Novel crystalline forms of (s)-7-oxa-2-aza-spiro [4.5] decane-2-carboxylic acid [7-(3, 6-dihydro-2h-pyran-4-yl)-4-methoxy-thiazolo [4, 5-c] pyridin-2-yl]-amide and co-crystalline forms thereof

Abstract

The present invention relates to novel crystalline forms of (S)-7-oxa-2-aza-spiro [4.5] decane-2-carboxylic acid [7-(3, 6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo [4, 5-c] pyridin-2-yl]-amide, processes for their preparation, medicaments and pharmaceutical formulations comprising these forms.

Description

[0001] The present invention relates to novel crystalline forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, processes for their preparation, medicaments and pharmaceutical preparations comprising these forms. Background of the Invention

[0003] WO 2020 / 152132 A1 (Compound 25) discloses (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide after chiral separation by HPLC. WO 2020 / 152132 A1 describes its preparation method and the yield of the amorphous state of the compound. Apart from this, no dedicated crystalline form is mentioned for this compound in WO 2020 / 152132 A1.

[0004] However, if the active substance is intended as an active substance in a medicinal product, the amorphous state, being a thermodynamically less stable form, is often responsible for chemical and physical stability, with negative effects on dissolution rate, bioavailability, efficacy and storage of the drug.

[0005] It was therefore an object of the present invention to develop alternative solid-state forms that overcome these disadvantages. SUMMARY OF THE INVENTION

[0007] Unexpectedly, we have discovered a new crystalline anhydrous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, designated A1.

[0008] In addition, we have discovered new hydrate forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, namely NF2, NF3, NF4 and NF12.

[0009] In addition, we have discovered novel anhydrous pure crystalline cocrystal forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide / fumaric acid, further referred to as monofumaric acid cocrystal Form A1 and hemifumaric acid cocrystal Form A2, which exhibit improved dissolution behavior in a biologically relevant intestinal environment (FaSSIF) compared to crystalline forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide. In addition to the above-mentioned cocrystal Form A1 of monofumaric acid and cocrystal Form A2 of hemifumaric acid, NF1 and NF2 were confirmed to be hemifumaric acid cocrystal forms.

[0010] In addition, we unexpectedly discovered new anhydrous pure crystalline cocrystal forms of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide of 3-hydroxybenzoic acid, which are further referred to as mono 3-hydroxybenzoic acid cocrystal forms NF1 and NF2.

[0011] Finally, we have surprisingly discovered that (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide reacts with tartaric acid, 1,5-naphthalene disulfonic acid, D - New crystalline cocrystal forms of malic acid and 3,4-dihydroxybenzoic acid, further referred to as hemi-tartrate cocrystal forms NF1 and NF2, mono- D -Malic acid cocrystal form NF1, 1,5-naphthalenedisulfonic acid cocrystal form NF1 and mono-3,4-dihydroxybenzoic acid cocrystal form NF1.

[0012] When (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is used in pharmaceutical products, the newly discovered crystalline form is thermodynamically more stable than the amorphous state, which has a positive impact on dissolution rate, bioavailability, efficacy and storage.

[0013] Thus, one embodiment of the present invention is a crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0014] Another embodiment of the present invention is the crystalline anhydrous Form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0015] Yet another embodiment of the present invention is a hydrate form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide selected from the hydrate forms NF2, NF3, NF4 and NF12.

[0016] Therefore, a further embodiment of the present invention is a crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide selected from

[0017] a) Monofumaric acid cocrystal Form A1,

[0018] b) Hemifumaric acid cocrystal Form A2,

[0019] c) Hemifumaric acid cocrystal form NF1,

[0020] d) Hemifumaric acid eutectic form NF2,

[0021] e) Mono-3-hydroxybenzoic acid cocrystal form NF1,

[0022] f) Mono-3-hydroxybenzoic acid cocrystal form NF2,

[0023] g) Hemi-tartrate eutectic form NF1,

[0024] h) Hemi-tartrate eutectic form NF2,

[0025] i) Single D -Malic acid eutectic form NF1,

[0026] j) 1,5-Naphthalenedisulfonic acid cocrystal form NF1 and

[0027] k) Mono-3,4-dihydroxybenzoic acid cocrystal Form NF1.

[0028] Compared to the amorphous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, the novel crystalline anhydrous form A1 exhibits the following properties:

[0029] -Crystalline form, very good crystallinity

[0030] -Anhydrous form

[0031] - Slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.), with no tendency to form hydrates when exposed to elevated RH levels.

[0032] Therefore, another embodiment of the present invention is the crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the crystalline anhydrous form A1 has characteristic peaks:

[0033]

[0034]

[0035] Another embodiment of the present invention is the monofumaric acid cocrystal form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the monofumaric acid cocrystal form A1 has characteristic peaks:

[0036] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 7.8 2 9.5 3 10.6 4 11.6 5 12.2 6 15.4 7 16.5 8 18.6 9 19.9 10 20.2 11 21.5 12 22.4 13 23.2 14 23.9 15 24.6 16 25.5 17 28.1 18 28.5

[0037] Compared to the amorphous state of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, the novel monofumaric acid cocrystal Form A1 exhibits the following properties:

[0038] -Crystalline form, very good crystallinity

[0039] -Anhydrous form

[0040] -1:1 ratio of API:fumaric acid

[0041] - Slightly hygroscopic according to the European Pharmacopoeia, with no tendency to form hydrates when exposed to elevated RH levels.

[0042] Another embodiment of the present invention is the hemifumaric acid cocrystal form A2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid cocrystal form A2 has characteristic peaks:

[0043] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 6.6 2 9.7 3 11.5 4 13.4 5 14.1 6 14.7 7 16.5 8 18.0 9 18.5 10 19.4 11 20.0 12 21.4 13 22.9 14 24.1 15 26.8

[0044] Another embodiment of the present invention is the hemifumaric acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid cocrystal form NF1 has characteristic peaks:

[0045]

[0046]

[0047] Another embodiment of the present invention is the hemifumaric acid cocrystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the hemifumaric acid cocrystal form NF2 has characteristic peaks:

[0048]

[0049]

[0050] Another embodiment of the present invention is the mono-3-hydroxybenzoic acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono-3-hydroxybenzoic acid cocrystal form NF1 has characteristic peaks:

[0051] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 7.3 2 10.6 3 13.9 4 14.5 5 16.1 6 16.6 7 17.4 8 18.1 9 18.7 10 19.4 11 20.0 12 20.8 13 21.3 14 23.1 15 23.5 16 25.1 17 25.7 18 27.2 19 28.1

[0052] Compared to the amorphous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, the novel mono-3-hydroxybenzoic acid cocrystal form NF1 exhibits the following benefits:

[0053] -Crystalline form, very good crystallinity

[0054] -Anhydrous form

[0055] -1:1 ratio of API:3-hydroxybenzoic acid

[0056] - Non-hygroscopic according to the European Pharmacopoeia, no tendency to form hydrates when exposed to elevated RH levels.

