New Crystal Forms

Information

  • Patent Application
  • 20100113550
  • Publication Number
    20100113550
  • Date Filed
    May 31, 2007
    17 years ago
  • Date Published
    May 06, 2010
    14 years ago
Abstract
Polymorphs of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and methods of their preparation.
Description

This invention relates to polymorphs of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and methods of their preparation.


(R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (the compound of formula 1, below) is a potent, non-toxic and peripherally selective inhibitor of D b H, 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 1, which precipitates as it forms as the amorphous form.


The present invention provides crystalline polymorphs of compound 1 which exhibit higher purity than the amorphous form prepared by the WO2004/033447 process. The crystalline forms are prepared from crystallisation or recrystallisation of pre-formed compound 1 (either the amorphous faun or one of the other crystalline forms). The present invention also provides a characterisation of the amorphous form of compound 1 and processes for its preparation. The amorphous form produced according to the processes of the present invention is also a part of the present invention.


The present invention further provides improved processes for preparing compound 1. The processes can be used to produce the precursor compound 1 in the preparation of the polymorphs and amorphous form of compound 1 of the present invention.


According to a first aspect of the present invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 8.3 and 26.8±0.2° 2#. The XRPD pattern for crystalline Form A may have further peaks at 15.0, 16.2, and 24.2±0.2° 2#. The XRPD pattern for crystalline Form A may have still further peaks at 4.9, 12.9, 19.8, 21.8 and 22.9±0.2° 2#.


According to another aspect of the invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 1.


In an embodiment, crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 0.09 to about 0.65 moles.


According to another aspect of the present invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having characteristic FT-IR peaks at 1491.90, 1220.70, 1117.50, 1039.50, 851.80 and 747.00 cm−1. The crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have further characteristic FT-IR peaks at 3053.30, 1599.80, 1406.10, 1330.70, 1287.60, 1194.00, 985.50 and 713.70 cm−1. The crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have still further characteristic FT-IR peaks at 2939.70, 1448.30 and 1244.50 cm−1.


According to another aspect of the present invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the FT-IR spectrum of FIG. 6.


According to another aspect of the present invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the DSC thermogram of FIG. 9.


According to another aspect of the present invention, there is provided crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%. The purity may be in the range of 99.0% to 99.9%. In an embodiment, the purity may be in the range of 99.0% to 99.8%. In particular, the purity may be in the range of 99.2% to 99.8%. More particularly, the crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have a purity of 99.5%.


According to another aspect of the present invention, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 8.0 and 8.6±0.2° 2#. The XRPD pattern for crystalline Form B may have further peaks at 13.6, 14.4, 16.0, 24.3 and 26.7±0.2° 2#. The XRPD pattern for crystalline Form B may have still further peaks at 4.8, 12.7, 13.6, 14.4, 15.2, 21.7 and 22.9±0.2° 2#.


According to another aspect of the present invention, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 2.


In an embodiment, crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 1.1 to about 1.4 moles. In a further embodiment, crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is a monohydrate.


According to another aspect of the present invention, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the DSC thermogram of FIG. 10.


According to another aspect of the present invention, there is provided crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%. The purity may be in the range of 99.0% to 99.9%. For example, the purity may be in the range of 99.0% to 99.8%. In particular, the purity may be in the range of 99.2% to 99.8%. More particularly, the crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have a purity of 99.5%.


According to another aspect of the present invention, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 13.9, 18.1, 22.1, 25.1 and 25.7±0.2° 2#. The XRPD pattern for Form C may have further peaks at 15.3, 17.7 and 20.2±0.2° 2#. The XRPD pattern for Form C may have still further peaks at 16.2, 16.7, 21.0 and 24.2 0.2° 2#.


According to another aspect of the present invention, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 3.


According to another aspect of the present invention, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having characteristic FT-IR peaks at 1492, 1220.2, 1117.4, 1033.4, 845.2, 792.6 and 750.1 cm−1. The crystalline Form C may have further characteristic FT-IR peaks at 3041.70, 1596.50, 1403.40, 1333.80, 1290.90, 1173.20, 1078.10, 984.90 and 713.20 cm−1.


According to another aspect of the present invention, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the FT-IR spectrum of FIG. 7.


According to another aspect of the present invention, there is provided crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%. The purity may be in the range of 99.0% to 99.9%. For example, the purity may be in the range of 99.0% to 99.8%. In particular, the purity may be in the range of 99.2% to 99.8%. More particularly, the crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have a purity of 99.5%.


According to another aspect of the present invention, there is provided crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 5.4, 10.2, 12.4 and 18.6±° 2#. The XRPD pattern for crystalline Form X may have further peaks at 6.2, 9.5, 11.2 and 16.2±° 2#.


According to another aspect of the present invention, there is provided crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 4.


According to another aspect of the present invention, there is provided crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%. The purity may be in the range of 99.0% to 99.9%. For example, the purity may be in the range of 99.0% to 99.8%. In particular, the purity may be in the range of 99.2% to 99.8%. More particularly, the crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride may have a purity of 99.5%.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising recrystallising (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in aqueous HCl.


In an embodiment, the recrystallisation comprises (a) dissolving (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in aqueous HCl, (b) filtering the solution, (c) cooling the solution with stirring, and (d) isolating, washing and drying the precipitated Form A.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising forming (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in situ and crystallising Form A using aqueous HCl. Thus, Form A of compound 1 crystallises and may be isolated, followed by optional recrystallisation to form one of the polymorphic forms.


In an embodiment, the crystallisation comprises (a) adding aqueous HCl to a solution of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride, (b) cooling the solution with stirring and (c) isolating, washing and drying the precipitated Form A.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising subjecting Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride to 43% to 90% relative humidity.


In an embodiment, the relative humidity is from 55% to 65%.


The subjecting step may take place within a time range from 1 day to 2 weeks. In an embodiment, the subjecting step takes place over 1 to 2 days. Preferably, the subjecting step takes place at 25° C.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising dissolving or slurrying Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in an organic solvent, or mixtures of organic solvents, filtering the solution and allowing the solvent to evaporate.


The organic solvent may be selected from ethyl ether, hexane, acetonitrile, 1,4-dioxane, ethanol, ethyl acetate, hexafluoroisopropanol, methanol, methylene chloride, methyl ethyl ketone, toluene, propionitrile, trifluorotoluene, cyclohexane, methyl iso-butyl ketone, n-butyl acetate, acetone, toluene, iso-propyl ether and mixtures thereof.


In an embodiment, the solvent is allowed to evaporate from an open vial. In an alternative embodiment, the solvent is allowed to evaporate from a vial covered with a perforated material.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising subjecting Form A or B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in a solution of ethanol or ethanol/solvent mixtures to evaporation under nitrogen.


According to another aspect of the present invention, there is provided a process for preparing crystalline Faun C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising: (a) stirring a mixture of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in a first organic solvent and an aqueous solution of a base, wherein the first organic solvent is immiscible with water; (b) extracting the organic phase and evaporating the product to dryness; (c) dissolving the product of (b) in dry ethanol; (d) acidifying the product of step (c) with HCl in ethanol; (e) collecting the precipitate; (f) washing the precipitate with ethanol; and (g) drying the product of step (f) to yield Form C.


The first organic solvent may be ethyl acetate. Preferably, the precipitate is collected hot.


In an embodiment, the (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is prepared prior to step (a) and converted to Form C in situ by steps (a) to (g). Thus, Form C of compound 1 crystallises and may be isolated, followed by optional recrystallisation to form one of the polymorphic forms.


In an alternative embodiment, the (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is prepared prior to step (a), isolated and then converted to Form C by steps (a) to (g).


According to another aspect of the present invention, there is provided a process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising slurrying Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in acetonitrile and isolating Form C by vacuum filtration.


In an embodiment, the slurrying is carried out for a period of time ranging from 4 days to 7 days.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising preparing a saturated solution of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in methanol at an elevated temperature, filtering the warm solution, cooling the solution, and isolating the Form C.


In an embodiment, the cooling brings the temperature of the solution to room temperature.


In another embodiment, the solids are isolated by decantation followed by air drying.


According to another aspect of the present invention, there is provided a process for preparing crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising dissolving Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in methanol, filtering the solution and evaporating the methanol under a stream of nitrogen.


In an embodiment, the evaporation is carried out at about 9% relative humidity.


In another embodiment, the evaporation is carried out at room temperature.


According to another aspect of the present invention, there is provided a pharmaceutical formulation comprising Form A according to the present invention, Form B according to the present invention, Form C according to the present invention or Form X according to the present invention of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and one or more pharmaceutically acceptable carriers or excipients.


According to another aspect of the present invention, there is provided Form A according to the present invention, Form B according to the present invention, Form C according to the present invention or Foam X according to the present invention of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride for use in medicine.


According to another aspect of the present invention, there is provided the use of Form A according to the present invention, Form B according to the present invention, Form C according to the present invention or Form X according to the present invention of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in the manufacture of a medicament for treatment of cardiovascular disorders such as congestive heart failure, treatment of angina, treatment of arrhythmias, treatment of circulatory disorders such as Raynaud's Phenomenon (sometimes known as ‘Raynaud's Disease’), treatment of migraine, and treatment of anxiety disorders.


According to another aspect of the present invention, there is provided the use of Form A according to the present invention, Form B according to the present invention, Form C according to the present invention or Form X according to the present invention of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in the manufacture of a medicament for peripherally-selective inhibition of D#H.


In this specification, the term ‘compound 1’ refers to (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride.


The polymorphs of the present invention are easily prepared and produced in a higher purity than compound 1 synthesised according to the WO2004/033447 process. The purity of the polymorphs of the present invention is particularly advantageous, as it has not previously been possible to achieve the levels of purity which are obtained by the processes of the present invention. Some of the polymorphs are stable to degradation under high humidity for long periods of time.





Reference is made to the accompanying Figures in which:


FIG. 1—XRPD pattern of Form A


FIG. 2—XRPD pattern of Form B


FIG. 3—XRPD pattern of Form C


FIG. 4—XRPD pattern of Form X


FIG. 5—XRPD pattern of amorphous form


FIG. 6—FT-IR spectrum of Form A


FIG. 7—FT-IR spectrum of Form C


FIG. 8—Stacked FT-IR spectrum of Forms C (top) and A (bottom)


FIG. 9—DSC thermogram for Form A


FIG. 10—DSC thermogram for Form B


FIG. 11—DSC thermogram for Form C


FIG. 12—DSC thermogram for Form X





The analysis of the products of the present invention has shown Faun A to be a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 0.09 to about 0.65 moles, Form B to be a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 1.1 to about 1.4 moles, Form C to be an anhydrous, unsolvated and non-hygroscopic crystalline solid, and Form X to be crystalline with a disordered crystalline pattern. Form X has also been characterised as a variable hydrate with the number of moles of water varying from 0.26 to 1.85 moles. In an embodiment, Form B is a monohydrate. The chemical structure of all forms was confirmed by 1H NMR spectroscopy.


