Improved multi-component crystals of tocopherol mixtures and methods of making same

Abstract

The invention relates to a multi-component crystal comprising a) an active substance which is a mixture of at least two different molecules of formula (1) wherein R is at least one selected from the group consisting of H, COCH3, COCH2CH3, CO (CH2) 14CH3, CO (CH2) 16CH3-wherein the methyl groups in positions 2, 4 ', 8' respectively have an S-configuration or an R-configuration; and b) a crystallizing agent (2) exhibiting the following properties: b1)-suitable for forming ions, and-containing H-bond receptors, and-suitable for forming zwitterionic structures, and-having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or-containing H-bond donors, and b2)-suitable for forming zwitterionic structures, and-having a molecular weight in the range of 100 g / mol to 135 g / mol. With the proviso that the combination of proline as the crystallizing agent of formula (2z) and tocopherol as the active substance is excluded from the teaching of claim 1.

Description

[0001] This invention relates to improved multicomponent crystals of α-tocopherol mixtures and methods for their preparation. Further aspects of the invention cover compositions comprising the multicomponent crystals and the uses of the multicomponent crystals and the compositions.

[0002] Synthetic α-tocopherol, also known as DL-α-tocopherol or D / L α-tocopherol, is a mixture of isomers containing at least two stereoisomers. It may also contain three, four, five, six, or seven stereoisomers, and in most cases, eight stereoisomers. It can be defined by equation (3).

[0003]

[0004] The methyl groups at positions 2', 4', and 8' have either an S-configuration or an R-configuration, respectively.

[0005] In the presence of all eight stereoisomers, the synthesis of α-tocopherol or DL-α-tocopherol is also referred to as racemic α-tocopherol. Racemic α-tocopherol has three stereocenters, namely at positions 2', 4', and 8' as shown in formula (3), and therefore it can form eight stereoisomers with the following configurations: RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR.

[0006] DL-α-tocopherol and racemic α-tocopherol are synthetically produced vitamin E active compounds or mixtures of active substances of formula (3). They are highly viscous oils that are sensitive to oxidation and therefore unstable for long-term storage. Considering this sensitivity to oxygen at position 6 of the OH- group on the aromatic ring derived from DL-α-tocopherol and racemic α-tocopherol (both shown in formula (3)), successful attempts have been made to protect the OH group of the active substances from oxidation by esterification.

[0007] Besides the active substances DL-α-tocopherol and racemic α-tocopherol (both shown in formula (3)), acetates, propionates, palmitates, and stearates of DL-α-tocopherol and racemic α-tocopherol have become important feed supplements, food supplements, and pharmaceutical ingredients. Therefore, commercially important mixtures of compounds exhibiting vitamin E activity are not only mixtures of compounds in formula (3), but also mixtures of a larger group of DL-α-tocopherol, racemic α-tocopherol, and their corresponding esters, all of which are classified under formula (1).

[0008]

[0009] Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3, wherein the methyl groups at positions 2, 4', and 8' have either an S-configuration or an R-configuration, respectively.

[0010] However, the active substances or mixtures of active substances of formula (1) are also highly viscous oils or brittle solids that are difficult to handle and formulate. They are all photosensitive and degrade upon application of elevated temperatures. They do not exhibit the properties of fine powders and are unfavorably prone to clumping or agglomeration. Complex formulation techniques are required to produce durable, free-flowing powders in order to protect the mixtures of formula (1) from oxidation or degradation by light or high temperatures and to obtain solids that are defined as non-hygroscopic. Carbohydrates, colloids, and / or silica are often used as adjuvants in expensive spray drying or bead processes to obtain good formulation properties.

[0011] Mei and colleagues attempted to overcome the aforementioned shortcomings in EP 3733657 A1 (hereinafter referred to as '657). They produced crystalline or partially crystalline "cocrystals" of tocopherol and proline (refer to paragraph 15), but failed to verify the molar ratio of proline to tocopherol in the formed crystals by measurement. Instead, the indicated stoichiometry in the formed crystals referred to the stoichiometry of the starting materials, and this stoichiometry should have been maintained in the formed crystals, as shown below, which was not the case. The cocrystals in the '657 document are disclosed to have ratios between tocopherol and proline of 2:1, 1:1, and 1:2.

