JP2019514862A - Anhydrous crystalline form of sodium (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylate - Google Patents

Abstract

The present invention relates to sodium of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid (EMA 401) in anhydrous crystalline form It is about salt. The invention also discloses a method of using the sodium salt of EMA 401 in anhydrous crystalline form for the treatment, prevention or attenuation of a neuropathic condition in a subject.

Description

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

  U.S. Pat. No. 5,246,943 discloses (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-. Substituted 1,2,3,4-tetrahydroisoquinol containing carboxylic acids are described.

  (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is (S) -5- (benzyloxy)- It is also known as EMA 401 or as PD 126055 as 2- (2,2-diphenylacetyl) -6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The structure of EMA 401 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, in particular the sodium salt, are described in WO 2012/010843.

  Polymorphism means that two or more crystal structures exist in one substance. Polymorphs are different solids that share the same molecular formula. Crystalline forms occur when the same composition in question crystallizes with different lattice configurations that result in different properties and stabilities specific to the particular crystal form.

  The crystalline form of the active pharmaceutical ingredient of a particular drug is the physicochemical properties of the drug, its ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, gastrointestinal fluid, in the gastrointestinal fluid It is well known that it is often an important determinant of the rate of dissolution of and the bioavailability in vivo. 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. Whether a particular compound or salt of the compound will form a polymorphism, if any of such polymorphisms would be suitable for commercial use in a therapeutic composition, or which polymorphism is such desirable. It is still impossible to predict what will be characteristic.

  Polymorphs of the compounds include, but are not limited to, methods including X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC) and solid state nuclear magnetic resonance (ssNMR) Can be distinguished from each other and from the amorphous phases of the compounds.

  The free acid of EMA 401 is amorphous. Salt formation is a well known technique for optimizing the physicochemical properties of compounds. The choice of salt is an important step in 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 the use of EMA 401 sodium salt. The sodium salt is very hygroscopic and partially recrystallizes as a hydrate after exposure at> 25 ° C. and 58% relative humidity. This not only makes handling difficult but also means that it is difficult to measure the exact amount of active moiety as the amount of water present in different samples can vary widely.

  Therefore, a form of EMA 401 that is physically stable, not sensitive when exposed to moisture, and easy to handle is needed.

  The present invention relates to anhydrous crystals of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid (EMA 401). Provide a shape. In another aspect, there is provided a method of preparing said anhydrous crystalline form of the sodium salt of EMA 401.

  The present invention relates to (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5-(-) of the invention for the treatment, prevention or attenuation of a neurological disorder condition in a subject. Further disclosed is a method of using the anhydrous crystalline form of the sodium salt of phenylmethoxy) -3-isoquinolinecarboxylic acid (EMA 401).

  The present invention relates to a therapeutically effective amount of sodium of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid (EMA 401) Further intended is a pharmaceutical composition comprising said anhydrous crystalline form of a salt and at least one pharmaceutically acceptable carrier, excipient, vehicle or excipient.

FIG. 6 illustrates the XRPD pattern of anhydrous crystalline form VII of the present invention. FIG. 7 illustrates an I-shaped XRPD pattern as described in WO 2012/010843. FIG. 5 illustrates thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of Form II as described in WO 2012/010843. It is a figure which illustrates the FT-IR spectrum of anhydrous crystalline form VII of this invention. FIG. 6 illustrates differential scanning calorimetry (DSC) of anhydrous crystalline form VII of the present invention. FIG. 6 illustrates thermogravimetric analysis (TGA) of anhydrous crystalline Form VII of the present invention. FIG. 6 illustrates the XRPD pattern of anhydrous crystalline Form VIII of the present invention. FIG. 6 illustrates differential scanning calorimetry (DSC) of anhydrous crystalline Form VIII of the present invention. FIG. 6 illustrates thermogravimetric analysis (TGA) of anhydrous crystalline Form VIII of the present invention. FIG. 5 illustrates the adsorption isotherms of different crystal forms by a dynamic water vapor adsorption technique at about 25 degrees.

Definitions As used herein, "polymorph" refers to a crystalline form having the same chemical composition but differing in the configuration 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 ion that further includes the molecules of the solvent incorporated into the crystal lattice structure. The solvent in the solvate may be present in the usual and / or unordered arrangement. Solvates may comprise either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, solvates with non-stoichiometric amounts of solvent molecules can result from partial loss of solvent from the solvate. Solvates can occur as dimers or oligomers containing more than one molecule or compound in the lattice structure.

