Co-crystals of pterostilbene and compositions containing them

Abstract

The present disclosure relates to a cocrystal of pterostilbene with a coformer capable of forming hydrogen bonding interactions, a process for preparing the same, and its use as a pharmaceutical or dietary supplement. The disclosure also relates to compositions comprising the cocrystal.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of European Patent Application No. 19383178.1, filed on December 20, 2019, and European Patent Application No. 20382170.7, filed on March 9, 2020.

[0002] The present disclosure relates to co - crystals of pterostilbene, a process for its preparation, and its use as a pharmaceutical or dietary supplement. The invention also relates to compositions containing them.

Background Art

[0003] Pterostilbene (trans - 3,5 - dimethoxy - 4 - hydroxystilbene) is a natural dietary compound and a major antioxidant constituent of blueberries. It has increased bioavailability compared to other stilbene compounds, improving its dietary benefits and potentially contributing to beneficial clinical effects.

[0004] The structure of pterostilbene corresponds to formula (I):

Chemical formula

[0005] Multiple studies have demonstrated the antioxidant activity of pterostilbene and its clinical potential in the prevention and treatment of various medical conditions, including neurological, cardiovascular, metabolic, and hematological disorders. In particular, the antioxidant activity of pterostilbene is associated with anti - cancer, regulation of neurological diseases, anti - inflammatory, attenuation of vascular diseases, and improvement of diabetes and other age - related diseases.

[0006] Pterostilbene is supplied as a crystalline solid with a melting point of 89 - 92°C. It is poorly soluble in water.

[0007] A basic requirement for sufficient bioavailability is that the active ingredient can be properly dissolved in the gastrointestinal tract. The low water solubility of pterostilbene causes some problems regarding its bioavailability.

[0008] Different solid forms of an active ingredient can have different characteristics and are known to provide certain advantages, for example, with respect to solubility or bioavailability. Thus, the discovery of new solid forms enables the improvement of the pharmacokinetic properties of the active ingredient and, as a result, the characteristics of the pharmaceutical formulation containing the active ingredient, since some forms are more suitable for one type of formulation and other forms are more appropriate for other different formulations.

[0009] In particular, in recent years, co-crystal formation has emerged as a viable strategy for improving the pharmacokinetic data of active ingredients. By co-crystallizing an active ingredient or a salt of the active ingredient with a coformer (the second component of the co-crystal), a new solid form of the active ingredient with unique properties is generated as compared to the existing solid forms of the active ingredient or its salts. Such different properties can provide principles for improving the formulation, for example, by promoting better processing or handling properties, changing the dissolution profile in a favorable direction, or improving stability and shelf life. However, co-crystal formation is not predictable and is not always possible in practice. Furthermore, there is no way to predict the properties of a specific co-crystal of a compound until the compound is formed. Finding the appropriate coformer and the correct conditions to obtain a specific co-crystal can require significant time, effort, and resources.

[0010] As is known in the art, there is still a need to find new, more soluble solid forms of pterostilbene in order to improve the pharmaceutical properties of pharmaceutical formulations containing pterostilbene, particularly with respect to bioavailability. Summary of the Invention Problems to be Solved by the Invention

[0011] The inventors have found that pterostilbene can form co-crystals with co-formers that can form hydrogen bond interactions as defined hereinafter in this specification. Since these co-crystals have better water solubility and a higher dissolution rate in aqueous media, which makes the co-crystals more bioavailable, by providing the above-mentioned co-crystals of pterostilbene, a new tool for overcoming the problems related to the water solubility of pterostilbene is obtained. This property makes the co-crystals more suitable for preparing pharmaceutical compositions or dietary compositions containing pterostilbene.

[0012] In particular, the formation of co-crystals with co-formers that can form hydrogen bond interactions cannot be predicted.

[0013] Therefore, the provision of an improved crystal form of pterostilbene in the co-crystal form with a co-former that can form hydrogen bond interactions as defined hereinafter in this specification is considered a contribution to the art.

Means for Solving the Problems

[0014] Therefore, a first aspect of the present disclosure relates to the provision of a co-crystal of pterostilbene and a co-former that can form hydrogen bond interactions.

[0015] A second aspect of the present disclosure relates to a composition comprising an effective amount of a co-crystal of pterostilbene and a co-former that can form hydrogen bond interactions as defined both above and below in this specification, together with one or more suitable acceptable excipients or carriers.

[0016] Finally, a third aspect of the present disclosure relates to a co-crystal of pterostilbene and a co-former that can form hydrogen bond interactions as defined above and below in this specification for use as a pharmaceutical.

Brief Description of the Drawings

[0017]

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[0018] All terms used in this specification in the context of this application shall be understood to have their ordinary meaning as known in the relevant art, unless otherwise specified. Other more specific definitions of particular terms used in this application are as set forth below and are intended to apply uniformly throughout the specification and the claims, unless an explicitly recited definition provides a broader definition.

[0019] For the purposes of this disclosure, a given range such as of temperature and time should be considered approximate unless otherwise specified.

[0020] For the purposes of this disclosure, the term "cocrystal" as used herein refers to a crystalline entity with at least two different components that form a unit cell and interact by intermolecular interactions at room temperature (20 - 25 °C). Thus, in a cocrystal, one component crystallizes together with one or more neutral components.

[0021] A cocrystal may contain one or more solvent molecules in the crystal lattice. Thus, the terms "cocrystal hydrate" or "hydrated cocrystal" have the same meaning and are used interchangeably. These refer to cocrystals that contain water as a solvent in the crystal lattice. Similarly, cocrystals can be formed that contain other solvents such as dichloromethane.

[0022] The expression "cocrystal obtained by" is used herein to define each particular cocrystal of the disclosure in terms of the process for obtaining it and refers to the product obtained by any of the corresponding processes disclosed herein. For the purposes of this disclosure, the expressions "obtainable", "obtained", and similar equivalent expressions are used interchangeably, and in each case, the expression "obtainable" encompasses the expression "obtained".

[0023] The term "coformer capable of forming hydrogen bond interactions" refers to a compound having a hydrogen atom bonded to a negative atom (e.g., nitrogen, oxygen, or sulfur), or a compound having a basic atom (such as nitrogen or oxygen) and having the ability to establish strong intermolecular hydrogen bonds. Examples of coformers capable of forming hydrogen bond interactions include phosphoric acid, carboxylic acid, alcohol, imidazole, thioamide, sulfinamide, pyrrole, urea, amide, sulfonamide, carbamate, amine, ketone, and sulfoxide.

[0024] When characteristic peak values of an X-ray diffractogram are given, these are said to be "approximate" values. This value is the value shown in the corresponding list or table, and it should be understood that it is ±0.3 degrees two-theta measured with an X-ray diffractometer using Cu-K α radiation, λ = 1.5418 Å.

[0025] When the ratio of the components of the cocrystal of the present disclosure is specified, it refers to the molar ratio of the components forming the cocrystal. The term "molar ratio" is used to represent the stoichiometric amount of each of the components of the cocrystal in moles. The molar ratio 1 can be determined by 1H NMR (proton nuclear magnetic resonance), thermogravimetric analysis (TGA), or single crystal X-ray diffraction (SCXRD). When the value of the molar ratio is given according to TGA or 1 1H NMR, these are said to be "approximate" values due to measurement error. When the molar ratio is mentioned, it should be understood that it corresponds to molar ratio ±0.2%. The variability of the results is due to the inherent sensitivity of the TGA or 1 1H NMR instrument.

[0026] The term "room temperature" refers to the temperature of an environment without heating or cooling, and is generally 20°C to 25°C.

