WO2018172950A1

WO2018172950A1 - Anhydrous crystalline forms of sodium (s)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate

Info

Publication number: WO2018172950A1
Application number: PCT/IB2018/051890
Authority: WO
Inventors: Arnaud Grandeury; Xiaoyang Wang; Franck Mallet; Lvfeng ZHU
Original assignee: Novartis Ag
Priority date: 2017-03-23
Filing date: 2018-03-21
Publication date: 2018-09-27
Also published as: TW201840539A; AR111254A1; JP2019514862A

Abstract

The present relates to the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid (EMA401) in anhydrous crystalline forms. The present invention also discloses methods of using the sodium salt of EMA401 in anhydrous crystalline forms for the treatment, prevention or attenuation of a neuropathic condition in a subject.

Description

ANHYDROUS CRYSTALLINE FORMS OF SODIUM (S)-2-(DIPHENYLACETYU-

1.2.3.4-TETRAHYDRO-6-METHOXY-5-(PHENYLMETHOXY)-3-

ISOQUINOLINECARBOXYLATE

FIELD OF THE INVENTION

The present invention relates to anhydrous crystalline forms of the sodium salt of (S)- 2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid, pharmaceutical formulations comprising said crystalline forms, their use in therapy and processes for preparing the same.

BACKGROUND OF THE INVENTION

US 5,246,943 describes substituted 1 ,2,3,4-tetrahydroisoquinoles including (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid.

(S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinolinecarboxylic acid is also known as (S)-5-(benzyloxy)-2-(2,2-diphenylacetyl)- 6-methoxy-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, as EMA401 , or as PD 126055. The structure of EMA401 is shown in formula (i) below:

WO 2006/066361 describes the use of EMA401 for the treatment of neuropathic pain and WO 2007/106938 its use in treating inflammatory pain. Salts and solvates, inter alia the sodium salt of EMA401 , are described in WO 2012/010843.

Polymorphism denotes the existence of more than one crystal structure of a substance. Polymorphs are distinct solids sharing the same molecular formula. Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different properties and stabilities specific to the particular crystalline form.

It is well known that the crystalline form of the active pharmaceutical ingredient of a particular drug is often an important determinant of the drug's physicochemical properties, its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity and could have, in extreme cases, an undesired or even toxic effect. It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will display such desirable properties.

Polymorphic forms of a compound may be distinguished from one another and from an amorphous phase of the compound by methods including but not limited to X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC) and solid state nuclear magnetic resonance (ssNMR).

The free acid of EMA401 is amorphous. Salt formation is a well-known technique to optimize the physical chemical properties of a compound. Salt selection is an important step of drug development and among the available cationic counterions, sodium is one of the most widely used for oral dosage forms. However, there are various problems associated with using EMA401 sodium salt. The sodium salt is very hygroscopic and recrystallizes partially as hydrate after exposure at 58% relative humidity and above 25°C. This not only makes it difficult to handle, but also means that it is difficult to measure precise quantities of the active moiety because the quantity of water present in different samples can vary widely.

There is therefore a need for forms of EMA401 that are physically stable, that are not sensitive when exposed to moisture and that are easy to handle. SUMMARY OF THE INVENTION

The present invention provides anhydrous crystalline forms of the sodium salt of (S)- 2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinolinecarboxylic acid (EMA401). In another aspect, there are provided methods of preparing said anhydrous crystalline forms of the sodium salt of EMA401.

The present invention further discloses methods of using anhydrous crystalline forms of the sodium salt of (S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid (EMA401) of the present invention for the treatment, prevention or attenuation of a neuropathic condition in a subject.

The invention is further directed to pharmaceutical compositions comprising a therapeutically effective amount of said anhydrous crystalline forms of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-iso- quinolinecarboxylic acid (EMA401) and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the XRPD pattern of the anhydrous crystalline form VII of the invention.

Figure 2 illustrates the XRPD pattern of form I as described in WO 2012/010843. Figure 3 illustrates the thermogravimetric analysis (TGA) and the differential scanning calorimetry (DSC) of form II as described in WO 2012/010843.

Figure 4 illustrates the FT-IR spectrum of the anhydrous crystalline form VII of the invention.

Figure 5 illustrates the differential scanning calorimetry (DSC) of the anhydrous crystalline form VII of the invention.

Figure 6 illustrates the thermogravimetric analysis (TGA) of the anhydrous crystalline form VII of the invention.

Figure 7 illustrates the XRPD pattern of the anhydrous crystalline form VIII of the invention.

Figure 8 illustrates the differential scanning calorimetry (DSC) of the anhydrous crystalline form VIII of the invention. Figure 9 illustrates the thermogravimetric analysis (TGA) of the anhydrous crystalline form VIII of the invention.

Figure 10 illustrates the sorption isotherms of the different crystalline forms by dynamic vapor sorption technique at about 25 degrees.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.

As used herein "solvate" refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. The solvent in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstochiometric amount of the solvent molecules. For example, a solvate with a nonstochiometric amount of solvent molecules may result from partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers comprising more than one molecule or compound within the lattice structure.

As used herein "amorphous" refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.

As used herein, the term "physically stable" means that the solid form will not suffer a transition from the current periodic long-range order to another type of periodic long- range order.

