Improved multicomponent crystals of tocopherol mixtures and process of making

Abstract

Multicomponent crystal comprising a) an active, said active being a mixture of at least two distinct molecules of formula (1) with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)14CH3, CO(CH2)16CH3, - with the methyl groups in position 2, 4', 8' respectively having a S-configuration or a R-configuration, and b) a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of b1) - being suitable to form ions and - containing a H-bond acceptor and - being suitable to form a zwitterionic structure and - having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or - containing a H-bond donor, with the proviso that the combination of proline as crystallizing agent of formula (2z) and tocopherol as active is excluded from the teaching of claim 1.

Description

[0001] Improved Multicomponent Crystals of Tocopherol Mixtures and Process of Making

[0002] This invention relates to improved multicomponent crystals of a-tocopherol mixtures as well as to a process of making same. A further aspect of the invention covers a composition comprising said multicomponent crystals as well as the use of said multicomponent crystals and said composition.

[0003] Synthetic a-tocopherol or syn a-tocopherol, also referred to as DL-a-tocopherol or D / L a-tocoph- erol is an isomeric mixture comprising at least two stereoisomers. It can also comprise three stereoisomers, four stereoisomers, five stereoisomers, six stereoisomers, seven stereoisomers and in most cases eight stereoisomers. It can be defined by formula (3) with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configu- ration.

[0004] In case of all eight stereoisomers being present, synthetic a-tocopherol or DL-a-tocopherol is also named all-rac a-tocopherol. All-rac a-tocopherol has three stereocenters viz. at position 2, 4’ and 8’as shown in formula (3) and thus it can form the eight stereoisomers having the following configuration: RRR, RRS, RSS, SSS, RSR, SRS, SRR and SSR.

[0005] DL-a-tocopherol as well as all-rac a-tocopherol are synthetically produced mixtures of Vitamin E active compounds or actives of formula (3). They are highly viscous oils, which are sensitive to oxidation and thus not stable for extended storage. Taking into account this sensitivity towards oxygen, stemming from the OH-group in position 6 of the aromatic ring of DL-a-tocopherol as well as all-rac a-tocopherol, both shown in formula (3), successful attempts were made to protect said OH group of said actives against oxidation by means of esterification.

[0006] Beside the actives DL-a-tocopherol as well as all-rac a-tocopherol, both shown in formula (3), the acetate, propionate, palmitate and stearate of DL-a-tocopherol as well as of all-rac a-to- copherol became important feed and food supplements and pharmaceutical ingredients. Thus, commercial important compound mixtures exhibiting Vitamin E activity are not only the compound mixtures of formula (3) but rather the mixtures of the larger group of DL-a-tocoph- erol, all-rac a-tocopherol and their respective esters, all of which are grouped under formula (1) with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3and with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration.

[0007] However, also the actives or active mixtures of formula (1) are either highly viscous oils difficult to handle and to formulate or fragile solids. All of them are light-sensitive and degrade upon application of elevated temperatures. They do not exhibit characteristics of a fine powder and unfavorably tend for clumping or caking. In order to preserve the mixtures of formula (1) from oxidation or degradation by light or high temperature and to achieve non-hygroscopic defined solids, sophisticated formulation technology is needed to produce a lasting free flowing powder. To obtain good formulation properties carbohydrates, colloids and / or silica are generally used as adjuvants in an expensive spray drying or beadlet process.

[0008] An attempt to overcome the previously mentioned drawbacks was made by Mei and coworkers in EP 3 733657 A1 hereinafter ‘657. They produced crystalline or partial crystalline “co-crystals” of tocopherol and proline (cf. para. 15), but no molar ratio of proline and tocopherol in the formed crystal is confirmed by measurement. The indicated stoichiometry in the crystals formed instead refers to the stoichiometry of the starting materials and this stoichiometry is supposed to be maintained in the crystals formed, which as shown below, is not the case. The co-crystal in the ‘657 document is disclosed to have a ratio between tocopherol and proline of 2:1 , 1 :1 and 1:2.

[0009] In this reference ‘657 tocopherol is understood to mean: “Tocopherols include natural tocopherol and synthetic tocopherol. Natural tocopherol comprises two types of tocopherols and to- cotrienols, and comprises 8 kinds of compounds, namely a-, p-, y-, b-tocopherols and a-, -, y-, b-tocotrienols. Synthetic tocopherol refers to a-tocopherol, and has 8 optical isomers. Among them, D-a-tocopherol is a form of tocopherol which is most widely distributed in nature, most abundant, and has the highest activity.” (cf. para. 0002) and “The tocopherol comprises natural tocopherol and synthetic tocopherol, the natural tocopherol comprises a-, p-, y-, b-tocopherols and a-, p-, y-, 6-tocotrienols; the synthetic tocopherol comprises DL-a-tocopherols.” (cf. claim 2).

[0010] Likewise, a definition is given for proline, which reads: “Preferably, the proline is D-proline, or L- proline, or a racemic mixture of the both.” (cf. para 7 of ‘657) and “The proline comprises D-pro- line, or L-proline, or a racemic mixture of the both.” (cf. claim 2).

[0011] Upon reworking the examples of ‘657, we found, that the onset temperatures To, the peak temperatures Tpand the transition enthalpy AH all measured by differential scanning calorimetry were low (cf. comparative examples below). Likewise, the temperature of decomposition Td as measured by differential gravimetric analysis (TGA) is reduced. This indicates crystallinity in ‘657 being moderate or only partially developed and samples being heterogeneous and partially amorphous or still containing not crystallized matter.

[0012] In Int. J. Pharm. 592 (2021) 120057, hereinafter ‘057, Mei and coworkers study co-crystals or partially crystalline co-crystals formed from the single molecule D-a- tocopherol, also named RRR-a-tocopherol and either 1 ,2-di (4-pyridyl)ethylene (DPE) or L-proline or betaine. This is to say, that mixtures like DL-a-tocopherol or all-rac a-tocopherol are not assayed for co-crystal formation, let alone mixtures of formula (1).

[0013] We reproduced the preparation indicated under 2.4. of ‘057 comprising D-a-tocopherol and betaine (cf. comparative examples below) and could only establish the partial formation of co-crys- tals.

[0014] The invention intends to overcome the drawbacks of the prior art. In particular, it is an object of the invention to obtain a more homogeneous or higher structured and thus more stable multicomponent crystal. Another object of the invention is to obtain this more stable multicomponent crystal not from D-a-tocopherol but from a mixture of at least two distinct molecules of formula (1) or of formula (3). Yet another inventive object is to obtain a multicomponent crystal which remains stable at higher temperatures than those disclosed in the prior art. A further inventive objective is to obtain a multicomponent crystal, which is free flowable and does not clot. It shall not tend to be hygroscopic, even after storage periods over weeks and months. Another object is to provide a multicomponent crystal, which can be readily formulated into a composition of the invention. Yet another object is to obtain a multicomponent crystal, in which the bioavailability is as in the mixture of formula (1) or of formula (3) prior to crystallization or is only slightly reduced with respect to the uncrystallized mixture of formula (1) or of formula (3).

[0015] A further object of the invention is to provide a process for obtaining the inventive multicomponent crystal. Said process is to be straight forward, shall avoid harmful operation steps or compounds and shall be inexpensive. The way of conducting said process shall not be excessively time-consuming and easy to realize. Furthermore, said process shall ensure a huge amount of active to become part of the multicomponent crystal. It shall avoid to the utmost extent having non-crystallized matter being part of the multicomponent crystal.

[0016] Yet another object of the invention is to provide a composition comprising the multicomponent crystal. Said composition shall be timely obtained. It shall exhibit at least the performance characteristics of state-of-the-art formulations of DL-a-tocopherol or of all-rac a-tocopherol and even perform better. Said composition shall have the same or a better bioavailability as prior art DL- a-tocopherol or of all-rac a-tocopherol compositions. It shall exhibit at least identical and even better rheology characteristics / flowability than prior art DL-a-tocopherol or of all-rac a-tocopherol compositions. Another object of the invention shall be to design said composition such that it can be made with low cost.

[0017] Another object of the invention is to provide uses for the inventive multicomponent crystal, its process of making and for the compositions comprising the multicomponent crystal.

[0018] These objects are fulfilled by a multicomponent crystal comprising a) an active, said active being a mixture of at least two distinct molecules of formula (1) with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3, with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration, and b) a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of b1) - being suitable to form ions and containing a H-bond acceptor and being suitable to form a zwitterionic structure and having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or b2) - containing a H-bond donor, with the proviso that the combination of proline as crystallizing agent of formula (2z) and tocopherol as active is excluded from the teaching of this embodiment. Said multicomponent crystal comprising as active a mixture of at least two distinct molecules of formula (1) and a crystallizing agent (2), which exhibits the property of being suitable to form ions and containing a H-bond acceptor and being suitable to form a zwitterionic structure and having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or containing a H- bond donor, with the proviso that the combination of proline as crystallizing agent of formula (2z) and tocopherol as active is excluded from the teaching of this embodiment, gives rise to advantages in comparison to neat DL-a-tocopherol or DL-a-tocopherol L-proline co-crystal with respect to flowability, stability, hygroscopicity, storage stability, bio-availability, purity, purification. This means that the new multicomponent crystal in solid form is stable at higher temperatures compared to those of the prior art. It is obtained as fines. It has for example better flowability without clotting, lower hygroscopicity even after storage periods over weeks and months, better storage stability, higher purity and better purification properties. The inventive multicomponent crystal does not require any further purification and can be directly formulated into a composition. Compared to compositions of the prior art containing an active of formula (1) or of formula (3) the inventive multicomponent crystal preferably exhibits higher bioavailability and bioavailability with less variability. The bioavailability of the mixture of formula (1) or of formula (3) in the new multicomponent crystal is higher, comparable or only slightly lower than this one of the uncrystallized mixture of formula (1) or of formula (3).