[0057] Another embodiment of the present invention is the mono-3-hydroxybenzoic acid cocrystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono-3-hydroxybenzoic acid cocrystal form NF2 has characteristic peaks:

[0058] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 8.1 2 8.5 3 10.0 4 12.6 5 14.0 6 15.7 7 16.8 8 19.6 9 20.4 10 20.9 11 22.9 12 23.6 13 29.5

[0059] Another embodiment of the present invention is a mono-3,4-dihydroxybenzoic acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the mono-3,4-dihydroxybenzoic acid cocrystal form NF1 has characteristic peaks:

[0060]

[0061]

[0062] Another embodiment of the present invention is the semi-tartrate cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the semi-tartrate cocrystal form NF1 has characteristic peaks:

[0063] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 11.2 2 16.0 3 17.0 4 18.5 5 19.6 6 20.4 7 23.3 8 24.2 9 27.9

[0064] Another embodiment of the present invention is the semi-tartrate cocrystal form NF2 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the semi-tartrate cocrystal form NF2 has characteristic peaks:

[0065] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.4°]]> 1 11.2 2 16.0 3 16.9 4 17.9 5 19.7 6 20.4 7 23.3 8 24.1 9 27.8

[0066] Another embodiment of the present invention is the 1,5-naphthalene disulfonic acid cocrystal form NF1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, wherein the 1,5-naphthalene disulfonic acid cocrystal form NF1 has characteristic peaks:

[0067]

[0068]

[0069] Another embodiment of the present invention is the monohydrate of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide. D -Malic acid cocrystal form NF1, wherein the single D -Malic acid cocrystal form NF1 has characteristic peaks:

[0070] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 17.0 2 19.6 3 20.4 4 21.6 5 23.4 6 28.1

[0071] All forms can be characterized according to standard methods, which can be found, for example:

[0072] - Rolf Hilfiker, 'Polymorphism in the Pharmaceutical Industry', Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction, Chapter 6: Vibrational Spectroscopy, Chapter 3: Thermal Analysis, Chapter 9: Water Vapour Sorption, and references therein)

[0073] - HG Brittain, 'Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6 and references therein)

[0074] The present invention also relates to (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide containing one or more co-crystal forms according to the present invention.

[0075] A further embodiment according to the present invention is (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide consisting essentially of one or more co-crystal forms according to the present invention.

[0076] The co-crystal form according to the invention is prepared as follows: (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is suspended in an organic solvent, preferably acetone, at elevated temperature and, after adding an equal amount of a co-former, crystallization is initiated by cooling and finally the residue is separated off and dried.

[0077] Therefore, another embodiment of the present invention is a method for preparing a co-crystal form according to the present invention, characterized in that (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is suspended in an organic solvent at elevated temperature, an equal amount of co-crystal former is added and cooling crystallization is carried out.

[0078] As already described, the crystalline form according to the invention is thermodynamically stable and is therefore particularly suitable as a pharmaceutical product. As described in WO 2020 / 152132 A1, (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide can be used for the treatment and / or prevention of physiological and / or pathophysiological states selected from hyperproliferative and infectious diseases and disorders, and in particular for the treatment and / or prevention of cancer.

[0079] The active ingredients can of course also be used as a mixture of crystalline forms according to the invention, which may contain more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the crystalline forms according to the invention. Mixtures with more than 70%, particularly preferably with more than 80% and particularly preferably with more than 90% by weight of the crystalline forms according to the invention are preferred according to the invention.

[0080] The present invention therefore also relates to medicaments for use in the treatment and / or prevention of cancer, which comprise one or more crystalline forms according to the invention or mixtures thereof in all ratios.

[0081] Another embodiment of the present invention is the use of one or more crystalline forms according to the invention or mixtures thereof in all ratios for the preparation of a medicament for the treatment and / or prevention of cancer.

[0082] Yet another embodiment of the present invention is a method for the treatment and / or prevention of cancer, wherein one or more crystalline forms according to the present invention or a mixture thereof are administered to a human in need thereof.

[0083] Furthermore, the invention relates to pharmaceutical preparations containing one or more crystalline forms according to the invention or mixtures thereof in all ratios and optionally further excipients and / or adjuvants.

[0084] Another embodiment of the invention is a process for the preparation of a pharmaceutical preparation, characterized in that one or more crystalline forms according to the invention or mixtures thereof in all ratios are brought into a suitable dosage form together with solid, liquid or semi-liquid excipients or adjuvants.

[0085] Even without further embodiments, it is believed that a person skilled in the art will be able to utilize the above description in the broadest scope. Therefore, the preferred embodiments should be considered as merely descriptive disclosure, which is absolutely not limiting in any way.

[0086] All references cited herein are hereby incorporated by reference into the present disclosure.

[0087] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable embodiments are described below. Within the embodiments, standard reagents and buffers (where feasible) free of contaminating activity are used. The embodiments should be interpreted in particular as making them not limited to the feature combinations clearly described, but the illustrated features can be combined again without restriction, provided that the technical problems of the present invention are solved. Similarly, the features of any claim can be combined with the features of one or more other claims. The present invention, which has been summarized and described in detail, is illustrated by the following examples and is not limited thereto.

[0088] abbreviation:

[0089] 2,4-DHBA:2,4-dihydroxybenzoic acid

[0090] 3,4-DHBA: 3,4-dihydroxybenzoic acid

[0091] 3-HBA:3-Hydroxybenzoic acid

[0092] DSC: Differential Scanning Calorimetry

[0093] TGA: Thermogravimetric analysis

[0094] SGF: Simulated Gastric Fluid

[0095] FeSSIF: fed state simulated intestinal fluid

[0096] FaSSIF: Fasting State Simulated Intestinal Fluid

[0097] Example 1 - Preparation of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0098] WO 2020 / 152132 A1 describes the chiral separation of intermediates by chiral HPLC to produce amorphous materials of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0099] The powder X-ray diffraction pattern has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th edition and is characterized by the X-ray powder diffraction pattern shown in Figure 1 (monochromatic Cu-Kα1 radiation, λ=1.5406, Stoe Stadi P 611KL transmission diffractometer).

[0100] The amorphous state is characterized by the following physical properties:

[0101] Thermal behavior showed no significant enthalpy events, and a total weight loss TGA of 2.9% (w / w) up to 150°C. The DSC and TGA curves are shown in Figures 2A and 2B. DSC scans of the amorphous state were acquired on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. TGA scans of the amorphous state were acquired on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min (see Figures 2A and 2B for DSC and TGA scans of the amorphous state).