As used herein, "substantially pure," when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90, 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of the anhydrous crystalline sodium salt of (S)-2-(Diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, an anhydrous crystalline sodium salt of (S)-2- (Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of EMA401 sodium salt and/or reaction impurities and/or processing impurities. The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.

Another way to define substantially pure is the following:

As used herein, the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1 % by weight of any other physical forms of the compound.

As used herein, the terms "about" and "substantially" indicate, with respect to wave number values, that such values for individual peaks can vary by ± 2cm ^~1.

The term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2theta) will show some inter-apparatus variability, typically as much as 0.1 °. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystal linity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.

By "neuropathic pain" is meant any pain syndrome initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous system. Examples of neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain, entrapment pain, and the like.

The term "pain" as used herein is given its broadest sense and includes an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage and includes the more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. There are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland's Illustrated Medical Dictionary, 28th Edition, W. B. Saunders Company, Philadelphia, Pa.). The present invention is particularly concerned with the alleviation of pain associated with neuropathic conditions. The goal of treatment of pain is to reduce the degree of severity of pain perceived by a treatment subject.

The term "therapeutically effective amount" as used herein typically refers to a drug amount which, when administered to a subject, is sufficient to provide a therapeutic benefit, e.g. is sufficient for treating, preventing or delaying the progression of the disease, condition or disorder (e.g. the amount provides an amelioration of symptoms, e.g. it leads to a reduction in at least one symptom associated with neuropathic pain).

Crystal forms

A physical characterization of different forms of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinolinecarboxylic acid as described in WO 2012/010843 or in paragraph [0028] of its equivalent EP 2 595 960 B1 was performed using X-ray powder diffraction (XRPD).

The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as an amorphous form, so called Form I. This amorphous form can also show short range order. The XRPD pattern of form I is reported in Figure 2. Form I is very hygroscopic and not physically stable under elevated relative humidity conditions (58% relative humidity at 25°C for 2 weeks). In addition, exposed to light, it shows a strong chemical degradation Thus, it is very challenging to provide a pharmaceutical dosage form containing form I.

The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as a non-solvated form as described in paragraph [0029] of EP 2 595 960 B1 , so called form II. The non- solvated sodium salt crystalline form, form II exhibits an XRPD pattern comprising at least one peak at about 9.6 degrees 2Θ. Preferably, the crystalline form II exhibits an XRPD pattern comprising a peak at about 9.6 degrees 2Θ and comprising at least one peak selected from the group consisting of about 6.0 and 19.6 degrees 2Θ. More preferably, the crystalline form II exhibits an XRPD pattern comprising a peak at about 9.6 degrees 2Θ, at least one peak selected from the grouping consisting of about 6.0, and 19.6 degrees 2Θ, and at least one peak selected from the group consisting of about 14.0, 17.9, 20.6, 21.8, 23.3 and 23.9 degrees 2Θ. Even more preferably, the crystalline form II exhibits an XRPD pattern substantially the same as Figure 1 of EP 2 595 960 B1. Most preferably, the non-solvated crystalline form II has an X-ray diffraction pattern with peaks at 2Θ = 5.5, 6.0, 6.9, 8.5, 9.6, 1 1.0, 13.3, 14.0, 16.1 , 16.7, 17.9, 18.4, 19.6, 20.6, 21.8, 22.3, 23.3, 23.9, 25.5, 26.3 and 27.6. The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as a ethanolate solvate form as described in [0031] of EP 2 595 960 B1 , so called form III. The ethanol solvate, form III exhibits an X-ray powder diffraction ("XRPD") pattern comprising a peak at about 14.3 degrees 2Θ. Preferably, the ethanol solvate sodium salt crystalline form III exhibits XRPD pattern comprising a peak at about 14.7 degrees 2Θ. More preferably, the ethanol solvate sodium salt crystalline form III exhibits XRPD pattern comprising a peak at least two of the group comprising about 14.3, 14.7, 26.9, and 29.7 degrees 2Θ. Even more preferably, the crystalline form III exhibits an XRPD pattern substantially the same as Figure 2 of EP 2 595 960 B1. Most preferably, the crystalline form III has an X-ray diffraction pattern with peaks at 2Θ = 5.5, 6.7, 8.0, 8.7, 9.3, 1 1.1 , 13.4, 14.3, 14.7, 15.8, 16.1 , 16.6, 17.4, 17.8, 18.8, 20.3, 20.9, 21.4, 22.2, 22.8, 24.2, 25.4, 26.9, 27.6, 28.7, 29.7, 30.3, 31.3, 32.1 , 33.5, 35.7 and 41.0.

The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as a isopropanol solvate form as described in [0034] of EP 2 595 960 B1 , so called form IV. The isopropanol solvate of the sodium salt crystalline form IV exhibits an XRPD pattern comprising at least one peak selected from the group consisting of about 26.0, 26.6, 27.2, 28.3, and 29.3 degrees 2Θ. Preferably, the crystalline form IV exhibits an XRPD pattern comprising at least two peaks selected from the group consisting of about 25.0, 26.0, 26.6, 27.2, 28.3, and 29.3 degrees 2Θ. More preferably, the crystalline form IV exhibits an XRPD pattern comprising at least one peak selected from the grouping consisting of about 26.0, 26.6, 27.2, 28.3, and 29.3 degrees 2Θ, and at least one peak selected from the group consisting of about 10.8, 14.0, 21.1 , 21.9, and 22.5 degrees 2Θ. Even more preferably, the crystalline form IV exhibits an XRPD pattern substantially the same as Figure 3 of EP 2 595 960 B1. Most preferably, this isopropanol solvate crystalline IV form has an X-ray diffraction pattern with peaks at 2Θ = 5.4, 6.6, 7.9, 8.6, 9.2, 10.8, 13.4, 14.0, 15.9, 16.4, 17.3, 17.6, 18.6, 20.0, 20.5, 21.1 , 21.9, 22.5, 23.0, 24.0, 25.0, 25.5, 26.0, 26.6, 27.2, 28.3 and 29.3.

