CN118871423A - Cocrystals or salts containing psilocybin - Google Patents

Abstract

The present invention relates to a co-crystal or salt comprising xylometacin and a co-crystal former. The co-crystals or salts are useful in a method of treating or preventing a disease or condition selected from depression, anxiety, death anxiety, mental retardation, maladaptation, despair, suicidal ideation, desire to accelerate death, cocaine-related disorders, opioid-related disorders, and stimulant-related disorders in a patient. Kits comprising the co-crystals or salts are also described.

Description

Co-crystals or salts comprising xylometacin

Technical Field

The present invention relates to a co-crystal or salt comprising xylometacin (psilocin). Methods of using the co-crystals or salts to treat and prevent disorders are also described.

Background

Cycloxin (4-hydroxy-N, N-dimethyltryptamine) is a tryptamine 5-hydroxytryptamine energy hallucinogen (TRYPTAMINE SEROTONINERGIC PSYCHEDELIC). The IUPAC name for xylol is 3- (2- (dimethylamino) ethyl) -1H-indol-4-ol. The structure of the xylometacin is shown below.

The pharmaceutical compounds may exist in a variety of different solid forms. This includes crystalline forms, salts, hydrates and solvates and amorphous phases. Different solid forms of pharmaceutical compounds have different properties, for example with respect to crystallinity, chemical and physical stability and processability. WO 2022/251169 describes solid forms of xylometacin, including solid forms comprising stearic acid or DL-lactic acid.

Silonew is currently being investigated in a variety of clinical settings as a potential treatment for a variety of psychiatric disorders, such as mental depression (demoralization), depression, anxiety and adaptation disorders. Thus, there is a need to develop new forms of cilobromide with particularly advantageous properties for use in such treatments.

Summary of The Invention

It was found in the present invention that co-crystals comprising xylometacin and a co-former provide crystalline forms with good properties such as high crystallinity and/or beneficial morphology. The co-crystals also have good physical and chemical stability and are suitable for secondary processing (including improved flowability and compactibility). The use of the co-crystals may also provide for modulation of dissolution rate and kinetic solubility, which may be useful in pharmaceutical applications.

In particular, the inventors have found that co-crystals or salts of celecoxib formed with co-crystal formations selected from the group consisting of L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid are very suitable for pharmaceutical formulations.

The present invention accordingly provides a co-crystal comprising xylon and a co-crystal former, wherein the co-crystal former is selected from the group consisting of L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid. The present invention alternatively provides a salt comprising xylon and a co-crystal former, wherein the co-crystal former is selected from the group consisting of L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid.

The present invention further provides a pharmaceutical composition comprising a co-crystal or salt as described herein; and a pharmaceutically acceptable excipient or diluent.

The invention also provides a method of treating or preventing a disease or condition selected from the group consisting of psychological, neurological and central nervous system disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a co-crystal or salt as described herein.

The invention also provides a kit comprising a co-crystal, salt or pharmaceutical composition as described herein; and instructions for use of the co-crystal, salt or pharmaceutical composition in a method of treating or preventing a disease or disorder as described herein.

Brief description of the drawings

Figure 1 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of cilobnew and decanoic acid.

Figure 2 shows an XRPD 2 theta diffraction pattern of pattern 2 comprising a co-crystal of cilobnew and decanoic acid.

Fig. 3 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and ethyl maltol.

Fig. 4 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and L-lactic acid.

Fig. 5 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and oleic acid.

Fig. 6 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and palmitic acid.

Fig. 7 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and p-coumaric acid.

Fig. 8 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and propyl gallate.

Fig. 9 shows an XRPD 2 theta diffraction pattern of pattern 1 comprising a co-crystal of xylometacin and stearic acid.

Fig. 10 shows an XRPD 2 theta diffraction pattern of pattern 2 comprising a co-crystal of xylometacin and stearic acid.

Detailed Description

The co-crystals according to the invention comprise xylometacin and a co-crystal former.

A co-crystal is a solid crystalline material comprising two or more different molecules and/or ionic compounds (e.g., an active agent and a co-crystal former). The active agent and the eutectic formation are located in the same crystal lattice. The co-crystal is typically neither a solvate nor a simple salt, although the co-crystal may also be hydrated or solvated (i.e., it may contain an active agent, a co-crystal former, and water or solvent molecules), or one of the components in the co-crystal (e.g., the co-crystal former) may itself be a salt.

The co-crystal may comprise an active agent and a co-crystal former. The active agent and the eutectic formation are typically arranged in a regularly repeating crystal structure. The co-crystals have a different crystal structure than the active agent or co-crystal former alone.

The co-crystals may consist essentially of the xylometacin and co-crystal former, and optionally water or solvent. If the co-crystal comprises a co-crystal former and one or more additional co-crystal formers, the co-crystal may consist essentially of xyloxin and the co-crystal former, and optionally water or solvent. The co-crystals may comprise at least 90 wt%, at least 95 wt% or at least 99 wt% of the xylometacin, co-crystal formations, and optionally water or solvent. The co-crystals may consist essentially of xylometacin and co-crystal formers. The co-crystals may comprise at least 90 wt%, at least 95 wt% or at least 99 wt% of the xylometacin and the co-crystal former. The co-crystals may consist of xylometacin and co-crystal formers. The term "consisting essentially of … …" as used herein means that the co-crystal contains only the specified components (i.e., the xylometacin, co-crystal former, and optionally water or solvent) and any additional components that do not materially affect the basic characteristics or function of the specified components.

The co-crystal former is typically selected from the group consisting of L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid. Preferably, the co-crystal former is selected from the group consisting of L-lactic acid, capric acid and propyl gallate. More preferably, the eutectic formation is L-lactic acid.

In one embodiment, the co-crystal is a co-crystal comprising xylol and decanoic acid, wherein the molar ratio of xylol to decanoic acid is about 1:1.2. The molar ratio may be 1:1.2. In one embodiment, the molar ratio is about 1:1. The molar ratio may be 1:1. Alternatively, the molar ratio may be about 1:0.5, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylocarpal and ethyl maltol, wherein the molar ratio of xylocarpal to ethyl maltol is about 1:0.8. The molar ratio may be 1:0.8. Alternatively, the molar ratio may be about 1:0.5, 1:1, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and L-lactic acid, wherein the molar ratio of xylometacin to L-lactic acid is about 1:1. The molar ratio may be 1:1. Alternatively, the molar ratio may be about 1:0.5, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and oleic acid, wherein the molar ratio of xylometacin to oleic acid is about 1:1.1. The molar ratio may be 1:1 or 1:1.1. Alternatively, the molar ratio may be about 1:0.5, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and palmitic acid, wherein the molar ratio of xylon to palmitic acid is about 1:1. The molar ratio may be 1:1. Alternatively, the molar ratio may be about 1:0.5, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and p-coumaric acid, wherein the molar ratio of xylon to p-coumaric acid is about 1:1. The molar ratio may be 1:1. Alternatively, the molar ratio may be about 1:0.5, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and propyl gallate, wherein the molar ratio of xylon to propyl gallate is about 1:0.6. The molar ratio may be 1:0.5 or 1:0.6. Alternatively, the molar ratio may be about 1:1, 1:1.5, or 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and stearic acid, wherein the molar ratio of xylometacin to stearic acid is about 1:1.6. The molar ratio may be 1:1.5 or 1:1.6. In one embodiment, the molar ratio of sirolimus to stearic acid is about 1:1. The molar ratio may be 1:1. Alternatively, the molar ratio may be about 1:0.5 or 1:2.

As described herein, the x-ray wavelength of radiation using cukα ₁ The value of °2θ was measured. If the x-ray powder diffraction pattern comprises a peak, the relative intensity of the peak is typically at least 5% or at least 10%. The error range of values of °2θ is typically ± 0.2 °2θ, but the error range may alternatively be ± 0.1 °2θ.

The co-crystal comprising cilobnew and capric acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of cilobnew and decanoic acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 5.9 °, 14.2 ° and 15.9 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of celecoxib and decanoic acid typically further comprises one or more peaks selected from 16.7 °, 24.0 ° and 24.7 ° ± 0.2 ° 2Θ. Pattern 1 comprising a co-crystal of cilobnew and decanoic acid may further comprise peaks at 16.7 °, 24.0 ° and 24.7 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising co-crystals of celecoxib and decanoic acid can comprise five or more peaks selected from the group consisting of 5.9 °, 14.2 °, 15.9 °, 16.7 °, 18.3 °, 20.7 °, 22.6 °, 24.0 ° and 24.7 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of co-crystals of cilobnew and decanoic acid may comprise the following peaks.

An XRPD pattern comprising pattern 1 of co-crystals of cilobnew and decanoic acid may be substantially as shown in figure 1.

The co-crystal comprising cilobnew and capric acid may be in a form designated as the crystalline form of pattern 2. Pattern 2, which comprises a co-crystal of cilobnew and decanoic acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 6.4 °, 16.9 ° and 25.2 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 2 comprising a co-crystal of celecoxib and decanoic acid typically further comprises one or more peaks selected from 22.3 °, 23.6 ° and 23.7 ° ± 0.2 ° 2Θ. Pattern 2 comprising a co-crystal of cilobnew and decanoic acid may further comprise peaks at 22.3 °, 23.6 ° and 23.7 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 2 comprising co-crystals of celecoxib and decanoic acid can comprise five or more peaks selected from the group consisting of 6.4 °, 16.9 °, 17.8 °, 19.2 °, 19.6 °, 22.3 °, 23.6 °, 23.7 ° and 25.2 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 2 of co-crystals of cilobnew and decanoic acid may comprise the following peaks.

An XRPD pattern comprising pattern 2 of co-crystals of xylol and decanoic acid may be substantially as shown in figure 2.

The co-crystal comprising xylometacin and ethyl maltol may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylometacin and ethyl maltol, generally has an x-ray powder diffraction (XRPD) pattern comprising peaks at 5.0 °, 15.1 ° and 18.0 ° ± 0.2 ° 2θ.

The XRPD pattern comprising pattern 1 of co-crystals of xylometacin and ethyl maltol typically further comprises one or more peaks selected from 21.7 °, 26.1 ° and 26.7 ° ± 0.2 ° 2Θ. Pattern 1 comprising a co-crystal of xylometacin and ethyl maltol may further comprise peaks at 21.7 °, 26.1 ° and 26.7 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and ethyl maltol may comprise five or more peaks selected from the group consisting of 5.0 °, 14.8 °, 15.1 °, 18.0 °, 18.5 °, 20.2 °, 21.7 °, 26.1 ° and 26.7 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of the co-crystal of xylometacin and ethyl maltol may comprise the following peaks.

XRPD pattern comprising pattern 1 of the co-crystal of xylometacin and ethyl maltol may be substantially as shown in figure 3.

The co-crystal comprising xylometacin and L-lactic acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylometacin and L-lactic acid, generally has an x-ray powder diffraction (XRPD) pattern comprising peaks at 13.4 °, 16.8 ° and 19.5 ° ± 0.2 ° 2θ.

The XRPD pattern comprising pattern 1 of co-crystals of xylometacin and L-lactic acid typically further comprises one or more peaks selected from 16.7 °, 23.0 ° and 24.3 ° ± 0.2 ° 2θ. Pattern 1 comprising a co-crystal of xylometacin and L-lactic acid may further comprise peaks at 16.7 °, 23.0 ° and 24.3 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising co-crystals of xylometacin and L-lactic acid can comprise five or more peaks selected from 13.4 °, 14.9 °, 16.7 °, 16.8 °, 19.5 °, 20.6 °, 23.0 °, 24.3 ° and 26.3 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of co-crystals of xylometacin and L-lactic acid may comprise the following peaks.

XRPD pattern comprising pattern 1 of co-crystals of xylometacin and L-lactic acid may be substantially as shown in figure 4.

The co-crystal comprising sirolimus and oleic acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylometacin and oleic acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 4.6 °, 15.9 ° and 19.4 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and oleic acid typically further comprises one or more peaks selected from 19.6 °, 20.4 ° and 23.5 ° ± 0.2 ° 2Θ. Pattern 1 comprising a co-crystal of xylometacin and oleic acid may further comprise peaks at 19.6 °, 20.4 ° and 23.5 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of celecoxib and oleic acid can comprise five or more peaks selected from the group consisting of 4.6 °, 15.9 °, 19.4 °, 19.6 °, 20.4 °, 21.1 °, 21.9 °, 22.1 ° and 23.5 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and oleic acid may comprise the following peaks.

An XRPD pattern comprising pattern 1 of a co-crystal of xylometacin and oleic acid may be substantially as shown in figure 5.

The co-crystal comprising xylon and palmitic acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylon and palmitic acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 4.7 °, 23.0 ° and 23.8 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylon and palmitic acid typically further comprises one or more peaks selected from 14.4 °, 16.1 ° and 20.3 ° ± 0.2 ° 2Θ. Pattern 1 comprising a co-crystal of xylometacin and palmitic acid may further comprise peaks at 14.4 °, 16.1 ° and 20.3 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylon and palmitic acid may comprise five or more peaks selected from the group consisting of 4.7 °, 14.4 °, 14.7 °, 16.1 °, 17.0 °, 20.3 °, 22.9 °, 23.0 ° and 23.8 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of a co-crystal of xylometacin and palmitic acid may comprise the following peaks.

The XRPD pattern of pattern 1 comprising the co-crystal of xylometacin and palmitic acid may be substantially as shown in figure 6.

The co-crystal comprising xylometacin and p-coumaric acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylon and p-coumaric acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 5.4 °, 15.5 ° and 20.5 ° ± 0.2 ° 2θ.

The XRPD pattern comprising pattern 1 of co-crystals of xylometacin and p-coumaric acid typically further comprises one or more peaks selected from the group consisting of 6.5 °, 16.4 ° and 19.7 ° ± 0.2 ° 2θ. Pattern 1 comprising a co-crystal of xylometacin and p-coumaric acid may further comprise peaks at 6.5 °, 16.4 ° and 19.7 ° ± 0.2 ° 2θ.

The XRPD pattern comprising pattern 1 of co-crystals of xylometacin and p-coumaric acid can comprise five or more peaks selected from 5.4 °, 6.5 °, 7.0 °, 15.5 °, 16.4 °, 17.3 °, 19.7 °, 20.5 ° and 21.9 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of a co-crystal of xylometacin and p-coumaric acid can comprise the following peaks.

An XRPD pattern comprising pattern 1 of co-crystals of xylometacin and p-coumaric acid may be substantially as shown in figure 7.