[0102] The water vapor sorption behavior revealed a water absorption level of >22% (w / w) over the complete relative humidity (RH) range of 0-98% RH. According to the European Pharmacopoeia standard (Section 5.11), the amorphous state can be classified as hygroscopic and it exhibits a tendency to deliquesce at humidity levels of >90% RH. The water vapor sorption isotherm (25°C) is shown in Figure 3 (Water vapor sorption isotherm (25°C) of the amorphous state). The water vapor sorption isotherm was obtained on a DVS intrinsic system from SMS.

[0103] Example 2 - Preparation of the Crystalline Anhydrous Form A1 of (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0104] Laboratory scale:

[0105] About 210 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 2 mL of acetone at 50° C. for 2 hours. Thereafter, the suspension was centrifuged and dried at 50° C. under a stream of N2 for 12 hours.

[0106] Gramm scale:

[0107] About 1.9 g of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide were dissolved in 20 mL of acetone, stored overnight at 0° C., separated and dried. Thereafter, the suspension was centrifuged and dried at 50° C. and <10 mbar for 90 hours.

[0108] The powder X-ray diffraction pattern of A1 has been obtained by standard techniques as described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia and is shown in FIG4 (monochromatic Cu-Kα1 radiation, The powder X-ray peak list of the A1 form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is shown in Table 1.

[0109] Table 1 - List of powder X-ray peaks of crystalline anhydrous form A1

[0110] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 7.8 2 9.5 3 10.6 4 11.6 5 12.2 6 15.4 7 16.5 8 18.6 9 19.9 10 20.2 11 21.5 12 22.4 13 23.2 14 23.9 15 24.6 16 25.5 17 28.1 18 28.5

[0111] Single crystal x-ray structural data of the A1 form were also obtained at 298 K (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer with graphite monochromator and CCD detector) (see Figure 5).

[0112] The A1 form crystallizes in the noncentrosymmetric monoclinic space group P21, with lattice parameters and β = 103.5 ± 0.5° (where α = γ = 90°). As is apparent from the single crystal structure, Form A1 represents an anhydrous form.

[0113] The A1 form is characterized by the following physical properties:

[0114] The thermal behavior of the A1 form shows a melting (~213°C) that overlaps with the TGA step, which is due to the heat release of the strongly bound residual solvent in the agglomerates. The DSC and TGA curves are shown in Figures 6A and 6B. The DSC scans of the A1 form were obtained on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. The TGA scans of the A1 form were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min.

[0115] The water vapor sorption behavior of Form A1 revealed a very small water uptake level of <1% (w / w) over the complete relative humidity (RH) range of 0-98% RH. Form A1 can be classified as slightly hygroscopic according to European Pharmacopoeia criteria (Section 5.11). The water vapor sorption isotherm (25° C.) of Form A1 is shown in FIG7 . The water vapor sorption isotherm was acquired on a DVS intrinsic system from SMS.

[0116] Example 3-(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF2 preparation method

[0117] About 17 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 500 μL of water at room temperature for about 7 days. The solid residue was centrifuged and not dried.

[0118] The powder X-ray diffraction pattern of the hydrate form NF2 has been obtained by standard techniques as described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia and is shown in Figure 8 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0119] Example 4-(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF3 preparation method

[0120] About 17 mg of amorphous (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was stirred in 500 μL of water at room temperature for about 7 days. The solid residue was centrifuged and dried under ambient conditions.

[0121] The powder X-ray diffraction pattern of the hydrate form NF3 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 9 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0122] Example 5-(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF4 preparation method

[0123] About 5 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF4 was suspended in 1 mL FeSSIF [pH 5.0] at 37° C. for 24 hours. Solid / liquid separation was performed by centrifugation.

[0124] The powder X-ray diffraction pattern of the hydrate form NF4 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 10 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0125] Example 6-(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF12 preparation method

[0126] About 5 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hydrate form NF12 was suspended in 1 mL USP phosphate buffer [pH 3.2] at 37° C. for 24 hours. Solid / liquid separation was performed by centrifugation.

[0127] The powder X-ray diffraction pattern of the hydrate form NF12 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 11 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0128] Example 7-8-Oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide cocrystal screening method

[0129] 8-Oxa-2-azaspiro [4.5] decane-2-carboxylic acid (4-methoxy-7-phenylthiazol [4,5-c] pyridine-2-yl)-amide (compound 53 in WO 2019 / 025099) was screened for cocrystals. Despite the use of a wide range of experimental types (e.g., eutectic, grinding, cooling crystallization), surprisingly, it only produced very few cocrystal formers, namely 3-hydroxybenzoic acid, tartaric acid and 2,4-dihydroxybenzoic acid in a ratio of 1: 1. For larger scales, the most promising results were observed in cooling crystallization experiments. Since 8-Oxa-2-azaspiro [4.5] decane-2-carboxylic acid (4-methoxy-7-phenylthiazol [4,5-c] pyridine-2-yl)-amide is not the subject of the present invention, detailed physicochemical information is not included.

[0130] Based on the results of the cocrystal screening, only cooling crystallization was applied for (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide, partially followed by vapor diffusion experiments, since the two compounds are structurally similar.

[0131] In Table 3 below, the experimental type and the co-crystal formers used for 8-oxa-2-aza-spiro[4.5]decane-2-carboxy(4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide are described.

[0132] Table 2

[0133] Eutectic Formation Grinding Eutectic Cooling crystallization Fumaric Acid × × √ Tert-Butyl Hydroquinone × × × 2,4-DHBA × √ √ 3,4-DHBA × × √ L-Tartaric acid × × √ Citric Acid × × √ 3-Hydroxybenzoic acid × × √ 2-Oxoglutaric acid × × × sulfuric acid × × ×

[0134] Example 8-S) Cocrystal Screening Method of 7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0135] Based on the experimental knowledge of 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide and 8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid (4-methoxy-7-phenylthiazolo[4,5-c]pyridin-2-yl)-amide and (S)-7-oxa-2-azaspiro[4.5]decane-2-carboxylic acid [7- The structural similarity between (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide also led to the successful experimental type "cooling crystallization". In a few experiments without any solid residue, an additional experimental step (vapor diffusion) was performed.

[0136] Table 3

[0137] Eutectic Formation Cooling crystallization / vapor diffusion Fumaric Acid √ 1,2-Ethanedisulfonic acid × 1,5-Naphthalene disulfonic acid √ Tert-Butyl Hydroquinone × 2,4-DHBA × 3,4-DHBA √ D-Tartaric acid √ L-Tartaric acid √ Citric Acid × 3-Hydroxybenzoic acid √ L-Malic Acid × D-Malic Acid √ sulfuric acid ×

[0138] Example 9 - Preparation of Novel Monofumaric Acid Cocrystal Form A1

[0139] Laboratory scale:

[0140] About 19 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 0.7 mL acetone at 50° C. About 6 mg of fumaric acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). The suspension was centrifuged for liquid / solid separation, and the solid was then dried at room temperature.