[0027] The term "overnight" refers to a time interval of 10 hours to 20 hours.

[0028] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more". Unless otherwise specified, the definite articles used herein, such as "the", also include the plural forms of nouns.

[0029] As described above, a first aspect of the present disclosure is the provision of a co-crystal of pterostilbene and a co-former capable of forming a hydrogen bond interaction. Also, as described above, the co-crystals of the present disclosure may be in a crystalline form as either a free solvate or a solvate (e.g., a hydrate or a dichloromethane solvate), and both forms are intended to be within the scope of the present disclosure. Methods of solvation are generally known in the art.

[0030] In particular, the co-former is selected from the group consisting of picolinic acid, 1,4-dimethylpiperazine, 2,3,5-trimethylpyrazine, theophylline, ethylenediamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,4,8,11-tetraazacyclotetradecane, 2,4-dihydroxybenzoic acid (2,4-DHBA), indole, lysine, orotic acid, phenanthroline, and urea.

[0031] In one embodiment, the co-former is a carboxylic acid, and in particular, a carboxylic acid selected from the group consisting of picolinic acid, 2,4-dihydroxybenzoic acid, orotic acid, indole, and lysine.

[0032] In one embodiment, the co-former is picolinic acid. In certain embodiments, the co-crystal of pterostilbene and picolinic acid is characterized by an X-ray powder diffractogram having peaks characteristic of approximately 5.6 and 14.0 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and picolinic acid of the present disclosure has peaks at 13.5, 21.8, and 24.4 ± 0.3 degrees two-theta (Cu-K αIt is characterized by having an X-ray powder diffractogram that includes peaks more characteristic of radiation, λ = 1.5418 Å. More specifically, the molar ratio of pterostilbene to picolinic acid is 1:1.

[0033] More specifically, the co-crystal [1:1] of pterostilbene and picolinic acid of the present disclosure is characterized by presenting a pattern of peaks represented in 2-theta units of 2θ (°) shown in Table 1 in the X-ray powder diffractogram.

[0034]

Table 1

[0035] The co-crystal [1:1] of pterostilbene and picolinic acid of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 1.

[0036] In another specific embodiment, the co-crystal of pterostilbene and picolinic acid has an X-ray powder diffractogram that includes peaks characteristic of approximately 18.3 and 26.0 ± 0.3 degrees 2-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and picolinic acid of the present disclosure has an X-ray powder diffractogram that includes peaks more characteristic of 3.2, 16.8, and 23.6 ± 0.3 degrees 2-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to picolinic acid is 2:1.

[0037] More specifically, the co-crystal [2:1] of pterostilbene and picolinic acid of the present disclosure is characterized by presenting a pattern of peaks represented in 2-theta units of 2θ (°) shown in Table 2 in the X-ray powder diffractogram (showing only peaks with a relative intensity of 1% or more).

[0038]

Table 2

[0039] The co-crystal [2:1] of pterostilbene and picolinic acid of the present disclosure may further be characterized by an X-ray diffraction pattern as shown in FIG. 2.

[0040] In another embodiment, the co-former is 1,4-dimethylpiperazine, and the co-crystal of pterostilbene and 1,4-dimethylpiperazine has an X-ray powder diffraction pattern comprising peaks characteristic of approximately 17.3 and 21.2 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and 1,4-dimethylpiperazine of the present disclosure has an X-ray powder diffraction pattern further comprising peaks characteristic of 6.9, 13.7, and 15.8 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to 1,4-dimethylpiperazine is 2:1.

[0041] More specifically, the co-crystal of pterostilbene and 1,4-dimethylpiperazine of the present disclosure is characterized by exhibiting a pattern of peaks represented in units of two-theta at the degrees of 2θ(°) shown in Table 2 in an X-ray powder diffraction pattern.

[0042] [Table 3]

[0043] The structural data of the co-crystal of pterostilbene and 1,4-dimethylpiperazine, as defined above, obtained by single crystal X-ray diffraction corresponds to the co-crystal and is shown below. [Number]

[0044] The co-crystal of pterostilbene and 1,4-dimethylpiperazine of the present disclosure may further be characterized by an X-ray diffraction pattern as shown in FIG. 3.

[0045] In another embodiment, the coformer is 2,3,5-trimethylpyrazine, and the co-crystal of pterostilbene and 2,3,5-trimethylpyrazine has an X-ray powder diffraction pattern including peaks characteristic of approximately 13.4 and 25.9 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and 2,3,5-trimethylpyrazine of the present disclosure has an X-ray powder diffraction pattern including further peaks characteristic of 11.4, 22.7, and 26.9 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to 2,3,5-trimethylpyrazine is 2:1.

[0046] More specifically, the co-crystal of pterostilbene and 2,3,5-trimethylpyrazine of the present disclosure is characterized by presenting a pattern of peaks represented in two-theta units of degrees of 2θ(°) shown in Table 4 in the X-ray powder diffraction pattern.

[0047] [Table 4]

[0048] The data of the structure of the co-crystal of pterostilbene and 2,3,5-trimethylpyrazine defined above obtained by single crystal X-ray diffraction corresponds to the co-crystal and is shown below. [Number]

[0049] The co-crystal of pterostilbene and 2,3,5-trimethylpyrazine of the present disclosure may further be characterized by an X-ray diffraction pattern as shown in FIG. 4.

[0050] In another embodiment, the coformer is theophylline, and the cocrystal of pterostilbene and theophylline has an X-ray powder diffractogram comprising peaks characteristic of approximately 8.5 and 11.7 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the cocrystal of pterostilbene and theophylline of the present disclosure has an X-ray powder diffractogram further comprising peaks characteristic of 13.7, 15.0, and 16.7 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene:theophylline is 1:1.

[0051] More specifically, the cocrystal of pterostilbene and theophylline of the present disclosure is characterized by exhibiting a pattern of peaks represented in units of two-theta at the degrees of 2θ(°) shown in Table 5 in the X-ray powder diffractogram.

[0052] [Table 5]

[0053] In another embodiment, the coformer is theophylline, and the cocrystal of pterostilbene and theophylline is in the form of a dichloromethane solvate and has an X-ray powder diffractogram comprising peaks characteristic of approximately 13.4 and 26.0 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the dichloromethane solvate cocrystal of pterostilbene and theophylline of the present disclosure has an X-ray powder diffractogram further comprising peaks characteristic of 10.8, 14.4, and 23.5 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene:theophylline:dichloromethane is 1:1:1.

[0054] More specifically, the co-crystal of pterostilbene:theophylline:dichloromethane solvate of the present disclosure is characterized by exhibiting a pattern of peaks represented in 2-theta units of 2θ (°) shown in Table 6 in an X-ray powder diffractogram.

[0055]

Table 6

[0056] The data on the structure of the co-crystal of pterostilbene:theophylline:dichloromethane solvate, defined above and obtained by single crystal X-ray diffraction, corresponds to the co-crystal and is shown below.

Number

[0057] The co-crystal of pterostilbene:theophylline:dichloromethane solvate of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 5.

[0058] In another embodiment, the coformer is 1,4,8,11-tetraazacyclotetradecane, and the co-crystal of pterostilbene and 1,4,8,11-tetraazacyclotetradecane has an X-ray powder diffractogram comprising peaks characteristic of approximately 10.8 and 23.6 ± 0.3 degrees 2-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and 1,4,8,11-tetraazacyclotetradecane of the present disclosure has an X-ray powder diffractogram further comprising peaks characteristic of 16.2, 18.0, and 20.6 ± 0.3 degrees 2-theta (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to 1,4,8,11-tetraazacyclotetradecane is 2:1.