The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as a tri-hydrate form as described in [0037] of EP 2 595 960 B1 , so called form V. Regardless of the exact amount of water, the hydrate form V can be isolated in crystalline form. The hydrate of the sodium salt crystalline form V having between three and 5 water molecules exhibits an XRPD pattern comprising a peak at about 15.2 degrees 2Θ. Preferably, the crystalline form V exhibits an XRPD pattern comprising a peak at about 15.2 degrees, and at least two peaks selected from the group consisting of about 4.8, 7.3, 12.0, 12.6, 23.5, and 24.5 degrees 2Θ. More preferably, the crystalline form V exhibits an XRPD pattern substantially the same as Figure 4 of EP 2 595 960 B1. Even more preferably, this hydrate crystalline form V has an X-ray diffraction pattern with peaks at 29 = 4.8, 5.5, 7.3, 8.3, 9.9, 12.0, 12.6, 15.2, 16.7, 17.2, 17.9, 19.0, 21.5, 23.5 and 24.5.

The sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid can exist as a di-hydrate form as described in [0040] of EP 2 595 960 B1 , so called form VI. Regardless of the exact amount of water, the hydrate of the sodium salt crystalline form having 1-2 water molecules exhibits an XRPD pattern comprising at least one peak at about 19.3 degrees 2Θ. Preferably, the crystalline form VI exhibits an XRPD pattern comprising peaks at about 19.3 and 18.2 degrees 2Θ. More preferably, the crystalline form VI exhibits an XRPD pattern substantially the same as Figure 5 of EP 2 595 960 B1. Even more preferably, this hydrate crystalline form VI has an X-ray diffraction pattern with peaks at 29 = 4.8, 5.5, 7.3, 8.2, 12.1 ,12.8, 15.8, 16.9, 18.2, 19.3 and 25.6.

In WO 2012/010843, it is described that form II, III and IV will convert into hydrated forms, namely form V and VI when exposed to relative humidity higher than 40%. It highlights that these forms are not stable when exposed to moisture at least higher than 40%. It is also described that further drying of form V and VI will lead to formation of form I. In addition form II showed a weight loss of 3.5% on the TGA, which was lost gradually until about 120°C, when the weight was lost more rapidly, coinciding with an endotherm observed from the DSC representing the melting of the crystalline form, as depicted in Figure 3.

We have surprisingly discovered anhydrous (water and solvent free), stable, crystalline forms of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenyl-methoxy)-3-isoquino-linecarboxylic acid (EMA401) that have particularly good pharmaceutical properties. They are essentially less hygroscopic in comparison to previous known forms, thereby facilitating pharmaceutical processing. Moreover these forms are not undergoing form change either upon drying or when exposed to moisture higher than at least 40%. They also have good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules. These crystal forms will be also respectively designated as "form VII" and "form VIII" in the present disclosure.

A comparison of the XRPD peaks and of the properties of crystalline form I to VIII is given in tables 1 and 2 respectively.

Table 1. Summary of the XRPD peaks of forms I to VIII (in degree 2Theta)

