Patent Application
20110053997
This invention relates to salts of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, polymorphs of the salts and methods of their preparation.
(R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihythoimidazole-2-thione hydrochloride (the compound of formula I, below) is a potent, non-toxic and peripherally selective inhibitor of DβM, which can be used for treatment of certain cardiovascular disorders. It is disclosed in WO2004/033447, along with processes for its preparation.
The process disclosed in WO2004/033447 for preparing compound 1 (see example 16) results in the amorphous form of compound 1. The process of example 16 is described in WO2004/033447 on page 5, lines 16 to 21 and in Scheme 2 on page 7. Prior to formation of compound 1, a mixture of intermediates is formed (compounds V and VI in scheme 2). The mixture of intermediates is subjected to a high concentration of HCl in ethyl acetate. Under these conditions, the primary product of the reaction is compound I, which precipitates as it forms as the amorphous form.
WO2007/139413 discloses polymorphic forms of compound 1.
The compounds disclosed in WO2004/033447 may exhibit advantageous properties. The polymorphs disclosed in WO2007/139413 may also exhibit advantageous properties. For example, the products may be advantageous in terms of their ease of production, for example easier filterability or drying. The products may be easy to store. The products may have increased processability. The products may be produced in high yield and/or high purity. The products may be advantageous in terms of their physical characteristics, such as solubility, melting point, hardness, density, hygroscopicity, stability, compatibility with excipients when formulated as a pharmaceutical. Furthermore, the products may have physiological advantages, for example they may exhibit high bioavailability.
We have now found certain new and advantageous salts of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione and new and advantageous polymorphs thereof.
Accordingly, the present invention provides salts of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, other than the hydrochloride salt, and crystalline polymorphs of the salts. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione has the following structure and is hereinafter referred to as compound 2.
The present invention provides salts of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione other than the hydrochloride salt. In particular, the present invention provides the following acid addition salts of compound 2: L-tartaric, malonic, toluenesulfonic, camphorsulfonic, fumaric, acetic, adipic, glutaric, glycolic, L-malic, citric, gentisic, maleic, hydrobromide, succinic, phosphoric and sulfuric. Each of the salts was found to exist in at least one crystalline polymorphic form and the present invention provides the characterisation of each of the forms.
Unless otherwise stated, all peak positions expressed in units of °2θ are subject to a margin of ±0.2 °2θ.
In the following description of the present invention, the polymorphic forms are described as having an XRPD pattern with peaks at the positions listed in the respective Tables. It is to be understood that, in one embodiment, the polymorphic form has an XRPD pattern with peaks at the °2θ positions listed±0.2 °2θ with any intensity (% (I/Io)) value; or in another embodiment, an XRPD pattern with peaks at the °2θ positions listed±0.1 °2θ. It is to be noted that the intensity values are included for information only and the definition of each of the peaks is not to be construed as being limited to particular intensity values.
According to one aspect of the present invention, there is provided the L-tartaric acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate.
In an embodiment, there is provided (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate in amorphous form.
In an embodiment, the amorphous form of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate has an XRPD as shown in
In another embodiment, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate.
Form A may be characterised as having an XRPD pattern with peaks at 4.7, 6.0, 10.5, 11.5 and 14.0 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.4, 17.6 and 19.1 °2θ±0.2 °2θ. Form A may be characterised as having an absence of XRPD peaks between 6.5 and 10.0 °2θ.
In an embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 1 below.
In another embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 2 below.
In yet another embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 3 below.
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate has the XRPD pattern as shown in
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate has the XRPD pattern as shown in
In another embodiment, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate.
Form B may be characterised as having an XRPD pattern with peaks at 5.4, 9.0 and 13.7 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.7 and 20.6 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 11.7, 13.1 and 14.9 °2θ±0.2°θ.
In an embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 4 below.
In another embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 5 below.
In yet another embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 6 below.
In an embodiment, Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-tartrate has the XRPD pattern as shown in
In another embodiment, Form B is characterised as being in the form of a solvate of tetrahydrofuran (THF). The number of moles of tetrahydrofuran per mole of Form B may range from 0.4 to 0.9. Typically, the number of moles ranges from 0.5 to 0.8. In an embodiment, there is 0.7 mole of THF per 1 mole of Form B.
According to another aspect of the present invention, there is provided the malonic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malonate.
In an embodiment, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malonate.
Form A may be characterised as having an XRPD pattern with peaks at 5.2, 12.1, 13.0, 13.6, 14.1 and 14.8 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 15.7 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 19.2 and 20.4 °2θ±0.2°θ.
In an embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 7 below.
In another embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 8 below.
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malonate has the XRPD pattern as shown in
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malonate has the XRPD pattern as shown in
Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malonate may also be characterised as having the DSC thermogram as shown in
According to another aspect of the present invention, there is provided the camphorsulfonic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione camphorsulfonate or camsylate.
In an embodiment, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione camsylate.
Form A may be characterised as having an XRPD pattern with a peak at 5.0 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 10.2 and 12.7 °2θ±0.2 °2θ. The XRPD pattern may have yet further peaks at 15.1, 15.6, 16.4, 16.7 and 17.4 °2θ±0.2 °2θ.
In an embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 9 below.
In another embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 10 below.
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione camsylate has the XRPD pattern as shown in
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione camsylate has the XRPD pattern as shown in
According to another aspect of the present invention, there is provided the fumaric acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione fumarate.
In an embodiment, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione fumarate.
Form A may be characterised as having an XRPD pattern with peaks at 12.5 and 14.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 13.3 and 13.7 °2θ±0.2 °2θ. The XRPD pattern may have yet further peaks at 15.8, 17.5, 22.5 and 23.6 °2θ±0.2 °2θ.
In an embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 11 below.
In another embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 12 below.
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione fumarate has the XRPD pattern as shown in
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione fumarate has the XRPD pattern as shown in
According to another aspect of the present invention, there is provided the toluenesulfonic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
In an embodiment, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Form A may be characterised as having an XRPD pattern with peaks at 7.3, 9.2 and 14.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 10.8, 13.8 and 14.9 °2θ±0.2 °2θ.
The XRPD pattern may have still further peaks at 16.1, 22.0 and 25.0 °2θ±0.2°θ.
In an embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 13 below.
In another embodiment, Form A has an XRPD pattern with peaks at the positions listed in Table 14 below.
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In another embodiment, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Form B may be characterised as having an XRPD pattern with peaks at 4.6, 8.3, 9.0 and 15.0 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.0 and 17.7 °2θ±0.2 °2θ.
In an embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 15 below.
In another embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 16 below.
In an embodiment, Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In an embodiment, Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate may also be characterised as having the DSC thermogram as shown in
In another embodiment, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate. Form C may be characterised as having an XRPD pattern with peaks at 11.8 and 12.1 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 4.8°2θ±0.2 °2θ. The XRPD pattern may have yet further peaks at 17.9, 19.2, 19.7 and 21.0 °2θ±0.2°θ.
In an embodiment, Form C has an XRPD pattern with peaks at the positions listed in Table 17 below.
In another embodiment, Form C has an XRPD pattern with peaks at the positions listed in Table 18 below.
In yet another embodiment, Form C has an XRPD pattern with peaks at the positions listed in Table 19 below.
In an embodiment, Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In an embodiment, Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate may be characterised as having the DSC thermogram as shown in
In another embodiment, Form C of the tosylate salt is characterised as being in the form of a solvate of isopropanol. The number of moles of isopropanol per mole of Form C may range from 0.5 to 2.0. Typically, the number of moles ranges from 0.8 to 1.5, more typically from 1 to 1.5. In an embodiment, there is 0.91 mole of isopropanol per 1 mole of Form C.
In another embodiment, there is provided crystalline Form E of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Form E may be characterised as having an XRPD pattern with a peak at 9.7 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 24.6 °2θ±0.2 °2θ. The XRPD pattern may have yet further peaks at 4.9 and 8.1 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 15.8 °2θ±0.2°θ. The XRPD pattern may have yet a further peak at 17.9 °2θ±0.2°θ.
In an embodiment, Form E has an XRPD pattern with peaks at the positions listed in Table 20 below.
In another embodiment, Form E has an XRPD pattern with peaks at the positions listed in Table 21 below.
In yet another embodiment, Form E has an XRPD pattern with peaks at the positions listed in Table 22 below.
In an embodiment, Form E of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In an embodiment, Form E of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
Form E of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate may also be characterised as having the DSC thermogram as shown in
In another embodiment, Form E of the tosylate salt is characterised as being in the form of a solvate of trifluoroethanol. The number of moles of trifluoroethanol per mole of Form E may range from 0.13 to 0.5. Typically, the number of moles ranges from 0.14 to 0.33. In an embodiment, there is 0.143 mole of trifluoroethanol per 1 mole of Form E.
In another embodiment, there is provided a crystal modification of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate. This crystal modification is hereinafter referred to as crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Crystal modification X may be characterised as having an XRPD pattern with peaks at 4.8 and 5.4 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.6, 16.7 and 25.0 °2θ±0.2 °2θ.
In an embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 23 below.
In another embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 24 below.
In an embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate the XRPD pattern as shown in
In an embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate the XRPD pattern as shown in
Crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate may also be characterised as having the DSC thermogram as shown in
In another embodiment, there is provided crystalline Form G of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Form G may be characterised as having an XRPD pattern with peaks at 3.6, 4.4, 5.3 and 14.2 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 7.1, 9.0 and 13.3 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 15.7 °2θ±0.2°θ.
In an embodiment, Form G has an XRPD pattern with peaks at the positions listed in Table 25 below.
In another embodiment, Form G has an XRPD pattern with peaks at the positions listed in Table 26 below.
In yet another embodiment, Form G has an XRPD pattern with peaks at the positions listed in Table 27 below.