[0019] Said multicomponent crystal is also suited to be employed as intermediate or starting material to produce a pure active out of a mixture of a multitude of compounds.

[0020] All this is due to the higher degree of crystallinity, to a more homogeneous or higher structured and thus more stable multicomponent crystal, as can be deduced from the respective onset temperature To, the respective peak temperature Tpand from the respective enthalpy AH as measured by DSC and shown below, and which are respectively higher than for neat DL-a-to- copherol or for co-crystals comprising a combination of proline as crystallizing agent (2z) and tocopherol as active.

[0021] This is astonishing, since the active of the invention is not a single distinct compound but a mixture of several distinct compounds and / or a mixture of several stereoisomers of a distinct compound. Distinct moieties of the molecules in such mixtures, due to their respective isomeric structure, have different spatial orientations. They are thus not prone to readily arrange in a highly ordered structure with the crystallizing agent (2a) as now achieved by this invention. One would rather expect to obtain an amorphous precipitate if at all or a multicomponent crystal of only one diastereomer, and not a well defined multicomponent crystal as shown in the PXRD- diagrams infra. Multicomponent crystal as understood under this invention means a crystal, viz a highly ordered structure comprising an active and a crystallizing agent (2). Crystalline parts of said crystal can have different orientations into one and the same particle. There can be also parts, which still have an amorphous character, however the degree of crystallinity in the multicomponent crystal is higher than in the co-crystals of the prior art. The word “multicomponent crystal” and “multicomponent crystals” are understood to have the same meaning and they are reciprocally used in this disclosure.

[0022] However, crystals formed from proline (2z) and tocopherol do not exhibit the increased stability, the better rheological properties and the more pronounced crystallinity of the multicomponent crystal.

[0023] Tocopherol as understood within the phrasing “with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this embodiment.” means natural tocopherol and synthetic tocopherol. Natural tocopherol comprises two types of tocopherols and tocotrienols, and comprises 8 kinds of compounds, namely a-, p-, y-, b-tocopherols and a-, -, y-, b-tocotrienols. Synthetic tocopherol refers to a-tocopherol, and has 8 optical isomers, viz. at least one, two, three, four, five, six, seven or eight of RRR, RRS, RSS, SSS, RSR, SRS, SRR and SSR.

[0024] Proline as understood within the phrasing “with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this embodiment.” means proline (2z) to comprise D-proline, or L-proline, or a racemic mixture of both. This is indicated by the waved bond which connects the proton to the carbon-atom in a-position to the carboxy group in proline of formula (2z) below.

[0025] An active of the invention in any case is a mixture of at least two distinct molecules and not a single compound like e.g. D-a- tocopherol. Distinct means that actives of the invention can be mixtures of different molecules having the same stereochemistry, like e.g. D-a-tocopherol and D-a-tocopherol acetate. Also at least one of propionate, palmitate and stearate of D-a-tocoph- erol combined with at least one of D-a-tocopherol or D-a-tocopherol acetate can be an active. Every permutation of the previously mentioned molecules is possible and stands for one embodiment of “at least two distinct molecules”.

[0026] Actives can also be mixtures of different stereoisomers of a molecule with a defined molecular weight, like e.g. DL-a-tocopherol having a variable amount of stereoisomers ranging from 2 to 8 or of all-rac a-tocopherol having eight stereoisomers. This meaning is also encompassed by the wording “at least two distinct molecules”. An active can also be a mixture of at least one distinct stereoisomer of a molecule with a defined molecular weight combined with mixtures of different molecules having the same stereochemistry. An example would be D-a-tocopherol palmitate combined with D-a-tocopherol and D- a-tocopherol stearate. Likewise, also this definition falls under the term “at least two distinct molecules”.

[0027] Finally, an active can be a mixture of distinct stereoisomers of a molecule with at least one molecule having a defined molecular weight. An example would be RRR-tocopherol acetate, RSS- tocopherol acetate and D-a-tocopherol stearate. This is a further definition, which is covered by the wording “at least two distinct molecules”.

[0028] A crystallizing agent (2) is any compound, which meets all of the conditions, being suitable to form ions and containing a H-bond acceptor and being suitable to form a zwitterionic structure and having a molecular weight, which ranges from 100 g / mol to 135 g / mol. It further or instead may contain a H-bond donor. Preferably a crystallizing agent (2) is any dietary acceptable compound, adapted to form ions and containing a H-bond acceptor and being suitable to form a zwitterionic structure and having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or containing a H-bond donor.

[0029] A H-bond acceptor is a group comprising an electronegative element with free electron pairs able to be involved into a hydrogen-bond like O in C=O, N in NH2.

[0030] A H-bond donor is a group comprising an electronegative element (e.g. O in form of OH, N in form of NH, NH2) to which a hydrogen atom is covalently attached.

[0031] The applicant in total tested 60 compounds for their ability to serve as crystallizing agent, out of which two (2) showed the ability to form multicomponent crystals with an active of formula (1), viz. with all-rac a-tocopherol.

[0032] Exemplary co-crystallizing agents (2) are betaine of formula (2a) nicotinic acid of formula (2h)

[0033] N-methylaminopropionic acid of formula (2b) malic acid of formula (2m)

[0034] From these exemplary compounds only two (2) were shown to form multicomponent crystals with the active of the invention. Compounds (2b), (2h), (2i) can change between their zwitterionic form and their non-ionized form. This is reflected in compound (2b) by indicating their mesomeric formulas.

[0035] However, proline of formula (2z), which can also be used as crystallizing agent, does not belong to exemplary crystalizing agents nor to the crystallizing agents of the invention.

[0036] A highly preferred crystallizing agent (2) is selected from the group consisting of betaine (2a) and N-methylaminopropionic acid (2b).

[0037] In a further embodiment of the invention the multicomponent crystal defines

[0038] - the active being a mixture of at least three distinct molecules of formula (1), preferably of at least four distinct molecules of formula (1), further preferred of at least five distinct molecules of formula (1), yet further preferred of at least six distinct molecules of formula (1), still further preferred of at least seven distinct molecules of formula (1) and mostly preferred of at least eight distinct molecules of formula (1), and

[0039] R in formula (1) being at least one selected from the group consisting of H and COCH3, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a) in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b) Upon using betaine as crystallizing agent of formula (2a) the advantages of claim 1 , viz. better flowability, stability, hygroscopicity, storage stability, bioavailability, purity, purification behavior are even improved, as can be seen below. This means that the solid form of the multicomponent crystal has better flowability, lower hygroscopicity, better storage stability, higher bioavailability, bioavailability with less variability, higher purity and better purification properties.

[0040] In a further developed embodiment of the multicomponent crystal of the invention

[0041] - the active is D / L-a-tocopherol of formula (3), with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R- configuration, inclusive of all-rac a-tocopherol, and

[0042] - the crystallizing agent (2) is one, which is selected from the group consisting of betaine of formula (2a) in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)

[0043] The stabilization of D / L-a-tocopherol or of all-rac a-tocopherol by means of esterification in order to reduce their sensitivity to oxidation also reduces to some extent their capacity of acting as antioxidant and their bioavailability. This somewhat small, however existing disadvantage can be overcome by using D / L-a-tocopherol of formula (3) synonymous to DL-a-tocopherol of formula (3), inclusive of all-rac a-tocopherol, since in these entities, there is free access to the OH-group in position 6 of formula (3). This however is not detrimental, since the molecule of formula (3) is part of the multicomponent crystal. Provided one uses an excess of active, not all of it can be incorporated into the multicomponent crystal. A deficiency of active on the other hand would reduce its deliverable quantity e.g. in a dietary supplement and thus reduces the amount to be bioavailably accessible for the body. This can be avoided with a multicomponent crystal of the invention exhibiting the molar ratio of the active to the crystallizing agent (2) to range from 3:1 to 1 :3, preferably from 2.1:1 to 1.9:1 or from 2: 1 to 1 :2 including a molar ratio of 1 : 1 and of 1 : 1.1 and further preferred being 2: 1. This can be avoided with a multicomponent crystal of the invention exhibiting the molar ratio of the active to the crystallizing agent (2a), (2b) to range from 3:1 to 1:3, preferably from 2.1 :1 to 1.9:1 or from 2:1 to 1:2 including a molar ratio of 1 :1 and of 1:1.1 and further preferred being 2:1.

[0044] The multicomponent crystal of the invention has, when betaine of formula (2a) is used as crystallizing agent (2), a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4, preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4.

[0045] One observes the peaks of the highly crystalline inventive multicomponent crystal comprising the active and betaine (2a) to be different compared to the co-crystal of D-a-tocopherol and betaine (2a) disclosed in comparative example 13, as shown in Fig. 12. This is also backed by the thermogravimetric analysis (TGA) results of example 1 and Fig. 2 showing a high temperature of decomposition TD of 200°C and by the high onset temperature To of 98°C, the high peak temperature TP of 103°C and the high phase transition enthalpy AH of 82 J / g as given in example 1 and Fig. 3, all of which indicating a well packed highly structured multicomponent crystal, which can only be disassembled at high temperatures and with an elevated amount of energy. As shown by HPLC analysis the multicomponent crystal comprises all eight stereoisomers in the same ratio as observed in all-rac a-tocopherol (cf. example 5, Fig. 7).