  As used herein, "amorphous" refers to non-crystalline solid forms of molecules, atoms, and / or ions. Amorphous solids do not exhibit a limiting x-ray diffraction pattern.

  As used herein, the term "physically stable" refers to solid forms that do not undergo 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 a reference to a form means a compound having a purity of greater than 90% by weight based on the weight of the compound, This includes (S) -2- (diphenylacetyl)-, having a purity of greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and also about 100% by weight. An anhydrous crystalline sodium salt of 1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid is included. The remaining material includes the other form (s) of the compound, and / or reaction and / or processing impurities resulting from its preparation. For example, the anhydrous crystalline sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid is known in the art. Can be considered substantially pure in that it has a purity of greater than 90% by weight, as measured by methods currently known and generally accepted in Substances of less than 10% by weight include other forms (one or more) of EMA 401 sodium salt and / or reaction and / or processing impurities. The presence of reaction 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 of determining being substantially pure is as follows:

  As used herein, the term "substantially pure" with respect to a particular polymorph refers to that polymorph by less than 10%, preferably less than 5%, more preferably less than 3% by weight. Most preferably, less than 1% of any other physical form of the compound is meant to be included.

As used herein, the terms "about" and "substantially" indicate that, for wavenumber values, such values for individual peaks may vary by plus or minus 2 cm.sup.- ¹ .

  The term "essentially the same" with respect to X-ray diffraction peak positions means that the variability of typical peak positions and intensities is taken into account. For example, one skilled in the art will appreciate that the peak position (2-theta) will exhibit some device-to-device variability, typically as low as 0.1 °. Furthermore, those skilled in the art will appreciate that the relative peak intensities will exhibit inter-apparatus variability as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art. It will be understood that it should only be considered as a qualitative measure.

  By "neuropathic pain" is meant any pain syndrome that is 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, strangular pain and the like.

  As used herein, the term "pain" has its broadest meaning and includes unpleasant sensory and emotional experiences associated with actual or potential tissue damage. Or it involves more or less localized sensations of discomfort, pain or distress, which are described for such injuries and result from the stimulation of specialized nerve endings. There are many types of pain including, but not limited to, lightning pain, phantom pain, lightning pain, acute pain, inflammatory pain, neuropathic pain, complex local pain, neuralgia, neuropathy, etc. (Dorland's Illustrated Medical Dictionary, 28th Edition, WB Saunders Company, Philadelphia, Pa.). The present invention relates in particular to the alleviation of pain associated with neuropathic conditions. The goal of treatment of pain is to reduce the severity of pain seen by the subject being treated.

  As used herein, the term "therapeutically effective amount" is sufficient to provide a therapeutic benefit when administered to a subject, eg, treatment of a disease, condition or disorder, Typically refers to an amount of drug that is sufficient for prevention or delay of progression (eg, the amount provides an improvement in symptoms, eg, it leads to a reduction in at least one symptom associated with neuropathic pain) .

Crystalline Form Different forms of (S) -2- (diphenylacetyl) -1 ,, as described in paragraph WO [0028] of European patent 2 595 960 or equivalent thereto. Physical characterization of the sodium salt of 2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid 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 exists as an amorphous form, the so-called form I It may be done. This amorphous form can also exhibit short range order. The XRPD pattern of Form I is reported in FIG. Form I is extremely hygroscopic and is not physically stable under high relative humidity conditions (58% relative humidity for 2 weeks at 25 ° C.). Furthermore, when exposed to light, it exhibits strong chemical degradation. Thus, it is extremely difficult to provide a pharmaceutical dosage form comprising Form I.

  The sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is specified in European Patent No. 2 595 960. It may exist as a non-solvated form as described in paragraph [0029] of the book, so-called form II. The unsolvated sodium salt crystal form, Form II, exhibits an XRPD pattern comprising at least one peak at about 9.6 degrees 2-theta. Preferably, 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, crystalline form II has a peak at about 9.6 degrees 2θ, at least one peak selected from the group consisting of about 6.0 and 19.6 degrees 2θ, and about 14.0, 17 9 shows an XRPD pattern comprising at least one peak selected from the group consisting of: .9, 20.6, 21.8, 23.3 and 23.9 degrees 2θ. Even more preferably, crystalline form II exhibits substantially the same XRPD pattern as FIG. 1 of EP 2 595 960. Most preferably, the non-solvated crystal form II has 2θ = 5.5, 6.0, 6.9, 8.5, 9.6, 11.0, 13.3, 14.0, 16.1, The peaks at 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 It has the X-ray diffraction pattern which it has.