I II III I IV I V I VI VII VIII 5.0 5.5 5.5 5.4 4.8 4.8 5.7 6.2

8.6 6.0 6.7 6.6 5.5 5.5 6.8 9.0

6.9 8.0 7.9 7.3 7.3 10.5 10.5

8.5 8.7 8.6 8.3 8.2 11.3 12.3

9.6 9.3 9.2 9.9 12.1 12.3 15.0

11.0 11.1 10.8 12.0 12.8 13.6 15.6

13.3 13.4 13.4 12.6 15.8 15.4 16.9

14.0 14.3 14.0 15.2 16.9 16.0 17.3

16.1 14.7 15.9 16.7 18.2 16.4 18.9

16.7 15.8 16.4 17.2 19.3 16.9 19.5

17.9 16.1 17.3 17.9 25.6 18.8 20.8

18.4 16.6 17.6 19.0 19.4 22.6

19.6 17.4 18.6 21.5 20.2 24.6

20.6 17.8 20.0 23.5 20.9 25.6

21.8 18.8 20.5 24.5 21.5 26.9

22.3 20.3 21.1 22.7

23.9 20.9 21.9 24.0

25.5 21.4 22.5 24.8

26.3 22.2 23.0 25.4

27.6 22.8 24.0 25.7

24.2 25.0 27.2

25.4 25.5 29.0

26.9 26.0 30.1

27.6 26.6 31.2

28.7 27.2 32.2

29.7 28.3

30.3 29.3

31.3

32.1

33.5

35.7

41.0

Table 2. Summary of the properties of forms I to VIII

I II III IV V VI VII VIII

Water 0.0 - 3.5% n.a n.a n.a n.a 0.3% 0.4% content 11.0%

Strong n.a n.a n.a n.a n.a Chemicall n.a chemical y and

Stability

degradati physically under

on, no stable, no light

racemizat racemi- ion zation

2 weeks n.a n.a n.a n.a n.a n.a

Converts Physical25°C,

to form V ly stable

58% RH

2 weeks n.a n.a n.a n.a n.a n.a

Converts Physicall

25°C,

to form V y stable

69% RH

2 weeks n.a n.a n.a n.a n.a n.a

Converts Physicall

50°C,

to form V y stable

65% RH

1 week n.a n.a n.a n.a n.a n.a

Converts Physicall

80°C,

to an oil y stable

61 % RH

* = According to EP 2

RH = relative humidity

In a first aspect, the anhydrous crystalline form VII of the sodium salt of EMA401 of the present invention is endowed with several advantageous properties as compared to the previously disclosed sodium salt as depicted in Table 2 and as such well suited for pharmaceutical and clinical development.

The anhydrous crystalline form VII of the sodium salt of EMA401 has a high melting onset at about 267°C and decomposes upon melting. It has low water and residual solvent content.

In one embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising four or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks at 5.6°± 0.1 °, at 6.8°± 0.1 °, at 10.5°± 0.1 °, at 11.3°± 0.1 °, at 13.6°± 0.1 °, at 15.4°± 0.1 °, at 16.4° ± 0.1 °, at 18.8°± 0.1 °, at 20.1 °± 0.1 °, at 20.9°± 0.1 °, at 22.7°± 0.1 °, at 24.0°± 0.1 °, at 25.4°± 0.1 °, at 27.2°± 0.1 °, at 29.0°± 0.1 °, at 31.2°± 0.1 °, when measured at a temperature of about 20 to 25°C.

In a preferred embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising five or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks at 5.6°± 0.1 °, at 6.8°± 0.1 °, at 10.5°± 0.1 °, at 11.3°±0.1°, at 13.6°±0.1°, at 15.4°± 0.1°, at 16.4° ±0.1°, at 18.8°±0.1°, at20.1°± 0.1°, at 20.9°± 0.1°, at 22.7°± 0.1°, at 24.0°± 0.1°, at 25.4°± 0.1°, at 27.2°± 0.1°, at 29.0°± 0.1°, at 31.2°± 0.1°, when measured at a temperature of about 20 to 25°C.

In a more preferred embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising six or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks at 5.6°± 0.1°, at6.8°± 0.1°, at 10.5°± 0.1°, at 11.3°±0.1°, at 13.6°±0.1°, at 15.4°± 0.1°, at 16.4° ±0.1°, at 18.8°±0.1°, at20.1°± 0.1°, at 20.9°± 0.1°, at 22.7°± 0.1°, at 24.0°± 0.1°, at 25.4°± 0.1°, at 27.2°± 0.1°, at 29.0°± 0.1°, at 31.2°± 0.1°, when measured at a temperature of about 20 to 25°C.

Alternatively or additionally, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2theta values (CuKa λ= 1.5418 A), at 10.5°± 0.1°, at 18.7°± 0.1° and at 31.2°± 0.1°, when measured at a temperature of about 20 to 25°C.

Alternatively or additionally, there is preferably provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2theta values (CuKa λ= 1.5418 A), at 6.8°± 0.1°, at 10.5°± 0.1°, at 11.3°± 0.1°, at 13.6°± 0.1°, at 18.7°±0.1°, at27.2°±0.1° and at 31.2°± 0.1 °, when measured at a temperature of about 20 to 25°C.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of EMA401 having an X-ray powder diffraction spectrum essentially the same as the X-ray powder diffraction spectrum shown in Figure 1.

The anhydrous crystalline form VII of the sodium salt of EMA401 may also be characterized by Fourier-Transform InfraRed (FTIR) spectroscopy.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid that exhibits an FTIR spectrum comprising four or more IR bands, in terms of wave number in cm^"1, selected from bands at about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071, 799, 751, 695, when measured at a temperature of about 20 to 25°C.

In a preferred embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid that exhibits an FTIR spectrum comprising six or more IR bands, in terms of wave number in cm^"1 , selected from bands at about 3087, 3062, 3031 , 2986, 2938, 2851 , 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071 , 799, 751 , 695, when measured at a temperature of about 20 to 25°C.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid that exhibits a FTIR spectrum essentially as exhibited in Figure 4.

The anhydrous crystalline form of the sodium salt of EMA401 may be characterized thermally. In one embodiment there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid having a differential scanning calorimetry thermogram (DSC) showing an onset of an endotherm at 267°C ± 2°C at a heating rate of 10°C per minute.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid having essentially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 5.

In another embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid having a thermos gravimetric analysis (TGA) diagram substantially the same as shown in Figure 6.

In one embodiment, an anhydrous crystalline form VII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid (EMA401) in substantially pure form is provided.

In one embodiment, an anhydrous crystalline form VII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid is provided that contains less than 0.7% (weight / weight) of water, preferably less than 0.5% (weight / weight) of water, more preferably less than 0.3% (weight / weight) of water.

In another embodiment, there is provided a process for preparing the anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid comprising steps of

(i) contacting the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro- 6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid with a suitable solvent (ii) isolating the crystalline form VII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid.