[0046] A further advanced embodiment of the inventive multicomponent crystal has, when betaine of formula (2a) is used as crystallizing agent (2), a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20(CuKa radiation), which is selected from the peaks located at 3.7, 5.5, 7.4, 9.2, 11.1, 12.9, 14.8, 15.6, 16.7, 17.0, 18.1, 18.5, 20.4, 21.8 and 24.2, preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.7, 5.5, 7.4, 9.2, 11.1 , 12.9, 14.8, 15.6, 16.7, 17.0, 18.1, 18.5, 20.4, 21.8 and 24.2, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.7, 5.5, 7.4, 9.2, 11.1 , 12.9, 14.8, 15.6, 16.7, 17.0, 18.1 , 18.5, 20.4, 21.8 and 24.2.

[0047] One observes the peaks of the highly crystalline inventive multicomponent crystal comprising D / L-a-tocopherol and betaine (2a) to be different compared to the co-crystal of D-a-tocopherol and betaine (2a) disclosed in comparative example 13, as shown in Fig. 12. This is also backed by the thermogravimetric analysis (TGA) results of example 1 and Fig. 2 showing a high temperature of decomposition TD of 200°C and by the high onset temperature To of 98°C, the high peak temperature TP of 103°C and the high phase transition enthalpy AH of 82 J / g as given in example 1 and Fig. 3, all of which indicating a well packed highly structured multicomponent crystal, which can only be disassembled at high temperatures and with an elevated amount of energy. Likewise, the total recovery and same repartition of different stereoisomers in the multicomponent crystal when compared to neat D / L-a-tocopherol, reveals a highly ordered and not easily dissolvable structure of the inventive multicomponent crystal. As shown by HPLC analysis the multicomponent crystal comprises all eight stereoisomers in the same ratio as observed in all-rac a-tocopherol (cf. example 5, Fig. 7).

[0048] Co-crystals of the prior art still comprise as non-crystallized matter free D / L-a-tocopherol as shown in comparative example 9. Non crystallized matter can be any active of formula (1) or of formula (3), which does not get appropriately located in the ordered structure of a crystal or sticks in an amorphous way either to its surface and / or in holes, gaps or interstitials of a less ordered or partially amorphous crystal. This likewise contributes to make the crystal less homogeneous and less structured as can be seen in the powder x-ray diffraction diagrams (PXRD) of Fig. 10 compared to Fig. 1 and Fig. 4, Fig. 10 exhibiting a greater background especially in the middle of the diagram.

[0049] In contrast, the multicomponent crystal of the invention comprises, when betaine of formula (2a) is used as crystallizing agent (2), less than 45 w% of not crystallized matter, preferably less than 30 w%, further preferred less than 20 w%, still further preferred less than 10 w% and highly preferred less than 5 w% including 1 w% and 0 w%.

[0050] As already mentioned, higher crystallinity of this embodiment provides better stability, flowability and lower hygroscopicity.

[0051] As previously mentioned, the inventive multicomponent crystal presents a highly ordered structure and only a small to no amount of excess or not crystallized active is present. Only then, elevated onset temperatures To, peak temperatures Tpand phase transition enthalpies AH can be observed. This is reflected by a further inventive embodiment, wherein, when betaine of formula (2a) is used as crystallizing agent (2), the multicomponent crystal exhibits a phase transition with an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 72°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 75°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 50 J / g, preferably an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 85°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 89°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 60 J / g, and further preferred an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 98°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 103°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 82 J / g.

[0052] Within the context of this disclosure, the onset temperature Toas obtained by differential scanning calorimetry (DSC) is defined to be the melting point of the multicomponent crystal or of any other compound to be analyzed, whereas the peak temperature Tpas measured by differential scanning calorimetry (DSC) is defined to be the point, where the respective peak in the DSC- chart shows its highest or its lowest value.

[0053] The highly ordered structure and only a small to no amount of excess or not crystallized active in the inventive multicomponent crystal is also revealed by its high temperature of decomposition Td. This is reflected by a further embodiment of the inventive multicomponent crystal exhibiting, when betaine of formula (2a) is used as crystallizing agent (2), a temperature of decomposition Td as measured by thermogravimetric analysis (TGA), which is at least 175°C, preferably at least 180°C, further preferred at least 185°C, still further preferred at least 190°C and yet further preferred it is 195°C or higher.

[0054] During the search of further candidates to be adapted to serve as crystallizing agent (2) for the active of formula (1), in particular for the active of formula (3) inclusive of all-rac a-tocopherol, the compound N-methylaminopropionic acid of formula (2b) was identified as a compound capable to form two different multicomponent crystal types (C1) and (C2) synonymous to two different crystal modifications (C1) and (C2).

[0055] The multicomponent crystal, when N-methylaminopropionic acid of formula (2b) is used as crystallizing agent (2), has in a crystal modification (C1) a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4, preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 5.1 , 6.8, 8.5, 10.2 and 20.4, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4, yet further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 5.1 , 6.8, 8.5, 10.2 and 20.4, still further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are located at 5.1 , 6.8, 8.5, 10.2 and 20.4, and still with further preference it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4.

[0056] The PXRD pattern is not as structured as obtained with the crystallizing agent (2a). However, as indicated above and exhibited in Fig. 13 as well as in inventive examples 14 to 16, individualized peaks can be observed, indicative for crystal formation. The further obtained thermodynamic data reveal, that the multicomponent crystal, when N-me- thylaminopropionic acid of formula (2b) is used as crystallizing agent (2), exhibits for the crystal modification (C1) a phase transition with an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 47°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 54°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 37 J / g, and a temperature of decomposition Tdas measured by thermogravimetric analysis (TGA) of at least 80°C.

[0057] These data show the crystal modification (C1) of the multicomponent crystal to be less stable than the co-crystal including betaine of formula (2a). In addition to the phase transition related to an onset temperature Toof 47°C and a peak temperature Tpof 54°C a second sharp phase transition at 72°C is observed (cf. Fig. 15).

[0058] This reveals the different nature of multicomponent crystals formed with different crystallizing agents of the invention. These multicomponent crystals have various degrees of crystallinity and thus show different thermodynamic characteristics. The idea is the more the multicomponent crystals are thermodynamically stable, which is shown by a higher onset temperature To, a higher peak temperature Tpand a higher transition enthalpy AH, the better it is. This idea is achieved in a variable extent with different crystallizing agents and with some crystallizing agents no crystallization takes place at all. Some crystallizing agents are likely to give multicomponent crystals with the single molecule D-a-tocopherol but fail with actives of formula (1) and even with actives of formula (3) including all-rac a-tocopherol or only provide multicomponent crystals which decompose already at room temperature.

[0059] This also reveals that by combining the teaching of one prior art document with the teaching of a further prior art document it cannot be forecasted, what the outcome will be and how multicomponent crystals will look like upon formation.

[0060] Having this in mind, It was therefore surprising, that N-methylaminopropionic acid of formula (2b) when combined with an active of formula (1), forms a second type of multicomponent crystals (C2). N-methylaminopropionic acid of formula (2b) when combined with the active of formula (1), in particular with the active of formula (3) inclusive of all-rac a-tocopherol, provides a second type of multicomponent crystal (C2). Said multicomponent crystal, when N-methylaminopropionic acid of formula (2b) is used as crystallizing agent (2), has in a crystal modification (C2) a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1 , preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 7.4, 12.9, 15.7, 16.9 and 28.1 , further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1 , yet further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 7.4, 12.9, 15.7, 16.9 and 28.1 , still further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) which are located at 7.4, 12.9, 15.7, 16.9 and 28.1 and still with further preference it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1.

[0061] The PXRD pattern obtained for the crystal modification (C2) of the inventive multicomponent crystal again reveals to be less structured than this one obtained with betaine of formula (2a) as crystallizing agent (2). However, it looks to be more structured than the pattern obtained for the crystal modification (C1) (cf. Fig. 16).

[0062] This more ordered structure is confirmed by thermodynamic data, i.e. a higher onset temperature To a higher peak temperature Tpand a higher phase transition enthalpy AH as obtained by differential scanning calorimetry (DSC). Also, the thermogravimetrically obtained temperature of decomposition Tdis higher than for the crystall modification (C1). The multicomponent crystal, when N-methylaminopropionic acid of formula (2b) is used as crystallizing agent (2), exhibits for the crystal modification (C2) a phase transition with an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 53°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 58°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 44 J / g and. a temperature of decomposition Td as measured by thermogravimetric analysis (TGA) of at least 150°C.

[0063] In addition to the phase transition observed at 53°C a further phase transition is observed at 161 °C (cf. Fig. 17).

[0064] The obtained thermodynamic data show multicomponent crystal (C2) to have a higher onset temperature To, a higher peak temperature Tp, a higher transition enthalpy AH and a higher temperature of decomposition Tdthan multicomponent crystal (C1). It is now investigated as to whether even more stable multicomponent crystal modifications can be obtained.