The co-crystal comprising xylon and propyl gallate may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylon and propyl gallate, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 12.6 °, 14.7 ° and 22.6 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and propyl gallate typically further comprises one or more peaks selected from the group consisting of 8.8 °, 15.8 ° and 18.6 ° ± 0.2 ° 2Θ. Pattern 1 comprising a co-crystal of xylometacin and propyl gallate may further comprise peaks at 8.8 °, 15.8 ° and 18.6 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising co-crystals of xylon and propyl gallate may comprise five or more peaks selected from the group consisting of 8.8 °, 12.6 °, 14.3 °, 14.7 °, 15.8 °, 18.6 °, 19.2 °, 22.0 ° and 22.6 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 1 of a co-crystal of xylometacin and propyl gallate may comprise the following peaks.

An XRPD pattern comprising pattern 1 of co-crystals of xylometacin and propyl gallate may be substantially as shown in figure 8.

The co-crystal comprising xylometacin and stearic acid may be in a form designated as the crystalline form of pattern 1. Pattern 1, which comprises a co-crystal of xylometacin and stearic acid, generally has an x-ray powder diffraction (XRPD) pattern comprising peaks at 21.4 °, 21.6 ° and 23.5 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and stearic acid typically further comprises one or more peaks selected from the group consisting of 5.4 °, 16.0 ° and 18.8 ° ± 0.2 ° 2θ. Pattern 1 comprising a co-crystal of xylometacin and stearic acid may further comprise peaks at 5.4 °, 16.0 ° and 18.8 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 1 comprising a co-crystal of celecoxib and stearic acid can comprise five or more peaks selected from the group consisting of 5.4 °, 16.0 °, 16.8 °, 18.3 °, 18.8 °, 21.4 °, 21.6 °, 23.5 ° and 23.7 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern of pattern 1 comprising a co-crystal of xylometacin and stearic acid may comprise the following peaks.

An XRPD pattern comprising pattern 1 of co-crystals of xylometacin and stearic acid may be substantially as shown in figure 9.

The co-crystal comprising xylometacin and stearic acid may be in a form designated as the crystalline form of pattern 2. Pattern 2, which comprises a co-crystal of xylometacin and stearic acid, typically has an x-ray powder diffraction (XRPD) pattern comprising peaks at 4.5 °, 14.3 ° and 24.0 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 2 comprising a co-crystal of xylometacin and stearic acid typically further comprises one or more peaks selected from 16.7 °, 20.0 ° and 23.3 ° ± 0.2 ° 2θ. Pattern 2 comprising a co-crystal of xylometacin and stearic acid may further comprise peaks at 16.7 °, 20.0 ° and 23.3 ° ± 0.2 ° 2θ.

The XRPD pattern of pattern 2 comprising a co-crystal of celecoxib and stearic acid can comprise five or more peaks selected from the group consisting of 4.5 °, 14.3 °, 16.3 °, 16.7 °, 20.0 °, 20.1 °, 20.8 °, 23.3 ° and 24.0 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks. XRPD pattern comprising pattern 2 of a co-crystal of xylometacin and stearic acid may comprise the following peaks.

An XRPD pattern comprising pattern 2 of co-crystals of xylometacin and stearic acid may be substantially as shown in figure 10.

The invention also provides a composition comprising the co-crystal, wherein at least 50 wt%, at least 80 wt% or at least 90 wt% of the co-crystal is in the form of a crystalline form of the co-crystal as defined herein.

Acid-containing co-crystals

Also disclosed herein is a co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is an acid. The acid may be any substance that can act as a proton donor. Alternatively, the acid may be any substance that can act as an electron pair acceptor. Alternatively, the acid may be any substance that increases the concentration of H ₃O⁺ ions in aqueous solution.

The eutectic formation may be an organic acid or an inorganic acid. Typically, the eutectic formation is an organic acid.

Typically, the co-crystal former is a compound comprising one or more acidic functional groups. The acidic functional group may be selected from, for example, a carboxylic acid moiety, a sulfonic acid moiety, a squaraine moiety, a sulfonamide moiety, a carboxysulfonimide moiety (carboxylic sulfonimide moiety), and a sulfonimide moiety (sulfimide moiety). Thus, the co-crystal former may be a compound comprising one or more of a carboxylic acid moiety, a sulfonic acid moiety, a squaric acid moiety, a sulfonamide moiety, a carboxysulfonimide moiety, and a sulfonimide moiety. Typically, the co-crystal former is a compound comprising a carboxylic acid moiety. The co-crystal former may be a compound comprising a sulfonic acid moiety. The eutectic formation may be a compound comprising a squaraine moiety. The co-crystal former may be a compound comprising a sulfonamide moiety. The co-crystal former may be a compound comprising a carboxysulfonimide moiety. The eutectic formation may be a compound comprising a sulfonimide moiety.

The strongly acidic co-crystal former can protonate tertiary amine groups in the xylometacin and thereby form simple salts with xylometacin. In general, when the pK _a of the acid is not low enough to promote complete transfer of protons to tertiary amine groups in the xyloxin, a eutectic is formed. Thus, the eutectic formation typically has a pK _a of greater than or equal to 1.3, such as greater than or equal to 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.5, 4.0, or 4.5. Typically, the eutectic forms typically have a pK _a greater than or equal to 1.5, 2.0, or 2.5. The eutectic formation may have a pK _a greater than or equal to 1.5. The eutectic formation may have a pK _a greater than or equal to 2.0. The eutectic formation may have a pK _a greater than or equal to 2.5.

The eutectic formation may have a pK _a of less than or equal to 7.0, for example less than or equal to 6.5, 6.0, 5.5 or 5.0. Typically, the eutectic formation has a pK _a that is less than or equal to 7.0, 6.0, or 5.0. The eutectic formation may have a pK _a of less than or equal to 7.0. The eutectic formation may have a pK _a of less than or equal to 6.0. The eutectic formation may have a pK _a of less than or equal to 5.0.

The eutectic formation may have a pK _a of 1.5 to 7.0. For example, the eutectic formation may have a pK _a of 1.5 to 6.0, or 1.5 to 5.0, or 1.5 to 4.5, or 1.5 to 4.0. The eutectic formation may have a pK _a of 2.0 to 6.0, or 2.0 to 5.0, or 2.0 to 4.5, or 2.0 to 4.0. The eutectic formation may have a pK _a of 2.5 to 6.0, or 2.5 to 5.0, or 2.5 to 4.5, or 2.5 to 4.0. Typically, the eutectic formation has a pK _a of 1.5 to 5.0.

The eutectic formation may be selected from: trichloroacetic acid, phosphoric acid, phosphinic acid, superphosphoric acid, hypophosphorous acid, biphosphoric acid, hydrobromic acid, hydrobromic acid, hypobromic acid, perbromic acid, hypoiodic acid, iodic acid, periodic acid, trichloroacetic acid, phosphoric acid, phosphinic acid, perphosphoric acid, hypophosphorous acid, diphosphoric acid, hydrobromic acid, hypobromous acid, perbromic acid, hypoiodic acid, iodic acid, periodic acid, and hydroiodic acid, hypofluoric acid, hydrofluoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, squaric acid, chromic acid, selenic acid, boric acid, telluric acid, citric acid, pyrocitric acid, isocitric acid, citric acid, and citric acid sorbic acid, permanganic acid, silicic acid, dichromic acid, cyanuric acid, malonic acid, tartronic acid, glycidic acid, tartaric acid (including L-tartaric acid, D-tartaric acid, or mixtures thereof), phthalic acid, barbituric acid, benzilic acid, cinnamic acid, fumaric acid, glutaric acid, gluconic acid, caproic acid, enanthic acid, lactic acid (including L-lactic acid, D-lactic acid, or mixtures thereof), malic acid (including L-malic acid, D-malic acid, or mixtures thereof), oleic acid, linoleic acid, folic acid, propynoic acid, propionic acid, 2-hydroxypropionic acid, 3-hydroxypropionic acid, 2, 3-dihydroxypropionic acid, acrylic acid, pyruvic acid, butyric acid, isobutyric acid, butynoic acid, valeric acid, pivalic acid, caproic acid, fulvic acid, mellitic acid, palmitic acid, adipic acid, phthalic acid, stearic acid, ascorbic acid (including L-ascorbic acid, ascorbic acid, D-ascorbic acid, or a mixture thereof), gallic acid, N-acetylglycine, alginic acid, tannic acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, 2- (3-hydroxybenzoyl) benzoic acid, 2- (2-hydroxybenzoyl) benzoic acid, 3- (3-hydroxybenzoyl) benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid 4- (2-hydroxybenzoyl) benzoic acid, 4- (3-hydroxybenzoyl) benzoic acid, 4- (4-hydroxybenzoyl) benzoic acid, gluconic acid, 1-naphthoic acid, 2-naphthoic acid 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 2-hydroxy-1-naphthoic acid, 3-hydroxy-1-naphthoic acid, orotic acid, acetoacetic acid, succinic acid, ketosuccinic acid, methylmalonic acid, ferulic acid, fumaric acid, gentisic acid, p-coumaric acid, m-coumaric acid, o-coumaric acid, disodium EDTA, nicotinic acid, glutaric acid, 2-ketoglutaric acid, 3-ketoglutaric acid, 2-furoic acid, tetrahydrofurfuryl acid, 4-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 2-hydroxyphenylacetic acid, maleic acid, oxalic acid, saccharin, phosphonic acid, ethylphosphonic acid, propylphosphonic acid, hippuric acid, sebacic acid, camphoric acid, aconitic acid and thiodipropionic acid.

The eutectic formation may be selected from: n-acetylglycine, alginic acid, 2- (4-hydroxybenzoyl) benzoic acid, gluconic acid, glucoheptonic acid, 2-naphthoic acid, orotic acid, succinic acid, L-ascorbic acid, L-tartaric acid, cinnamic acid, ferulic acid, fumaric acid, gentisic acid, gallic acid, citric acid, p-coumaric acid, L-lactic acid, disodium EDTA, nicotinic acid, 1-hydroxy-2-naphthoic acid, 2-ketoglutaric acid, 4-hydroxyphenylacetic acid, L-malic acid, maleic acid, oxalic acid and saccharin.

Typically, the co-crystal former is selected from the group consisting of citric acid, succinic acid, fumaric acid, gluconic acid, L-tartaric acid, L-ascorbic acid, L-lactic acid, saccharin, disodium EDTA, and niacin.

The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being N-acetylglycine. The co-crystals may comprise xylometacin and a co-crystal former, which is alginic acid. The co-crystal may comprise xylometacin and a co-crystal former, which is 2- (4-hydroxybenzoyl) benzoic acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being gluconic acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being glucoheptonic acid. The co-crystal may comprise xylon and a co-crystal former, which is 2-naphthoic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being orotic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being succinic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being L-ascorbic acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-tartaric acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being cinnamic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being ferulic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being fumaric acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being gentisic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being gallic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being citric acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being p-coumaric acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-lactic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being disodium EDTA. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being niacin. The co-crystal may comprise xylon and a co-crystal former, which is 1-hydroxy-2-naphthoic acid. The co-crystals may comprise xylometacin and a co-crystal former, which is 2-ketoglutaric acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being 4-hydroxyphenylacetic acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-malic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being maleic acid. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being oxalic acid. The co-crystals may comprise xylometacin and a co-crystal former, which is saccharin.

Eutectic containing alkali

Also disclosed herein is a co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is a base. The base may be any substance that can act as a proton acceptor. Alternatively, the base may be any substance that can act as an electron pair donor. Alternatively, the base may be any substance that increases the concentration of OH ^- ions in aqueous solution.

The eutectic formation may be an organic base or an inorganic base. Typically, the eutectic formation is an organic base.

Typically, the eutectic formation is a compound comprising one or more basic functional groups. The basic functional group may be selected from, for example, an amine moiety, a pyridine moiety, a piperazine moiety, an amide moiety, a xanthine moiety, and a morpholine moiety. Thus, the co-crystal former may be a compound comprising one or more of an amine moiety, a pyridine moiety, a piperazine moiety, an amide moiety, a xanthine moiety, and a morpholine moiety. Typically, the eutectic formation is a compound comprising an amine moiety. The co-crystal former may be a compound comprising a pyridine moiety. The co-crystal former may be a compound comprising a piperazine moiety. The co-crystal former may be a compound comprising an amide moiety. The co-crystal former may be a compound comprising a xanthine moiety. The co-crystal former may be a compound comprising a morpholine moiety.

The co-crystal former as a strong base can deprotonate the hydroxyl groups in the xylometacin and thereby form simple salts with xylometacin. In general, when the pK _b of the base is not low enough to promote complete transfer of protons from the hydroxyl residues in xylometacin, a co-crystal will form.

Thus, the eutectic formation typically has a pK _b greater than or equal to 3.5, for example greater than or equal to 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or 7.5. Typically, the eutectic forms typically have a pK _b greater than or equal to 3.5, 4.5, or 5.5. The eutectic formation may have a pK _b greater than or equal to 3.5. The eutectic formation may have a pK _b greater than or equal to 4.5. The eutectic formation may have a pK _b greater than or equal to 5.5.

The eutectic formation may have a pK _b of less than or equal to 11.0, for example less than or equal to 10.5, 10.0, 9.5, 9.0, 8.5 or 8.0. Typically, the eutectic formation has a pK _b of less than or equal to 11.0, 10.0, or 9.0. The eutectic formation may have a pK _b of less than or equal to 11.0. The eutectic formation may have a pK _b of less than or equal to 10.0. The eutectic formation may have a pK _b of less than or equal to 9.0.

The eutectic formation may have a pK _b of 3.5 to 11.0. For example, the eutectic formation may have a pK _b of 3.5 to 10.5, or 3.5 to 10.0, or 3.5 to 9.5, or 3.5 to 9.0. The eutectic formation may have a pK _b of 4.5 to 11.0, or 4.5 to 10.5, or 4.5 to 10.0, or 4.5 to 9.5, or 4.5 to 9.0. The eutectic formation may have a pK _b of 5.5 to 11.0, or 5.5 to 10.5, or 5.5 to 10.0, or 5.5 to 9.5, or 5.5 to 9.0. Typically, the eutectic formation has a pK _b to 11.0.