In a preferred embodiment, the suitable solvent of step (i) is selected from the list consisting of ethyl acetate, heptane, hexane, pentane, isopropyl ether, cyclopentanone, dichloromethane, acetone, tetrahydrofuran and methyltetrahydrofuran and methanol. In a particularly preferred embodiment the solvent is ethyl acetate.

In one embodiment there is provided an anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid that remains physically stable when stored at a relative humidity of 69% and at a temperature of 25° C for 2 weeks.

In one embodiment there is provided an anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid that remains physically stable when stored at a relative humidity of 65% at a temperature of 50°C for 2 weeks.

In another embodiment, there is provided an anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid that is stable when exposed to light. An anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid is provided that contains less than 1 %, preferably less than 0.5% of degradation products after exposure to light of an overall illumination of not less than 1.2 million lux hours.

In another embodiment, a composition is provided consisting essentially of the anhydrous crystalline form VII of sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid. The composition of this embodiment may comprise at least 90 weight % of the anhydrous crystalline form VII, based on the weight of the anhydrous EMA401 sodium salt in the composition.

In another embodiment, there is provided a pharmaceutical composition comprising the anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid and a pharmaceutically acceptable carrier or diluent. Such pharmaceutical compositions may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure. In a preferred embodiment, the pharmaceutical compositions are solid oral dosage forms, such as tablets or capsules.

Such compositions may be prepared by mixing the anhydrous crystalline sodium salt form VII of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid with pharmaceutically acceptable carriers, excipients, binders, diluents or the like.

The compositions of the invention may show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics may be determined, e.g. by measuring decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20, 40 or 60° C.

In another embodiment, there is provided a use of the anhydrous crystalline form VII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid for the treatment, prevention or attenuation of pain, in particular for the treatment of neuropathic pain or inflammatory pain.

In another aspect, the anhydrous crystalline form VIII of the sodium salt of EMA401 of the present invention is endowed with several advantageous properties as compared to the previously disclosed sodium salt (l-VI) as depicted in Table 3 and as such well suited for pharmaceutical and clinical development.

Table 3 Summary of the properties of EMA401 sodium salt form VIII

The anhydrous crystalline form VIII of the sodium salt of EMA401 has a high melting onset at about 271 °C and decomposes upon melting. It has low water and residual solvent content.

In one embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising four or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks at 6.2°± 0.1 °, at 9°± 0.1 °, at 10.5°± 0.1 °, at 12.3°± 0.1 °, at 15.0°± 0.1 °, at 15.6°± 0.1 °, at 16.9° ± 0.1 °, at 17.3°± 0.1 °, at 18.9°± 0.1 °, at 19.5°± 0.1 °, at 20.8°± 0.1 °, at 22.6°± 0.1 °, at 24.6°± 0.1 °, at 25.6°± 0.1 °, at 26.9°± 0.1 when measured at a temperature of about 20 to 25°C.

In a preferred embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising five or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks 6.2°± 0.1 °, at 9°± 0.1 °, at 10.5°± 0.1 °, at 12.3°± 0.1 °, at 15.0°± 0.1 °, at 15.6°± 0.1 °, at 16.9° ± 0.1 °, at 17.3°± 0.1 °, at 18.9°± 0.1 °, at 19.5°± 0.1 °, at 20.8°± 0.1 °, at 22.6°± 0.1 °, at 24.6°± 0.1 °, at 25.6°± 0.1 °, at 26.9°± 0.1 when measured at a temperature of about 20 to 25°C.

In a more preferred embodiment of the invention, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising six or more peaks, in terms of 2theta values (CuKa λ= 1.5418 A), selected from peaks at peaks at 6.2°± 0.1 °, at 9°± 0.1 °, at 10.5°± 0.1 °, at 12.3°± 0.1 °, at 15.0°± 0.1 °, at 15.6°± 0.1 °, at 16.9° ± 0.1 °, at 17.3°± 0.1 °, at 18.9°± 0.1 °, at 19.5°± 0.1 °, at 20.8°± 0.1 °, at 22.6°± 0.1 °, at 24.6°± 0.1 °, at 25.6°± 0.1 °, at 26.9°± 0.1 °, when measured at a temperature of about 20 to 25°C.

Alternatively or additionally, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2theta values (CuKa λ= 1.5418 A), at 6.2°± 0.1 °, at 9.0°± 0.1 ° and at 15.6°± 0.1 °, when measured at a temperature of about 20 to 25°C.

Alternatively or additionally, there is preferably provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2theta values (CuKa λ= 1.5418 A), at 6.2°± 0.1 °, at 9.0°± 0.1 °, at 15.6°± 0.1 °, at 20.9°± 0.1 °, at 22.6°± 0.1 ° and at 24.6°± 0.1 °, when measured at a temperature of about 20 to 25°C.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of EMA401 having an X-ray powder diffraction spectrum essentially the same as the X-ray powder diffraction spectrum shown in Figure 7.

The anhydrous crystalline form VIII of the sodium salt of EMA401 may be characterized thermally. In one embodiment there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid having a differential scanning calorimetry thermogram (DSC) showing an onset of an endotherm at 271 °C ± 2°C at a heating rate of 10°C per minute.

In one embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid having essentially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 8.