  The sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is specified in European Patent No. 2 595 960. It may be present as an ethanolate solvate form as described in [0031] of the book, so-called III form. Ethanol solvate, Form III, exhibits an X-ray powder diffraction ("XRPD") pattern that includes a peak at about 14.3 degrees 2θ. Preferably, ethanol solvate sodium salt crystal form III exhibits an XRPD pattern comprising a peak at about 14.7 degrees 2θ. More preferably, ethanol solvate sodium salt crystal form III has an XRPD pattern comprising at least two peaks of the group comprising about 14.3, 14.7, 26.9, and 29.7 degrees 2θ. Show. Even more preferably, crystalline form III exhibits substantially the same XRPD pattern as FIG. 2 of EP 2 595 960. Most preferably, the crystalline form III has 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, 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 having an X-ray diffraction pattern.

  The sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is specified in European Patent No. 2 595 960. It may exist as an isopropanol solvate form as described in [0034] of the book, so-called IV form. The isopropanol solvate of sodium salt crystal form IV has an XRPD comprising at least one peak selected from the group consisting of approximately 26.0, 26.6, 27.2, 28.3, and 29.3 degrees 2θ. Indicates a pattern. Preferably, crystalline form IV comprises at least two peaks selected from the group consisting of approximately 25.0, 26.0, 26.6, 27.2, 28.3 and 29.3 degrees 2θ XRPD Indicates a pattern. More preferably, Form IV has at least one peak selected from the group consisting of about 26.0, 26.6, 27.2, 28.3, and 29.3 degrees 2θ, and about 10.8. 1 shows an XRPD pattern comprising at least one peak selected from the group consisting of: 14.0, 21.1, 21.9, and 22.5 degrees 2θ. Even more preferably, crystalline form IV exhibits substantially the same XRPD pattern as FIG. 3 of EP 2 595 960. Most preferably, this isopropanol solvate crystal form IV has 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, 25.0 It has an X-ray diffraction pattern with peaks at 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 is specified in European Patent No. 2 595 960. It may be present as the trihydrate form as described in [0037] of the book, the so-called V form. Regardless of the exact amount of water, Hydrate Form V can be isolated in crystalline form. The hydrate of sodium salt crystal form V, having between 3 and 5 water molecules, exhibits an XRPD pattern comprising a peak at about 15.2 degrees 2θ. Preferably, Form V is selected from the group consisting of a peak at about 15.2 degrees, and about 4.8, 7.3, 12.0, 12.6, 23.5, and 24.5 degrees 2θ. XRPD pattern comprising at least two peaks. More preferably, crystalline form V exhibits an XRPD pattern substantially the same as FIG. 4 of EP 2 595 960. Even more preferably, this hydrate crystalline form V has 2θ = 4.8, 5.5, 7.3, 8.3, 9.9, 12.0, 12.6, 15.2, 16. It has an X-ray diffraction pattern having peaks of 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 is specified in European Patent No. 2 595 960. It may be present as the dihydrate form as described in [0040] of the book, the so-called form VI. Regardless of the exact amount of water, the hydrate of the sodium salt crystal form with one to two water molecules exhibits an XRPD pattern that includes at least one peak at about 19.3 degrees 2θ. Preferably, crystalline form VI exhibits an XRPD pattern comprising peaks at about 19.3 and 18.2 degrees 2θ. More preferably, crystalline form VI exhibits substantially the same XRPD pattern as FIG. 5 of EP 2 595 960. Even more preferably, this hydrate crystalline form VI has 2θ = 4.8, 5.5, 7.3, 8.2, 12.1, 12.8, 15.8, 16.9, 18. It has an X-ray diffraction pattern having peaks of 2, 19.3 and 25.6.

  In WO 2012/010843 pamphlet, forms II, III and IV are converted to the hydrated form, ie forms V and VI, when exposed to relative humidity higher than 40%. It is stated that it becomes. It emphasizes that these forms are not stable when exposed to moisture higher than at least 40%. It is also described that further drying of Forms V and VI will lead to the formation of Form I. In addition, Form II shows a weight loss of 3.5% in TGA, which, as shown in FIG. 3, gradually loses to about 120 ° C. when weight is lost more rapidly. Consistent with the endotherm observed from DSC representing melting of the crystalline form.

  We have surprisingly found that (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenyl-methoxy) with particularly good pharmaceutical properties. A stable anhydrous (water and solvent free) crystal form of the sodium salt of -3-isoquinoline carboxylic acid (EMA 401) was discovered. They are inherently less hygroscopic compared to previously known forms, thereby facilitating pharmaceutical processing. Furthermore, these forms do not undergo any form change when exposed to moisture greater than at least 40% when dried. They also have good storage properties and can be easily formulated into pharmaceutical compositions such as tablets and capsules. These crystal forms will also be designated as "Form VII" and "Form VIII" respectively in the present disclosure.