[0141] kg scale:

[0142] About 4.3 kg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide and about 1.3 kg of fumaric acid are suspended in 15 V acetone at ˜25° C. at a medium stirrer speed for at least 10 minutes. The suspension is heated to ˜65° C. within 1 hour. A cooling ramp is then started (˜65–˜10° C. within 7 hours). The suspension is stirred at ˜10° C. for at least 4 hours and filtered by suction for liquid / solid separation and finally washed with 1 V acetone. The solid is dried at ˜70° C. under vacuum for at least 8 hours.

[0143] The powder X-ray diffraction pattern of the monofumaric acid cocrystal Form A1 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 12 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0144] NMR data of monofumaric acid cocrystal Form A1:

[0145] 1H NMR(700MHz,DMSO-d6)δ13.18–13.06(m,2H),11.39–11.30(m,1H),7.94(s,1 H),6.62(s,2H),6.25–6.23(m,1H),4.29(q,J=2.8Hz,2H),3.99(s,3H),3.87( t,J=5.4Hz,2H),3.66–3.42(m,5H),3.40(d,J=11.3Hz,1H),3.31–3.28(m,1H) ,3.26–3.08(m,1H),2.57–2.53(m,2H),1.90–1.74(m,1H),1.74–1.47(m,5H).

[0146] Table 4 - Powder X-ray Peak List of Monofumaric Acid Cocrystal Form A1

[0147]

[0148]

[0149] Single crystal x-ray structural data (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer with graphite monochromator and CCD detector) were obtained for monofumaric acid cocrystal Form A1 as shown in FIG. 13 .

[0150] Monofumaric acid cocrystal Form A1 crystallizes in monoclinic space group P21 with lattice parameters of and β = 101.3 ± 0.5° (where α = γ = 90°). As is apparent from the single crystal structure, monofumaric acid cocrystal Form A1 represents the monofumaric acid cocrystal anhydrous form.

[0151] Monofumaric acid cocrystal Form A1 is characterized by the following physical properties:

[0152] -1 equivalent of fumaric acid (determined by NMR)

[0153] -The thermal behavior of the monofumaric acid eutectic Form A1 form shows an overlapping melting / decomposition process (>207°C) with only a small weight loss (<1% (w / w) before melting / decomposition). DSC and TGA curves are shown in Figures 14A and 14B. DSC scans of monofumaric acid eutectic Form A1 were obtained on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. TGA scans of monofumaric acid eutectic Form A1 were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min.

[0154] -The water vapor sorption behavior of the monofumaric acid eutectic Form A1 form reveals a very small water absorption level of <3% (w / w) in the complete relative humidity (RH) range of 0-98% RH. According to the European Pharmacopoeia standard (Section 5.11), the monofumaric acid eutectic Form A1 can be classified as slightly hygroscopic. The water vapor sorption isotherm (25°C) of the monofumaric acid eutectic Form A1 is shown in Figure 15. The water vapor sorption isotherm was obtained on a DVS intrinsic system from SMS.

[0155] - The concentration levels of monofumaric acid cocrystal Form A1 were determined in non-sink-dissolution experiments after 15 minutes and 30 minutes at 37°C.

[0156] Table 5 - Dissolution levels of monofumaric acid cocrystal Form A1

[0157]

[0158]

[0159] In the following, several examples are described where the formation of monofumaric acid cocrystal Form A1 failed.

[0160] Table 6

[0161]

[0162]

[0163] Example 10 - Preparation of Novel Hemifumaric Acid Cocrystal Form A2

[0164] Preparation method:

[0165] About 140 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 8 mL of isopropanol at 50° C. and a cooling ramp was started (50-5° C. at 0.1 K / min). Precipitation was observed at 5° C.

[0166] NMR data of hemifumaric acid cocrystal form A2

[0167] 1H NMR(500MHz,DMSO-d6)δ13.31–12.94(m,1H),11.44–11.23(m,1H),7.94(s,1 H),6.61(s,1H),6.26–6.22(m,1H),4.29(q,J=2.8Hz,2H),3.99(s,3H),3.87( t,J=5.4Hz,2H),3.68–3.40(m,5H),3.40(d,J=11.2Hz,1H),3.35–3.30(m,1H ),3.26–3.08(m,1H),2.58–2.53(m,2H),1.90–1.73(m,1H),1.73–1.46(m,5H)

[0168] The powder X-ray diffraction pattern of hemifumaric acid cocrystal Form A2 has been obtained by standard techniques as described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia and is shown in Figure 16 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0169] Table 7 - Powder X-ray Peak List of Hemifumaric Acid Cocrystal Form A2

[0170] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 6.6 2 9.7 3 11.5 4 13.4 5 14.1 6 14.7 7 16.5 8 18.0 9 18.5 10 19.4 11 20.0 12 21.4 13 22.9 14 24.1 15 26.8

[0171] Single crystal x-ray structural data (Oxford Diffraction Supernova Single Crystal X-ray Diffractometer with graphite monochromator and CCD detector) were also obtained for hemifumaric acid cocrystal Form A2, see FIG. 17 .

[0172] Hemifumaric acid cocrystal Form A2 crystallizes in triclinic space group P1 with lattice parameters of and α = 66.5 ± 0.5°, β = 77.5 ± 0.5° and γ = 76.9 ± 0.5°. It is evident from the single crystal structure that the hemifumaric acid cocrystal Form A2 represents an anhydrous form.

[0173] Hemifumaric acid cocrystal Form A2 is characterized by the following physical properties:

[0174] -0.5 equivalent fumaric acid (determined by NMR)

[0175] -The thermal behavior of hemifumaric acid eutectic Form A2 shows overlapping melting / decomposition processes (>207°C) with only a small weight loss (<1% (w / w) before melting / decomposition). DSC and TGA curves are shown in Figures 18A and 18B. DSC scans of hemifumaric acid eutectic Form A2 were obtained on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. TGA scans of hemifumaric acid eutectic Form A2 were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min.

[0176] -The water vapor sorption behavior of hemifumaric acid cocrystal form A2 reveals a very small water absorption level of ≤0.7% (w / w) in the relative humidity (RH) range of 0-80% RH. According to the European Pharmacopoeia standard (section 5.11), hemifumaric acid cocrystal form A2 can be classified as slightly hygroscopic. The water vapor sorption isotherm (25°C) of hemifumaric acid cocrystal form A2 is shown in Figure 19. The water vapor sorption isotherm was obtained on the DVS intrinsic system from SMS.