[0012] In reference '657, tocopherol should be understood to mean: "Tocopherol includes natural tocopherol and synthetic tocopherol. Natural tocopherol includes two types of tocopherol and tocotrienol, and includes eight categories of compounds, namely α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol. Synthetic tocopherol refers to α-tocopherol, which has eight optical isomers. Among them, D-α-tocopherol is the most widely distributed, abundant, and most active form of tocopherol in nature." (Ref. 0002) and "Tocopherol includes natural tocopherol and synthetic tocopherol, wherein the natural tocopherol includes α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol; and the synthetic tocopherol includes DL-α-tocopherol." (Ref. 2).

[0013] Similarly, proline is defined and interpreted as: "Preferredly, proline is a racemic mixture of D-proline or L-proline or both." (Refer to paragraph 7 of '657) and "The proline comprises a racemic mixture of D-proline or L-proline or both." (Refer to claim 2).

[0014] In reworking the '657 embodiment, we found that the initial temperature T measured by differential scanning calorimetry o Peak temperature T p Both the transformation enthalpy ΔH and the decomposition temperature ΔH are lower (see the comparative examples below). Similarly, the decomposition temperature Tdecomposition is also lower, as measured by differential gravimetric analysis (TGA). d The crystallinity in '657 is reduced. This indicates that the crystallinity in the sample is moderate or only partially developed, and that the sample is heterogeneous and partially amorphous or still contains uncrystallized material.

[0015] In the International Journal of Pharmaceutical Sciences (Int. J. Pharm.) 592 (2021) 120057 (hereinafter referred to as '057), Mei and colleagues investigated cocrystals or partially crystalline cocrystals formed from monomolecules of D-α-tocopherol (also known as RRR-α-tocopherol) and 1,2-bis(4-pyridyl)ethylene (DPE) or L-proline or betaine. That is, no cocrystal formation of mixtures like DL-α-tocopherol or racemic α-tocopherol was determined, let alone mixtures of formula (1).

[0016] We replicated the formulation shown in section 2.4 of '057, which contains D-α-tocopherol and betaine (see the comparative examples below), and was only able to establish a partial formation of the co-crystal.

[0017] This invention aims to overcome the shortcomings of the prior art. In particular, an object of the invention is to obtain more homogeneous or more structured and therefore more stable multicomponent crystals. Another object of the invention is to obtain such more stable multicomponent crystals not from D-α-tocopherol, but from a mixture of at least two different molecules of formula (1) or formula (3). Yet another object of the invention is to obtain a multicomponent crystal that remains stable at temperatures higher than those disclosed in the prior art. A further object of the invention is to obtain a multicomponent crystal that is free-flowing and does not condense. It should not tend to be hygroscopic, even after a storage period of several weeks and months. Another object is to provide a multicomponent crystal that can be readily formulated into the compositions of the invention. Yet another object is to obtain a multicomponent crystal in which the bioavailability is the same as that in the uncrystallized mixture of formula (1) or formula (3), or only slightly reduced relative to the uncrystallized mixture of formula (1) or formula (3).

[0018] Another object of the present invention is to provide a method for obtaining the multicomponent crystals of the present invention. The method should be direct, avoid harmful operational steps or compounds, and should be inexpensive. The method should be carried out in a manner that is not overly time-consuming and is easy to implement. Furthermore, the method should ensure that a large amount of active material becomes part of the multicomponent crystal. The inclusion of unectic material in the multicomponent crystal should be minimized.

[0019] Another object of the present invention is to provide a composition comprising the multi-component crystals. The composition should be readily available. It should exhibit at least the performance characteristics of prior art formulations of DL-α-tocopherol or racemic α-tocopherol, and even better. The composition should have the same or better bioavailability as prior art DL-α-tocopherol or racemic α-tocopherol compositions. It should exhibit at least the same and even better rheological properties / flowability as prior art DL-α-tocopherol or racemic α-tocopherol compositions. Another object of the present invention is to design the composition such that it can be prepared at low cost.

[0020] Another object of the present invention is to provide the use of the multi-component crystal of the present invention, its preparation method, and the use of compositions comprising the multi-component crystal.

[0021] These objectives are achieved by a multi-component crystal comprising:

[0022] a) An active substance, which is a mixture of at least two different molecules of formula (1).

[0023]

[0024] - Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3

[0025] -The methyl groups at positions 2', 4', and 8' have either S-configuration or R-configuration, respectively.