[0065] A process for preparing a multicomponent crystal of the invention from at least two solids or from at least one solid and at least one liquid comprises the steps: i) providing an active, said active being a mixture of at least two distinct molecules of formula (1) with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3, with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration, ii) adding to the active of step i) a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of ii.i) - being suitable to form ions and

[0066] - containing a H-bond acceptor and

[0067] - being suitable to form a zwitterionic structure and

[0068] - having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or ii.ii) - containing a H-bond donor, iii) mixing the active and the crystallizing agent (2) to obtain a mixture, iv) optionally concentrating the mixture of step iii) or adding a solvent and / or an antisolvent to the mixture of step iii), while stirring, v) cooling the mixture of step iii) or of step iv) for crystallization, and / or stirring the mixture of step iii) or of step iv) for crystallization, vi) incubating the mixture of step v) in order to get the formed multicomponent crystal settled, vii) removing the supernatant formed in step vi) by decanting or by evaporation or by filtration, viii) optionally washing the formed multicomponent crystal of step vii) with the solvent and / or with the antisolvent ix) and drying the formed multicomponent crystal of step vii) or viii), with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this process.

[0069] Said process of obtaining the inventive multicomponent crystal is straight forward since all process steps can be realized within hours and only exceptionally over-night runs are required. Highly trained stuff is not required since every process step is self explaining. The active and the crystallizing agents (2a) and (2b) are not harmful when handled with ordinary lab skills. This further applies when both the active and the crystallizing agent (2a), (2b) in a preferred embodiment have the GRAS-status, which means they are Generaly Recognized As Save by the FDA. The process provides for using the active and the crystallizing agent (2) as such or in dilution. All process steps can be safely realized and are not harmful as well. It is apparent to the skilled person that the process steps are not expensive either. The way of conducting said process is easy to realize. By said inventive process the double molar amount of active with respect to crystallizing agent (2) and even more can become an integral, viz properly allocated part of the new multicomponent crystal. As already explained supra, non-crystallized matter can be avoided to a large extent or even completely to become a part of the multicomponent crystal. A further advantage of the inventive process is that it provides the inventive multicomponent crystal as fines, which can be directly further processed.

[0070] Tocopherol as understood within the phrasing “with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this process” means natural tocopherol and synthetic tocopherol. Natural tocopherol comprises two types of tocopherols and tocotrienols, and comprises 8 kinds of compounds, namely a-, p-, y-, b-tocopherols and a-, -, y-, b-tocotrienols. Synthetic tocopherol refers to a-tocopherol, and has 8 optical isomers, viz. at least one, two, three, four, five, six, seven or eight of RRR, RRS, RSS, SSS, RSR, SRS, SRR and SSR.

[0071] Proline as understood within the phrasing “with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this process” means proline (2z) to comprise D-proline, or L-proline, or a racemic mixture of the both.

[0072] The terms “active”, “crystallizing agent”, “H-bond acceptor” and “H-bond donor” for the inventive process have the same meaning as given supra for the inventive multicomponent crystal. A solvent is understood to be any solvent which solubilizes at least the active, but also the active and the crystallizing agent (2). Appropriate solvents are selected form the group consisting of methanol, ethanol, iso-propanol, heptane, acetonitrile and ethyl acetate and mixtures thereof.

[0073] An antisolvent is meant to be each solvent, which reduces the amount of solubilized active and / or of solubilized crystallizing agent (2) or completely prevents solubilization of the active and / or of the crystallizing agent (2). It is also understood to prevent multicomponent crystals from solubilization. An antisolvent is understood to be a solvent that causes precipitation when added to a solution or another solvent. Nitromethane or water is used as antisolvent.

[0074] Incubating in step vi) is meant to leave the mixture of step v) with or without stirring at a reduced temperature, preferably at the temperature at which it was cooled in step v) or to leave the mixture of step v) with or without stirring at the temperature at which it was stirred in step v).

[0075] The supernatant of step vii) is understood to be the liquid which remains above the formed multicomponent crystal of the invention.

[0076] Filtration in step vii) is understood to be any measure by which the supernatant can be removed from the multicomponent crystal. Filtration thus includes any filtering means used without pressure or under pressure. It also includes removing the supernatant by transferring the settled multicomponent crystal onto a sheet or several sheets of at least one of filter paper and tissue paper and soaking the supernatant into the filter paper and / or the tissue paper.

[0077] As can be seen from the examples below, it is sometimes difficult to work with an active and a crystallizing agent (2a), (2b), especially, if the amount of active is increased with respect to the amount of crystallizing agent (2a), (2b). This is fixed with an extension of the inventive process, wherein the active is diluted with or dissolved in an active solubilization solvent prior to providing it in step i) of the inventive process or the crystallizing agent (2) is diluted with or dissolved in an active solubilization solvent prior to adding it in step ii) of the inventive process or the active and the crystallizing agent (2) are diluted with or dissolved in an active solubilization solvent prior to mixing them in step iii) of the inventive process and / or at least one of the group consisting of the active and the crystallizing agent (2) is readded in one or several portions after step ii) or step iii) of the inventive process. An active solubilization solvent is a solvent which solubilizes either the active or the crystallizing agent (2) or both of them. The special feature of the active solubilization solvent is, that it is used prior to step i) of the inventive process in order to solubilize the active or it is used prior to step ii) of the inventive process in order to solubilize the crystallizing agent (2), or it is used prior to step iii) in order to solubilize both the active and the crystallizing agent (2).

[0078] Provided at least one of the group consisting of the active and the crystallizing agent (2) is readded in several portions after step ii) or step iii) of the inventive process, the active solubilization solvent can be used but is not required to be used for solubilizing at least one of the active or the crystallizing agent (2) prior to adding it in one or several portions after step ii) or step iii) of the inventive process.

[0079] Appropriate active solubilization solvents are selected form the group consisting of methanol, ethanol, iso-propanol, heptane, acetonitrile and ethyl acetate and mixtures thereof.

[0080] Instead of first solubilizing the active and second solubilizing the crystallizing agent (2) an alternative process embodiment of the inventive process is realized as follows:

[0081] Said process embodiment for preparing a multicomponent crystal of the invention from at least two solids or from at least one solid and at least one liquid comprises the steps: i) providing an active, said active being a mixture of at least two distinct molecules of formula (1) with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3, with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration, ii) providing a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of ii.i) - being suitable to form ions and

[0082] - containing a H-bond acceptor and

[0083] - being suitable to form a zwitterionic structure and

[0084] - having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or ii.ii) - containing a H-bond donor, iii) solubilizing the crystallizing agent (2) in an active solubilization solvent, iv) adding to the solubilized crystallizing agent (2) the active and mixing, in order to obtain a mixture, v) optionally concentrating the mixture of step iv) or adding a solvent and / or an antisolvent to the mixture of step iv), while stirring, vi) cooling the mixture of step iv) or of step v) for crystallization, and / or stirring the mixture of step iv) or of step v) for crystallization, vii) incubating the mixture of step vi) in order to get the formed multicomponent crystal settled, viii) removing the supernatant formed in step vii) by decanting or by evaporation or by filtration, ix) optionally washing the formed multicomponent crystal of step viii) with the solvent and / or with the antisolvent x) and drying the formed multicomponent crystal of step viii) or ix), with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of this process.

[0085] For this previously mentioned embodiment the active added in step iv) is added in solid form or solubilized in the active solubilization solvent.

[0086] The meaning of the terms in the previously disclosed embodiment, e.g. filtration is the same as for the process embodiment disclosed supra.

[0087] A further developed embodiment of the inventive process provides the active being a mixture of at least three distinct molecules of formula (1), preferably of at least four distinct molecules of formula (1), further preferred of at least five distinct molecules of formula (1), yet further preferred of at least six distinct molecules of formula (1), still further preferred of at least seven distinct molecules of formula (1) and mostly preferred of at least eight distinct molecules of formula (1), and

[0088] R being at least one selected from the group consisting of H and COCH3, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a) in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)

[0089] Upon using the process features given supra, multicomponent crystals of high stability are obtained.

[0090] This is even further pronounced with the following advancement of the inventive process, which defines said active being D / L-a-tocopherol of formula (3) with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R- configuration, inclusive of all-rac a-tocopherol, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula

[0091] (2a) in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)

[0092] The multi-component crystal according to the invention in one alternative may be used directly in the form of powders, granules, suspensions. In another alternative it may be combined with other dietary or pharmaceutically acceptable ingredients by admixing the multicomponent crystal and the ingredients to obtain a mixture and optionally finely grinding said mixture , and then filling it into capsules. Said capsules may be composed for example of hard or soft gelatin.

[0093] Part of the invention is also a composition comprising the multicomponent crystal as defined in at least one of the embodiments mentioned supra or as obtained in at least one of the process embodiments as previously defined and at least one dietary acceptable constituent.

[0094] Said composition in one embodiment is a dietary supplement.

[0095] In another embodiment it is a pharmaceutical composition, preferably a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier, and / or at least one diluent, and / or further ingredients, and / or at least one pharmaceutical excipient.

[0096] The composition in one extension is a pre-formulation, an oral formulation, a solid formulation such as a powder, a capsule, a tablet, a pill, a troche, or a liquid suspension formulation.

[0097] A further important aspect of the invention is the use of a multicomponent crystal as previously defined or as obtained in a process as identified supra, or the use of the above disclosed composition in a food formulation or a feed formulation or in a pharmaceutical preparation.

[0098] In the following, the present invention will be further illustrated by particular embodiments as disclosed in the examples and with reference made to figures. However, said detailed description and examples are not understood to narrow the gist of the invention down thereto. They merely serve to illustrate the invention in more details.