In an embodiment, Form G of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In an embodiment, Form G of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In another embodiment, there is provided another crystal modification of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate. This crystal modification is hereinafter referred to as crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate.
Crystal modification Y may be characterised as having an XRPD pattern with peaks at 4.7 and 11.8 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 17.7, 19.2, 19.9 and 20.8 °2θ±0.2 °2θ.
In an embodiment, crystal modification Y has an XRPD pattern with peaks at the positions listed in Table 28 below.
In another embodiment, crystal modification Y has an XRPD pattern with peaks at the positions listed in Table 29 below.
In an embodiment, crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
In another embodiment, crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate has the XRPD pattern as shown in
Crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione tosylate may also be characterised as having the DSC thermogram as shown in
According to another aspect of the present invention, there is provided the acetic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione acetate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione acetate.
Form 1 may be characterised as having an XRPD pattern with peaks at 11.0 and 12.9 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.2, 16.2, 19.6, 21.0, 21.8 and 22.2 °2θ±0.2 °2θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 30 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 31 below.
In a further embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione acetate has the XRPD pattern as shown in
In a further embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione acetate has the XRPD pattern as shown in
Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione acetate may also be characterised as having a DSC thermogram as shown in
According to another aspect of the present invention, there is provided the adipic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione adipate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione adipate.
Form 1 may be characterised as having an XRPD pattern with a peak at 7.8 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 4.5, 12.6, 13.6 and 15.0 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 19.6 and 21.5 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 32 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 33 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 34 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione adipate has an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione adipate has an XRPD pattern as shown in
Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione adipate may also be characterised by having a DSC thermogram as shown in
According to another aspect of the present invention, there is provided the glutaric acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glutarate.
In an embodiment, there is provided Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glutarate.
Form 1 may be characterised as having an XRPD pattern with peaks at 4.4, 8.0, 10.7, 12.4, 13.6 and 14.2 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.5 and 16.1 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 19.1 and 19.8 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 35 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 36 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glutarate has the XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glutarate has the XRPD pattern as shown in
According to another aspect of the present invention, there is provided the succinic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate.
Form 1 may be characterised as having an XRPD pattern with peaks at 4.6, 8.1, and 12.7 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 9.0 °2θ±0.2 °2θ. The XRPD pattern may have yet a further peak at 14.0 °2θ±0.2 °2θ. The XRPD pattern may have yet further peaks at 15.7, 20.5 and 24.7 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 37 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 38 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 39 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
In another embodiment, there is provided crystalline Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate.
Form 2 may be characterised as having an XRPD pattern with a peak at 14.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 13.0 and 17.1 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 12.2 and 15.9 °2θ±0.2°θ. The XRPD pattern may have still further peaks at 17.7 and 22.6 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 40 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 41 below.
In yet another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 42 below.
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate.
Form 3 may be characterised as having an XRPD pattern with a peak at 7.6 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 3.7 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 11.1, 14.0 and 14.4 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 15.6, 19.2 and 24.0 °2θ±0.2°θ.
In an embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 43 below.
In another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 44 below.
In yet another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 45 below.
In yet another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 46 below.
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione succinate is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the hydrobromide salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide.
Form 1 may be characterised as having an XRPD pattern with a peak at 6.9 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 14.8 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 13.7, 16.5 and 18.0 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 22.0 and 27.5 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 47 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 48 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 49 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 50 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide may also be characterised by having a DSC thermogram as shown in
In an embodiment, there is provided crystalline Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide.
Form 2 may be characterised as having an XRPD pattern with peaks at 9.7, 11.8 and 12.3 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 14.5 or 16.0 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 18.7, 23.3 and 26.8 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 51 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 52 below.
In yet another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 53 below.
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide.
Form 3 may be characterised as having an XRPD pattern with peaks at 6.0, 8.9 and 13.2 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.1, 15.6 and 16.9 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 12.1 and 14.5 °2θ±0.2°θ. The XRPD pattern may have still further peaks at 17.9 and 26.2 °2θ±0.2°θ.
In an embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 54 below.
In another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 55 below.
In yet another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 56 below.
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrobromide is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the maleic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate.
Form 1 may be characterised as having an XRPD pattern with peaks at 11.3, 14.1 and 14.4 °2θ±0.2°2θ. The XRPD pattern may have a further peak at 9.1 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 15.6 and 16.4 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 19.7 and 25.2 °θ0±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 57 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 58 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 59 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate is characterised as having an XRPD pattern as shown in
In an, embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 1+peaks of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate. Hereinafter, this crystalline form shall be referred to as Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate.
Form 2 may be characterised as having an XRPD pattern with peaks at 4.0, 8.1, 8.8 and 11.0 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 16.2 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 12.3 and 14.5 °2θ±0.2°θ. The XRPD pattern may have a yet further peak at 15.8 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 60 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 61 below.
In yet another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 62 below.
In another embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate is characterised as having an XRPD pattern as shown in
In another embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione maleate is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the phosphoric acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 1 may be characterised as having an XRPD pattern with peaks at 4.6, 8.5, 9.3 and 11.0 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 16.4 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 21.0, 23.0 and 27.2 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 63 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 64 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 2 may be characterised as having an XRPD pattern with peaks at 4.5, 8.3, 9.0, 10.4, 11.1 and 12.7 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.1 and 17.5 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 20.9 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 65 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 66 below.
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 3 may be characterised as having an XRPD pattern with peaks at 8.4, 9.3, 10.7 and 12.6 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 16.2 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 26.5 °2θ±0.2°θ.
In an embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 67 below.
In another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 68 below.
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 4 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 4 may be characterised as having an XRPD pattern with peaks at 4.3, 10.8 and 13.1 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 17.2 and 20.5 °2θ±0.2°2θ.
In an embodiment, Form 4 has an XRPD pattern with peaks at the positions listed in Table 69 below.
In another embodiment, Form 4 has an XRPD pattern with peaks at the positions listed in Table 70 below.
In an embodiment, Form 4 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 4 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided a crystal modification of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate. This crystal modification is hereinafter referred to as crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Crystal modification X may be characterised as having an XRPD pattern with peaks at 4.6, 9.2, 12.5, 15.2 and 15.9 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.6, 18.1 and 21.3 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 26.1 °2θ±0.2°θ.
In an embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 71 below.
In another embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 72 below.
In an embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In another embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 6 may be characterised as having an XRPD pattern with a peak at 6.6 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 3.3 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 11.8, 12.1 and 13.2 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 17.8, 20.1 and 22.2 °2θ±0.2°θ.
In an embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 73 below.
In another embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 74 below.
In yet another embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 75 below.
In yet another embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 76 below.
In an embodiment, Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 7 may be characterised as having an XRPD pattern with peaks at 4.1 and 6.0 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 11.8 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 16.6, 21.2 and 23.5 °2θ±0.2°θ.
In an embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 77 below.
In another embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 78 below.
In yet another embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 79 below.
In an embodiment, Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate.
Form 8 may be characterised as having an XRPD pattern with peaks at 11.7, 12.2, 15.2 and 16.6 °2θ±0.2°2θ. The XRPD pattern may have a further peak at 18.1 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 22.8 and 26.1 °2θ±0.2°θ.
In an embodiment, Form 8 has an XRPD pattern with peaks at the positions listed in Table 80 below.
In another embodiment, Form 8 has an XRPD pattern with peaks at the positions listed in Table 81 below.
In an embodiment, Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate is characterised as having an XRPD pattern as shown in
Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate may also be characterised by having a DSC thermogram as shown in
According to another aspect of the present invention, there is provided the gentisic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate.
Form 1 may be characterised as having an XRPD pattern with peaks at 18.2 and 18.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 12.9 and 14.0 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 17.1 and 21.6 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 24.8 and 25.7 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 82 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 83 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 84 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate.
Form 2 may be characterised as having an XRPD pattern with a peak at 3.9 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 19.3 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 12.9 and 13.7 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 15.4 and 16.6 °2θ±0.2°θ. The XRPD pattern may have still yet further peaks at 25.5 and 26.1 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 85 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 86 below.
In yet another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 87 below.
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione gentisate is characterised as having an XRPD pattern as shown in
In another embodiment, Form 2 of the gentisate salt is characterised as being in the form of a solvate of ethyl acetate. The number of moles of ethyl acetate per mole of Form 2 may range from about 0.4 to about 1.0. Typically, the number of moles ranges from about 0.5 to about 0.9, more typically from about 0.6 to about 0.8. In an embodiment, there is 0.7 mole of ethyl acetate per 1 mole of Form 2.
According to another aspect of the present invention, there is provided the citric acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate.
Form 1 may be characterised as having an XRPD pattern with peaks at 10.6 and 13.7 °2θ±0.2°2θ. The XRPD pattern may have a further peak at 8.9 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 12.3 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 15.6 and 15.9 °2θ±0.2°θ. The XRPD pattern may have still yet further peaks at 23.2 and 26.4 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 88 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 89 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 90 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate is characterised as having an XRPD pattern as shown in
In another embodiment, there is provided crystalline Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate.
Form 2 may be characterised as having an XRPD pattern with peaks at 6.1 and 7.4 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 13.4 and 14.7 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 15.7 °2θ±0.2°θ.
In an embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 91 below.
In another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 100 below.
In yet another embodiment, Form 2 has an XRPD pattern with peaks at the positions listed in Table 101 below.
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione citrate is characterised as having an XRPD pattern as shown in
Form 2 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione phosphate may also be characterised by having a DSC thermogram as shown in
According to another aspect of the present invention, there is provided the lactic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione lactate. In another embodiment, there is provided crystalline (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione lactate. Crystalline (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione lactate may be characterised by having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the L-malic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-malate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione L-malate.
