the methods or working examples described in WO2010/018857 or WO2017/104838, without being limited to the routes given therein. Depending on the process and re-crystallization procedures, compound I can be ob- tained as an amorphous substance or a crystalline substance. The prior art does not describe if the obtained form is present in a defined crystal form, or which crystal characteristics this form has.
  • broflanilide may exist in three different crystalline modifications.
  • Form B triclinic crystalline form of broflanilide.
  • Form A and form B can be converted into each other under defined conditions. Single crystal structures of both forms were obtained by X-ray analysis, which showed that the two forms A and B differ from each other by the conformation of the central NH-aryl bond. Thus, form A and form B can be regarded as conformational polymorphs, differing on the bond conformation.
  • the present description relates to a crystalline form A of broflani- lide.
  • it relates to the following embodiments:
  • a crystalline form A of broflanilide which, in an X-ray powder diffractogram at 25°C and Cu- K radiation, shows at least four of the twelve following reflexes, given as °20 values:
  • the crystalline form A according to embodiment A1 which, in an X-ray powder diffracto- gram at 25°C and Cu-Ka radiation, shows at least six of the twelve following reflexes, given as °20 values: 1 1 .5 ⁇ 0.2, 13.4 ⁇ 0.2, 16.4 ⁇ 0.2, 17.4 ⁇ 0.2, 19.3 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 22.2 ⁇ 0.2, 22.7 ⁇ 0.2, 24.0 ⁇ 0.2, 28.6 ⁇ 0.2 and 31 .2 ⁇ 0.2, and preferably shows at least the following six reflexes, given as °20 values: 1 1.5 ⁇ 0.2, 13.4 ⁇ 0.2,, 17.4 ⁇ 0.2, 20.2 ⁇ 0.2, 22.2 ⁇ 0.2 and 31 .2 ⁇ 0.2.
  • the crystalline form A according to embodiment A1 or A2 which, in a DSC curve measured by a differential scanning calorimeter at a scan rate of 10°C per minute, exhibits an endo- thermic peak with an onset temperature in the range of 150 to 156 °C and/or a peak tem- perature in the range of 157 to 161 °C.
  • DSC curve as shown in Figure 6 onset 142°C, peak 145°C X-ray powder diffractogram of crystalline form B ( Figure 2) with the following peaks: 1 1 .5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, 17.4 ⁇ 0.2, 18.5 ⁇ 0.2, 19.7 ⁇ 0.2, 20.1 ⁇ 0.2, 21 .3 ⁇ 0.2, 21 .8 ⁇ 0.2, 22.3 ⁇ 0.2, 23.4 ⁇ 0.2, 25.2 ⁇ 0.2, 25.7 ⁇ 0.2, 27.7 ⁇ 0.2, 29.4 ⁇ 0.2, 29.8 ⁇ 0.2 and 31 .1 ⁇ 0.2.
  • the diffractogram peak pattern of form A and form B is quite similar. However, there are a few peaks that are more prominent in form B. In particular, the main peaks to distinguish form B from form A are the following peaks in form B: 15.5 ⁇ 0.2, 18.5 ⁇ 0.2, 21 .8 ⁇ 0.2.
  • the present description relates to a crystalline form B of broflani- lide.
  • it relates to the following embodiments:
  • a crystalline form B of broflanilide which, in an X-ray powder diffractogram at 25°C and Cu- K radiation, shows at least four of the seventeen following reflexes, given as °20 values: 1 1.5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, 17.4 ⁇ 0.2, 18.5 ⁇ 0.2, 19.7 ⁇ 0.2, 20.1 ⁇ 0.2, 21 .3 ⁇ 0.2,
  • the crystalline form B according to embodiment B1 which, in an X-ray powder diffracto- gram at 25°C and Cu-K radiation, shows at least six of the seventeen following reflexes, given as °20 values: 1 1 .5 ⁇ 0.2, 13.4 ⁇ 0.2, 15.5 ⁇ 0.2, 17.4 ⁇ 0.2, 18.5 ⁇ 0.2, 19.7 ⁇ 0.2, 20.1 ⁇ 0.2, 21 .3 ⁇ 0.2, 21 .8 ⁇ 0.2, 22.3 ⁇ 0.2, 23.4 ⁇ 0.2, 25.2 ⁇ 0.2, 25.7 ⁇ 0.2, 27.7 ⁇ 0.2, 29.4 ⁇ 0.2, 29.8 ⁇ 0.2 and 31 .1 ⁇ 0.2, and preferably shows at least the following nine re- flexes, given as °20 values: 15.5 ⁇ 0.2, 18.5 ⁇ 0.2, 19.7 ⁇ 0.2, 21 .3 ⁇ 0.2, 21 .8 ⁇ 0.2, 23.4
  • the crystalline form B according to embodiment B1 or B2 which, in a DSC curve measured by a differential scanning calorimeter at a scan rate of 10°C per minute, exhibits an endo- thermic peak with an onset temperature in the range of 140 to 143°C and/or a peak temper- ature in the range of 144 to 148°C.
  • the crystalline forms A and B of compound I are advantageous in terms of storability and trans- portability. Furthermore, crystalline forms A and B are advantageous for the use against inverte- brate pests because, although they have a low solubility in water, they can effectively be applied as an aqueous suspension concentrate.
  • the crystalline forms can show differing physicochemi- cal characteristics, higher bulk density (which is advantageous e.g. in terms of transportability of the technical ai), a different (preferably better) pesticidal activity, or activity in formulation, or speed of action, less toxicity to beneficial organisms, stability as technical ai, stability in formula- tion, rainfastness, or other parameters relevant for pesticides.
  • crystalline forms of a compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behaviour, flow properties and/or solid state stability, there remains an interest to find crystalline forms of compound I, which may be advantageous in terms of some of the above listed properties, e.g. in terms of the solubility.
  • crys- talline forms which are described herein, are essentially free from solvent, which means that the crystalline forms comprise no detectable amounts of solvents incorporated into the crystal lattice, i.e. in the 3-dimensional crystal lattice, wherein the molecules are positioned.
  • the amount of solvent in the crystal lattice is less than 10 mol%, preferably less than 5 mol%, more preferably less than 1 mol% based on compound I.
  • the intensity of the reflexes is typically plotted versus the °20 angle to obtain a diffractogram.