  A comparison of the XRPD peaks and a comparison of the characteristics of crystal forms I to VIII are shown in Tables 1 and 2, respectively.

  In a first aspect, anhydrous crystalline Form VII of the sodium salt of EMA 401 of the present invention, as compared to the sodium salt previously disclosed, as shown in Table 2, and in pharmaceutical and clinical development Some advantageous properties are given that are well suited to:

  Anhydrous Form VII of the sodium salt of EMA 401 has a high onset of melting at about 267 ° C. and decomposes upon melting. It has low water and residual solvent content.

  In one embodiment of the present invention, 5.6 ° ± 0.1 °, 6.8 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) 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 ° ± Selected from the peaks of 0.1 °, 25.4 ° ± 0.1 °, 27.2 ° ± 0.1 °, 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 ° , (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline showing an X-ray powder diffraction pattern containing four or more peaks. Anhydrous form of sodium salt of carboxylic acid provided It is.

  In a preferred embodiment of the present invention, 5.6 ° ± 0.1 °, 6.8 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) 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 ° ± Selected from the peaks of 0.1 °, 25.4 ° ± 0.1 °, 27.2 ° ± 0.1 °, 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 ° , (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline showing an X-ray powder diffraction pattern containing five or more peaks. Anhydrous form of sodium salt of carboxylic acid It is provided.

  In a more preferred embodiment of the present invention, 5.6 ° ± 0.1 °, 6.8 ° when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) ± 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 ° Selected from the peaks of ± 0.1 °, 25.4 ° ± 0.1 °, 27.2 ° ± 0.1 °, 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 ° (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-, which exhibits an X-ray powder diffraction pattern containing six or more peaks. Anhydrous condensation of sodium salt of isoquinoline carboxylic acid Form is provided.

  Alternatively or additionally, 10.5 ° ± 0.1 °, 18.7 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy- showing an X-ray powder diffraction pattern comprising the peaks at 0.1 ° and 31.2 ° ± 0.1 ° An anhydrous crystalline form of the sodium salt of 5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is provided.

  Alternatively or additionally, 6.8 ° ± 0.1 °, 10.5 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) 0.1 °, 11.3 ° ± 0.1 °, 13.6 ° ± 0.1 °, 18.7 ° ± 0.1 °, 27.2 ° ± 0.1 ° and 31.2 ° ± (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline showing an X-ray powder diffraction pattern containing a 0.1 ° peak An anhydrous crystalline form of the sodium salt of carboxylic acid is preferably provided.

  In one embodiment, an anhydrous crystalline form of the sodium salt of EMA 401 having an X-ray powder diffraction spectrum essentially the same as the X-ray powder diffraction spectrum shown in FIG. 1 is provided.

  Anhydrous form VII of the sodium salt of EMA 401 may also be characterized by Fourier transform infrared (FTIR) spectroscopy.

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

In a preferred embodiment, for wavenumbers in cm ⁻¹ , measured at a temperature of about 20 to 25 ° C., about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, (S) -2- (Diphenylacetyl) -1,2,3,4 showing a FTIR spectrum comprising 6 or more IR bands selected from the bands of 1422, 1278, 1093, 1071, 799, 751, 695 An anhydrous crystalline form of the sodium salt of -tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid is provided.

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

  The anhydrous crystalline form of the sodium salt of EMA 401 can be characterized thermally. In one embodiment, (S) -2- (diphenylacetyl) -1,2 having a differential scanning calorimetry thermogram (DSC) indicating onset of endotherm at 267 ° C. ± 2 ° C. at a heating rate of 10 ° C. per minute There is provided an anhydrous crystalline form of the sodium salt of 3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid.

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

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

  In one embodiment, substantially pure form of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid Anhydrous Form VII of the sodium salt of (EMA 401) is provided.

  In one embodiment, less than 0.7% (w / w) water, preferably less than 0.5% (w / w) water, more preferably less than 0.3% (w / w) water Anhydrous Form VII of the Sodium Salt of (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic Acid Containing Be done.

In another embodiment,
(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) (S) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid sodium salt Form VII Isolating the (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid sodium salt A method is provided for preparing anhydrous crystalline form VII.

  In a preferred embodiment, suitable solvents of step (i) are 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, (S) -2- (diphenylacetyl) -1,2,3,4- remains physically stable when stored at 69% relative humidity and a temperature of 25 ° C. for 2 weeks. Anhydrous Form VII of the sodium salt of tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid is provided.