Form 1 may be characterised as having an XRPD pattern with peaks at 8.0, 9.0, 10.7, 12.0, 12.6 and 13.9 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.6 and 20.2 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 20.8 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 102 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 103 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione malate is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the glycolic acid salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glycolate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glycolate.
Form 1 may be characterised as having an XRPD pattern with peaks at 5.2, 11.8, and 12.9 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 14.8 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 15.2, 16.7, 17.1, 17.6 and 18.5 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 104 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 105 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glycolate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glycolate is characterised as having an XRPD pattern as shown in
Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione glycolate may also be characterised by having a DSC thermogram as shown in
According to another aspect of the present invention, there is provided (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
In an embodiment, there is provided crystalline Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Form 1 may be characterised as having an XRPD pattern with a peak at 8.9 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 17.7 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 11.0, 12.4, 12.7 and 13.7 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 16.0, 17.0 and 22.1 °2θ±0.2°θ.
In an embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 106 below.
In another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 107 below.
In yet another embodiment, Form 1 has an XRPD pattern with peaks at the positions listed in Table 108 below.
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
Form 1 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate may also be characterised by having a DSC thermogram as shown in
In an embodiment, there is provided a crystal modification of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate. This crystal modification is hereinafter referred to as crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Crystal modification X may be characterised as having an XRPD pattern with peaks at 12.7 and 15.8 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 21.6 and 24.1 °2θ±0.2°θ.
In an embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 109 below.
In another embodiment, crystal modification X has an XRPD pattern with peaks at the positions listed in Table 110 below.
In an embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In another embodiment, crystal modification X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Form 3 may be characterised as having an XRPD pattern with a peak at 9.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.4 °2θ±0.2 °2θ. The XRPD pattern may have a still further peak at 12.8 °2θ±0.2°θ. The XRPD pattern may have yet further peaks at 17.0, 19.1 and 27.1 °2θ±0.2°θ.
In an embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 112 below.
In another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 113 below.
In yet another embodiment, Form 3 has an XRPD pattern with peaks at the positions listed in Table 114 below.
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 3 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided another crystal modification of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate. This crystal modification is hereinafter referred to as crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Crystal modification Y may be characterised as having an XRPD pattern with peaks at 17.2 and 19.1 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 24.1, 24.6, 27.7 and 29.3 °2θ±0.2°2θ.
In an embodiment, crystal modification Y has an XRPD pattern with peaks at the positions listed in Table 115 below.
In another embodiment, crystal modification Y has an XRPD pattern with peaks at the positions listed in Table 116 below.
In an embodiment, crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In another embodiment, crystal modification Y of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Form 6 may be characterised as having an XRPD pattern with peaks at 6.2 and 12.7 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 15.5, 16.8 and 18.3 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 21.7, 24.7 and 25.4 °2θ±0.2°θ.
In an embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 117 below.
In another embodiment, Form 6 has an XRPD pattern with peaks at the positions listed in Table 118 below.
In an embodiment, Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 6 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Form 7 may be characterised as having an XRPD pattern with a peak at 3.8 °2θ±0.2 °2θ. The XRPD pattern may have a further peak at 17.5 °2θ±0.2°2θ. The XRPD pattern may have still further peaks at 12.8 and 14.7 °2θ±0.2°θ. The XRPD pattern may have a yet further peak at 20.2 °2θ±0.2°θ.
In an embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 119 below.
In another embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 120 below.
In yet another embodiment, Form 7 has an XRPD pattern with peaks at the positions listed in Table 121 below.
In an embodiment, Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 7 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate.
Form 8 may be characterised as having an XRPD pattern with a peak at 4.9 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 9.2, 12.4, 13.8 and 14.9 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 18.2 and 21.5 °2θ±0.2°θ.
In an embodiment, Form 8 has an XRPD pattern with peaks at the positions listed in Table 122 below.
In another embodiment, Form 8 has an XRPD pattern with peaks at the positions listed in Table 123 below.
In yet another embodiment, Form 8 has an XRPD pattern with peaks at the positions listed in Table 124 below.
In an embodiment, Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form 8 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided the hydrosulfate salt of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate.
In an embodiment, the (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate is in crystalline form. The crystalline forms of the hydrosulfate salt were found in the experiments on the sulfate salt. The sulfate salt designated the number “crystalline 2 minus peaks” (
In an embodiment, Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate has an XRPD pattern with a peak at a °2θ value between 29.8 and 30.5 and a peak at a °2θ value between 32.0 and 32.8. The XRPD of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate may have a further peak at a °2θ value between 13.5 and 14.2. The XRPD of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate may have a still further peak at a °2θ value between 21.2 and 21.8, a still further peak at a ° 20 value between 21.9 and 22.5 and a still further peak at a °2θ value between 23.6 and 24.3. The XRPD of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate may have a yet further peak at a °2θ value between 12.2 and 12.8 and a yet further peak at a °2θ value between 15.5 and 16.1. In one embodiment, crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate is characterised as having an XRPD pattern as shown in
In an embodiment, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate
Form B may be characterised as having an XRPD pattern with peaks at 4.6, 9.2 and 12.6 °2θ±0.2 °2θ. The XRPD pattern may have further peaks at 16.0 and 18.2 °2θ±0.2 °2θ. The XRPD pattern may have still further peaks at 13.4, 14.0 and 14.9 °2θ±0.2°θ.
In an embodiment, Form B has an XRPD pattern with peaks at the positions listed in Table 125 below.
In another embodiment, Form 5 has an XRPD pattern with peaks at the positions listed in Table 126 below.
In another embodiment, crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrosulfate is characterised as having an XRPD pattern as shown in
In an embodiment, Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione sulfate is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided compound 2 in amorphous form, i.e. (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione in amorphous form. In an embodiment, the amorphous form of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione is characterised as having an XRPD pattern as shown in
According to another aspect of the present invention, there is provided processes for preparing the salts and polymorphs described above. Each of the processes detailed in the Experimental represent alternative embodiments of the processes of the present invention.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a salt or polymorph as described above together with one or more pharmaceutical excipients. The pharmaceutical compositions may be as described in WO2004/033447.
In this specification, crystalline and low crystalline forms of the same polymorph are described. For example, the adipate salt exists in crystalline Form 1, as well as low crystalline Form 1. Forms having the same number but specified as being either crystalline or low crystalline refer to the same polymorph. Reasons for XRPD patterns showing the form as a low crystalline form are well known to those skilled in the art.
In this specification, the term “compound 2” refers to (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione free base.
Reference is made to the accompanying Figures, which show:
a XRPD pattern of L-tartrate
b XRPD pattern of Malonate
c XRPD pattern of Tosylate, Form A
d XRPD pattern of (1R)-10-Camphorsulfonate
e XRPD pattern of Fumarate
a XRPD pattern of L-tartrate salt: Form A
b XRPD pattern of L-tartrate salt: Form B
a XRPD pattern of tosylate salt: Form A (same as
b XRPD pattern of tosylate salt: Form B
c XRPD pattern of tosylate salt: Form C
d XRPD pattern of tosylate salt: Form D
e XRPD pattern of tosylate salt: Form E
f XRPD pattern of tosylate salt: Form F (also called crystal modification X)
g XRPD pattern of tosylate salt: Form G
h XRPD pattern of tosylate salt: Form H (also called crystal modification Y)
a XRPD pattern of acetate salt: crystalline 1, scale-up
b XRPD pattern of acetate salt: crystalline 1, wellplate, well no. A3
a XRPD pattern of adipate salt: crystalline 1, scale-up
b XRPD pattern of adipate salt: crystalline 1, well plate, well no. B2
c XRPD pattern of adipate salt: low crystalline 1, well plate, well no. B1
d XRPD pattern of adipate salt: crystalline 1-peaks, well plate, well no. B6
a XRPD pattern of citrate salt: crystalline 1, scale-up
b XRPD pattern of citrate salt: crystalline 2, scale-up
c XRPD pattern of citrate salt: crystalline 1, well plate, well no. C3
d XRPD pattern of citrate salt: low crystalline 1, well plate, well no. C4
a XRPD pattern of gentisate salt: crystalline 1, scale-up
b XRPD pattern of gentisate salt: crystalline 1, well plate, well no. D5
c XRPD pattern of gentisate salt: crystalline 2, well plate, well no. D6
a XRPD pattern of glutarate salt: crystalline 1, scale-up
b XRPD pattern of glutarate salt: crystalline 1, well plate, well no. E1
c XRPD pattern of glutarate salt: low crystalline 1, well plate, well no. E3
a XRPD pattern of glycolate salt: crystalline 1, scale-up
b XRPD pattern of glycolate salt: crystalline 1, well plate, well no. F1
c XRPD pattern of glycolate salt: low crystalline 1, well plate, well no. F2
a XRPD pattern of hydrobromide salt: crystalline 1, scale-up
b XRPD pattern of hydrobromide salt: crystalline 3, scale-up
c XRPD pattern of hydrobromide salt: crystalline 1, well plate, well no. All
d XRPD pattern of hydrobromide salt: crystalline 2, well plate, well no. A9
e XRPD pattern of hydrobromide salt: low crystalline 2, well plate, well no. A2
a XRPD pattern of L-malate salt: crystalline 1, scale-up
b XRPD pattern of L-malate salt: crystalline 1, well plate, well no. G6
a XRPD pattern of maleate salt: crystalline 1+peaks, scale-up
b XRPD pattern of maleate salt: crystalline 1, well plate, well no. C5
c XRPD pattern of maleate salt: crystalline 1+one peak, well plate, well no. C11
d XRPD pattern of maleate salt: low crystalline 1, well plate, well no. C11
a XRPD pattern of phosphate salt: crystalline 1, well plate, well no. G11
b XRPD pattern of phosphate salt: crystalline 1+peaks, well plate, well no. G6
c XRPD pattern of phosphate salt: low crystalline 1, well plate, well no. G5
d XRPD pattern of phosphate salt: crystalline 2, wellplate, well no. G1
e XRPD pattern of phosphate salt: crystalline 3, wellplate, well no. G7
f XRPD pattern of phosphate salt: crystalline 4, wellplate, well no. G8
g XRPD pattern of phosphate salt: crystalline 5 (also called crystal modification X), scale-up
h XRPD pattern of phosphate salt: crystalline 6, scale-up
i XRPD pattern of phosphate salt: low crystalline 7, scale-up
a XRPD pattern of sulfate salt: crystalline 1, well plate, well no. F2
b XRPD pattern of sulfate salt: low crystalline 1, well plate 95730, well no. F4
d XRPD pattern of sulfate salt: crystal modification X (also referred to as crystalline 2), well plate 95730, well no. F6
e XRPD pattern of hydrosulfate salt: Form A (also referred to as crystalline 2 minus peaks), well plate 96343, well no. F6
f XRPD pattern of sulfate salt: crystalline 3, well plate, well no. F1
g XRPD pattern of sulfate salt: crystal modification Y (also referred to as crystalline 4), well plate, well no. F5
h XRPD pattern of sulfate salt: crystalline 1, scale-up
i XRPD pattern of hydrosulfate salt: Form B (also referred to as crystalline 5), scale-up
j XRPD pattern of sulfate salt: crystalline 6, scale-up
k XRPD pattern of sulfate salt: crystalline 7, scale-up
A salt and polymorph screen was undertaken which involved various crystallisation techniques, as explained below.