Forms B and C of the present invention are advantageous in terms of their stability in that they remain stable under high relative humidities for long periods of time. Furthermore, Form C has been found to be non-hygroscopic.


A further advantage of the polymorphs of the present invention is that they are produced with a high purity, particularly compared to the compound 1 produced according to WO2004/033997. The compound 1 produced according to the WO2004/033997 process has a typical purity of 97%. Typically, the crystalline forms A, B, C and X of the present invention have a purity greater than 97.0% More particularly, the polymorphs have a purity greater than or equal to 97.5%. Advantageously, the polymorphs have a purity greater than or equal to 98.0%. More advantageously, the polymorphs have a purity greater than or equal to 98.5%. Still more advantageously, the polymorphs have a purity greater than or equal to 99.0%. In a preferred embodiment, the polymorphs have a purity greater than or equal to 99.5%.


Form A has been found to be produced by recrystallising compound 1 in aqueous HCl. In an embodiment, the recrystallisation comprises (a) dissolving compound 1 in aqueous HCl, (b) filtering the solution, (c) cooling the solution with stirring, and (d) isolating, washing and drying the precipitated Form A.


Form A may also be produced by forming compound 1 in situ and crystallising


Form A using aqueous HCl. In other words, compound 1 is not isolated to form a solid before being converted to Form A. In an embodiment, the crystallisation comprises (a) adding aqueous HCl to a solution of compound 1, (b) cooling the solution with stirring and (c) isolating, washing and drying the precipitated Form A.


It has also been found that Form A converts to Form B under high laboratory humidity, typically 43% to 90% relative humidity, and particularly, at 55% to 65% relative humidity. The conversion may take place within a time range from 1 day to 2 weeks, and typically after 1 to 2 days. Form B can be dehydrated upon desorption (drying) to convert back to Form A.


Form B has also been found to be produced from vapour stress in ethyl acetate and from experiments using aqueous mixtures of acetone, acetonitrile and ethanol.


Further, Form B has been found to be produced by recrystallising compound 1 from ethanol and toluene.


Form C has been found to be produced by stirring a mixture of compound 1 in a first organic solvent and an aqueous solution of a base, wherein the first organic solvent is immiscible with water; (b) extracting the organic phase and evaporating the product to dryness; (c) dissolving the product of (b) in dry ethanol; (d) acidifying the product of step (c) with HCl in ethanol; (e) collecting the precipitate; (f) washing the precipitate with ethanol; and (g) drying the product of step (f) to yield Form C.


Compound 1 may be isolated before formation of Form C, or compound 1 may be reacted in situ to produce Form C. In other words, compound 1 may be synthesised and converted to Form C without compound 1 being isolated as a solid.


Form C has been found to form during evaporation experiments under nitrogen that used ethanol or ethanol mixtures with other solvents.


Form C was frequently obtained when ethanol, ethyl acetate, and acetonitrile were used for crystallisation.


Form X has been found to be produced by dissolving Form A of compound 1 in methanol, filtering the solution and evaporating the methanol under a stream of nitrogen.


Interconversion studies on Forms A and C in ethanol and acetone:water 99:1 indicated that Form C may be more thermodynamically stable than Form A.


The amorphous form may be prepared by lyophilisation of an aqueous solution of Form A of compound 1.


The amorphous form produced according to the processes of the present invention exhibits higher solubilities in most organic solvents and water compared to Forms A, B, and C of compound 1.


The amorphous form prepared by lyophilisation of Form A will exhibit the same purity as that of the Form A from which it is lyophilised. Thus, the amorphous form prepared in this way will exhibit higher purity than the amorphous form prepared by the WO2004/033447 process.


The invention will now be described with reference to the following non-limiting examples.


EXAMPLE 1
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form A

A sample of compound 1 (20 g) prepared according to the method disclosed in WO2004/033447 was stirred in 2N HCl (500 mL) at 75° C. until a clear solution was obtained. The solution was filtered, cooled in the ice bath, and left in the ice bath for 1 h with stirring. Precipitate was collected, washed with cold 2N HCl (ca. 100 mL), cold IPA (ca. 100 mL), dried in vacuum at 40° C. to constant weight. Yield 17.5 g (88%). HPLC purity 99.0%.


EXAMPLE 2
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form A

A sample of compound 1 was prepared. Before isolation of the compound 1 to form a solid, 6N HCl (40 mL) was added to a solution of compound 1, the suspension was cooled in ice for 1 h with stirring, the precipitate was collected, washed with cold 3N HCl (75 mL), cold IPA (50 mL), and dried in a vacuum at 50° C. Yield 11.58 g (73%). HPLC purity 99.8%.


EXAMPLE 3
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form B

A sample of Form A of compound 1 (1 g) was kept at 65% relative humidity and 25° C. for 48 h. Yield 1.05 g. HPLC purity 99.8%.


Karl Fisher analysis showed Form B to contain approximately 6.6% or 1.3 moles of water.


Form B was found to be stable at 90% relative humidity and no deliquescence was observed at 90% relative humidity after 10 days.


Further preparations of Form B were carried out at varying relative humidities. The number of moles of water depended on the relative humidity and varied from about 1.1 to about 1.4 moles.


Thus, Form B is a variable hydrate of compound 1.


EXAMPLE 4
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form C

Form A as prepared above, or compound 1 prepared according to the method disclosed in WO2004/033997 was stirred in the mixture of ethyl acetate (150 mL) and 10% NaHCO3 solution in water for 15 min at room temperature. Organic phase was separated, evaporated to dryness under reduced pressure, the residue was taken up into dry ethanol (100 mL). The solution was acidified with 3M HCl in ethanol to pH 2 and stirred at 65-70° C. for 2 h. The precipitate was collected hot, washed with ethanol dried in vacuum at 40° C. to constant weight. Yield 8.24 g (82%). HPLC purity 99.5%.


EXAMPLE 5
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl-1,3-dihydroimidazole-2-thione hydrochloride Form C

The free base of compound 1 produced in situ was dissolved with heating in a mixture of absolute EtOH (15 mL) and 3M HCl in absolute EtOH (1.5 mL, pH of the mixture approximately 2). The resulting solution was stirred at 65-70° C. for 2 hours, the crystals were collected, washed with EtOH, and dried in vacuum at 40° C. Yield 1.12 g (71%). HPLC purity 99.5%.


EXAMPLE 6
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form C

Form A was stirred in acetonitrile at room temperature for 96 h under nitrogen. Solid was collected, dried in vacuum at 40° C. to constant weight. Yield 1.8 g (90%). HPLC purity 99.8%.


Form C did not deliquesce after one week at approximately 65% relative humidity, nor after 11 days at approximately 90% relative humidity.


EXAMPLE 7
Preparation of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride Form X

Form A of compound 1 (200 mg) was dissolved in methanol (5 mL), the solution was filtered through a 0.2-μm nylon filter and evaporated at room temperature under a stream of nitrogen (ca 9% relative humidity).


EXAMPLE 8
Crystallisation Experiments on Forms A, B, C, X and the Amorphous Form

Crystallisation experiments were carried out on the different Forms of compound 1. The methods used were slurrying, fast evaporation, slow evaporation, crash cooling, c rash precipitation and slow cool, as described below. Interconversion experiments were also undertaken.


Slurrying


Slurries of compound 1 were prepared by adding enough solids to a given solvent at ambient 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 temperature or elevated temperature for a certain period of time, typically 7 days. The solids were isolated by vacuum filtration or by drawing the liquid phase off with a pipette and allowing the solids to air dry at ambient conditions prior to analysis.


Fast Evaporation


Solutions of compound 1 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 temperature in an open vial. The solids were isolated and analyzed.


Slow Evaporation


Solutions of compound 1 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 in a vial covered with aluminum foil perforated with pinholes. The solids were isolated and analyzed.


Crash Cooling


A saturated solution of compound 1 was prepared in methanol at an elevated temperature and filtered warm through a 0.2-μm nylon filter into an open vial while still warm. The vial was capped and cooled to room temperature. Solids were isolated by decanting the solvent and allowed to air-dry prior to analysis.


Crash Precipitation (CP)


Saturated solutions of compound 1 were prepared in various solvents and filtered through a 0.2-μm nylon filter into an open vial. Aliquots of various antisolvents were dispensed until precipitation occurred. Solids were collected by vacuum filtration or by drawing solvent off with a pipette and allowing the solids to air dry at ambient conditions prior to analysis.


Slow Cool (SC)


Saturated solutions of compound 1 were prepared in various solvents at an elevated temperature and filtered warm through a 0.2-μm nylon filter into an open vial while still warm. The vial was capped and left on the hot plate, and the hot plate was turned off to allow the sample to slow cool to ambient temperature. The solids were isolated by vacuum filtration and analyzed.


Interconversion Experiments


A slurry of compound 1, Form A, was prepared in a given solvent and loaded on an orbit shaker at either ambient or elevated temperature for at least 1 day. The liquid phase of the slurry was drawn off with a pipette and filtered through a 0.2-μm filter. A slurry containing compound 1 forms A and C was prepared using the filtered liquid phase from the Form A slurry. The mixture was then loaded on an orbit shaker in a sealed vial at either ambient or elevated temperature for 1 or 7 days. The solids were isolated by vacuum filtration or by drawing the liquid phase off with a pipette and allowing the solids to air dry at ambient conditions prior to analysis.


The resulting Forms were characterised by XRPD.


A capillary screen was conducted on Form A and the amorphous form using solvent/antisolvent crystallisations and vapor stress experiments. Various crystallisation techniques were employed. These techniques are described below. X-ray powder diffraction quality capillaries were used. Once solids were observed from the crystallisation attempts, they were examined under a microscope for birefringence and morphology. Any crystalline shape was noted, but sometimes the solid exhibited unknown morphology, in some cases due to the packing in the capillary or to small particle size. When sufficient, solid samples were then analyzed by XRPD.


CentriVap Crystallisations—Form A


A solution of Form A in a given solvent at an approximate concentration of 87 mg/mL was prepared and filtered through a 0.2-μm filter. A capillary was filled with 15 μL of solution, and then 25 μL of an antisolvent was added. The capillary was centrifuged. The solvent was evaporated in a Labconco CentriVap® centrifugal evaporator under reduced pressure using a mechanical vacuum pump. The evaporator temperature was maintained at ambient temperature.


CentriVap Crystallisations (CentriVap)—Amorphous form


A solution of compound 1, amorphous, in a given solvent was prepared and filtered through a 0.2-μm filter. A capillary was filled with 45 μL of solution via syringe. The capillary was centrifuged. The solvent was evaporated in a Labconco CentriVap® centrifugal evaporator under reduced pressure using a mechanical vacuum pump. The evaporator temperature was maintained at ambient temperature.


Crystallisations by Fast Evaporation


A solution of Form A in a given solvent at an approximate concentration of 87 mg/mL was prepared and filtered through a 0.2-μm filter. A capillary was filled with 15 μl, of solution, and then 25 μL of an antisolvent was added. The capillary was centrifuged. Evaporations were performed in open capillaries at ambient temperature.