[0099] Abbreviations

[0100] HPLC high pressure liquid chromatography

[0101] ATR-IR attenuated total reflectance infrared spectroscopy MeOH methanol

[0102] NMR nuclear magnetic resonance

[0103] TG / TGA thermogravimetry / thermogravimetric analysis r.h. relative humidity (air, if not indicated otherwise) w% weight% v / v volume by volume

[0104] PXRD powder X-ray diffraction DSC differential scanning calorimetry

[0105] Figures:

[0106] Fig. 1 : PXRD pattern of an all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH with the molar ratio of all-rac-a-tocopherol to betaine (2a) in the crystal being 2:1 ; Cu Ka radiation.

[0107] Fig. 2: TGA data of an all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in

[0108] MeOH with the molar ratio of all-rac-a-tocopherol to betaine (2a) in the crystal being 2:1 , heating rate 10°C / min.

[0109] Fig. 3: DSC data of an all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in

[0110] MeOH with the molar ratio of all-rac a-tocopherol to betaine (2a) in the crystal being 2:1 , heating rate 10°C / min, recording of the exothermal phase transition during heating up.

[0111] Fig. 4: PXRD pattern of an all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH with the molar ratio of all-rac a-tocopherol to betaine (2a) in the crystal being 2:1 ; Cu Ka radiation.

[0112] Fig. 5: PXRD pattern of anall-rac a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH with the molar ratio of all-rac a-tocopherol to betaine (2a) in the crystal being 2:1 ; Cu Ka radiation.

[0113] Fig. 6: ATR-IR spectrum of an all-rac-a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH with the molar ratio of all-rac a-tocopherol to betaine (2a) in the crystal being 2:1.

[0114] Fig. 7: HPLC data of all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in

[0115] MeOH with the molar ratio of all-rac a-tocopherol to betaine (2a) in the crystal being 2:1 , 295 nm.

[0116] Fig. 8: TGA data of an all-rac a-tocopherol - L-proline (2z) co-crystal from crystallization in

[0117] MeOH with the molar ratio of all-rac a-tocopherol to L-proline (2z) in the crystal being 2:1 , heating rate 10°C / min.

[0118] Fig. 9: DSC data of an all-rac a-tocopherol - L-proline (2z) co-crystal from crystallization in

[0119] MeOH with the molar ratio of all-rac a-tocopherol to L-proline (2z) in the crystal being 2:1 , heating rate 10°C / min, recording of the exothermal phase transition during heating up.

[0120] Fig. 10: PXRD pattern of an all-rac a-tocopherol - L-proline (2z) co-crystal from crystallization in MeOH : nitromethane (1 :1 v / v) with the molar ratio of all-rac a-tocopherol to L-proline (2z) in the crystal being 2:1 ; Cu Ka radiation. Fig. 11 : PXRD pattern of a D-a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH with the molar ratio of D-a-tocopherol to betaine (2a) in the crystal being 2:1; Cu Ka radiation.

[0121] Fig. 12: PXRD pattern of an all-rac a-tocopherol - betaine (2a) co-crystal 2:1 (bottom, example 1 and Fig. 1) in comparison to D-a-tocopherol - betaine (2a) co-crystal from example 13 and Fig. 11 (top; counts + 500); Cu Ka radiation.

[0122] Fig. 13: PXRD pattern of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) cocrystal form (C1) with the molar ratio of all-rac a-tocopherol to N-methylaminopropi- onic acid (2b) in the experiment being 1 :1.1; Cu Ka radiation.

[0123] Fig. 14: TGA data of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) co-crystal form (C1) with the molar ratio of all-rac a-tocopherol to N-methylaminopropionic acid (2b) in the experiment being 1 :1.1, heating rate 10°C / min.

[0124] Fig. 15: DSC data of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) co-crystal form (C1) with the molar ratio of all-rac a-tocopherol to N-methylaminopropionic acid (2b) in the experiment being 1 :1.1, heating rate 10°C / min, recording of the exothermal phase transition during heating up.

[0125] Fig. 16: PXRD pattern of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) cocrystal form (C2) with the molar ratio of all-rac a-tocopherol to N-methylaminopropi- onic acid (2b) in the crystal being 2:1; Cu Ka radiation.

[0126] Fig. 17: DSC data of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) co-crystal form (C2) with the molar ratio of all-rac a-tocopherol to N-methylaminopropionic acid (2b) in the crystal being 2:1, heating rate 10°C / min, recording of the exothermal phase transition during heating up.

[0127] Fig. 18: TGA data of an all-rac a-tocopherol - N-methylaminopropionic acid (2b) co-crystal form (C2) with the molar ratio of all-rac a-tocopherol to N-methylaminopropionic acid (2b) in the crystal being 2:1, heating rate 10°C / min.

[0128] Fig. 19: PXRD pattern of an all-rac a-tocopherol - betaine (2a) co-crystal from crystallization in MeOH as given in example 19 with the molar ratio in the crystal of all-rac-a-to- copherol to betaine (2a) being 2:1 ; Cu Ka radiation.

[0129] Fig. 20: PXRD pattern of all-rac a-tocopherol - betaine (2a) co-crystal 2:1 (bottom as obtained from example 19, Fig. 19) in comparison to all-rac a-tocopherol - betaine (2a) co-crystal 2:1 (top as obtained from example 1 , Fig. 1; counts + 5000); Cu Ka radiation. Examples

[0130] Wherever noted, in the following, room temperature depicts a temperature from the range 22-25 °C, ambient temperature is defined as 25±10 °C and percentages are given by weight, if not indicated otherwise.

[0131] Instrumental:

[0132] Powder X-ray diffraction:

[0133] The measurements were carried out with a Panalytical X'Pert Pro diffractometer (manufacturer: Panalytical) or with a MiniFlex600 X-ray diffractometer (manufacturer: Rigaku) using Cu Ka radiation in the Bragg-Brentano reflection geometry. Generally, the 20 values are accurate within an error of ±0.1 -0.2°. The relative peak intensities can vary considerably for different samples of the same crystalline form because of different preferred orientations of the crystals. The samples were prepared without any special treatment other than the application of slight pressure to get a flat surface. Generally, silicon single crystal sample holders of 0.2 mm depth were used. The tube voltage and current were 45 kV and 40 mA, respectively. Diffraction patterns were recorded in the range from 20 =3°-40° with increments of 0.0167°-0.02°. The samples were rotated during the measurement.

[0134] Thermogravimetry:

[0135] TGA data were recorded with a TG / DTA 7200 (Sil Nano Technology Inc). The samples were placed in platinum standard pans. The sample size in each case was 2 to 15 mg. The heating rate was 10°C / min. The samples were purged with a stream of synthetic air during the experiment.

[0136] Differential scanning calorimetry (DSC):

[0137] DSC data were recorded with a Mettler Toledo DSC 823e / 700 / 229 module. The samples were placed in aluminum standard pans. The sample size in each case was 1 to 10 mg. The heating rate was 10°C / min. The samples were purged with a stream of nitrogen during the experiment. The onset point of the endothermic event is reported as melting point.

[0138] 1H-NMR:

[0139] The1H-NMR spectra were recorded on a Bruker AVN-600 spectrometer using deuterated solvents.

[0140] ATR-IR spectroscopy:

[0141] ATR-IR spectra were measured at room temperature on a Nicolet iS50_2 apparatus. 32 scans with a resolution of 4 cm’1were measured in the range 4000 cm’1to 400 cm’1. HPLC:

[0142] Approximately 10 mg solid material was dissolved in approximately 8 g of isopropanol. The solution was directly used for analysis by HPLC on an Agilent 1200 apparatus, equipped with a DAD1 UV detector (evaluation at 295 nm) and Sampler Type G1313A. Chromeleon 7.2.8 software was used to record the chromatograms and to calculate the chromatographic parameters. Gradient elution (solvent A: ACN + 0.1 % formic acid I solvent B: water + 0.1 % formic acid, gradient see below) was achieved using CHIRALPAK IG-3, 150*2.1 mm, 3pm, Daicel. Injection volume was set to 5 pL by auto injector. The analysis was performed with a flux rate of 0.5 ml / min. Gradient time % solvent A % solvent B 0.0 45 55

[0143] 23.0 30 70

[0144] 35.0 20 80

[0145] 35.1 0 100

[0146] 40.0 0 100

[0147] 40.1 45 55

[0148] 51.0 45 55

[0149] Solvents: For all experiments, standard grade solvents are used.

[0150] Examples:

[0151] Example 1 : (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0152] The all-rac -a-tocopherol - betaine co-crystal 2:1 is prepared from all-rac a-tocopherol and betaine (2a).

[0153] The PXRD pattern is displayed in Figure 1. Characteristic PXRD peaks (expressed in °20 ± O.2°20; Cu Ka radiation) are observed at 3.7, 5.5, 7.4, 9.2, 11.1 , 12.9, 14.8, 15.6, 16.7, 17.0, 18.1 , 18.5, 20.4, 21.8 and 24.2. The ATR-IR data is presented in Fig. 6. Characteristic peaks are observed at 2953, 2897, 1647, 1639, 1223, 1029 and 721 cm-1.

[0154] Example 1a: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1): 431 mg all-rac a-tocopherol (1 mmol) and 117 mg betaine (2a) (1 mmol) (ratio 1 :1) were dissolved in 4 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated multicomponent crystal was filtered and dried in vacuum at room temperature. The solid material shows a PXRD pattern as in Figure 1 having characteristic PXRD peaks (expressed in °20 ± O.2°20; Cu Ka radiation) as indicated in example 1.1H-NMR spectroscopy indicates a molar ratio of all-rac a-tocopherol to betaine (2a) of about 2:1. TGA data show no significant weight loss up to the melting peak and above, first significant weight loss is observed around 200°C (cf. Fig. 2). DSC data show a melting point with an onset of 98°C and a peak maximum of 103°C as well as a transition enthalpy AH of 82 J / g (cf. Fig. 3).