In another embodiment, there is provided an anhydrous crystalline form of the sodium salt of (S)-2-(Diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid having a thermos gravimetric analysis (TGA) diagram substantially the same as shown in Figure 9.

In one embodiment, an anhydrous crystalline form VIII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid (EMA401) in substantially pure form is provided.

In one embodiment, an anhydrous crystalline form VIII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid is provided that contains less than or equal to 1.1 % water, preferably less than 0.7% (weight / weight) of water, more preferably less than 0.4% (weight / weight) of water, even more preferably less than 0.3% (weight / weight) of water.

In another embodiment, there is provided a process for preparing the anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6- methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid comprising steps of

(i) contacting the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro- 6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid with a suitable solvent

(ii) isolating the crystalline form VIII of the sodium salt of (S)-2- (diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid. In a preferred embodiment, the suitable solvent of step (i) is selected from the list consisting of ethyl acetate, heptane, hexane, pentane, isopropyl ether, cyclopentanone, dichloromethane, acetone, tetrahydrofuran and methyltetrahydrofuran and methanol. In a particularly preferred embodiment the solvent is ethyl acetate.

In one embodiment there is provided an anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid that remains physically stable when stored at a relative humidity of 40%.

In another embodiment, a composition is provided consisting essentially of the anhydrous crystalline form VIII of sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid. The composition of this embodiment may comprise at least 90 weight % of the anhydrous crystalline form VIII, based on the weight of the anhydrous EMA401 sodium salt in the composition.

In another embodiment, there is provided a pharmaceutical composition comprising the anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)- 1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid and a pharmaceutically acceptable carrier or diluent. Such pharmaceutical compositions may optionally include one or more other components selected, for example, from the group consisting of excipients, carriers, and one of other active pharmaceutical ingredients active chemical entities of different molecular structure. In a preferred embodiment, the pharmaceutical compositions are solid oral dosage forms, such as tablets or capsules.

Such compositions may be prepared by mixing the anhydrous crystalline sodium salt form VIII of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinoline-carboxylic acid with pharmaceutically acceptable carriers, excipients, binders, diluents or the like.

In another embodiment, there is provided a use of the anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid for the preparation of a medicament for the treatment, prevention or attenuation of pain, in particular for the treatment of neuropathic pain or inflammatory pain. In another embodiment, there is provided an anhydrous crystalline sodium salt of (S)- 2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinolinecarboxylic acid form VIII for use in the treatment of neuropathic pain.

In another embodiment, a method is provided for the prevention or treatment of neuropathic conditions, in particular for the prevention or treatment of neuropathic pain, wherein the method comprises administering to a subject having a neuropathic condition a therapeutically effective amount of the anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid.

In another embodiment, there is provided a use of the anhydrous crystalline form VIII of the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy)-3-isoquinoline-carboxylic acid for the preparation of a medicament for the treatment, prevention or attenuation of pain, in particular for the treatment of neuropathic pain or inflammatory pain.

In another embodiment, there is provided an anhydrous crystalline sodium salt of (S)- 2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- isoquinolinecarboxylic acid form VIII for use in the treatment of neuropathic pain.

In one embodiment, a kit-of-parts is provided comprising (i) a pharmaceutical composition comprising the anhydrous crystalline form VII of the sodium salt of EMA401 and (ii) instructions for use of the composition.

In one embodiment, a kit-of-parts is provided comprising (i) a pharmaceutical composition comprising the anhydrous crystalline form VIII of the sodium salt of EMA401 and (ii) instructions for use of the composition.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. Various analytical methods may be used for the characterization of the anhydrous crystalline form VII or form VIII of EMA401 sodium salt.

X-ray Powder Diffraction Measurements

One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.

The following methodology and instruments were used:

Instrument Bruker D8 Advance

Geometry Bragg- Brentano

Detector LYNXEYE (1 D mode), open angle: 1.198°, slit

opening: 5.0 mm

Radiation CuKa (0.15406 nm)

X-ray generator power 40 kV, 40 mA

Step size, resolution 0.020 degrees

Scan range 2° to 45° (2 theta value)

Scan time 863.6 seconds

Slits primary soller slit: 2.5°, secondary soller slit: 2.5°, divergent slit: 0.6 mm, antiscatter slit: 5.0 mm

Temperature 20-25°C

Differential Scanning Calorimetry (DSC) The following methodology and instruments were used:

Instrument TA Discovery,

Sample mass -10 mg

The DSC cell/sample chamber was purged with 50 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about ± 1°C and the heat of fusion can be measured within a relative error of about ±5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 10 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10°C per minute in the temperature range between 25 and 300°C.

The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram ("W/g"). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.

Thermogravimetric Analysis (TGA)

The following methodology and instruments were used:

Instrument TA Discovery

Temperature range 30 to 300°C

Scan rate 10°C/min

Nitrogen flow 20 mL/min

Sample mass -2-10 mg

Thermogravimetric analysis was conducted for each crystalline form using a TA Discovery instrument. For each analysis, the cell/sample chamber was purged with 20 ml/min of ultra-high purity nitrogen gas. A weight calibration was performed using standard weights under nitrogen purge. The heating rate was 10°C per minute in the temperature range between 30°C and 300°C. The weight percentage change (wt%) was plotted versus the measured sample temperature.

FT-IR Measurements The following instrument was used: ThermoFisher Nicolet 6700 with ATR.