[0177] - The concentration levels of hemi-fumaric acid cocrystal Form A2 were determined in a non-sedimenting dissolution experiment after 15 minutes and 30 minutes at 37°C.

[0178] Table 8 - Dissolution levels of hemifumaric acid cocrystal form A2

[0179]

[0180] Example 11-(S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide hemifumaric acid cocrystal form NF1

[0181] Preparation method of novel hemifumaric acid eutectic form NF1

[0182] About 15 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 500 μL 1,4-dioxane hexane at 25° C. and stirred for 5 days. For liquid / solid separation, the suspension was centrifuged and the solid was dried at room temperature.

[0183] NMR data of hemifumaric acid cocrystal NF1

[0184] 1H NMR (500MHz, DMSO-d6) δ11.36–11.29(m,1H),7.94(s,1H),6.25–6.22(m,1H),4.29(q,J=2.8Hz,2H),3.99(s,3H),3. 87(t,J=5.4Hz,2H),3.67–3.38(m,6H),3.34–3.28(m,2H),2.58–2.53(m,2H),1.90–1.75(m,1H),1.73–1.47(m,5H).

[0185] The powder X-ray diffraction pattern of the hemifumaric acid cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 20 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0186] Table 9 - Powder X-ray Peak List of Hemifumaric Acid Cocrystal Form NF1

[0187] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 6.7 2 8.1 3 10.1 4 12.3 5 16.1 6 16.3 7 16.7 8 19.3 9 21.5 10 22.9 11 25.7

[0188] Hemifumarate cocrystal Form NF1 is characterized by the following physical properties:

[0189] -0.5 equivalent fumaric acid (determined by NMR)

[0190] -Thermal behavior of hemi-fumaric acid eutectic form NF1 shows a small endothermic event before melting at ~220°C, which has only a small weight loss (<1% (w / w) before melting). DSC and TGA curves are shown in Figures 21A and 21B. DSC scans of hemi-fumaric acid eutectic form NF1 were obtained on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 10 K / min. TGA scans of hemi-fumaric acid eutectic form NF1 were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 10 K / min.

[0191] Example 12 - Hemifumaric Acid Cocrystal Form NF2 of (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0192] Preparation method of novel hemifumaric acid eutectic / salt form NF2

[0193] About 60 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 2.5 mL acetone / methanol (mixture 1:1) at 50°C. About 17 mg of fumaric acid was added and a cooling ramp was started three times (50-5°C at 0.1 K / min). Precipitation was observed at 5°C.

[0194] NMR data of hemifumaric acid cocrystal / salt form NF2

[0195] 1H NMR (500MHz, DMSO-d6) δ11.41–11.23(m,1H),7.93(s,1H),6.25–6.22(m,1H),4.29(q,J=2.8Hz,2H),3.99(s,3H),3.87 (t,J=5.4Hz,2H),3.67–3.10(m,6H),3.31(d,J=11.3Hz,2H),2.58–2.52(m,2H),1.90–1.74(m,1H),1.73–1.46(m,5H).

[0196] The powder X-ray diffraction pattern of the hemifumaric acid cocrystal form NF2 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 22 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0197] Table 10 - Powder X-ray Peak List of Hemifumaric Acid Cocrystal Form NF2

[0198] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 6.2 2 8.1 3 9.4 4 10.5 5 11.3 6 14.2 7 14.9 8 16.8 9 17.5 10 19.1 11 20.3 12 20.9 13 21.6 14 22.6 15 24.4 16 25.9

[0199] Hemifumarate cocrystal Form NF2 is characterized by the following physical properties:

[0200] -0.5 equivalent fumaric acid (determined by NMR)

[0201] -The thermal behavior of the hemi-fumaric acid eutectic form NF2 shows an overlapping melting / decomposition process (>191°C) with only a small weight loss (<1% (w / w) before melting / decomposition). DSC and TGA curves are shown in Figures 23A and 23B. DSC scans of the hemi-fumaric acid eutectic form NF2 were obtained on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5K / min. TGA scans of the hemi-fumaric acid eutectic form NF2 were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5K / min.

[0202] Example 13-(S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide 3-hydroxybenzoic acid cocrystal form NF1

[0203] Preparation method of novel mono-3-hydroxybenzoic acid cocrystal form NF1

[0204] About 16 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 0.7 mL acetone at 50° C. About 7 mg of 3-hydroxybenzoic acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). Precipitation was observed at 5° C.

[0205] NMR data of mono-3-hydroxybenzoic acid cocrystal form NF1

[0206] 1H NMR(500MHz,DMSO-d6)δ12.79–12.68(m,1H),11.35–11.26(m,1H),9.67(s,1H),7.94(s,1H),7.39 –7.35(m,1H),7.34–7.32(m,1H),7.28(t,J=7.9Hz,1H),7.01–6.97(m,1H),6.26–6.22(m,1H),4.2 9(q,J=2.8Hz,2H),4.00(s,3H),3.87(t,J=5.4Hz,2H),3.67–3.42(m,5H),3.41(d,J=11.2Hz,1H), 3.32(d,J=11.2Hz,1H),3.26–3.12(m,1H),2.58–2.52(m,2H),1.90–1.74(m,1H),1.74–1.46(m,5H)

[0207] The powder X-ray diffraction pattern of the mono-3-hydroxybenzoic acid cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 24 as the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0208] Table 11 - Powder X-ray Peak List of Mono-3-Hydroxybenzoic Acid Cocrystal Form NF1

[0209]

[0210]

[0211] Mono-3-hydroxybenzoic acid cocrystal Form NF1 is characterized by the following physical properties:

[0212] -3-Hydroxybenzoic acid content (by 1 H-NMR spectroscopy revealed that 1 equivalent of 3-hydroxybenzoic acid

[0213] -Thermal behavior of mono-3-hydroxybenzoic acid cocrystal form NF1 shows a small weight loss step before melting (Δm@116°C: 0.4% (w / w), Δm 116-175°C: 0.8% (w / w)) and a strong weight loss in the TGA curve at >175°C. This can be attributed to the release of residual solvent and the subsequent decomposition process of mono-3-hydroxybenzoic acid cocrystal form NF1. The DSC and TGA curves are shown in Figures 25A and 25B. The DSC scans of mono-3-hydroxybenzoic acid cocrystal form NF1 were acquired on a Mettler-Toledo DSC1 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. The TGA scans of mono-3-hydroxybenzoic acid cocrystal form NF1 were acquired on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min.

[0214] - The water vapor adsorption isotherm (25°C) of mono-3-hydroxybenzoic acid cocrystal Form NF1 is shown in FIG. 26 .

[0215] Example 14-S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide 3-hydroxybenzoic acid cocrystal form NF2

[0216] Preparation of Mono-3-Hydroxybenzoic Acid Cocrystal Form NF2

[0217] About 13 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.5 mL tetrahydrofuran at 50° C. About 5 mg of 3-hydroxybenzoic acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). Since no precipitation was observed at 5° C., a vapor diffusion experiment was increased by using n-pentane as antisolvent. After 4 months, very few particles were obtained.

