TW201840539A - Anhydrous crystalline forms of sodium (s)-2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate - Google Patents

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

(S)-2-(Diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid anhydrous Crystalline

The present invention relates to (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- An anhydrous crystalline form of a sodium carboxylate salt, a pharmaceutical formulation comprising such crystalline forms, the use of such crystalline forms in therapy, and methods for preparing the same.

US 5,246,943 describes the inclusion of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate Acid-substituted 1,2,3,4-tetrahydroisoquinoline. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid is also known as (S)-5-(Benzyloxy)-2-(2,2-diphenylethenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid It is called EMA401 or PD 126055. The structure of EMA401 is shown in the following formula (i): WO 2006/066361 describes the use of EMA 401 for the treatment of neuropathic pain and WO 2007/106938 describes its use in the treatment of inflammatory pain. Salts and solvates of EMA 401, especially sodium salts, are described in WO 2012/010843. Polymorphism indicates the presence of more than one crystal structure in a substance. Polymorphs are distinct solids that share the same molecular formula. Crystallinity occurs when substances of the same composition are crystallized in different lattice arrangements, resulting in different properties and stability specificities for a particular crystalline form. The crystalline form of an effective pharmaceutical ingredient that is well known for a particular drug is usually the physicochemical properties of the drug, its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids, and in vivo living organisms. An important determinant of usability. Different polymorphs may have different rates of absorption in the body, resulting in lower or higher biological activity and, in extreme cases, may have undesirable or even toxic effects. However, it is not yet predictable whether a particular compound or salt of a compound will form a polymorph, whether any such polymorph will be suitable for commercial use in a therapeutic composition, or which polymorph will exhibit such a need characteristic. The polymorphic form of the compound can be distinguished from each other by the following methods and is distinguished from the amorphous phase of the compound, including but not limited to X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy. (Raman spectroscopy), differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR). The free acid of EMA 401 is amorphous. Salt formation is a well known technique for optimizing the physicochemical properties of a compound. Salt selection is an important step in drug development and among the available cationic relative ions, sodium is one of the most commonly used in oral dosage forms. However, there are various problems associated with the use of EMA401 sodium salt. The sodium salt is extremely hygroscopic and partially recrystallized to a hydrate after exposure to 58% relative humidity and above 25 °C. Not only does this make it difficult to handle, but it also means that it is difficult to measure the exact amount of active portion because the amount of water present in different samples can vary widely. There is therefore a need for an EMA 401 form that is physically stable, non-sensitive and easy to handle when exposed to moisture.

The present invention provides (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid (EMA401) An anhydrous crystalline form of the sodium salt. In another aspect, a method of preparing an anhydrous crystalline form of the EMA401 sodium salt is provided. The invention further discloses the use of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- of the present invention. An anhydrous crystalline form of the isoquinolinecarboxylic acid (EMA401) sodium salt to treat, prevent or attenuate a neurological condition in an individual. The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of the (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5- An anhydrous crystalline form of the sodium salt of (phenylmethoxy)-3-isoquinolinecarboxylic acid (EMA 401) and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.

definition As used herein, "polymorph" refers to a crystalline form of a different spatial arrangement of molecules, atoms, and/or ions that have the same chemical composition but form crystals. As used herein, "solvate" refers to a crystalline form of a molecule, atom, and/or ion that further comprises a molecule that is incorporated into one or more solvents in the lattice structure. The solvent in the solvate may be present in a conventional arrangement and/or a disordered arrangement. Solvates can comprise stoichiometric or non-stoichiometric solvent molecules. For example, solvates with non-stoichiometric solvent molecules may result from partial loss of solvent from the solvate. The solvate may be present in the lattice structure in the form of a dimer or oligomer comprising more than one molecule or compound. As used herein, "amorphous" refers to a solid form of a molecule, atom, and/or ion that is amorphous. The amorphous solid does not exhibit a defined X-ray diffraction pattern. As used herein, the term "physically stable" means that the solid form will not undergo a periodic long range order that is converted from the current periodic long range order to another type. As used herein, "substantially pure" when used in reference to a form, means that the purity is greater than 90% by weight, including greater than 90% by weight, 91% by weight, 92% by weight, 93% by weight of the compound. %, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight and 99% by weight and also containing equal to about 100% by weight of (S)-2-(diphenylethenyl)-1 A compound of anhydrous crystalline sodium salt of 2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline-carboxylic