1. Solvent-Based Crystallization Techniques
a. Fast Evaporation (FE)
Solutions of compound 2 were prepared in various solvents in which samples were vortexed or sonicated between aliquot additions. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2-μm nylon filter. The filtered solution was allowed to evaporate at ambient conditions in an open vial. The solids were isolated and analyzed.
b. Slow Evaporation (SE)
Solutions of compound 2 were prepared in various solvents in which samples were vortexed or sonicated between aliquot additions. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2-μm nylon filter. The filtered solution was allowed to evaporate at ambient conditions in a vial covered with a loose cap or perforated aluminum foil. The solids were isolated and analyzed.
c. Slurry Experiments
Solutions of compound 2 were prepared by adding enough solids to a given solvent at ambient conditions so that undissolved solids were present. The mixture was then loaded on a rotary wheel or an orbit shaker in a sealed vial at either ambient or elevated temperature for a certain period of time, typically 7 days. The solids were isolated by vacuum filtration or by drawing off or decanting the liquid phase and allowing the solids to air dry at ambient conditions prior to analysis.
d. Crash Precipiation
Solutions of compound 2 were prepared in various solvents in which samples were agitated or sonicated to facilitate dissolution. The resulting solutions (sometimes filtered) were transferred into vials containing a known volume of antisolvent and/or aliquots of antisolvent were added to the solutions until precipitation persisted. If precipitation was insufficient, some samples were left at ambient temperature. The solids were isolated by decanting the liquid phase and allowing the solids to air dry at ambient conditions prior to analysis.
e. Slow Cool
Solutions of compound 2 were prepared in various solvents in which samples were heated with agitation to facilitate dissolution. The solutions were cooled by shutting off the heat source. If precipitation was insufficient, samples were refrigerated or evaporated. The solids were isolated by vacuum filtration.
2. Well Plate Crystallization Techniques
a. Wellplate Salt Preparations
Preparation of salts was carried out in 96-well polypropylene plates using the following general procedure. API solutions were prepared by dissolving compound 2 free base in acetone, methanol, methyl ethyl ketone, tetrahydrofuran or 2,2,2-trifluoroethanol at approximately 10 mg/mL, adding 0.1 mL of these solutions per well. Dilute acid solutions were added (methanol solutions, generally 0.1M) to the wells at slightly more than one molar equivalent with respect to the API. Each API/acid combination was prepared in triplicate and wells with only the API solutions: were also prepared for comparison. The plates were covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 or 11 days. Some evaporation occurred during mixing. The plates were observed after 3 days by optical microscopy and returned to the shaker. Upon removal from the shaker, they were observed visually for color under standard laboratory lighting. The plates were left uncovered to complete evaporation under ambient conditions for final microscopic evaluation and XRPD analysis.
b. General Salt Preparation procedure
To a glass vial of compound 2 dissolved in various solvents, slightly more than one molar equivalent of various counterion solutions were added. Samples were allowed to slurry and/or evaporate at ambient temperature in a laboratory fume hood. Often, antisolvent was added to precipitate solids. The resulting solids were isolated by filtration or solvent decantation (often preceded by centrifugation), examined by polarized light microscopy and generally submitted for XRPD analysis.
c. Fast Evaporation
A well plate containing various solutions was allowed to stand, uncovered, at ambient conditions to allow the solutions to evaporate. The solids were analyzed in the well plate.
d. Recrystallization Techniques
Solutions were prepared by dispensing 75 μL of methanol into each well of a well plate containing solids from previous experiments. The well plate was then covered and attached to an orbit shaker for 30 minutes to 1 hour. An equal volume (75 μL) of various antisolvents was added to each well, and the solutions were allowed to fast evaporate at ambient conditions. The solids were analyzed in the well plate.
Instrumental Techniques
The characterisation of the polymorphs involved various analytical techniques, as explained below.
A. X-Ray Powder Diffraction (XRPD)
Shimadzu XRD-6000 Diffractometer
Analyses were carried out on a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Kα radiation. The instrument is equipped with a long fine focus X-ray tube. The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A theta-two theta continuous scan at 3°/min (0.4 sec/0.02° step) from 2.5 to 40 °2θ was used. A silicon standard was analyzed each day to check the instrument alignment. Samples were analyzed in an aluminum sample holder with a silicon well.
Inel XRG-3000 Diffractometer
X-ray powder diffraction (XRPD) analyses were performed using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 20 range of 120°. Real time data were collected using Cu-Kα radiation starting at approximately 4 °2θ at a resolution of 0.03 °2θ. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The monochromator slit was set at 5 mm by 160 μm. The pattern is displayed from 2.5-40 °2. Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for 5 or 10 min. Instrument calibration was performed using a silicon reference standard.
Bruker D-8 Discover Diffractometer
XRPD patterns were collected with a Bruker D-8 Discover diffractometer and Bruker's General Area Diffraction Detection System (GADDS, v. 4.1.20). An incident beam of Cu Kα radiation was produced using a fine-focus tube (40 kV, 40 mA), a Göbel mirror, and a 0.5 mm double-pinhole collimator. The samples were positioned for analysis by securing the well plate to a translation stage and moving each sample to intersect the incident beam. The samples were analyzed using a transmission geometry. The incident beam was scanned and rastered over the sample during the analysis to optimize orientation statistics. A beam-stop was used to minimize air scatter from the incident beam at low angles. Diffraction patterns were collected using a Hi-Star area detector located 15 cm from the sample and processed using GADDS. The intensity in the GADDS image of the diffraction pattern was integrated using a step size of 0.04 °2θ. The integrated patterns display diffraction intensity as a function of 2θ. Prior to the analysis a silicon standard was analyzed to verify the Si 111 peak position. The instrument was operated under non-cGMP conditions, and the results are non-cGMP.
PatternMatch 2.4.0 software, combined with visual inspection, was used to identify peak positions for each form. “Peak position” means the maximum intensity of a peaked intensity profile. Where data collected on the INEL diffractometer was used, it was first background-corrected using PatternMatch 2.4.0.
PatternMatch 2.4.0 was used for all peak identification. Peak positions were reproducible to within 0.1 °2θ. Therefore, all peak positions reported in tables used this precision as indicated by the number following the ± in the 2θ column. All peak positions have been converted to (wavelength-independent) d space using a wavelength of 1.541874 Å and the precision at each position is indicated as well (note that the precision is not constant in d space). It will be noted that the precision of within 0.1 °2θ was used to determine reproducability of peak positions. It will be appreciated that peak positions may vary to a small extent depending on which apparatus is used to analyse a sample. Therefore, all definitions of the polymorphs which refer to peak positions at °2θ values are understood to be subject to variation of ±0.2 °2θ. Unless otherwise stated (for example in the Tables with ±values), the °2θ values of the peak positions are ±0.2 °2θ.
B. Differential Scanning Calorimetry (DSC)
Differential scanning calorimetry (DSC) was performed using a TA Instruments differential scanning calorimeter 2920 and Q1000. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and then crimped or non-crimped pan configuration was used. The sample cell was equilibrated at 25° C. and heated under a nitrogen purge at a rate of 10° C./min, up to a final temperature of 250, or 300° C. Indium metal was used as the calibration standard. Reported temperatures are at the transition maxima.
C. Thermogravimetry (TG)
Thermogravimetric (TG) analyses were performed using a TA Instruments 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was either equilibrated at 25° C. or directly heated under nitrogen at a rate of 10° C./min, up to a final temperature of 350° C. Nickel and Alumel™ were used as the calibration standards.
D. NMR Spectroscopy
Solution 1D 1H NMR Spectroscopy
Solution 1H NMR spectra were acquired at ambient temperature with a Varian UNITYINOVA-400 spectrometer at a 1H Larmor frequency of 399.795 MHz. The sample was dissolved in MeOH-d4. The spectrum was acquired with a 1H pulse width of 8.2, 8.4, 8.5 or 10 μs, a 2.50 second acquisition time, a 5 second delay between scans, a spectral width of 6400 Hz with 32000 data points, and 40 co-added scans. The free induction decay (FID) was processed using Varian VNMR 6.1C software with 32000 points. The residual peak from incompletely deuterated methanol is at approximately 3.3 ppm. The relatively broad peak at approximately 4.88 ppm is due to water. The spectrum was referenced to internal tetramethylsilane (TMS) at 0.0 ppm.