[0059] More specifically, the co-crystal of pterostilbene and 1,4,8,11-tetraazacyclotetradecane of the present disclosure is characterized by exhibiting a pattern of peaks represented in 2θ (°) units shown in Table 7 in an X-ray powder diffractogram.

[0060]

Table 7

[0061] The data on the structure of the co-crystal of pterostilbene and 1,4,8,11-tetraazacyclotetradecane, defined above and obtained by single crystal X-ray diffraction, corresponds to the co-crystal and is shown below.

Number

[0062] The co-crystal of pterostilbene and 1,4,8,11-tetraazacyclotetradecane of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 6.

[0063] In another embodiment, the coformer is ethylenediamine, and the co-crystal of pterostilbene and ethylenediamine is an anhydrous co-crystal characterized by having an X-ray powder diffractogram containing peaks characteristic of approximately 14.3 and 19.3 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and ethylenediamine of the present disclosure is characterized by having an X-ray powder diffractogram containing further peaks characteristic of 6.7, 13.4, and 22.0 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to ethylenediamine is 2:1.

[0064] More specifically, the anhydre co-crystal of pterostilbene and ethylenediamine of the present disclosure is characterized by exhibiting a peak pattern represented in 2θ (°) units shown in Table 8 in an X-ray powder diffractogram.

[0065]

Table 8

[0066] The data on the structure of the co-crystal of pterostilbene and ethylenediamine defined above obtained by single crystal X-ray diffraction corresponds to the co-crystal and is shown below.

Number

[0067] The co-crystal of pterostilbene and ethylenediamine of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 7.

[0068] In another embodiment, the coformer is ethylenediamine, and the co-crystal of pterostilbene and ethylenediamine is a hydrated co-crystal characterized by having an X-ray powder diffractogram containing peaks characteristic of approximately 14.3 and 19.3 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). In particular, the hydrated co-crystal of pterostilbene and ethylenediamine of the present disclosure is characterized by having an X-ray powder diffractogram containing further peaks characteristic of 17.5, 21.5, 23.6, and 29.3 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). More specifically, the co-crystal of pterostilbene and ethylenediamine is a hydrate, and the molar ratio of pterostilbene, ethylenediamine, and water is 2:1:2.

[0069] More specifically, the hydrated cocrystal of pterostilbene and ethylenediamine of the present disclosure is characterized by exhibiting a pattern of peaks represented in units of 2θ (°) shown in Table 9 in an X-ray powder diffractogram.

[0070] [Table 9]

[0071] The hydrated cocrystal of pterostilbene and ethylenediamine of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 8.

[0072] In another embodiment, the coformer is 1,4-diazabicyclo[2.2.2]octane (DABCO), and the cocrystal of pterostilbene and DABCO has an X-ray powder diffractogram including peaks characteristic of approximately 17.9 and 21.7 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). In one embodiment, the cocrystal of pterostilbene and DABCO of the present disclosure has an X-ray powder diffractogram further including peaks characteristic of 10.6, 16.0, and 19.0 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å). More specifically, the molar ratio of pterostilbene to DABCO is 2:1.

[0073] More specifically, the cocrystal of pterostilbene and DABCO of the present disclosure is characterized by exhibiting a pattern of peaks represented in units of 2θ (°) shown in Table 10 in an X-ray powder diffractogram.

[0074] [Table 10]

[0075] Data on the structure of the co-crystal of pterostilbene and DABCO, as defined above and obtained by single crystal X-ray diffraction, corresponds to the co-crystal and is shown below.

Number

[0076] The co-crystal of pterostilbene and DABCO of the present disclosure may be further characterized by an X-ray diffraction pattern such as that in FIG. 9.

[0077] In another embodiment, the co-former is 2,4-dihydroxybenzoic acid, and the co-crystal of pterostilbene and 2,4-dihydroxybenzoic acid has an X-ray powder diffraction pattern including peaks characteristic of approximately 11.3 and 27.9 ± 0.3 degrees 2 theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and 2,4-dihydroxybenzoic acid has an X-ray powder diffraction pattern including peaks more characteristic of 13.2, 13.3, and 15.8 ± 0.3 degrees 2 theta (Cu-K α radiation, λ = 1.5418).

[0078] More specifically, the co-crystal of pterostilbene and 2,4-dihydroxybenzoic acid of the present disclosure exhibits a peak pattern represented in units of 2 theta at the degrees of 2θ(°) shown in Table 11 in the X-ray powder diffraction pattern (showing only peaks with a relative intensity of 1% or more).

[0079]

Table 11

[0080] In another embodiment, the co-former is indole, and the co-crystal of pterostilbene and indole has an X-ray powder diffraction pattern including peaks characteristic of approximately 10.8 and 18.0 ± 0.3 degrees 2 theta (Cu-K αIt is characterized by having an X-ray powder diffraction pattern that includes peaks characteristic of radiation (λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and indole has an X-ray powder diffraction pattern that further includes peaks characteristic of radiation (λ = 1.5418 Å) at 16.3, 20.6, and 23.7 ± 0.3 degrees two-theta (Cu-K α It is characterized by having an X-ray powder diffraction pattern that further includes peaks characteristic of radiation (λ = 1.5418 Å).

[0081] More specifically, the co-crystal of pterostilbene and indole of the present disclosure is characterized by presenting a peak pattern represented in two-theta units of the degrees of 2θ(°) shown in Table 12 in the X-ray powder diffraction pattern (showing only peaks with a relative intensity of 1% or more).

[0082]

Table 12

[0083] The co-crystal of pterostilbene and indole of the present disclosure may be further characterized by an X-ray diffraction pattern as shown in FIG. 10.

[0084] In another embodiment, the coformer is lysine, and the co-crystal of pterostilbene and lysine has an X-ray powder diffraction pattern that includes peaks characteristic of approximately 15.5 and 20.0 ± 0.3 degrees two-theta (Cu-K α It is characterized by having an X-ray powder diffraction pattern that includes peaks characteristic of radiation (λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and lysine of the present disclosure has an X-ray powder diffraction pattern that further includes peaks characteristic of radiation (λ = 1.5418 Å) at 3.5, 23.6, and 25.7 ± 0.3 degrees two-theta (Cu-K α It is characterized by having an X-ray powder diffraction pattern that further includes peaks characteristic of radiation (λ = 1.5418 Å).

[0085] More specifically, the co-crystal of pterostilbene and lysine of the present disclosure is characterized by presenting a peak pattern represented in two-theta units of the degrees of 2θ(°) shown in Table 13 in the X-ray powder diffraction pattern (showing only peaks with a relative intensity of 1% or more).

[0086]

Table 13

[0087] The co-crystal of pterostilbene and lysine of the present disclosure may further be characterized by an X-ray diffraction pattern as shown in FIG. 11.

[0088] In another embodiment, the coformer is orotic acid, and the co-crystal of pterostilbene and orotic acid has an X-ray powder diffraction pattern including peaks characteristic of approximately 19.3 and 25.5 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and orotic acid of the present invention has an X-ray powder diffraction pattern including peaks further characteristic of 10.7, 16.1, and 20.1 ± 0.3 degrees two-theta (Cu-K α radiation, λ = 1.5418 Å).

[0089] More specifically, the co-crystal of pterostilbene and orotic acid of the present disclosure exhibits a peak pattern represented in units of two-theta of 2θ (°) shown in Table 14 in the X-ray powder diffraction pattern (showing only peaks with a relative intensity of 1% or more).