acid. The remaining material contains other forms of the compound, and/or its reactive impurities and/or processing impurities resulting from the preparation. For example, (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline- The anhydrous crystalline sodium salt of a carboxylic acid can be considered to be substantially pure because it has a purity of greater than 90% by weight as measured by the manner known and generally accepted in the art at the time, wherein the remainder is less than 10% by weight of the material contains other forms of EMA401 sodium salt and/or reactive impurities and/or treated impurities. The presence of reactive impurities and/or treated impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry or infrared spectroscopy. Another way to define substantially pure is as follows: As used herein, the term "substantially pure" with respect to a particular polymorphic form means that the polymorphic form comprises less than 10% by weight, preferably less than 5% by weight, More preferably less than 3% by weight, optimally less than 1% by weight of any other physical form of the compound. As used herein, with respect to wave values, the terms "about" and "substantially" indicate that such values may vary by ± 2 cm for individual peaks.^{- 1} . The term "substantially identical" with respect to the position of the X-ray diffraction peak means that typical peak position and intensity variations are taken into account. For example, those skilled in the art should appreciate that the peak position (2θ) should exhibit some inter-device variation, typically as much as 0.1°. In addition, those skilled in the art will appreciate that relative peak intensities should exhibit variations between devices and variations due to crystallinity, preferred orientation, prepared sample surfaces, and other factors known to those skilled in the art, and should only be considered For qualitative measurement. By "neural pain" is meant any pain syndrome caused or caused by primary damage 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, oppressive pain, and the like. As used herein, the term "pain" is given its broadest meaning and includes uncomfortable sensory and emotional experiences associated with actual or potential tissue damage, or is described in terms of such damage and includes the stimulation of specific nerve endings. More or less localized sensation of discomfort, pain, or illness. There are many types of pain including, but not limited to, mild pain, imaginary pain, shooting pain, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy and the like. (Dorland's Illustrated Medical Dictionary, 28th edition, WB Saunders Company, Philadelphia, Pa.). The present invention is particularly concerned with alleviating pain associated with neurological conditions. The goal of treating pain is to reduce the severity of the pain perceived by the individual being treated. As used herein, the term "therapeutically effective amount" typically refers to an amount of a drug that is sufficient to provide a therapeutic benefit, such as sufficient to treat, prevent, or delay the progression of a disease, condition, or condition, when administered to an individual (eg, the amount provides symptoms) The mitigation, for example, causes at least one symptom associated with neuropathic pain to be alleviated).Crystal type (S)-2-(Diphenylethenyl)-1,2,3,4-tetrahydro-6 as described in paragraph [0028] of WO 2012/010843 or its equivalent EP 2 595 960 B1 The physical characterization of the different forms of the sodium salt of methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate is carried out using X-ray powder diffraction (XRPD). (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt Amorphous type exists, so it is called type I. This amorphous type can also exhibit a short range order. The XRPD pattern of Type I is reported in Figure 2. Type I is extremely hygroscopic and physically unstable under elevated relative humidity conditions (2 weeks at 58% relative humidity at 25 °C). In addition, it exhibits strong chemical degradation when exposed to light. Therefore, it is extremely challenging to provide a pharmaceutical dosage form containing Formula I. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt The non-dissolved form as described in paragraph [0029] of EP 2 595 960 B1 is therefore referred to as Form II. The non-fused sodium salt crystalline form, Form II exhibits an XRPD pattern comprising at least one peak at about 9.6 degrees 22. Preferably, 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 degrees 2θ and 19.6 degrees 2θ. More preferably, crystalline Form II exhibits an XRPD pattern comprising a peak at about 9.6 degrees 2θ, at least one peak selected from the group consisting of about 6.0 degrees 2θ and 19.6 degrees 2θ, and at least one selected from the group consisting of Peaks in the group: about 14.0 degrees 2θ, 17.9 degrees 2θ, 20.6 degrees 2θ, 21.8 degrees 2θ, 23.3 degrees 2θ, and 23.9 degrees 2θ. Even more preferably, crystalline Form II exhibits an XRPD pattern substantially identical to that of Figure 1 of EP 2 595 960 B1. Most preferably, the non-fused crystalline form II has an X-ray diffraction pattern having 2θ = 5.5, 6.0, 6.9, 8.5, 9.6, 11.0, 13.3, 14.0, 16.1, 16.7, 17.9, 18.4, Peaks at 19.6, 20.6, 21.8, 22.3, 23.3, 23.9, 25.5, 26.3 and 27.6. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt The form of the ethanolate solvate as described in [0031] of EP 2 595 960 B1 is referred to as Formula III. The ethanol solvate, Form III, exhibits an X-ray powder diffraction ("XRPD") pattern comprising a peak at about 14.3 degrees 22. Preferably, the ethanol solvate sodium salt crystalline form III exhibits an XRPD pattern comprising a peak at about 14.7 degrees 22. More preferably, the ethanol solvate sodium salt crystalline form III exhibits an XRPD pattern comprising peaks at at least two of the group comprising about 14.3 degrees 2 theta, 14.7 degrees 2 theta, 26.9 degrees 2 theta, and 29.7 degrees 2 theta. Even more preferably, 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 having 2θ = 5.5, 6.7, 8.0, 8.7, 9.3, 11.1, 13.4, 14.3, 14.7, 15.8, 16.1, 16.6, 17.4, 17.8. Peaks at 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. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt Form IV is present in the form of an isopropanol solvate as described in [0034] of EP 2 595 960 B1. 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 degrees 2θ, 26.6 degrees 2θ, 27.2 degrees 2θ, 28.3 degrees 2θ, and 29.3 Degree 2θ. Preferably, crystalline Form IV exhibits an XRPD pattern comprising at least two peaks selected from the group consisting of: about 25.0 degrees 2θ, 26.0 degrees 2θ, 26.6 degrees 2θ, 27.2 degrees 2θ, 28.3 degrees 2θ, and 29.3 Degree 2θ. More preferably, the crystalline form IV exhibits an XRPD pattern comprising at least one peak selected from the group consisting of about 26.0 degrees 2θ, 26.6 degrees 2θ, 27.2 degrees 2θ, 28.3 degrees 2θ, and 29.3 degrees 2θ, and at least one selected from the group consisting of A peak in a group consisting of 10.8 degrees 2θ, 14.0 degrees 2θ, 21.1 degrees 2θ, 21.9 degrees 2θ, and 22.5 degrees 2θ. Even more preferably, crystalline Form IV exhibits an XRPD pattern substantially the same as Figure 3 of EP 2 595 960 B1. Most preferably, the isopropanol solvate crystalline Form IV has an X-ray diffraction pattern having 2θ = 5.4, 6.6, 7.9, 8.6, 9.2, 10.8, 13.4, 14.0, 15.9, 16.4, Peaks at 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. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt The form of the trihydrate as described in [0037] of EP 2 595 960 B1 is referred to as V. Regardless of the exact amount of water, the hydrate form V can be crystallized. A hydrate having a sodium salt crystalline form V between three and five water molecules exhibits an XRPD pattern comprising a peak at about 15.2 degrees 22. 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 degrees 2θ, 7.3 degrees 2θ, 12.0 degrees 2θ, 12.6 degrees 2θ, 23.5 degrees 2θ, and 24.5 degrees 2θ. More preferably, crystalline Form V exhibits an XRPD pattern substantially the same as Figure 4 of EP 2 595 960 B1. Even more preferably, the hydrate crystal form V has an X-ray diffraction pattern having 2θ = 4.8, 5.5, 7.3, 8.3, 9.9, 12.0, 12.6, 15.2, 16.7, 17.2, 17.9, 19.0. , peaks at 21.5, 23.5 and 24.5. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt Form VI, as in the form of the dihydrate described in [0040] of EP 2 595 960 B1. Regardless of the exact amount of water, a hydrate having a sodium salt crystalline form of 1-2 water molecules exhibits an XRPD pattern comprising at least one peak at about 19.3 degrees 22. Preferably, crystalline Form VI exhibits an XRPD pattern comprising peaks at about 19.3 degrees 2 theta and 18.2 degrees 2θ. More preferably, the crystalline form VI exhibits an XRPD pattern substantially the same as that of Figure 5 of EP 2 595 960 B1. Even more preferably, the hydrate crystalline form VI has an X-ray diffraction pattern having 2θ = 4.8, 5.5, 7.3, 8.2, 12.1, 12.8, 15.8, 16.9, 18.2, 19.3, and 25.6. peak. In WO 2012/010843, the descriptions II, III and IV will be converted to the hydrated form, ie the forms V and VI, upon exposure to a relative humidity above 40%. It emphasizes that these forms are not stable when exposed to at least 40% humidity. It also describes that further drying of Forms V and VI will result in Form I. In addition, Type II showed a weight loss of 3.5% on the TGA, which gradually lost until about 120 ° C. The faster the weight loss, the more consistent the endotherm observed with the molten DSC representing the crystalline form, as depicted in Figure 3. . We have unexpectedly discovered (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl-methoxy)-3-isoquine The anhydrous (anhydrous and solvent), stable crystalline form of the sodium salt of porphyrincarboxylic acid (EMA401) has particularly good pharmaceutical properties. It is substantially less hygroscopic than previously known forms, thereby facilitating medical treatment. Moreover, such forms are not subject to formal changes upon drying or upon exposure to humidity above at least 40%. It also has good storage characteristics and can be easily formulated into pharmaceutical compositions such as tablets and capsules. In the present disclosure, these crystal forms will also be referred to as "Form VII" and "Type VIII", respectively. Comparison of the XRPD peaks and characteristics of the crystalline forms I to VIII are given in Tables 1 and 2, respectively. Table 1. Overview of XRPD peaks of Forms I to VIII (in degrees 2θ) Table 2. Overview of the characteristics of Types I through VIII *=According to EP 2 595 960 RH = Relative Humidity In the first aspect, the anhydrous crystalline Form VII of the sodium salt of EMA401 of the present invention has several advantageous properties compared to the previously disclosed sodium salt as depicted in Table 2. And therefore more suitable for medical and clinical research and development. The anhydrous crystalline form VII of the sodium salt of EMA 401 has a high melting beginning at about 267 ° C and decomposes upon melting. It has a lower water and residual solvent content. In one embodiment of the invention, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. An anhydrous crystalline form of sodium salt of -3-isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising four or more than four peaks, in terms of 2θ values ( For CuKα l=1.5418 Å), the peaks are selected from the group consisting of 5.6°±0.1°, 6.8°±0.1°, 10.5°±0.1°, 11.3°±0.1°, 13.6°±0.1°, 15.4°±0.1°, 16.4°±0.1°, 18.8°±0.1°, 20.1°±0.1°, 20.9°±0.1°, 22.7°±0.1°, 24.0°±0.1°, 25.4°±0.1°, 27.2°±0.1°, 29.0° Peak at ±0.1°, 31.2° ± 0.1°. In a preferred embodiment of the invention, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl) group is provided An anhydrous crystalline form of sodium salt of oxy)-3-isoquinolinecarboxylic acid which, when measured at a temperature of from about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising five or more peaks, as in 2θ For the value (CuKα l = 1.5418 Å), the peaks are selected from the group consisting of 5.6 ° ± 0.1 °, 6.8 ° ± 0.1 °, 10.5 ° ± 0.1 °, 11.3 ° ± 0.1 °, 13.6 ° ± 0.1 °, 15.4 ° ± 0.1 °, 16.4 ° ± 0.1 °, 18.8 ° ± 0.1 °, 20.1 ° ± 0.1 °, 20.9 ° ± 0.1 °, 22.7 ° ± 0.1 °, 24.0 ° ± 0.1 °, 25.4 ° ± 0.1 °, 27.2 ° ± 0.1 °, Peak at 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 °. In a further preferred embodiment of the invention, there is provided (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl-phenyl) An anhydrous crystalline form of sodium salt of oxy)-3-isoquinoline carboxylic acid which, when measured at a temperature of from about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising six or more than six peaks, as in 2θ For the value (CuKα l = 1.5418 Å), the peaks are selected from the group consisting of 5.6 ° ± 0.1 °, 6.8 ° ± 0.1 °, 10.5 ° ± 0.1 °, 11.3 ° ± 0.1 °, 13.6 ° ± 0.1 °, 15.4 ° ± 0.1 °, 16.4 ° ± 0.1 °, 18.8 ° ± 0.1 °, 20.1 ° ± 0.1 °, 20.9 ° ± 0.1 °, 22.7 ° ± 0.1 °, 24.0 ° ± 0.1 °, 25.4 ° ± 0.1 °, 27.2 ° ± 0.1 °, Peak at 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 °. Alternatively or additionally, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising a peak, in terms of a 2θ value (CuKα l = 1.5418 Å), The peaks are at 10.5 ° ± 0.1 °, 18.7 ° ± 0.1 ° and 31.2 ° ± 0.1 °. Alternatively or additionally, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) group is preferably provided. An anhydrous crystalline form of sodium salt of -3-isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising a peak, in terms of 2θ (CuKα l = 1.5418 Å) For example, the peaks are at 6.8 ° ± 0.1 °, 10.5 ° ± 0.1 °, 11.3 ° ± 0.1 °, 13.6 ° ± 0.1 °, 18.7 ° ± 0.1 °, 27.2 ° ± 0.1 °, and 31.2 ° ± 0.1 °. In one embodiment, an anhydrous crystalline form of the sodium salt of EMA 401 is provided having an X-ray powder diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in FIG. The anhydrous crystalline Form VII of the sodium salt of EMA 401 can also be characterized as a Fourier-Transform Infrared (FTIR) spectrum. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an FTIR spectrum comprising four or more IR bands, in cm^{- 1} For the wavenumber of the unit, the bands are selected from the group consisting of about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071, 799, 751, 695. The band. In a preferred embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)- An anhydrous crystalline form of sodium 3-isoquinolinecarboxylate, which exhibits an FTIR spectrum comprising six or more than six IR bands when measured at a temperature of about 20 to 25 ° C, in cm^{- 1} For the wavenumber of the unit, the bands are selected from the group consisting of about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071, 799, 751, 695. The band. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid which exhibits an FTIR spectrum substantially identical to the spectrum presented in Figure 4. The anhydrous crystalline form of the sodium salt of EMA 401 can be characterized thermally. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having a differential scanning calorimetry thermogram (DSC) showing the endotherm at 267 ° C ± 2 ° C at a heating rate of 10 ° C / min. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having a differential scanning calorimetry (DSC) thermogram is substantially the same as that shown in FIG. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having a thermogravimetric analysis (TGA) pattern substantially the same as that shown in FIG. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl) is provided in substantially pure form. Anhydrous crystalline form VII of the sodium salt of methoxy)-3-isoquinolinecarboxylic acid (EMA401). In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form VII of the sodium salt of isoquinolinecarboxylic acid containing less than 0.7% by weight of water, preferably less than 0.5% by weight of water, more preferably less than 0.3% by weight/weight ) the water. In another embodiment, a method for preparing (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. a method of anhydrous crystalline Form VII of sodium 3-isoquinolinecarboxylate, the method comprising the steps of: (i) (S)-2-(diphenylethenyl)-1,2,3, The sodium salt of 4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate is contacted with a suitable solvent, (ii) (S)-2-(diphenylacetamidine) Separation of crystalline form VII of the base salt of -1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate. In a preferred embodiment, the suitable solvent for 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, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided The anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid remains physically stable when stored at a relative humidity of 69% and a temperature of 25 ° C for 2 weeks. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided The anhydrous crystalline form VII of the sodium salt of isoquinolinecarboxylic acid remains physically stable when stored at a relative humidity of 65% and a temperature of 50 ° C for 2 weeks. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided An anhydrous crystalline form VII of the sodium salt of isoquinolinecarboxylic acid which is stable upon exposure to light. Providing a sodium (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate Anhydrous crystalline Form VII of the salt which contains less than 1%, preferably less than 0.5%, of degradation products upon exposure to light having an overall illuminance of not less than 1.2 million lux hours. In another embodiment, a substantially (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. A composition of the anhydrous crystalline form VII of the sodium salt of 3-isoquinolinecarboxylic acid. The composition of this example may comprise at least 90% by weight of anhydrous crystalline Form VII, based on the weight of anhydrous EMA 401 sodium salt in the composition. In another embodiment, a pharmaceutical composition comprising (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(benzene) is