COCRYSTALS OF STEROID AND SECOSTEROID COMPOUNDS AND COMPOSITIONS COMPRISING THEM

Abstract

It is provided a cocrystal of a compound of formula (I) or of a compound formula (II) wherein X and Y are independently selected from —CH.sub.2— and —C(CH.sub.2)—, provided that al least one of X or Y is —CH.sub.2—; R.sup.1 is —CHCH.sub.3—Z.sub.m—W.sub.n—(CH.sub.2).sub.o-T.sub.p-S, wherein Z is O, and m is 0 or 1; W is R.sup.4CH CHR.sup.5, wherein either R.sup.4 and R.sup.5 are H and the dashed line indicates that there is a single bond, or R.sup.4 and R.sup.5 together are forming a bond and the dashed line indicates that there is a double bond, and n is 0 or 1; o is 0, 1 or 3; T is selected from the group consisting of —CHR.sup.6—, —C(O), wherein R.sup.6 is —OH or —CH.sub.3, and p is 0 or 1; S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl optionally substituted by —OH, cyclopropyl, or; and R.sup.2 is —H or —OH; R.sup.3 is H or CH.sub.3; and the dashed line in formula (II) indicates a single or a double bond; and a hydrogen bond donor coformer which is a phenolic compound. It is also provided a composition comprising the cocrystal and a personal care product comprising the composition.

##STR00001##

Claims

1. A cocrystal of a compound of formula (I) or of formula (II) ##STR00010## wherein X and Y are independently selected from —CH.sub.2— and —C(CH.sub.2)—, provided that at least one of X or Y is —CH.sub.2—; R.sup.1 is —CHCH.sub.3—Z.sub.m—W.sub.n—(CH.sub.2).sub.o-T.sub.p-S, wherein Z is O; m is 0 or 1; W is R.sup.4CHCHR,.sup.5 wherein either R.sup.4 and R.sup.5 are H and the dashed line in W indicates a single bond; or R.sup.4 and R.sup.5 together are forming a bond and the dashed line in W indicates a double bond; n is 0 or 1; o is 0, 1 or 3; T is selected from the group consisting of —CHR.sup.6— and —C(O), wherein R.sup.6 is —OH or —CH.sub.3; p is 0 or 1; S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl optionally substituted by —OH, cyclopropyl, and ##STR00011## R.sup.2 is —H or —OH; R.sup.3 is H or CH.sub.3, and the dashed line in formula (II) indicates a single or a double bond; and a phenolic compound, wherein the phenolic compound is a hydrogen bond donor coformer.

2. The cocrystal of claim 1, wherein R.sup.1 is selected from the group consisting of —CHCH.sub.3—(CH.sub.2).sub.3—CH(CH.sub.3).sub.2, —CHCH.sub.3—(CH.sub.2).sub.5—C(CH.sub.3).sub.2OH, —CHCH.sub.3—(CH.sub.2).sub.3—C(CH.sub.3).sub.2OH, —CHCH.sub.3—(CH.sub.2).sub.2—CH.sub.2OH—C(CH.sub.3).sub.2 OH, —CHCH.sub.3—(CH.sub.2).sub.2—CH.sub.2OH—CH(CH.sub.3).sub.2, —CHCH.sub.3—(CH.sub.2).sub.2—CO—C(CH.sub.3).sub.2OH, —CHCH.sub.3—(CH.sub.2).sub.2—CO—CH(CH.sub.3).sub.2, —CHCH.sub.3—CH═CH—CHCH.sub.3—CH(CH.sub.3).sub.2, —CHCH.sub.3—CH═CH—CHCH.sub.3—C(CH.sub.3).sub.2OH, —CHCH.sub.3—CH.sub.2—CH.sub.3, —CHCH.sub.3—(CH.sub.2).sub.3—C(CF.sub.3).sub.2OH, —CHCH.sub.3—O—(CH.sub.2).sub.2—C(CH.sub.3).sub.2OH, —CHCH.sub.3—CH═CH—CHOH—(CH).sub.3, and ##STR00012##

3. The cocrystal of claim 2, wherein the compound of formula (I) is selected from the group consisting of ergocalciferol, cholecalciferol, calcifediol, ercalcidiol, calcitriol, ercalcitriol, alfacalcidol, tacalcitol, becocalcidiol, doxercalciferon, paricalcitol, calcipotriene, calcitroic acid, calcitetrol, 24-oxo-1alpha,25-dihydroxyvitamin D3, calcitriol-26,23-lactone, 1a,25-dihydroxy-cholecalciferol-26,23-peroxylactone, 26,26,26,27,27,27-hexafluoro-1alpha,25-dihydroxycholecalciferol, 24-hydroxyvitamin D3, 1alpha-hydroxy-24-oxocholecalciferol, calcifediol lactone, (23S,25R)-25-hydroxycholecalciferol-26,23-peroxylactone, 1,25-dihydroxy-24-oxo-vitamin D3, 24,25-dihydroxycholecalciferol, 25-hydroxy-24-oxo-cholecalciferol, and maxacalcitol; and wherein the compound of formula (II) is selected from the group consisting of ergosterol and 7-dehydrocholesterol.

4. The cocrystal of claim 3, wherein the cocrystal is a cocrystal of a compound of formula (I) selected from the group consisting of ergocalciferol, cholecalciferol, calcifediol, ercalcidiol, calcitriol, ercalcitriol, and alfacalcidol; and the phenolic compound.

5. The cocrystal according to claim 1, wherein the phenolic compound is orcinol or resorcinol.

6. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.3 and resorcinol polymorph A, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.6, 11.2, 14.6, 16.2, and 17.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

7. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.3 and resorcinol polymorph B, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.5, 9.4, 11.2, 15.7, and 17.5±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

8. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.2 and resorcinol, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.4, 11.1, 15.5, 16.3, and 17.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

9. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.3 and orcinol, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.3, 9.9, 11.4, 16.0 and 17.7±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

10. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.2 and orcinol polymorph A, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.2, 9.8, 11.2, 15.7, and 17.5±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

11. The cocrystal according to claim 3, wherein the cocrystal is a cocrystal of vitamin D.sub.2 and orcinol polymorph B, characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.1, 9.7, 14.6, 17.0, and 17.3±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

12. A composition comprising: an effective amount of the cocrystal of a compound of formula (I) or of formula (II); the phenolic compound as defined in claim 1; and one or more appropriate acceptable excipients or carriers.

13. The composition according to claim 12, wherein the composition is a pharmaceutical or veterinary composition, a cosmetic composition, a dietary supplement, a functional food, a functional beverage, a medical food, a premix, an animal feed, or a pet food.

14. A personal care product comprising the composition of claim 12.

15. A method for prophylaxis and/or treatment of Vitamin D deficiency, rickets, osteomalacia, osteoporosis, cancer, type 1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, influenza, Alzheimer's disease, Parkinson's disease, topical dermatitis, macular degeneration, wherein the method comprises: administering to a mammal an effective amount of the cocrystal according to claim 1, together with one or more acceptable excipients or carriers.

16. The cocrystal according to claim 2, wherein the phenolic compound is orcinol or resorcinol.

17. The cocrystal according to claim 3, wherein the phenolic compound is orcinol or resorcinol.

18. The cocrystal according to claim 4, wherein the phenolic compound is orcinol or resorcinol.

19. A composition comprising: an effective amount of the cocrystal of a compound of formula (I) or of formula (II); the phenolic compound as defined in claim 5; and one or more appropriate acceptable excipients or carriers.

20. The composition according to claim 19, wherein the composition is a pharmaceutical or veterinary composition, a cosmetical composition, a dietary supplement, a functional food, a functional beverage, a medical food, a premix, an animal feed, or a pet food.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0032] FIG. 1 shows the X-ray powder diffractogram (XRPD) of VD.sub.3:resorcinol cocrystal polymorph A (1:1). VD.sub.3 stands for vitamin D.sub.3.

[0033] FIG. 2 shows the XRPD of VD.sub.3:resorcinol cocrystal polymorph B (1:1).