[0090]

Table 14

[0091] The co-crystal of pterostilbene and orotic acid of the present disclosure may further be characterized by an X-ray diffraction pattern as shown in FIG. 12.

[0092] In another embodiment, the coformer is 1,10-phenanthroline, and the co-crystal of pterostilbene and 1,10-phenanthroline has approximately 13.7 and 22.5 ± 0.3 degrees two-theta (Cu-K αIt is characterized by having an X-ray powder diffractogram containing peaks characteristic of radiation (λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and 1,10-phenanthroline of the present invention has 2-theta values of 7.2, 19.0, and 21.4 ± 0.3 degrees (Cu-K α It is further characterized by having an X-ray powder diffractogram containing peaks characteristic of radiation (λ = 1.5418 Å).

[0093] More specifically, the co-crystal of pterostilbene and 1,10-phenanthroline of the present disclosure exhibits a peak pattern represented in units of 2-theta, which is the degree of 2θ (°) shown in Table 15, in the X-ray powder diffractogram (showing only peaks with a relative intensity of 1% or more).

[0094]

Table 15

[0095] The co-crystal of pterostilbene and 1,10-phenanthroline of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 13.

[0096] In another embodiment, the co-former is urea, and the co-crystal of pterostilbene and urea has an X-ray powder diffractogram containing peaks characteristic of approximately 14.6 and 21.5 ± 0.3 degrees 2-theta (Cu-K α It is characterized by having an X-ray powder diffractogram containing peaks characteristic of radiation (λ = 1.5418 Å). In particular, the co-crystal of pterostilbene and urea of the present invention has 2-theta values of 15.7, 20.1, and 23.3 ± 0.3 degrees (Cu-K α It is further characterized by having an X-ray powder diffractogram containing peaks characteristic of radiation (λ = 1.5418 Å).

[0097] More specifically, the co-crystal of pterostilbene and urea of the present disclosure is characterized by exhibiting a peak pattern represented in 2θ (°) units shown in Table 16 in an X-ray powder diffractogram (showing only peaks with a relative intensity of 1% or more).

[0098]

Table 16

[0099] The co-crystal of pterostilbene and urea of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 14.

[0100] An X-ray powder diffractogram including peaks characteristic of approximately 11.8 and 19.5 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å) is also disclosed for polymorph VI of pterostilbene. In particular, polymorph VI of pterostilbene of the present disclosure has an X-ray powder diffractogram including peaks further characteristic of 15.3, 23.4, and 25.8 ± 0.3 degrees 2θ (Cu-K α radiation, λ = 1.5418 Å).

[0101]

[0102]

Table 17

[0103] The structural data of polymorph VI of pterostilbene as defined above obtained by single crystal X-ray diffraction corresponds to the polymorph of pterostilbene and is shown below.

Number

[0104] Form VI of the pterostilbene of the present disclosure may be further characterized by an X-ray diffractogram as shown in FIG. 15.

[0105] Also provided is a process for preparing a co-crystal of pterostilbene and a co-former as defined above, which is also part of the present disclosure.

[0106] In one example, the process includes the following steps: (a) Mixing pterostilbene and picolinic acid in the presence of toluene as a solvent, (b) Stirring the mixture of step (a) at room temperature until a co-crystal is formed, and (c) Isolating the co-crystal thus obtained.

[0107] In another example, the process includes the following steps: (a) Mixing pterostilbene and a co-former, (b) Stirring the mixture of step (a) at room temperature until a co-crystal is formed, and (c) Isolating the co-crystal thus obtained.

[0108] In a specific example, the co-former is selected from 1,4-dimethylpiperazine, 2,3,5-trimethylpyrazine, and ethylenediamine.

[0109] In another example, the process includes the following steps: (a) Mixing pterostilbene and dichloromethane, and then adding theophylline to form a suspension, (b) Stirring the mixture of step (a) at room temperature until a co-crystal is formed, (c) Isolating the co-crystal thus obtained, and (d) Optionally, desolvating the co-crystal by heating.

[0110] In another example, the process includes the following steps: (a) Mixing pterostilbene and 1,4,8,11-tetraazacyclotetradecane, and then adding theophylline to form a suspension; (b) Stirring the mixture of step (a) at room temperature until a co-crystal is formed; (c) Isolating the co-crystal thus obtained.

[0111] In another example, the process includes the following steps: (a) Dissolving 1,4-diazabicyclo[2.2.2]octane (DABCO) in xylene and then adding pterostilbene; (b) Stirring the mixture of step (a) at room temperature until a co-crystal is formed; (c) Isolating the co-crystal thus obtained.

[0112] Co-crystals of pterostilbene with 2,4-DHBA, indole, lysine, orotic acid, phenanthroline, and urea are obtained as described below.

[0113] The co-crystals of pterostilbene and co-formers as defined above in the present disclosure may also be defined by their preparation process. Thus, this aspect of the present disclosure can optionally be formulated as the co-crystals of pterostilbene and co-formers as defined above, which can be obtained by the previous process, including any preferred or specific embodiments of the process and some possible combinations of the features of the process disclosed above.

[0114] A second aspect of the present disclosure relates to a composition comprising a cocrystal of pterostilbene and the coformer as defined above in an effective amount, together with one or more suitable acceptable excipients or carriers. Also disclosed are compositions comprising a crystalline form VI of pterostilbene as defined above in an effective amount, together with one or more suitable acceptable excipients or carriers, such as pharmaceutical compositions, nutraceuticals, cosmetic compositions, functional foods or beverages, premixes, pet foods, or medical food compositions. The term "effective amount" refers to the amount of the cocrystal that provides a therapeutic effect upon its application.

[0115] In one embodiment, the composition of the second aspect of the present disclosure is a pharmaceutical composition comprising a cocrystal of pterostilbene, which is a pharmaceutically effective amount, and the coformer as defined above, together with one or more suitable pharmaceutically acceptable excipients or carriers. The term "pharmaceutical composition" refers to a mixture of cocrystals of pterostilbene disclosed herein and other chemical constituents such as diluents or carriers. Pharmaceutical compositions facilitate the administration of cocrystals to organisms. In particular, pharmaceutical compositions can be formulated for inhalation, intramuscular, subcutaneous, oral, or topical administration.

[0116] In one embodiment, the composition of the second aspect of the present disclosure is a nutraceutical comprising a cocrystal of pterostilbene, which is an effective amount, and the coformer as defined above, together with one or more suitable orally acceptable excipients or carriers. The term "nutraceutical" refers to an orally ingested product containing ingredients intended to supplement the diet. Nutraceuticals can be in the form of tablets, capsules, softgels, gelcapsules, liquids, powders, bars, beverages, shakes, and other foods. As an example, the nutraceutical may be for enhancing athletic performance.

[0117] The term "acceptable excipient or carrier" refers to an acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, binder, lubricant, disintegrant, solvent, or encapsulating material. Each component must be acceptable in the sense that it is compatible with the other components of the composition. It must also be suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic reaction, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. In a pharmaceutical composition, an acceptable excipient or carrier is a pharmaceutically acceptable excipient or carrier.