provided Anhydrous crystalline form VII of sodium methoxy)-3-isoquinolinecarboxylate and a pharmaceutically acceptable carrier or diluent. Such pharmaceutical compositions may optionally include one or more active chemical entities selected from the group consisting of, for example, excipients, carriers, and other active pharmaceutical ingredients of different molecular structures. In a preferred embodiment, the pharmaceutical composition is a solid oral dosage form such as a lozenge or capsule. Such a composition can be obtained by (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- The anhydrous crystalline sodium salt form VII of isoquinolinecarboxylic acid is prepared by mixing with a pharmaceutically acceptable carrier, excipient, binder, diluent or the like. The compositions of the present invention can exhibit good stability characteristics as indicated by standard stability tests, such as having shelf life stability of up to one, two or three years, and even longer. The stability characteristics can be determined, for example, by measuring the decomposition products by HPLC analysis after storage for a specific time at a specific temperature, for example, 20 ° C, 40 ° C, or 60 ° C. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided Anhydrous crystalline form VII of the sodium salt of isoquinolinecarboxylic acid for use in the treatment, prevention or attenuation of pain, especially for the treatment of neuropathic or inflammatory pain. In another aspect, the anhydrous crystalline form VIII of the EMA401 sodium salt of the present invention has several advantageous properties compared to the previously disclosed sodium salt (I-VI) as depicted in Table 3, and thus is more suitable for pharmaceutical use. Academic and clinical research and development.table 3 EMA401 Sodium salt type VIII Overview of the characteristics The anhydrous crystalline form VIII of the EMA401 sodium salt has a high melting starting at about 271 ° C and decomposes upon melting. It has a lower water and residual solvent content. In one embodiment of the invention, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. An anhydrous crystalline form of sodium salt of -3-isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising four or more than four peaks, in terms of 2θ values ( For CuKα l=1.5418 Å), the peaks are selected from the group consisting of 6.2°±0.1°, 9°±0.1°, 10.5°±0.1°, 12.3°±0.1°, 15.0°±0.1°, 15.6°±0.1°, 16.9°±0.1°, 17.3°±0.1°, 18.9°±0.1°, 19.5°±0.1°, 20.8°±0.1°, 22.6°±0.1°, 24.6°±0.1°, 25.6°±0.1°, 26.9° Peak at ±0.1. In a preferred embodiment of the invention, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl) group is provided An anhydrous crystalline form of sodium salt of oxy)-3-isoquinolinecarboxylic acid which, when measured at a temperature of from about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising five or more peaks, as in 2θ For the value (CuKα l = 1.5418 Å), the peaks are selected from the group consisting of 6.2 ° ± 0.1 °, 9 ° ± 0.1 °, 10.5 ° ± 0.1 °, 12.3 ° ± 0.1 °, 15.0 ° ± 0.1 °, 15.6 ° ± 0.1 °, 16.9 ° ± 0.1 °, 17.3 ° ± 0.1 °, 18.9 ° ± 0.1 °, 19.5 ° ± 0.1 °, 20.8 ° ± 0.1 °, 22.6 ° ± 0.1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, Peak at 26.9 ° ± 0.1. In a further preferred embodiment of the invention, there is provided (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenyl-phenyl) An anhydrous crystalline form of sodium salt of oxy)-3-isoquinoline carboxylic acid which, when measured at a temperature of from about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising six or more than six peaks, as in 2θ For the value (CuKα l = 1.5418 Å), the peaks are selected from the group consisting of 6.2 ° ± 0.1 °, 9 ° ± 0.1 °, 10.5 ° ± 0.1 °, 12.3 ° ± 0.1 °, 15.0 ° ± 0.1 °, 15.6 ° ± 0.1 °, 16.9 ° ± 0.1 °, 17.3 ° ± 0.1 °, 18.9 ° ± 0.1 °, 19.5 ° ± 0.1 °, 20.8 ° ± 0.1 °, 22.6 ° ± 0.1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, Peak at 26.9 ° ± 0.1 °. Alternatively or additionally, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising a peak, in terms of a 2θ value (CuKα l = 1.5418 Å), The peaks are at 6.2 ° ± 0.1 °, 9.0 ° ± 0.1 ° and 15.6 ° ± 0.1 °. Alternatively or additionally, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) group is preferably provided. An anhydrous crystalline form of sodium salt of -3-isoquinolinecarboxylic acid which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising a peak, in terms of 2θ (CuKα l = 1.5418 Å) For example, the peaks are at 6.2 ° ± 0.1 °, 9.0 ° ± 0.1 °, 15.6 ° ± 0.1 °, 20.9 ° ± 0.1 °, 22.6 ° ± 0.1 ° and 24.6 ° ± 0.1 °. In one embodiment, an anhydrous crystalline form of the EMA 401 sodium salt is provided having an X-ray powder diffraction spectrum substantially identical to the X-ray powder diffraction spectrum shown in FIG. The anhydrous crystalline form VIII of the EMA401 sodium salt can be characterized thermally. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having a differential scanning calorimetry thermogram (DSC) showing the endotherm at 271 ° C ± 2 ° C at a heating rate of 10 ° C / min. In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having substantially the same differential scanning calorimetry (DSC) thermogram as that shown in FIG. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided An anhydrous crystalline form of the sodium salt of isoquinolinecarboxylic acid having substantially the same thermogravimetric analysis (TGA) pattern as shown in Figure 9. In one embodiment, a substantially pure (S)-2-(diphenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. Anhydrous crystalline form VIII of the sodium salt of -3-isoquinolinecarboxylic acid (EMA401). In one embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided An anhydrous crystalline form VIII of a sodium salt of isoquinolinecarboxylic acid containing less than or equal to 1.1% water, preferably less than 0.7% (w/w) water, more preferably less than 0.4% (w/w) water Even more preferably less than 0.3% (w/w) water. In another embodiment, a method for preparing (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy) is provided. a method of anhydrous crystalline form VIII of sodium 3-isoquinolinecarboxylate, the process comprising the steps of: (i) (S)-2-(diphenylethenyl)-1,2,3, The sodium salt of 4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate is contacted with a suitable solvent, (ii) (S)-2-(diphenylacetamidine) Separation of crystalline form VIII of the sodium salt of -1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate. In a preferred embodiment, the suitable solvent for 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, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- is provided The anhydrous crystalline form VIII of the isoquinolinecarboxylic acid sodium salt remains physically stable when stored at 40% relative humidity. In another embodiment, a composition is provided substantially consisting of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5- ( The anhydrous crystalline form VIII of sodium phenyl methoxy)-3-isoquinolinecarboxylate. The composition of this example may comprise at least 90% by weight of anhydrous crystalline Form VIII, based on the weight of anhydrous EMA 401 sodium salt in the composition. In another embodiment, a pharmaceutical composition comprising (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(benzene) is provided An anhydrous crystalline form VIII of sodium methoxy)-3-isoquinolinecarboxylic acid salt and a pharmaceutically acceptable carrier or diluent. Such pharmaceutical compositions may optionally include one or more active chemical entities selected from the group consisting of, for example, excipients, carriers, and other active pharmaceutical ingredients of different molecular structures. In a preferred embodiment, the pharmaceutical composition is a solid oral dosage form such as a lozenge or capsule. Such a composition can be obtained by (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3- The anhydrous crystalline sodium salt form VIII of isoquinolinecarboxylic acid is prepared by mixing with a pharmaceutically acceptable carrier, excipient, binder, diluent or the like. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided - The anhydrous crystalline form VIII of the sodium salt of isoquinolinecarboxylic acid is used for the preparation of a medicament for the treatment, prevention or attenuation of pain, especially for the treatment of neuropathic pain or inflammatory pain. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided - Anhydrous crystalline sodium salt VIII of isoquinolinecarboxylic acid is used to treat neuropathic pain. In another embodiment, a method for preventing or treating a neurological condition, particularly for preventing or treating neuropathic pain, wherein the method comprises administering a therapeutically effective amount to an individual having a neurological condition (S) Anhydrous crystalline form of sodium 2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate VIII. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided - The anhydrous crystalline form VIII of the sodium salt of isoquinolinecarboxylic acid is used for the preparation of a medicament for the treatment, prevention or attenuation of pain, especially for the treatment of neuropathic pain or inflammatory pain. In another embodiment, a (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3 is provided - Anhydrous crystalline sodium salt VIII of isoquinolinecarboxylic acid is used to treat neuropathic pain. In another embodiment, a method for preventing or treating a neurological condition, particularly for preventing or treating neuropathic pain, wherein the method comprises administering a therapeutically effective amount to an individual having a neurological condition (S) Anhydrous crystalline form of sodium 2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate VIII. In one embodiment, a kit of parts comprising (i) a pharmaceutical composition comprising anhydrous crystalline Form VII of EMA 401 sodium salt and (ii) instructions for use of the composition is provided. In one embodiment, a kit of parts comprising (i) a pharmaceutical composition comprising anhydrous crystalline Form VIII of EMA401 sodium salt and (ii) instructions for use of the composition is provided. 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, unless otherwise defined. All patents and publications cited in this specification are incorporated by reference. Various analytical methods can be used to characterize anhydrous crystalline Form VII or Form VIII of the EMA401 sodium salt.X Ray powder diffraction Measure Those skilled in the art will appreciate that an X-ray diffraction pattern having a measurement error can be obtained depending on the measurement conditions employed. In particular, it is generally known that the intensity in the X-ray diffraction pattern can vary depending on the measurement conditions employed. It should be further understood that the relative intensity can also vary depending on the experimental conditions and therefore the exact level of intensity should not be considered. In addition, the measurement error of the diffraction angle of a conventional X-ray diffraction pattern is typically about 5% or less, and such a degree of measurement error should be considered with respect to the aforementioned diffraction angle. Accordingly, it should be understood that the crystal form of the present invention is not limited to providing a crystal form of an X-ray diffraction pattern that is identical to the X-ray diffraction pattern depicted in the figures disclosed herein. Any crystal form that provides substantially the same X-ray diffraction pattern as those disclosed in the drawings is within the scope of the invention. The ability to determine the distinctive marking of an X-ray diffraction pattern is well within the skill of those in the art. Use the following methods and instruments: Differential scanning calorimetry ( DSC ) Use the following methods and instruments: The DSC unit/sample