Evaporation in Capillary (EC)


A solution of compound 1, amorphous, in a given solvent was prepared and filtered through a 0.2-μm filter. A capillary was filled with 45 μL of solution via syringe. The capillary was centrifuged. Evaporations were preformed in open capillaries at ambient and elevated temperatures or under nitrogen flow with low (approximately 19%) relative humidity at ambient temperature.


Solvent/Antisolvent Crystallisations in Capillary


A solution of compound 1, amorphous, in a given solvent was prepared and filtered through a 0.2-μm filter. A capillary was filled with 15 μL of solution and centrifuged down. Then 30 μL of an antisolvent was added. The capillary was centrifuged. If a clear solution resulted the capillary was left at ambient to allow the solvents to evaporate or evaporation was performed in a Labconco Centrivap centrifugal evaporator under reduced pressure using mechanical pump at ambient. Evaporation was carried out also under nitrogen flow with low (approximately 19%) relative humidity.


Vapor Diffusion into Solid or Vapor Stress (VS)—Form A


Capillaries were packed with approximately 1 cm of Form A. The capillaries were placed in tall vials containing about 5 mL of solvents or solvent mixtures. The capillaries were removed after approximately 8 days.


Vapor Diffusion into Solid or Vapor Stress (VS)—Amorphous Form


Capillaries were packed with approximately 1 cm of compound 1, amorphous. The solids were exposed to vapor diffusion by placing the capillaries in tall vials containing about 5 mL of solvents. The capillaries were removed after approximately 10 days.


Results
Polymorph Screen of Compound 1, Form A

Approximate solubilities of compound 1, Form A in aqueous mixtures containing high concentrations of organic solvents are given in Table 1.









TABLE 1







Approximate Solubilities of compound 1, Form A










Solvent
Solubility (mg/mL)a














acetone:water 90:10
>23



acetone:water 99:1
1



acetonitrile:water 90:10
>23



acetonitrile:water 95:5
<23



1,4-dioxane:water 99:1
<24



ethanol:water 90:10
>21



ethanol:water 99:1
<25








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.














TABLE 2







Crystallisation Results on compound 1, Form A










Solvent
Methoda
Observations
XRPD Results





ethyl ether
slurry
light yellow solid
B


hexane
slurry
light yellow solid
B


acetonitrile
slurry, 7 d
white solid
C



slurry, 4 d
white solid
C


1,4-dioxane
slurry
viscous yellow oil



ethanol
FE
white solid
B


ethyl acetate
slurry
white solid
B


hexafluoroisopropanol
FE
white solid
B


methanol
CC
white solid
C



FE
white solid,
B




dendridic




formations


methylene chloride
slurry
white solid
B


methyl ethyl ketone
slurry
light yellow solid
A


toluene
slurry
white solid
B


propionitrile
slurry
white solid
B


trifluorotoluene
slurry
white solid
B


ethanol:acetonitrile
SE
light yellow solid
B


1:1


ethanol:1,4-dioxane
SE
yellow oil



1:1


ethanol:ethyl
SE
light yellow solid
B


acetate 1:1


ethanol:methyl
SE
light brown oil



ethyl ketone 1:1


ethanol:toluene 1:1
SE
light yellow solid
B


ethanol:cyclohexane
SE
white solid
B


1:1


ethanol:methyl iso-
SE
light beige solid
B


butyl ketone 1:1


ethanol:n-butyl
SE
light yellow solid
B


acetate 1:1


ethanol
SE
white solid
B


methanol:methylene
SE
white solid
B


chloride


methanol:acetone
SE
white solid
B


methanol:acetonitrile
SE
white solid
B


methanol:1,4-
SE
light yellow solid
low crystalline B


dioxane


methanol:ethyl
SE
white solid
B


acetate


methanol:methyl
SE
pink solidb
low crystalline B


ethyl ketone


methanol:toluene
SE
white solid
B


methanol:cyclohexane
SE
white solid
B


methanol:iso-propyl
SE
white solid
B


ether


methanol
SE
white solid
B






aFE = fast evaporation, SE = slow evaporation, CC = crash cooling; times are approximate




bpossible impurity/degradation







As the initial polymorph screen results were affected by the laboratory humidity, additional crystallisation experiments were carried out under nitrogen at approximately 9% relative humidity. Methanol, ethanol, and their mixtures with other solvents were used.









TABLE 3







Crystallisation by evaporation under nitrogen













XRPD



Solvent/Solvent Mixture
Observations
Result







methanol
white solid
X



methanol:acetone 1:1
white solid
X



methanol:ethyl acetate 1:1
white solid
X



methanol:isopropyl ether
white solid
X



1:1



methanol:methyl iso-butyl
light yellow solid
Amorphous



ketone 1:1



methanol:n-butyl acetate
white solid, wet
X



1:1



Ethanol
white solid
C



Ethanol:acetonitrile 1:1
white solid
C



ethanol:ethyl acetate 1:1
white solid
C



ethanol:propionitrile 1:1
light yellow solid
C



ethanol:iso-propyl acetate
white solid
C



1:1

















TABLE 4







Capillary screen of Form A by solvent/antisolvent crystallisation















XRPD


Solvent
Antisolvent
Methoda
Morphology
Resultf





MeOH
acetone
FE
White,
C + B





morphology
l.c.





unknown,





not birefringent




CentryVap
White,
X





broken





glass, not birefringent



acetonitrile
FE
White,
B





morphology





unknown,





not birefringent




CentryVap
White,
X





morphology





unknown,





not birefringent



methyl ethyl
FE
Pink




ketone

needles, birefringentb




CentryVap
White, small
B





part





crystalline,





birefrigent,





mostly glass,





not birefringent



ethyl
Precipitation
White,
amorphous +



acetate

dendridic
C peaks





formations,





birefringentc




Precipitation
White,
C





morphology





unknown,





not birefringent



CH2Cl2
Precipitation
White, tiny
C





plates and





needles, birefringent




Precipitation
White, tiny
C





plates, birefringent



methyl t-
Precipitation
White,
B



butyl ether

dendridic





and tiny





plates, birefringent




Precipitation
White,
C + B





dendridic
l.c.





and plates,





birefringent



iso-propyl
Precipitation
White,
C



acetate

morphology





unknown,





not birefringent




Precipitation
White,
B





irregular and





tiny, birefringent



tetrahydrofuran
FE
Off-white,
low





morphology
crystalline





unknown,
B, shifted





not birefringent




CentryVap
White,
amorphous





morphology
or no solid





unknown,





not birefringent



toluene
Precipitation
White,
amorphous +





morphology
C peaks





unknown,





birefringentd




Precipitation
White,
C (l.c.)





morphology





unknown, in





solution, birefringent



2,2,2-triflouro-ethanol
FE
Needles on






sides of





capillarye,





birefringent;





clear viscous





liquid on





bottom


CentryVap

White,
C + B




morphology
l.c.




unknown,




not birefringent






aFE = fast evaporation, CentryVap = evaporation under reduced pressure using centrifugal evaporator




bpink solid (possible impurity/degradation)




cthe solid only on the sides of capillary




dthe solid moved from the originally marked spot




einsufficient for XRPD analysis




fl.c. = low crystalline, i.e. crystalline product having a disordered crystalline pattern














TABLE 5







Vapour stress on Form A













XRPD



Solvent
Morphology
Result







EtOAc
White, morphology
B




unknown, not birefringent



i-PrOH
White, morphology
A




unknown, not birefringent



acetone:water 1:1
White, morphology
B




unknown, not birefringent



acetonitrile:water 4:1
White, morphology
B




unknown, not birefringent



ethanol:water 1:1
White, morphology
B




unknown, not birefringent










Thus, Form A remained unchanged under iso-propanol vapor. Form B resulted from a vapor stress in ethyl acetate (possibly due to the affect of laboratory humidity). Form B also resulted from experiments using aqueous mixtures of acetone, acetonitrile and ethanol.


A further, abbreviated polymorph screen was carried out on Form A by fast evaporation and slimy experiments at ambient temperature and 40° C. The results for the screen are summarized in Table 6 and Table 7. Forms A, B, C, and amorphous material were all produced from these experiments. Whether Form A or Form B was produced is thought to depend on the drying conditions and laboratory humidity.


Form B resulted from t-butyl methyl ether, acetone:water 99:1, and iso-propanol: water 90:10 slurries, likely due to laboratory humidity or drying conditions.


Form C was often produced when ethanol, ethyl acetate, and acetonitrile were used for crystallisation.


Form X was often produced from methanol solutions.









TABLE 6







Crystallisation Experiments on compound 1, Form A










Solvent
Conditionsa
Habit/Description
XRPD Result





t-butyl methyl ether
slurry,
white solid
A



3 days


dichloromethane
slurry,
white, morphology
A



7 days
unknown, not birefringent


ethyl acetate:hexane
slurry,
white, morphology
A


1:1
7 days
unknown, partially




birefringent


acetone:water
FE
white, morphology
B


90:10

unknown, partially




birefringent


acetone:water
slurry,
white, morphology
A


99:1
7 days
unknown, not birefringent



FE (filtrate from
clear glassy slurry)





irregular particles,




partially birefringent


acetonitrile:water
FE
white, morphology
A + B (minor)


90:10

unknown, not birefringent


acetonitrile:water
slurry,
white plates, birefringent
C


95:5
7 days



FE (liquid phase from
white spherulites of




slurry)
fibers, birefringent


1,4-dioxane:water
slurry,
light pink,
A


99:1
7 days
morphology




unknown, not birefringent



FE (liquid phase
yellow glassy film,




from slurry)
not birefringent;




yellow, morphology




unknown, birefringent


ethanol:water
FE
white fibers, birefringent
B + A (minor)


90:10


ethanol:water
slurry,
white blades, birefringent
C


99:1
7 days
white, morphology
C + A (minor)




unknown, partially




birefringent



FE (liquid phase
white fibers, birefringent
amorphous



from slurry)


isopropanol:water
slurry,
white, morphology
B


90:10
7 days
unknown, not birefringent


0.1 N HCl
FE, ambient
white, needles, birefringent
B



FE under N2
white, dendridic
B



~12% RH
formations, birefringent
















TABLE 7







Crystallisation Experiments on compound 1 Form A, at 40° C.













XRPD


Solvent
Conditions
Habit/Description
Resulta





t-butyl methyl
slurry, 40° C.,
off-white solid
B


ether
3 days


ethanol
slurry, 40° C.,
white blades, birefringent
C



7 days


ethyl acetate
slurry, 40° C.,
white, morphology
C



7 days
unknown, birefringent




white, morphology
B + C




unknown, partially




birefringent


ethyl
slurry, 40° C.,
white, morphology
B + A


acetate:hexane
7 days
unknown, not birefringent
(minor)


1:1


methyl ethyl
slurry, 40° C.,
white, morphology
A, l.c.


ketone
7 days
unknown, not birefringent


toluene
slurry, 40° C.,
white, morphology
A



7 days
unknown, not birefringent


acetone:water
slurry, 40° C.,
white, morphology
B


99:1
7 days
unknown, not birefringent


acetonitrile:water
slurry, 40° C.,
white plates, birefringent
C


95:5
7 days


ethanol:water
slurry, 40° C.,
white needles and
C, l.c.