  • Such a diffractogram typically shows at least 2, preferably at least 4, more preferably at least 6, still more preferably at least 7, particularly preferably at least 10 reflexes.
  • °20 val- ues which can be determined from the diffractogram and which are provided herein, often rep- resent approximate values within an error margin in the range of from 0.1 to 0.4, preferably from 0.1 to 0.2.
  • a °20 value of, e.g., 7.01 may be understood as a °20 value of 7.01 ⁇ 0.2, pref- erably 7.01 ⁇ 0.1 , more preferably 7.01 ⁇ 0.05, particularly preferably exactly 7.01.
  • DSC curves as provided herein can be obtained using a differential scanning calorimeter (e.g. a Mettler Toledo DSC 823e module) at a scan rate of 10°C per minute, wherein the sample is heated in crimped aluminum pans. The heat flux is then plotted versus the temperature.
  • the ex- othermic and endothermic peaks represent, e.g., crystallization or re- crystallization processes (exothermic) or melting processes (endothermic).
  • the peaks are typi- cally defined by their onset temperature, i.e. the temperature, at which an exothermic or endo- thermic process begins, and their peak temperature, i.e. the temperature at the peak maximum or minimum.
  • Mixtures of two crystalline forms may be identified by comparing the recorded °2Q values and DSC curves with the respective data of both crystalline forms alone. If the diffractogram shows characteristic reflexes of both crystalline forms, it can be concluded that a mixture of the two crystalline forms is present.
  • complete conversion means that at least 90 wt.-%, preferably at least 95 wt.-%, more preferably at least 98 wt.-%, most preferably at least 99 wt.-%, based on the total weight of the crystalline form with which the conversion process was started (e.g. form B), is converted into the target crystalline form (e.g. form A).
  • target crystalline form e.g. form A
  • complete conversion means that crystalline form B is quantitatively converted into crystalline form A, respectively that crystal- line form A is quantitatively converted into crystalline form B.
  • the term“chemically pure” means that a substance, e.g. compound I or a crys- talline form thereof or the amorphous form thereof or any mixture thereof, is provided in a purity of at least 95%, preferably at least 97%, more preferably at least 98%, most preferably at least 99%, wherein the percent values refer to the substance weight based on the total weight of the substance together with any impurities.
  • the chemical purity of compound I may be determined by NMR, quantitative HPLC and the like.
  • organic solvent includes any organic solvent including aprotic and protic solvents, unpolar and polar solvents, water-immiscible and water-miscible solvents, aro- matic and non-aromatic solvents, and mixtures thereof.
  • Preferred organic solvents according to the present invention or specific embodiments are given in the present description and claims.
  • Mixtures of aqueous solvents and organic solvents may be biphasic solvent systems or mo- nophasic solvent systems depending on the miscibility of the solvents. Preferred solvent mix- tures according to the present invention will be listed below.
  • the present invention also relates in one embodiment to the use of crystalline form B of compound I as a pesticide for controlling invertebrate pests.
  • the present invention relates to the use of crystalline form B of compound I for combating insects, acarids or nematodes.
  • the present invention relates in one embodiment to a method of contacting the invertebrate pests, in particular insects, acarids or nematodes, or their food supply, habitat, breeding grounds or their locus with a pesticidally effective amount of crys- talline form B of compound I.
  • Preferred weight ratios of crystalline form B to crystalline form A in such mixtures may e.g. be in the range of from 60:40 to 40:60 or from 10:90 to 40:60 or from 90:10 to 60:40. It is preferred that the amorphous form is only pre- sent in such mixtures in minor amounts, e.g. in an amount of less than 10 wt.-% or less than 5 wt.-% based on the total weight of the mixture, or not contained in the mixtures at all.
  • the present invention relates to the use of a mixture of crystalline form B and crystalline form A and/or the amorphous form of compound I as a pesticide for controlling invertebrate pests, in particular insects, acarids or nematodes.
  • the present invention relates to a method of contacting the invertebrate pests, in particular insects, acarids or nematodes, or their food supply, habitat, breeding grounds or their locus with a pesti- cidally effective amount of a mixture of crystalline form B, crystalline form A and/or the amor- phous form of compound I.
  • the crystalline form B and mixtures thereof with crystalline form A and/or the amorphous form of compound I are particularly suitable for efficiently controlling arthropodal pests such as arach- nids, myriapedes and insects as well as nematodes. Specific pests are listed, e.g., in
  • crystalline form B of compound I should be suitable for efficiently controlling the same pests as disclosed for the amorphous form and crystalline form A of compound I. How- ever, due to different physicochemical characteristics, and a potentially higher bioavailability re- sulting thereof, crystalline form B should provide for certain advantages when being used for controlling invertebrate pests. Ideally, a better pesticidal effect can be shown for crystalline form B.
  • the crystalline form B or a mixture thereof with crystalline form A and/or the amorphous form of compound I as defined above can be converted into customary formulations, for example solu- tions, emulsions, suspensions, dusts, powders, pastes and granules.
  • customary formulations for example solu- tions, emulsions, suspensions, dusts, powders, pastes and granules.
  • the use depends on the particular intended purpose; in each case, it should ensure a fine and even distribution of the mixtures according to the invention.
  • Form B may allow for easier formulation, due to its physico- chemical characteristics.
  • the invention also relates to agrochemical compositions comprising at least one auxil- iary and crystalline form B or a mixture thereof with crystalline form A and/or the amorphous form of compound I as defined above.
  • the common formulation details are e.g. provided in WO2015/055752, WO2015/055755 or WO2018011056 in the context of mixtures of compound I.
  • organic solvents are understood to be the organic solvents known to the person skilled in the art.
  • the solvents may be a polar pro- tic solvents, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, ethyl acetate and butyl acetate, and is preferably ethanole or acetone.
  • the solvent may be a pure solvent or a mixture of solvents.
  • the solvent or the solvent mixture comprises maximum 50vol% water, preferably maximum 30vol% water, preferably maximum 25 vol% water, preferably less than 10 vol% wa- ter, preferably less than 5vol% water.
  • the solvent comprises at least one water miscible solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, acetone, methanol, ethanole, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, butanone, dimethylformamide, dimethylacetam- ide, N-methyl-2-pyrrolidone and dimethyl sulfoxide.
  • water miscible solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, acetone, methanol, ethanole, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, butanone, dimethylformamide, dimethylacetam- ide, N-methyl-2-pyrrolidone and dimethyl sulfoxide.