[0155] Said transition enthalpy is almost the double of the value obtained for an all-rac a-tocopherol - L-proline co-crystal as indicated in comparative example 8. Likewise, the onset of 98°C and the peak maximum of 103°C is about 30°C higher than this one obtained for the co-crystal of comparative example 8. The significant weight loss starts at about 200°C which is about 30°C higher than the value obtained for said all-rac a-tocopherol - L-proline co-crystal as indicated in comparative example 8. These observations prove that much more energy is required to disassemble the multicomponent crystal of example 1a, which is only possible if said crystal is much more structured and thus has a higher crystallinity compared to the co-crystal of comparative example 8.

[0156] Example 2: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0157] 431 mg all-rac a-tocopherol (1 mmol) and 117 mg betaine (2a) (1 mmol) (ratio 1 :1) were dissolved in 4 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated multicomponent crystal was filtered and dried in vacuum at room temperature to yield 303 mg all-rac a-tocopherol - betaine co-crystal. The PXRD pattern is comparable to the pattern presented in Figure 1.

[0158] Example 3: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0159] 1725 mg all-rac a-tocopherol (4 mmol) and 235 mg betaine (2a) (2 mmol) (ratio 2:1) were dissolved in 4 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated multicomponent crystal was filtered and dried in vacuum at room temperature to yield 1093 mg all-rac a-tocopherol - betaine co-crystal. The PXRD pattern is comparable to the pattern presented in Figure 1.

[0160] Example 4: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0161] 6.9 g all-rac a-tocopherol (16 mmol)l and 0.94 g betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 200 rpm). The precipitated multicomponent crystal was filtered and dried in vacuum at room temperature to yield 5.0 g all-rac a-tocopherol - betaine co-crystal. The PXRD pattern is comparable to the pattern presented in Figure 1. The DSC data show a melting point with an onset of 98°C and a peak temperature of 104°C as well as an enthalpy AH of 70 J / g.

[0162] Example 5: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0163] 6.9 g all-rac a-tocopherol (16 mmol) and 0.94 g betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 200 rpm). The precipitated multicomponent crystal was filtered, washed with 5 mL methanol and dried in vacuum at room temperature to yield 4.4 g all-rac a-tocopherol - betaine co-crystal. The PXRD pattern is presented in Figure 5. The DSC data show a melting point with an onset of 100°C and a peak temperature of 104°C (72 J / g). The ATR-IR spectrum is displayed in Figure 6. The result of the HPLC measurement is shown Fig 7. The chiral HPLC method does not separate all eight isomers of all-rac a-tocopherol, but the ratio of 1 (12.12 area%) : 3 (37.57 area%) : 1 (12.74 area%) : 2 (25.16 are%) : 1 (12.41 area%) is the same as in all-rac a-tocopherol (1 (12.18 area%) : 3 (37.81 area%) : 1 (12.66 area%) : 2 (25.11 area%) : 1 (12.25 area%)) (Figure 7). The data confirm that all eight all-rac a-tocopherol isomers are incorporated into the co-crystal.

[0164] Example 6: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0165] 6.9 g all-rac a-tocopherol (16 mmol) and 0.94 g betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 200 rpm). The precipitated multicomponent crystal was filtered, washed with 5 mL nitromethane and dried in vacuum at room temperature to yield 4.8 g all-rac a-tocopherol - betaine co-crystal. The solid material shows a PXRD pattern as in Figure 4. The DSC data show a melting point with an onset of 101°C and a peak temperature of 103°C as well as an enthalpy AH of 60 J / g.

[0166] Example 7: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1):

[0167] 6.9 g (16 mmol) all-rac a-tocopherol and 0.94 g betaine (2a) (8 mmol) (ratio 2:1) was dissolved in 16 mL MeOH at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 200 rpm). The precipitate was filtered, washed with 5 mL heptane and dried in vacuum at room temperature and yielded 2.8 g all-rac a-tocopherol - betaine co-crystal. The PXRD pattern is comparable to the pattern presented in Figure 1. The DSC data show a melting point with an onset of 101 °C and a peak temperature of 105°C as well as an enthalpy AH of 81 J / g.

[0168] Example 7b: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1): 139 g all-rac a-tocopherol (323 mmol) and 18 g betaine (2a) (154 mmol) (ratio 2:1) were added to a 250 mL glass tail-form beaker cooled via an ice bath. The mixture was blended using a Pol- ytron PT3100 D high shear mixer at 30000 rpm for 40 seconds fitted with a rotor-stator- head. Afterwards, the mixture was stirred via an I KA Eurostar 20 stirrer fitted with a dissolver. The temperature was kept below 50°C. The mixture was agitated for 2.25 h. After 50 minutes, the stirrer speed was stepwise reduced from the initial 5000 rpm because of the increasing viscosity. After 1 h and 23 min, the stirrer speed was kept at 1000 rpm. Starting 30 minutes after the beginning of the agitation, periodically over the course of the experiment, the material was manually homogenized as the dissolver was not able to effectively agitate the complete reaction mixture. The PXRD pattern is comparable to the pattern presented in Figure 1.

[0169] Comparative Experiments

[0170] All-rac a-tocopherol - L-proline co-crystal is described in WO 2019 / 128175 A1 (corresponding to EP 3733657 A1) with PXRD patterns of low crystallinity and amorphous content. The following examples 8 to 13 are modified examples from said WO 2019 / 128175 A1.

[0171] Example 8: (all-rac a-Tocopherol - L-Proline Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - L-proline of 2:1):

[0172] 431 mg all-rac a-tocopherol (1 mmol)) and 115 mg L-proline (2z) (1 mmol) (ratio 1 :1) were dissolved in 4 mL methanol : nitro-methane (1 :1) at 60°C. After 1 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated co-crystal was filtered and dried in vacuum at room temperature and an all-rac a-tocopherol - L-proline co-crystal was obtained. The solid material shows a poor PXRD pattern as given in Fig. 10.

[0173] 1H-NMR spectroscopy indicates a molar ratio of all-rac a-tocopherol to L-proline (2z) of about 2:1.

[0174] As said, an all-rac a-tocopherol - L-proline co-crystal is described in WO 2019 / 128175 A1 (corresponding to EP 3 733 657 A1). However, the stoichiometry presented is 1 :1 , which is the stoichiometry of the starting material. No analytical method nor any result is presented to determine the stoichiometry of all-rac a-tocopherol and L-proline of formula (2z) in the co-crystal. The molar ratio of all-rac a-tocopherol and L-proline of formula (2z) in the co-crystal of the prior art remains obscure.

[0175] TGA data show no significant weight loss up to the melting peak and above, first significant weight loss is observed around 170°C (cf. Fig. 8), which is about 30°C below the co-crystal obtained from all-rac a-tocopherol and betaine. DSC data show a melting point with an onset of 69°C and 72°C peak maximum (44 J / g), which is about 30°C and 40 J / g below the values obtained for the co-crystals obtained from all-rac a-tocopherol and betaine. These values being low compared to those of example one, show a lower stability of the cocrystal obtained in comparative example 8.

[0176] Example 9: (all-rac a-Tocopherol - L-Proline Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - L-proline of 2:1):

[0177] 473 mg all-rac a-tocopherol (1.1 mmol) and 127 mg L-proline (2z) (1.1 mmol) (ratio 1 :1) were dissolved in 4 mL methanol : nitromethane (1 :1) at 60°C. After 1 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated co-crystal was filtered and dried in vacuum at room temperature to yield -150 mg all-rac a-tocopherol - L-proline co-crys- tal. The PXRD pattern of the solid material is displayed in Figure 10.

[0178] Example 10: (all-rac a-Tocopherol - L-Proline Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - L-proline of 2:1):

[0179] 529 mg all-rac a-tocopherol (1.2 mmol) and 71 mg L-proline (2z) (0.6 mmol) (ratio 2:1) was dissolved in 4 mL methanol : nitromethane (1 :1) at 60°C. After 1 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated co-crystal was filtered and dried in vacuum at room temperature, yield -100 mg all-rac a-tocopherol - L-proline co-crystal. The solid material shows a PXRD pattern as in Figure 10.

[0180] Example 11 : (all-rac a-Tocopherol - L-Proline Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - L-proline of 2:1):

[0181] 529 mg all-rac a-tocopherol (1.2 mmol) and 71 mg L-proline (2z) (0.6 mmol) (ratio 2:1) was dissolved in 4 mL MeOH at 60°C. After 1 h the solution was cooled down to -10°C (cooling rate - 5°C / h, stirring rate 120 rpm). The precipitated co-crystal was filtered and dried in vacuum at room temperature, yielding 9 mg of an all-rac a-tocopherol - L-proline co-crystal. The solid material shows a PXRD pattern as in Figure 10.

[0182] Example 12: (all-rac a-Tocopherol - L-Proline Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - L-proline of 2:1):

[0183] 473 mg all-rac a-tocopherol (1.1 mmol) and 127 mg L-proline (2z) (1.1 mmol) (ratio 1 :1) were dissolved in 4 mL MeOH at 60°C. After 1 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated co-crystal was filtered and dried in vacuum at room temperature to yield 89 mg all-rac a-tocopherol - L-proline co-crystal. The solid material shows a PXRD pattern as in Figure 10.