[0034] FIG. 3 shows the XRPD of VD.sub.2:resorcinol cocrystal. VD.sub.2 stands for vitamin D.sub.2.

[0035] FIG. 4 shows the XRPD of cocrystal VD.sub.3:orcinol.

[0036] FIG. 5 shows the XRPD of VD.sub.2:orcinol cocrystal (polymorph A).

[0037] FIG. 6 shows the XRPD of VD.sub.2:orcinol cocrystal (polymorph B).

[0038] FIG. 7 shows the XRPD of VD.sub.2:beta-sitosterol (2:1).

[0039] FIG. 8 shows the XRPD of VD.sub.2:propionic acid cocrystal (2:1).

[0040] FIG. 9 shows the changes in Vitamin D.sub.2 content during storage at 23° C. with an illuminance of 5000 lx.

[0041] FIG. 10 shows the changes in Vitamin D.sub.3 content during storage at 23° C. with an illuminance of 5000 lx.

[0042] FIG. 11 shows the dissolution profiles of VD.sub.2, VD.sub.3, VD.sub.2-VD.sub.3 and VD.sub.3-resorcinol solids forms.

[0043] FIG. 12 shows the remaining VD.sub.3 or VD.sub.3:resorcinol after 12, 32, 60 and 90 days at 25° C./57% humidity, or after 12 days at 40° C./75% humidity. XRPD diagrams express intensity (I; counts) versus angle 2 theta (°).

DETAILED DESCRIPTION OF THE INVENTION

[0044] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0045] For the purposes of the present invention, ranges given, such as of temperatures, times, and the like, should be considered approximate, unless specifically stated.

[0046] For the purposes of the invention, the term “cocrystal” refers herein to a crystalline entity with at least two different components constituting the unit cell at room temperature (20-25° C.) and interacting by intermolecular interactions. Thus, in a cocrystal, one component crystallizes together with one or more neutral components.

[0047] The expression “cocrystal obtainable by” is used here to define each specific cocrystal of the invention by the process for obtaining it and refers to the product obtainable by any of the corresponding processes disclosed herein. For the purposes of the invention the expressions “obtainable”, “obtained” and equivalent expressions are used interchangeably and, in any case, the expression “obtainable” encompasses the expression “obtained”.

[0048] The term “hydrogen-bond donor coformer” refers to a compound having hydrogen atoms bound to an electronegative atom (such as nitrogen, oxygen, or sulfur) and with the ability to stablish strong intermolecular hydrogen-bonds with a hydrogen-bond acceptor. The term “hydrogen-bond acceptor” refers to a compound having at least one electronegative atom (such as oxygen, nitrogen, or halogen) capable of interacting with an electropositive hydrogen atom through a hydrogen bond.

[0049] The term “alkyl” refers to a saturated straight, or branched hydrocarbon chain which contains the number of carbon atoms specified in the description or claims. Examples include, among others, the group methyl, ethyl, propyl, and isopropyl. Alkyl groups can be unsubstituted or substituted as described herein, being the substituents placed on any available position.

[0050] The terms “halo” or “halogen”, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C.sub.1-C.sub.3 haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and 1,1,1,3,3,3-hexafluoro-2-propyl, the later being particularly preferred.

[0051] When values of characteristic peaks of an X-ray diffractogram are given it is said that these are “approximate” values. It should be understood that the values are the ones shown in the corresponding lists or tables ±0.3 degrees 2 theta measured in an X-ray diffractometer with Cu—K.sub.α radiation λ=1.5418 Å.

[0052] When a ratio of components of the cocrystals of the invention is specified it refers to the molar ratio of the components that forms the cocrystal. The term “molar ratio” has been used to express the stoichiometric amount in moles of each of the components of a cocrystal. The molar ratio can be determined by .sup.1H NMR (Proton nuclear magnetic resonance), thermogravimetric analysis (TGA) or single crystal X-ray diffraction (SCXRD).

[0053] The term “room temperature” refers to a temperature of the environment, without heating or cooling, and is generally from 20° C. to 25° C.

[0054] The term “overnight” refers to a time interval of from 10 h to 20 h.

[0055] It is noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0056] As mentioned above, the first aspect of the invention is the provision of cocrystal of a compound of formula (I) or of formula (II) as defined above and a hydrogen bond donor coformer which is a phenolic compound such as orcinol or resorcinol.

[0057] In an embodiment of the first aspect of the invention, m is 0. In another embodiment, m, n and p are 0, o is 1, and S is

##STR00008##

[0058] wherein R.sup.3 is as defined above.

[0059] In another embodiment of the first aspect of the invention, m is 0, n is 1 and S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl (particularly isopropyl) optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl (particularly 1,1,1,3,3,3-hexafluoro-2-propyl) optionally substituted by —OH, and cyclopropyl.

[0060] In another embodiment of the first aspect of the invention, R.sup.1 is selected from the group consisting of

[0061] —CHCH.sub.3—(CH.sub.2).sub.3—CH(CH.sub.3).sub.2,

[0062] —CHCH.sub.3—(CH.sub.2).sub.5—C(CH.sub.3).sub.2OH,

[0063] —CHCH.sub.3—(CH.sub.2).sub.3—C(CH.sub.3).sub.2OH,

[0064] —CHCH.sub.3—(CH.sub.2).sub.2—CH.sub.2OH—C(CH.sub.3).sub.2OH,

[0065] —CHCH.sub.3—(CH.sub.2).sub.2—CH.sub.2OH—CH(CH.sub.3).sub.2,

[0066] —CHCH.sub.3—(CH.sub.2).sub.2—CO—C(CH.sub.3).sub.2OH,

[0067] —CHCH.sub.3—(CH.sub.2).sub.2—CO—CH(CH.sub.3).sub.2,

[0068] —CHCH.sub.3—CH═CH—CHCH.sub.3—CH(CH.sub.3).sub.2,

[0069] —CHCH.sub.3—CH═CH—CHCH.sub.3—C(CH.sub.3).sub.2OH,

[0070] —CHCH.sub.3—CH.sub.2—CH.sub.3,

[0071] —CHCH.sub.3—(CH.sub.2).sub.3—C(CF.sub.3).sub.2OH,

[0072] —CHCH.sub.3—O—(CH.sub.2).sub.2—C(CH.sub.3).sub.2OH,

[0073] —CHCH.sub.3—CH═CH—CHOH—(CH).sub.3,

##STR00009##

[0074] wherein Z, R.sup.3 and m are as defined above.

[0075] In another embodiment, the compound of formula (I) is selected from the group consisting of ergocalciferol, cholecalciferol, calcifediol, ercalcidiol, calcitriol, ercalcitriol, alfacalcidol, tacalcitol, becocalcidiol, doxercalciferon, paricalcitol, calcipotriene, calcitroic acid, calcitetrol, 24-oxo-1alpha,25-dihydroxyvitamin D.sub.3, calcitriol-26,23-lactone, 1a,25-dihydroxy-cholecalciferol-26,23-peroxylactone, 26,26,26,27,27,27-hexafluoro-1alpha,25-dihydroxycholecalciferol, 24-hydroxyvitamin D3, 1alpha-hydroxy-24-oxocholecalciferol, calcifediol lactone, (23S,25R)-25-hydroxycholecalciferol-26,23-peroxylactone, 1,25-dihydroxy-24-oxo-vitamin D3, 24,25- di hydroxycholecalciferol, 25-hydroxy-24-oxo-cholecalciferol, and maxacalcitol; and the compound of formula (II) is selected from ergosterol and 7-dehidrocholesterol.

[0076] In another embodiment, the cocrystal is a cocrystal of a compound of formula (I) selected from the group consisting of ergocalciferol, cholecalciferol, calcifediol, ercalcidiol, calcitriol, ercalcitriol, and alfacalcidol; and a phenolic compound.

[0077] In another embodiment, the cocrystal is a cocrystal of ergosterol or 7-dehidrocholesterol and a phenolic compound.

[0078] In an embodiment, optionally in combination with one or more features of the particular embodiments defined above, the hydrogen bond donor coformer is a phenolic compound, particularly an orcinol or resorcinol.