The eutectic formation may be selected from: 1-aminopentane, 3-aminopentane, N-butylamine, sec-butylamine, tert-butylamine, cyclohexylpropylmethylamine, cycloprotamin, benzphetamine, cycloprotamin, dibutylamine, diethylamine, diisopropylamine, N-diisopropylethylamine, dimethylamine, 1, 3-dimethylbutylamine, N, N-dimethylethylamine, dipropylamine, ethylamine, ethylmethylamine, hexylamine, isobutylamine, isopropylamine, methylamine, methylhexylamine, N-diethylmethylamine, ottodrine, t-octylamine, propylamine, tributylamine, triethylamine, triisopropylamine, trimethylamine, trioctylamine, 2-aminoheptane, tromethamine, 1, 2-diaminocyclohexane, trans-1, 2-diaminocyclohexane, 4-diaminodicyclohexylmethane, diaminomaleonitrile, 1, 8-diaminonaphthalene, 1, 5-diaminonaphthalene, diaminopropane, 1, 2-diaminopropane, 1, 3-diaminopropane, 2, 4-diaminotoluene, 2, 5-diaminotoluene, 1, 4-diazacycloheptane, 1, 5-diazacyclooctane, diazinoethane (diazinane), N' -dimethyl-1, 3-propanediamine, dimethyl-4-phenylenediamine, dimethylaminopropylamine, dimethylethylenediamine, 1-dimethylethylenediamine, 1, 2-dimethylethylenediamine, diphenylethylenediamine, ethylenediamine, diethanolamine, N-diethylethanolamine, N-dimethylethanolamine (dianot), N-diisopropylaminoethanol, ethanolamine, methanolamine, pyridine, 1-methylpyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2, 4-dimethylpyridine, 2, 6-dimethylpyridine, 1-ethylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2, 4-diethylpyridine, 2, 6-diethylpyridine, 2-bipyridine, 2, 3-bipyridine, 2, 4-bipyridine, 3-bipyridine, 3, 4-bipyridine, 4-bipyridine, pyridoxine, pyridoxal, pyridoxamine, piperazine, 1-benzylpiperazine, 1-methyl-4-benzylpiperazine, 1, 4-dibenzylpiperazine, 3, 4-methylenedioxy-1-benzylpiperazine, methoxypiperazine amide, 1-phenylpiperazine, 2-methylphenylpiperazine, 2-methoxyphenylpiperazine, 3-methylphenylpiperazine, 3-methoxyphenylpiperazine, 4-methylphenylpiperazine, 4-methoxyphenylpiperazine, 2, 3-methylphenylpiperazine, acetamide, benzamide, N-methylbenzamide, 4-methylbenzamide, 3-methylbenzamide, dimethylformamide, dimethylacetamide, diethylacetamide, butyramide, N-methylbutanamide, formamide, N-methylformamide, propionamide, 2-methylpropanamide, N-methylpropanamide, nicotinamide, isonicotinamide, morpholine, N-methylmorpholine, 2-methylmorpholine, 3-methylmorpholine, N-ethylmorpholine, 2-ethylmorpholine, 3-ethylmorpholine, N-propylmorpholine, 2-propylmorpholine, 3-propylmorpholine, N-methylmorpholine N-oxide, 4- (2-hydroxyethyl) -morpholine, 4- (1-hydroxyethyl) -morpholine, 4- (3-hydroxypropyl) -morpholine, 4- (2-hydroxypropyl) -morpholine, 1, 3-dimethylxanthine (theophylline), 1-methylxanthine, 3-methylxanthine, 1, 3-diethylxanthine, 1-ethylxanthine, 2-ethylxanthine, xanthine, indole, purine, isoindole, carbazole, quinoline and isoquinoline.

The eutectic formation may be selected from: 4, 4-bipyridine, pyridoxine, diadenox, 4- (2-hydroxyethyl) -morpholine, piperazine, theophylline, nicotinamide, isonicotinamide, tromethamine, tert-butylamine, and diethylamine.

Typically, the co-crystal former is selected from theophylline, nicotinamide, isonicotinamide, and tromethamine.

The co-crystals may comprise xylometacin and a co-crystal former, which is 4, 4-bipyridine. The co-crystals may comprise xylometacin and a co-crystal former, which is pyridoxine. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being diadenox. The co-crystals may comprise xylometacin and a co-crystal former, which is 4- (2-hydroxyethyl) -morpholine. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being piperazine. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being theophylline. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being nicotinamide. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being isonicotinamide. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being tromethamine. The co-crystal may comprise sirolimus and a co-crystal former, the co-crystal former being tert-butylamine. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being diethylamine.

Co-crystals containing neutral compounds

Also disclosed herein is a co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is a neutral compound. The neutral compounds are: (i) an amphiphilic compound; (ii) a zwitterionic compound; (iii) A compound containing neither an acidic moiety nor a basic moiety; or (iv) an inorganic salt compound.

The eutectic formation may be an amphiphilic compound. The eutectic formation may be a zwitterionic compound. Typically, the co-crystal former is an amino acid or an amino acid derivative.

The eutectic formation may be selected from: DL-alanine, D-alanine, L-alanine, DL-arginine, D-arginine, L-arginine, DL-asparagine, D-asparagine, L-asparagine, DL-aspartic acid, D-aspartic acid, L-aspartic acid, DL-cysteine, D-cysteine, L-cysteine, DL-glutamine, D-glutamine, L-glutamine, DL-glutamic acid, D-glutamic acid, L-glutamic acid, glycine, DL-histidine, D-histidine, L-histidine, DL-isoleucine, D-isoleucine, L-isoleucine, DL-leucine, D-leucine, L-leucine DL-lysine, D-lysine, L-lysine, DL-methionine, D-methionine, L-methionine, DL-phenylalanine, D-phenylalanine, L-phenylalanine, DL-proline, D-proline, L-proline, DL-serine, D-serine, L-serine, DL-threonine, D-threonine, L-threonine, DL-tryptophan, D-tryptophan, L-tryptophan, DL-tyrosine, D-tyrosine, L-tyrosine, DL-valine, D-valine, L-valine, DL-pyroglutamic acid, D-pyroglutamic acid, L-pyroglutamic acid, DL-selenocysteine, L-serine, D-selenocysteine, L-selenocysteine, DL-pyrrolysine, D-pyrrolysine, L-pyrrolysine, N-formylmethionine, hydroxyproline, selenomethionine, carnitine, gamma-aminobutyric acid, levothyroxine, 2-aminoisobutyric acid, ornithine, citrulline and beta-alanine.

The eutectic formation may be selected from: l-lysine, L-histidine, L-tyrosine, L-pyroglutamic acid, DL-cysteine and L-glutamic acid.

Typically, the co-crystal is selected from the group consisting of L-pyroglutamic acid, DL-cysteine, and L-glutamic acid.

The eutectic formation may be a compound that contains neither an acidic moiety nor a basic moiety. Typically, the co-crystal former is a compound comprising one or more functional groups selected from the group consisting of: an ester moiety, an ether moiety, an alcohol moiety, a phenol moiety, and a carboxamide moiety. Typically, the co-crystal former is a compound comprising an alcohol moiety and/or a phenol moiety. The co-crystal former may be a compound comprising an alcohol moiety. The eutectic formation may be a compound comprising a phenolic moiety. The eutectic formation may be a compound comprising an ester moiety. The eutectic formation may be a compound comprising an ether moiety. The co-crystal former may be a compound comprising a carboxamide moiety.

The eutectic formation may be selected from the group consisting of methyl nitrate, methyl formate, methyl acetate, methyl acrylate, methyl propionate, methyl butyrate, methyl valerate, methyl benzoate, methyl anthranilate, methyl salicylate, methyl phenylacetate, methyl cinnamate, ethyl formate, ethyl acetate, ethyl propionate, ethyl lactate, ethyl butyrate ethyl valerate, ethyl isovalerate, ethyl caproate, ethyl heptanoate, ethyl benzoate, ethyl salicylate, ethyl octanoate, ethyl cinnamate, ethyl caprate, propyl acetate propyl propionate, propyl caproate, allyl caproate, isopropyl acetate, isopropyl salicylate, isopropyl palmitate, butyl formate, butyl acetate, Isobutyl formate, isobutyl acetate, sec-butyl formate, sec-butyl acetate, tert-butyl formate, tert-butyl acetate, butyl butyrate, amyl acetate, amyl butyrate, amyl propionate, amyl caproate, sec-amyl acetate, benzyl acetate, aspartame, ascorbyl palmitate (ascorbyl 6-hexadecanoate, including L-ascorbyl 6-hexadecanoate and D-ascorbyl 6-hexadecanoate), dimethyl ether, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, anisole, crown ethers, polyethylene glycols, polypropylene glycols, maltol, ethyl maltol, meso-erythritol (meso-erythritol), Threitol, mannitol (including D-mannitol, L-mannitol), sorbitol (including D-sorbitol, L-sorbitol, maltitol, xylitol (including D-xylitol, L-xylitol), inosine, phenol, 2-methylphenol, 3-methylphenol, 4-methylphenol, 2-ethylphenol, 3-ethylphenol, 4-ethylphenol, 2-propylphenol, 3-propylphenol, 4-propylphenol, 2-butylphenol, 3-butylphenol, 4-butylphenol, 2, 6-dimethyl-4-methylphenol, 2, 6-diethyl-4-methylphenol, 2, 6-dipropyl-4-methylphenol, 2, 6-di-tert-butyl-4-methylphenol, 2, 6-dimethyl-4-ethylphenol, 2, 6-diethyl-4-ethylphenol, 2, 6-dipropyl-4-ethylphenol, 2, 6-di-tert-butyl-4-ethylphenol, 2-tert-butyl-4-methylphenol, 2-tert-butyl-4-ethylphenol, 2, 6-di-tert-butyl-4-ethylphenol, 2-methoxyphenol, 3-methoxyphenol, 4-methoxyphenol, 2-ethoxyphenol, 3-ethoxyphenol, 4-ethoxyphenol, 2-methyl-4-methoxyphenol, 2-methyl-3-methoxyphenol, 2-methyl-4-ethoxyphenol, 2-methyl-3-ethoxyphenol, 2-tert-butyl-4-methoxyphenol, 2-tert-butyl-3-methoxyphenol, 2-tert-butyl-4-ethoxyphenol, 2-tert-butyl-3-ethoxyphenol, 2-sec-butyl-4-methoxyphenol, 2-sec-butyl-3-methoxyphenol, 2-sec-butyl-4-ethoxyphenol, 2-sec-butyl-3-ethoxyphenol, vanillin, ethyl vanillin, methyl p-hydroxybenzoate (C ₁ p-hydroxybenzoate), ethyl p-hydroxybenzoate (C ₂ p-hydroxybenzoate), ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate (C ₃ p-hydroxybenzoate), butyl p-hydroxybenzoate (C ₄ p-hydroxybenzoate), propyl 3,4, 5-trihydroxybenzoate (propyl gallate), ethyl 3,4, 5-trihydroxybenzoate, methyl 3,4, 5-trihydroxybenzoate and urea.

The eutectic formation may be selected from: ethyl maltol, meso-erythritol, D-mannitol, D-sorbitol, D-xylitol, inosine, and L-ascorbic acid 6-hexadecanoate. The eutectic formation may be selected from: 2, 6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4-methoxyphenol, vanillin, ethyl vanillin, C1-4 p-hydroxybenzoate, propyl gallate and urea.

Typically, the eutectic formation is selected from: ethyl maltol, meso-erythritol, D-mannitol, D-sorbitol, D-xylitol, inosine, L-ascorbic acid 6-hexadecanoate, propyl gallate, 2, 6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4-methoxyphenol and urea.

The eutectic formation may be an inorganic salt compound.

The eutectic formation may be selected from: calcium chloride, potassium dichromate, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate, magnesium dihydrogen phosphate, magnesium hydrogen phosphate, magnesium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium bisulfate, sodium sulfate, calcium sulfate, magnesium sulfate, potassium bisulfate, sodium sulfite, calcium sulfite, magnesium sulfite, potassium sulfite, sodium bisulfate, calcium bisulfate, magnesium bisulfate, potassium bisulfide, sodium acesulfame and sodium formaldehyde sulfoxylate.

The eutectic formation may be selected from: sodium dihydrogen phosphate, sodium hydrogen sulfite, acesulfame potassium and sodium formaldehyde sulfoxylate.

Typically the eutectic formation is selected from: sodium bisulfite, acesulfame potassium and sodium formaldehyde sulfoxylate.

The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-lysine. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-histidine. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-tyrosine. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-pyroglutamic acid. The co-crystal may comprise xylometacin and a co-crystal former, which is DL-cysteine. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being L-glutamic acid. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being ethyl maltol. The co-crystals may comprise xylometacin and a co-crystal former, which is meso-erythritol. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being D-mannitol. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being D-sorbitol. The co-crystals may comprise xylometacin and a co-crystal former, which is D-xylitol. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being inosine. The co-crystals may comprise xylometacin and a co-crystal former, which is L-ascorbic acid 6-hexadecanoate. The co-crystals may comprise xylometacin and a co-crystal former which is 2, 6-di-tert-butyl-4-methylphenol. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being 2-tert-butyl-4-methoxyphenol. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being vanillin. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being ethyl vanillin. The co-crystals may comprise xylometacin and a co-crystal former, which is C1-4 p-hydroxybenzoate. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being propyl gallate. The co-crystal may comprise xylometacin and a co-crystal former, the co-crystal former being urea. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being sodium dihydrogen phosphate. The co-crystals may comprise xylometacin and a co-crystal former, which is sodium bisulphite. The co-crystals may comprise xylometacin and a co-crystal former, which is acesulfame potassium. The co-crystals may comprise xylometacin and a co-crystal former, the co-crystal former being sodium formaldehyde sulfoxylate.

The co-crystals may comprise one or more additional co-crystal formers. Typically, however, the co-crystals comprise a single co-crystal former.

The eutectic formation is typically a compound having a molar mass of not more than 500g/mol, not more than 350g/mol or not more than 200 g/mol. The co-crystal former may have a molar mass of at least 30g/mol, at least 50g/mol, or at least 100 g/mol.

The co-crystal former may contain one or more chiral centers. Unless otherwise indicated, references herein to co-crystal formations encompass all enantiomeric and diastereomeric forms of the co-crystal formations, mixtures thereof (e.g., racemic mixtures), and enantiomerically and diastereomerically pure forms thereof.

Chemometrics of

The molar ratio of xylometacin to co-crystal former in the co-crystal may be 1:0.25 to 1:4. The molar ratio of the xylometacin to the co-crystal former may be 1:0.25 to 1:3, or 1:0.5 to 1:2, or 1:0.5 to 1:1.5. Typically, the molar ratio of xylometacin to co-crystal former in the co-crystal is 1:0.5 to 1:3, or 1:0.5 to 1:2.