Solution 1D 1H NMR Spectroscopy (SDS, Inc.)
The solution 1H NMR spectrum was acquired by Spectral Data Services of Champaign, Ill. at 25° C. with a Varian UNITYINOVA-400 spectrometer at a 1H Larmor frequency of 399.798 MHz. The sample was dissolved in methanol-d4. The spectrum was acquired with a 1H pulse width of 7.0 μs, a 5 second delay between scans, a spectral width of 7000 Hz with 35K data points, and 40 co-added scans. The free induction decay (FID) was processed with 64K points and an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio. The residual peak from incompletely deuterated methanol is at approximately 3.3 ppm.
Results—Solvent-Based Crystallization Screen
Camsylate Salt
The initial lot of the camsylate salt was prepared as follows.
To a suspension of compound 2 (0.93 g, 3 mmol) in MeOH (20 ml) was added a solution of (1R)-(−)-camphorsulfonic acid (0.70 g, 3 mmol) in MeOH (5 ml) at 50° C. with stirring. The mixture was heated to reflux, allowed to cool naturally to 20-25° C. with stirring, aged at 20-25° C. for 2 h. The precipitate was collected, washed with MeOH (10 ml), dried in vacuum at 45° C. to a constant weight. Yield 1.39 g (85%).
A polymorph screen was carried out on the (1R)-10-camphorsulfonate salt (camsylate salt) of compound 2 using slurry and slow evaporation experiments (Table 1A). The XRPD pattern of the camsylate salt is shown in
aSE = slow evaporation
Fumarate Salt
The initial lot of the fumarate salt was prepared as follows.
Compound 2 (0.93 g, 3 mmol) was dissolved in a mixture of MeOH (20 ml) and DCM (5 ml) with heating to 40-45° C. and stirring. To the resulting clear solution fumaric acid (0.35 g, 3 mmol) in MeOH (10 ml) was added, the mixture was allowed to cool naturally to 20-25° C. with stirring (crystallisation occurred). The mixture was aged in ice for 1 h, the precipitate was collected, washed with MeOH (5 ml), dried in vacuum at 45° C. to a constant weight. Yield 0.82 g (74%).
A polymorph screen was carried out on the fumarate salt of compound 2 using slurry and fast evaporation experiments (Table 2A). The XRPD pattern of the fumarate salt is shown in
aFE = fast evaporation
bl.c. = low crystallinity
Malonate Salt
The initial lot of the malonate salt was prepared as follows.
To a suspension of compound 2 (0.93 g, 3 mmol) in MeOH (10 ml) was added a solution of malonic acid (0.31 g, 3 mmol) in MeOH (5 ml) at 50° C. with stirring. The mixture was heated to reflux to obtain a clear solution, allowed to cool naturally to 20-25° C. with stirring (crystallisation occurred), aged in ice for 30 min. The precipitate was collected, washed with MeOH (3 ml), dried in vacuum at 45° C. to a constant weight. Yield 1.12 g (90%).
A polymorph screen of the malonate salt was carried out using slurry and fast evaporation crystallization techniques (Table 3A). The XRPD pattern of the initial lot of the malonate salt is shown in
aFE = fast evaporation
The malonate salt was characterized using thermal techniques (Table 4A,
L-Tartrate Salt
The initial lot of the L-tartrate salt was prepared as follows.
Compound 2 (0.93 g, 3 mmol) was dissolved in a mixture of MeOH (20 ml) and DCM (5 ml) with heating to 40-45° C. and stirring. To the resulting clear solution L-tartaric acid (0.45 g, 3 mmol) in MeOH (10 ml) was added, the solution was concentrated under reduced pressure to half of the initial volume and diluted with 2-propanol (20 ml) (crystallisation occurred). The suspension was cooled in ice to 0-5° C., aged for 30 min, the precipitate was collected, washed with 2-propanol (5 ml), dried in vacuum at 45° C. to a constant weight. Yield 1.08 g (78%).
A polymorph screen of the L-tartrate salt was carried out using slurry and fast evaporation crystallization techniques (Table 5A). The XRPD pattern of the initial lot of the L-tartrate salt exhibited an amorphous character (
aFE = fast evaporation
bIS = insufficient sample
A low crystalline Form A and crystalline Form B resulted from slurry experiments in acetonitrile and ethyl acetate, respectively (Table 6A and Table 7A). The XRPD patterns of both forms are presented in
1H NMR
1H NMR
Tosylate Salt
The initial lot of the tosylate salt was prepared as follows.
To a suspension of compound (0.93 g, 3 mmol) in MeOH (10 ml) was added a solution of p-toluenesulfonic acid monohydrate (0.57 g, 3 mmol) in MeOH (5 ml) at 50° C. with stirring. The mixture was heated to reflux to obtain a clear solution, allowed to cool naturally to 20-25° C. with stirring (crystallisation occurred), aged in ice for 30 min. The precipitate was collected, washed with MeOH (3 ml), dried in vacuum at 45° C. to a constant weight. Yield 1.07 g (74%)
A polymorph screen of the tosylate salt was carried out using slurry and fast evaporation crystallization techniques (Table 8A). The initial lot of the tosylate salt was designated as Form A (
aFE = fast evaporation
Form A was analyzed by NMR and thermal techniques (Table 9A,
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Form B resulted from fast evaporation in acetonitrile. No solvent was present in the material based on the proton NMR spectrum (
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Form C was obtained in slurry experiments in isopropanol after four and seven days. The thermal data for Form C are included in Table 11A and shown in
1H NMR
bendo = endotherm, exo = exotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
cweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Form D resulted from a slurry experiment in tetrahydrofuran after seven days. The characterization data for Form D are summarized in Table 12A. Peak shifts in the proton NMR indicated a different structure that was, nonetheless, related to the structure of the tosylate salt (
1H NMR
Form E was obtained in a fast evaporation experiment in 2,2,2-trifluoroethanol. The thermal data for Form E are included in Table 13A and shown in
1H NMR
aTFE = 2,2,2-trifluoroethanol
bendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
cweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Form F (also referred to as crystal modification X) was produced in slurry experiments in ethyl acetate after four and seven days. No solvent was present in the material based on the 1H NMR spectrum (
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Form G obtained from fast evaporation in water was likely a hydrate. The XRPD and proton NMR data for Form G are summarized in Table 15A (structure confirmed by NMR,
1H NMR
Form H (also called crystal modification Y) was produced in a slurry experiment in tetrahydrofuran after four and seven days. The thermal data for Form H are included in Table 16A and shown in
1H NMR
bendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
cweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Results—Wellplate Salt Screen
Wellplate 1
Salt preparation results for wellplate 1 are summarized in Table 17A and Table 18A. The following acids were used in the screen:
acetic,
adipic,
citric,
gentisic,
glutaric,
glycolic,
L-malic.
The acids were dissolved in methanol and added to solutions of the freebase dissolved in acetone, methanol, methyl ethyl ketone, and tetrahydrofuran. Solids were obtained from slurry/fast evaporation experiments in the wells.
The free base (i.e. compound 2) was also dissolved in acetone, MeOH, MEK and THF) and solids obtained (well plate numbers H1, H2, H4, H5, H7, H8, H10 and H11 Table 17A). These experiments resulted in the amorphous form of compound 2.
aMeOH = methanol, MEK = methyl ethyl ketone, THF = tetrahydrofuran.
bB = birefringence, E = extinction; samples observed under microscope with
aMeOH = methanol, MEK = methyl ethyl ketone, THF = tetrahydrofuran.
bB = birefringence, E = extinction; samples observed under microscope with
aMeOH = methanol, MEK = methyl ethyl ketone, THF = tetrahydrofuran.
bB = birefringence, E = extinction; samples observed under microscope with
aMeOH = methanol, MEK = methyl ethyl ketone, THF = tetrahydrofuran.
bB = birefringence, E = extinction; samples observed under microscope with
aAcids were dissolved in methanol then added to a solution containing freebase. The solvent that dissolved the freebase was the major component in the mixture.
bACN = acetonitrile, EtOAc = ethyl acetate, IPA = isopropanol, MeOH = methanol, MEK = methyl ethyl ketone, TFE = 2,2,2-trifluoroethanol.
Wellplate 2
Salt preparation results for wellplate 2 are summarized in Table 19A and Table 18A above. The following acids were used in the screen:
hydrobromic,
lactic,
maleic,
methanesulfonic,
succinic,
sulfuric,
phosphoric.
The acids were dissolved in methanol and added to solutions of compound 2 dissolved in acetone, methanol, methyl ethyl ketone, and 2,2,2-trifluoroethanol. Solids were obtained from slurry/fast evaporation experiments in the wells.
aMeOH = methanol, MEK = methyl ethyl ketone, TFE = 2,2,2-trifluoroethanol.
bB = birefringence, E = extinction; samples observed under microscope with crossed polarized
cViolet solution produced upon acid addition
aMeOH = methanol, MEK = methyl ethyl ketone, TFE = 2,2,2-trifluoroethanol.
bB = birefringence, E = extinction; samples observed under microscope with crossed polarized
cViolet solution produced upon acid addition
aMeOH = methanol, MEK = methyl ethyl ketone, TFE = 2,2,2-trifluoroethanol.
bB = birefringence, E = extinction; samples observed under microscope with crossed polarized
aMeOH = methanol, MEK = methyl ethyl ketone, TFE = 2,2,2-trifluoroethanol.
bB = birefringence, E = extinction; samples observed under microscope with crossed polarized
cWhite precipitate produced upon acid addition.