99:1
7 days
blades, birefringent


isopropanol:water
slurry, 40° C.,
off-white dendridic
B


9:1
7 days
needles, birefringent






al.c. = low crystallinity







Polymorph Screen of Compound 1, Form B


Form B showed higher solubilities in aqueous solvent mixtures compared to organic solvents (Table 8).









TABLE 8







Approximate Solubilities of compound 1, Form Ba










Solvent
Solubility (mg/mL)b














acetone
2



ethanol
4



methanol
15



acetone:water 99:1
<29



acetonitrile:water 95:5
<27



ethanol:water 99:1
<28








aprepared from Form A at 90% RH





bSolubilities 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.







An abbreviated polymorph screen was carried out on Form B by slow evaporation and slurry experiments at ambient conditions, 40° C., and lower relative humidities under nitrogen gas (approximately 12-20% RH). The results of the screen are summarized in Tables 9, 10 and 11. Forms A, B, C, and X were all produced.


Forms A, B, and a mixture of Forms B and A were isolated from ambient slurries in acetone, and aqueous acetone, acetonitrile and ethanol (Table 9). It is thought that Forms A and B resulted from different drying conditions.









TABLE 9







Crystallisation Experiments on compound 1, Form Ba










Solvent
Conditions
Habit/Description
XRPD Result





acetone
slurry,
clear solution




3 days


acetone:water 99:1
slurry,
white, morphology
B



7 days
unknown, not




birefringent


acetonitrile:water
slurry,
white, morphology
B + A


95:5
7 days
unknown, partially




birefringent


ethanol:water 99:1
slurry,
white, morphology
A



7 days
unknown, not




birefringent; white




fibers, birefringent






aprepared from Form A at 90% RH














TABLE 10







Crystallisation Experiments on compound 1, Form Ba,


by Evaporation under Nitrogen (~20% RH)










Solvent
Conditionsa
Habit/Description
XRPD Result





acetone
SE




ethanol
SE
white flakes, not birefringent
C


methanol
SE
white needles, birefringent
X






aprepared from Form A at 90% RH



b. SE = slow evaporation


c. Samples were exposed to ambient conditions due to a gap in nitrogen gas flow.













TABLE 11







Crystallisation Experiments on compound 1, Form Ba, at 40° C.










Solvent
Conditions
Habit/Description
XRPD Result





ethanol
slurry, 40° C.,
white blades and
C



7 days
needles, birefringent


ethyl acetate
slurry, 40° C.,
white, morphology
A



7 days
unknown, not birefringent


methyl ethyl ketone
slurry, 40° C.,
white, morphology
A



7 days
unknown, not birefringent


toluene
slurry, 40° C.,
white, morphology
B + A (very minor)



7 days
unknown, not birefringent


acetone:water 99:1
slurry, 40° C.,
white and yellow,
A



3 days
morphology




unknown, not birefringent


acetonitrile:water
slurry, 40° C.,
white plates and
C + B (very minor)


95:5
7 days
blades, birefringent


ethanol:water 99:1
slurry, 40° C.,
white blades, birefringent;
C



7 days
white




fibers, partially birefringent






aprepared from Form A at 90% RH







Polymorph Screen of Compound 1, Form C


Approximate solubilities of compound 1, Form C are given in Table 12. The material was poorly soluble in most organic solvents, except in methanol. It was slightly soluble in ethanol, hexafluoroisopropanol, 2,2,2-trifluoroethanol, and some aqueous mixtures. Overall, the solubilities of Form C were lower compared to the solubilities of Form A.









TABLE 12







Approximate Solubilities of compound 1 Form C










Solvent
Solubility (mg/mL)a














acetone
<1



acetonitrile
<1



dichloromethane
<1



diethyl ether
<1



1,4-dioxane
<1



ethanol
2



ethyl acetate
<1



hexafluoro isopropanol
1



hexane
<1



iso-propanol
<1



methanol
21



methyl ethyl ketone
<1



n-propanol
<1



tetrahydrofuran (THF)
<1



toluene
<1



2,2,2-trifluoroethanol
1.7



water
23



acetone:water 9:1
>23



acetone:water 99:1
<24



acetonitrile:water 4:1
>40



acetonitrile:water 9:1
<25



1,4-dioxane: water 9:1
>22



1,4-dioxane:water 99:1
<22



ethanol:water 9:1
<22



THF:water 9:1
>23



THF:water 99:1
<24








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.







A polymorph screen was carried out on Form C by fast and slow evaporation, crash precipitation, crash cooling, slow cooling, rotary evaporation, and slurry experiments at ambient and lower relative humidity conditions. The results of the screen are summarized in Table 13 and Table 14. Forms A, B, C, X, and amorphous material were all produced.


Form B or low crystalline Form B resulted from most of the fast evaporation experiments. Form B was also produced from crash cooling and slow cooling experiments in water. Low crystalline Form B resulted from slow evaporation in acetone: methanol 4:1.


Form C remained unchanged in all the slurry experiments. Forms A, B, or the amorphous form were isolated from solution-based crystallisations. Form C also resulted from slow evaporation experiments in 4:1 acetonitrile:methanol and ethyl acetate: methanol, and from rotary evaporation in ethanol. This is similar to results discussed above from the polymorph screens of Forms A and B, where experiments utilizing acetonitrile, ethyl acetate, and ethanol most often produced Form C.


Form X was mostly produced from experiments utilizing methanol.


Based on XRPD, Form C did not change after 2 months at 95% relative humidity.









TABLE 13







Crystallisation Experiments on compound 1 Form C










Solvent
Conditionsa
Habit/Description
XRPD Resultb





acetone
slurry,
white solid
C



8 days


acetone:methanol
SE
white, morphology
B, small amount of


4:1

unknown, not birefringent
sample


acetonitrile
slurry,
white solid
C



8 days


acetonitrile:methanol
SE
white dendridic
C


4:1

formations, birefringent;




light




brown, morphology




unknown, not birefringent


dichloromethane
slurry,
white solid
C



7 days


diethyl ether
slurry,
white, morphology
C



7 days
unknown, not birefringent



FE (liquid phase
clear glassy film,




from slurry)
not birefringent



CP w/methanol
white spherulites of
amorphous with




fibers and
peaks from X




morphology




unknown, birefringent


1,4-dioxane
slurry,
white solid
C



8 days


ethanol
FE
white spherulites of
B




needles, birefringent



SC
clear solution




RE
off-white,
C, l.c.




morphology




unknown, not birefringent


ethyl acetate
slurry,
white solid
C



8 days


ethyl acetate:methanol
SE
white fibers, not birefringent;
C


4:1

yellow,




morphology




unknown, birefringent


hexafluoro iso-
FE
white fibers,
B


propanol

partially birefringent


hexane
slurry,
white, morphology
C + peaks



7 days
unknown, not birefringent



FE (liquid phase
translucent oily film,




from slurry)
not birefringent


hexane:methanol
stand (capped) at
clear solution, two



2:1
ambient conditions
layers present;




sample was




discarded


iso-propanol
slurry,
white solid
C



8 days


methanol
FE
white, dendridic
B, small amount of




formations, birefringent
material



CC
white, morphology
X




unknown, birefringent



SC
clear solution




RE
off-white,
X




morphology




unknown, partially




birefringent


methyl ethyl ketone
slurry,
white solid
C



8 days


methyl ethyl ketone:methanol
SE
dark red viscous



4:1

liquid, not birefringent;




yellow,




morphology




unknown, birefringent


n-propanol
slurry,
white, morphology
C



7 days
unknown, not birefringent



FE (liquid phase
light brown
X



from slurry)
spherulites of fibers,




birefringent



FE (sat. solution)
white solid
X


tetrahydrofuran
slurry,
white solid
C


(THF)
8 days


toluene
slurry,
white solid
C



8 days


toluene:methanol
SE
white fibers and
X, l.c.


4:1

needles, partially birefringent


2,2,2-trifluoroethanol
FE
white, morphology
B, small amount of




unknown
material


water
FE
white dendridic
A




formations, birefringent



CC
white solid
B



SC
white solid
B


acetone:water 9:1
FE
white, morphology
B




unknown, partially




birefringent


acetone:water 99:1
slurry,
white, morphology
C



7 days
unknown, not birefringent



FE (liquid phase
clear glassy film,




from slurry)
not birefringent;




clear morphology




unknown, birefringent


acetonitrile:water
FE
white dendridic
B


4:1

formations, birefringent;




white,




morphology




unknown, not birefringent



stand (capped) at
clear solution




ambient conditions



1 day



FE
white with brown at
B




edge of solid,




morphology




unknown, not birefringent


acetonitrile:water
slurry,
white needles, birefringent;
C


9:1
7 days
white,




morphology




unknown, not birefringent



FE (liquid phase
light yellow fibers,
B, small amount of



from slurry)
birefringent; light
material




yellow, morphology




unknown, not birefringent


1,4-dioxane:water
FE
yellow fibers, birefringent;
amorphous with


9:1

yellow,
peaks from X




morphology




unknown, not birefringent


1,4-dioxane:water
slurry,
yellow, morphology
C


99:1
7 days
unknown, not birefringent



FE (liquid phase
clear glassy film,




from slurry)
not birefringent;




clear spherulites of




fibers, birefringent


ethanol:water 9:1
slurry,
white, morphology
C



7 days
unknown, not birefringent



FE (liquid phase
white spherulites of
B, small amount of



from slurry)
fibers and needles,
material




birefringent


THF:water 9:1
FE
yellow, morphology
amorphous with




unknown, not birefringent
peaks from A


THF:water 99:1
slurry,
yellow, morphology
C, small amount of



7 days
unknown, partially
material




birefringent



FE (liquid phase
clear, morphology




from slurry)
unknown, birefringent



95% RH,

C



~2 months






aCC = crash cool, CP = crash precipitation, FE = fast evaporation, RE = rotary evaporation, SC = slow cool, SE = slow evaporation.




bl.c. = low crystallinity.














TABLE 14







Crystallisation Experiments on compound 1 Form C, by Evaporation


under Nitrogen (~17% RH)












Habit/



Solvent
Conditionsa
Description
XRPD Result





1,4-dioxane:methanol
SE
orange,
amorphous


4:1

morphology




unknown, not




birefringent


tetrahydrofuran:methanol
SE
brown plates,
amorphous


4:1

not birefringent






aSE = slow evaporation.



b. Sample was exposed to ambient conditions due to a gap in nitrogen gas flow.






Polymorph Screen of Compound 1, Amorphous Material


The amorphous form was reproducibly prepared by lyophilisation (freeze drying) of an aqueous solution of compound 1, Form A (see Table 15).