Example 1 - Preparation of EMA401 sodium salt

2.0 g of EMA401 sodium salt form V (isopropanol solvate) as obtained, e.g. from WO2012/010843, was dissolved in 30 mL water at 40°C. The majority of water was removed at 50°C under vacuum. The obtained solid was suspended in 50 mL of MTBE (methyl tertiary butyl ether) and the solvent was removed at 25°C under vacuum. The suspension and evaporation process was repeated 4 times. 1.63 g of EMA401 Na salt form I was obtained as white solid in 90.7% yield

Example 2 - Preparation of anhydrous crystalline EMA401 Na salt form VII

EMA401 sodium salt was suspended in dry ethyl acetate (99.9%) at 50°C so that a saturated solution (slurry) was formed. After approximately 30 minutes of stirring the anhydrous EMA401 sodium salt crystallized. The so obtained crystals were used as seed crystals for further preparations.

5.0 g of EMA401 Na form V (isopropanol solvate) (8.5 mmol) was dissolved in 50 mL ethyl acetate at 25°C. After filtration, the obtained clear solution was heated to 50°C and held for 0.5 hours. After addition of a small amount of the anhydrous EMA401 sodium salt (seed crystals), a large quantity of white solid crystallized out in minutes. The resulted suspension was held at 50°C for 10 hours, then cooled to 25°C within 5 hours and held for 5 hours. The suspension was further cooled to 0°C within 5 hours and held for 24 hours. After filtration and being dried at 40°C under vacuum overnight, 3.4 g of the anhydrous crystalline form VII of EMA401 sodium salt was obtained as white solid in 75.3% yield.

Example 3 - Preparation of anhydrous crystalline EMA401 Na salt form VII

2 g of EMA401 sodium form I are dissolved into 100 mL of ethyl acetate at RT. The product is let to recrystallize at RT and the solid is then filtered under vacuum at RT. The material is dried at 40-45 °C under vacuum.

Table 4 - Stability testing, degradation products and appearance

Test Conditions Forms

I VII

Initial Purity by HPLC (%), color 99.95 99.92

Solid state, 1 week, 50°C, tight container Test Conditions Forms

I VII

Initial Purity by HPLC (%), color 99.95 99.92

Bulk (DP by HPLC) (%) 0.1 0.07

Bulk (XRPD) no change no change

Solid state, 1 week, 50°C, 50% RH

Bulk (DP by HPLC) (%) 0.11 0.07

Bulk (XRPD) Converts to form V no change

Solid state, 1 week, 50°C, 70% RH

Bulk (DP by HPLC) (%) 0.06

Bulk (XRPD) no change

Solid state, 1 week, 80°C, tight container

Bulk (DP by HPLC) (%) 0.61 0.13

Bulk (XRPD) no change no change

Solid state, 1 week, 80°C, 50% RH

Bulk (DP by HPLC) (%) 8.58 0.20

Bulk (XRPD) sticky oil/gel no change

Solid state, 1 week, 80°C, 61 % RH

Bulk (DP by HPLC) (%) 0.72

Bulk (XRPD) no change

Xenon light (approx. 1200 kLuxh, 25°C)

Clear quartz vial

Bulk (DP by HPLC) (%) 12.10 0.33

Bulk (XRPD) no change no change

Degradation products (DP) are analyzed by HPLC. They are calculated as area-% products or against external standard (1 %). Example 4 - Preparation of anhydrous crystalline EMA401 Na salt form VIII

5.0g EMA401 Na salt was dissolved in 170mL ethanol. Resulting solution was heated to 60°C with mechanical agitation. The obtained clear solution is held for 1 h at 60°C, then cooled to 25°C within 6h and kept for 10h at 25°C. Ethanol is removed under vacuum at 25°C to reduce solution volume to about 20mL. This material is introduced in a 100mL inerted reactor under N₂ protection at 30°C and heated sequentially to 210°C within 22 min and held 2 min, then cooled to 100°C within 11 min, cooled to 30°C within 30 min. 4.3g EMA401 sodium salt form VIII is obtained as a white solid. Table 5 - Stability testing, degradation products and appearance

Test Conditions Form VIII

Initial Purity by HPLC (%), color 99.71 white

Solid state, 1 month, 25°C, 75% RH

Bulk (DP by HPLC) (%) - white

Solid state, 1 month, 40°C, 75% RH

Bulk (DP by HPLC) (%) - white

Solid state, 1 month, 25°C, 69% RH

Bulk (DP by HPLC) (%) - white

Solid state, 1 month, 40°C, 69% RH

Bulk (DP by HPLC) (%) - white

Solid state, 1 month, 80°C, tight container

Bulk (DP by HPLC) (%) 0.07 white

Solid state, 1 month, 80°C, 65% RH

Bulk (DP by HPLC) (%) 1 .48 white

Example 5 : Advantages of form VII and VIII over form I

The sorption isotherms of the different crystalline forms at 25 degree Celsius are presented in Figure 10.

The different crystalline forms, starting after sample conditioning at 0% RH can clearly be distinguished with regards of their hygroscopicity behavior. Form I is extremely sensitive towards water uptake when exposed at any relative humidity whereas Form VIII is only slightly affected up to 60% RH (about 1 % water uptake) while form VII does uptake less than 0.5% weight/ weight in these conditions. Form VII shows also a less sensitive behavior at 70% relative humidity in those conditions.