The molar ratio of sirolimus to co-crystal former in the co-crystal may be about 1:0.25, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.75, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.25, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.75, about 1:1.8, about 1:1.9, about 1:2, about 1:2.5, about 1:3.5, or about 1:4. Typically, the molar ratio of xylometacin to co-crystal former in the co-crystal is about 1:0.5, about 1:1, or about 1:2. The molar ratio of xylometacin to co-crystal former in the co-crystal may be 1:0.5, for example 1.0:0.50. The molar ratio of xylometacin to co-crystal former in the co-crystal may be 1:1, for example 1.0:1.0. The molar ratio of xylometacin to co-crystal former in the co-crystal may be 1:2, for example 1.0:2.0.

If the co-crystal comprises more than one co-crystal former, the molar ratio of xylometacin to each co-crystal former may be as defined above. Alternatively, the molar ratio of the total amount of the co-crystal form of cilobroma may be as defined above.

The term "about" as used herein refers to any value that a skilled artisan will appreciate, the value being a reasonable variation of the value to which the term "about" refers. Typically, "about" means ± 10% or ± 5%.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and citric acid, wherein the molar ratio of xylometacin to citric acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and citric acid, wherein the molar ratio of xylometacin to citric acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and citric acid, wherein the molar ratio of xylometacin to citric acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and fumaric acid, wherein the molar ratio of xylometacin to fumaric acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and fumaric acid, wherein the molar ratio of xylometacin to fumaric acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and fumaric acid, wherein the molar ratio of xylometacin to fumaric acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and succinic acid, wherein the molar ratio of xylon to succinic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylon and succinic acid, wherein the molar ratio of xylon to succinic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylon and succinic acid, wherein the molar ratio of xylon to succinic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and gluconic acid, wherein the molar ratio of xylometacin to gluconic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and gluconic acid, wherein the molar ratio of xylometacin to gluconic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and gluconic acid, wherein the molar ratio of xylometacin to gluconic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and L-tartaric acid, wherein the molar ratio of xylon to L-tartaric acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylon and L-tartaric acid, wherein the molar ratio of xylon to L-tartaric acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylon and L-tartaric acid, wherein the molar ratio of xylon to L-tartaric acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and L-ascorbic acid, wherein the molar ratio of xylometacin to L-ascorbic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-ascorbic acid, wherein the molar ratio of xylometacin to L-ascorbic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-ascorbic acid, wherein the molar ratio of xylometacin to L-ascorbic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and L-lactic acid, wherein the molar ratio of xylometacin to L-lactic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-lactic acid, wherein the molar ratio of xylometacin to L-lactic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-lactic acid, wherein the molar ratio of xylometacin to L-lactic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and saccharin, wherein the molar ratio of xylometacin to saccharin is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and saccharin, wherein the molar ratio of xylometacin to saccharin is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and saccharin, wherein the molar ratio of xylometacin to saccharin is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and disodium EDTA, wherein the molar ratio of xylometacin to disodium EDTA is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and disodium EDTA, wherein the molar ratio of xylometacin to disodium EDTA is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and disodium EDTA, wherein the molar ratio of xylometacin to disodium EDTA is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and niacin, wherein the molar ratio of xylometacin to niacin is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and niacin, wherein the molar ratio of xylometacin to niacin is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and niacin, wherein the molar ratio of xylometacin to niacin is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and theophylline, wherein the molar ratio of xylometacin to theophylline is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and theophylline, wherein the molar ratio of xylometacin to theophylline is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and theophylline, wherein the molar ratio of xylometacin to theophylline is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and nicotinamide, wherein the molar ratio of xylometacin to nicotinamide is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and nicotinamide, wherein the molar ratio of xylometacin to nicotinamide is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and nicotinamide, wherein the molar ratio of xylometacin to nicotinamide is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and isonicotinamide, wherein the molar ratio of xylometacin to isonicotinamide is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and isonicotinamide, wherein the molar ratio of xylometacin to isonicotinamide is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and isonicotinamide, wherein the molar ratio of xylometacin to isonicotinamide is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and tromethamine, wherein the molar ratio of xylometacin to tromethamine is 1:1. Alternatively, the co-crystal may be a co-crystal comprising sirolimus and tromethamine, wherein the molar ratio of sirolimus to tromethamine is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising sirolimus and tromethamine, wherein the molar ratio of sirolimus to tromethamine is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and L-pyroglutamic acid, wherein the molar ratio of xylometacin to L-pyroglutamic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-pyroglutamic acid, wherein the molar ratio of xylometacin to L-pyroglutamic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-pyroglutamic acid, wherein the molar ratio of xylometacin to L-pyroglutamic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and DL-cysteine, wherein the molar ratio of xylometacin to DL-cysteine is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and DL-cysteine, wherein the molar ratio of xylometacin to DL-cysteine is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and DL-cysteine, wherein the molar ratio of xylometacin to DL-cysteine is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and L-glutamic acid, wherein the molar ratio of xylometacin to L-glutamic acid is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-glutamic acid, wherein the molar ratio of xylometacin to L-glutamic acid is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-glutamic acid, wherein the molar ratio of xylometacin to L-glutamic acid is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylocarpal and ethyl maltol, wherein the molar ratio of xylocarpal to ethyl maltol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylocarposin and ethyl maltol, wherein the molar ratio of xylocarposin to ethyl maltol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylocarposin and ethyl maltol, wherein the molar ratio of xylocarposin to ethyl maltol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xyloside and meso-erythritol, wherein the molar ratio of xyloside to meso-erythritol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xyloside and meso-erythritol, wherein the molar ratio of xyloside to meso-erythritol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xyloside and meso-erythritol, wherein the molar ratio of xyloside to meso-erythritol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and D-mannitol, wherein the molar ratio of xylometacin to D-mannitol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-mannitol, wherein the molar ratio of xylometacin to D-mannitol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-mannitol, wherein the molar ratio of xylometacin to D-mannitol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and D-sorbitol, wherein the molar ratio of xylometacin to D-sorbitol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-sorbitol, wherein the molar ratio of xylometacin to D-sorbitol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-sorbitol, wherein the molar ratio of xylometacin to D-sorbitol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and D-xylitol, wherein the molar ratio of xylometacin to D-xylitol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-xylitol, wherein the molar ratio of xylometacin to D-xylitol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and D-xylitol, wherein the molar ratio of xylometacin to D-xylitol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and inosine, wherein the molar ratio of xylometacin to inosine is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and inosine, wherein the molar ratio of xylometacin to inosine is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and inosine, wherein the molar ratio of xylometacin to inosine is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and L-ascorbic acid 6-hexadecanoate, wherein the molar ratio of xylon to L-ascorbic acid 6-hexadecanoate is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-ascorbic acid 6-hexadecanoate, wherein the molar ratio of xylometacin to L-ascorbic acid 6-hexadecanoate is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and L-ascorbic acid 6-hexadecanoate, wherein the molar ratio of xylometacin to L-ascorbic acid 6-hexadecanoate is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylon and propyl gallate, wherein the molar ratio of xylon to propyl gallate is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylon and propyl gallate, wherein the molar ratio of xylon to propyl gallate is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylon and propyl gallate, wherein the molar ratio of xylon to propyl gallate is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and 2, 6-di-tert-butyl-4-methylphenol, wherein the molar ratio of xylometacin to 2, 6-di-tert-butyl-4-methylphenol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and 2, 6-di-tert-butyl-4-methylphenol, wherein the molar ratio of xylometacin to 2, 6-di-tert-butyl-4-methylphenol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and 2, 6-di-tert-butyl-4-methylphenol, wherein the molar ratio of xylometacin to 2, 6-di-tert-butyl-4-methylphenol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylocarpin and 2-tert-butyl-4-methoxyphenol, wherein the molar ratio of xylocarpin to 2-tert-butyl-4-methoxyphenol is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and 2-tert-butyl-4-methoxyphenol, wherein the molar ratio of xylometacin to 2-tert-butyl-4-methoxyphenol is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and 2-tert-butyl-4-methoxyphenol, wherein the molar ratio of xylometacin to 2-tert-butyl-4-methoxyphenol is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and urea, wherein the molar ratio of xylometacin to urea is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and urea, wherein the molar ratio of xylometacin to urea is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and urea, wherein the molar ratio of xylometacin to urea is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and sodium bisulfite, wherein the molar ratio of xylometacin to sodium bisulfite is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and sodium bisulfite, wherein the molar ratio of xylometacin to sodium bisulfite is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and sodium bisulfite, wherein the molar ratio of xylometacin to sodium bisulfite is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and acesulfame potassium, wherein the molar ratio of xylometacin to acesulfame potassium is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and acesulfame potassium, wherein the molar ratio of xylometacin to acesulfame potassium is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and acesulfame potassium, wherein the molar ratio of xylometacin to acesulfame potassium is 1:2.

In one embodiment, the co-crystal is a co-crystal comprising xylometacin and sodium formaldehyde sulfoxylate, wherein the molar ratio of xylometacin to sodium formaldehyde sulfoxylate is 1:1. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and sodium formaldehyde sulfoxylate, wherein the molar ratio of xylometacin to sodium formaldehyde sulfoxylate is 1:0.5. Alternatively, the co-crystal may be a co-crystal comprising xylometacin and sodium formaldehyde sulfoxylate, wherein the molar ratio of xylometacin to sodium formaldehyde sulfoxylate is 1:2.

Solvates and hydrates

The co-crystals may be in the form of solvates. The term "solvate" as used herein describes a co-crystal having solvent molecules (typically organic solvents) incorporated into its co-crystal lattice. Thus, the eutectic solvate comprises an active agent, a eutectic formation and a solvent molecule. Solvates may contain molecules of organic solvents and water. Hydrates are solvates that contain incorporated water molecules as the only solvent molecules.

The solvate is typically a solvate with an organic solvent. Suitable organic solvents are known to the person skilled in the art. For example, the organic solvent may be carbon tetrachloride, 1, 2-dichloroethane, 1-trichloroethane, acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentylmethyl ether, 1, 2-dichloroethylene, dichloromethane, 1, 2-dimethoxyethane, N-dimethylacetamide, N, N-dimethylformamide, 1, 4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, methyl ethyl ketone, methyl ethyl methyl ketone, methyl ethyl ketone, methyl, methyl ethyl ketone, N-butyl, tertiary butanol, tetrahydrofuran, tetrahydronaphthalene, toluene, 1, 2-trichloroethylene, xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tertiary butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, ethyl acetate, ethyl methyl, ethyl a methyl, ethyl methyl, ethyl tertiary butanol, tetrahydrofuran, tetrahydronaphthalene, toluene, 1, 2-trichloroethylene, xylene, acetic acid, acetone, anisole, 1-butanol 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid.

Typically, the organic solvent is selected from: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentylmethyl ether, 1, 2-dichloroethylene, methylene chloride, 1, 2-dimethoxyethane, N-dimethylacetamide, N, N-dimethylformamide, 1, 4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, methyl ethyl ketone, methyl ethyl methyl ketone, methyl ethyl ketone, methyl, methyl ethyl ketone, N-butyl, tertiary butanol, tetrahydrofuran, tetrahydronaphthalene, toluene, 1, 2-trichloroethylene, xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tertiary butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, ethyl acetate, ethyl methyl, ethyl a methyl, ethyl methyl, ethyl tertiary butanol, tetrahydrofuran, tetrahydronaphthalene, toluene, 1, 2-trichloroethylene, xylene, acetic acid, acetone, anisole, 1-butanol 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid.

Typically, the organic solvent is a pharmaceutically acceptable organic solvent.

The co-crystals may be in the form of hydrates. Alternatively, the co-crystals may be in a non-hydrated form. The co-crystal may be anhydrous.

The solvates and/or hydrates may be stoichiometric, i.e. have a 1:1 molar ratio of co-crystal to solvent. Alternatively, the solvates and/or hydrates may be non-stoichiometric, i.e. have a non-integer molar ratio of co-crystal to solvent of, for example, 1:1.1. Non-stoichiometric solvates and/or hydrates may also be referred to as channel solvates and/or hydrates.

Method for producing eutectic

The methods of producing co-crystals described herein include mixing the celecoxib with a co-crystal former, e.g., an acid, base, or neutral compound. Suitable methods are well known to those skilled in the art.

The method may comprise reactive crystallization. Reactive crystallization typically involves mixing a solution of xylometacin with a solution of a eutectic former, stirring, and isolating the resulting eutectic.

The method may comprise crystallization. Crystallization typically involves dissolving (directly or by mechanical milling) the celecoxib and the co-crystal formation in a solvent or solvent system to produce a clear solution, supersaturating it, and separating the resulting co-crystal.

The method may comprise slurry or suspension mediated crystallization. Slurry or suspension mediated crystallization typically involves suspending the xylometacin and the co-crystal former in a solvent or solvent system such that a small portion remains in excess, stirring the suspension, and isolating the resulting co-crystal.

The method may comprise solid state milling. Solid state milling typically involves milling the xylometacin and the co-crystal formation together and separating the resulting co-crystals.

The method may comprise liquid assisted milling. Liquid-assisted milling typically involves mixing the xylometacin and co-crystal formation in a small volume (typically, but not limited to, a volume: total solids weight ratio of 1:4 (volume: weight ratio of total solid)) of solvent/solvent system, milling the xylometacin with the co-crystal formation (including milling using a resonant sonic mixer), and separating the resulting co-crystals.

The method may comprise a solid-state mediated process. Solid-state mediated processes typically comprise mixing the xylometacin and the co-crystal former, and exposing to laser irradiation or an electrochemical source, followed by separation of the resulting co-crystal.

The method may comprise melt-mediated crystallization. Melt-mediated crystallization typically involves simultaneously mixing and melting both the xylometacin and the co-crystal former, and separating the resulting co-crystals.

Pharmaceutical composition

The present invention provides a pharmaceutical composition comprising a co-crystal and a pharmaceutically acceptable excipient or diluent. The co-crystals may be further defined herein.

Suitable conventional excipients or diluents will depend on the mode of administration used. Pharmaceutically acceptable excipients and diluents are well known to the skilled person. The pharmaceutical composition may further comprise one or more of a buffer, lubricant, diluent or carrier.

Therapeutic method

The co-crystals of the present invention may be used as medicaments. In one embodiment, the invention provides a co-crystal as described herein for use as a medicament.