[0184] A D-a-tocopherol - betaine co-crystal was described in Int. J. Pharm. 592 (2021) 120057. The experiment was reproduced as it was possible. No dissolution at room temperature was observed. Therefore, the solid was dissolved at 60°C before cooling was started. Example 13: (d-a-Tocopherol - Betaine Co-Crystal with a molar ratio in the co-crystal of d-a- tocopherol - betaine of 2:1):

[0185] 4.3 g d-aToc (10 mmol) and 0.585 g betaine (2a) (5 mmol) (ratio 2:1) were dissolved in 10 mL methanol at 60°C and the solution was cooled down to-20°C (cooling rate -5°C / h, stirring rate 1200 rpm). The powder was filtered and dried in vacuum at room temperature. The PXRD pattern of the solid material is displayed in Figure 11.

[0186] The PXRD pattern of all-rac a-tocopherol - betaine multicomponent crystal 2:1 (bottom chart, from example 1) was compared with the D-a-tocopherol - betaine co-crystal (upper chart, from example 13) by superposition in Figure 12.

[0187] Two things are apparent: First the bottom chart shows different signals, which are shifted to lower 20-values with increasing differences which originate from differing unit cell dimensions, when comparing them with the 20-values of the upper chart. In addition, new signals appear in the bottom chart whereas others disappear. All this indicates another type of crystal to be formed. Second the bottom chart looks much more homogenous and does not exhibit a large background when comparing with the upper chart.

[0188] However, multicomponent crystal formation from all-rac a-tocopherol and betaine (2a) is more than surprising taking into account, that all-rac a-tocopherol in the multicomponent crystal of the bottom chart is a mixture of eight isomers, whereas D-a-tocopherol in the co-crystal of the upper chart is only one molecule much easier to crystalize. Despite this fact, the inventive all-rac a- tocopherol - betaine multicomponent crystal is more structured and thermodynamically more stable than the corresponding D-a-tocopherol - betaine co-crystal of the prior art.

[0189] Further inventive examples obtained with N-Methylaminopropanoic acid (2b) as crystallizing agent

[0190] Example 14: (all-rac a-Tocopherol - N-Methylaminopropionic Acid Co-Crystal (C1)):

[0191] 158 mg all-rac a-tocopherol (0.37 mmol) and 42 mg N-methylaminopropionic acid (2b)

[0192] (0.41 mmol) (ratio 1 :1.1) were weighed into an Eppendorf cap and a steel ball was added. The mixture was dissolved in 200 pL of acetone and the solvent was evaporated. 20 pL of acetone was again added and the mixture was milled for 30 min at 20 Hz using a ball mill (Retsch MM- 301). The solvent was evaporated. 20 pL of ethanol was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL of ethyl acetate was added and the mixture was milled for 30 min at 20 Hz. The solid material (C1) obtained shows a PXRD pattern as in Figure 13. Example 15: (all-rac a-Tocopherol - N-Methylaminopropionic Acid Co-Crystal (C1)):

[0193] 158 mg all-rac a-tocopherol (0.37 mmol) and 42 mg N-methylaminopropionic acid (2b) (0.41 mmol) (ratio 1 :1.1) were weighed into an Eppendorf cap and a steel ball was added. The mixture was dissolved in 200 pL of acetone and the solvent was evaporated. 20 pL of acetone was added and the mixture was milled for 30 min at 20 Hz using a ball mill (Retsch MM-301). The solvent was evaporated. 20 pL of ethanol was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL of ethyl acetate was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL toluene was added and the mixture was milled for 30 min at 20 Hz. The PXRD pattern of the multicomponent crystal material (C1) obtained is comparable to the pattern presented in Figure 13.

[0194] Example 16: (all-rac a-Tocopherol - N-Methylaminopropionic Acid Co-Crystal (C1)):

[0195] 158 mg all-rac a-tocopherol (0.37 mmol) and 42 mg N-methylaminopropionic acid (2b) (0.41 mmol) (ratio 1 :1.1) were weighed into an Eppendorf cap and a steel ball was added. The mixture was dissolved in 200 pL of acetone and the solvent was evaporated. 20 pL of acetone was added and the mixture was milled for 30 min at 20 Hz using a ball mill (Retsch MM-301). The solvent was evaporated. 20 pL of ethanol was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL of ethyl acetate was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL of toluene was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. 20 pL of water was added and the mixture was milled for 30 min at 20 Hz. The solvent was evaporated. The PXRD pattern of the obtained crystalline material (C1) is comparable to the pattern presented in Figure 13. TGA data show almost no significant weight loss up to the temperature of decomposition Td of 80°C (Fig. 14). The DSC data show a melting point with an onset temperature Toof 47°C, a peak temperature Tpof 54°C (strong front tailing, cf. Fig. 15) and a phase transition enthalpy AH of 37 J / g.

[0196] Example 17: (all-rac a-Tocopherol - N-Methylaminopropionic Acid Co-Crystal (C2) with a molar ratio in the co-crystal of all-rac a-tocopherol - N-methylaminopropionic acid of 2:1):

[0197] 1750 mg all-rac a-tocopherol (4 mmol) and 210 mg N-methylaminopropionic acid (2b) (2 mmol) (ratio 2:1) were dissolved in 4 mL of methanol at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated multicomponent crystal (C2) showed a PXRD pattern as presented in Fig. 16. Example 18: (all-rac a-Tocopherol - N-Methylaminopropionic Acid Co-Crystal (C2) with a molar ratio in the co-crystal of d-a-tocopherol - N-methylaminopropionic acid of 2:1):

[0198] 1750 mg all-rac a-tocopherol (4 mmol) and 210 mg N-methylaminopropionic acid (2b) (2 mmol) (ratio 2:1) were dissolved in 4 mL of methanol : nitromethane (1 :1) at 60°C. After 0.5 h the solution was cooled down to -10°C (cooling rate -5°C / h, stirring rate 120 rpm). The precipitated multicomponent crystal was filtered and dried in vacuum at room temperature to yield 133 mg all- rac a-tocopherol - N-methylaminopropionic acid co-crystal form (C2). The PXRD pattern is as presented in Figure 16.1H-NMR spectroscopy indicates a molar ratio of all-rac a-tocopherol to N-methylaminopropionic acid (2b) of about 2: 1. The DSC data show a melting point with an onset temperature Toof 53°C, with a peak temperature Tpof 58°C (strong front tailing) and with a phase transition enthalpy AH of 44 J / g, (Fig. 17) and a temperature of decomposition Tdas measured by thermogravimetric analysis (TGA) of at least 150°C (Fig. 18).

[0199] It is apparent from examples 14 to 18, that all-rac a-tocopherol is capable to form two multicomponent crystal modifications (C1) and (C2), depending on the stoichiometry and the preparation conditions applied. These multicomponent crystals (C1) and (C2) do not exhibit the unexpected high thermodynamic stability of the multicomponent crystals obtained from all-rac a-tocopherol and betaine of formula (2a). However, also N-methylaminopropionic acid (2b) was shown to be a crystallizing agent (2) suitable to form multicomponent crystals with all-rac a-tocopherol.

[0200] Further inventive examples exhibiting additional processes for forming multicomponent crystals of all-rac a-tocopherol and betaine of formula (2a)

[0201] Example 19: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1 prepared at ambient temperature):

[0202] 0.18 g of betaine (1.5 mmol) was dissolved in 1.6 g of methanol (50 mmol) in a 5 ml glass vial within 5 min at room temperature using a magnetic stir bar for agitation. The agitation speed was 400 rpm.1.9 g (4.4 mmol) of all-rac a-tocopherol was added to this solution. The mixture obtained was agitated using a magnetic stir bar at 400 rpm for 24 h at room temperature. The solid obtained was separated from the solution by placing the precipitate formed on a filter paper, folding it to obtain a closed package and wrapping said package in paper towels serving as tissue paper. By manually applying pressure onto said wrapped package the precipitate was press-dried. After said press-drying process, the solid was further dried at ambient temperature. About 50 mg of the multicomponent crystal were obtained, the PXRD-pattern of which is shown in Fig. 19. It is comparable to the PXRD pattern of Fig. 1 , as can be seen in Fig. 20. This means that even prepared in a different way, multicomponent crystals of all-rac a-tocopherol and betaine of formula (2a) show the same PXRD pattern and thus have the same stoichiometry in the multicomponent crystal formed.

[0203] Example 19 can also be realized with first dissolving the active all-rac a-tocopherol and thereafter adding to this solution the crystallizing agent betaine of formula (2).

[0204] Example 20: (all-rac a-Tocopherol - Betaine Co-Crystal with a molar ratio in the multicomponent crystal of all-rac a-tocopherol - betaine of 2:1 sequentially prepared at ambient temperature):

[0205] 47.9 g all-rac a-tocopherol (111 mmol) and 3.6 g betaine (30.7 mmol) were added to 46.1 g methanol (1439 mmol) in a 100 ml glass bottle at room temperature. The mixture was agitated using a magnetic stir bar at 400 rpm. In two portions, one after 4 h of stirring and one after further 18 h of stirring, mixtures of all-rac a-tocopherol and betaine were added to the mixture. The two portions added in total made 8.8 g of all-rac a-tocopherol (20.4 mmol) and 1.2 g of betaine (10.2 mmol). The mixture was agitated for an additional 24 h at 200 rpm. The obtained solid was separated from the solution by pressing the precipitate dry between a folded filter paper covered in paper towels as explained in example 19. The obtained solid was redispersed in 10 mL of acetonitrile at room temperature. The process of press-drying and redispersing in acetonitrile was repeated four times. After a final press-drying step, the solid was dried in vacuum.