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

  In another embodiment, (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3- is stable when exposed to light. Anhydrous Form VII of the sodium salt of isoquinoline-carboxylic acid is provided. (S) -2- (Diphenylacetyl) -1,2,3, containing less than 1%, preferably less than 0.5% of degradation products after exposure to total illumination light of less than 1.2 million lux hours. Anhydrous Form VII of the sodium salt of 4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid is provided.

  In another embodiment, the anhydrous crystal of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid A composition is provided which consists essentially of Form VII. The composition of this embodiment may comprise at least 90% by weight anhydrous crystalline form VII, based on the weight of anhydrous EMA 401 sodium salt in the composition.

  In another embodiment, the anhydrous crystalline form of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid There is provided a pharmaceutical composition comprising VII and a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions optionally have one or more other ingredients selected from the group consisting of, for example, one of additives, carriers, and other active pharmaceutical ingredients of different molecular structure active chemical entities. May be included. In a preferred embodiment, the pharmaceutical composition is a solid oral dosage form, such as a tablet or capsule.

  Such a composition is the anhydrous crystalline sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid Form VII May be prepared by mixing with pharmaceutically acceptable carriers, additives, binders, excipients and the like.

  The compositions of the present invention may exhibit good stability properties as shown by standard stability tests, having, for example, storage stability up to 1, 2 or 3 years, and even longer. Stability properties can be determined, for example, by measuring degradation products by HPLC analysis after storage for a specific time, for example at a specific temperature, for example 20, 40 or 60 ° C.

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

  In another aspect, anhydrous crystalline Form VIII of the sodium salt of EMA 401 of the present invention is as shown in Table 3 and pharmaceuticals as compared to the previously disclosed sodium salts (I-VI) and Several advantageous properties are given that are well suited for development and clinical development.

  Anhydrous Form VIII of the sodium salt of EMA 401 has a high onset of melting at about 271 ° C. and decomposes upon melting. It has low water and residual solvent content.

  In one embodiment of the present invention, when measured at a temperature of about 20 to 25 ° C., for two-theta values (CuKα λ = 1.5418 Å), 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. X-ray powder diffraction with four or more peaks selected from the peaks at 1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, 26.9 ° ± 0.1 ° 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 exhibiting a pattern is provided. Ru.

  In a preferred embodiment of the present invention, for two-theta values (CuKα λ = 1.5418 Å), measured at a temperature of about 20 to 25 ° C. 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. X-ray powder diffraction with five or more peaks, selected from the peaks at 1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, 26.9 ° ± 0.1 ° 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 exhibiting a pattern is provided. Ru.

  In a more preferred embodiment of the present invention, 6.2 ° ± 0.1 °, 9 ° ± 0 when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) .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 X-ray powder containing six or more peaks selected from the peaks of 1 °, 24.6 ° ± 0.1 °, 25.6 ° ± 0.1 °, 26.9 ° ± 0.1 ° An anhydrous crystalline form of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid exhibiting a diffraction pattern is provided Be done.

  Alternatively or additionally, 6.2 ° ± 0.1 °, 9.0 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy- showing an X-ray powder diffraction pattern comprising peaks at 0.1 ° and 15.6 ° ± 0.1 ° An anhydrous crystalline form of the sodium salt of 5- (phenylmethoxy) -3-isoquinolinecarboxylic acid is provided.

  Alternatively or additionally, 6.2 ° ± 0.1 °, 9.0 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) X-ray with peaks at 0.1 °, 15.6 ° ± 0.1 °, 20.9 ° ± 0.1 °, 22.6 ° ± 0.1 ° and 24.6 ° ± 0.1 ° An anhydrous crystalline form of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid exhibiting a powder diffraction pattern Preferably provided.

  In one embodiment, an anhydrous crystalline form of the sodium salt of EMA 401 having an X-ray powder diffraction spectrum essentially the same as the X-ray powder diffraction spectrum shown in FIG. 7 is provided.

  Anhydrous Form VIII of the sodium salt of EMA 401 may be thermally characterized. In one embodiment, (S) -2- (diphenylacetyl) -1,2 having a differential scanning calorimetry thermogram (DSC) indicating onset of endotherm at 271 ° C. ± 2 ° C. at a heating rate of 10 ° C. per minute There is provided an anhydrous crystalline form of the sodium salt of 3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid.

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

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

  In one embodiment, substantially pure form of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid Anhydrous Form VIII of the sodium salt of (EMA 401) is provided.