  • polymorph B is more stable than form A.
  • the present description relates to a process (B-1 ) for con- verting the crystalline form A as described herein into a crystalline form B of broflanilide as de- scribed herein,
  • insectsAs described herein means that the respective form is identified and identifiable by the charac- teristics as described in the present description, e.g. the reflexes in the X-ray powder diffracto- gram at 25°C and Cu-K radiation, preferably the presence of a certain number of characteristic reflexes.
  • the conversion in step (b) is preferably at least 99% con- version, preferably at least 95% conversion, preferably at least 90% conversion, preferably at least 80% conversion.
  • the present description relates to the process (B-1-1 ), which is the abovementioned process (B-1), wherein in step (b) no seeding crystal of form B is added.
  • the present description relates to the process (B-1 -2), which is the abovementioned process (B-1 ), wherein in step (b) at least one seeding crystal of form B is added.
  • At least one seeding crystal which is obtained as described above, needs to be added (process B-1 -2).
  • the present description relates to a process (B-2) for converting the crystalline form A as described herein into a crystalline form B of broflanilide as described herein,
  • step (c) causing crystallization by evaporating the solvent from the solution at the temperature given in step (b) and/or cooling the solution, at a suitable cooling or evaporation rate;
  • the present description relates to the process (B-2-1 ), which is the abovementioned process (B-2), wherein in step (b) no seeding crystal of form B is added.
  • the present description relates to the process (B-2-2), which is the abovementioned process (B-2), wherein in step (b) at least one seeding crystal of form B is added.
  • the seeding crystals of form B can be obtained as described above. Slurry equilibration experiments were performed at 80°C and gave the following results:
  • polymorph A is more stable than form B.
  • the present description relates to a process (A-1 ) for con- verting the crystalline form B, as described above, into a crystalline form A of broflanilide, as de- scribed above, the process comprising the steps of
  • form A of broflanilide can be characterized by an X-ray powder diffracto- gram at 25°C and Cu-K radiation, which shows at least four of the twelve following reflexes, given as °2Q values: 11.5 ⁇ 0.2, 13.4 ⁇ 0.2, 16.4 ⁇ 0.2, 17.4 ⁇ 0.2, 19.3 ⁇ 0.2, 19.9 ⁇ 0.2, 20.2 ⁇ 0.2, 20.5 ⁇ 0.2, 22.2 ⁇ 0.2, 22.7 ⁇ 0.2, 24.0 ⁇ 0.2, 28.6 ⁇ 0.2 and 31.2 ⁇ 0.2.
  • the conversion in step (b) is preferably at least 99% con- version, preferably at least 95% conversion, preferably at least 90% conversion, preferably at least 80% conversion.
  • the present description relates to the process (A- 1 - 1 ) , which is the abovementioned process (A-1), wherein in step (b) no seeding crystal of form A is added.
  • the present description relates to the process (A-1 -2), which is the abovementioned process (A-1 ), wherein in step (b) at least one seeding crystal of form A is added.
  • Seeding crystals of form A can be obtained analogously as described above for form B, e.g. by processes of type (A-1-1 ), or as described in Example 4.
  • the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is suspended in the solvent in a concentration of gram crystalline form B to gram solvent from 0.05 g/g to 1.0 g/g, preferably 0.1 g/g to 1.0 g/g.
  • the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is provided in chemically pure form.
  • the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is provided as a mixture with the crystalline form A.
  • the embodiment relates to a process as described above, wherein, in step (a), the solvent is a polar protic solvent, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xy- lene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, ethyl acetate and butyl acetate, and is preferably ethanole or acetone.
  • the solvent is a polar protic solvent, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xy- lene, diethyl ether, diisopropyl ether, methyl tert-butyl ether,
  • the embodiment relates to a process as described above, wherein, in step (a), the solvent comprises maximum 50vol% water, preferably maximum 30vol% water, preferably maxi- mum 25 vol% water, preferably less than 10 vol% water, preferably less than 5vol% water; especially the process as described above, wherein the solvent comprises at least one water miscible solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, ac- etone, methanol, ethanol, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, butanone, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide.
  • the solvent comprises maximum 50vol% water, preferably maximum 30vol% water, preferably maxi- mum 25 vol% water, preferably less than 10 vol% water, preferably less than 5vol% water; especially the process as described above, wherein
  • the embodiment relates to a process as described above, wherein step (b) is per- formed for a duration time, which is sufficient for a complete conversion of form B into form A.
  • the embodiment relates to a process as described above, wherein step (b) is per- formed for a duration time of at least 10 minutes, preferably at least one hour, more preferably at least 1 day, most preferably from 1 day to 10 days.
  • the present description relates to a process (A-2) for converting the crystalline form B as described herein into a crystalline form A of broflanilide as described herein,
  • Form A and form B were subjected to bead milling separately and analyzed afterwards. No con- version had taken place, i.e. form A turned out as form A after bead milling, and form B turned out as form B after bead milling.

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Abstract

The present invention relates to crystalline forms of the insecticide broflanilide (compound I), in particular to a crystalline form B, and to different processes for converting said crystalline form B into a crystalline form A or vice versa.

Description

Crystalline forms of broflanilide
The present invention relates to crystalline forms of the insecticide broflanilide, in particular to a crystalline form B, and to different processes for converting said crystalline form B into a crystal- line form A or vice versa.
The compound broflanilide [3-(benzoylmethylamino)-N-[2-bromo-4-[1 ,2,2,2-tetrafluoro- 1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide] belongs to the class of carboxamide insecticides. The compound is depicted below, and will be referred to as broflani- lide or compound I in the following.
Figure imgf000002_0001
Compound I
Compound I is described in W02010/018714. Preparation of compound I can be accomplished according to standard methods of organic chemistry, e.g. by the methods or working examples described in WO2010/018857 or WO2017/104838, without being limited to the routes given therein. Depending on the process and re-crystallization procedures, compound I can be ob- tained as an amorphous substance or a crystalline substance. The prior art does not describe if the obtained form is present in a defined crystal form, or which crystal characteristics this form has.
By the conversion experiments of the present invention, it has been found that broflanilide may exist in three different crystalline modifications.
• Form A: monoclinic crystalline form of broflanilide
• Form B: triclinic crystalline form of broflanilide.
• Form C: metastable form of broflanilide.