Amorphous material exhibited higher solubilities in most organic solvents and water compared to Forms A, B, and C (Table 16). Solubilities in ethanol and 2,2,2-trifluoroethanol at elevated temperatures are given in Table 17.









TABLE 15







Preparation of Amorphous compound 1










Solvent
Methoda
Observations
Result





water
FD,
white, morphology
amorphous



3 days
unknown, not birefringent


water
FD,
white, morphology
amorphous



3 days
unknown, not birefringent


water
FD,
white solid
amorphous



4 days






aFD = freeze dry














TABLE 16







Approximate Solubilities of compound 1, Amorphous










Solvent
Solubility (mg/mL)a














acetone
49



acetonitrile
<1



ethanol
10



ethyl acetate
<1



iso-propanol
16



methanol
50



methyl ethyl ketone
64



methyl iso-butyl ketone
<1



tetrahydrofuran (THF)
100



2,2,2-trifluoroethanol
8



water
36








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.














TABLE 17







Approximate Solubilities of compound 1, Amorphous,


at Elevated Temperatures











Solvent
Temperature
Solubility (mg/mL)a















ethanol
53° C.
11



2,2,2-trifluoroethanol
50° C.
8








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.







A polymorph screen was carried out on the amorphous material by fast and slow evaporation, crash precipitation, crash cooling, slow cooling, and slurry experiments at ambient temperature and lower relative humidity (Table 18, Table 19). Forms A, B, C, X, and amorphous material were all produced.


At ambient conditions, Farms A and B were produced mostly from evaporation and crash precipitation experiments. It is thought that they resulted from different laboratory humidity and drying conditions.


The results are similar to results discussed above where experiments utilizing ethanol and acetonitrile often produced Form C.


Form X was produced by fast evaporation in 1-propanol at laboratory humidity (approx. 20-50% RH) when the amorphous material was dissolved at a concentration of approximately 3 mg/mL. However, a mixture of Form A and Form C, as a minor component, resulted from the same solvent when the amorphous material was dissolved at a higher concentration of approx. 14 mg/mL.


At lower relative humidities under nitrogen, Form C resulted from fast and slow evaporations in mixtures, most of which contained ethanol (Table 19). Form X was produced from slow evaporation experiments in methanol and mixtures containing methanol, which further supports the previous statement that Form X was frequently produced from methanol solutions.









TABLE 18







Crystallisation Experiments on compound 1, Amorphous Material


(~20-50% RH)










Solvent
Conditionsa
Habit/Description
XRPD Resultb





acetone
FE
white, morphology
amorphous




unknown, not birefringent



spontaneous precipitation
white, morphology
amorphous +




unknown, not birefringent
unknown peaks



spontaneous precipitation
white, morphology
C




unknown, not birefringent


acetonitrile
slurry,
white, morphology
C



1 day
unknown, not birefringent



filtrate from slurry
sample discarded




CP w/acetone
white, morphology
A + one peak from C




unknown, partially




birefringent



CP w/methyl ethyl
white flakes, not birefringent
A + peaks from C



ketone



CP w/THF
light yellow flakes,
A + B




birefringent


ethanol
FE
white spherulites,
B




birefringent



CC
clear solution




SE
white needles, birefringent;
B + C




white,




morphology




unknown, not birefringent



SC
clear solution



ethyl acetate
slurry,
white plates and
C, l.c.



4 days
morphology




unknown, birefringent



FE (liquid phase
clear glassy film,




from slurry)
not birefringent



CP w/acetone
white, morphology
A




unknown, not birefringent



CP w/methyl ethyl
white, morphology
amorphous



ketone
unknown, not birefringent



CP w/THF
yellow, morphology
A




unknown, not birefringent


iso-propanol
FE
white, morphology
amorphous +




unknown, partially
unknown peaks




birefringent



spontaneous crystallisation
light yellow,
C



at 51° C.
morphology




unknown, not birefringent



SC, FE
whites flakes, not
A



(filtrate from
birefringent



spontaneous recrystallisation



at 51° C.)


methanol
FE
white fibers, birefringent
A


methyl ethyl ketone
spontaneous crystallisation
white solid
A + amorphous


methyl iso-butyl
slurry,
translucent flake,



ketone
4 days
not birefringent



FE (liquid phase
dark brown viscous




from slurry)
liquid, not birefringent



CP w/THF
yellow flakes, not
B, l.c.




birefringent


n-propanol - 14 mg/ml
FE
white solid
A +


amorphous concentration


C (minor)


n-propanol - 3 mg/ml
FE
white solid
X


amorphous concentration


tetrahydrofuran
FE
yellow, morphology
amorphous


(THF)

unknown, not birefringent



spontaneous precipitation
white, morphology
C + amorphous




unknown, birefringent


2,2,2-trifluoroethanol
FE
white fibers, birefringent;
B +




white,
A (minor)




morphology




unknown, not birefringent



CC
white, morphology





unknown, birefringent



SC
white, morphology





unknown, not birefringent


water
FE
white dendridic, birefringent
B






aCC = crash cool, CP = crash precipitation, FE = fast evaporation, SC = slow cool, SE = slow evaporation.




bl.c. = low crystallinity.














TABLE 19







Crystallisation Experiments on compound 1, Amorphous, by Evaporation


under Nitrogen (~12-20% RH)c










Solvent
Conditionsa
Habit/Description
XRPD Result





acetone
SE
yellow solid,
amorphous




morphology




unknown, not birefringent



FE
yellow solid,
amorphous




morphology




unknown, not birefringent


acetonitrile:ethanol
SE
white blades and
C


4:1

morphology




unknown, birefringent


acetonitrile:methanol
SE
white, morphology
C


8:1

unknown, birefringent


2-butanone (MEK)
SE
dark brown solidb



ethanol
SE
white flakes, not birefringent
C +





A (minor)



FE
white fibers, birefringent;
C




white




flakes, not birefringent


ethanol:acetonitrile
SE
white flakes, not birefringent
C


1:1


ethanol:ethyl
SE
white fibers, birefringent
C + peaks from A


acetate 1:1


ethyl acetate:ethanol
SE
white, morphology
C


4:1

unknown, not birefringent


ethyl acetate:methanol
SE
white, morphology
C


8:1

unknown, birefringent


methanol
SE
white fibers, birefringent
X


X


methanol:acetone
SE
white, morphology
X


1:1

unknown, partially




birefringent


methanol:acetonitrile
SE
white blades and
C


1:1

spherulites of fibers,




birefringent


methanol:ethyl
SE
white spherulites,
X


acetate 1:1

partially birefringent


methanol:methyl
SE
yellow dendridic
X + peak


iso-butyl ketone 1:1

needles, birefringent


methyl iso-butyl
SE
orange glassy film,



ketone:acetone 8:1

not birefringent;




orange, morphology




unknown, birefringent


methyl iso-butyl
SE
brown oil, not birefringent



ketone:ethanol 4:1


methyl iso-butyl
SE
white spherulites of



ketone:methanol

needles, birefringent;


8:1

orange




glassy film, not birefringent


methyl iso-butyl
SE
orange glassy film,



ketone:methyl ethyl

not birefringent;


ketone 8:1

clear fibers, birefringent


tetrahydrofuran
SE
yellow, morphology
amorphous


(THF)

unknown, not birefringent






aSE = slow evaporation




bDiscoloration possibly due to decomposition




cSome samples were exposed to ambient conditions due to a gap in nitrogen gas flow







A capillary polymorph screen was carried out on the amorphous material using evaporation experiments at ambient temperature, 40° C., and lower relative humidity under nitrogen. Solvent/antisolvent crystallisations and vapor stress experiments were also utilized. The results for the screen are summarized in Tables 20, 21 and 22. Forms A, B, C, X, amorphous, and various mixtures of those forms resulted.









TABLE 20







Capillary Polymorph Screen of compound 1, Amorphous










Solvent
Methoda
Habit/Description
XRPD Resultb





acetone
EC, ambient
Off-white,
A + C + X




morphology




unknown, not




birefringent



EC, 40° C.
Off-white,
amorphous




morphology




unknown, not




birefringent



EC under N2
white,
C



(19% RH)
morphology




unknown, not




birefringent



CentriVap
Off-white,
amorphous




morphology




unknown, not




birefringent


2-butanone
EC, ambient
white,
A


(MEK)

morphology




unknown, not




birefringent



EC, 40° C.
white,
A




morphology




unknown, not




birefringent



EC under N2
white,
A



(12% RH)
morphology




unknown, not




birefringent



CentriVap
white,
A




morphology




unknown, not




birefringent


MeOH
EC, ambient
White needles,
C




birefringent



EC, 40° C.
white, needles,
IS




birefringent



EC under N2
White, dendridic
IS



(19% RH)
formations,




birefrngent



CentriVap
white,
X, l.c.




morphology




unknown,




partially birefringent


tetrahydrofuran
EC, ambient
white,
C




morphology




unknown, not




birefringent



EC, 40° C.
white,
C




morphology




unknown, not




birefringent



EC under N2
white,
C, l.c.



(12% RH)
morphology




unknown, not




birefringent



CentriVap
white,
A + C




morphology




unknown, not




birefringent


water
EC, ambient
off-white,
B, l.c.




morphology




unknown, birefringent



EC, 40° C.
off-white,
IS




needles, birefringent



EC under N2
white,
B, l.c.



(19% RHd)
dendridic




formations, birefringent



CentriVap
white,
B




morphology




unknown, birefringent






aEC = evaporation in capillary, RH = relative humidity




bIS = insufficient amount for XRPD analysis, l.c. = low crystallinity, PO = preferred orientation



c. XRPD results for LIMS 94755 and LIMS 95240 are non-GMP



dSample was exposed to ambient conditions due to a gap in nitrogen gas flow.














TABLE 21







Capillary Polymorph Screen of compound 1, Amorphous















XRPD


Solvent
Antisolvent
Methoda
Habit/Description
Resultb





acetone
acetonitrile
precipitation
white,
C





morphology





unknown,





not birefringent



n-butyl
precipitation
white,
C + A



acetate

morphology





unknown,





not birefringent



ethyl acetate
precipitation
white,
C





morphology





unknown,





not birefringent



hexane
precipitation
white,
C + B





morphology





unknown,





not birefringent



isopropyl
precipitation
white,
C, l.c.



acetate

morphology





unknown,





not birefringent



MIBK
EC
clear brown
IS





glassy solid,





not birefringent



MIBK
CentriVap
off-white,
amorphous +





morphology
unknown





unknown,
peaks





not birefringent



MIBK
EC under N2
white,
C




(19% RH)
morphology





unknown,





not birefringent


toluene
precipitation
white,
IS




morphology




unknown,




birefringent


THF
acetonitrile
precipitation
white,
C





morphology





unknown,





not birefringent



n-butyl
precipitation
white,
A



acetate

morphology





unknown,





birefringent



ethyl acetate
precipitation
white,
C





morphology





unknown,





birefringent



hexane
precipitation
white,
A





morphology





unknown,





not birefringent



MIBK
EC
white,
A





morphology





unknown,





not birefringent



MIBK
CentriVap
white,
amorphous





morphology





unknown,





not birefringent



toluene
precipitation
white,
A





morphology





unknown,





birefringent






aXRPD results are non-GMP.