[0218] NMR data of mono-3-hydroxybenzoic acid cocrystal form NF2

[0219] 1H NMR(500MHz,DMSO-d6)δ13.02–12.37(m,1H),11.37–11.21(m,1H),9.73–9.62(m,1H),7.93(s,1H), 7.38–7.35(m,1H),7.34–7.32(m,1H),7.28(t,J=7.8Hz,1H),7.00–6.97(m,1H),6.25–6.22(m,1H),4 .29(q,J=2.7Hz,2H),3.99(s,3H),3.87(t,J=5.4Hz,2H),3.67–3.43(m,5H),3.40(d,J=11.4Hz,1H), 3.32(d,J=11.5Hz,1H),3.26–3.10(m,1H),2.58–2.52(m,2H),1.89–1.78(m,1H),1.72–1.47(m,5H).

[0220] The powder X-ray diffraction pattern of the mono-3-hydroxybenzoic acid cocrystal form NF2 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 27 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0221] Table 12 - Powder X-ray Peak List of Mono-3-Hydroxybenzoic Acid Cocrystal Form NF2

[0222]

[0223]

[0224] Mono-3-hydroxybenzoic acid cocrystal Form NF2 is characterized by the following physical properties:

[0225] -3-Hydroxybenzoic acid content (by 1H-NMR spectroscopy revealed that 1 equivalent of 3-hydroxybenzoic acid

[0226] Example 15 - 3,4-dihydroxybenzoic acid cocrystal form NF1 of S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0227] Preparation method of mono-3,4-dihydroxybenzoic acid cocrystal form NF1

[0228] About 14 mg of the anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide was dispersed in 0.7 mL of acetone at 50°C. About 10 mg of 3,4-dihydroxybenzoic acid was added and a cooling ramp was started three times (50-5°C at 0.1 K / min). Since no precipitation was observed at 5°C, the vapor diffusion experiment was increased by using n-pentane as antisolvent. After 4 months, very few particles were obtained.

[0229] NMR data of mono-3,4-dihydroxybenzoic acid cocrystal form NF1

[0230] 1H NMR(500MHz,DMSO-d6)δ12.41–12.11(m,1H),11.40–11.17(m,1H),9.74–9.39(m,1H),9.39–9.01(m,1H) ),7.93(s,1H),7.33(d,J=2.1Hz,1H),7.28(dd,J=8.2,2.1Hz,1H),6.77(d,J=8.3Hz,1H),6.25–6.22(m, 1H),4.29(q,J=2.8Hz,2H),3.99(s,3H),3.87(t,J=5.4Hz,2H),3.67–3.43(m,5H),3.40(d,J=11.2Hz,1 H),3.32(d,J=11.2Hz,1H),3.25–3.11(m,1H),2.58–2.52(m,2H),1.89–1.76(m,1H),1.72–1.47(m,5H).

[0231] The powder X-ray diffraction pattern of the mono-3,4-dihydroxybenzoic acid cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 28 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0232] Table 13 - Powder X-ray Peak List of Mono-3,4-Dihydroxybenzoic Acid Cocrystal Form NF1

[0233] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 7.3 2 10.8 3 13.9 4 15.2 5 15.9 6 16.5 7 17.4 8 18.0 9 18.6 10 19.3 11 20.2 12 21.3 13 23.0 14 23.5 15 25.1 16 25.8 17 27.2 18 28.2 19 29.5

[0234] Mono-3,4-dihydroxybenzoic acid cocrystal Form NF1 is characterized by the following physical properties:

[0235] -3,4-dihydroxybenzoic acid content (by 1 H-NMR spectroscopy revealed that 1 equivalent of 3,4-dihydroxybenzoic acid

[0236] Example 16 - Tartaric acid cocrystal form NF1 of S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0237] Preparation method of tartaric acid eutectic form NF1

[0238] About 13 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 0.7 mL acetone at 50° C. About 7 mg of tartaric acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). Precipitation was observed at 5° C.

[0239] NMR data of hemi-tartaric acid cocrystal NF1

[0240] 1H NMR (500MHz, DMSO-d6): δ12.73–12.53(m,1H),11.35–11.23(m,1H),7.94(s,1H),6. 25–6.22(m,1H),5.13–4.93(m,1H),4.31(s,1H),4.29(q,J=2.8Hz,2H),4.00(s,3H) ,3.87(t,J=5.4Hz,2H),3.66–3.43(m,5H),3.41(d,J=11.3Hz,1H),3.32(d,J=11.2H z,1H),3.26–3.12(m,1H),2.58–2.53(m,2H),1.91–1.75(m,1H),1.73–1.47(m,5H).

[0241] The powder X-ray diffraction pattern of the hemi-tartrate cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia and is shown in Figure 29 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0242] Table 14 - Powder X-ray Peak List of Hemi-Tartrate Cocrystal Form NF1

[0243] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 11.2 2 16.0 3 17.0 4 18.5 5 19.6 6 20.4 7 23.3 8 24.2 9 27.9

[0244] Hemi-tartrate cocrystal Form NF1 is characterized by the following physical properties:

[0245] -Tartaric acid content (determined by 1H-NMR spectroscopy) revealed 0.6 equivalents of tartaric acid

[0246] -Thermal behavior of the semi-tartrate eutectic form NF1 shows a broad endothermic event of <100°C, which occurs with a weight loss step in the TGA curve (up to ~85°C 1.8% (w / w)). This is most likely due to the release of water from the weak crystalline phase. A broad melting / decomposition process can be observed at 13°C (start) in the DSC trace. The DSC and TGA curves are shown in Figures 30A and 30B. DSC scans of the semi-tartrate eutectic form NF1 were obtained at a heating rate of 5K / min using a nitrogen purge gas of 50mL / min on a Mettler-Toledo DSC 821. TGA scans of the semi-tartrate eutectic form NF1 were obtained at a heating rate of 5K / min using a nitrogen purge gas of 50mL / min on a Mettler-Toledo TGA 851.

[0247] Example 17 - Tartaric acid cocrystal form NF2 of S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0248] Preparation method of semi-tartaric acid eutectic form NF2

[0249] About 67 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 1.5 mL acetone at 50° C. About 12 mg of tartaric acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). Precipitation was observed at 5° C.