[0079] In another embodiment, the phenolic compound is resorcinol and the cocrystal is cocrystal VD.sub.3 and resorcinol polymorph A which is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.6 and 17.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). In an embodiment, the cocrystal of VD.sub.3 and resorcinol polymorph A of the invention is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 11.2, 14.6 and 16.2±0.3 degrees 2 theta (Cu-K.sub.α radiation, λ=1.5418 Å).

[0080] More specifically, cocrystal VD.sub.3 and resorcinol polymorph A is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 1.

TABLE-US-00001 TABLE 1 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.5557 86.9 7.1031 1.85 8.8861 12.22 10.205 3.53 11.2358 52.28 12.4358 15.41 14.2056 5.11 14.6249 26.68 14.9464 9.72 15.4682 7.47 16.1696 61.6 16.6788 28.8 17.0359 100 17.3108 31.19 17.5323 30 17.7721 46.34 18.0268 18.28 18.3846 11.33 19.1441 29.1 19.591 8.63 21.057 8.44 22.1658 5.35 22.8201 21.55 23.0291 6.77 23.3722 18.44 23.8622 5.51 24.4407 6.21 27.4303 7.15 30.5995 9.26

[0081] Cocrystal VD.sub.3 and resorcinol polymorph A may be further characterized by an X-ray diffractogram as in FIG. 1.

[0082] In another embodiment, the phenolic compound is resorcinol and the cocrystal is cocrystal of VD.sub.3 and resorcinol polymorph B which is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.5 and 17.5±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). In an embodiment, the cocrystal of VD.sub.3 and resorcinol polymorph B of the invention is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 9.4, 11.2 and 15.7±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

[0083] More specifically, the cocrystal of VD.sub.3 and resorcinol polymorph B of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 2.

TABLE-US-00002 TABLE 2 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.5121 100 7.0611 2.33 9.3967 26.3 11.2281 54.09 13.756 6.9 14.1806 9.63 14.4488 9.73 14.6733 28.44 15.7142 50.51 16.6739 46.9 16.9052 48.8 17.0974 62.83 17.4732 97.78 17.8455 24.08 18.5082 37.86 18.8918 22.25 19.5187 7.58 19.816 7.36 20.5003 24.09 20.9378 6.58 22.7477 23.44 23.6647 11.52 24.1567 5.58 24.9865 3.77 26.6257 13.09 28.4853 4.84 29.1555 5.34 30.5169 5.98 32.001 3.14

[0084] Cocrystal VD.sub.3 and resorcinol polymorph B may be further characterized by an X-ray diffractogram as in FIG. 2.

[0085] In another embodiment, the phenolic compound is resorcinol and the cocrystal is cocrystal of VD.sub.2 and resorcinol which is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.4 and 17.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). In another embodiment, the cocrystal of cocrystal of VD.sub.2 and resorcinol is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 11.1, 15.5, and 16.3±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

[0086] More specifically, the cocrystal of VD.sub.2 and resorcinol of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 3.

TABLE-US-00003 TABLE 3 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.4426 100 6.8571 4.19 8.9277 7.08 10.1549 6.39 11.1191 30.53 12.2469 8.92 13.6994 7.11 14.9856 23.66 15.4683 45.31 16.2717 42.35 17.028 73.26 17.3677 43.75 17.6116 18.28 17.8599 7.41 18.9022 10.34 18.9022 10.34 19.5311 7.2 19.8988 10.74 20.3623 4.53 20.8612 7.66 22.4078 2.98 22.8716 4.79 23.1277 7.37 23.4393 5.67 23.897 5.78 24.234 8.86 27.8047 2.85 28.2209 3.38 29.397 6.49 30.7228 4.07

[0087] The cocrystal of VD.sub.2 and resorcinol of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 3.

[0088] In another embodiment, the phenolic compound is orcinol and the cocrystal is the cocrystal of VD.sub.3 and orcinol which is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.3 and 17.7±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). In another embodiment, the cocrystal of VD.sub.3 and orcinol of the present disclosure is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 9.9, 11.4 and 16.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

[0089] More specifically, the cocrystal of VD.sub.3 and orcinol of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 4.

TABLE-US-00004 TABLE 4 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.2756 100 6.5193 2.05 7.207 1.1 7.6186 2.18 9.8746 21.67 11.3682 29.49 13.5005 4.9 14.4209 11.97 15.2374 7.36 16.0216 26.7 17.2023 16.23 17.7451 54.72 18.1937 15.97 18.6688 14.43 19.7831 3.47 20.4617 5.37 20.726 5.6 21.0948 8.71 22.4295 5.69 22.7491 9.36 23.2177 4.33 24.0603 2.75 24.6764 2.41 24.8689 4.13 25.0754 3.15 25.8751 2.53 28.8817 2.45 29.8323 2.46 31.7361 2.29

[0090] The cocrystal of VD.sub.3 and orcinol of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 4.

[0091] In another embodiment, the cocrystal of VD.sub.2 and orcinol polymorph A of the present disclosure is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.2 and 17.5±0.3 degrees 2 theta (Cu—K.sub.α radiation, A=1.5418 Å). In another embodiment, the cocrystal of VD.sub.2 and orcinol polymorph A of the present disclosure is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 9.8, 11.2 and 15.7±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). Particularly, the molar ratio of VD.sub.2 and orcinol is 1:1.

[0092] More specifically, the cocrystal of VD.sub.2 and orcinol polymorph A of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 5.

TABLE-US-00005 TABLE 5 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.1632 100 5.2574 1.82 6.3217 5.53 9.8018 41.83 11.2318 41.99 12.66 3.21 13.2807 6.46 14.4638 10.33 14.8114 27.21 15.7114 45.23 17.207 60.6 17.509 98.82 18.3585 11.78 18.6069 23.75 19.28 15.38 19.6904 9.92 20.9205 9.92 21.3985 13.95 22.2391 1.59 22.5599 7.16 23.4526 12.97 23.9518 9.14 24.5035 10.54 25.4993 2.05 25.7339 3.37 26.6215 2.34 26.8976 3.26 28.2378 2.66 29.1439 7.87 31.856 4.6

[0093] The cocrystal of VD.sub.2 and orcinol polymorph A of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 5.

[0094] The data of the structure of the cocrystal VD.sub.2 and orcinol polymorph A defined above obtained by single crystal X-ray diffraction are shown below:

TABLE-US-00006 Structure VD.sub.2 and orcinol polymorph A Temperature (K)   304(2) Wavelength (Å) 0.71073 Crystal system Monoclinic Space group P 2 1 a, b, c (A) 18.3814(13), 9.5459(6), 28.663(2) α, β, γ (°) 90, 102.513(3), 90 Volume (Å.sup.3) 4910.0(6) Z, Density (calc.) (Mg/m.sup.3) 6, 1.057 Final R indices [I > 2σ(I)] R1 = 0.0973, wR2 = 0.1693

[0095] In another embodiment, the cocrystal of VD.sub.2 and orcinol polymorph B of the present present disclosure is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 3.1 and 17.3±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). In another embodiment, the cocrystal of VD.sub.2 and orcinol polymorph B of the present disclosure is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 9.7, 14.6 and 17.0±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). Particularly, the molar ratio of VD.sub.2 and orcinol is 1:1.

[0096] More specifically, the cocrystal of VD.sub.2 and orcinol polymorph B of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 6.

TABLE-US-00007 TABLE 6 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 3.1494 100 6.3291 5.3 7.2614 0.82 8.6481 1.86 9.741 23.81 10.6399 0.32 11.1929 24.37 11.7503 0.53 12.2478 0.92 12.7075 3.8 13.2647 5.18 14.2234 5.75 14.5779 18.73 15.7269 35.79 16.9783 35.58 17.2823 58.16 18.1443 7.29 18.501 13.35 19.1298 14.15 19.5111 8.42 20.8513 8.31 21.2671 13.64 22.5198 6.4 22.7905 6.42 23.3578 14.17 23.9146 9.47 24.2888 5.96 25.6839 3.68 26.5732 3.39 26.7428 4.44 28.6805 5.03 29.3903 3.53

[0097] The cocrystal of VD.sub.2 and orcinol polymorph B of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 6.