TABLE 22







Capillary Polymorph Screen of compound 1, Amorphous by Vapor Stress











Solvent
Habit/Description
XRPD Resultb







acetonitrile
white, morphology
C




unknown, not birefringent



n-butyl acetate
white, morphology
A




unknown, not birefringent



ethanol
Broken capillary




ethyl acetate
white, morphology
C




unknown, not birefringent



heptane
white, morphology
amorphous




unknown, not birefringent



hexane
white, morphology
amorphous




unknown, not birefringent



toluene
white, morphology
amorphous




unknown, not birefringent



95% RH
white, morphology
B




unknown, not birefringent







a. XRPD results are non-GMP.






Experiments Producing Form C


The majority of the experiments that produced Form C from all the compound 1 forms were slurries in different solvents and solvent mixtures (Table 23). Form C was generated in slurries at room temperature and 40° C. from both Forms A and B using ethanol, ethanol:water 99:1, and acetonitrile:water 95:5.


Form C remained unchanged in slurry and slow evaporation experiments involving various solvents and aqueous mixtures. Evaporation of solutions prepared from the amorphous material under nitrogen, as well as slurry, crash precipitation, and capillary evaporation experiments in various solvents and mixtures also resulted in Form C. Amorphous material also spontaneously crystallised to produce Form C in acetone at room temperature and in iso-propanol at 51° C.









TABLE 23







Summary of Experiments Producing compound 1, Form C









Starting




Form
Solvent
Conditionsa





A
ethanol
slurry, 40° C.,




7 days



ethyl acetate
slurry, 40° C.,




7 days



acetonitrile:water 95:5
slurry,




7 days



acetonitrile:water 95:5
slurry, 40° C.,




7 days



ethanol:water 99:1
slurry,




7 days



ethanol:water 99:1
slurry, 40° C.,




7 days


B
ethanol
slurry, 40° C.,




7 days




SE under N2



ethanol:water 99:1
slurry, 40° C.,




7 days


C
acetone
slurry,




8 days



acetonitrile
slurry,




8 days



acetonitrile:methanol 4:1
SE



dichloromethane
slurry,




7 days



diethyl ether
slurry,




7 days



1,4-dioxane
slurry,




8 days



ethyl acetate
slurry,




8 days



ethyl acetate:methanol 4:1
SE



iso-propanol
slurry,




8 days



methyl ethyl ketone
slurry,




8 days



n-propanol
slurry,




7 days



tetrahydrofuran (THF)
slurry,




8 days



toluene
slurry,




8 days



acetone:water 99:1
slurry,




7 days



acetonitrile:water 9:1
slurry,




7 days



1,4-dioxane:water 99:1
slurry,




7 days



ethanol:water 9:1
slurry,




7 days



THF:water 99:1
slurry,




7 days


amorphous
acetone
spontaneous precipitation



acetonitrile:ethanol 4:1
SE under N2



acetonitrile
slurry,




1 day



acetonitrile:methanol 8:1
SE under N2



ethyl acetate
slurry,




4 days



ethyl acetate:ethanol 4:1
SE under N2



iso-propanol
spontaneous recrystallisation




at 51° C.



ethanol
FE under N2



methanol:acetonitrile
SE under N2



1:1



THF
EC, ambient




EC, 40° C.




CP w/ acetonitrile




CP w/ ethyl acetate



ethanol:acetonitrile 1:1
SE under N2



ethyl acetate:methanol 8:1
SE under N2






aCP = crash precipitation, EC = evaporation in capillary, FE = fast evaporation, SE = slow evaporation.



b. XRPD results are non-GMP.






Interconversion Studies of Forms A and C


Interconversion studies of Forms A and C in ethanol and acetone:water 99:1 were conducted (Table 24). Form C resulted from a 1-day slurry at 40° C. in ethanol. After one week, Form C resulted at both ambient temperature and 40° C.


A mixture of Forms C and B, with Form B as a minor component, was produced from the 1-day slurries at room temperature in both solvents. A mixture of Forms C and A, with Form A as a minor component, resulted from a 1-day slurry at 40° C. in acetone:water 99:1. Note that Form A did not change in a 1-week slurry in acetone: water 99:1 (Table 6).


The interconversion studies indicate that Form C may be more thermodynamically stable than Form A.









TABLE 24







Interconversion Studies of Forms A and C











Starting
Solvent/Solvent





Forms
System
Method
Time
XRPD Result





A + C
EtOH
Slurry, RT
1 week
C



EtOH
Slurry, RT
1 day
C +






B (minor)



Acetone:water
Slurry, RT
1 week
C



99:1
Slurry, RT
1 day
C +






B (minor)



EtOH
Slurry, 40° C.
1 week
C



EtOH
Slurry, 40° C.
1 day
C



Acetone:water
Slurry, 40° C.
1 week
C



99:1
Slurry, 40° C.
1 day
C +






A (one peak)









Polymorph Characterisation


The polymorphs were characterised by a number of methods, including 1H NMR, X-ray powder diffraction (XRPD), FT-IR spectroscopy, Differential Scanning Calorimetry (DSC), Karl-Fischer Analysis, Thermogravimetry (TG).



1H NMR


Solution 1H nuclear magnetic resonance (NMR) spectra were acquired at ambient temperature with a Varian UNITYINOVA-400 spectrometer at a 1H Larmor frequency of 399.8 MHz. The samples were dissolved in methanol-d4. The spectra were acquired with a 1H pulse width of 8.3-8.4 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 or 80 coadded scans. The free induction decay (FID) was processed using the Varian VNMR 6.1C software with 65536 points and an exponential line broadening factor of 0.2 Hz to improve the signal-to-noise ratio. The spectrum was referenced to TMS at 0.0 ppm or solvent at 3.31 ppm (CD3OD).


The structures of the amorphous form and all the polymorphs were found to conform to that of compound 1.


Form X samples generated by evaporation from n-propanol and methanol also showed a residual amount of solvent—from 0.009 to 0.088 moles per one mole of compound 1.


X-Ray Powder Diffraction (XRPD)


The following Shimadzu parameters were used to generate peak lists for Forms A, B and C and X.
















Measurement






Condition
Form A
Form B
Form C
Form X















X-ray tube











target
Cu
Cu
Cu
Cu


voltage
40.0 (kV)
40.0 (kV)
40.0 (kV)
40.0 (kV)


current
40.0 (mA)
40.0 (mA)
40.0 (mA)
40.0 (mA)







Slits











divergence slit
1.00000 (deg)
1.00000 (deg)
1.00000 (deg)
1.00000 (deg)


scatter slit
1.00000 (deg)
1.00000 (deg)
1.00000 (deg)
1.00000 (deg)


receiving slit
0.15000 (mm)
0.15000 (mm)
0.15000 (mm)
0.15000 (mm)







Scanning











drive axis
2Theta/Theta
2Theta/Theta
2Theta/Theta
2Theta/Theta


scan range
2.500-40.000
2.500-40.000
2.500-40.000
2.500-40.000


scan mode
Continuous
Continuous
Continuous
Continuous



Scan
Scan
Scan
Scan


scan speed
3.0000
3.0000
3.0000
3.0000



(deg/min)
(deg/min)
(deg/min)
(deg/min)


sampling pitch
0.0200 (deg)
0.0200 (deg)
0.0200 (deg)
0.0200 (deg)


preset time
0.40 (sec)
0.40 (sec)
0.40 (sec)
0.40 (sec)







Data Process Condition











Smoothing
[MANUAL]
[AUTO]
[AUTO]
[MANUAL]


smoothing
35
19
19
27


points


B.G. Subtraction
[AUTO]
[AUTO]
[AUTO]
[AUTO]


sampling points
45
25
21
37


repeat times
30
30
30
30


Ka1-a2
[MANUAL]
[MANUAL]
[MANUAL]
[MANUAL]


Separate


Ka1 a2 ratio
50.0 (%)
50.0 (%)
50.0 (%)
50.0 (%)


Peak Search
[AUTO]
[AUTO]
[AUTO]
[AUTO]


differential
39
21
19
31


points


FWHM
0.050 (deg)
0.050 (deg)
0.050 (deg)
0.050 (deg)


threshold


intensity
30 (par mil)
30 (par mil)
30 (par mil)
30 (par mil)


threshold


FWHM ratio
 2
 2
 2
 2


(n − 1)/n


System Error
[NO]
[NO]
[NO]
[NO]


Correction


Precise Peak
[NO]
[NO]
[NO]
[NO]


Correction









The XRPD peak lists generated were as follows.