[0250] NMR data of hemi-tartaric acid cocrystal NF2

[0251] 1H NMR(500MHz,DMSO-d6)δ13.11–12.14(m,1H),11.29(s,1H),7.93(s,1H),6.25–6 .22(m,1H),5.24–4.70(m,1H),4.31(s,1H),4.29(q,J=2.8Hz,2H),3.99(s,3H), 3.87(t,J=5.4Hz,2H),3.68–3.45(m,5H),3.40(d,J=11.4Hz,1H),3.33–3.29(m, 1H),3.26–3.09(m,1H),2.58–2.52(m,2H),1.89–1.75(m,1H),1.72–1.46(m,5H).

[0252] The powder X-ray diffraction pattern of the hemi-tartrate cocrystal form NF2 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 31 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0253] Table 15 - Powder X-ray Peak List of Hemi-Tartrate Cocrystal Form NF2

[0254]

[0255]

[0256] Hemi-tartrate cocrystal Form NF2 is characterized by the following physical properties:

[0257] -Tartaric acid content (by 1 H-NMR spectroscopy revealed 0.5 equivalent of tartaric acid

[0258] The dissolution level of the hemi-tartrate cocrystal form NF2 in fasting state simulated intestinal fluid [FaSSIF, pH 6.5] at 37°C was determined to be about 145 μg / mL (after 30 minutes).

[0259] Example 18 - 1,5-naphthalene disulfonic acid cocrystal form NF1 of S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide

[0260] Preparation method of 1,5-naphthalene disulfonic acid cocrystal form NF1

[0261] About 15 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 0.7 mL acetone at 50° C. About 12 mg of 1,5-naphthalene disulfonic acid was added and a cooling ramp was started three times (50-5° C. at 0.1 K / min). Precipitation was observed at 5° C.

[0262] The powder X-ray diffraction pattern of 1,5-naphthalene disulfonic acid cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the European Pharmacopoeia 6th Edition and is shown in Figure 32 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0263] Table 16- Powder X-ray Peak List of 1,5-Naphthalene Disulfonic Acid Cocrystal Form NF1

[0264]

[0265]

[0266] 1,5-Naphthalenedisulfonic acid cocrystal Form NF1 is characterized by the following physical properties:

[0267] -1,5-naphthalene disulfonic acid cocrystal form NF1 thermal behavior shows no significant enthalpy events before decomposition. In the temperature range up to 110 ° C, a weight loss of 2.2% (w / w) was observed, followed by a second weight loss step of 1.0% (w / w) from 110-184 ° C. DSC and TGA curves are shown in Figures 33A and 33B. DSC scans of 1,5-naphthalene disulfonic acid cocrystal form NF1 were obtained on a Mettler-Toledo DSC 821 using a nitrogen purge gas of 50 mL / min at a heating rate of 5K / min. TGA scans of 1,5-naphthalene disulfonic acid cocrystal form NF1 were obtained on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5K / min.

[0268] Example 19 - Preparation of S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide D -Malic acid eutectic form NF1

[0269] one D - Preparation method of malic acid eutectic form NF1

[0270] About 12 mg of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide anhydrous form A1 was dispersed in 0.5 mL of acetone at 50°C. About 8 mg of D -malic acid and started a cooling ramp three times (50-5°C at 0.1 K / min). Precipitation was observed at 5°C.

[0271] one D -NMR data of malic acid cocrystal form NF1

[0272] 1H NMR (500MHz, DMSO-d6) δ12.57–12.11(m,2H),11.30(s,1H),7.94(s,1H),6.26–6.22(m,1H),5.49–5. 29(m,1H),4.29(q,J=2.8Hz,2H),4.26(dd,J=7.7,4.9Hz,1H),4.00(s,3H),3.87(t,J=5.4Hz,2H),3. 66–3.43(m,5H),3.41(d,J=11.2Hz,1H),3.32(d,J=11.2Hz,1H),3.25–3.12(m,1H),2.61(dd,J=15.6 ,4.9Hz,1H),2.58–2.53(m,2H),2.44(dd,J=15.6,7.8Hz,1H),1.89–1.74(m,1H),1.74–1.46(m,5H).

[0273] one D The powder X-ray diffraction pattern of the -malic acid cocrystal form NF1 has been obtained by standard techniques as described in Chapter 2.9.33 of the 6th edition of the European Pharmacopoeia and is shown in Figure 34 by the X-ray powder diffraction pattern (monochromatic Cu-Kα1 radiation, The results were characterized by Stoe StadiP 611KL transmission diffractometer).

[0274] Table 17 - Single D - List of powder X-ray peaks of malic acid cocrystal form NF1

[0275] No. <![CDATA[°2θ (Cu-Kα1 radiation) ±0.2°]]> 1 17.0 2 19.6 3 20.4 4 21.6 5 23.4 6 28.1

[0276] one D -Malic acid cocrystal form NF1 is characterized by the following physical properties:

[0277] - The malic acid content (determined by 1H-NMR spectroscopy) revealed 1 equivalent of malic acid.

[0278] -oneD The thermal behavior of the NF1-malic acid cocrystal showed a very small endothermic event at ∼137 °C. This can be attributed to the mono D -malic acid eutectic form NF1 melting process. In the temperature range up to 136 ° C, a weight loss of 2.8% (w / w) was observed. DSC and TGA curves are shown in Figures 35A and 35B. The single crystal was acquired on a Mettler-Toledo DSC 821 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. D -DSC scan of malic acid cocrystal form NF1. Single crystals were acquired on a Mettler-Toledo TGA 851 using a nitrogen purge gas of 50 mL / min at a heating rate of 5 K / min. D -TGA scan of malic acid cocrystal form NF1. BRIEF DESCRIPTION OF THE DRAWINGS

[0280] Figure 1 shows the powder X-ray diffraction pattern of a prior art amorphous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0281] Figure 2 shows (2A) DSC scan (5 K / min) and (2B) TGA scan (5 K / min) of the amorphous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0282] Figure 3 shows the water vapor sorption isotherm (25°C) of the amorphous form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0283] Figure 4 shows the powder X-ray diffraction pattern of the crystalline anhydrous Form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

[0284] Figure 5 shows the single crystal x-ray structure data for the crystalline anhydrous Form A1.

[0285] Figure 6 shows (6A) a DSC scan (5 K / min) of the crystalline anhydrous Form A1 and (6B) a TGA scan (5 K / min) of the crystalline anhydrous Form A1.

[0286] Figure 7 shows the water vapor sorption isotherm (25°C) of the crystalline anhydrous Form A1.

[0287] FIG8 shows the powder X-ray diffraction pattern of the hydrate form of NF2.

[0288] FIG9 shows the powder X-ray diffraction pattern of the hydrate form of NF3.

[0289] FIG10 shows the powder X-ray diffraction pattern of the hydrate form NF4.

[0290] FIG. 11 shows the powder X-ray diffraction pattern of the hydrate form NF12.

[0291] FIG. 12 shows the powder X-ray diffraction pattern of monofumaric acid cocrystal Form A1.

[0292] Figure 13 shows the single crystal structure of monofumaric acid cocrystal Form A1.