  In one embodiment, less than 1.1% water, preferably less than 0.7% (w / w) water, more preferably less than 0.4% (w / w) water, even more preferably , (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline containing less than 0.3% (w / w) water An anhydrous crystalline Form VIII of the sodium salt of a carboxylic acid is provided.

In another embodiment,
(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) (S) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid sodium salt of Form VIII Isolating the (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid sodium salt A method is provided for preparing anhydrous crystalline Form VIII.

  In a preferred embodiment, suitable solvents of step (i) are 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, (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5 remains physically stable when stored at 40% relative humidity. Anhydrous Form VIII of the sodium salt of-(phenylmethoxy) -3-isoquinoline-carboxylic acid is provided.

  In another embodiment, the anhydrous crystal of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid A composition is provided which consists essentially of Form VIII. The composition of this embodiment may comprise at least 90% by weight anhydrous crystalline Form VIII, based on the weight of anhydrous EMA 401 sodium salt in the composition.

  In another embodiment, the anhydrous crystalline form of the sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid There is provided a pharmaceutical composition comprising VIII and a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions optionally have one or more other ingredients selected from the group consisting of, for example, one of additives, carriers, and other active pharmaceutical ingredients of different molecular structure active chemical entities. May be included. In a preferred embodiment, the pharmaceutical composition is a solid oral dosage form, such as a tablet or capsule.

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

  In another embodiment, (S) -2- (diphenylacetyl) 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 There is provided use of anhydrous crystalline Form VIII of the sodium salt of -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid.

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

  In another embodiment, a method is provided for the prevention or treatment of a neuropathic condition, in particular for the prevention or treatment of neuropathic pain, wherein the method comprises a therapeutically effective amount of (S) -2 Anhydrous crystalline Form VIII of the sodium salt of-(diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid for subjects with a neuropathic condition Administration is included.

  In another embodiment, (S) -2- (diphenylacetyl) 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 There is provided use of anhydrous crystalline Form VIII of the sodium salt of -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid.

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

  In another embodiment, a method is provided for the prevention or treatment of a neuropathic condition, in particular for the prevention or treatment of neuropathic pain, wherein the method comprises a therapeutically effective amount of (S) -2 Anhydrous crystalline Form VIII of the sodium salt of-(diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid for subjects with a neuropathic condition Administration is included.

  In one embodiment, a kit of parts is provided comprising (i) a pharmaceutical composition comprising anhydrous Form VII of the sodium salt of EMA 401 and (ii) instructions for using the composition.

  In one embodiment, a kit of parts is provided which comprises (i) a pharmaceutical composition comprising anhydrous crystalline Form VIII of the sodium salt of EMA 401 and (ii) instructions for using 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 herein are incorporated by reference.

  A variety of analytical methods may be used to characterize the anhydrous crystalline Form VII or Form VIII of the EMA 401 sodium salt.

X-Ray Powder Diffraction Measurement One skilled in the art will understand that an X-ray diffraction pattern can be obtained with measurement errors depending on the measurement conditions used. In particular, it is generally known that the intensity in the X-ray diffraction pattern can vary depending on the measurement conditions used. It should be further understood that the relative strength may also vary depending on the experimental conditions, and thus the exact number of magnitudes of the strength should not be taken into account. Furthermore, the measurement error of the diffraction angle for conventional x-ray diffraction patterns is typically less than about 5%, and such a measurement error should be taken into account as being associated with the above-mentioned diffraction angles. As a result, the crystalline forms of the present invention are not limited to those that provide an X-ray diffraction pattern that is completely identical to the X-ray diffraction pattern shown in the accompanying drawings disclosed herein. I want you to understand. All crystal forms which provide substantially the same X-ray diffraction pattern as disclosed in the attached drawings are classified within the scope of the present invention. The ability to confirm substantial identity of x-ray diffraction patterns is within the purview of one skilled in the art.

  The following methodology and equipment were used:

Differential scanning calorimetry (DSC)
The following methodology and equipment were used:

  The DSC cell / sample chamber was purged with 50 ml / min ultra-high purity nitrogen gas. This instrument was calibrated with high purity indium. The accuracy of the sample temperature measured in this way is within about ± 1 ° C., and the heat of fusion can be measured within a relative error of about ± 5%. The samples were placed in an open aluminum DSC pan and measured against an empty reference pan. About 10 mg of sample powder was placed in the bottom of the pan and patted to make contact with the pan. The weight of the sample was accurately measured and recorded to 1/100 milligrams. The instrument was programmed to heat at 10 ° C. per minute in a temperature range between 25 and 300 ° C.