[0098] It is also disclosed a cocrystal of VD.sub.2 and beta-sitosterol which is characterized by having an X-ray powder diffractogram that comprises characteristic peaks at approximately 2.5 and 15.6±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å). Particularly, the cocrystal of VD.sub.2 and beta-sitosterol is characterized by having an X-ray powder diffractogram that further comprises characteristic peaks at 5.0, 8.7, 12.5 and 14.7±0.3 degrees 2 theta (Cu—K.sub.α radiation, λ=1.5418 Å).

[0099] More specifically, the cocrystal of VD.sub.2 and beta-sitosterol of the present disclosure is characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees, 2θ(°), which is shown in Table 7.

TABLE-US-00008 TABLE 7 List of selected peaks (only peaks with relative intensity greater than or equal to 1% are indicated): Pos. [° 2Th.] Rel. Int. [%] 2.4587 100 3.5631 15.8 4.0233 5.09 4.9518 33.35 6.0364 7.92 8.7215 18.79 12.019 17.8 12.4654 26.52 12.655 9.7 13.4025 8.99 13.9072 26.89 14.6596 60.29 14.9134 12 15.0804 9.64 15.3827 7.54 15.6257 72.58 15.8282 43.26 16.4068 49.28 17.5333 75.7 18.0097 33.5 18.2834 5.26 19.987 7.74 20.1733 10.84 20.4972 7.49 22.3944 6.64 22.6588 8.95 25.506 5.4 26.215 1.69 28.3857 1.92

[0100] The cocrystal of VD.sub.2 and beta-sitosterol of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 7.

[0101] It is also part of the present disclosure the provision of a process for the preparation of the cocrystal of a compound of formula (I) or of a compound formula (II) as defined above and a hydrogen bond donor coformer which is a phenolic compound such as orcinol or resorcinol, said process comprising the steps of: [0102] a) either preparing a solution of the compound of formula (I) or of a compound formula (II) in an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, methyl ethyl ketone, methyl isobutyl ketone, acetone, acetonitrile, dimethylformamide, pentane, heptane, cyclohexane, toluene, xylene, ethyl acetate, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, acetic acid, benzyl alcohol, formic acid, dimethyl sulfoxide, ethylene glycol, water, aqueous ammonia, diethylamine, and mixtures thereof; and adding the phenolic compound until a suspension is observed; [0103] or, alternatively, preparing a concentrated solution of the phenolic compound in the organic solvent and adding the compound of formula (I) or of a compound formula (II) until a suspension is observed; [0104] or, alternatively, preparing a suspension of the compound of formula (I) or of a compound formula (II) and the phenolic compound in the organic solvent; [0105] b) stirring the suspension at room temperature until the cocrystal is formed; and [0106] c) isolating the cocrystal thus obtained; [0107] or [0108] a′) preparing a suspension of the compound of formula (I) or of a compound formula (II) and the phenolic compound in an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, methyl ethyl ketone, methyl isobutyl ketone, acetone, acetonitrile, dimethylformamide, pentane, heptane, cyclohexane, toluene, xylene, ethyl acetate, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, acetic acid, benzyl alcohol, formic acid, dimethyl sulfoxide, ethylene glycol, water, aqueous ammonia, diethylamine, and mixtures thereof until a suspension is observed; adding another solvent until total dissolution; and removing the solvent under vacuum until a crystallized solid is obtained; [0109] or [0110] a″) grinding the compound of formula (I) or of a compound formula (II) and the phenolic compound together in order to obtain the cocrystal.

[0111] Particularly, in step a) the solvent is selected from methyl ethyl ketone, acetonitrile and toluene, and in step a′) the organic solvent is pentane.

[0112] The isolation step c) may include removing the organic solvent, for example, by one or more of the following operations: filtration, filtration under vacuum, decantation, and centrifugation, or other suitable techniques as known to a person skilled in the art. Particularly, step c) is carried out by filtration of the solid. In another embodiment, step c) further comprises drying the isolated cocrystal. More particularly, the cocrystal is dried at room temperature, more particularly under vacuum conditions. Generally, the vacuum involves a pressure from 0.5 mbar to 3 mbar.

[0113] The cocrystals of a compound of formula (I) or of a compound formula (II) as defined above and a hydrogen bond donor coformer which is a phenolic compound such as orcinol or resorcinol as defined above may also be defined by its preparation process. Accordingly, this aspect of the invention can be formulated as the cocrystals of a compound of formula (I) or of a compound formula (II) as defined above and a hydrogen bond donor coformer which is a phenolic compound such as orcinol or resorcinol by the process disclosed above and, specifically, by the particular processes for each of the cocrystals disclosed in the examples.

[0114] Formulations for the stabilization of the cocrystal are also object of the present invention. Vitamin cocrystals can be formulated using conventional formulation techniques including, without being limited to, silica adsorbing, ethylcellulose coating, fat coating, drum drying, spray drying, spray congealing, and cross-linked spray congealing, in order to obtain, for example, pulverized particles, granulates, microspheres, flakes, pulverized round particles, spherical or spheroidal beadlets, flakes, irregular or spherical agglomerates, encapsulated oil.

[0115] Depending on the technique and final result the usual additives for each technique can be used. The same additive may play different roles depending on the final formulation. For example, gelatin can be used as emulsifier, as texturing agent, or as encapsulating agent.

[0116] Examples of additives that can be used in vitamin formulations include, without being limited to, tricalciumphosphate, silicon dioxide, starches (modified or not), proteins from animal sources (including gelatins), proteins from plant sources, casein, pectin, alginate, agar, guar, maltodextrins, lignin sulfonates, cellulose derivatives, sugars, saccharides, sorbitols, gums, and mixtures thereof.

[0117] For oil containing formulations, examples of oils include, without being limited to, babassu, coconut, cohune, sunflower, murumyru tallow, palm kernel, tucum oil, and mixtures thereof.

[0118] Small quantities of other ingredients may be incorporated including, without being limited to, antioxidants such as 6-ethoxy-1,2-dihydroxy-2,2,4-trimethylquinoline (ethoxyquine), 3,5-di-tertiary-4-butyl hydroxytoluene (BHT), 3-tertiary butyl-hydroxyanisole (BHA), tocopherols, humectants such as glycerol, sorbitol, polyethylene glycol, and propylene glycol, extenders and solubilizers.

[0119] As mentioned above, a second aspect of the invention refers to a composition comprising an effective amount of the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above together with one or more appropriate acceptable excipients or carriers. The term “effective amount” refers to the amount of the cocrystal which provides a therapeutic effect after its application.

[0120] Particularly, the composition is a pharmaceutical or veterinary composition, a cosmetical composition, a dietary supplement including functional food and functional beverages, a medical food, a premix, an animal feed, or a pet food. Additionally, the composition of the present disclosure can be included in a personal care product other than the listed above.

[0121] In an embodiment, the composition of the second aspect of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above together with one or more appropriate pharmaceutically acceptable excipients or carriers. The pharmaceutical composition facilitates administration of the cocrystal to an organism. Particularly, the pharmaceutical composition can be formulated for inhaled, intramuscular, subcutaneous, oral, or topical, administration. Pharmaceutical compositions encompass also veterinary compositions.

[0122] In another embodiment, the composition of the second aspect of the invention is a dietary supplement comprising an effective amount of the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above together with one or more appropriate orally acceptable excipients or carriers. The term “dietary supplement” refers to a product taken orally that contains an ingredient intended to supplement the diet, including an animal feed supplement. Dietary supplements can be in form of tablets, capsules, softgels, gelcaps, liquids, powders, bars, drinks, shakes and other food products. As an example, the dietary supplement may be to enhance athletic performance.

[0123] The term “pharmaceutically acceptable excipients or carriers” or “dietary acceptable excipients or carriers” refers to pharmaceutically or dietary acceptable materials, compositions or vehicles, respectively. Each component must be pharmaceutically or dietary acceptable in the sense of being compatible with the other ingredients of the pharmaceutical or dietary composition, respectively. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

[0124] In an embodiment, the composition of the second aspect of the invention is a cosmetical composition comprising a safe and effective amount of the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above together with one or more cosmetically acceptable excipients or carriers.