TABLE 25







XRPD Peak List for Form A











Peak No.
Position (°2#)
d-spacing
I (intensity)
I/Io














1
4.9
17.6
30
12


2
8.3
10.5
23
9


3
10.8
8.1
20
8


4
12.9
6.8
50
20


5
15.0
5.8
78
30


6
16.2
5.4
94
37


7
16.7
5.2
15
6


8
19.3
4.5
22
9


9
19.8
4.4
34
13


10
20.6
4.2
15
6


11
21.1
4.1
15
6


12
21.8
4.0
37
14


13
22.9
3.8
46
18


14
24.2
3.6
101
39


15
25.1
3.5
38
15


16
26.8
3.3
256
100


17
28.2
3.1
44
17


18
28.7
3.0
32
13


19
29.3
3.0
26
10


20
29.9
2.9
17
7


21
30.6
2.9
24
9


22
32.2
2.7
46
18


23
33.1
2.7
40
16


24
33.9
2.6
25
10


25
34.6
2.5
8
3


26
36.0
2.4
11
4


27
36.7
2.4
12
5


28
38.3
2.3
17
7


29
39.1
2.2
24
9
















TABLE 26







XRPD Peak List for Form B











Peak No.
Position (°2#)
d-spacing
I (intensity)
I/Io














1
4.8
18.3
46
14


2
8.0
10.9
20
6


3
8.6
10.2
26
8


4
10.8
8.1
22
7


5
12.7
6.9
44
13


6
13.2
6.6
11
3


7
13.6
6.4
36
11


8
14.4
6.1
49
15


9
15.2
5.7
42
13


10
15.6
5.6
32
10


11
16.0
5.5
110
34


12
19.3
4.5
23
7


13
19.8
4.4
31
10


14
20.3
4.3
17
5


15
20.6
4.3
16
5


16
21.2
4.1
17
5


17
21.7
4.0
49
15


18
22.9
3.8
59
18


19
23.8
3.7
27
8


20
24.3
3.6
112
34


21
25.1
3.5
22
7


22
25.6
3.4
11
3


23
26.3
3.3
140
43


24
26.7
3.3
326
100


25
27.1
3.2
123
38


26
27.5
3.2
40
12


27
27.8
3.1
39
12


28
28.1
3.1
15
5


29
29.0
3.0
43
13


30
29.4
3.0
18
6


31
30.7
2.9
15
5


32
31.0
2.8
12
4


33
32.2
2.7
40
12


34
32.5
2.7
43
13


35
33.0
2.7
27
8


36
33.5
2.6
15
5


37
33.9
2.6
18
6


38
34.3
2.6
21
6


39
34.9
2.5
13
4


40
36.1
2.4
19
6


41
36.4
2.4
18
6


42
36.8
2.4
11
3


43
39.1
2.2
25
8
















TABLE 27







XRPD Peak List for Form C












Position





Peak No.
(°2#)
d-spacing
I (intensity)
I/Io














1
13.5
6.5
12
3


2
13.9
6.3
122
35


3
14.7
5.9
22
6


4
15.3
5.7
74
22


5
16.2
5.4
59
17


6
16.7
5.2
39
11


7
17.7
4.9
85
25


8
18.1
4.8
36
10


9
20.2
4.3
77
22


10
20.6
4.2
40
12


11
21.0
4.2
44
13


12
21.6
4.0
74
22


13
22.1
4.0
322
94


14
23.2
3.8
26
8


15
23.8
3.7
33
10


16
24.2
3.6
57
17


17
24.7
3.5
28
8


18
25.1
3.5
237
69


19
25.7
3.4
106
31


20
26.1
3.4
23
7


21
27.3
3.2
69
20


22
27.7
3.2
344
100


23
28.1
3.1
109
32


24
28.4
3.1
86
25


25
28.7
3.1
87
25


26
29.8
2.9
42
12


27
30.5
2.9
51
15


28
30.9
2.8
26
8


29
31.7
2.8
25
7


30
32.3
2.7
26
8


31
32.7
2.7
56
16


32
33.5
2.6
31
9


33
34.7
2.5
41
12


34
35.6
2.5
20
6


35
35.8
2.5
22
6


36
38.9
2.3
17
5


37
39.1
2.2
26
8


38
39.6
2.2
23
7
















TABLE 28







XRPD Peak List for Form X.











Peak No.
Position (°2#)
d-spacing
I (intensity)
I/Io














1
5.4
16.3
16
10


2
6.2
14.2
6
4


3
8.2
10.6
6
4


4
9.5
9.2
9
5


5
10.2
8.6
23
14


6
10.9
8.0
6
4


7
11.2
7.8
7
4


8
12.4
7.1
12
7


9
15.5
5.6
29
18


10
16.2
5.4
164
100


11
17.5
5.0
40
24


12
18.6
4.7
11
7


13
19.5
4.5
13
8


14
20.3
4.3
39
24


15
21.4
4.1
11
7


16
21.9
4.0
14
9


17
22.8
3.8
30
18


18
23.2
3.8
58
35


19
24.4
3.6
40
24


20
24.8
3.5
39
24


21
25.7
3.4
29
18


22
26.4
3.3
18
11


23
27.0
3.2
31
19


24
27.7
3.2
15
9


25
28.4
3.1
22
13


26
29.7
3.0
14
9


27
30.1
2.9
10
6


28
30.9
2.8
5
3


29
32.9
2.7
12
7


30
33.4
2.6
9
5


31
33.9
2.6
11
7


32
34.6
2.5
6
4


33
35.6
2.5
7
4


34
36.1
2.4
5
3


35
38.2
2.3
5
3









The characterising peaks for Form A are at 8.3 and 26.8° 2#. Form A is also characterised by the absence of peaks in the 13.3 to 14.7° 2# region.


The most intense peaks for Form A are at 15.0, 16.2, 24.2 and 26.8° 2#. Less intense peaks are at 4.9, 12.9, 19.8, 21.8 and 22.9° 2#.


Form B is characterised by peaks at 8.0 and 8.6° 2#. Form B has a further unique peak at 14.4° 2#. Another peak at 13.6° 2# distinguishes Form B from Form A.


The most intense peaks for Form B are at 16, 24.3 and 26.7° 2#. Further, less intense peaks are at 4.8, 12.7, 15.2, 21.7 and 22.9° 2#.


Form C is characterised by peaks at 13.9 and 18.1° 2#. Other peaks which distinguish Form C from Form X are at 17.7, 22.1 and 23.2 and 24.7° 2#. Peaks which distinguish Form C from Form A are at 15.3 and 20.2° 2#. A peak which distinguishes Form C from Form B is at 16.7° 2#.


The most intense peaks for Form C are at 13.9, 22.1, 25.1, 25.7 and 27.7° 2#.


Further less intense peaks are at 16.2, 16.7, 18.1, 21.0 and 24.2° 2#.


Form X is characterised by peaks at 5.4, 10.2, 12.4 and 18.6° 2#. Further peaks are at 6.2, 9.5 and 11.2° 2#. An intense peak is at 16.2° 2#.


FT-IR Spectroscopy


Infrared spectra were acquired on a Magna-IR 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector. A Thunderdome accessory was used for sampling. A background data set was acquired with a clean Ge crystal. A Log 1/R(R=reflectance) spectrum was acquired by taking a ratio of these two data sets against each other. Wavelength calibration was performed using polystyrene. Further parameters are as follows.









TABLE 29







FT-IR Parameters










Form A
Form C















Number of sample scans
128
256



Number of background
128
256



scans



Resolution/cm−1
4.000
4.000



Sample gain
2.0
2.0



Mirror velocity
0.6329
0.6329



Aperture
100.00
100.00



Detector
DTGS KBr
DTGS KBr



Beamsplitter
XT-KBr
XT-KBr










The FT-IR spectra differentiate Form A from Form C.


Differential Scanning Calorimetry (DSC) & Thermogravimetry (TG)


The DSC analysis was carried out on a TA Instruments differential scanning calorimeter 2920. The instrument was calibrated using indium as the reference material. The sample was placed into a standard aluminum DSC pan, the pan was crimped, and the weight accurately recorded. The sample was equilibrated at 25° C. and heated under a nitrogen purge at a rate of 10° C./min up to 350° C. Indium metal was used as calibration standard.


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 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.


The DSC thermogram of Form A exhibited an endotherm at approximately 210 (206-213) and two minor endotherms at 220, and 260° C., followed by an exotherm at approximately 295° C. (FIG. 9). Based on hot stage data (not shown), the first two endotherms were identified as melting endotherms, and the third endotherm and the exotherm corresponded to decomposition.


Thermal data for Form B (FIG. 10) appeared very similar to thermal data for Form A (FIG. 9). The initial broad endotherm at approximately 67° C. likely corresponded to loss of water. As the other three endotherms in DSC occurred in the same temperature range, Form B most likely converted to Form A on drying at elevated temperatures.


Thermal data for Form C are presented in FIG. 11. The TG data showed an insignificant weight loss of approximately 0.4% from 25 to 220° C. suggesting that the material was not solvated or hydrated. The baseline in DSC between 25 and 220° C. indicated that the weight loss in TG might be due to loss of residual solvent (water). The DSC thermogram exhibited a sharp endotherm at approximately 241° C. followed by decomposition. Hotstage data confirmed that the endotherm was due to the melt.


Coulometric Karl Fischer Titration


Coulometric Karl Fischer (KF) analysis for water determination was performed using a Mettler Toledo DL39 Karl Fischer titrator. Samples were placed in the KF titration vessel containing approximately Hydranal—Coulomat AD and mixed for 60 seconds to ensure dissolution. The sample was then titrated by means of a generator electrode which produces iodine by electrochemical oxidation: 2I−=>I2+2e. Three replicates were obtained to ensure reproducibility. A NIST-traceable water standard (Hydranal Water Standard 10.0) was analyzed to check the operation of the coulometer. Data were collected and analyzed using LabX Pro Titration v2.10.000.


An initial batch of Form A contained approximately 2.75% or 0.6 moles of water.


After it had been vacuum-dried at approximately 70° C. for 1 week, the water content was reduced to approximately 0.44% (0.09 mole). The XRPD pattern of the dry material was very similar to that of the starting Form A, except for the peak shifts observed at lower degrees 2 Theta and between approximately 20 and 24 degrees 2 Theta.


Form A was found to be stable at 31% relative humidity after two weeks, and at 43% relative humidity after five days.


Form A samples were stored at lower relative humidities of approximately 9-11, 23 and 32% RH and analyzed by XRPD and Karl-Fischer titration analysis after four weeks (Tables 30 and 31). The samples appeared to be Form A by XRPD. The water content was found to be approximately 1.7% (0.33 mole), 2.96% (0.59 mole), and 3.24% (0.65 mole), respectively. Note that the water content in the samples at 23 and 32% RH was slightly higher compared to the initial batch of Form A.









TABLE 30







Karl-Fischer Data for compound 1, Form A











% RH
Time
Observations
% water
Moles of water





~9-11
11 days

1.70
0.33


~23
 4 weeks
looks dry
2.96
0.59


~32
 4 weeks
looks dry
3.24
0.65
















TABLE 31







RH Stability of compound 1, Form A









% RH
Time
XRPD Result





~9-11
36 days
A


~23
 4 weeks
A


~32
 4 weeks
A









After two days, the water content in Form B samples at 75 and 90% RH was 6.2% (1.28 mole) and 6.7% (1.39 mole), respectively (Table 32). As the starting Form A contained approximately 2.75% (0.6 mole) of water, less than one mole of water was gained in the relative humidity jars at both relative humidities (Table 33).


Form B samples were stable based on the observation that the XPRD patterns did not change after 2 days, 3, 7, and 8 weeks at both relative humidities. No significant changes in the water content were observed for the samples after 2 days, 3 weeks, and 8 weeks at both 75 and 90% RH.









TABLE 32







Karl-Fischer Data for compound 1, Form B











% RH
Time
Observations
% water
Moles of water














~55
8 days
looks dry
5.34
1.1


~75
2 days

6.23
1.28



3 weeks
looks dry
6.02
1.24



8 weeks
looks dry
6.12
1.26


~90
2 days

6.70
1.39



3 weeks
looks dry
5.99
1.23



8 weeks
looks dry
6.46
1.33
















TABLE 33







RH Stability of compound 1, Form B















Weight
Weight
XRPD


% RH
Time
Observations
change, mg
change, %
Result





~55
8 days
looks dry
10.7
9.5
B


~75
2 days

11.0
4.5
B



3 weeks
looks dry


B



7 weeks
looks dry


B



8 weeks
looks dry


B


~90
2 days

11.6
4.6
B



3 weeks
looks dry


B



7 weeks
looks dry


B



8 weeks
looks dry


B









Karl-Fischer data for Form C showed that the water content for a range of Form C samples varied from 0.04 moles to 0.07 moles. This result further indicates that Form C is anhydrous, the water present being residual water.


Form X did not change by XRPD after 6 days and 2 weeks of drying at approximately 70° C. Based on the proton NMR the resulting material contained no methanol. The water content in the dried samples was reduced to approximately 2.72% (0.55 mole) and 1.31% (0.26 mole), respectively.


Form X converted to Form B after 4 days and 5 weeks at 90% RH. As mentioned above, Form B can be dehydrated upon desorption (drying) to convert back to Form A. Thus, if Form X is generated in the crystallisation process as a side-product it can be converted to the desired Form A by subjecting it to high relative humidities with subsequent drying.