Recrystallization of Salts in Wellplates
Wellplate 3
Recrystallization of wellplate 3 was conducted using solvent/antisolvent evaporation. The solids in wells were dissolved in methanol. Acetonitrile, ethyl acetate, 1-propanol, and toluene were used as the antisolvents. The wells with sufficient amounts of non-glassy solids were analyzed by XRPD and the results are summarized in Table 20A and Table 18A above.
aMeOH = methanol.
bACN = acetonitrile, EtOAc = ethyl acetate, 1-PrOH = 1-propanol.
cB = birefringence, samples observed under microscope with crossed polarized light; Y = yes, N = no, Part. = partial.
Wellplate 4
Recrystallization of wellplate 3 was conducted using solvent/antisolvent evaporation. The solids in wells were dissolved in methanol. Acetonitrile, ethyl acetate, 1-propanol, and toluene were used as the antisolvents. The wells with sufficient amounts of non-glassy solids were analyzed by XRPD and the results are summarized in Table 21A and Table 18A above.
aMeOH = methanol.
bACN = acetonitrile, EtOAc = ethyl acetate, IPA = isopropanol.
cB = birefringence, E = extinction; samples observed under microscope with crossed polarized light; Y = yes, N = no.
Summary of Crystalline Salts from Wellplates: Salt MicroScreen™
The following new crystalline salts were discovered from wellplate crystallization experiments:
acetate,
adipate,
citrate,
gentisate,
glutarate,
glycolate,
hydrobromide,
lactate,
L-malate,
maleate,
phosphate,
succinate,
sulfate.
The crystalline salts are summarized in Table 18A above. The preparation and crystallization experiments are discussed below.
Acetate Salt
A new crystalline XRPD pattern (crystalline 1) was observed in the experiments with acetic acid in acetone and methanol (
The acetate salt (crystalline 1) was initially prepared on approximately 50-mg scale from methanol solution (evaporation to dryness, Table 22A). The salt structure was confirmed by proton NMR (
The acetate salt (crystalline 1) was crystallized with approximately 70% yield by fast evaporation from methanol (Table 24A). The material was characterized using thermal techniques (
The aqueous solubility of the acetate salt was approximately 14 mg/mL (Table 64A).
aAcid/API molar ratio is 1:1 unless specified otherwise
bCP = crash precipitation, FE = fast evaporation, SE = slow evaporation, RT = ambient
cSamples observed under microscope with crossed polarized light
dIS = insufficient solids for analysis
ePrecipitate generated upon acid addition
fOpaque liquid generated upon antisolvent addition
g1:1 equivalents Acid/API
aAcid/API molar ratio is 1:1 unless specified otherwise
bCP = crash precipitation, FE = fast evaporation, SE = slow evaporation, RT = ambient
cSamples observed under microscope with crossed polarized light
dIS = insufficient solids for analysis
eOpaque liquid generated upon antisolvent addition
fPrecipitate generated upon acid addition
g1:1 equivalents Acid/API
aAcid/API molar ratio is 1:1 unless specified otherwise
bCP = crash precipitation, FE = fast evaporation, SE = slow evaporation, RT = ambient
cSamples observed under microscope with crossed polarized light
dIS = insufficient solids for analysis
ePrecipitate generated upon acid addition
f1:1 equivalents Acid/API
1H NMR
aFE = fast evaporation, SC = slow cool
bpossible dihydrate, acetone solvate, or mixed hydrate/solvate obtained
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Adipate
A new crystalline XRPD pattern and a similar low crystalline pattern (crystalline 1 and low crystalline 1) were observed in the experiments with adipic acid in acetone. Material exhibiting the XRPD pattern of crystalline 1 without some peaks was produced from methanol (
Material exhibiting the XRPD pattern of crystalline 1 also resulted from the microplate recrystallization experiment using methanol:acetonitrile 1:1 and methanol: ethyl acetate 1:1 (see summary table).
The adipate salt (crystalline 1) was prepared on approximately 50-mg scale by fast evaporation in methanol (to dryness, Table 22A above). The salt structure was confirmed by proton NMR (
The adipate salt (crystalline 1) was crystallized by fast evaporation in methanol (approx. 72% yield) and acetonitrile:methanol 1:1 (approx. 58% yield) (Table 24A above). The sample prepared from methanol was analyzed by thermal techniques (
The aqueous solubility of the adipate salt was approximately 10 mg/mL (Table 64A).
1H NMR
Citrate
A new crystalline XRPD pattern (crystalline 1) was observed in the experiment with citric acid in acetone. A similar low crystalline XPRD pattern (low crystalline 1) was observed in the experiments utilizing acetone, methanol, and methyl ethyl ketone as solvents (
Material exhibiting the XRPD pattern of crystalline 1 also resulted from a microplate recrystallization experiment using methanol:acetonitrile 1:1 and methanol: ethyl acetate 1:1 (see summary table).
Two crystalline forms of the citrate salt were prepared from scale-up experiments (Table 22A). Material exhibiting the XRPD pattern of crystalline 1 resulted from a fast evaporation experiment in methanol. A new material with an XRPD pattern designated as crystalline 2 was produced in a slow evaporation experiment in acetone:methanol 96:4 (Table 22A). The salt structure was confirmed by proton NMR for both samples (
The citrate salt (crystalline 2) was scaled up by crystallization in acetone:methanol 98:2 (slow cool, Table 24A). Approximately 110% yield was calculated, however, an insignificant weight loss (0.3%) was observed after the material had been dried in vacuum for three days. Based on proton NMR, approximately 0.5 moles of acetone were found per one mole of the compound (
The citrate salt was characterized by thermal techniques (
The aqueous solubility of the citrate salt was approximately 12 mg/mL (Table 64A).
1H NMR
1H NMR
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Gentisate
No crystalline materials were generated in the experiments with gentisic acid in the original wellplate salt preparation (Table 17A).
Two crystalline materials exhibiting XRPD patterns designated as crystalline 1 and crystalline 2 resulted from wellplate recrystallization experiments in methanol: ethyl acetate 1:1 (
The crystalline 1 material was obtained in a scale-up attempt by fast evaporation in methanol: ethyl acetate 1:1 (evaporation to dryness,). Based on 1H NMR, the material was a likely mixture of the free base and the gentisate salt (
The aqueous solubility of the gentisate salt was lower than 1 mg/mL (Table 63A)
1H NMR
1H NMR
Glutarate
No crystalline materials were generated in the experiments with glutaric acid in the original wellplate salt preparation (Table 17A).
Material exhibiting an XRPD pattern designated as crystalline 1 was generated in the microplate recrystallization experiments using methanol:acetonitrile 1:1 and methanol: ethyl acetate 1:1 (
The glutarate salt (crystalline 1) was crystallized by fast evaporation in methanol: ethyl acetate 1:1 (evaporation to dryness, Table 22A). The salt structure was confirmed by 1H NMR (
The aqueous solubility of the glutarate salt was approximately 3 mg/mL (Table 63A).
1H NMR
Glycolate
No crystalline materials were generated in the experiments with glycolic acid in the original wellplate salt preparation (Table 17A).
Material exhibiting an XRPD pattern designated as crystalline 1 resulted from the microplate recrystallization experiment in methanol:acetonitrile 1:1 (
The glycolate salt (crystalline 1) was produced on approx. 50-mg scale by fast evaporation using methanol:acetonitrile 1:1 (Table 22A). The salt structure was confirmed by 1H NMR (
The glycolate salt was prepared with approx. 80% yield by slow cooling in acetonitrile:methanol 1:1 (Table 24A). The material was analyzed using thermal techniques (
The aqueous solubility of the glycolate salt was approximately 27 mg/mL (Table 64A).
1H NMR
Hydrobromide
The crystalline XRPD patterns of the hydrobromide salt found in the screen are presented in
Two new crystalline XRPD patterns were observed in the wellplate preparation experiments with hydrobromic acid in trifluoroethanol (crystalline 1) and in acetone and methyl ethyl ketone (crystalline 2) (Table 19A).
Material exhibiting the XRPD pattern of crystalline 1 was also produced in wellplate recrystallization experiments using methanol: ethyl acetate, methanol: isopropanol, and methanol:toluene 1:1 solvent systems (Table 21A).
Material exhibiting the XRPD pattern of crystalline 2 was obtained in wellplate recrystallization experiments using methanol: acetonitrile and methanol:isopropanol 1:1 (Table 21A). Presence of impurities was noted in proton NMR (
Two crystalline forms of the HBr salt were prepared from the scale-up experiments (Table 22A). Material exhibiting the XRPD pattern of crystalline 1 resulted from a fast evaporation experiment in 2,2,2-trifluoroethanol (TFE) and contained residual trifluoroethanol, based on 1H NMR (
The hydrobromide salt was crystallized from acetonitrile:methanol 1:1 with approx. 64% yield and characterized by thermal techniques (Table 24A,
The aqueous solubility of the hydrobromide salt was approximately 16 mg/mL (Table 64A).
1H NMR
1H NMR
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Lactate
No crystalline materials were generated in the experiments with lactic acid in the original wellplate salt preparation (Table 19A).
Material exhibiting an XRPD pattern designated as crystalline 1 resulted from the microplate recrystallization experiment in methanol:toluene 1:1 (
A scale-up attempt by fast evaporation using the same solvent system was unsuccessful and resulted in amorphous material (Table 22A).
1H NMR
L-Malate
A new crystalline XRPD pattern (crystalline 1) was observed in the original wellplate salt preparation with L-malic acid in methanol (
The L-malate salt was also prepared on approx. 50-mg scale by fast evaporation in methanol (evaporation to dryness, Table 22A). The salt structure was confirmed by proton NMR (
The aqueous solubility of the L-malate salt was approximately 4 mg/mL (Table 63A).