[0118] In certain embodiments, the pharmaceutical composition as defined above further comprises one or more active ingredients selected from the group consisting of anti-inflammatory agents, chemotherapeutic agents, immunomodulatory agents, cancer hormone therapeutic agents, targeted cancer therapeutic agents, anti-diabetic agents, lipid-lowering agents, anti-arthritis agents, dementia therapeutic agents, anti-atherosclerotic agents, anti-obesity agents, anti-osteoporosis agents, and age-related disease agents. In certain embodiments, the dietary supplement as defined above further comprises one or more active ingredients selected from the group consisting of L-carnitine, xylitol, vitamins, carotenoids, omega-3 fatty acids, flavonoids, coenzyme Q10, natural products that inhibit 5-LOX, harpagoside (Figwort or Devil's Claw), copper, zinc, and manganese. The active ingredients mentioned can be in any solid form, including its possible pharmaceutically acceptable salts, solvates, polymorphs, and co-crystals.

[0119] Examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylates including acetylsalicylic acid, diflunisal, salicylic acid and its salts, salsalate; propionic acid derivatives including ibuprofen, dexibuiprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen; acetic acid derivatives including indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone; enolic acid (oxicam) derivatives including piroxicam, meloxicam, tenoxicam, droxicam, lornopxicam, isoxicam, phenylbutazone; anthranilic acid derivatives (fenamate) including mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid; selective COX-2 inhibitors (coxibs) including celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, filocoxib; sulfonanilides including nimesulide; and clonixin, licofelone. Anti-inflammatory agents also include antileukotrienes such as sodium meclofenamate, zileuton; and immunoselective anti-inflammatory derivatives (ImSAIDs) such as sub mandibular gland peptide-T (SGP-T), tripeptide phenylalanine-glutamine-glycine (FEC), and its D-isomer (feG).

[0120] Examples of chemotherapeutic agents include alkylating agents such as asmechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitros-N-mdthylurea, carmustine, lomustine, semustine, fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone, cisplatin, carboplatin, oxaliplatin, procarbazine, hexamethylmelamine; antimetabolites such as methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, mercaptopurine; microtubule inhibitors such as vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, podophyllotoxin, etoposide, teniposide; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, melvalone, aclarubicin; cytotoxic antibiotics such as mitomycin C, actinomycin, doxorubicin, daunorubicin, epirubicin, aclarubicin, mitoxantrone, bleomycin; and Janus kinase inhibitors as previously described.

[0121] Examples of immunomodulators include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, semipilimumab, rituximab, oncolin, talimogen, laherparecvec, tisagenlecleucel, axicabtagene, ciloleucel, interferon alpha 2a, interferon alpha 2b, human leukocyte interferon alpha, interferon beta 1a, interferon beta 1b, PEGylated versions of interferon, interleukin-2, interleukin-7, interleukin-12, chemokine ligand-3, chemokine ligand-26, chemokine ligand-7, BCG vaccine, thalidomide, lenalidomide, pomalidomide, apremilast, cytosine phosphate-guanosine, oligonucleotides, glucan, and sipuleucel-T vaccine.

[0122] Examples of cancer hormone therapeutic agents include tamoxifen, anastrozole, letrozole, exemestane, raloxifene, and fulvestrant.

[0123] Examples of targeted cancer therapeutic agents include imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, lapatinib, nilotinib, bortezomib, tamoxifen, tofacitinib, crizotinib, obatoclax, navitoclax, gossypol, iniparib, olaparib, perifosine, apatinib, vemurafenib, dabrafenib, trametinib, salinomycin, vintafolide, temsirolimus, everolimus, vemurafenib, trametinib, dabrafenib, pembrolizumab, rituximab, trastuzumab, alemtuzumab, cetuximab, panitumumab, bevacizumab, and ipilimumab.

[0124] Examples of antidiabetic agents include biguanides (i.e., metformin, buformin, phenformin), sulfonylureas (i.e., acetohexamide, carbutamide, chlorpropamide, glibenclamide, gliclazide, glimepiride, glibizide, glipizide, gliquidone, glysocpid, glibritide, glibutiazole, glibuzole, glyhexamide, glymidine, glypinamide, fenbutamide, tolazamide, tolbutamide, tolcyclamide), thiazolidinediones (i.e., pioglitazone, rosiglitazone, troglitazone), beta adrenergic blockers, and other antidiabetic agents such as acarbose, calcium mesoxalate, miglitol, nateglinide, repaglinide, and voglibose.

[0125] Examples of lipid-lowering agents include statins such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; bile acid sequestrants such as cholestyramine, colesevelam, and cholestyramine; cholesterol absorption inhibitors such as ezetimibe; PCSK9 inhibitors such as alirocumab, evolocumab; fibrates such as fenofibrate, gemfibrozil; and niacin.

[0126] Examples of anti-arthritis agents include analgesics including acetaminophen, tramadol, oxycodone, hydrocodone; the aforementioned non-steroidal anti-inflammatory drugs (NSAIDs); counterirritant creams and ointments containing menthol or capsaicin; disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and hydroxychloroquine; biological response modifiers such as tumor necrosis factor (TNF) inhibitors including etanercept, infliximab; interleukin-1 (IL-1), interleukin-6 (IL-6), Janus kinase enzymes, B cells, and T cells.

[0127] Examples of dementia therapeutics include anti-Alzheimer agents such as cholinesterase inhibitors like donepezil, galantamine, rivastigmine, tacrine, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, caffeine, rosmarinic acid, alpha-pinene, edrophonium, fuperez A, ladostigil, ungeremine, lactopicrocin, and acotiamide; and NMDA receptor antagonists such as memantine. Examples of anti-Parkinson agents include carbidopa-levodopa; dopamine agonists such as pramipexole, ropinirole, rotigotine, apomorphine, lergotrile, pergolide, bromocriptine, lisuride, aripiprazole, fencicline, quinpirole, salvianoline A, cabergoline, sila-dopa, dihydroxidine, dinapsoline, doxanthrine, epitriptine, piribedil, pramipexole, propylnorapomorphine, quinagolide, roxindole, sumanirole, and phenoldopam; MAO B inhibitors such as isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, befiradol, moclobemide, pirindole, troxatone, rasagiline, selegiline, safinamide, linezolidbenmoxine, iproclozide, iproniazid, menabazine, octamonics, pheniprazine, phenoxypropazine, pivalylbenzohydrazine, safrazine, caroxazone, minaprine, brofaromine, eproximide, methylene blue, metralindole, curcumin, harmaline, harmine, amiflamine, befloxatone, simoxatone, espron, seliclomide, tetrindole, CX157; catechol o-methyltransferase (COMT) inhibitors such as entacapone, tolcapone, nebicapone, niticapone, opicapone; and anticholinergics such as benztropine, trihexyphenidyl, clozapine, ketiapiine, atropine, biperiden, chlorpheniramine, and certain SSRIs (e.g., citalopram).

[0128] Examples of anti-atherosclerotic agents include the lipid-lowering agents described above; irreversible cyclooxygenase inhibitors including aspirin and trifar, adenosine diphosphate (ADP) receptor inhibitors including cangrelol, phosphodiesterase inhibitors including clopidogrel, prasugrel, ticagrelor, ticlopidine, cilostazol, protease-activated receptor-1 (PAR-1) antagonists including vorapaxar, glycoprotein IIb / IIIa inhibitors including abciximab, eptifibatide, tirofiban, adenosine reuptake inhibitors including dipyridamole, antiplatelet agents such as thromboxane inhibitors; non-selective beta blockers including propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol; beta1-selective beta blockers such as acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol; beta-2-selective beta blockers such as butaxamine, ICI-118,551; beta3-selective beta blockers such as SR 59230A; angiotensin-converting enzyme (ACE) inhibitors such as enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, antihypertensive peptides, alfalasin; calcium channel blockers, for example,; loop diuretics including bumetanide, furosemide, ethacrynic acid, torsemide, thiazides including bendroflumethiazide, hydrochlorothiazide, arginine vasopressin receptor 2 antagonists including amphotericin B, lithium, selective vasopressin V2 antagonists including tolvaptan, conivaptan, Na-H exchanger antagonists including dopamine, carbonic anhydrase inhibitors including acetazolamide and dorzolamide, potassium-sparing diuretics including amiloride, spironolactone, eplerenone, triamterene, potassium canrenoate, xanthines including caffeine, theophylline, theobromine, and other diuretics including glucose, mannitol, calcium chloride, and ammonium chloride.