[0125] The term “safe and effective amount” is defined as any amount sufficient to significantly improving the cosmetic appearance of the skin without substantial irritation, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement. The safe and effective amount of [active ingredients] will vary with the age and physical condition of the consumer, the condition of the skin, the duration of the treatment, the nature of any concurrent treatment, the specific combination of active ingredients employed, the particular cosmetically acceptable carrier utilized, and like factors in the knowledge and expertise of any attending physician.

[0126] The term “cosmetically acceptable” refers to that excipients or carriers suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, among others.

[0127] In an embodiment, the composition of the second aspect of the invention is a premix, particularly, a premix comprising minerals, choline chloride or a combination thereof. Minerals are known to accelerate vitamins degradation. Choline chloride is highly aggressive towards other nutrients, including vitamins.

[0128] The term “premix” refers to a composition comprising microingredients such as vitamins, minerals, nucleotides, amino acids, chemical preservatives, antibiotics, fermentation products, and other ingredients such as carotenoids and polyphenols. Premixes are for blending into commercial rations, for fortification of food products, or for the preparation of animal feeds.

[0129] In an embodiment, the composition of the second aspect of the invention is a medical food. Medical foods are foods that are specially formulated and intended for the dietary management of a disease that has distinctive nutritional needs that cannot be met by normal diet alone.

[0130] In a particular embodiment, the pharmaceutical composition as defined above further comprises one or more active ingredients selected from the group consisting of antiosteoporotic agents, antipsoriatic agents, chemotherapeutic agents, immunomodulatory agents, cancer hormone therapeutic agents, targeted cancer therapeutic agents, antidiabetic agents, antihypertensive agents, multiple sclerosis therapeutic agents, antiviral agents, anti-Alzheimer agents, anti-Parkinson agents, therapeutic agents for topical dermatitis, and agents for the treatment of macular degeneration. In another particular embodiment, the dietary supplement as defined above further comprises one or more active ingredients selected from the group consisting of L-carnitine, xylitol, vitamins, carotenoids, flavonoids, copper, zinc, and manganese.

[0131] Examples of antiosteoporotic agents include bisphosphonates, such as alendronate, risedronate, ibandronate, etidronate, zoledronate or zolendronic acid; teriparatide, abaloparatide and parathyroid hormone, raloxifene, calcitonin, denosumab, strontium ranelate, and hormone replacement therapy, such as with estrogen.

[0132] Examples of antipsoriatic agents include topical corticosteroids, such as clobetasol propionate, betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, desoximetasone, triamcinolone acetonide, mometsone furoate, fluticasone propionate, halometasone, fluocinolone acetonide, hydrocortisone valerate, hydrocortisone butyrate, flurandrenolide, desonide, alclometasone dipropionate, hydrocortisone; vitamin D analogues, such as calcifediol, calcijex, calcitriol, doxercalciferol, hectorol, paricalcitol, rayaldee, rolcatrol, zemplar; anthralin; topical retinoids, such as retinol, tretinoin, adapalene, tazarotene, alitretinoin, bexarotene; calcineurin inhibitors, such as tacrolimus, pimecrolimus; Janus Kinase (JAK) inhibitors, such as ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF-04965842, curcubitazin, CHZ868; salicylic acid, coal tar and moisturizers.

[0133] Examples of chemotherapeutic agents include alkylating agents, such as mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-mdthylurea, carmustine, lomustine, semustine, fotemustine, streptozotocin, dacarbazide, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone, cisplatin, carboplatin, oxaliplatin, procarbazine, hexamethylmelamine; antimetabolites, such as methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacytidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, mercaptopurine; anti-microtubule agents, such as vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, podophyllotoxin, etoposide, teniposide; topoisomerase inhibitors, such as irinotecan, topotecan, etoposide, doxorubicin, mitoxantrone, teniposide, novobiocin, merbarone, aclarubicin; cytotoxic antibiotics, such as mitomycin C, actinomycin, doxorubicin, daunorubicin, epirubicin, aclarubicin, mitoxantrone, bleomycin; and janus kinase inhibitors such as previously described.

[0134] Examples of immunomodulatory agents include ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, rituximab, oncorine, talimogene, laherparecvec, tisagenlecleucel, axicabtagene, ciloleucel, interferon alpha 2a, interferon alpha 2b, human leukocyte interferon-alpha, interferon beta 1a, interferon beta, 1b, interferon PEGylated versions, interleukin-2, interleukin-7, interleukin-12, chemokine ligand-3, chemokine ligand-26, chemokine ligand-7, BCG vaccine, thalidomide, lenalidomide, pomalidomide, apremilast, cytosine phosphate-guanosine, oligodeoxynucleotides, and glucans, sipuleucel-T vaccine.

[0135] Examples of cancer hormone therapeutic agents include tamoxifen, anastrozole, letrozole, exemestane, raloxifene, and fulvestrant.

[0136] 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, temsitolimus, everolimus, vemurafenib, trametinib, dabrafenib, prembolizumab, rituximab, trastuzumab, alemtuzumab, cetuximab, panitumumab, bevacizumab, and ipilimumab.

[0137] Examples of antidiabetic agents include biguanides (i.e., metformin, buformin, phenformin), sulfonylureas (i.e., acetohexamide, carbutamide, chlorpropamide, glibomuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepid, glyburide, glybuthiazole, glybuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclomide), thiazolidinediones (i.e., piogliatazone, rosiglitazone, troglitazone), beta andrenergic blockers, and other antidiabetics such as acarbose, calcium mesoxalate, miglitol, nateglinide, repaglinide, voglibose.

[0138] Examples of antihypertensive agents include diuretics, such as bumetanide, ethacrynic acid, furosemide, torsemide, epitizide, hydrochlorothiazide, chlorothiazide, Bendroflumethiazide, methyclothiazide, polythiazide, indapamide, chlorthadolide, metalozone, xipmide, clopamide, amiloride, triamterene, spironolactone, eplerenone; calcium channel blockers such as amplodipine, cilnidipine, clevidipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, diltiazem, verapamil; angiotensin-converting enzyme inhibitors such as captopril, enalapril, fosinopril, lisinopril, moexiproil, perindopril, quinapril, ramipril, trandolapril, benazepril; angiotensin II receptor antagonists such as azilsartan, candesartan, eprosartan, ibersartan, losartan, Olmesartan, telmisartan, valsartan, fimasartan; adrenergic receptor antagonists such as acebutonol, atenolol, bisoprolol, betaxodol, carteolol, carvediol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, timolol, doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin, tolazoline, bucindolol, carvedilol, labetalol; vasodilators such as sodium nitroprusside, hydralazine, dihydralazine, cadralazine, endralazine; renin inhibitors, such as aliskiren; aldosterose receptor antagonists such as eplerenone, spironolactone; alpha-2 adrenergic receptor agonists such as clonidine, guanabenz, guanfacine, methyldopa, moxonidine, guanethidine, mecamylamine, reserpine, kinoxidil; and endothelium receptor blockers, such as bosentan.

[0139] Examples of multiple sclerosis therapeutic agents include corticosteroids such as prednisolone, methylprednisolone; modifying progression treatments, such as ocrelizumab, natalizumab, alemtuzumab, mitoxantrone, beta interferons, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, siponimod; signs and symptoms treatments such as muscle relaxants (i.e. baclofen, tizanidine); fatigue redactors (i.e. amantadine, modafinil, methylphenidate; and agents increasing walking speed (i.e. dalfampridine).

[0140] Examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, ampligen, amprenavir, arbidol, atazanavir, atripla, balavir, baloxavir marboxil, bikarvy, cidofovir, combivir, darunavir, delavirdine, descovy, didanosine, docosanol, dolutegravir, ecoliever, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ibacitabine, idoxuridine, imiquimod, imunovir, indinavir, inosine, integrase inhibitor, interferon (type I, II, III), lamivudine, lopinavir, loviride, nelfinavir, nevirapine, nexavir, nitazoxanide, norvir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, pyramidine, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, saquinavir, sofosbuvir, stavudine, telaprevir, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine.