[0293] FIG. 14 shows (14A) a DSC scan (5 K / min) of monofumaric acid cocrystal Form A1 and (14B) a TGA scan (5 K / min) of monofumaric acid cocrystal Form A1.

[0294] Figure 15 shows the water vapor sorption isotherm (25°C) of monofumaric acid cocrystal Form A1.

[0295] FIG. 16 shows the powder X-ray diffraction pattern of hemi-fumaric acid cocrystal Form A2.

[0296] Figure 17 shows the single crystal structure of hemifumaric acid cocrystal Form A2.

[0297] FIG. 18 shows (18A) DSC scan (5 K / min) of hemifumaric acid cocrystal Form A2 and (18B) TGA scan (5 K / min) of hemifumaric acid cocrystal Form A2.

[0298] Figure 19 shows the water vapor sorption isotherm (25°C) of hemifumaric acid cocrystal Form A2.

[0299] FIG. 20 shows the powder X-ray diffraction pattern of hemi-fumaric acid cocrystal Form NF1.

[0300] FIG. 21 shows (21A) DSC scan (10 K / min) of hemifumaric acid cocrystal form NF1 and (21B) TGA scan (10 K / min) of hemifumaric acid cocrystal form NF1.

[0301] FIG. 22 shows the powder X-ray diffraction pattern of hemi-fumaric acid cocrystal Form NF2.

[0302] FIG. 23 shows (23A) a DSC scan (5 K / min) of hemifumaric acid cocrystal form NF2 and (23B) a TGA scan (5 K / min) of hemifumaric acid cocrystal form NF2.

[0303] FIG. 24 shows the powder X-ray diffraction pattern of mono-3-hydroxybenzoic acid cocrystal Form NF1.

[0304] FIG. 25 shows (25A) a DSC scan (5 K / min) of mono-3-hydroxybenzoic acid cocrystal Form NF1 and (25B) a TGA scan (5 K / min) of mono-3-hydroxybenzoic acid cocrystal Form NF1.

[0305] FIG. 26 shows the water vapor adsorption isotherm (25° C.) of the mono-3-hydroxybenzoic acid cocrystal form NF1

[0306] FIG. 27 shows the powder X-ray diffraction pattern of mono-3-hydroxybenzoic acid cocrystal Form NF2.

[0307] FIG. 28 shows the powder X-ray diffraction pattern of mono-3,4-dihydroxybenzoic acid cocrystal Form NF1.

[0308] FIG. 29 shows the powder X-ray diffraction pattern of hemi-tartrate cocrystal Form NF1.

[0309] FIG. 30 shows (30A) DSC scan (5 K / min) of hemi-tartrate cocrystal Form NF1 and (30B) TGA scan (5 K / min) of hemi-tartrate cocrystal Form NF1.

[0310] FIG. 31 shows the powder X-ray diffraction pattern of hemi-tartrate cocrystal Form NF2.

[0311] FIG. 32 shows the powder X-ray diffraction pattern of 1,5-naphthalene disulfonic acid cocrystal Form NF1.

[0312] FIG. 33 shows (33A) a DSC scan of 1,5-naphthalene disulfonic acid cocrystal Form NF1 and (33B) a TGA scan (5 K / min) of 1,5-naphthalene disulfonic acid cocrystal Form NF1.

[0313] Figure 34 shows a single D - Powder X-ray diffraction pattern of malic acid cocrystal form NF1.

[0314] Figure 35 shows (35A) a single D -DSC scan of malic acid cocrystal form NF1 and (35B) D -TGA scan of malic acid cocrystal form NF1.

Claims

1. A crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide.

2. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is the crystalline anhydrous Form A1.

3. A crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is selected from the hydrate forms NF2, NF3, NF4 and NF12.

4. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 1, wherein the crystalline form is a co-crystal form selected from the following a) Monofumaric acid cocrystal Form A1, b) Hemifumaric acid cocrystal Form A2, c) Hemifumaric acid cocrystal form NF1, d) Hemifumaric acid eutectic form NF2, e) Mono-3-hydroxybenzoic acid cocrystal form NF1, f) Mono-3-hydroxybenzoic acid cocrystal form NF2, g) Hemi-tartrate eutectic form NF1, h) Hemi-tartrate eutectic form NF2, i) Single D -Malic acid eutectic form NF1, j) 1,5-Naphthalenedisulfonic acid cocrystal form NF1 and k) Mono-3,4-dihydroxybenzoic acid cocrystal Form NF1.

5. The crystalline anhydrous form A1 of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 2, wherein the crystalline anhydrous form A1 has characteristic peaks:

6. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the monofumaric acid cocrystal form A1 has characteristic peaks:

7. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the hemifumaric acid cocrystal form A2 has characteristic peaks:

8. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the hemifumaric acid cocrystal form NF1 has characteristic peaks:

9. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the hemifumaric acid cocrystal form NF2 has characteristic peaks:

10. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the mono-3-hydroxybenzoic acid cocrystal form NF1 has characteristic peaks:

11. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the mono-3-hydroxybenzoic acid cocrystal form NF2 has characteristic peaks:

12. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the mono-3,4-dihydroxybenzoic acid cocrystal form NF1 has characteristic peaks:

13. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the semi-tartrate cocrystal form NF1 has characteristic peaks:

14. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the semi-tartrate cocrystal form NF2 has characteristic peaks:

15. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro 2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the 1,5-naphthalene disulfonic acid cocrystal form NF1 has characteristic peaks:

16. The crystalline form of (S)-7-oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide according to claim 4, wherein the mono D -Malic acid cocrystal form NF1 has characteristic peaks:

17. (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide containing one or more crystalline forms according to claims 1 to 16.

18. (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide consisting essentially of one or more crystalline forms according to claims 1 to 16.

19. A process for preparing the crystalline form according to claim 4, characterized in that (S)-7-Oxa-2-aza-spiro[4.5]decane-2-carboxylic acid [7-(3,6-dihydro2H-pyran-4-yl)-4-methoxy-thiazolo[4,5-c]pyridin-2-yl]-amide is suspended in an organic solvent at elevated temperature, an equal amount of the cocrystal former is added and crystallization is carried out by cooling.

20. A medicament for use in the treatment and / or prevention of cancer, comprising one or more crystalline forms according to claims 1 to 16 or mixtures thereof in all ratios.

21. Pharmaceutical preparation containing one or more crystalline forms according to claims 1 to 16 or mixtures thereof in all ratios, and optionally further excipients and / or adjuvants.

22. A method for preparing a pharmaceutical preparation, characterized in that One or more crystalline forms according to claims 1 to 16 or mixtures thereof in all ratios are brought into a suitable dosage form together with solid, liquid or semi-liquid excipients or adjuvants.

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