Form A and form B can be converted into each other under defined conditions. Single crystal structures of both forms were obtained by X-ray analysis, which showed that the two forms A and B differ from each other by the conformation of the central NH-aryl bond. Thus, form A and form B can be regarded as conformational polymorphs, differing on the bond conformation.
Form A has the following characteristics:
monoclinic;
melting peak 159°C;
DSC curve as shown in Figure 5: onset 153°C, peak 159°C
X-ray powder diffractogram of crystalline form A (Figure 1 ) with the following peaks: 11.5 ± 0.2, 13.4 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 24.0 ± 0.2, 28.6 ± 0.2 and 31 .2 ± 0.2 (Cu Ka radiation, in °20). Most prominent peaks are 1 1.5 ± 0.2, 13.4 ± 0.2„ 17.4 ± 0.2, 20.2 ± 0.2, 22.2 ± 0.2 and 31 .2 ± 0.2 (Cu Ka radiation, in °20 )
Details of crystal structure of Form A:
Figure imgf000003_0001
Therefore, in embodiment A, the present description relates to a crystalline form A of broflani- lide. In particular, it relates to the following embodiments:
A1 . A crystalline form A of broflanilide, which, in an X-ray powder diffractogram at 25°C and Cu- K radiation, shows at least four of the twelve following reflexes, given as °20 values:
1 1.5 ± 0.2, 13.4 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 24.0 ± 0.2, 28.6 ± 0.2 and 31 .2 ± 0.2.
A2. The crystalline form A according to embodiment A1 , which, in an X-ray powder diffracto- gram at 25°C and Cu-Ka radiation, shows at least six of the twelve following reflexes, given as °20 values: 1 1 .5 ± 0.2, 13.4 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 24.0 ± 0.2, 28.6 ± 0.2 and 31 .2 ± 0.2, and preferably shows at least the following six reflexes, given as °20 values: 1 1.5 ± 0.2, 13.4 ± 0.2,, 17.4 ± 0.2, 20.2 ± 0.2, 22.2 ± 0.2 and 31 .2 ± 0.2.
A3. The crystalline form A according to embodiment A1 or A2, which, in a DSC curve measured by a differential scanning calorimeter at a scan rate of 10°C per minute, exhibits an endo- thermic peak with an onset temperature in the range of 150 to 156 °C and/or a peak tem- perature in the range of 157 to 161 °C.
Form B has the following characteristics:
triclinic;
melting peak 145°C;
DSC curve as shown in Figure 6: onset 142°C, peak 145°C X-ray powder diffractogram of crystalline form B (Figure 2) with the following peaks: 1 1 .5 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2, 21 .3 ± 0.2, 21 .8 ± 0.2, 22.3 ± 0.2, 23.4 ± 0.2, 25.2 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2, 29.4 ± 0.2, 29.8 ± 0.2 and 31 .1 ± 0.2. Most prominent peaks to distinguish from form I are 15.5 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 21 .3 ± 0.2, 21.8 ± 0.2, 23.4 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2 and 29.4 ± 0.2.
The diffractogram peak pattern of form A and form B is quite similar. However, there are a few peaks that are more prominent in form B. In particular, the main peaks to distinguish form B from form A are the following peaks in form B: 15.5 ± 0.2, 18.5 ± 0.2, 21 .8 ± 0.2.
Details of crystal structure of Form B:
Figure imgf000004_0001
Therefore, in embodiment B, the present description relates to a crystalline form B of broflani- lide. In particular, it relates to the following embodiments:
B1 . A crystalline form B of broflanilide, which, in an X-ray powder diffractogram at 25°C and Cu- K radiation, shows at least four of the seventeen following reflexes, given as °20 values: 1 1.5 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2, 21 .3 ± 0.2,
21.8 ± 0.2, 22.3 ± 0.2, 23.4 ± 0.2, 25.2 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2, 29.4 ± 0.2, 29.8 ± 0.2 and 31 .1 ± 0.2T preferably at least four of the nine following reflexes: 15.5 ± 0.2, 18.5 ± 0.2,
19.7 ± 0.2, 21 .3 ± 0.2, 21 .8 ± 0.2, 23.4 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2 and 29.4 ± 0.2.
B2. The crystalline form B according to embodiment B1 , which, in an X-ray powder diffracto- gram at 25°C and Cu-K radiation, shows at least six of the seventeen following reflexes, given as °20 values: 1 1 .5 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2, 21 .3 ± 0.2, 21 .8 ± 0.2, 22.3 ± 0.2, 23.4 ± 0.2, 25.2 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2, 29.4 ± 0.2, 29.8 ± 0.2 and 31 .1 ± 0.2, and preferably shows at least the following nine re- flexes, given as °20 values: 15.5 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 21 .3 ± 0.2, 21 .8 ± 0.2, 23.4 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2 and 29.4 ± 0.2. B3. The crystalline form B according to embodiment B1 or B2, which, in a DSC curve measured by a differential scanning calorimeter at a scan rate of 10°C per minute, exhibits an endo- thermic peak with an onset temperature in the range of 140 to 143°C and/or a peak temper- ature in the range of 144 to 148°C.
The crystalline forms A and B of compound I are advantageous in terms of storability and trans- portability. Furthermore, crystalline forms A and B are advantageous for the use against inverte- brate pests because, although they have a low solubility in water, they can effectively be applied as an aqueous suspension concentrate. The crystalline forms can show differing physicochemi- cal characteristics, higher bulk density (which is advantageous e.g. in terms of transportability of the technical ai), a different (preferably better) pesticidal activity, or activity in formulation, or speed of action, less toxicity to beneficial organisms, stability as technical ai, stability in formula- tion, rainfastness, or other parameters relevant for pesticides.
Given that different crystalline forms of a compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behaviour, flow properties and/or solid state stability, there remains an interest to find crystalline forms of compound I, which may be advantageous in terms of some of the above listed properties, e.g. in terms of the solubility.
On the other hand, if storability and transportability of compound I come into focus, it may be re- quired to be able to convert such crystalline forms into a desired crystalline form, e.g. crystalline form A, in an energy-saving and cost-efficient manner. Furthermore, it may be required to achieve conversion within short duration times.