In one embodiment, the invention provides a method of treating or preventing a disease or condition selected from the group consisting of psychological, neurological and central nervous system disorders.

The disease or condition may be selected from: destructive mood disorders, depression, major Depressive Disorder (MDD), treatment-resistant depression, persistent depressive disorder (dysthymia), mental depression, despair, premenstrual anxiety disorder, substance/drug-induced depressive disorder, post-partum depression, depressive disorder caused by another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, anxiety, death anxiety, substance-drug-induced anxiety disorder, anxiety disorder caused by another medical condition, somatic symptom disorder, disease anxiety disorder (suspicion), conversion disorder (functional neurological symptom disorder), sexual disorder post-traumatic stress disorder (PTSD), accommodation disorder, acute pain disorder, obsessive-compulsive disorder, somniform disorder, stocking disorder, dehairing (dehairing) disorder, skin-scratch disorder, substance/drug-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders caused by another medical condition, substance-related disorders, alcohol-related disorders, cannabis-related disorders, hallucinogen-related disorders, inhalant-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-or anxiolytic-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling or gaming disorders), migraine, cluster headache (including chronic cluster headache), periodic vomiting, tension-type headache, dysphoria, pica, anorexia nervosa, bulimia nervosa, binge eating, oppositional defiant disorder, intermittent fulminant disorder, conduct disorder, antisocial personality disorder, psychotic condition, pyrosis, kleptomania, autism spectrum disorder, antisocial personality disorder, attention deficit/hyperactivity disorder, schizophrenic (personality) disorder, delusional disorder, schizophrenia, schizoaffective disorder, insomnia disorder, somnolence disorder, narcolepsy, primary central sleep apnea, bipolar disorder type I, bipolar disorder type II, circulatory personality disorder, pain, phantom limb pain, chronic pain, spinal cord disease, traumatic brain injury, intellectual disability, mania, neurodegeneration, sexual desire for pouring disorder (e.g., autism disorder), suicidal behavior disorder, suicidal desire for accelerated death (desire for HASTENED DEATH), non-suicidal self-disability, persistent complexity disorder, funeral syndrome, restless syndrome, and restless legs.

In one embodiment, the method is a method of treating or preventing a disease or condition selected from depression, anxiety, death anxiety, mental retardation, maladaptation, despair, suicidal ideation, and the desire to accelerate death.

In one embodiment, the method is a method of treating or preventing a cocaine-related disorder, an opioid-related disorder, or an agonist-related disorder.

The method may be a method of treating or preventing depression in a patient. The method may be a method of treating or preventing anxiety in a patient. As used herein, treating or preventing depression and/or anxiety includes alleviating symptoms of depression and/or anxiety or effecting relief of depression and/or anxiety. In one embodiment, treating or preventing depression and/or anxiety comprises alleviating symptoms of depression and/or anxiety. The patient may report relief of symptoms of depression and/or anxiety.

In one embodiment, the patient has been identified as in need of treatment to alleviate depression and/or anxiety. In one embodiment, the patient has indicated that he or she has depression and/or anxiety.

Symptoms of depression and/or anxiety can be measured using the hospital anxiety and depression scales (HADS; zigmond and Snaith (1983), "The hospital anxiety and depression Scale", ACTA PSYCHIATRICA SCAND, 67:361-370). In this test, lower numbers indicate lower levels of depression and/or anxiety. Sub-scale scores for depression (HADS-D) and anxiety (HADS-A) may be calculated. A sub-scale score equal to or higher than 8 and a total scale score of greater than 12 indicates that a clinical disorder may exist.

Thus, in the methods of the invention, the patient's total hospital anxiety and depression scale score may be reduced after administration of the co-crystal. In one embodiment, the patient's total HADS score decreases to below about 12 after administration of the co-crystal.

A Beck depression scale-II (Beck Depression Inventory-II) (BDI-II; beck et al (1988),"Psychometric properties of the Beck Depression Inventory:Twenty-five years of evaluation",Clin Psych Rev,8:77–100)) may also be used to measure the severity of depression.

Thus, in the methods of the invention, the Beck depression scale-II score of a patient may be reduced after administration of the co-crystal. In one embodiment, the Beck depression scale-II score of the patient is reduced to below about 12 after administration of the co-crystal.

The method may be a method of treating or preventing death anxiety. The method may be a method of treating or preventing mental retardation (i.e., loss of life). The method may be a method of treating or preventing despair. Death anxiety, mental retardation, and despair are all aspects of survival suffering. Thus, the method may also be a method of treating or preventing survival afflictions in a patient, wherein treating or preventing survival afflictions comprises reducing the level of at least one of death anxiety, despair, and mental retardation.

In a method of treating or preventing death anxiety in a patient, the death anxiety is reduced relative to the death anxiety of the patient prior to administration of the co-crystal. Death anxiety is typically measured according to the death anxiety scale (Templer (1970), "The construction and validation of a death anxiety scale", JGen Psychol, 82:165-177). Scores below 8 are considered baseline levels of death anxiety. Thus, in the methods of the invention, the patient's death anxiety score may be reduced to below 8 after administration of the co-crystal.

In a method of treating or preventing mental retardation in a patient, mental retardation is reduced as compared to mental retardation in the patient prior to administration of the co-crystal. A score above 30 is considered to be indicative of a clinical level of mental depression, thus, in the methods of the invention, the mental depression score of the patient may be reduced to below 30 after administration of the co-crystal.

In a method of treating or preventing destination in a patient, destination is reduced relative to destination in the patient prior to administration of the co-crystal. The destination is typically measured on a scale of 0-16 according to the destination assessment (Hopelessness ASSESSMENT IN ILLNESS) tool (Rosenfeld et al .(2011),"Assessing hopelessness in terminally ill cancer patients:Development of the Hopelessness Assessment in Illness Questionnaire",Psychol Assess,23:325–336). Higher scores indicate higher destination levels. Thus, in the methods of the invention, the destination assessment score of a patient may be reduced to below 8 after administration of the co-crystal.

The method may be a method of treating or preventing suicidal ideation in a patient. As used herein, treating or preventing suicidal ideation includes reducing or preventing suicidal ideation, suicidal plans, and/or suicidal attempts. The patient may report a decrease in suicide thoughts and/or suicide plans. The patient may not try suicide any more frequently.

In one embodiment, the patient has been identified as in need of treatment to prevent or reduce suicidal ideation. Thus, the method of the invention may comprise the step of assessing the level of suicidal ideation in the patient prior to administering the co-crystal to the patient. In one embodiment, the patient has shown that he or she has suicidal ideation.

The suicidal ideation can be measured using a comprehensive test containing elements from the Beck depression scale-II (BDI-II; beck et al (1988),"Psychometric properties of the Beck Depression Inventory:Twenty-five years of evaluation",Clin Psych Rev,8:77–100) and the brief symptoms scale (BSI; derogatis 1993) in BDI, item 9 asks for the suicidal ideation, options are as follows: 0 = i does not have any idea of suicidal; 1 = i has the idea of suicidal ideation but i does not implement; 2 = i wants to suicidal; 3 = i would suicide if i has an opportunity in BSI, item 9 ("idea of your life ended") is also related to the suicidal ideation and measured in the Likert scale: 0 = none at all; 1 = very few; 2 = medium; 3 = quite many; 4 = extremely by summing the scores of BDI-II item 9 with the scores of BSI 9.

Thus, in the methods of the invention, the patient's integrated suicidal ideation score may be reduced after the co-crystal is administered. Typically, the patient's integrated suicidal ideation score is reduced by at least 20%, at least 30%, at least 40%, at least 50%, or at least 75% after the co-crystal is administered. In one embodiment, the patient's integrated suicidal ideation score is less than 50, less than 45, or less than 40 after the co-crystal is administered.

The method may be a method of treating or preventing the desire for accelerated death in a patient. The desire to treat or prevent accelerated death as used herein includes the desire to prevent or reduce death faster than naturally occurring death. The patient may report a reduction in the desire to die faster than naturally occurring death.

In one embodiment, the patient has been identified as in need of treatment to prevent or reduce the desire for accelerated death. Thus, the method of the invention may comprise the step of assessing the level of desire for accelerated death in the patient prior to administering the co-crystal to the patient. In one embodiment, the patient has indicated that he or she has a desire to accelerate death.

The wish to accelerate death can be measured using the accelerated death attitude Scale (SAHD) (Rosenfeld 2000). SAHD is a true/false measurement questionnaire containing 20 items for measuring the desire to accelerate death, which has been validated in cancer patients. Alternatively, DHD may be measured using loss of meaning factors in the mental retardation scale (Kissane et al (2004)). Specifically, a composite score for the desire to accelerate death can be derived from the following five factors of loss of meaning, measured on the Likert scale from 0 to 4: "life no longer deserves to live", "me prefers to not live anymore", "my life seems meaningless", "me role in life has lost" and "activity in my life has no purpose".

Thus, in the methods of the invention, the desired overall score for accelerated death of a patient may be reduced after administration of the co-crystal. Typically, the desired overall score for accelerated death of the patient is reduced by at least 20%, at least 40%, at least 60%, or at least 80% after administration of the co-crystal.

The method of the invention comprises administering to a patient a therapeutically effective amount of a co-crystal as defined herein. The therapeutically effective amount may be any amount of co-crystals containing a quantity of cilobnew effective to treat and/or prevent a disease or condition as described herein. An effective amount of xylometacin may be about 0.001mg/kg to about 10mg/kg, for example about 0.01mg/kg to about 1mg/kg, wherein mg/kg is milligrams per kilogram of patient body weight at the time of co-crystal administration. In general, an effective amount of xylometacin may be a dose of about 0.1mg/kg to about 0.5mg/kg or about 0.2mg/kg to about 0.4 mg/kg. In one embodiment, the effective amount of xylometacin is about 0.3mg/kg.

In the methods of the invention, a therapeutically effective amount of the co-crystal may be administered as a single dose or as multiple doses. Typically, a therapeutically effective amount of the co-crystal is administered as a single dose.

A single dose of co-crystal may contain from about 0.1 to about 100mg of xylometacin. In one embodiment, the xylometacin is administered in a single effective dose of about 10mg to about 40 mg. Typically, the single dose may be about 10mg to about 35mg, or about 15mg to about 30mg, or about 20mg to about 30mg. In one embodiment, the single dose is about 25mg. In one embodiment, the single dose is from about 1mg to about 10mg.

The co-crystals may be administered to a patient by any acceptable route of administration, including, but not limited to, inhalation, oral, nasal, topical (including transdermal), and parenteral modes of administration. The co-crystals may be administered, for example, as the following dosage forms: tablets, capsules, powders, solutions or suspensions for oral administration; solutions or suspensions for injection; or a solution, suspension or powder for inhalation.

The patient to be treated may suffer from life threatening diseases. The life threatening disease may be any chronic disease that may reduce the normal life expectancy of a patient suffering from the disease. The life threatening disease may be selected from cancer, heart disease, chronic Obstructive Pulmonary Disease (COPD), diabetes, alzheimer's disease, dementia, motor neuron disease, amyotrophic Lateral Sclerosis (ALS), parkinson's disease, epilepsy, multiple sclerosis, and Myalgia Encephalopathy (ME). In one embodiment, the life threatening disease is cancer.

The invention also provides co-crystals as described herein for use in the treatment or prevention of a disease or disorder as described herein. In one embodiment, the invention provides a co-crystal as described herein for use in the treatment or prevention of a disease or condition selected from depression, anxiety, death anxiety, mental retardation, accommodation disorders, despair, suicidal ideation and the desire to accelerate death. In one embodiment, the disease or condition is selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders.

The invention further provides the use of a co-crystal as described herein in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition as described herein. In one embodiment, the invention provides the use of a co-crystal as described herein in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition selected from depression, anxiety, death anxiety, mental retardation, adaptation disorders, desperate, suicidal ideation and the desire to accelerate death. In one embodiment, the disease or condition is selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders. The treatment or prevention of the disease or condition may be as described herein.

Kit for detecting a substance in a sample

Kits of the invention comprise a co-crystal or pharmaceutical composition as described herein, and instructions for using the co-crystal or pharmaceutical composition in a method of treating or preventing a disease or condition selected from depression, anxiety, death anxiety, mental retardation, maladaptation, despair, suicidal ideation, and a desire to accelerate death. The kit may comprise instructions for using the co-crystal or pharmaceutical composition in a method of treating or preventing a disease or condition selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders.

Salt

The invention also provides salts comprising xylometacin and a co-crystal former as described herein. In general, if the xylometacin and the co-crystal former have Δpk _a(pK_a (conjugate acid of base) -pK _a (acid). Gtoreq.1, a large amount of proton transfer occurs between the xylometacin and the co-crystal former, and thus salts may be formed.

For example, the present invention provides salts of siloxanil with capric acid. The salt of cilobnew with capric acid may be in a crystalline form designated as either capric acid pattern 1 or pattern 2. The invention also provides a salt of xylometacin and ethyl maltol. The salt of xylometacin with ethyl maltol may be in a crystalline form designated ethyl maltol pattern 1. The invention also provides a salt of xylometacin with L-lactic acid. The salt of xylometacin with L-lactic acid may be in a crystalline form designated as L-lactic acid pattern 1. The invention also provides a salt of xylometacin and oleic acid. The salt of cilostatin with oleic acid may be in a crystalline form designated oleic acid pattern 1. The invention also provides a salt of xylometacin and palmitic acid. The salt of xylon with palmitic acid may be in a crystalline form designated palmitic acid pattern 1. The invention also provides a salt of xylometacin and p-coumaric acid. The salt of xylon with p-coumaric acid may be in a crystalline form designated p-coumaric acid pattern 1. The invention also provides a salt of the xylometacin and propyl gallate. The salt of xylon with propyl gallate may be in a crystalline form designated propyl gallate pattern 1. The invention also provides a salt of the xylometacin with stearic acid. The salt of celecoxib with stearic acid may be in a crystalline form designated stearic acid pattern 1 or pattern 2.

The salt of cilobnew with decanoic acid may be in a crystalline form designated as decanoic acid pattern 1, wherein pattern 1 has an x-ray powder diffraction (XRPD) pattern comprising peaks at 5.9 °, 14.2 ° and 15.9 ° ± 0.2 ° 2Θ. The XRPD pattern of pattern 1 of a salt of celecoxib and decanoic acid typically further comprises one or more peaks selected from 16.7 °, 24.0 ° and 24.7 ° ± 0.2 ° 2Θ. Pattern 1 of the salt of siloneo and decanoic acid may further comprise peaks at 16.7 °, 24.0 ° and 24.7 ° ± 0.2 ° 2θ. The XRPD pattern of pattern 1 of a salt of celecoxib and decanoic acid can comprise five or more peaks selected from the group consisting of 5.9 °, 14.2 °, 15.9 °, 16.7 °, 18.3 °, 20.7 °, 22.6 °, 24.0 ° and 24.7 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks.