Claims

An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 ,

2,

3,

4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising four or more peaks, in terms of 2 theta values (CuKa λ= 1.5418 A), selected from peaks at 5.6°± 0.1 °, at 6.8°± 0.1 °, at 10.

5°± 0.1 °, at 11.3°± 0.1 °, at 13.

6°± 0.1 °, at 15.4°± 0.1 °, at 16.4° ± 0.1 °, at 18.8°± 0.1 °, at 20.1 °± 0.1 °, at 20.9°± 0.1 °, at 22.7°± 0.1 °, at 24.0°± 0.1 °, at 25.4°± 0.1 °, at 27.2°± 0.1 °, at 29.0°± 0.1 °, at 31.2°± 0.1 °, when measured at a temperature of about 20 to 25°C.

An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2 theta values (CuKa λ= 1.5418 A), at 10.5°± 0.1 °, at 18.

7°± 0.1 ° and at 31.2°± 0.1 °, when measured at a temperature of about 20 to 25°C

The anhydrous crystalline sodium salt of claims 1 or 2 that exhibits a X-ray powder diffraction pattern essentially the same as exhibited in Figure 1.

An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits a Fourier-Transform InfraRed spectrum comprising four or more IR bands, in terms of wave number in cm^"1 , selected from bands at about 3087, 3062, 3031 , 2986, 2938, 2851 , 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071 , 799, 751 , 695, when measured at a temperature of about 20 to 25°C.

The anhydrous crystalline sodium salt of claim 3 that exhibits a FTIR spectrum essentially the same as exhibited in Figure 4.

An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid having a differential scanning calorimetry thermogram (DSC) showing an onset of an endotherm at 267°C ± 2°C at a heating rate of 10°C per minute.

The anhydrous crystalline sodium salt of claim 6 having a differential scanning calorimetry (DSC) thermogram essentially the same as that shown in Figure 5.

8. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid having a thermogravimetric analysis (TGA) diagram essentially the same as shown in Figure 6.

9. The anhydrous crystalline sodium salt according to any of the preceding claims in substantially pure form.

10. The anhydrous crystalline sodium salt according to any of the preceding claims that contains less than 0.7% (weight /weight) of water.

11. A process for preparing the anhydrous crystalline sodium salt according to any of the preceding claims comprising the steps of (i) contacting the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-

6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid with a suitable solvent

(ii) isolating the crystalline form of the sodium salt of (S)-2-(diphenylacetyl)- 1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid.

12. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising four or more peaks, in terms of 2 theta values (CuKa λ= 1.5418 A), selected from peaks at 6.2°±

0.1 °, at 9.0°± 0.1 °, at 10.5°± 0.1 °, at 12.3°± 0.1 °, at 15.0°± 0.1 °, at 15.6°± 0.1 °, at 16.9° ± 0.1 °, at 17.3°± 0.1 °, at 18.9°± 0.1 °, at 19.5°± 0.1 °, at 20.8°± 0.1 °, at 22.6°± 0.1 °, at 24.6°± 0.1 °, at 25.6°± 0.1 °, at 26.9°± 0.1 °, when measured at a temperature of about 20 to 25°C.

13. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid that exhibits an X-ray powder diffraction pattern comprising peaks, in terms of 2 theta values (CuKa λ= 1.5418 A), at °6.2± 0.1 °, at 9°± 0.1 ° and at 15.6°± 0.1 °, when measured at a temperature of about 20 to 25°C.

14. The anhydrous crystalline sodium salt of claims 12 or 13 that exhibits a X-ray powder diffraction pattern essentially the same as exhibited in Figure 7.

15. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid having a differential scanning calorimetry thermogram (DSC) showing an onset of an endotherm at 271 °C ± 2°C at a heating rate of 10°C per minute.

16. The anhydrous crystalline sodium salt of claim 15 having a differential scanning calorimetry (DSC) thermogram essentially the same as that shown in Figure 8.

17. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid having a thermogravimetric analysis (TGA) diagram essentially the same as shown in Figure 9.

18. The anhydrous crystalline sodium salt according to any of claims 12 to 17 in substantially pure form.

19. The anhydrous crystalline sodium salt according to any of claims 12 to 18 that contains less than or equal to 1.1 % (weight /weight) of water.

20. A process for preparing the anhydrous crystalline sodium salt according to any of the preceding claims 12-19 comprising the steps of

(iii) contacting the sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro- 6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid with a suitable solvent

(iv) isolating the crystalline form of the sodium salt of (S)-2-(diphenylacetyl)- 1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- carboxylic acid.

21. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid according to any of claims 1-10 or 12-19 for use as a medicament.

22. A pharmaceutical composition comprising an anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)- 3-isoquinolinecarboxylic acid according to any of claims 1-10 and 12-19 a pharmaceutically acceptable carrier or diluent.

23. A method of treating neuropathic pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount of an anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 ,2,3,4-tetrahydro- 6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid according to claims 1-10 or 12-19.

24. An anhydrous crystalline sodium salt of (S)-2-(diphenylacetyl)-1 , 2,3,4- tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid according to claims 1-10 or 12-19 for use in the treatment of neuropathic pain.

25. A kit-of-parts comprising

(i) the pharmaceutical composition according to claim 22

(ii) instructions for use of the composition.