In the context of the present invention, the terms, which are used, are each defined as follows: The ability of a substance to exist in more than one crystalline form is generally referred to as polymorphism and the different“crystalline forms” are also named“polymorphs” and may be characterized by certain analytical properties such as their X-ray powder diffraction (XRPD) pat- terns or their DSC curves measured by a differential scanning calorimeter. Preferably, the crys- talline forms, which are described herein, are essentially free from solvent, which means that the crystalline forms comprise no detectable amounts of solvents incorporated into the crystal lattice, i.e. in the 3-dimensional crystal lattice, wherein the molecules are positioned. In particu- lar, the amount of solvent in the crystal lattice is less than 10 mol%, preferably less than 5 mol%, more preferably less than 1 mol% based on compound I.
X-ray powder diffraction (XRPD) data as provided herein can be obtained using a Panalytical X’pert Pro diffractometer (manufacturer: Panalytical) in reflection geometry in the range of °2Q = 3°-35° with increments of 0.0167° using Cu-K radiation (at 25°C). The intensity of the reflexes is typically plotted versus the °20 angle to obtain a diffractogram. Such a diffractogram typically shows at least 2, preferably at least 4, more preferably at least 6, still more preferably at least 7, particularly preferably at least 10 reflexes. The skilled person will understand that the °20 val- ues, which can be determined from the diffractogram and which are provided herein, often rep- resent approximate values within an error margin in the range of from 0.1 to 0.4, preferably from 0.1 to 0.2. Thus, a °20 value of, e.g., 7.01 may be understood as a °20 value of 7.01 ±0.2, pref- erably 7.01 ±0.1 , more preferably 7.01 ±0.05, particularly preferably exactly 7.01.
DSC curves as provided herein can be obtained using a differential scanning calorimeter (e.g. a Mettler Toledo DSC 823e module) at a scan rate of 10°C per minute, wherein the sample is heated in crimped aluminum pans. The heat flux is then plotted versus the temperature. The ex- othermic and endothermic peaks, which can be measured, represent, e.g., crystallization or re- crystallization processes (exothermic) or melting processes (endothermic). The peaks are typi- cally defined by their onset temperature, i.e. the temperature, at which an exothermic or endo- thermic process begins, and their peak temperature, i.e. the temperature at the peak maximum or minimum.
Mixtures of two crystalline forms may be identified by comparing the recorded °2Q values and DSC curves with the respective data of both crystalline forms alone. If the diffractogram shows characteristic reflexes of both crystalline forms, it can be concluded that a mixture of the two crystalline forms is present.
The term“complete conversion” means that at least 90 wt.-%, preferably at least 95 wt.-%, more preferably at least 98 wt.-%, most preferably at least 99 wt.-%, based on the total weight of the crystalline form with which the conversion process was started (e.g. form B), is converted into the target crystalline form (e.g. form A). Particularly preferably,“complete conversion” means that crystalline form B is quantitatively converted into crystalline form A, respectively that crystal- line form A is quantitatively converted into crystalline form B.
As used herein, the term“chemically pure” means that a substance, e.g. compound I or a crys- talline form thereof or the amorphous form thereof or any mixture thereof, is provided in a purity of at least 95%, preferably at least 97%, more preferably at least 98%, most preferably at least 99%, wherein the percent values refer to the substance weight based on the total weight of the substance together with any impurities. The chemical purity of compound I may be determined by NMR, quantitative HPLC and the like.
As used herein, the term“organic solvent” includes any organic solvent including aprotic and protic solvents, unpolar and polar solvents, water-immiscible and water-miscible solvents, aro- matic and non-aromatic solvents, and mixtures thereof. Preferred organic solvents according to the present invention or specific embodiments are given in the present description and claims. Mixtures of aqueous solvents and organic solvents may be biphasic solvent systems or mo- nophasic solvent systems depending on the miscibility of the solvents. Preferred solvent mix- tures according to the present invention will be listed below.
Accordingly, the present invention also relates in one embodiment to the use of crystalline form B of compound I as a pesticide for controlling invertebrate pests. In another embodiment, the present invention relates to the use of crystalline form B of compound I for combating insects, acarids or nematodes. Furthermore, the present invention relates in one embodiment to a method of contacting the invertebrate pests, in particular insects, acarids or nematodes, or their food supply, habitat, breeding grounds or their locus with a pesticidally effective amount of crys- talline form B of compound I.
In certain situations, it can be advantageous to provide mixtures of crystalline form B and crys- talline form A and/or the amorphous form of compound I. Preferred weight ratios of crystalline form B to crystalline form A in such mixtures may e.g. be in the range of from 60:40 to 40:60 or from 10:90 to 40:60 or from 90:10 to 60:40. It is preferred that the amorphous form is only pre- sent in such mixtures in minor amounts, e.g. in an amount of less than 10 wt.-% or less than 5 wt.-% based on the total weight of the mixture, or not contained in the mixtures at all.
In another embodiment, the present invention relates to the use of a mixture of crystalline form B and crystalline form A and/or the amorphous form of compound I as a pesticide for controlling invertebrate pests, in particular insects, acarids or nematodes. In yet another embodiment, the present invention relates to a method of contacting the invertebrate pests, in particular insects, acarids or nematodes, or their food supply, habitat, breeding grounds or their locus with a pesti- cidally effective amount of a mixture of crystalline form B, crystalline form A and/or the amor- phous form of compound I.
The crystalline form B and mixtures thereof with crystalline form A and/or the amorphous form of compound I are particularly suitable for efficiently controlling arthropodal pests such as arach- nids, myriapedes and insects as well as nematodes. Specific pests are listed, e.g., in
WO2015/055752, WO2015/055755 or WO2018011056 in the context of mixtures of compound I. In principal, crystalline form B of compound I should be suitable for efficiently controlling the same pests as disclosed for the amorphous form and crystalline form A of compound I. How- ever, due to different physicochemical characteristics, and a potentially higher bioavailability re- sulting thereof, crystalline form B should provide for certain advantages when being used for controlling invertebrate pests. Ideally, a better pesticidal effect can be shown for crystalline form B.
Further, it is convenient to have reactions from form A to form B and vice versa, so that the de- sired form can be obtained in a customized manner, according to needs. This may be also a fur- ther opportunity to purify compound I.
The crystalline form B or a mixture thereof with crystalline form A and/or the amorphous form of compound I as defined above can be converted into customary formulations, for example solu- tions, emulsions, suspensions, dusts, powders, pastes and granules. The use depends on the particular intended purpose; in each case, it should ensure a fine and even distribution of the mixtures according to the invention. Form B may allow for easier formulation, due to its physico- chemical characteristics.