  Heat flow, normalized by sample weight, was plotted against the measured sample temperature. This data was reported in watts / gram ("W / g"). The plot was made to point to the endothermic peak. Endothermic melting peaks were evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.

Thermogravimetric analysis (TGA)
The following methodology and equipment were used:

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

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

Example 1
Preparation of EMA 401 Sodium Salt For example, 2.0 g of EMA 401 sodium salt Form V (isopropanol solvate) as obtained from WO 2012/010843 was dissolved in 30 mL water at 40 ° C. Most of the water was removed at 50 ° C. under vacuum. The resulting solid was suspended in 50 mL of MTBE (methyl tertiary butyl ether) and the solvent was removed at 25 ° C. under vacuum. The process of suspension and evaporation was repeated four times. 1.63 g of EMA 401 Na salt form I was obtained as a white solid in 90.7% yield.

Example 2
Preparation of Anhydrous Crystalline EMA 401 Na Salt Form VII EMA 401 sodium salt was suspended in dry ethyl acetate (99.9%) at 50 ° C., thereby forming a saturated solution (slurry). After stirring for about 30 minutes, the anhydrous EMA 401 sodium salt crystallized. The crystals thus obtained were used as seed crystals for further preparation.

  5.0 g of EMA 401 N V (isopropanol solvate) (8.5 mmol) was dissolved in 50 mL of ethyl acetate at 25 ° C. After filtration, the resulting clear solution was heated to 50 ° C. and held for 0.5 hours. After the addition of a small amount of anhydrous EMA 401 sodium salt (seed crystals), a large amount of white solid crystallized out in a few minutes. The resulting 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 drying at 40 ° C. under vacuum overnight, 3.4 g of anhydrous crystalline Form VII of the EMA 401 sodium salt was obtained as a white solid in a yield of 75.3%.

[Example 3]
Preparation of Anhydrous Crystalline EMA 401 Na Salt Form VII 2 g of EMA 401 sodium form I is dissolved in 100 ml of ethyl acetate at room temperature. The product is recrystallised at room temperature and then the solid is filtered under vacuum at room temperature. The material is dried at 40-45 ° C. under vacuum.

  The degradation products (DP) are analyzed by HPLC. They are calculated as area% product or against an external standard (1%).

Example 4
Preparation of Anhydrous Crystalline EMA 401 Na Salt Form VIII 5.0 g of EMA 401 Na salt was dissolved in 170 mL of ethanol. The resulting solution was heated to 60 ° C. with mechanical stirring. The resulting clear solution is held at 60 ° C. for 1 hour, then cooled to 25 ° C. within 6 hours and maintained at 25 ° C. for 10 hours. The ethanol is removed under vacuum at 25 ° C. to reduce the solution volume to about 20 mL. This material is placed in a 100 mL inactivated reactor at 30 ° C. under N ₂ protection, heated continuously to 210 ° C. within 22 minutes and held for 2 minutes, then cooled to 100 ° C. within 11 minutes And cool to 30 ° C. within 30 minutes. 4.3 g of EMA 401 sodium salt Form VIII are obtained as a white solid.

[Example 5]
Advantages of Forms VII and VIII Over Form I The adsorption isotherms of the different crystal forms at 25 degrees Celsius are shown in FIG.

The different crystal forms can be clearly distinguished in view of their hygroscopic behavior, starting after sample conditioning at 0% RH. Form I is very sensitive to water absorption when exposed at any relative humidity, whereas Form VIII is only slightly affected (up to about 60% RH) 1% water absorption), whereas form VII absorption occurs less than 0.5% w / w at these conditions. Form VII also exhibits less sensitive behavior at 70% relative humidity in those conditions.

Claims (25)