The salt of cilobnew with decanoic acid may be in a crystalline form designated decanoic acid pattern 2, wherein pattern 2 has an x-ray powder diffraction (XRPD) pattern comprising peaks at 6.4 °, 16.9 ° and 25.2 ° ± 0.2 ° 2Θ. The XRPD pattern of pattern 2 of a salt of celecoxib and decanoic acid typically further comprises one or more peaks selected from 22.3 °, 23.6 ° and 23.7 ° ± 0.2 ° 2Θ. Pattern 2 of the salt of siloneo and decanoic acid may further comprise peaks at 22.3 °, 23.6 ° and 23.7 ° ± 0.2 ° 2θ. The XRPD pattern of pattern 2 of a salt of celecoxib and decanoic acid can comprise five or more peaks selected from the group consisting of 6.4 °, 16.9 °, 17.8 °, 19.2 °, 19.6 °, 22.3 °, 23.6 °, 23.7 ° and 25.2 ° ± 0.2 ° 2Θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks.

The salt of celecoxib with L-lactic acid may be in a crystalline form designated as L-lactic acid pattern 1, wherein pattern 1 has an x-ray powder diffraction (XRPD) pattern comprising peaks at 13.4 °, 16.8 ° and 19.5 ° ± 0.2 ° 2Θ. The XRPD pattern of pattern 1 of a salt of xylometacin with L-lactate typically further comprises one or more peaks selected from 16.7 °, 23.0 ° and 24.3 ° ± 0.2 ° 2θ. Pattern 1 of the salt of xylometacin with L-lactic acid may further comprise peaks at 16.7 °, 23.0 ° and 24.3 ° ± 0.2 ° 2θ. The XRPD pattern of pattern 1 of a salt of xylometacin with L-lactate may comprise five or more peaks selected from 13.4 °, 14.9 °, 16.7 °, 16.8 °, 19.5 °, 20.6 °, 23.0 °, 24.3 ° and 26.3 ° ± 0.2 ° 2θ. The XRPD pattern may comprise seven or more of these peaks. The XRPD pattern may comprise all of these peaks.

The invention is described in more detail by the following examples. Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the following claims.

The references cited in this disclosure are incorporated by reference in their entirety.

Examples

Example 1 preparation method

The eutectic is prepared according to the following method.

(A) Reaction crystallization

The pre-defined molar equivalents of the feed solutions, each containing the xylon or co-crystal former in a solvent/solvent system, are mixed together and stirred manually, mechanically or using ultrasound (sonication). Supersaturation is achieved by evaporation, cooling, addition of an anti-solvent, spray drying or freeze drying. The resulting eutectic is separated and dried.

(B) Crystallization

The pre-defined molar equivalent ratio of the xylometacin and the co-crystal former are dissolved directly in a solvent/solvent system at a defined temperature or by mechanical milling (e.g. using a pestle and mortar) to produce a clear solution. Supersaturation is achieved by evaporation, cooling, addition of an anti-solvent, spray drying or freeze drying. The resulting eutectic is separated and dried.

(C) Slurry or suspension mediated crystallization

The pre-defined molar equivalents of the xylometacin and the co-crystal former are suspended in a solvent/solvent system such that the solid fraction remains in excess. The suspension is then stirred by hand, mechanically or using ultrasound or using a shear granulation process. The experiments were performed under isothermal conditions, or with a temperature gradient or thermal cycling. The resulting eutectic is separated and dried.

(D) Solid state milling

The pre-defined molar equivalents of xylometacin and the co-crystal former are mixed and milled by manual or mechanical means (e.g. using a ball mill or an extruder). The resulting eutectic is separated.

(E) Liquid assisted milling

The pre-defined molar equivalents of the xylometacin and the co-crystal former are mixed together with a small volume (typically 1:4 volume: weight ratio of total solids) of solvent/solvent system and milled either manually, mechanically (e.g. using a ball mill) or using a resonant sonic mixer. The resulting eutectic is separated and dried.

(F) Solid state mediation

The pre-defined molar equivalents of the xylometacin and the co-crystal former are mixed together and exposed to high power laser irradiation or electrochemical sources. The resulting eutectic is separated.

(G) Melt-mediated crystallization

The pre-defined molar equivalents of the xylon and the co-crystal former are mixed together and melted simultaneously and mixed directly or mechanically (e.g. by a hot melt extruder). The resulting molten mixture is then cooled to obtain the resulting eutectic.

Example 2 screening

Salt/co-crystal screening of xylometacin was performed using 23 co-crystal formers, namely adenine, ascorbic acid, citric acid, capric acid, ethyl maltol, glutathione, isonicotinamide, L-alanine, L-lactic acid, L-phenylalanine, L-proline, L-tryptamine, L-tryptophan, nicotinamide, oleic acid, palmitic acid, propyl gallate, coumaric acid, saccharin, stearic acid, theophylline, tyrosine and urea, more than 140 experiments were performed based on solvents and non-solvents. Experiments were performed on a scale of about 25mg with a stoichiometric range of 1:1 to 1:1.1 xylometacin to co-crystal formation.

A 0.2M stock solution of celecoxib was prepared by dosing celecoxib (about 612.8 mg) into a vial. Acetone (15 mL) was added and the solution was thoroughly mixed before use. A 0.2M stock solution of some co-crystal forms was prepared in ethanol (decanoic acid, p-coumaric acid, palmitic acid, nicotinamide, propyl gallate, L-tryptamine), acetone (citric acid) or water (L-lactic acid, L-alanine, isonicotinamide, urea). All other eutectic forms were weighed directly into vials in solid form.

Precipitation experiment

A 0.2M stock solution of celecoxib (490 μl) was added to the vial and mixed with the selected co-crystal formation (1 eq.) as a solid or stock solution in the selected solvent (about 490 μl). If precipitation occurs, the solids are separated by centrifugation and decanted before analysis by XRPD. If no precipitation occurred, the solution was allowed to stand overnight, then cyclohexanone (400. Mu.L) was added and allowed to stand at 20℃for three days.

Slurry experiments

The xylometacin and the co-crystal former (either as stock solutions or directly weighed) were mixed in a 1:1.05 xylometacin to co-crystal former ratio and stirred at 5 ℃ or 20 ℃ for 2-6 days. The solids were separated by filtration/centrifugation and air dried for about 2-5 minutes before analysis by XRPD.

Planetary mill (PLANETARY MILLING)

A stock solution of 0.2M xylometacin (490. Mu.L) was drawn into an HPLC vial and evaporated to dryness. The eutectic formation (as stock solution or directly weighed) was added to the vial along with three 3mm steel milling balls. The vial was sealed and the contents were milled using a Fritsch planetary mill (Pulverisette 5 classical series). The vial was first ground at 200rpm for 30 minutes followed by a 30 minute resting stage. This sequence was repeated 99 times. The resulting abrasive material was analyzed by XRPD.

Solvent (10 μl) was added to the sample where no unique solid formed. The vials were reground for 40 cycles (30 minutes at 200rpm followed by a 30 minute rest period) using the same procedure as described above. The resulting abrasive material was analyzed by XRPD.

Based on the results of these experiments, the co-crystal formations were further studied and analyzed. Specifically, the eutectic formations L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid were found to be able to form crystalline eutectics with sirolimus.

Example 3 analytical method

In the following examples, the following analytical methods were used.

X-ray powder diffraction (XRPD)

XRPD analysis was performed using PANALYTICAL EMPYREAN diffractometer equipped with Cu X-ray tube and PIXcel 1D-Medipix3 detector system. The samples were analyzed in transmission mode at ambient temperature and held between low density PVC films. Almac default XRPD procedure (range 3-40 degrees 2. Theta., step 0.01313 °, count time 20 seconds, about 5min run time), count time 48 seconds, about 10min run time and count time 98 seconds, about 20min run time) was used. During data collection, the samples were spun at 60 rpm. XRPD patterns were classified and manipulated using HighScore Plus v4.9 software.

Differential Scanning Calorimetry (DSC)

DSC analysis was performed on PERKIN ELMER DSC8500 differential scanning calorimeter. Accurately weighed samples were placed in crimped aluminum pans (i.e., closed but not airtight). Each sample was heated to a maximum of 220 ℃ under nitrogen at a rate of 10 ℃/min. Indium metal was used as a calibration standard. The temperature at the beginning of the transition is reported to the nearest 0.01 degree.

Some DSC analysis was performed on Mettler Toledo DSC 3+STARe system. The temperature and enthalpy of the instrument were calibrated using indium. Nitrogen was used as a shielding gas (20 mL/min). Accurately weighed samples were placed in crimped aluminum pans (i.e., closed but not airtight). Each sample was heated to a maximum of 200 ℃ under nitrogen at a rate of 10 ℃/min.

Thermogravimetric differential thermal analysis (TG/DTA)

Thermogravimetric analysis was performed on Mettler Toledo TGA/DSC1 STARe. Calibration standards are indium and tin. Samples were placed in aluminum sample trays, inserted into TG ovens and accurately weighed. The heat flow signal was stabilized at 30℃for 1 minute at a rate of 10℃per minute under a nitrogen stream and then heated to 300 ℃.

NMR

NMR analyses were performed on a Bruker 500MHz instrument in d6-DMSO or d 4-MeOD. The instrument parameters are listed on the corresponding spectrograms.

Dynamic vapor adsorption (DVS)

Dynamic vapor adsorption (DVS) was performed using HIDEN ANALYTICAL Instruments IGAsorp vapor adsorption balance (Vapour Sorption Balance). About 20-30mg of the sample was placed in a wire mesh vapor adsorption balance, loaded into an IGAsorp vapor adsorption balance, and maintained at 25 ℃ ± 0.1 ℃. Samples were subjected to stepwise analysis from 0% rh to 90% rh in 10% increments, followed by desorption from 90% rh to 0% rh, and a second adsorption cycle from 0% rh to 40% rh. The balance criteria were set to 99.0% step completion, with each increment being 60 minutes minimum and 5 hours maximum. The change in weight during the adsorption cycle is monitored to determine the hygroscopic properties of the sample. The data collection interval is in seconds.

Solubility in FaSSiF

The FaSSIF buffer concentrate (1.04125 g) was weighed into a vial. Water (24 mL) was added and the buffer solution was mixed. FaSSIF powder (about 56 mg) is added to the buffer and mixed thoroughly. The sample was stirred for 10 minutes until the powder dissolved. The samples were equilibrated for 2 hours prior to use.

The HPLC method for determining the solubility of xylometacin in FaSSIF is outlined below.

The retention time of the xylometacin was about 6.056min.

Example 4: preparation of the Co-crystals

(I) Capric acid

An aliquot of the stock solution of celecoxib (490 μl;1mol eq; acetone) was added to the vial and evaporated to dryness under a stream of nitrogen. An aliquot of the decanoic acid stock solution (511. Mu.L; 1.05mol eq.) was added to the vial and evaporated to dryness under a stream of nitrogen. The two solids were mixed and placed in a planetary milling chamber containing 3 milling balls. The material was ground at 200rpm for 30 minutes followed by a 30 minute rest period for a total of 100 cycles. The samples were analyzed by XRPD, which indicates a new solid form designated herein as decanoic acid pattern 1, with XRPD characteristics as shown in table 1 and figure 1 below.

Decanoic acid (265.62 mg, about 1.05mol eq.) and xylometacin (299.76 mg,1mol eq.) were separately filled into vials. Acetone (2 volumes) was added and after less than 1 minute a thick white suspension was observed. To the mixture (white) was added more acetone (3 x 1 volume) and stirred at room temperature overnight. After stirring overnight, MTBE (3 volumes) was added to aid in stirring. Cold MTBE (3 volumes) was added to the mixture to aid flowability. The solid was isolated by vacuum filtration and dried for about 2-3 minutes. The liquid was placed back into the vial and the solid was washed with the liquid. The vial and solids were further washed with cold MTBE (2 volumes). The solid was dried on the sinter for about 15 minutes and then returned to the pre-weighed vial. A wet weight of about 0.44g was recorded. The solids were dried in a vacuum oven for 2-3 days, then about 0.44g dry weight was recorded, recovery% = about 80%. XRPD analysis showed that this material consisted of a crystalline form designated herein as decanoic acid pattern 2, with XRPD characteristics as shown in table 2 and figure 2 below.

Table 1: XRPD peak listing of decanoic acid pattern 1

Further analysis of decanoic acid pattern 1 revealed the following results.

● Samples were analyzed by ¹ H NMR spectroscopy and the spectra were consistent with molecular structure. The stoichiometry was confirmed to be 1:about 1.2 (siloneo: decanoic acid).

TABLE 2 XRPD peak listing for decanoic acid pattern 2

Further analysis of decanoic acid pattern 2 revealed the following results:

● The 1H-NMR spectrum was in line with the molecular structure and negligible residual solvent was observed. The stoichiometry was determined to be about 1:1 (siloneo: decanoic acid).

● DSC analysis showed an endothermic peak with an onset temperature of about 90℃consistent with TG/DTA data.

● DVS analysis showed that the total weight change observed between ambient (i.e. 40% rh) and 80% rh was about 0.02% w/w. XRPD analysis of the material after DVS analysis showed no change in its physical form.

● The co-crystals were strained at 40 ℃/75% rh and 20 ℃/60% rh for 7 days. No change in form was observed by XRPD.

● HPLC solubility was estimated in FaSSIF at about 37 ℃. The material had a solubility of about 3.18mg/mL after 15 minutes and about 2.99mg/mL after 22 hours.

(Ii) Ethyl maltol

Celopirox (about 100mg,1mol equivalent) and ethyl maltol (44.344 mg; about 1.01mol equivalent) are filled into vials. Acetone (300 μl) was added and the suspension stirred at 20deg.C. Most of the samples (bulk samples) were separated by centrifugation and decantation. Acetone (100 uL) was added to the separated solid, which was slurried to try to remove excess ethyl maltol. The solids were separated and the material was dried under a nitrogen stream overnight. The product was analyzed by XRPD and confirmed to consist of the new crystalline form designated herein as ethyl maltol pattern 1, with XRPD characteristics as shown in table 3 and figure 3 below.