[0141] Examples of anti-Alzheimer agents include cholinesterase inhibitors such as donepezil, galantamine, rivastigmine, tacrine, physostigmine, neostigmine, pyridostigmine, ambenonium, demacarium, caffeine, rosmarinic acid, alpha-pipene, edrophonium, huperize A, ladostigil, ungeremine, lactucopicrin, acotiamide; and NMDA receptor antagonists such as memantine.

[0142] Examples of anti-Parkinson agents include carbidopa-levodopa; dopamine agonists, such as pramipexole, ropinirole, rotigotine, apomorphine, lergotrile, pergolide, bromocriptine, lisuride, aripiprazole, phencyclidine, quinpirole, salvinorin A, cabergolide, ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine, piribedil, pramipexole, propylnorapomorphine, quinagolide, roxindole, sumanirole, fenoldopam; MAO B inhibitors such as isocarboxacid, nialamine, phenelzine, hydracarbazine, tranylcypromine, bifemelane, moclobemide, pirlindole, toloxatone, rasagiline, selegiline, safinamide, linezolidbenmoxin, iproclozide, iproniazid, menabazine, octamonix, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, safrazine, caroxazone, minaprine, brofaromine, eprobemide, methylene blue, metralindole, curcumin, harmaline, harmine, amiflamine, befloxatone, cimoxatone, esuprone, sercloremide, tetrindole, CX157; catechol o-methyltransferase (COMT) inhibitors such as entacapone, tolcapone, nebicapone, nitecapone, opicapone; anticholinergics such as benztropine, trihexyphenidyl, clozapine, quetiapine, atropine, biperiden, chlorpheniramine, certain SSRIs (such as citalopram), dicyclomine (dicycloverine), dimenhydrinate, diphenhydramine, doxepin, doxylamine, glycopyrrolate, glycopyrronium, hoscyamine, ipratropium, orphenadrine, oxitropium, oxybutynin, promethazine, propantheline bromide, scopolamine, solifenacin, tolterodine, tiotropium, tricyclic antidepressants (28 compounds with numerous trade names), tropicamide, bupropion, dextromethorphan, doxacurium, hexamethonium, mecamylamine, tubocurarine; and amantadine.

[0143] Examples of therapeutic agents for topical dermatitis include creams that control itching and repair the skin (that may contain corticosteroids, and/or calcineurin inhibitors such as tacrolimus, pimecrolimus; drugs to fight the infection (oral or topical antibiotic containing formulations; oral corticosteroids; janus kinase inhibitors such as previously described; and dupilumab.

[0144] Examples agents for the treatment of macular degeneration include bevacizumab, ranibizumab, aflibercept, vitamin C, vitamin E, lutein, zeaxantin.

[0145] In a particular embodiment, the cosmetical composition, the dietary supplement, the functional food or beberage, the premix, the animal feed, the pet food, or the medical food composition as defined above further comprises one or more nutraceutical ingredient such as vitamins, carotenoids, and flavonoids.

[0146] Examples of vitamins include but are not limited to Vitamin A (acetate or palmitate, betacarotene), vitamin B1 (thiamine (aneurine)) (hydrochloride or mononitrate), B2 (riboflavin), vitamin B6 (pyridoxine hydrochloride), vitamin B12 (cobalamin), vitamin B12 (cyanocobalamin), vitamin B12 (mecobalamin), vitamin C (ascorbic acid), nicotinic acid, vitamin D2 (ergo-calciferol), vitamin E (alpha tocopheryl acetate, alpha tocopheryl succinate, alpha tocopherol, γ-tocopherol), vitamin K (phylloquinone, menadione etc), and nicotinamide riboside.

[0147] Examples of carotenoids include, but are not limited to, lutein, lycopene, α-carotene, β-carotene, γ-carotene, β-cryptoxanthin, Capsanthin, Zeaxanthin, Astaxanthin.

[0148] Examples of flavonoids include, but are not limited to, kaempferol, myricetin, quercetin, rutin, catechin, epicatechin, ECG, gallocatechin, EGC, EGCG, cyanidin, caffeic acid, theaflavin, theaflavin gallate, luteolin, daidzein, genestein, and glycitein.

[0149] The compositions of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.

[0150] All the embodiments disclosed above for the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above also applies to the compositions of the invention.

[0151] As mentioned above, the third aspect of the invention refers to a cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above for use as a medicament.

[0152] Particularly, the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above is for use in the prophylaxis and/or treatment of Vitamin D deficiency, rickets, osteomalacia, osteoporosis, cancer, type1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, influenza and other diseases mediated by the immune system such as Alzheimer Disease, Parkinson, topical dermatitis, macular degeneration. This aspect could be also formulated as the use of the a cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above, for the preparation of a medicament for the prophylaxis and/or treatment of Vitamin D deficiency, rickets, osteomalacia, osteoporosis, cancer, type1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, influenza and other diseases mediated by the immune system such as Alzheimer Disease, Parkinson, topical dermatitis, macular degeneration. It also relates to a method for the prophylaxis and/treatment of Vitamin D deficiency, rickets, osteomalacia, osteoporosis, cancer, type1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, influenza and other diseases mediated by the immune system such as Alzheimer Disease, Parkinson, topical dermatitis, macular degeneration, wherein the method comprises administering to said mammal an effective amount of the cocrystal of a compound of formula (I) or of formula (II) and a hydrogen bond donor coformer as defined above, together with one or more acceptable excipients or carriers.

[0153] Throughout the description and claims the word “comprise” and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”.

[0154] The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

EXAMPLES

General Considerations

[0155] Ergocalciferol, cholecalciferol, calcifediol, ercalcidiol, calcitriol, ercalcitriol and alfacalcidol 7-dehydrocholesterol, are commercially available.

[0156] Powder X-Ray diffraction (PXRD) analyses were performed by sandwiching the powder samples between polyester films of 3.6 microns of thickness analysed in a PANalytical X'Pert PRO MPD θ/θ powder diffractometer of 240 millimetres of radius, in a configuration of convergent beam with a focalizing mirror and a flat sample transmission geometry, in the following experimental conditions: Cu Kα radiation (λ=1.5418 Å); Work power: 45 kV and 40 mA; Incident beam slits defining a beam height of 0.4 millimetres; Incident and diffracted beam 0.02 radians Soller slits; PIXcel detector: Active length=3.347°; 2θ/θ scans from 2 to 40° 2θ with a step size of 0.026° 2θ and a measuring time of 76 seconds per step.

Example 1.—Preparation of Form VD.SUB.3.:Resorcinol Cocrystal Polymorph A

[0157] VD.sub.3 (500 mg, 1.30 mmol) and resorcinol (143 mg, 1.30 mmol) were stirred in pentane (3.0 mL). Then, acetone (2.0 mL) was added until total dissolution. The clear solution was air-opened and kept at 4-6° C. A yellow glassy oil was observed after 23 days and it was dried under vacuum until a solid crystallized.

Example 2.—Preparation of Form VD.SUB.3.:Resorcinol Cocrystal Polymorph B

[0158] A concentrated solution of resorcinol in ACN was prepared (300 mg in 0.1 mL). A suspension was prepared by adding VD.sub.3 (150 mg, 0.39 mmol) and it was stirred overnight at room temperature. A clear solution was obtained the day after and it was air-opened and kept at 4-6° C. A solid was observed after 9 days and it was filtered and dried under vacuum.

Example 3.—Preparation of a Cocrystal of Form VD.SUB.2.:Resorcinol

[0159] Concentrated solution of VD.sub.2 in MEK was prepared (100 mg in 0.1 mL). Resorcinol was added until a suspension was observed. The suspension was stirred overnight at room temperature. The solid was filtered and dried under vacuum.

Example 4.—Preparation of a Cocrystal of VD.SUB.3.:Orcinol

[0160] VD.sub.3 (378.1 mg, 0.983 mmol) and orcinol (121.9 mg, 0.983 mmol) were stirred in hexane (2.0 mL) overnight at room temperature. The solid was filtered and dried under vacuum.