Therefore the invention also relates to agrochemical compositions comprising at least one auxil- iary and crystalline form B or a mixture thereof with crystalline form A and/or the amorphous form of compound I as defined above. The common formulation details are e.g. provided in WO2015/055752, WO2015/055755 or WO2018011056 in the context of mixtures of compound I.
If, in the present description, organic solvents are mentioned, these solvents are understood to be the organic solvents known to the person skilled in the art. The solvents may be a polar pro- tic solvents, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, ethyl acetate and butyl acetate, and is preferably ethanole or acetone.
The solvent may be a pure solvent or a mixture of solvents. Preferably, the solvent or the solvent mixture comprises maximum 50vol% water, preferably maximum 30vol% water, preferably maximum 25 vol% water, preferably less than 10 vol% wa- ter, preferably less than 5vol% water.
Preferably, the solvent comprises at least one water miscible solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, acetone, methanol, ethanole, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, butanone, dimethylformamide, dimethylacetam- ide, N-methyl-2-pyrrolidone and dimethyl sulfoxide.
Slurry equilibration experiments were performed at room temperature (20 to 25°C) and gave the following results:
Figure imgf000008_0001
Apart from water as solvent, the experiments result in form B. Without being bound to theory, it seems that due to the low water solubility, there is not enough time for equilibration, which ex- plains that the conversion of form A to form B does not take place readily.
As a conclusion, it can be said that at room temperatue, polymorph B is more stable than form A.
Therefore, in a further embodiment, the present description relates to a process (B-1 ) for con- verting the crystalline form A as described herein into a crystalline form B of broflanilide as de- scribed herein,
the process (B-1 ) comprising the steps of
(a) forming a suspension of the crystalline form A as described herein in an organic solvent or mixtures of organic solvents mixtures thereof, optionally comprising water but not more than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; if heating is needed, not heating to more than 40°; and
(b) stirring or shaking the suspension at a temperature of maximum 40°C, preferably maximum 30°C, preferably between 0 and 30°C, for a duration time, which is sufficient for a complete conversion of form A into form B;
optionally with addition of at least one seeding crystal of form B. „As described herein" means that the respective form is identified and identifiable by the charac- teristics as described in the present description, e.g. the reflexes in the X-ray powder diffracto- gram at 25°C and Cu-K radiation, preferably the presence of a certain number of characteristic reflexes.
In one embodiment of process (B-1 ), the conversion in step (b) is preferably at least 99% con- version, preferably at least 95% conversion, preferably at least 90% conversion, preferably at least 80% conversion.
In a further embodiment, the present description relates to the process (B-1-1 ), which is the abovementioned process (B-1), wherein in step (b) no seeding crystal of form B is added.
In a further embodiment, the present description relates to the process (B-1 -2), which is the abovementioned process (B-1 ), wherein in step (b) at least one seeding crystal of form B is added.
It is well-known that from a suspension or a solution of compound I in some solvents or solvent mixtures, the desired crystal form can easily crystallize as such. By these reactions, seeding crystals can be obtained. For example, seeding crystals of form B can be obtained as described in Example 1. Therefore, these reactions can be used for a conversion at a preparative scale, or for obtaining seed crystals at a smaller scale, or both.
In solvents or solvent mixtures, where the desired crystal form does not readily form, at least one seeding crystal, which is obtained as described above, needs to be added (process B-1 -2).
In a further embodiment, the present description relates to a process (B-2) for converting the crystalline form A as described herein into a crystalline form B of broflanilide as described herein,
the process comprising the steps of
(a) forming a solution of the crystalline form A as described herein in a solvent selected from organic solvents and mixtures thereof, comprising not more water than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; if heating is needed, not heating to more than 40°; and
(b) keeping the solution at a temperature of maximum 40°C, preferably maximum 30°C, prefer- ably between 0 and 30°C; and
(c) causing crystallization by evaporating the solvent from the solution at the temperature given in step (b) and/or cooling the solution, at a suitable cooling or evaporation rate;
optionally with addition of at least one seeding crystal of form B.
In a further embodiment, the present description relates to the process (B-2-1 ), which is the abovementioned process (B-2), wherein in step (b) no seeding crystal of form B is added.
In a further embodiment, the present description relates to the process (B-2-2), which is the abovementioned process (B-2), wherein in step (b) at least one seeding crystal of form B is added.
The seeding crystals of form B can be obtained as described above. Slurry equilibration experiments were performed at 80°C and gave the following results:
Figure imgf000010_0001
Apart from water as solvent, the experiments result in form A. Without being bound to theory, it seems that due to the low water solubility, there is not enough time for equilibration, which ex- plains that the conversion of form B to form A does not take place readily.
As a conclusion, it can be said that at 80°C, polymorph A is more stable than form B.
Therefore, in a further embodiment, the present description relates to a process (A-1 ) for con- verting the crystalline form B, as described above, into a crystalline form A of broflanilide, as de- scribed above, the process comprising the steps of
(a) forming a suspension of the crystalline form B according to any one of claims 1 to 3 in an organic solvent or mixtures of organic solvents mixtures thereof, optionally comprising wa- ter but not more than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; and
(b) stirring or shaking the suspension at a temperature of at least 60°C, preferably at least 70° C, preferably at least 80°C, for a duration time, which is sufficient for a complete conversion of form B into form A;
optionally with addition of at least one seeding crystal of form A.
As described above, form A of broflanilide can be characterized by an X-ray powder diffracto- gram at 25°C and Cu-K radiation, which shows at least four of the twelve following reflexes, given as °2Q values: 11.5 ± 0.2, 13.4 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 24.0 ± 0.2, 28.6 ± 0.2 and 31.2 ± 0.2.
In one embodiment of process (A-1 ), the conversion in step (b) is preferably at least 99% con- version, preferably at least 95% conversion, preferably at least 90% conversion, preferably at least 80% conversion.
In a further embodiment, the present description relates to the process (A- 1 - 1 ) , which is the abovementioned process (A-1), wherein in step (b) no seeding crystal of form A is added.
In a further embodiment, the present description relates to the process (A-1 -2), which is the abovementioned process (A-1 ), wherein in step (b) at least one seeding crystal of form A is added. Seeding crystals of form A can be obtained analogously as described above for form B, e.g. by processes of type (A-1-1 ), or as described in Example 4.