[0129] Examples of anti-obesity agents include orlistat, cetilistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, liraglutide, semaglutide, amylin, pramlintide, phentermine / topiramate, bupropion / naltrexone, tesofensine, dexfenfluramine, and fenfluramine / phentermine.

[0130] Examples of anti-osteoporosis agents include bisphosphonates such as alendronate, risedronate, ibandronate, etidronate, zoledronate, or zoledronic acid; hormone replacement therapies using teriparatide, abaloparatide, and parathyroid hormone, raloxifene, calcitonin, denosumab, strontium ranelate, and estrogen, among others.

[0131] In certain embodiments, the cosmetic composition, dietary supplement, functional food or beverage, premix, animal feed, pet food, or medical food composition as defined above further comprises one or more dietary supplement ingredients such as vitamins, carotenoids, omega-3 fatty acids, or flavonoids.

[0132] Examples of vitamins include, but are not limited to, vitamin A (acetate or palmitate, beta-carotene), vitamin B1 (thiamine (aneurin)) (hydrochloride or mononitrate), B2 (riboflavin), vitamin B6 (pyridoxine hydrochloride), vitamin B12 (cobalamin), vitamin B12 (cyanocobalamin), vitamin B12 (methylcobalamin), vitamin C (ascorbic acid), nicotinic acid, vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), vitamin E (alpha-tocopheryl acetate, alpha-tocopheryl succinate, alpha-tocopherol, gamma-tocopherol), vitamin K (phylloquinone, menadione, etc.), and nicotinamide riboside.

[0133] Examples of carotenoids include, but are not limited to, lutein, lycopene, α-carotene, β-carotene, γ-carotene, β-cryptoxanthin, capsanthin, canthaxanthin, zeaxanthin, and astaxanthin.

[0134] Examples of omega-3 fatty acids include, but are not limited to, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

[0135] Examples of flavonoids include, but are not limited to, quercetin, myricetin, kaempferol, rutin, catechin, epicatechin, ECG, gallocatechin, EGC, EGCG, cyanidin, caffeic acid, theaflavin, theaflavin gallate, luteolin, daidzein, genistein, and glycitein.

[0136] Examples of natural products that inhibit 5-LOX include, but are not limited to, baicalein, caffeic acid, curcumin, hyperforin, and St. John's wort.

[0137] The compositions of the present disclosure can be prepared according to methods well known in the art. Suitable excipients and / or carriers, and their amounts, can be readily determined by those skilled in the art according to the type of formulation to be prepared.

[0138] All embodiments disclosed above for the co-crystals of pterostilbene as defined above also apply to the compositions of the present disclosure.

[0139] A third aspect of the present disclosure relates to co-crystals of pterostilbene and the co-former as defined above for use as a pharmaceutical. Also disclosed is crystalline form VI of pteroltilbene as defined above for use as a pharmaceutical.

[0140] In particular, the co-crystal of pterostilbene and coform as defined above or the crystalline form VI of pterostilbene is for use in the prevention and / or treatment of neurological, cardiovascular, metabolic, hematological disorders, cancer, atherosclerosis, type 2 diabetes, inflammation, dyslipidemia, osteoporosis, and other age-related diseases not mentioned above.

[0141] This aspect can also be formulated as the use of the co-crystal of pterostilbene and coform as defined above for the preparation of a pharmaceutical for preventing and / or treating neurological, cardiovascular, metabolic, and hematological disorders, cancer, atherosclerosis, type 2 diabetes, inflammation, dyslipidemia, osteoporosis, and other age-related diseases not mentioned above. The present invention also relates to a method for preventing and / or treating a mammal suffering from or susceptible to neurological, cardiovascular, metabolic, or hematological disorders, cancer, atherosclerosis, type 2 diabetes, inflammation, dyslipidemia, osteoporosis, and other age-related diseases not mentioned above, wherein the method comprises administering to the mammal an effective amount of the co-crystal of pterostilbene and coform as defined above, or the crystalline form VI of pteroltilbene, together with one or more acceptable excipients or carriers.

[0142] Throughout this specification and the claims, the word "comprising" and variations of this word are not intended to exclude other technical features, additives, components, or steps. Further, the word "comprise" includes the case of "consisting of". Further objects, advantages, and features of the present disclosure will become apparent to those skilled in the art by reviewing this specification, or may be learned by practicing the present disclosure. The following examples and drawings are presented for illustrative purposes and are not intended to limit the present disclosure. Further, the present disclosure encompasses all possible combinations of the specific preferred embodiments described herein.

Examples

[0143] General Considerations Pterostilbene, picolinic acid, 1,4-dimethylpiperazine, 2,3,5-trimethylpyrazine, theophylline, 1,4,8,11-tetraazacyclotetradecane, ethylenediamine, 1,4-diazabicyclo[2.2.2]octane (DABCO) are commercially available.

[0144] Powder X-ray diffraction (PXRD) analysis was performed by sandwiching a powder sample between polyester films with a thickness of 3.6 μm, which was analyzed with a PANalytical X’Pert PRO MPD θ / θ powder diffractometer with a radius of 240 millimeters, in a configuration of a convergent beam with a focusing mirror and a flat sample transmission shape, under the following experimental conditions: Cu Kα radiation (λ = 1.5418 Å); working power: 45 kV and 40 mA; an incident beam slit defining a beam height of 0.4 millimeter; incident and diffracted beams with 0.02 radian Soller slits; PIXcel detector: effective length = 3.347°; 2θ / θ was scanned from 2 to 40° 2θ with a step size of 0.026° 2θ and a measurement time of 76 seconds per step.

[0145] Example 1. - Preparation of a co-crystal of pterostilbene: picolinic acid (1:1) Pterostilbene (200 mg, 0.780 mmol) and picolinic acid (24 mg, 0.195 mmol) were mixed and stirred overnight at room temperature in toluene (0.8 mL). The resulting suspension was filtered and dried under vacuum.

[0146] Example 2. - Preparation of a co-crystal of pterostilbene: picolinic acid (2:1) A saturated solution of pterostilbene (5000 mg) in toluene (23.6 mL) was prepared at 60 °C. Then, the solution was cooled to 25 °C and picolinic acid (1635 mg) was added. The suspension was stirred at 25 °C for 2 hours, filtered, and dried under vacuum.

[0147] Example 3. - Preparation of a co-crystal of pterostilbene: 1,4-dimethylpiperazine (2:1) Pterostilbene (97.6 mg, 0.381 mmol) and 1,4-dimethylpiperazine (0.3 mL) were mixed and stirred overnight at room temperature. The resulting suspension was filtered and dried under vacuum.

[0148] Example 4. - Preparation of a co-crystal of pterostilbene: 2,3,5-trimethylpyrazine (2:1) Pterostilbene (61.3 mg, 0.239 mmol) and 2,3,5-trimethylpyrazine (0.05 mL) were mixed and stirred overnight at room temperature. The resulting suspension was filtered and dried under vacuum.