1H NMR
Maleate
Two new crystalline XRPD patterns were observed in the experiments with maleic acid in acetone and methanol (crystalline 1 and crystalline 1 plus one peak). Both results were obtained from both solvents. A low crystalline material with the XRPD pattern similar to crystalline 1 (low crystalline 1) resulted from trifluoroethanol (
Two crystalline materials exhibiting the XRPD patterns of crystalline 1 and crystalline 1 plus peak were produced in the wellplate recrystallization experiments in methanol: acetonitrile and methanol: ethyl acetate 1:1 solvent systems (
The maleate salt (crystalline 1 plus peaks) was prepared on approximately 50-mg scale by fast evaporation in methanol and acetone:methanol 96:4 (Table 22A). The salt structure was confirmed by proton NMR (
The aqueous solubility of the maleate salt was approximately 3 mg/mL (Table 63A).
1H NMR
Phosphate
Four new crystalline XRPD patterns were found in the wellplate experiments with phosphoric acid (
Material exhibiting an XRPD pattern designated as crystalline 2 resulted from experiments in acetone.
Two crystalline materials exhibiting XRPD patterns designated as crystalline 3 and crystalline 4 were produced in experiments in methyl ethyl ketone.
All the four new crystalline materials were reproduced in wellplate recrystallization experiments by addition of antisolvents such as acetonitrile, ethyl acetate, toluene, and isopropanol to methanol solutions (Table 21A). Based on proton NMR, materials of crystalline 2, crystalline 3, and crystalline 4 had impurities (
The phosphate salt exhibiting a new XRPD pattern of crystalline 5 (also called crystal modification X) was produced in a scale-up experiment by fast evaporation to dryness in methanol (Table 22A). The salt structure was confirmed by proton NMR (
Attempts to prepare additional quantities of crystalline materials 1-4 were not successful. Amorphous material resulted from fast evaporation to dryness in acetone.
The phosphate salt (crystalline 2) was crystallized with approx. 89% yield by precipitation from methanol at approx. 55° C. (Table 24A).
The phosphate salt exhibiting a new XRPD pattern designated as crystalline 8 was prepared with approx. 82% yield by fast evaporation from methanol (Table 24A). Crystalline 8 is probably a more thermodynamically stable form of the phosphate salt. After comparison of the XRPD data, crystalline pattern 5 appeared to be very similar to crystalline pattern 8 with some peaks (
The phosphate salt, crystalline 8, was reproduced in the second scale-up experiment using the same crystallization conditions (Table 24A). The material was analyzed using proton NMR and thermal techniques (
The aqueous solubility of the phosphate salt was approximately 2-3 mg/mL (Table 64A).
1H NMR
1H NMR
1H NMR
1H NMR
1H NMR
aendo = endotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
Succinate
Material exhibiting an XRPD pattern designated as crystalline 1 was observed in the experiments with succinic acid in acetone, methanol, and trifluoroethanol (
Material exhibiting the XRPD pattern of crystalline 1 was then produced in recrystallization experiments using methanol: acetonitrile and methanol: ethyl acetate 1:1 (Table 21A).
Two new crystalline materials exhibiting XRPD patterns designated as crystalline 2 and crystalline 2 minus peaks were generated in recrystallization experiments in methanol:toluene 1:1 (Table 21A). Based on 1H NMR, impurities were present in the succinate salt of crystalline 2 (
Two crystalline forms of the succinate salt were prepared from the scale-up experiments (Table 22A). Material exhibiting the XRPD pattern of crystalline 1 resulted from the following experiments: fast evaporation in methanol, fast evaporation in toluene:methanol 1:1, and slow evaporation in methanol: TFE 1:10. The structure of the succinate salt produced from methanol was confirmed by 1H NMR (
A new material with an XRPD pattern designated as crystalline 3 was produced from a fast evaporation experiment in methanol: TFE 1:10. Based on proton NMR, the succinate salt of crystalline 3 had residual amounts of trifluoroethanol (
The aqueous solubility of the succinate salt was approximately 7-8 mg/mL (Table 63A).
1H NMR
1H NMR
1H NMR
Sulfate
Four new crystalline XRPD patterns were observed in the wellplate experiments with sulfuric acid (
Five crystalline forms of the sulfate salt were prepared from the scale-up experiments (Table 22A). Material exhibiting the XRPD pattern of crystalline 1 resulted from a fast evaporation experiment in methanol. Two equivalents of the free base were utilized in the salt preparation. The structure of the sulfate salt was confirmed by proton NMR (
The sulfate salt (crystalline 1) was characterized using thermal techniques (
Materials with crystalline patterns 2-4 observed earlier in the wellplate preparations were not reproduced. Material of crystalline 2 minus peaks was determined to be the hydrosulfate salt by proton NMR (one equivalent of sulfuric acid used
Materials exhibiting new XRPD patterns designated as crystalline 5, 6, 7, and low crystalline 8 were prepared from the scale-up experiments as summarized in
The aqueous solubility of the sulfate salt was lower than 1 mg/mL, and the hydrosulfate salt approximately 1 mg/mL (Table 63A).
1H NMR
aendo = endotherm, exo = exotherm, temperatures (C.°) reported are transition maxima. Temperatures are rounded to the nearest degree.
bweight loss (%) at a certain temperature; weight changes (%) are rounded to 2 decimal places; temperatures are rounded to the nearest degree
cactual ratio used to make the salt
1H NMR
1H NMR
aactual ratio used to make the salt
1H NMR
aactual ratio used to make the salt
1H NMR
aactual ratio used to make the salt
Solubility of the Salts
(1R)-10-Camphorsulfonate Salt
Approximate solubilities of (1R)-10-camphorsulfonate (camsylate) salt were determined in solvents listed in Table 56A. The (1R)-10-camphorsulfonate salt showed low solubilities in methanol and 2,2,2-trifluoroethanol (approx. 3 mg/mL) and was practically insoluble in other organic solvents and water.
Fumarate Salt
Approximate solubilities of the fumarate salt were determined in solvents listed in Table 57A. The fumarate salt was poorly soluble in water (approx. 1.4 mg/mL) and insoluble in organic solvents.
Malonate Salt
Approximate solubilities of the malonate salt were determined in solvents listed in Table 58A. The malonate salt showed low solubilities in methanol, water, acetone, and 2,2,2-trifluoroethanol and no solubility in other organic solvents.
L-Tartrate Salt
Approximate solubilities of the L-tartrate salt were determined in solvents listed in Table 59A. The L-tartrate salt showed low solubilities in methanol (approx. 8 mg/mL), acetone and water (approx. 1 mg/mL) and no solubility in other organic solvents.
Tosylate Salt
Approximate solubilities of the tosylate salt were determined in solvents listed in Table 60A.
Other Salts
Aqueous solubilities of the crystalline salts from the wellplates or scale-up preparations were estimated (Table 63A).
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
bA more precise measurement of solubility was required for this solvent.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
1b
1c
1b
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
bDissolved after approximately 2 days.
cDissolved after approximately 0.5 h.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.
aSolubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution.
bMean value of 22.5 mg/mL (2449-53-01) and 10.4 mg/mL (2449-84-01).
The most preferred methods of preparing the various polymorphic forms are given below. Each process description defines a further aspect of the present invention.
After each process, the resulting material was analyzed by XRPD and in some instances other analytical methods and designated as the titled material.
20.1 mg of L-Tartrate salt was left to slurry in 20 mL of acetonitrile for 7 days under ambient conditions.
24.0 mg of L-Tartrate salt was left to slurry in 20 mL of ethyl acetate for 7 days under ambient conditions.
24.5 mg malonate salt was left to slurry in 20 mL of methyl ethyl ketone for 7 days under ambient conditions.
A filtered solution of 21.2 mg of tosylate salt in 1.1 mL of methanol was allowed to fast evaporate under ambient conditions.
21.6 mg of tosylate salt was left to slurry in 20 mL of acetonitrile for 7 days under ambient conditions.
44.5 mg of tosylate salt was left to slurry in 2 mL of iso-propanol for 4 days under ambient conditions.
(a) 49.1 mg of tosylate salt was dissolved in 10 mL of 2,2,2-trifluoroethanol with sonication. 3 of 10 mL of 2,2,2-trifluoroethanol were added with sonication, the rest without. Solution was filtered then allowed to fast evaporate under ambient conditions in a hood.
(b) A filtered solution of 21.6 mg of tosylate salt in 5.0 mL of 2,2,2-trifluoroethanol was allowed to fast evaporate under ambient conditions.
20.3 mg of tosylate salt was left to slurry in 20 mL of ethyl acetate for 7 days under ambient conditions.
A filtered solution of tosylate salt in 4 mL of water was allowed to fast evaporate under ambient conditions.
51.8 mg of tosylate salt was left to slurry in 2 mL of tetrahydrofuran (THF) for 4 days under ambient conditions.
21.1 mg of camsylate salt was left to slurry in 10 mL of acetone under ambient conditions.
22.8 mg of fumarate salt was left to slurry in 20 mL of acetone for 7 days under ambient conditions.
5 mL of methanol was dispensed into 50.0 mg of compound 2 with sonication. 10 μL of glacial acetic acid was dispensed into the solution with stirring. The solution was then allowed to fast evaporate to dryness under ambient conditions.
Approximately 200 mg of compound 2 was dissolved in 5.5 mL of methanol with stirring on a hot plate. Temperature in the solution was measured at 55° C. 98.9 mg of adipic acid were dissolved in 0.3 mL of methanol at 55° C. The clear acid solution was added to the compound 2 solution with stirring. The solution was allowed to fast evaporate to dryness under ambient conditions in a hood.
51.1 mg of compound 2 was dissolved in 3.5 mL of methanol with sonication. 23.1 mg of glutaric acid were dissolved in 0.5 mL of methanol and added to the free base solution. 4 mL of ethyl acetate was added to the solution. The solution was allowed to fast evaporate to dryness under ambient conditions in a hood.