Example 5.—Preparation of Form VD.SUB.2.:Orcinol Cocrystal Polymorph A

[0161] VD.sub.2 (500 mg, 1.261 mmol) was stirred in toluene (0.65 mL) during 30 minutes until total dissolution. Orcinol (104.3 mg, 0.839 mmol) was added and a suspension was observed. The suspension was stirred at room temperature for 3 days. The solid was filtered and dried under vacuum.

Example 6.—Preparation of Form VD.SUB.2.:Orcinol Cocrystal Polymorph B

[0162] Form VD.sub.2:orcinol cocrystal polymorph B was obtained by heating of solid of VD.sub.2:orcinol cocrystal polymorph A between 70° C. and 80° C. in DSC or XRPD temperature variable experiment.

Example 7.—Preparation of a Cocrystal of VD.SUB.2.:Beta-Sitosterol

[0163] VD.sub.2 (200 mg, 0.504 mmol) was dissolved in ACN (25 mL) at 50° C. The solution was cooled down at room temperature and no solid was observed. Beta-sitosterol (83 mg, 0.200 mmol) was added to form a suspension. The suspension was stirred at room temperature overnight. The solid was filtered and dried under vacuum.

Comparative Example 1.—Preparation of a Cocrystal of VD.SUB.2.:Propionic Acid

[0164] VD.sub.2 (50 mg, 0.126 mmol) and propionic acid (0.05 mL) were grinded at 30 Hz during 15 minutes at room temperature. A cocrystal of VD.sub.2:propionic acid was obtained. The cocrystal was characterized by exhibiting in the X-ray powder diffractogram a pattern of peaks, expressed in 2 theta units in degrees (Cu—K.sub.α radiation, λ=1.5418 Å), which is shown in Table 8.

TABLE-US-00009 Pos. [° 2Th.] Rel. Int. [%] 6.0043 15.16 6.9213 7.62 9.1577 16.05 11.3523 8.5 12.0067 1.92 12.4096 9.51 12.7661 6.55 13.8106 2.08 15.0963 25.17 15.3395 59.85 16.1007 79.47 16.5378 18.43 16.9253 100 18.3533 9.86 19.3294 12.96 19.5146 11.18 19.8962 1.55 20.4662 8.02 20.8186 2.31 21.049 4.09 21.6802 7.23 21.9149 7.3 22.1914 4.41 22.7132 7.56 24.0852 7.48 24.512 4.9 25.1064 8.46 26.8357 4.28 29.9381 4.29

[0165] The cocrystal of VD.sub.2:propionic acid of the present disclosure may be further characterized by an X-ray diffractogram as in FIG. 8.

Example 8.—Photostability of the New VD.SUB.2 .and VD.SUB.3 .Cocrystals Versus VD.SUB.2./VD.SUB.3 .Cocrystal

[0166] In order to compare the photostability of the new VD.sub.2 and VD.sub.3 cocrystals with the one of VD.sub.2/VD.sub.3 (form A) cocrystal and of pure VD.sub.2 and VD.sub.3, the different samples were subjected to accelerated storage conditions at 23° C. and illumination with 5000 lx for 90 days. VD.sub.2/VD.sub.3 (form A) cocrystal was prepared according to the procedure described in Wang et al. Chem. Commun., 2016, 52, 3572.

[0167] The samples under study were periodically analyzed by HPLC as follows:

[0168] Determination of vitamin D.sub.2/D.sub.3 content in each sample was performed by HPLC (Agilent 1100 Series H PLC) equipped with a quaternary bomb (G1311A), a degasifier (G1322A), an injector (G1329A) and diode-array detector (G1315B) using a Kinetex C18 column (100 mm×4.6 mm, 2.6 μm) and a mobile phase (A: Water 0.1% formic acid, and B: Acetonitrile) with a flow rate of 0.8 mL.Math.min-1 and an isocratic at 95% B (8 min analysis time) gradient and it was acquired at a wavelength of 270 nm.

[0169] FIGS. 9 and 10 show the decrease in VD.sub.2 and VD.sub.3 content of new VD.sub.2 and VD.sub.3 cocrystals compared to VD.sub.2/VD.sub.3 (form A) cocrystal and pure VD.sub.2 and VD.sub.3, respectively, during storage at 23° C. with an illuminance of 5000 lx.

Example 9.—Stability Under Stress Conditions

[0170] Comparative Vitamin D.sub.3 (VD) Vs Vitamin D.sub.3 Cocrystals Under Different Stress Conditions

[0171] Similarly as above, the stability of the VD.sub.3:orcinol cocrystal was studied and compared to stability of VD.sub.3 (Form A) under stress conditions (40° C.—75% RH). The samples were stored under these conditions inside a Series FD Binder chamber and they were analyzed periodically by PXRD. A saturated solution of sodium chloride (75%) was used to control relative humidity.

[0172] As shown in Table 3, VD.sub.3 (Form A) exhibited a very low stability under stress conditions since it converted into a liquid phase in five days. However, VD.sub.3:orcinol cocrystal exhibited a very high stability under stress conditions since it remained as the same starting solid form after 230 days.

TABLE-US-00010 TABLE 3 Time 40° C.-75% RH (days) VD.sub.3 VD.sub.3:orcinol 0 Form A VD.sub.3:orcinol 5 liquid VD.sub.3:orcinol 14 — VD.sub.3:orcinol 30 — VD.sub.3:orcinol 60 — VD.sub.3:orcinol 150 — VD.sub.3:orcinol 230 — VD.sub.3:orcinol
Comparative of Vitamin D.sub.2 (VD.sub.2) Vs Vitamin D.sub.2 Cocrystals Under Different Stress Conditions

[0173] The stability of the VD.sub.2 cocrystal with beta-sitosterol and VD.sub.2 cocrystal with orcinol was studied and compared to the stability of VD.sub.2 (Form A) under two stress conditions. The samples were stored under both stress conditions inside a Series FD Binder chamber and they were analyzed periodically by PXRD. The two stress conditions were the following: [0174] condition A: 25° C. and 57% relative humidity; [0175] condition B: 40° C. and 75% relative humidity.

[0176] A saturated solution of sodium bromide salt (for 57% RH) and a saturated solution of sodium chloride (for 75% RH) were used to control relative humidity.

[0177] Table 1 and 2 show the evolution of the different solid forms over time.

TABLE-US-00011 TABLE 1 25° C.-57% RH Time VD.sub.2: VD.sub.2: (days) VD.sub.2 beta-sitosterol orcinol 0 Form A VD.sub.2: VD.sub.2:gorcinol beta-sitosterol 7 — — — 14 — — VD.sub.2:gorcinol 25 Form A with presence VD.sub.2: — of amorphous phase.sup.1 beta-sitosterol 50 — — VD.sub.2:gorcinol 130 — VD.sub.2:gorcinol 210 Form A with presence VD.sub.2: — of amorphous phase.sup.2 beta-sitosterol 370 Amorphous phase VD.sub.2: — beta-sitosterol

TABLE-US-00012 TABLE 2 40° C.-75% RH Time VD.sub.2: VD.sub.2: (days) VD.sub.2 beta-sitosterol orcinol 0 Form A VD.sub.2: VD.sub.2:gorcinol beta-sitosterol 7 — — — 14 — — VD.sub.2:gorcinol 25 Form A with presence VD.sub.2: — of amorphous phase.sup.1 beta-sitosterol 50 — — VD.sub.2:gorcinol 130 — — VD.sub.2:gorcinol with presence of Form A 210 Liquid phase Amorphous — 370 — Amorphous — .sup.1The solid has a brown colour and its PXRD shows the characteristic halo of amorphous phase. .sup.2The solid shows the amorphous solid as the major solid phase, with traces of crystalline VD.sub.2 (form A) in the mixture and the sample shows a brown colour.