Form X samples were stored at relative humidities of approximately 43, 75 and 90% RH and analyzed by XRPD and Karl-Fischer titration analysis after five weeks (Tables 34 and 35).









TABLE 34







Karl-Fischer Data for Low Crystalline Form X
















Moles of
Resulting


% RH
Time
Observations
% water
water
Form





43
5 weeks
looks dry
5.52
1.13
X


75
5 weeks
looks dry
8.74
1.85
X


90
5 weeks
looks dry
6.47
1.34
B
















TABLE 35







RH Stability of compound 1, Low Crystalline Form X















Weight
Weight
XRPD


% RH
Time
Observations
change, mg
change, %
Result





~43
7 days
looks dry
1.2
3.4
X



5 weeks
looks dry


X


~75
7 days
looks dry
2.4
6.0
X



5 weeks
looks dry


X


~90
1 day

2.3
5.6
X



4 days



B



7 days
looks dry
0.9
2.1




5 weeks
looks dry


B









For the preparation of pharmaceutical compositions of the polymorphs of (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride, inert pharmaceutically acceptable carriers are admixed with the active compound. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be an encapsulating material.


Preferably the pharmaceutical preparation is in unit dosage form, e.g. packaged preparation, the package containing discrete quantities of preparation such as packeted tablets, capsules and powders in vials or ampoules.


The dosages may be varied depending on the requirement of the patient, the severity of the disease and the particular compound being employed. For convenience, the total daily dosage may be divided and administered in portions throughout the day. It is expected that once or twice per day administration will be most suitable. Determination of the proper dosage for a particular situation is within the skill of those in the medical art.


It will be appreciated that the invention may be modified within the scope of the appended claims.

Claims
  • 1. Crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 8.3 and 26.8 0.2° 2#.
  • 2. Crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 1, having an XRPD pattern with further peaks at 15.0, 16.2, and 24.2±0.2° 2#.
  • 3. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 1 or 2, having an XRPD pattern with further peaks at 4.9, 12.9, 19.8, 21.8 and 22.9±0.2° 2#.
  • 4. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 1.
  • 5. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to any preceding claim, wherein Form A is a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 0.09 to about 0.65 moles.
  • 6. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having characteristic FT-IR peaks at 1491.90, 1220.70, 1117.50, 1039.50, 851.80 and 747.00 cm−1.
  • 7. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 6, further having characteristic FT-IR peaks at 3053.30, 1599.80, 1406.10, 1330.70, 1287.60, 1194.00, 985.50 and 713.70 cm−1.
  • 8. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 6 or 7, further having characteristic FT-IR peaks at 2939.70, 1448.30 and 1244.50 cm−1.
  • 9. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the FT-IR spectrum of FIG. 6.
  • 10. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the DSC spectrum of FIG. 9.
  • 11. Crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%.
  • 12. Crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity in the range of 99.0% to 99.8%.
  • 13. Crystalline Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity of 99.5%.
  • 14. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 8.0 and 8.6±0.2° 2#.
  • 15. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 14, having an XRPD pattern with further peaks at 13.6, 14.4, 16.0, 24.3 and 26.7±0.2° 2#.
  • 16. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 14 or 15, having an XRPD pattern with further peaks at 4.8, 12.7, 13.6, 14.4, 15.2, 21.7 and 22.9±0.2° 2#.
  • 17. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 2.
  • 18. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to any one of claims 14 to 17, wherein Form B is a variable hydrate with the number of moles of water being dependent on the relative humidity and varying from about 1.1 to about 1.4 moles.
  • 19. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to any one of claims 14 to 18, wherein Form B is a monohydrate.
  • 20. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the DSC spectrum of FIG. 10.
  • 21. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%.
  • 22. Crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity in the range of 99.0% to 99.8%.
  • 23. Crystalline Form B of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity of 99.5%.
  • 24. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 13.9, 18.1, 22.1, 25.1 and 25.7±0.2° 2#.
  • 25. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 24, having an XRPD pattern with further peaks at 15.3, 17.7 and 20.2±0.2° 2#.
  • 26. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 24 or 25, having an XRPD pattern with further peaks at 16.2, 16.7, 21.0 and 24.2±0.2° 2#.
  • 27. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 3.
  • 28. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having characteristic FT-IR peaks at 1492, 1220.2, 1117.4, 1033.4, 845.2, 792.6 and 750.1 cm−1.
  • 29. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 28, further having characteristic FT-IR peaks at 3041.70, 1596.50, 1403.40, 1333.80, 1290.90, 1173.20, 1078.10, 984.90 and 713.20 cm−1.
  • 30. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the FT-IR spectrum of FIG. 7.
  • 31. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%.
  • 32. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity in the range of 99.0% to 99.8%.
  • 33. Crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity of 99.5%.
  • 34. Crystalline Form X of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having an XRPD pattern with peaks at 5.4, 10.2, 12.4 and 18.6±° 2#.
  • 35. Crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride according to claim 34, having an XRPD pattern with further peaks at 6.2, 9.5, 11.2 and 16.2±° 2#.
  • 36. Crystalline Form X of (R)-5-(2-Amino ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having the XRPD pattern of FIG. 4.
  • 37. Crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity greater than or equal to 99.0%.
  • 38. Crystalline Form X of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity in the range of 99.0% to 99.8%.
  • 39. Crystalline Form X of (R)-5-(2-Amino ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride having a purity of 99.5%.
  • 40. A process for preparing crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising recrystallising (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione ydrochloride in aqueous HCl.
  • 41. A process according to claim 41, wherein the recrystallisation comprises (a) dissolving (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in aqueous HCl, (b) filtering the solution, (c) cooling the solution with stirring, and (d) isolating, washing and drying the precipitated Form A.
  • 42. A process for preparing crystalline Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising forming (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in situ and crystallising Form A using aqueous HCl.
  • 43. A process according to claim 42, wherein the crystallisation comprises (a) adding aqueous HCl to a solution of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride, (b) cooling the solution with stirring and (c) isolating, washing and drying the precipitated Form A.
  • 44. A process for preparing crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising subjecting Form A of (R)-5-(2-Amino ethyl)-1-(6,8-difluoro chroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride to 43% to 90% relative humidity.
  • 45. A process according to claim 44, wherein the relative humidity is from 55% to 65%.
  • 46. A process according to claim 44 or 45, wherein the subjecting step takes place within a time range from 1 day to 2 weeks.
  • 47. A process according to claim 44 or 45, wherein the subjecting step takes place over 1 to 2 days.
  • 48. A process according to claim 44, 45, 46 or 47, wherein the subjecting step takes place at 25° C.
  • 49. A process for preparing crystalline Form B of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising dissolving or slurrying Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in an organic solvent, or mixtures of organic solvents, filtering the solution and allowing the solvent to evaporate.
  • 50. A process according to claim 49, wherein the organic solvent is selected from ethyl ether, hexane, acetonitrile, 1,4-dioxane, ethanol, ethyl acetate, hexafluoroisopropanol, methanol, methylene chloride, methyl ethyl ketone, toluene, propionitrile, trifluorotoluene, cyclohexane, methyl iso-butyl ketone, n-butyl acetate, acetone, toluene, iso-propyl ether and mixtures thereof.
  • 51. A process according to claim 49 or 50, wherein the solvent is allowed to evaporate from an open vial.
  • 52. A process according to claim 49 or 50, wherein the solvent is allowed to evaporate from a vial covered with a perforated material.
  • 53. A process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising subjecting Form A or B of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in a solution of ethanol or ethanol/solvent mixtures to evaporation under nitrogen.
  • 54. A process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising: (a) stirring a mixture of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in a first organic solvent and an aqueous solution of a base, wherein the first organic solvent is immiscible with water; (b) extracting the organic phase and evaporating the product to dryness; (c) dissolving the product of (b) in dry ethanol; (d) acidifying the product of step (c) with HCl in ethanol; (e) collecting the precipitate; (f) washing the precipitate with ethanol; and (g) drying the product of step (f) to yield Form C.
  • 55. A process according to claim 54, wherein the first organic solvent is ethyl acetate.
  • 56. A process according to claim 54 or 55, wherein the precipitate is collected hot.
  • 57. A process according to any of claims 54 to 56, wherein the (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is prepared prior to step (a) and converted to Form C in situ by steps (a) to (g).
  • 58. A process according to any of claims 54 to 56, wherein the (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride is prepared prior to step (a), isolated and then converted to Form C by steps (a) to (g).
  • 59. A process for preparing crystalline Form C of (R)-5-(2-Amino ethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising slurrying Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in acetonitrile and isolating Form C by vacuum filtration.
  • 60. A process according to claim 59, wherein the slurrying is carried out for a period of from 4 days to 7 days.
  • 61. A process for preparing crystalline Form C of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising preparing a saturated solution of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in methanol at an elevated temperature, filtering the warm solution, cooling the solution, and isolating the Form C.
  • 62. A process according to claim 61, wherein the cooling brings the temperature of the solution to room temperature.
  • 63. A process according to claim 61 or 62, wherein the solids are isolated by decantation followed by air drying.
  • 64. A process for preparing crystalline Form X of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising dissolving Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in methanol, filtering the solution and evaporating the methanol under a stream of nitrogen.
  • 65. A process according to claim 64, wherein the evaporation is carried out at about 9% relative humidity.
  • 66. A process according to claim 64 or 65, wherein the evaporation is carried out at room temperature.
  • 67. A pharmaceutical formulation comprising Form A according to any of claims 1 to 13, Form B according to any of claims 14 to 23, Form C according to any of claims 24 to 33 or Form X according to any of claims 34 to 39 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride and one or more pharmaceutically acceptable carriers or excipients.
  • 68. Form A according to any of claims 1 to 13, Foam B according to any of claims 14 to 23, Form C according to any of claims 24 to 33 or Form X according to any of claims 34 to 39 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride for use in medicine.
  • 69. Use of Form A according to any of claims 1 to 13, Form B according to any of claims 14 to 23, Form C according to any of claims 24 to 33 or Form X according to any of claims 34 to 39 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in the manufacture of a medicament for treatment of cardiovascular disorders.
  • 70. Use of Form A according to any of claims 1 to 13, Form B according to any of claims 14 to 23, Faun C according to any of claims 24 to 33 or Form X according to any of claims 34 to 39 of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride in the manufacture of a medicament for peripherally-selective inhibition of D#H.
  • 71. A process for preparing the amorphous form of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride comprising lyophilising an aqueous solution of Form A of (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride.
  • 72. A process according to claim 71, wherein the lyophilisation takes place over a period of 2 to 5 days.
  • 73. A process according to claim 72, wherein the lyophilisation takes place over a period of 3 to 4 days.
Priority Claims (2)
Number Date Country Kind
0610804.7 May 2006 GB national
0706647.5 Apr 2007 GB national
PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/PT07/00023 5/31/2007 WO 00 1/23/2009