202.8 mg of compound 2 was dissolved in 6 mL of methanol with stirring on a hot plate. Temperature in the solution was measured at 50° C. 52.0 mg of glycolic acid were dissolved in 0.1 mL of methanol at 50° C. The clear acid solution was added to the free base solution. 6.1 mL of acetonitrile was added to the solution. The solution was allowed to slow cool under ambient conditions.
51.5 mg of compound 2 was dissolved in 4 mL of methanol with sonication. 23.8 mg of L-malic acid were dissolved in 0.1 mL of methanol and added to the free base solution. The solution was allowed to fast evaporate to dryness under ambient conditions in a hood.
Preparation of the citric salt crystalline form 1 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in acetone at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute citric acid solution was added (in methanol, 0.1M) to the well at slightly more than half a molar equivalent with respect to the active pharmaceutical ingredient (API). The plate was covered with a selfadhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient temperature orbital shaker for 11 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 25 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 1 hour. 75 μL of acetonitrile were added to the well C03. Finally, the plate was placed in a hood and allowed to evaporate until dry under ambient conditions.
Approximately 200 mg of compound 2 was dissolved in 8 mL of acetone with stirring on a hot plate. Temperature in the solution was measured at 50° C. 141.9 mg of citric acid monohydrate were dissolved in 0.2 mL of methanol on a hot plate with stirring. The citric acid solution was added to the free base solution with stirring. Temperature in the solution was measured at 50° C. The solution was allowed to slow cool under ambient conditions.
50.8 mg of compound 2 was dissolved in 3.5 mL of methanol with sonication. 26.9 mg of gentisic acid were dissolved in 0.5 mL of methanol and added to the free base solution. 4 mL of ethyl acetate was added to the solution. The solution was allowed to fast evaporate to dryness in a hood under ambient conditions.
Preparation of the gentisic salt crystalline form 2 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in methanol at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute gentisic acid solution was added (in methanol, 0.1M) to the well at slightly more than one molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 11 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 1 hour. 75 μL of ethyl acetate were added to the well D06. Finally, the plate was placed in a hood and allowed to evaporate until dry under ambient conditions. The resulting material was analyzed by XRPD and designated as gentisate salt crystalline form 2.
Preparation of the maleic salt crystalline pattern 1 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in methanol at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute maleic acid solution was added (in methanol, 0.1M) to the well at slightly more than half a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μL of ethyl acetate were added to the well C05. Finally, the plate was fast evaporated until dry under ambient conditions.
50.3 mg of compound 2, batch AB060109/1 was dissolved in 4 mL of methanol with sonication. 19.6 mg of maleic acid were dissolved in 0.2 mL of methanol and added to the free base solution. The solution was fast evaporated until dryness under ambient conditions in a hood.
Preparation of the hydrobromide salt crystalline form 1 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in 2,2,2-trifluoroethanol at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute HBr acid solution was added (in methanol, 0.1M) to the well at slightly more than one molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μl, of toluene were added to the well A12. Finally, the plate was fast evaporated until dry under ambient conditions.
Preparation of the hydrobromide salt crystalline form 2 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in acetone at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute HBr acid solution was added (in methanol, 0.1M) to the well at slightly more than one molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 0.8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μL of acetonitrile were added to the well A01. Finally, the plate was fast evaporated until dry under ambient conditions.
50.2 mg of compound 2 was dissolved in 6 mL of acetone with sonication. 18.7 μL of HBr acid were dispensed into the free base solution with sieving. The solution was fast evaporated until dryness under ambient conditions.
Preparation of the succinate salt crystalline form 1 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in methanol at approximately 10 mg/mL, adding 0.1 mL of the solution in a well. Dilute succinic acid solution was added (in methanol, 0.1M) to the well E06 at slightly more than half a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions.
Preparation of the succinate salt crystalline form 2 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in 2,2,2-trifluoroethanol at approximately 10 mg/mL, adding 0.1 mL of the solution in well E12. Dilute succinic acid solution was added (in methanol, 0.1M) to the well at slightly more than half a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μL of toluene were added to the well. Finally, the plate was fast evaporated until dry under ambient conditions.
102.4 mg of compound 2, batch AB060109/1 was dissolved in 8 mL of 2,2,2-trifluoroethanol. 41.3 mg of succinic acid was dissolved in 0.8 mL of methanol and added to the free base solution. 4.4 mL of the solution were taken out for another sample. The remaining solution was fast evaporated until dryness under ambient conditions in a hood.
Preparation of the phosphoric salt crystalline form 1 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in 2,2,2-trifluoroethanol at approximately 10 mg/mL, adding 0.1 mL of the solution in well G12. Dilute phosphoric acid solution was added (in methanol, 0.1M) to the well at slightly more than a third of a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions.
Preparation of the phosphoric salt crystalline form 2 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in acetone at approximately 10 mg/mL, adding 0.1 mL of the solution in well G02. Dilute phosphoric acid solution was added (in methanol, 0.1M) to the well at slightly more than a third of a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions.
Preparation of the phosphoric salt crystalline form 3 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in methyl ethyl ketone at approximately. 10 mg/mL, adding 0.1 mL of the solution in well G07. Dilute phosphoric acid solution was added (in methanol, 0.1M) to the well at slightly more than a third of a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μL of isopropanol were added to the well. Finally, the plate was fast evaporated until dry under ambient conditions.
Preparation of the phosphoric salt crystalline form 4 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving compound 2 in methyl ethyl ketone at approximately 10 mg/mL, adding 0.1 mL of the solution in well G08. Dilute phosphoric acid solution was added (in methanol, 0.1M) to the well at slightly more than a third of a molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was left uncovered to complete evaporation under ambient conditions. The plate was then used in a recrystallization experiment. 75 μL of methanol was added to the well and the plate was loaded on an ambient-temperature orbital shaker at approximately 150 RPM for 30 minutes. 75 μL of isopropanol were added to the well. Finally, the plate was fast evaporated until dry under ambient conditions.
49.7 mg of Compound 2 was dissolved in 5 mL of methanol with sonication. Dispensed 11.5 μL of phosphoric acid into the free base solution with stirring. The solution was allowed to fast evaporate until dryness under ambient conditions.
1 mL of Compound 2 was dissolved in 1 mL of methanol. The solution was stirred on a RT plate at 60 RPM. 73 μL of phosphoric acid was added. The experiment was performed in a dark fume hood.
10 mg of Compound 2 was dissolved in 5 mL of methanol and 1 mL of 2,2,2-trifluoroethanol. The solution was stirred on a RT plate at 60 RPM. 73 μL of phosphoric acid was added. The experiment was performed in a dark fume hood. A white precipitate (solids) was instantly generated upon acid addition.
103 mg of Compound 2 was dissolved in 10 mL of methanol with sonication. 22.6 μL of 85% phosphoric acid were added to the free base solution with stirring. The solution was allowed to fast evaporate until dryness under ambient conditions in a hood.
64 mg of Compound 2 was dissolved in 2 mL of methanol. 98 mg of sulfuric acid was dissolved in 1 mL of methanol and added to the free base solution. The solution was shaken then allowed to fast evaporate until dryness under ambient conditions.
Preparation of the sulfuric salt crystalline form 2 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving Compound 2 in methanol at approximately 10 mg/mL, adding 0.1 mL of the solution in well F06. Dilute sulfuric acid solution was added (in methanol, 0.1M) to the well at slightly more than half the molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions.
Preparation of the sulfuric salt crystalline form 3 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving Compound 2 in acetone at approximately 10 mg/mL, adding 0.1 mL of the solution in well F06. Dilute sulfuric acid solution was added (in methanol, 0.1M) to the well, at slightly more than half the molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 0.8 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions.
Preparation of the sulfuric salt crystalline form 4 was carried out in a 96-well polypropylene plate using the following procedure. A solution was prepared by dissolving Compound 2 in methanol at approximately 10 mg/mL, adding 0.1 mL of the solution in well F05. Dilute sulfuric acid solution was added (in methanol, 0.1M) to the well at slightly more than half the molar equivalent with respect to the API. The plate was covered with a self-adhesive aluminum foil cover and allowed to mix at approximately 25 RPM on an ambient-temperature orbital shaker for 8 days. Some evaporation occurred during mixing. The plate was observed after 3 days by optical microscopy and returned to the shaker. The plate was left uncovered to complete evaporation under ambient conditions.
64 mg of Compound 2 was dissolved in 5 mL of acetone. 99 mg of sulfuric acid was dissolved in 1 mL of acetone and added to the free base solution. The solution was shaken and sonicated, then allowed to fast evaporate until dryness under ambient conditions.
49.9 mg of Compound 2 was dissolved in 4 mL of methanol with sonication. 9.4 μL of sulfuric acid were added to the free base solution. 4 mL of ethyl acetate were added to the free base solution. The solution was allowed to fast evaporate until dryness under ambient conditions.
62 mg of Compound 2 was dissolved in 5 mL of acetone. 99 mg of sulfuric acid was dissolved in 1 mL of acetone and added to the free base solution. The solution was shaken and sonicated, then allowed to fast evaporate until dryness under ambient conditions.
41 mg of the material were weighed into a vial. 2 mL of acetone were added. The mixture was shaken and sonicated then slurried at ambient temperature.
1 mL of Compound 2 was dissolved in 1 mL of 2,2,2-trifluoroethanol. The solution was stirred on a RT plate at 60 RPM. 73 μL of sulfuric acid was added. After a few minutes, the stir rate was briefly increased to 200 RPM, then reduced back to 60 RPM. The experiment was performed in a dark fume hood.
30.9 mg of compound 2 was dissolved in 1 mL of acetonitrile with sonication. The solution was left to slurry for 7 days under ambient conditions.
It will be appreciated that the invention may be modified within the scope of the appended claims.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/PT08/00052 | 12/5/2008 | WO | 00 | 10/4/2010 |
| Number | Date | Country | |
|---|---|---|---|
| 60992398 | Dec 2007 | US |