  5.6 ° ± 0.1 °, 6.8 ° ± 0.1 °, 10.5 when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) ° ± 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 Includes four or more peaks selected from the peaks at ± 0.1 °, 27.2 ° ± 0.1 °, 29.0 ° ± 0.1 °, 31.2 ° ± 0.1 ° Anhydrous crystalline sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid exhibiting an X-ray powder diffraction pattern.   10.5 ° ± 0.1 °, 18.7 ° ± 0.1 ° and 31.2 when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3 showing an X-ray powder diffraction pattern including a peak of ± 0.1 ° Anhydrous crystalline sodium salt of isoquinoline carboxylic acid.   An anhydrous crystalline sodium salt according to claim 1 or 2 exhibiting an X-ray powder diffraction pattern essentially the same as shown in FIG. When measured at a temperature of about 20 to 25 ° C. for wave numbers at cm ⁻¹ , about 3087, 3062, 3031, 2986, 2938, 2851, 1639, 1594, 1493, 1454, 1594, 1422, 1278, 1093 , (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro, which exhibits a Fourier transform infrared spectrum including four or more IR bands, selected from the bands 1071, 799, 751, and 695 Anhydrous crystalline sodium salt of -6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid.   An anhydrous crystalline sodium salt according to claim 3, which exhibits an FTIR spectrum essentially the same as shown in FIG.   (S) -2- (Diphenylacetyl) -1,2,3,4- with a differential scanning calorimetry thermogram (DSC) indicating the onset of an endotherm at 267 ° C. ± 2 ° C. at a heating rate of 10 ° C. per minute Anhydrous crystalline sodium salt of tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid.   7. An anhydrous crystalline sodium salt according to claim 6, having a differential scanning calorimetry (DSC) thermogram essentially the same as shown in FIG.   (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (having a thermogravimetric analysis (TGA) diagram essentially the same as shown in FIG. Anhydrous crystalline sodium salt of phenylmethoxy) -3-isoquinolinecarboxylic acid.   Anhydrous crystalline sodium salt according to any of the preceding claims, which is in substantially pure form.   Anhydrous crystalline sodium salt according to any of the preceding claims, comprising less than 0.7% (w / w) water. (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 And (ii) crystal form of sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid 11. A process for preparing anhydrous crystalline sodium salt according to any of claims 1 to 10, comprising the steps of isolating.   6.2 ° ± 0.1 °, 9.0 ° ± 0.1 °, 10.5 when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) ° ± 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 Indicates an X-ray powder diffraction pattern including four or more peaks selected from the peaks of ± 0.1 °, 25.6 ° ± 0.1 °, 26.9 ° ± 0.1 ° (S) 2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid anhydrous crystalline sodium salt.   6.2 ° ± 0.1 °, 9 ° ± 0.1 ° and 15.6 ° ± when measured at a temperature of about 20 to 25 ° C. for a two-theta value (CuKα λ = 1.5418 Å) (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline showing an X-ray powder diffraction pattern containing a 0.1 ° peak Anhydrous crystalline sodium salt of carboxylic acid.   Anhydrous crystalline sodium salt according to claim 12 or 13 exhibiting an X-ray powder diffraction pattern essentially the same as shown in FIG.   (S) -2- (Diphenylacetyl) -1,2,3,4- with a differential scanning calorimetry thermogram (DSC) indicating the onset of an endotherm at 271 ° C. ± 2 ° C. at a heating rate of 10 ° C. per minute Anhydrous crystalline sodium salt of tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid.   16. An anhydrous crystalline sodium salt according to claim 15, having a differential scanning calorimetry (DSC) thermogram essentially the same as shown in FIG.   (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (having a Thermogravimetric Analysis (TGA) diagram essentially the same as shown in FIG. Anhydrous crystalline sodium salt of phenylmethoxy) -3-isoquinolinecarboxylic acid.   Anhydrous crystalline sodium salt according to any of claims 12 to 17 in substantially pure form.   19. Anhydrous crystalline sodium salt according to any of claims 12 to 18 comprising less than 1.1% (w / w) water. (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) crystal form of sodium salt of (S) -2- (diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline-carboxylic acid 20. A method for preparing anhydrous crystalline sodium salt according to any of claims 12-19, comprising the steps of:   (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5-l according to any of claims 1 to 10 or 12 to 19 for use as a medicament Anhydrous crystalline sodium salt of (phenylmethoxy) -3-isoquinolinecarboxylic acid.   20. (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinoline according to any of claims 1 to 10 and 12 to 19 Pharmaceutical composition comprising anhydrous crystalline sodium salt of carboxylic acid and a pharmaceutically acceptable carrier or excipient.   21. A method of treating neuropathic pain in a patient in need of such treatment comprising: (S) -2- (diphenylacetyl) -1,2 according to any of claims 1 to 10 or 12 to 19 in an effective amount. Administration of anhydrous crystalline sodium salt of 3,4-tetrahydro-6-methoxy-5- (phenylmethoxy) -3-isoquinolinecarboxylic acid to said patient.   21. (S) -2- (Diphenylacetyl) -1,2,3,4-tetrahydro-6-methoxy-5 according to claims 1-10 or 12-19 for use in the treatment of neuropathic pain Anhydrous crystalline sodium salt of (phenylmethoxy) -3-isoquinolinecarboxylic acid. (I) The pharmaceutical composition according to claim 22. (ii) A kit of parts comprising instructions for using the composition.