TABLE 3 XRPD peak listing for ethyl maltol pattern 1

Further analysis of ethyl maltol pattern 1 gave the following results.

● The stoichiometry was determined to be 1:about 0.8 by ¹ H-NMR spectroscopy (xylogen: ethyl maltol).

● DSC analysis (FIG. 68) showed two endothermic peaks with onset temperatures of about 86℃and about 131℃respectively, consistent with TG/DTA data.

● The material samples were strain treated at 40 ℃/75% rh for 6 days to determine their stability. No change in physical form was observed.

(Iii) L-lactic acid

L-lactic acid (23.65 mg, about 1.05mol equivalent) and xylometacin (49.36 mg,1mol equivalent) were filled into vials. Acetone (2 volumes) was added and some of the mixture started to dissolve. Additional acetone (2 x1 volumes) was added. After about 10 minutes, the mixture began to precipitate. After 30 minutes, a thick suspension was observed, which was not flowable. MTBE (2 x1 volume) was added to aid in stirring. The sample was stirred at room temperature overnight. The isolated product was used as seed in subsequent experiments.

L-lactic acid (140.31 mg, about 1.05mol eq.) and xylometacin (301.26 mg,1mol eq.) were filled into vials. Acetone (2 volumes) was added and precipitation was immediately observed. To the mixture (off-white in color) was added additional acetone (1 volume) and stirred at room temperature overnight. After stirring overnight, MTBE (4 volumes) was added to aid stirring because the suspension was very thick. The product of the above experiment was inoculated into the suspension and stirred for 3 days. Cold MTBE (11 volumes total) was added to the mixture to aid in flow. The solid was isolated by vacuum filtration and dried for about 10-15 minutes. The vials were washed with a portion of MTBE (11 volumes) to increase recovery of solids. The solid was dried on the sinter for about 15 minutes and then recovered to a pre-weighed vial. A wet weight of about 0.35g was recorded. The solids were dried overnight in a vacuum oven and then dry weight was recorded to be about 0.35g with% recovery =about 81%. XRPD analysis showed that the product consisted of a crystalline form designated herein as L-lactic acid pattern 1, with XRPD characteristics as shown in table 4 and fig. 4 below.

Table 4:L XRPD peak listing of lactic acid pattern 1

Further analysis of L-lactic acid pattern 1 gave the following results.

● Samples were analyzed by ¹ H NMR spectroscopy and the spectra were consistent with molecular structure, with negligible residual solvent observed. The stoichiometry was determined to be about 1:1 (xylometacin: L-lactic acid).

● Samples were analyzed by TG/DTA. Weight loss is not observed until the temperature exceeds 200 ℃, which may be related to decomposition. An endothermic peak with an onset temperature of about 151℃was observed, consistent with DSC analysis.

● DVS analysis showed that the total weight increase observed between ambient (i.e. 40% rh) and 80% rh was about 0.03% w/w. XRPD analysis was performed on samples after DVS and no change in form was observed.

● The eutectic was strained at 40 ℃/75% rh and 20 ℃/60% rh for 7 days. No change in form was observed.

● Solubility in FaSSIF was assessed by adding aliquots at about 20 ℃. The material has a solubility of 90-107 mg/mL. Because of the high solubility of the crystalline form, no HPLC solubility determination was performed on this sample.

(Iv) Oleic acid

Stock solutions of xylometacin (490. Mu.L; 1mol eq; acetone) and oleic acid (about 36.4. Mu.L; 1.05mol eq) were added to the vials. The mixture was stirred at 20 ℃ for 2 days and kept as a solution. Heptane (500 μl) was added to aid crystallization and the solution was stirred at 5 ℃. No solid precipitation occurred after 8 days. The solution was evaporated to half volume under nitrogen and a suspension formed. The suspension was stirred at 5 ℃ for another day and then separated by centrifugation and decantation. The recovered solid was used as seed in the following experiments.

Cycloxin (about 100mg,1mol equivalent) and oleic acid (182. Mu.L; 1.05mol equivalent) were filled into vials containing acetone (100. Mu.L). The mixture was stirred at 5 ℃. After 1 day, heptane (100 μl) was added and the sample was stirred at 5 ℃. After 3 days, the eutectic obtained in the above experiment was inoculated into a sample and stirred at 5 ℃ for another 4 days, and then separated by centrifugation and decantation. XRPD analysis confirmed that this material consisted of a crystalline form designated herein as oleic acid pattern 1, the XRPD characteristics of which are shown in table 5 below and in fig. 5.

Table 5: XRPD peak listing of oleic acid pattern 1

Further analysis of oleic acid pattern 1 revealed the following results.

● Samples were analyzed by ¹ H NMR spectroscopy and the spectra were consistent with molecular structure. The stoichiometry was confirmed to be 1:about 1.1 (xyloside: oleic acid).

● DSC analysis showed an endothermic peak with an onset temperature of about 56℃and was consistent with TG/DTA data.

(V) Palmitic acid

Cycloxin (about 60mg,1mol equivalent) and palmitic acid (75.976 mg;1.01mol equivalent) were charged into a vial containing THF (20. Mu.L) and four grinding balls. The material was subjected to a planetary milling procedure at 400rpm for 30 minutes followed by a 30 minute rest period. This sequence was repeated 19 times. The sample was dried under a nitrogen stream overnight. XRPD analysis of the product revealed a new crystalline form designated herein as palmitic acid pattern 1, the XRPD characteristics of which are shown in table 6 and figure 6 below.

TABLE 6 XRPD peak listing for palmitic acid pattern 1

Further analysis of palmitic acid pattern 1 gave the following results.

● Samples were analyzed by ¹ H NMR spectroscopy and the spectra were consistent with molecular structure. No solvent was detected in the sample. The stoichiometry was estimated to be 1:about 1 xylosidac to palmitic acid.

● DSC analysis showed an endothermic peak with an onset temperature of about 82℃consistent with TG/DTA data.

(Vi) P-coumaric acid

Aliquots of the stock solution of sirolimus (490. Mu.L; 1mol eq; acetone) and the stock solution of p-coumaric acid (518. Mu.L; 1.05mol eq; ethanol) were added to the vials and the solution was stirred for 2 days at 20 ℃. After 2 days, the sample remained a solution. Heptane (500 μl) was added to aid crystallization and the solution was stirred at 5 ℃ for 14 days. The experiment was kept as a solution and evaporated to half volume under nitrogen, which resulted in an oil/solution. MTBE (200. Mu.L) was added and the sample was stirred at 5℃for an additional 3 days, then separated by centrifugation and decantation. The sample was analyzed by XRPD and shown to consist of the new solid form designated herein as p-coumaric acid pattern 1, the XRPD characteristics of which are shown in table 7 and fig. 7 below.

TABLE 7 XRPD peaks for coumaric acid pattern 1

Further analysis of coumaric acid pattern 1 revealed the following results.

Samples were analyzed by ¹ H NMR spectroscopy and the spectra were consistent with molecular structure. The stoichiometry was confirmed to be 1:about 1 (xylol: p-coumaric acid).

(Vii) Propyl gallate

Celloxin (303.5 mg,1mol equivalent) and propyl gallate (327.5 mg, about 1.05mol equivalent) were filled into vials. Acetone (3 volumes) was added and some of the solids dissolved. Precipitation began to occur after less than 1 minute. To the mixture (off-white) was added additional acetone (2 volumes) and stirred at room temperature overnight. Cold MTBE (10 volumes total) was added to the mixture to aid in flow. The majority of the sample was isolated by vacuum filtration and dried for about 10-15 minutes. The vials were washed with a portion of MTBE (10 volumes) to increase recovery of solids. The mixture was filtered thoroughly and the solid was dried on the sinter for about 15 minutes and then recovered into a pre-weighed vial. A wet weight of about 0.38g was recorded. The solid was dried in a vacuum oven overnight. About 0.39g dry weight was recorded. Recovery% = about 63%. XRPD analysis of the product showed that the sample consisted of a crystalline form designated herein as propyl gallate pattern 1, the XRPD characteristics of which are shown in table 8 below and fig. 8.

TABLE 8 XRPD peaks for propyl gallate pattern 1

Further analysis of propyl gallate pattern 1 gave the following results.

● The stoichiometry was determined to be 1:about 0.6 (xyloside: propyl gallate) by ¹ H-NMR spectroscopy.

● Samples were analyzed by TG/DTA and a weight loss of about 1.13% was observed between about 40-188 ℃ corresponding to about 0.08mol equivalent of acetone. Weight loss was observed at temperatures exceeding 200 ℃, and may be associated with decomposition. An endothermic peak was observed with an onset temperature of about 155 ℃, consistent with DSC data.

● DVS analysis showed that the total weight increase observed between ambient (i.e. 40% rh) and 80% rh was about 0.66% w/w. XRPD analysis was performed on samples following DVS and showed no change in form was observed.

● The propyl xyloside co-crystals were treated for 8 days at 40 ℃/75% rh and 20 ℃/60% rh strain. No change in form was observed.

● HPLC solubility was estimated in FaSSIF at about 37 ℃. The material had a solubility of about 3.39mg/mL after 15 minutes and about 2.65mg/mL after 22 hours.

(Viii) Stearic acid

A stock solution of xylometacin (490. Mu.L; 1mol eq; acetone) and stearic acid (30.2 mg;1.05mol eq) were placed in a vial. The suspension was stirred at 20 ℃ for 2 days, then the solids were separated by centrifugation and decantation. XRPD analysis of the solid indicated that the material consisted of a new solid form designated herein as stearic acid pattern 1, the XRPD characteristics of which are shown in table 9 below and in fig. 9.

Cycloxin (about 60mg,1mol equivalent) and stearic acid (88.383 mg; about 1.05mol equivalent) were separately filled into vials containing acetone (600. Mu.L). The sample was stirred at 20 ℃. The sample was inoculated with stearic acid pattern 1 and stirred at 20 ℃ for another 5 days, then separated by centrifugation and decantation. Most of the samples were dried overnight under a nitrogen flow. XRPD analysis confirmed that this material consisted of a new solid form designated stearic acid pattern 2, with XRPD characteristics as shown in table 10 and figure 10 below.

TABLE 9 XRPD peak listing for stearic acid pattern 1

Further analysis of stearic acid pattern 1 gave the following results.

● The stoichiometry was determined to be 1:about 1.6 (siloxin: stearic acid) by ¹ H-NMR spectroscopy.

● XRPD foil was re-analyzed after 5 days and no change in form was observed.

TABLE 10 XRPD peak listing for stearic acid pattern 2

Further analysis of stearic acid pattern 2 gave the following results.

● The stoichiometry was determined to be 1:about 1 (siloxin: stearic acid) by ¹ H-NMR spectroscopy.

● Samples were analyzed by TG/DTA and no weight loss was observed. An endothermic peak was observed with an onset temperature of about 87 ℃.

● The material samples were treated at 40 ℃/75% rh strain for 6 days to determine their stability. After this time the material was analyzed by XRPD. No change in physical form was observed.

Summary

It has been demonstrated that xylometacin forms co-crystals with these co-crystal formers. The co-crystals have properties that make them useful in the pharmaceutical field, such as low hygroscopicity and high solubility. In particular, the crystalline form formed with L-lactic acid has extremely high solubility and is not hygroscopic.

Aspects of the invention

In one embodiment, the present invention provides the following aspects:

1. A co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is an acid.

2. The co-crystal according to aspect 1, wherein the co-crystal former is an organic acid.

3. The co-crystal according to aspect 1 or aspect 2, wherein the co-crystal former is a compound comprising one or more of a carboxylic acid moiety, a sulfonic acid moiety, a squaric acid moiety, a sulfonamide moiety, a carboxysulfonimide moiety, and a sulfonimide moiety.

4. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former is a compound comprising a carboxylic acid moiety.

5. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _a of less than or equal to 7.0.

6. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _a of less than or equal to 6.0.

7. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _a greater than or equal to 1.5.

8. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _a greater than or equal to 2.5.

9. The co-crystal according to any one of the preceding aspects, wherein the molar ratio of xylometacin to co-crystal former is from 1:0.25 to 1:4.

10. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:0.5.

11. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:1.

12. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:2.

13. The co-crystal according to any one of the preceding aspects, wherein the co-crystal is in the form of a solvate or hydrate.

14. The co-crystal according to aspect 13, wherein the solvate or hydrate is stoichiometric or non-stoichiometric.

15. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former is selected from the group consisting of: n-acetylglycine, alginic acid, 2- (4-hydroxybenzoyl) benzoic acid, gluconic acid, glucoheptonic acid, 2-naphthoic acid, orotic acid, succinic acid, L-ascorbic acid, L-tartaric acid, cinnamic acid, ferulic acid, fumaric acid, gentisic acid, gallic acid, citric acid, p-coumaric acid, L-lactic acid, disodium EDTA, nicotinic acid, 1-hydroxy-2-naphthoic acid, 2-ketoglutaric acid, 4-hydroxyphenylacetic acid, L-malic acid, maleic acid, oxalic acid and saccharin.

16. The co-crystal according to aspect 15, wherein the co-crystal former is selected from the group consisting of: citric acid, fumaric acid, succinic acid, gluconic acid, L-tartaric acid, L-ascorbic acid, L-lactic acid, saccharin and nicotinic acid.

17. A pharmaceutical composition comprising:

(a) A co-crystal as defined in any one of the preceding aspects; and

(B) Pharmaceutically acceptable excipients or diluents.

18. A method of producing a co-crystal as defined in any one of aspects 1 to 16, the method comprising mixing xylometacin and a co-crystal former, the co-crystal former being an acid.

19. A method of treating or preventing a disease or condition selected from psychological, neurological and central nervous system disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a co-crystal as defined in any one of aspects 1 to 16.

20. The method of aspect 19, wherein the disease or disorder is selected from the group consisting of depression, anxiety, death anxiety, mental retardation, accommodation disorder, despair, suicidal ideation, and a desire to accelerate death.

21. The method of aspect 19, wherein the disease or disorder is selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders.

22. A co-crystal as defined in any one of aspects 1 to 16 for use in the treatment or prophylaxis of a disease or condition as defined in any one of aspects 19 to 21.

23. Use of a co-crystal as defined in any one of aspects 1 to 16 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition as defined in any one of aspects 19 to 21.

24. A kit, comprising:

A co-crystal as defined in any one of aspects 1 to 16 or a pharmaceutical composition as defined in aspect 17; and

Instructions for using the co-crystal or pharmaceutical composition in a method of treating or preventing a disease or disorder as defined in any one of aspects 19 to 21.