Preferably, the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is suspended in the solvent in a concentration of gram crystalline form B to gram solvent from 0.05 g/g to 1.0 g/g, preferably 0.1 g/g to 1.0 g/g.
Preferably, the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is provided in chemically pure form.
Preferably, the embodiment relates to a process as described above, wherein, in step (a), the crystalline form B is provided as a mixture with the crystalline form A.
Preferably, the embodiment relates to a process as described above, wherein, in step (a), the solvent is a polar protic solvent, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xy- lene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, ethyl acetate and butyl acetate, and is preferably ethanole or acetone.
Preferably, the embodiment relates to a process as described above, wherein, in step (a), the solvent comprises maximum 50vol% water, preferably maximum 30vol% water, preferably maxi- mum 25 vol% water, preferably less than 10 vol% water, preferably less than 5vol% water; especially the process as described above, wherein the solvent comprises at least one water miscible solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, ac- etone, methanol, ethanol, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, butanone, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide.
Preferably, the embodiment relates to a process as described above, wherein step (b) is per- formed for a duration time, which is sufficient for a complete conversion of form B into form A. Preferably, the embodiment relates to a process as described above, wherein step (b) is per- formed for a duration time of at least 10 minutes, preferably at least one hour, more preferably at least 1 day, most preferably from 1 day to 10 days.
In a further embodiment, the present description relates to a process (A-2) for converting the crystalline form B as described herein into a crystalline form A of broflanilide as described herein,
the process comprising the steps of
(a) forming a solution of the crystalline form B as described herein in a solvent selected from organic solvents and mixtures thereof, comprising not more water than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; and
(b) keeping the solution at a temperature of at least 60°C, preferably at least 70°C, preferably at least 80°C; and
(c) causing crystallization by evaporating the solvent from the solution at the temperature given in step (b) and/or shock-cooling the solution,
optionally with addition of at least one seeding crystal of form A. Slurry equilibration experiments were performed at 50°C and gave the following results:
Figure imgf000012_0001
With water as solvent, the crystal form remains the same, as mentioned above for the experi- ments at room temperature respectively 80°C. For the remaining solvents, it is not distinguisha- ble on the basis of these experimental results, which form is more stable at 50°C. The two poly- morphs seem to have a similar stability.
Form A and form B were subjected to bead milling separately and analyzed afterwards. No con- version had taken place, i.e. form A turned out as form A after bead milling, and form B turned out as form B after bead milling.
Examples
The crystal forms A and B can be obtained, as described in the following examples:
Example 1 : Preparation of broflanilide crystal form B without seeding crystal
200 mg broflanilide was suspended in 3 ml. 1 ,2-dichlorobenze and stirred at 20-25°C using magnet stirring bar (650 rpm) for 32 days. The obtained crystals were of crystal form B, as de- termined by X-ray diffraction.
Example 2: Preparation of broflanilide crystal form B, using a seeding crystal
200 mg broflanilide was suspended in 3 ml. toluene and stirred at 20-25°C using magnet stirring bar (650 rpm) for 32 days when approx. 5 mg broflanilide crystal form B (as obtained in Exam- pie 1) was added. The X-ray powder diffractogram showed conversion to form B after 3 days. Example 3: Preparation of broflanilide crystal form B, from a solution using a seeding crystal Example 3.1 : Broflanilide is dissolved in methylenchloride, until a saturated solution is obtained. During evaporation, some seeding crystals of form B (as obtained in Example 1) is added. The obtained crystals are of crystal form B, as determined by X-ray diffraction.
Example 3.2: Broflanilide was dissolved in 1 ,2-dichlorobenzene or methyl-ethyl-ketone, until a saturated solution was obtained. The solvent was evaporated at room temperature using nitro- gen flow. The obtained crystals were of crystal form B, as determined by X-ray diffraction.
Example 4: Preparation of broflanilide crystal form A without seeding crystal
Broflanilide is suspended in 1 ,2-dichlorobenze and stirred at 80°C for 32 days. After quick cool- ing, the obtained crystals are of crystal form A, as determined by X-ray diffraction.
Example 5: Preparation of broflanilide crystal form A, using a seeding crystal
Example 5.1 : Broflanilide is suspended in toluene, and heated to 80°C. Some seeding crystals of form A (as obtained in Example 4) is added. The suspension is stirred at 80°C for 32 days. The obtained crystals are of crystal form A, as determined by X-ray diffraction.
Example 5.2: Broflanilide was suspended in acetone/water (1 :4), and heated to 80°C. Some seeding crystals of form A (as obtained in Example 4) were added. The suspension was stirred at 80°C for 9 days. The obtained crystals were of crystal form A, as determined by X-ray diffrac tion.
Example 6: Preparation of broflanilide crystal form A, from a solution using a seeding crystal Example 6.1 : Broflanilide is dissolved in toluene at 80°C, until a saturated solution is obtained. During evaporation, some seeding crystals of form A (as obtained in Example 4) is added. The obtained crystals are of crystal form A, as determined by X-ray diffraction.
Example 7: Preparation of broflanilide crystal form A, from a solution without seeding crystal Broflanilide was dissolved in solvent at 60°C, until a saturated solution is obtained. The solvent was evaporated at 60°C using nitrogen flow. The obtained crystals are of crystal form A, as de- termined by X-ray diffraction.
Solvents (one per experiment): acetonitrile, chlorobenzene, 1 ,2-dichlorobenzene, DMF, DMSO, acetic acid, ethanol, ethyl acetate, ethyl benzene, 2-propanol, methyl ethyl ketone, methanol, methyl isobutyl ketone, nitromethane, NMP, p-xylene, 1 -butanol, 1 ,4-dioxane, toluene

Claims

Claims:
1 . A crystalline form B of broflanilide, which, in an X-ray powder diffractogram at 25°C and Cu- K radiation, shows at least four of the seventeen following reflexes, given as °20 values:
1 1.5 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2, 21 .3 ± 0.2,
21.8 ± 0.2, 22.3 ± 0.2, 23.4 ± 0.2, 25.2 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2, 29.4 ± 0.2, 29.8 ± 0.2 and 31 .1 ± 0.2, preferably at least four of the nine following reflexes: 15.5 ± 0.2, 18.5 ± 0.2,
19.7 ± 0.2, 21 .3 ± 0.2, 21 .8 ± 0.2, 23.4 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2 and 29.4 ± 0.2.