[0149] Example 5. - Preparation of a co-crystal of pterostilbene: theophylline (1:1) Pterostilbene (113 mg, 0.441 mmol) was dissolved in dichloromethane (0.2 mL) at room temperature. Then, theophylline (20 mg, 0.111 mmol) was added, and the resulting suspension was stirred overnight, filtered, and dried under vacuum. Subsequently, the solid was placed in a round-bottom flask and heated in a silicone oil bath under vacuum to a maximum of 80 °C for 1 hour until complete desolvation.

[0150] Example 6. - Preparation of a co-crystal solvate of pterostilbene: theophylline:dichloromethane (1:1:1) Pterostilbene (113 mg, 0.441 mmol) was dissolved in dichloromethane (0.2 mL) at room temperature. Then, theophylline (20 mg, 0.111 mmol) was added, and the resulting suspension was stirred overnight, filtered, and dried under vacuum.

[0151] Example 7. - Preparation of a co-crystal of pterostilbene: 1,4,8,11-tetraazacyclotetradecane co-crystal (2:1) Pterostilbene (50 mg, 0.195 mmol) and 1,4,8,11-tetraazacyclotetradecane (20 mg, 0.0998 mmol) were mixed and dissolved in chloroform (0.3 mL) at room temperature. Then, the solution was kept sealed at room temperature. After 35 days, the resulting crystals were filtered and dried under vacuum.

[0152] Example 8. - Preparation of Pterostilbene: Ethylenediamine Cocrystal (2:1) Pterostilbene (50 mg, 0.195 mmol) was dissolved in ethylenediamine (0.05 mL) at 50 °C. Then, the mixture was slowly cooled to room temperature and left sealed at room temperature. After 5 days, the mixture crystallized, which was filtered and dried under vacuum.

[0153] Example 9. - Preparation of Pterostilbene: Ethylenediamine: H2O Cocrystal Hydrate (2:1:2) Pterostilbene (162 mg, 0.632 mmol) and ethylenediamine (2 mL) were mixed and stirred overnight at room temperature. The resulting suspension was filtered and dried under vacuum.

[0154] Example 10. - Preparation of Pterostilbene: DABCO Cocrystal (2:1) DABCO (100.0 mg, 0.892 mmol) was dissolved in xylene (1.5 mL) at 50 °C. Then, the solution was slowly cooled to room temperature, pterostilbene (197.1 mg, 0.769 mmol) was added, and the mixture was stirred overnight. The resulting suspension was filtered and dried under vacuum.

[0155] Example 11. - Preparation of Pterostilbene: 2,4-Dihydroxybenzoic Acid Cocrystal A saturated solution of pterostilbene (100 mg) in IPA (0.25 mL) was prepared at 25 °C. Then, 2,4-dihydroxybenzoic acid (131.7 mg) was added and stirred overnight at 25 °C. The resulting suspension was filtered and dried under vacuum.

[0156] Example 12. Preparation of Pterostilbene: Indole Cocrystal Pterostilbene (20 mg, 0.0780 mmol) and indole (9.2 mg, 0.078 mmol) were ground in benzyl alcohol at 25 °C for 15 minutes.

[0157] Example 13. - Preparation of Pterostilbene: Lysine Cocrystal A saturated solution of pterostilbene (50 mg) in ACN (0.1 mL) was prepared at 25 °C. Then, lysine (34.9 mg) was added and this was stirred at 25 °C overnight. The resulting suspension was filtered and dried under vacuum.

[0158] Example 14. - Preparation of pterostilbene: orotic acid cocrystal Pterostilbene (20 mg, 0.0780 mmol) and orotic acid (12.2 mg, 0.078 mmol) were ground in DMSO at 25 °C for 15 minutes.

[0159] Example 15. - Preparation of pterostilbene: 1,10 - phenanthroline cocrystal [1:1] A saturated solution of pterostilbene (100 mg) in MEK (0.2 mL) was prepared at 25 °C. Then, 1,10 - phenanthroline (70.3 mg) was added and the suspension was stirred at 25 °C overnight. The resulting suspension was filtered and dried under vacuum.

[0160] Example 16. - Preparation of pterostilbene: urea cocrystal Pterostilbene (20 mg, 0.0780 mmol) and urea (4.7 mg, 0.078 mmol) were ground in benzyl alcohol at 25 °C for 15 minutes.

[0161] Example 17. - Preparation of polymorph VI of pterostilbene Pterostilbene (20 mg, 0.0780 mmol) and acetone (1 drop) were ground at room temperature for 15 minutes at a vibration frequency of 30 Hz to obtain polymorph VI.

[0162] Example 18. - Dissolution rate of pterostilbene vs. cocrystal 1. Determination of Molar Extinction Coefficient (MEC) in FaSSIF v2 medium The molar extinction coefficients of pterostilbene and each conformer were determined by UV titration using a GlpKa™ titration device (Sirius Analytical Instruments, UK). Briefly, a 10 mM stock solution of the sample was prepared in DMSO. 50 μL of the sample stock solution and 0.25 mL of 15 mM potassium phosphate buffer were added to 10 mL of 0.15 M KCl solution, followed by the addition of 17.9 mg of FaSSIF v2 powder. Before starting the titration, the pH of the sample solution was adjusted to 2 with 0.5 M HCl and then titrated to pH 12 with 0.5 M KOH. The UV absorption spectrum of the solution (250 nm to 450 nm) was recorded with an optical fiber dip probe at each addition of the titrant. The collected data were refined using RefinamentPro software and the pKa values and molar extinction coefficients obtained by target factor analysis.

[0163] 2. Dissolution rate experiment - Tablet manufacture: Tablets with a diameter of 3 mm were prepared using a manual hydraulic tablet press (Applied Measurements Ltd., UK). The pressure applied was 100 Kg for 2 minutes. 10 - 15 mg of each solid form of pterostilbene or co-crystal was weighed. The total exposed surface area was 0.5 cm 2 was. - Medium: FaSSIF v2 (pH 6.5), with the corresponding amount of phosphoric acid (28.4 mM) instead of maleic acid. - Dissolution tests were carried out using a small-scale dissolution assay installed in a GlpKa™ titration device (Sirius Analytical Instruments, UK). - Dissolution time and temperature: 120 minutes and 25 °C. - Procedure: 15 mL of FaSSIF v2 was added to a sample vial containing the tablets. Spectral collection was started immediately. Spectra were recorded every 30 seconds between 250 nm and 450 nm with a Sirius D-PAS spectrometer equipped with a bifurcated optical fiber dip probe (Hellma Analytics). The medium was stirred at a constant rate.

[0164] 3. UV-vis Quantification The concentration of pterostilbene in the solution at each time point was determined from spectroscopic data by applying Lambert-Beer's law using the predetermined molar extinction coefficient of pure pterostilbene. Spectral regions where the signal was saturated (A > 1.5) or showed moderate interference were discarded. The concentration data were then converted to absolute sample weights and used to generate a graph of sample weight versus time.

[0165] 4. Determination of Dissolution Rate The dissolution rate was obtained by fitting the primary Noyes-Whitney exponential equation to the data.

Equation

[0166] In this equation, [X] t is the weight in grams of the compound in the solution at the experimental time (in minutes), S is the extrapolated solubility (g) of pterostilbene, k d is the rate constant of dissolution (in min -1 ), and t0 (in minutes) is the period allowing for a time offset. The results were calculated using a refinement process that varied S, k d , and t0 to minimize the root mean square deviation between the model concentration and the measured concentration. The dissolution rate (in g min -1 ) was obtained by multiplying k d by S (T. Gravestock et al., 2011). The results are shown in Table 18.