chamber was purged with ultra-high purity nitrogen at 50 ml/min. The instrument is calibrated with high purity indium. The accuracy of the sample temperature measured using 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 in an open aluminum DSC pan and measured relative to an empty reference disc. Approximately 10 mg of sample powder was placed in the bottom of the pan and gently photographed to contact the pan. The weight of the sample was accurately measured and recorded as one hundredth of a milligram. The instrument was programmed to heat at 10 °C/min in a temperature range between 25 °C and 300 °C. The sample temperature is plotted by heat flow comparison normalized by sample weight. Information is reported in watts per gram ("W/g"). The curve is drawn with an endothermic peak pointing downwards. In this analysis, the endothermic melting peak was extrapolated from the onset temperature, peak temperature, and heat of fusion.Thermogravimetric analysis ( TGA ) Use the following methods and instruments: Thermogravimetric analysis was performed for each crystal form using a TA Discovery instrument. For each analysis, the unit/sample chamber was purged with ultra-high purity nitrogen at 20 ml/min. The weight calibration was performed using a standard weight under a nitrogen purge. The heating rate was 10 ° C / min in a temperature range between 30 ° C and 300 ° C. The percent change in weight (% by weight) is plotted against the measured sample temperature.FT - IR Measure The following instruments were used: ThermoFisher Nicolet 6700 with ATR.Instance 1 - preparation EMA401 Sodium salt 2.0 g of the EMA401 sodium salt form V (isopropanol solvate) obtained, for example, from WO2012/010843, was dissolved in 30 mL of water at 40 °C. Most of the water was removed under vacuum at 50 °C. The resulting solid was suspended in 50 mL of MTBE (methyl tert-butyl ether) under vacuum at 25 ° C and the solvent was removed. The suspension and evaporation methods were repeated 4 times. 1.63 g of EMA401 Na salt form I was obtained as a white solid in a yield of 90.7%.Instance 2 - Preparation of anhydrous crystals EMA401 Na Salt type VII The EMA401 sodium salt was suspended in anhydrous ethyl acetate (99.9%) at 50 ° C to form a saturated solution (slurry). After stirring for about 30 minutes, anhydrous EMA401 sodium salt crystallized. The crystal system thus obtained was used as a seed crystal for further preparation. 5.0 g of EMA 401 Na-type V (isopropanol solvate) (8.5 mmol) was dissolved in 50 mL of ethyl acetate at 25 °C. After filtration, the obtained clear solution was heated to 50 ° C for 0.5 hours. After adding a small amount of anhydrous EMA401 sodium salt (seed), a large amount of white solid crystallized within a few minutes. The resulting suspension was kept at 50 ° C for 10 hours, then cooled to 25 ° C over 5 hours and held for 5 hours. The suspension was further cooled to 0 ° C over 5 hours and held for 24 hours. After filtration and drying under vacuum at 40 ° C overnight, 3.4 g of anhydrous crystalline form VII as a white solid was obtained as a white solid.Instance 3 - Preparation of anhydrous crystals EMA401 Na Salt type VII 2 g of EMA401 sodium Form I was dissolved in 100 mL of ethyl acetate at RT. The product was recrystallized at RT and then the solid was filtered under vacuum at RT. The material was dried under vacuum at 40-45 °C.table 4 - Stability test, Degradation products and appearance The degradation product (DP) was analyzed by HPLC. It is calculated as area % product or relative to external standards (1%).Instance 4 - Preparation of anhydrous crystals EMA401 Na Salt type VIII 5.0 g of EMA401 Na salt was dissolved in 170 mL of ethanol. The resulting solution was heated to 60 ° C with mechanical stirring. The obtained clear solution was kept at 60 ° C for 1 h, then cooled to 25 ° C in 6 h and kept at 25 ° C for 10 h. The ethanol was removed under vacuum at 25 °C to reduce the solution volume to approximately 20 mL. At 30 ° C at N₂ This material was introduced into a 100 mL inerting reactor under protection and continuously heated to 210 ° C for 22 min for 22 min, then cooled to 100 ° C in 11 min and cooled to 30 ° C in 30 min. 4.3 g of EMA401 sodium salt type VIII was obtained as a white solid.table 5 - Stability testing, degradation products and appearance Instance 5 : type VII and VIII Compared to type I Advantage The adsorption isotherms of different crystal forms at 25 degrees Celsius are presented in Figure 10. The different crystalline forms that begin after the sample is adjusted at 0% RH can be clearly highlighted with respect to its hygroscopic behavior. Type I is extremely sensitive to moisture uptake when exposed to any relative humidity, whereas Form VIII is only slightly affected by up to 60% RH (about 1% moisture uptake), while Form VII does absorb less than 0.5% under these conditions. Weight / weight. Type VII also exhibits less sensitive behavior at 70% relative humidity under these conditions.

Figure 1 illustrates an XRPD pattern of the anhydrous crystalline form VII of the present invention. Figure 2 illustrates an XRPD pattern of Form I as described in WO 2012/010843. Figure 3 illustrates thermogravimetric analysis (TGA) and 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 present invention. Figure 5 illustrates the differential scanning calorimetry (DSC) of the anhydrous crystalline Form VII of the present invention. Figure 6 illustrates the thermogravimetric analysis (TGA) of the anhydrous crystalline Form VII of the present invention. Figure 7 illustrates an XRPD pattern of the anhydrous crystalline form VIII of the present invention. Figure 8 illustrates the differential scanning calorimetry (DSC) of anhydrous crystalline Form VIII of the present invention. Figure 9 illustrates the thermogravimetric analysis (TGA) of anhydrous crystalline Form VIII of the present invention. Figure 10 illustrates adsorption isotherms of different crystalline forms by dynamic gas phase adsorption techniques at about 25 degrees.