In a second embodiment, the present invention provides the following aspects:

1. a co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is a base.

2. The co-crystal according to aspect 1, wherein the co-crystal former is an organic base.

3. The co-crystal according to aspect 1 or aspect 2, wherein the co-crystal former is a compound comprising one or more of an amine moiety, a pyridine moiety, a piperazine moiety, an amide moiety, a xanthine moiety, and a morpholine moiety.

4. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former is a compound comprising an amine moiety.

5. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _b of less than or equal to 11.0.

6. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _b of less than or equal to 9.0.

7. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _b greater than or equal to 3.5.

8. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former has a pK _b greater than or equal to 4.5.

9. The co-crystal according to any one of the preceding aspects, wherein the molar ratio of xylometacin to co-crystal former is from 1:0.25 to 1:4.

10. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:0.5.

11. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:1.

12. The co-crystal according to aspect 9, wherein the molar ratio of xylometacin to co-crystal former is about 1:2.

13. The co-crystal according to any one of the preceding aspects, wherein the co-crystal is in the form of a solvate or hydrate.

14. The co-crystal according to aspect 13, wherein the solvate or hydrate is stoichiometric or non-stoichiometric.

15. The co-crystal according to any one of the preceding aspects, wherein the co-crystal former is selected from the group consisting of: 4, 4-bipyridine, pyridoxine, diadenox, 4- (2-hydroxyethyl) -morpholine, piperazine, theophylline, nicotinamide, isonicotinamide, tromethamine, tert-butylamine, and diethylamine.

16. The co-crystal according to aspect 15, wherein the co-crystal former is selected from the group consisting of: theophylline, nicotinamide, isonicotinamide and tromethamine.

17. A pharmaceutical composition comprising:

(a) A co-crystal as defined in any one of the preceding aspects; and

(B) Pharmaceutically acceptable excipients or diluents.

18. A method of producing a co-crystal as defined in any one of aspects 1 to 16, the method comprising mixing xylometacin and a co-crystal former, the co-crystal former being a base.

19. A method of treating or preventing a disease or condition selected from psychological, neurological and central nervous system disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a co-crystal as defined in any one of aspects 1 to 16.

20. The method of aspect 19, wherein the disease or disorder is selected from the group consisting of depression, anxiety, death anxiety, mental retardation, despair, suicidal ideation, and a desire to accelerate death.

21. The method of aspect 19, wherein the disease or disorder is selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders.

22. A co-crystal as defined in any one of aspects 1 to 16 for use in the treatment or prophylaxis of a disease or condition as defined in any one of aspects 19 to 21.

23. Use of a co-crystal as defined in any one of aspects 1 to 16 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition as defined in any one of aspects 19 to 21.

24. A kit, comprising:

A co-crystal as defined in any one of aspects 1 to 16 or a pharmaceutical composition as defined in aspect 17; and

Instructions for using the co-crystal or pharmaceutical composition in a method of treating or preventing a disease or disorder as defined in any one of aspects 19 to 21.

In a third embodiment, the present invention provides the following aspects:

1. a co-crystal comprising xylometacin and a co-crystal former, wherein the co-crystal former is a neutral compound that is:

(i) An ampholytic compound;

(ii) A zwitterionic compound;

(iii) A compound containing neither an acidic moiety nor a basic moiety; or (b)

(Iv) An inorganic salt compound.

2. The co-crystal according to aspect 1, wherein the co-crystal former is an ampholytic compound.

3. The co-crystal according to aspect 2, wherein the co-crystal former is an amino acid or an amino acid derivative.

4. The co-crystal according to aspect 3, wherein the co-crystal former is selected from the group consisting of: l-lysine, L-histidine, L-tyrosine, L-pyroglutamic acid, DL-cysteine and L-glutamic acid.

5. The co-crystal according to aspect 4, wherein the co-crystal former is selected from the group consisting of: l-pyroglutamic acid, DL-cysteine and L-glutamic acid.

6. The co-crystal according to aspect 1, wherein the co-crystal former is a compound that contains neither an acidic moiety nor a basic moiety.

7. The co-crystal according to aspect 6, wherein the co-crystal former is a compound comprising an ester moiety.

8. The co-crystal according to aspect 6, wherein the co-crystal former is a compound comprising an ether moiety.

9. The co-crystal according to aspect 6, wherein the co-crystal former is a compound comprising an alcohol moiety.

10. The co-crystal according to aspect 6, wherein the co-crystal former is selected from the group consisting of: ethyl maltol, meso-erythritol, D-mannitol, D-sorbitol, D-xylitol, inosine, and L-ascorbic acid 6-hexadecanoate.

11. The co-crystal according to aspect 6, wherein the co-crystal former is a compound comprising a phenol moiety.

12. The co-crystal according to aspect 11, wherein the co-crystal former is selected from the group consisting of: 2, 6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4-methoxyphenol, vanillin, ethyl vanillin, C _1-4 p-hydroxybenzoate, propyl gallate.

13. The co-crystal according to aspect 12, wherein the co-crystal former is selected from the group consisting of: propyl gallate, 2, 6-di-tert-butyl-4-methylphenol and 2-tert-butyl-4-methoxyphenol.

14. The co-crystal according to aspect 6, wherein the co-crystal former is a compound comprising a carboxamide moiety.

15. The co-crystal according to aspect 14, wherein the co-crystal former is urea.

16. The co-crystal according to aspect 1, wherein the co-crystal former is an inorganic salt.

17. The co-crystal according to aspect 16, wherein the co-crystal former is selected from the group consisting of: sodium dihydrogen phosphate, sodium hydrogen sulfite, acesulfame potassium and sodium formaldehyde sulfoxylate.

18. The co-crystal according to aspect 17, wherein the co-crystal former is selected from the group consisting of: sodium bisulfite, acesulfame potassium and sodium formaldehyde sulfoxylate.

19. The co-crystal according to any one of the preceding aspects, wherein the molar ratio of xylometacin to co-crystal former is from 1:0.25 to 1:4.

20. The co-crystal according to aspect 19, wherein the molar ratio of xylometacin to co-crystal former is about 1:0.5.

21. The co-crystal according to aspect 19, wherein the molar ratio of xylometacin to co-crystal former is about 1:1.

22. The co-crystal according to aspect 19, wherein the molar ratio of xylometacin to co-crystal former is about 1:2.

23. The co-crystal according to any one of the preceding aspects, wherein the co-crystal is in the form of a solvate or hydrate.

24. The co-crystal according to aspect 23, wherein the solvate or hydrate is stoichiometric or non-stoichiometric.

25. A pharmaceutical composition comprising:

(a) A co-crystal as defined in any one of the preceding aspects; and

(B) Pharmaceutically acceptable excipients or diluents.

26. A method of producing a co-crystal as defined in any one of aspects 1 to 22, the method comprising mixing xylometacin and a co-crystal former, the co-crystal former being as defined in aspect 1.

27. A method of treating or preventing a disease or condition selected from psychological, neurological and central nervous system disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a co-crystal as defined in any one of aspects 1 to 24.

28. The method of aspect 27, wherein the disease or disorder is selected from the group consisting of depression, anxiety, death anxiety, mental retardation, despair, suicidal ideation, and a desire to accelerate death.

29. The method of aspect 27, wherein the disease or disorder is selected from the group consisting of cocaine-related disorders, opioid-related disorders, and agonist-related disorders.

30. A co-crystal as defined in any one of aspects 1 to 24 for use in the treatment or prophylaxis of a disease or condition as defined in any one of aspects 27 to 29.

31. Use of a co-crystal as defined in any one of aspects 1 to 24 in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition as defined in any one of aspects 27 to 29.

32. A kit, comprising:

a co-crystal as defined in any one of aspects 1 to 24 or a pharmaceutical composition as defined in aspect 25; and

Instructions for using the co-crystal or pharmaceutical composition in a method of treating or preventing a disease or disorder as defined in any one of aspects 27 to 29.

Claims (32)

1. A co-crystal or salt comprising siloxane and a co-crystal former, wherein the co-crystal former is selected from the group consisting of L-lactic acid, capric acid, ethyl maltol, oleic acid, palmitic acid, p-coumaric acid, propyl gallate and stearic acid. 2. A co-crystal or salt according to claim 1, wherein the co-crystal former is L-lactic acid. 3. The co-crystal or salt according to claim 2, wherein the molar ratio of psilocin:L-lactic acid is about 1:1. 4. A co-crystal or salt according to claim 2 or claim 3, wherein the co-crystal or salt is in the form of crystalline L-lactic acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 13.4°, 16.8° and 19.5°±0.2° 2θ. 5. The co-crystal or salt according to claim 4, wherein the x-ray powder diffraction pattern further comprises peaks at 16.7°, 23.0° and 24.3° ± 0.2° 2θ. 6. A co-crystal or salt according to claim 4 or claim 5, wherein the x-ray powder diffraction pattern comprises seven or more peaks selected from 13.4°, 14.9°, 16.7°, 16.8°, 19.5°, 20.6°, 23.0°, 24.3° and 26.3°±0.2° 2θ. 7. The co-crystal or salt according to claim 1, wherein the co-crystal former is decanoic acid. 8. The co-crystal or salt according to claim 7, wherein the molar ratio of psilocin:decanoic acid is about 1:1.2. 9. The co-crystal or salt according to claim 7, wherein the molar ratio of psilocin:decanoic acid is about 1:1. 10. A co-crystal or salt according to claim 7 or claim 8, wherein the co-crystal or salt is in the form of crystalline decanoic acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 5.9°, 14.2° and 15.9° ± 0.2° 2θ. 11. The co-crystal or salt according to claim 10, wherein the x-ray powder diffraction pattern further comprises peaks at 16.7°, 24.0° and 24.7°±0.2° 2θ. 12. A co-crystal or salt according to claim 10 or claim 11, wherein the x-ray powder diffraction pattern comprises seven or more peaks selected from 5.9°, 14.2°, 15.9°, 16.7°, 18.3°, 20.7°, 22.6°, 24.0° and 24.7°±0.2° 2θ. 13. A co-crystal or salt according to claim 7 or claim 9, wherein the co-crystal or salt is in the form of crystalline decanoic acid pattern 2 having an x-ray powder diffraction pattern comprising peaks at 6.4°, 16.9° and 25.2° ± 0.2° 2θ. 14. The co-crystal or salt according to claim 13, wherein the x-ray powder diffraction pattern further comprises peaks at 22.3°, 23.6° and 23.7° ± 0.2° 2θ. 15. A co-crystal or salt according to claim 13 or claim 14, wherein the x-ray powder diffraction pattern comprises seven or more peaks selected from 6.4°, 16.9°, 17.8°, 19.2°, 19.6°, 22.3°, 23.6°, 23.7° and 25.2° ± 0.2° 2θ. 16. A co-crystal or salt according to claim 1, wherein the co-crystal former is propyl gallate. 17. The co-crystal or salt according to claim 16, wherein the molar ratio of psilocin:propyl gallate is about 1:0.6. 18. A co-crystal or salt according to claim 16 or claim 17, wherein the co-crystal or salt is in the form of crystalline propyl gallate pattern 1 having an x-ray powder diffraction pattern comprising peaks at 12.6°, 14.7° and 22.6° ± 0.2° 2θ. 19. The co-crystal or salt according to claim 18, wherein the x-ray powder diffraction pattern further comprises peaks at 8.8°, 15.8° and 18.6° ± 0.2° 2θ. 20. A co-crystal or salt according to claim 18 or claim 19, wherein the x-ray powder diffraction pattern comprises seven or more peaks selected from 8.8°, 12.6°, 14.3°, 14.7°, 15.8°, 18.6°, 19.2°, 22.0° and 22.6°±0.2° 2θ. 21. The co-crystal or salt according to claim 1, wherein the co-crystal former is ethyl maltol and the co-crystal or salt is in the form of crystalline ethyl maltol pattern 1 having an x-ray powder diffraction pattern comprising peaks at 5.0°, 15.1° and 18.0° ± 0.2° 2θ. 22. The co-crystal or salt according to claim 1, wherein the co-crystal former is oleic acid and the co-crystal or salt is in the form of crystalline oleic acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 4.6°, 15.9° and 19.4° ± 0.2° 2θ. 23. The co-crystal or salt according to claim 1, wherein the co-crystal former is palmitic acid and the co-crystal or salt is in the form of crystalline palmitic acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 4.7°, 23.0° and 23.8° ± 0.2° 2θ. 24. The co-crystal or salt according to claim 1, wherein the co-crystal former is p-coumaric acid and the co-crystal or salt is in the form of crystalline p-coumaric acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 5.4°, 15.5° and 20.5° ± 0.2° 2θ. 25. A co-crystal or salt according to claim 1, wherein the co-crystal former is stearic acid and (i) the co-crystal or salt is in the form of crystalline stearic acid pattern 1 having an x-ray powder diffraction pattern comprising peaks at 21.4°, 21.6° and 23.5°±0.2° 2θ, or (ii) the co-crystal or salt is in the form of crystalline stearic acid pattern 2 having an x-ray powder diffraction pattern comprising peaks at 4.5°, 14.3° and 24.0°±0.2° 2θ. 26. A pharmaceutical composition comprising: (a) a co-crystal or salt as defined in any one of the preceding claims; and (b) a pharmaceutically acceptable excipient or diluent. 27. A method of treating or preventing a disease or condition selected from psychological, neurological and central nervous system disorders in a patient, the method comprising administering to the patient a therapeutically effective amount of a co-crystal or salt as defined in any one of claims 1 to 25 or a composition as defined in claim 26. 28. The method of claim 27, wherein the disease or condition is selected from depression, anxiety, death anxiety, low spirits, adjustment disorder, hopelessness, suicidal ideation, and a desire to hasten death. 29. The method of claim 27, wherein the disease or condition is selected from the group consisting of a cocaine-related disorder, an opioid-related disorder, and a stimulant-related disorder. 30. A co-crystal or salt as defined in any one of claims 1 to 25 or a composition as defined in claim 26 for use in treating or preventing a disease or condition as defined in any one of claims 27 to 29. 31. Use of a co-crystal or salt as defined in any one of claims 1 to 25 or a composition as defined in claim 26 for the preparation of a medicament for the treatment or prevention of a disease or condition as defined in any one of claims 27 to 29. 32. A kit comprising: A co-crystal or salt as defined in any one of claims 1 to 25 or a pharmaceutical composition as defined in claim 26; and Instructions for use of the co-crystal, salt or pharmaceutical composition in a method of treating or preventing a disease or condition as defined in any one of claims 27 to 29.