[0167]

Table 18

[0168] A comparison between the dissolution rate curves of the solid forms listed in Table 18 is shown in Figures 16 and 17.

[0169] Example 19. - Pharmacokinetics of Pterostilbene vs. Co-crystal of Pterostilbene and Picolinic Acid Lifetime phase Animal: Male Sprague-Dawley rats (weight: 417.9 - 458.6 g) Administration: Oral (single dose) Dose: 20 mg / kg of P56 (pterostilbene, free base) 20 mg / kg of P56-VIII (co-crystal of pterostilbene and picolinic acid; 13.5 mg / kg as pterostilbene free base) Formulation: Suspension (0.5% carboxymethylcellulose, CMC) Volume of administration: 10 mL / kg Feeding / fasting state: Fasting (at least 8 hours before administration) Sampling: 6 blood samples / animal (at 1, 2, 4, 6, 8, and 24 hours after administration) Plasma samples: Plasma samples using K3-EDTA as anticoagulant. Samples were immediately frozen at -80°C until analysis.

[0170] Pharmacokinetic analysis was performed by non-compartmental pharmacokinetic analysis using Kinetica v5 software (Alfasoft Limited, Luton, UK). Descriptive statistics were performed using Microsoft Excel spreadsheet 2007 (Microsoft Inc, Redmond, US). Plasma bioanalysis was performed by LC-MS / MS.

[0171] Concentration values below the limit of quantitation (BLQ) were set to 0, but missing concentration values were not considered for statistical and pharmacokinetic evaluations. All calculations using nominal sampling times, nominal doses, and concentration levels were expressed as free base. The numerical data presented below were computer-generated. Due to rounding, recalculation of derived values from the individual data presented herein may, in some cases, result in minor variations.

[0172] Area under the plasma concentration-time curve from 0 to t (AUC0~ t) was determined using the trapezoidal rule. In the intravenous bolus study, the extrapolated AUC from time 0 to the first data point did not exceed 20%. The terminal half-life was determined according to the following rules: (a) time intervals equal to at least 1.5×t 1 / 2 and (b) regression analysis (a straight line on a logarithmic transformation scale) containing data from at least three different time points in the terminal phase and as many data points as possible (always including the last quantifiable concentration but excluding C max ), and (c) the coefficient of determination (r 2 ) was ≧0.85. If at least one of these three conditions was not met, the terminal half-life and parameters dependent on t 1 / 2 were flagged as enumerated but not definitely calculated. If the percentage of the extrapolated AUC exceeded 20%, the individual AUC inf results were flagged as enumerated but not definitely calculated. Flagged parameters were not included in the descriptive statistics and statistical test procedures.

[0173] The pharmacokinetics of P56 in rat plasma after a single oral dose are shown in Tables 19 and 20 below (Figure 18).

[0174]

Table 19

[0175]

Table 20

[0176] The pharmacokinetics of P56-VIII in rat plasma after a single oral dose are shown in Tables 21 and 22 (Figure 19).

[0177]

Table 21

[0178]

Table 22

[0179] The comparison of the plasma concentration-time profiles of pterostilbene in rats after single oral administration of P56 (20 mg / kg pterostilbene) and P56-VIII (13.5 mg / kg pterostilbene) is shown in Figure 20.

[0180] After single oral administration of 20 mg / kg of P56 (pterostilbene, free base) to male SD rats, plasma C max was achieved. The average C max value was 124.8 ng / mL, and the plasma levels were detected in 4 out of 5 animals up to 8 hours after administration at a concentration level close to the limit of quantification (5 ng / mL). The terminal half-life of pterostilbene was estimated to be 3.7 hours, but the variability of C max and AUC inf was 31.5% and 41.2%, respectively.

[0181] After administration of a single oral dose of 20 mg / kg of pterostilbene-picolinic acid cocrystal (13.5 mg / kg as pterostilbene), higher variability in oral absorption was observed compared to the P56 formulation, and the t max value was in the range of 1 to 6 hours after administration. The terminal half-life was 3.3 hours. This is comparable to the half-life seen with the P56 formulation. Compared to the previous formulation, there were significant increases in C max and AUC inf values, accounting for approximately 6-fold and approximately 10-fold, respectively. These results confirm that the systemic bioavailability with picolinic acid is substantially increased for pterostilbene as the picolinic acid cocrystal, and the relative bioavailability (f rel ) is 9.9. However, an approximately 20% increase in the variability of pterostilbene C max and AUC inf values was observed for the cocrystal formulation.

[0182] The results obtained in this study are comparable to those seen in the literature after oral administration. However, it is noteworthy that a decrease in the systemic clearance of pterostilbene was observed when oral administration increased beyond 25 mg / kg and an increase in oral bioavailability was seen in the fed state.

Claims

1. A co-crystal of pterostilbene and picolinic acid.

2. 5.6 and 14.0 ± 0.3 degrees 2 theta (Cu-K α radiation, λ = 1.5418 Å) and having an X-ray powder diffractogram comprising peaks characteristic thereof, the cocrystal according to claim 1.

3. The co-crystal according to claim 2, further comprising peaks characteristic of 13.5, 21.8, and 24.4 ± 0.3 degrees two-theta (Cu-Kα radiation, λ = 1.5418 Å).

4. The co-crystal according to claim 3, wherein the molar ratio of pterostilbene to picolinic acid is 1:

1.

5. 18.3 and 26.0 ± 0.3 degrees 2 theta (Cu-K α radiation, λ = 1.5418 Å), and having an X-ray powder diffractogram containing peaks characteristic thereof, the cocrystal according to claim 1.

6. The co-crystal according to claim 5, further comprising peaks characteristic of 3.2, 16.8, and 23.6 ± 0.3 degrees two-theta (Cu-Kα radiation, λ = 1.5418 Å).

7. The co-crystal according to claim 6, wherein the molar ratio of pterostilbene to picolinic acid is 2:

1.

8. A composition comprising an effective amount of the co-crystal of pterostilbene and picolinic acid according to any one of claims 1 to 7 together with one or more suitable acceptable excipients or carriers.

9. The composition according to claim 8, which is a pharmaceutical composition, a dietary supplement, a cosmetic composition, a functional food or beverage, a premix, pet food, or a medical food composition.

10. The composition according to claim 9, which is a pharmaceutical composition further comprising one or more active ingredients selected from the group consisting of anti-inflammatory agents, chemotherapeutic agents, immunomodulatory agents, cancer hormone therapy agents, targeted cancer therapy agents, anti-diabetic agents, lipid-lowering agents, anti-arthritis agents, dementia therapy agents, anti-atherosclerotic agents, anti-obesity agents, anti-osteoporosis agents, and age-related disease agents.

11. The composition according to claim 9, which is a dietary supplement further comprising one or more active ingredients selected from the group consisting of L-carnitine, xylitol, vitamins, carotenoids, omega-3 fatty acids, flavonoids, coenzyme Q10, natural products that inhibit 5-LOX, harpagoside (Figwort or Devil's Claw), copper, zinc, and manganese.

12. Use of the co-crystal of pterostilbene and picolinic acid according to any one of claims 1 to 7 in the manufacture of a medicament.

13. Use of the co-crystal of pterostilbene and picolinic acid according to any one of claims 1 to 7 in the manufacture of a medicament for the prevention and / or treatment of neurological, cardiovascular, metabolic, or hematological disorders, cancer, atherosclerotic arteriosclerosis, type 2 diabetes, inflammation, dyslipidemia, osteoporosis, or other age-related diseases.

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