Claims (25)

An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid a crystalline sodium salt which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising four or more than four peaks, in terms of 2θ values (CuKα l = 1.5418 Å), The peak is selected from the group consisting of 5.6°±0.1°, 6.8°±0.1°, 10.5°±0.1°, 11.3°±0.1°, 13.6°±0.1°, 15.4°±0.1°, 16.4°±0.1°, 18.8°±0.1°. 20.1°±0.1°, 20.9°±0.1°, 22.7°±0.1°, 24.0°±0.1°, 25.4°±0.1°, 27.2°±0.1°, 29.0°±0.1°, 31.2°±0.1° peak. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid The crystalline sodium salt, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising peaks, which are at 10.5 ° ± 0.1 for 2θ values (CuKα l = 1.5418 Å) °, 18.7 ° ± 0.1 ° and 31.2 ° ± 0.1 °. An anhydrous crystalline sodium salt of claim 1 or 2 which exhibits substantially the same X-ray powder diffraction pattern as presented in FIG. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid crystalline sodium salt, when measured at a temperature of about 20 to 25 deg.] C, exhibiting comprising four or more than four IR bands of the Fourier transform infrared spectroscopy, with regard to cm ^{- 1} is the wave number of the unit concerned, The bands are selected from the bands of about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093, 1071, 799, 751, 695. An anhydrous crystalline sodium salt of claim 3 which exhibits substantially the same FTIR spectrum as presented in Figure 4. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid A crystalline sodium salt having a differential scanning calorimetry thermogram (DSC) showing the onset of heat absorption at a heating rate of 10 ° C/min at 267 ° C ± 2 ° C. An anhydrous crystalline sodium salt of claim 6 having substantially the same differential scanning calorimetry (DSC) thermogram as shown in FIG. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid A crystalline sodium salt having substantially the same thermogravimetric analysis (TGA) pattern as shown in Figure 6. The anhydrous crystalline sodium salt of any of 2, 4 and 6 to 8, which is substantially pure. The anhydrous crystalline sodium salt of any of 2, 4 and 6 to 8 which contains less than 0.7% by weight of water. A method for producing an anhydrous crystalline sodium salt according to any one of claims 1 to 10, which comprises the steps of: (i) (S)-2-(diphenylethenyl)-1,2 , 3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt is contacted with a suitable solvent, (ii) (S)-2-(diphenyl) Crystalline separation of sodium salt of -1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid a crystalline sodium salt which, when measured at a temperature of about 20 to 25 ° C, exhibits an X-ray powder diffraction pattern comprising four or more than four peaks, in terms of 2θ values (CuKα l = 1.5418 Å), The peak is selected from the group consisting of 6.2°±0.1°, 9.0°±0.1°, 10.5°±0.1°, 12.3°±0.1°, 15.0°±0.1°, 15.6°±0.1°, 16.9±±°°, 17.3°±0.1°. , peaks at 18.9 ° ± 0.1 °, 19.5 ° ± 0.1 °, 20.8 ° ± 0.1 °, 22.6 ° ± 0.1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, 26.9 ° ± 0.1 °. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid The crystalline sodium salt, when measured at a temperature of about 20 to 25 ° C, exhibits a diffraction pattern of X-ray powder containing peaks, which are at 6.2 ± 0.1 ° for 2θ values (CuKα l = 1.5418 Å) , 9 ° ± 0.1 ° and 15.6 ° ± 0.1 °. An anhydrous crystalline sodium salt of claim 12 or 13 which exhibits substantially the same X-ray powder diffraction pattern as presented in FIG. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid A crystalline sodium salt having a differential scanning calorimetry thermogram (DSC) showing the onset of heat absorption at a heating rate of 10 ° C/min at 271 ° C ± 2 ° C. An anhydrous crystalline sodium salt of claim 15 having substantially the same differential scanning calorimetry (DSC) thermogram as shown in FIG. An anhydrous of (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid A crystalline sodium salt having substantially the same thermogravimetric analysis (TGA) pattern as shown in Figure 9. The anhydrous crystalline sodium salt of any one of claims 12, 13 and 15 to 17, which is substantially pure. An anhydrous crystalline sodium salt according to any one of claims 12, 13 and 15 to 17, which contains less than or equal to 1.1% by weight of water. A method for the preparation of the anhydrous crystalline sodium salt according to any one of claims 12 to 19, which comprises the steps of: (i) (S)-2-(diphenylethenyl)-1,2 , 3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid sodium salt is contacted with a suitable solvent, (ii) (S)-2-(diphenyl) Crystalline separation of sodium salt of -1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylate. (S)-2-(diphenylethenyl)-1,2,3,4-tetra as one of claims 1, 2, 4, 6 to 8, 12, 13 and 15 to 17 An anhydrous crystalline sodium salt of hydrogen-6-methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid, which is used as a medicament. A pharmaceutical composition comprising (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6-, as claimed in any one of claims 1 to 10 and 12 to 19 An anhydrous crystalline sodium salt of methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid and a pharmaceutically acceptable carrier or diluent. (S)-2-(Diphenylethenyl)-1,2,3,4-tetrahydro-6-methoxy-5- (a) according to any one of claims 1 to 10 and 12 to 19 Use of an anhydrous crystalline sodium salt of phenyl methoxy)-3-isoquinolinecarboxylic acid for the manufacture of a medicament for the treatment of neuropathic pain. (S)-2-(diphenylethenyl)-1,2,3,4-tetrahydro-6- as claimed in claims 1, 2, 4, 6 to 8, 12, 13 and 15 to 17 An anhydrous crystalline sodium salt of methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid for use in the treatment of neuropathic pain. A kit of parts comprising (i) the pharmaceutical composition of claim 22, (ii) instructions for use of the composition.