[0178] VD.sub.2 (Form A) exhibited a very low stability under both stress conditions since it started to convert into an amorphous phase in 25 days. However, VD.sub.2:orcinol cocrystal exhibited a very high stability under both stress conditions since it remained as the same starting solid form after 130 days under 25° C. and 57% of relative humidity and 50 days under 40° C. and 75% of relative humidity. On the other hand, VD.sub.2:beta-sitosterol cocrystal exhibited also a very high stability under both stress conditions since it remained as the same starting solid form after 370 days under 25° C. and 57% of relative humidity and 25 days under 40° C. and 75% of relative humidity.

Example 10. Dissolution Rate of the Cocrystal of VD.SUB.2 .and VD.SUB.3 .in FaSSIF v2 Medium

1. Molar Extinction Coefficient (MEC) Determination in FaSSIF v2 Medium

[0179] Molar extinction coefficients of VD.sub.2, VD.sub.3 and of the coformer were determined by UV-metric titration using a GIpKa™ titrator (Sirius Analytical Instruments, UK). Briefly, a 10 mM stock solution of sample was prepared in DMSO. 50 μL of sample stock solution and 0.25 mL of a 15 mM potassium phosphate buffer were added to 10 mL of a 0.15 M KCl solution, which in turn contained 17.9 mg of FaSSIF v2 powder. The pH of the sample solution was adjusted to 2 with 0.5 M HCl before starting the titration, and then the titration was done using 0.5 M KOH up to pH 12. The UV absorption spectra (between 250 and 450 nm) of the solution were recorded at each titrant addition by a fiber optic dip-probe. The collected data were refined through the RefinamentPro software, and the pKa values and Molar Extinction Coefficients obtained by Target Factor Analysis.

2. Dissolution Rate Experiments

[0180] Tablet production: tablets of 3 mm diameter were done using a manual hydraulic tablet press (Applied Measurements Ltd, UK). The applied pressure was 100 Kg for 2 min. From 6 to 10 mg of each solid form, vitamin or cocrystal, were weighted. The total exposed surface area was 0.5 cm.sup.2. [0181] Medium: FaSSIF v2 (pH 6.5), with corresponding amount of phosphoric (28.4 mM) acid instead of maleic acid. [0182] Dissolution tests were performed with a small-scale dissolution assay installed in a GIpKa™ titrator (Sirius Analytical Instruments, UK). [0183] Dissolution time and temperature: 120 minutes and 25° C. [0184] Procedure: 15 mL of FaSSIF v2 was added into the sample vial containing the tablet. Spectra collection started immediately after. Spectra were recorded every 30 seconds between 250 and 450 nm through a Sirius D-PAS spectrometer with a bifurcated optic fibre dip probe (Hellma Analytics). The medium was stirred at a constant rate.

3. UV-Vis Quantification

[0185] The concentration of cholecalciferol (VD.sub.3) or ergocalciferol (VD.sub.2) in solution at each time point is determined from the spectroscopic data by applying the Beer-Lambert law, using previously determined molar extinction coefficients of the pure APIs and the coformers. Spectrum regions where signal is saturated (A>1.5) or presenting medium interferences were discarded. Then, the concentration data were converted into absolute sample quantities, and used to generate the graphs showing the sample quantity vs. time.

4. Determination of the Dissolution Rate

[0186] Dissolution rate is obtained through the fit of the first order Noyes-Whitney exponential equation to the data:

[X]t=S(1−e−kd(t−t0))

[0187] In this equation, [X].sub.t is the weight in grams of compound in solution at the experiment time (min); S is the extrapolated solubility (g) of the vitamin; k.sub.d is the rate constant for dissolution (min.sup.−1); and t.sub.0 (min) is a term allowing for a temporal offset. Results are calculated using a refinement process in which S, k.sub.d and t.sub.0 are varied in order to minimize the root mean square deviation between the modelled concentrations and the measured concentrations. The dissolution rate (g min.sup.−1) is given by the product k.sub.dS (T. Gravestock et al., Anal. Methods, 2011, 3, 560). Results are shown in Table 3.

TABLE-US-00013 TABLE 3 Solid form dissolution rate (nmol/min) VD.sub.2 0.74 ± 0.23 VD.sub.3 0.58 ± 0.14 VD.sub.3-VD.sub.2 0.63 ± 0.21 VD.sub.3-resorcinol 0.94 ± 0.22

[0188] The comparison between dissolution rate curves of the solid forms listed in Table 3 is shown in FIG. 11.

[0189] It can be seen that VD.sub.3-resorcinol dissolved faster than VD.sub.2, VD.sub.3, or VD.sub.2-VD.sub.3.

Example 10.—Stability of Vitamin D.SUB.3 .(VD) Vs Vitamin D.SUB.3.:Resorcinol Cocrystal in a Premix

[0190] The stability of the VD.sub.3:resorcinol cocrystal mixed in a premix that was a standard mineral-vitamin mix containing choline was studied under normal and high environmental temperature/humidity and compared to the stability of commercial VD.sub.3 for animal nutrition (Orffa D3 500) in the same premix under de same conditions.

Environmental Conditions

[0191] 25° C. and 57% humidity (temperature controlled chambers with a saturated solution of NaBr to maintain humidity at 57%); [0192] 40° C. and 75% humidity (temperature controlled chambers with a saturated solution of NaCl to maintain humidity at 75%).

[0193] The tested VD.sub.3:resorcinol and VD.sub.3 were mixed in a standard vitamin and mineral mix containing components shown in Table 4.

TABLE-US-00014 TABLE 4 Nutritional additive mg/kg Copper (copper sulfate pentahydrated) 4,350 Zinc (Zinc Sulfate monohydrate) 17,920 Manganese (Magnesium sulfate monohydrate) 5,394 Iodine (Potassium iodine) 137 Selenium (Sodium Selenite) 91 Cobalt (Cobalt Acetate tetrahydrate) 47 Zinc (Zinc-AA quelate, Hydrated) 5,000

[0194] The mineral mix was supplemented to contain 750,000 UI/kg Vitamin A, 5,000 mg/kg vitamin E and 12.5% choline chloride (choline chloride, vegetal coating, 60%). VD.sub.3 final content was 1,600,000 UI/Kg (both for the cocrystal VD.sub.3:resorcinol and for the commercial VD.sub.3.

Procedures

[0195] Samples (2 g) were weighted in 50 mL plastic tubes and incubated in the experimental conditions (see above). Samples for each individual time were incubated in quadruplicates to account for potential variation. Samples were prepared to be retrieved from incubators at 2, 4, 8 and 12 weeks. After each time, samples were processed and analyzed immediately (no storage).

[0196] Samples were subjected to an extraction process done in the incubation tube with the full sample to avoid sub-sampling problems. Extracted supernatant was analysed for vitamin D using and HPLC (Model 1260 Series, Agilent, Darmstadr, Germany) coupled with a MS-QQQ (Model G6420, Agilent) against a calibrated curve using a standard vitamin D.sub.3. Results are reported as a percent degradation compared with the original Vitamin concentration.

Results

[0197] Temperature and humidity were maintained within the pre-planned conditions. Concentrations of VD.sub.3 for the Control and of VD.sub.3:resorcinol are presented in FIG. 12. VD.sub.3 was more stable at 25° C./57% H compared with 40° C./75% H, as expected. At 25° C./57% H VD.sub.3:resorcinol was more stable than VD.sub.3. At 40° C./75% H, both products had a sharp reduction in stability, but VD.sub.3:resorcinol has a better performance than commercial VD.sub.3. It should be noted that the mineral mix contained high levels of choline chloride which is highly aggressive towards other nutrients, including vitamins.

[0198] These results indicate a consistent evolution of the degradation kinetics of VD.sub.3 and of VD.sub.3:resorcinol and at the different conditions. In both conditions, VD.sub.3:resorcinol remains more stable than VD.sub.3.

CITATION LIST

[0199] 1. Wang, J R et al. 2013 “Stabilizing vitamin D by conformationally selective co-crystallization” Chem. Commun., 2014, Vol. 50, pp. 855-858. [0200] 2. Wang J. R. et al. “Drug-drug co-crystallization presents a new opportunity for the development of stable vitamins” Chem. Commun., 2016, Vol. 52, pp. 3572-3575.