2. The crystalline form B according to claim 1 , which, in an X-ray powder diffractogram at 25° C and Cu-Ka radiation, shows at least six of the seventeen following reflexes, given as °20 values: 1 1.5 ± 0.2, 13.4 ± 0.2, 15.5 ± 0.2, 17.4 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 20.1 ± 0.2,
21.3 ± 0.2, 21 .8 ± 0.2, 22.3 ± 0.2, 23.4 ± 0.2, 25.2 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2, 29.4 ± 0.2,
29.8 ± 0.2 and 31 .1 ± 0.2, and preferably shows at least the following nine reflexes, given as °20 values: 15.5 ± 0.2, 18.5 ± 0.2, 19.7 ± 0.2, 21.3 ± 0.2, 21 .8 ± 0.2, 23.4 ± 0.2, 25.7 ± 0.2, 27.7 ± 0.2 and 29.4 ± 0.2, and preferably shows at least the following three reflexes:
15.5 ± 0.2, 18.5 ± 0.2, 21 .8 ± 0.2.
3. The crystalline form B according to claim 1 or 2, which, in a DSC curve measured by a dif- ferential scanning calorimeter at a scan rate of 10°C per minute, exhibits an endothermic peak with an onset temperature in the range of 140 to 143°C and/or a peak temperature in the range of 144 to 148°C.
4. A process (A-1 ) for converting the crystalline form B of any of claims 1 to 3 into a crystalline form A of broflanilide, which, in an X-ray powder diffractogram at 25°C and Cu-K radiation, shows at least four of the twelve following reflexes, given as °20 values: 1 1.5 ± 0.2, 13.4 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 19.3 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 24.0 ± 0.2, 28.6 ± 0.2 and 31 .2 ± 0.2,
the process comprising the steps of
(a) forming a suspension of the crystalline form B according to any one of claims 1 to 3 in an organic solvent or mixtures of organic solvents mixtures thereof, optionally compris- ing water but not more than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%;; and
(b) stirring or shaking the suspension at a temperature of at least 60°C, preferably at least 70°C, preferably at least 80°C, for a duration time, which is sufficient for a complete conversion of form B into form A;
optionally with addition of at least one seeding crystal of form A.
5. The process according to claim 4, wherein, in step (a), the crystalline form B is suspended in the solvent in a concentration of gram crystalline form B to gram solvent from 0.05 g/g to 1 .0 g/g, preferably 0.1 g/g to 1.0 g/g.
6. The process according to claim 4 or 5, wherein, in step (a), the crystalline form B is pro- vided in chemically pure form.
7. The process according to any one of claims 4 to 6, wherein, in step (a), the crystalline form B is provided as a mixture with the crystalline form A.
8. The process according to any one of claims 4 to 7, wherein, in step (a), the solvent is a po- lar protic solvent, preferably C2-C6-alkylalcohol, preferably ethanole, or an aprotic organic solvent, preferably an aprotic solvent selected from the group consisting of toluene, xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, acetonitrile, acetone, ethyl acetate and butyl acetate, and is preferably ethanole or acetone.
9. The process according to any one of claims 4 to 8, wherein, in step (a), the solvent corn- prises maximum 50vol% water, preferably maximum 30vol% water, preferably maximum 25 vol% water, preferably less than 10 vol% water, preferably less than 5vol% water.
10. The process according to claim 9, wherein the solvent comprises at least one water misci- ble solvent selected from the group consisting of tetrahydrofuran, acetonitrile, dioxane, ace- tone, methanol, ethanol, n-propanol, isopropanol, tert-butanol or 2-methylbutan-2-ol, buta- none, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and dimethyl sulfox- ide.
1 1. The process according to any one of claims 4 to 10, wherein step (b) is performed for a du- ration time, which is sufficient for a complete conversion of form B into form A.
12. The process according to any one of claims 4 to 11 , wherein step (b) is performed for a du- ration time of at least 10 minutes, preferably at least one hour, more preferably at least 1 day, most preferably from 1 day to 10 days.
13. A process (A-2) for converting the crystalline form B of any of claims 1 to 3 into a crystalline form A of broflanilide as described in claim 4,
the process comprising the steps of
(a) forming a solution of the crystalline form B according to any one of claims 1 to 3 in a solvent selected from organic solvents and mixtures thereof, comprising not more wa- ter than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; and
(b) keeping the solution at a temperature of at least 60°C, preferably at least 70°C, prefer- ably at least 80°C; for a duration time, which is sufficient for a complete conversion of form B into form A; and
(c) causing crystallization by evaporating the solvent from the solution at the temperature given in step (b) and/or shock-cooling the solution,
optionally with addition of at least one seeding crystal of form A.
14. A process (B-1 ) for converting the crystalline form A as described in claim 4 into a crystal- line form B of broflanilide as described in any of claims 1 to 3,
the process comprising the steps of
(a) forming a suspension of the crystalline form A as described in claim 4 in an organic sol- vent or mixtures of organic solvents mixtures thereof, optionally comprising water but not more than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; if heating is needed, not heating to more than 40°; and
(b) stirring or shaking the suspension at a temperature of maximum 40°C, preferably maxi- mum 30°C, preferably between 0 and 30°C, for a duration time, which is sufficient for a complete conversion of form A into form B;
optionally with addition of at least one seeding crystal of form B.
15. A process (B-2) for converting the crystalline form A as described in claim 4 into a crystal- line form B of broflanilide as described in any of claims 1 to 3,
the process comprising the steps of
(a) forming a solution of the crystalline form A as described in claim 4 in a solvent selected from organic solvents and mixtures thereof, comprising not more water than 50vol%, preferably not more than 25 vol%, preferably not more than 10 vol%, preferably not more than 5 vol%; if heating is needed, not heating to more than 40°; and
(b) keeping the solution at a temperature of maximum 40°C, preferably maximum 30°C, preferably between 0 and 30°C; and
(c) causing crystallization by evaporating the solvent from the solution at the temperature given in step (b) and/or cooling the solution, at a suitable cooling or evaporation rate; optionally with addition of at least one seeding crystal of form B.
PCT/EP2019/052834 2018-02-13 2019-02-06 Crystalline forms of broflanilide WO2019158408A1 (en)

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