[0206] 11.6 g of dry multicomponent crystal were obtained which showed a PXRD pattern as given in Fig. 19.

Claims

Claims1. Multicomponent crystal comprising a) an active, said active being a mixture of at least two distinct molecules of formula (1)- with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3,- with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration, and b) a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of b1) - being suitable to form ions and- containing a H-bond acceptor and- being suitable to form a zwitterionic structure and- having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or b2) - containing a H-bond donor, with the proviso that the combination of proline as crystallizing agent of formula (2z) and tocopherol as active is excluded from the teaching of claim 1.

2. The multicomponent crystal of claim 1, wherein said active being a mixture of at least three distinct molecules of formula (1), preferably of at least four distinct molecules of formula (1), further preferred of at least five distinct molecules of formula (1), yet further preferred of at least six distinct molecules of formula (1), still further preferred of at least seven distinct molecules of formula (1) and mostly preferred of at least eight distinct molecules of formula (1), andR being at least one selected from the group consisting of H and COCH3, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a)in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)3. The multicomponent crystal according to claim 1 or 2, wherei n said active being D / L-a-tocopherol of formula (3)with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R- configuration, inclusive of all-rac a-tocopherol, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a)in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)4. The multicomponent crystal according to any one of claims 1 to 3, wherei nthe molar ratio of said active to said crystallizing agent (2) ranges from 3:1 to 1 :3, preferably from 2.1 :1 to 1.9:1 or from 2:1 to 1 :2 including a molar ratio of 1 :1 and of 1 :1.1 and further preferred being 2:1.

5. The multicomponent crystal according to any one of claims 1 to 4, wherei n when betaine of formula (2a) is used as crystallizing agent (2), it has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4, preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4.

6. The multicomponent crystal according to any one of claims 1 to 4, wherei n when betaine of formula (2a) is used as crystallizing agent (2), it has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 3.7, 5.5, 7.4, 9.2, 11.1 , 12.9, 14.8, 15.6, 16.7, 17.0, 18.1 , 18.5, 20.4, 21.8 and 24.2, preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.7, 5.5, 7.4, 9.2, 11.1 , 12.9, 14.8, 15.6, 16.7, 17.0, 18.1 , 18.5, 20.4, 21.8 and 24.2, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.7, 5.5, 7.4, 9.2, 11.1 12.9, 14.8, 15.6, 16.7, 17.0, 18.1 , 18.5, 20.4, 21.8 and 24.2.

7. The multicomponent crystal according to any one of claims 1 to 6, wherei n when betaine of formula (2a) is used as crystallizing agent (2), it comprises less than 45 w% of not crystallized matter, preferably less than 30 w%, further preferred less than 20 w%, still further preferred less than 10 w% and highly preferred less than 5 w% including 1 w% and 0 w%.

8. The multicomponent crystal according to any one of claims 1 to 7, wherei n when betaine of formula (2a) is used as crystallizing agent (2), it exhibits a phase transition withan onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 72°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 75°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 50 J / g, preferably an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 85°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 89°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 60 J / g, and further preferred an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 98°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 103°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 82 J / g.

9. The multicomponent crystal according to any one of claims 1 to 8, wherei n when betaine of formula (2a) is used as crystallizing agent (2), its temperature of decomposition Tdas measured by thermogravimetric analysis (TGA) is at least 175°C, preferably at least 180°C, further preferred at least 185°C, still further preferred at least 190°C and yet further preferred it is 195°C or higher.

10. The multicomponent crystal according to any one of claims 1 to 4, wherei n when N-me- thylaminopropionic acid of formula (2b) is used as crystallizing agent (2), it has in a crystal modification (C1) a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4, preferablyit has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 5.1 , 6.8, 8.5, 10.2 and 20.4, further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4, yet further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 5.1 , 6.8, 8.5, 10.2 and 20.4, still further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are located at 5.1 , 6.8, 8.5, 10.2 and 20.4, and still with further preference it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.4, 5.1 , 6.8, 8.5, 10.2, 13.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2 and 27.4.

11. The multicomponent crystal according to claims 10, wherein when N-methylaminopropionic acid of formula (2b) is used as crystallizing agent (2), it exhibits for the crystal modification (C1) a phase transition with an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 47°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 54°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 37 J / g, and a temperature of decomposition Td as measured by thermogravimetric analysis (TGA) of at least 80°C.

12. The multicomponent crystal according to any one of claims 1 to 4, wherei n when N-me- thylaminopropionic acid of formula (2b) is used as crystallizing agent (2), it has in a crystal modification (C2) a powder x-ray diffraction pattern (PXRD pattern) with at least onecharacteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1 , preferably it has a powder x-ray diffraction pattern (PXRD pattern) with at least one characteristic peak expressed in °20 ± O.2°20 (CuKa radiation), which is selected from the peaks located at 7.4, 12.9, 15.7, 16.9 and 28.1 , further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1 , yet further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with at least three characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation), which are selected from the peaks located at 7.4, 12.9, 15.7, 16.9 and 28.1 , still further preferred it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) which are located at 7.4, 12.9, 15.7, 16.9 and 28.1 and still with further preference it has a powder x-ray diffraction pattern (PXRD pattern) with the following characteristic peaks expressed in °20 ± O.2°20 (CuKa radiation) and located at 3.7, 5.5, 7.4, 11.1 , 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1.

13. The multicomponent crystal according to claims 12, wherei n when N-methylaminopropi- onic acid of formula (2b) is used as crystallizing agent (2), it exhibits for the crystal modification (C2) a phase transition with an onset temperature Toas measured by differential scanning calorimetry (DSC) of at least 53°C, and a peak temperature Tpas measured by differential scanning calorimetry (DSC) of at least 58°C, and a phase transition enthalpy AH as measured by differential scanning calorimetry (DSC) of at least 44 J / g and a temperature of decomposition Td as measured by thermogravimetric analysis (TGA) of at least 150°C.

14. Process for preparing a multicomponent crystal as defined in any one of claims 1 to 13 from at least two solids or from at least one solid and at least one liquid comprising the steps: i) providing an active, said active being a mixture of at least two distinct molecules of formula (1)with R being at least one selected from the group consisting of H, COCH3, COCH2CH3, CO(CH2)I4CH3, CO(CH2)I6CH3, with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R-configuration, ii) adding to the active of step i) a crystallizing agent (2), said crystallizing agent (2) exhibiting the property of ii.i) - being suitable to form ions and- containing a H-bond acceptor and- being suitable to form a zwitterionic structure and- having a molecular weight, which ranges from 100 g / mol to 135 g / mol and / or ii.ii) - containing a H-bond donor, iii) mixing the active and the crystallizing agent (2) to obtain a mixture, iv) optionally concentrating the mixture of step iii) or adding a solvent and / or an antisolvent to the mixture of step iii), while stirring, v) cooling the mixture of step iii) or of step iv) for crystallization, and / or stirring the mixture of step iii) or of step iv) for crystallization, vi) incubating the mixture of step v) in order to get the formed multicomponent crystal settled, vii) removing the supernatant formed in step vi) by decanting or by evaporation or by filtration, viii) optionally washing the formed multicomponent crystal of step vii) with the solvent and / or with the antisolvent ix) and drying the formed multicomponent crystal of step vii) or viii), with the proviso that the combination of proline as crystallizing agent (2z) and tocopherol as active is excluded from the teaching of claim 14.

15. The process according to claim 14, wherei n- the active is diluted with or dissolved in an active solubilization solvent prior to providing it in step i) of claim 14or- the crystallizing agent (2) is diluted with or dissolved in an active solubilization solvent prior to adding it in step ii) of claim 14 or- the active and the crystallizing agent (2) are diluted with or dissolved in an active solubilization solvent prior to mixing them in step iii) of claim 14 and / or- at least one of the group consisting of the active and the crystallizing agent (2) is readded in one or several portions after step ii) or step iii) of claim 14.

16. The process according to claim 14 or 15, wherei n the active being a mixture of at least three distinct molecules of formula (1), preferably of at least four distinct molecules of formula (1), further preferred of at least five distinct molecules of formula (1), yet further preferred of at least six distinct molecules of formula (1), still further preferred of at least seven distinct molecules of formula (1) and mostly preferred of at least eight distinct molecules of formula (1), andR being at least one selected from the group consisting of H and COCH3, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a)in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)17. The process according to any one of claims 14 to 16, wherei n said active being D / L-a-tocopherol of formula (3)with the methyl groups in position 2, 4’, 8’ respectively having a S-configuration or a R- configuration, inclusive of all-rac a-tocopherol, and the crystallizing agent (2) being one selected from the group consisting of betaine of formula (2a)in its ionic form, which it adopts during crystallization and of N-methylaminopropionic acid of formula (2b)18. A composition comprising a multicomponent crystal as defined in any one of claims 1 to 13 or as obtained in a process according to any one of claims 14 to 17 and at least one dietary acceptable constituent.

19. Use of a multicomponent crystal as defined in any one of claims 1 to 13 or as obtained in a process according to any one of claims 14 to 17, or of a composition according to claim 18 in a food formulation or a feed formulation or in a pharmaceutical preparation.

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