[0026] and

[0027] b) Crystallizing agent (2), which exhibits the following properties:

[0028] b1)- is suitable for forming ions, and

[0029] - Contains H-bond receptors, and

[0030] -Suitable for forming zwitterionic structures, and

[0031] - Having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or

[0032] b2)- Contains an H-bond donor,

[0033] The condition is that the combination of proline as a crystallizing agent of formula (2z) and tocopherol as an active substance is excluded from the teachings of this implementation scheme.

[0034] The multicomponent crystals comprising a mixture of at least two different molecules of formula (1) as active substances and a crystallizing agent (2) exhibit advantages in flowability, stability, hygroscopicity, storage stability, bioavailability, purity, and purification compared to pure DL-α-tocopherol or DL-α-tocopherol-L-proline cocrystals. These multicomponent crystals demonstrate properties suitable for forming ions and containing H-bond acceptors, and suitable for forming zwitterionic structures and having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or containing H-bond donors, provided that the combination of proline as a crystallizing agent of formula (2z) and tocopherol as an active substance is excluded from the teachings of this embodiment. This means that the new multicomponent crystals in solid form are stable at higher temperatures compared to prior art crystals. They are obtained as fine powders. They exhibit, for example, better flowability without clumping, lower hygroscopicity even after storage periods of several weeks and months, better storage stability, higher purity, and better purification performance. The multicomponent crystals of the present invention do not require any further purification and can be directly formulated into compositions. Compared with prior art compositions containing active substances of formula (1) or formula (3), the multicomponent crystals of the present invention preferably exhibit higher bioavailability and less variability in bioavailability. The bioavailability of the mixture of formula (1) or formula (3) in the new multicomponent crystals is higher than, equivalent to or only slightly lower than the bioavailability of the uncrystallized mixture of formula (1) or formula (3).

[0035] The multicomponent crystals are also suitable as intermediates or starting materials to produce pure active substances from mixtures of multiple compounds.

[0036] All of this is due to higher crystallinity, due to more uniform or higher structure, and therefore more stable multicomponent crystals, as can be obtained from the corresponding onset temperature T. o The corresponding peak temperature T p And derived from the corresponding enthalpy ΔH, as measured by DSC and shown below, and which are respectively higher than pure DL-α-tocopherol or cocrystals containing a combination of proline as a crystallizing agent (2z) and tocopherol as an active substance.

[0037] This is surprising because the active material of the present invention is not a single, distinct compound, but a mixture of several different compounds and / or a mixture of several stereoisomers of different compounds. In such mixtures, the different parts of the molecules have different spatial orientations due to their respective isomeric structures. Therefore, they are not readily arranged in a highly ordered structure with the crystallizing agent (2a) as is now achieved in the present invention. Instead, one would expect to obtain amorphous precipitates (if any) or multicomponent crystals of only one diastereomer, rather than well-defined multicomponent crystals as shown in the PXRD diagram below.

[0038] As understood in this invention, a multicomponent crystal means a highly ordered structure comprising an active substance and a crystallizing agent (2). The crystalline portions of the crystal may have different orientations within the same and identical particles. Portions that still possess amorphous characteristics may also exist; however, the crystallinity in the multicomponent crystal is higher than that in the prior art eutectic crystals. The terms "multicomponent crystal" and "multicomponent crystals" are understood to have the same meaning and are used interchangeably in this disclosure.

[0039] However, crystals formed from proline (2z) and tocopherol did not exhibit the increased stability, better rheological properties, and more significant crystallinity of multicomponent crystals.

[0040] As understood in the phrase “the condition that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this embodiment,” tocopherol refers to both natural and synthetic tocopherols. Natural tocopherols include two types of tocopherols and tocotrienols, and comprise eight categories of compounds: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. Synthetic tocopherol refers to α-tocopherol and has at least one, two, three, four, five, six, seven, or eight optical isomers: RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR.

[0041] As understood in the phrase “the condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this embodiment,” proline (2z) means that proline (2z) includes D-proline or L-proline or a racemic mixture of both. This is indicated by a wavy bond that links a proton to the carbon atom at the α-position of the carboxyl group in proline of the following formula (2z).

[0042] In any case, the active material of the present invention is a mixture of at least two different molecules, rather than a single compound, such as, for example, D-α-tocopherol. This does not mean that the active material of the present invention can be a mixture of different molecules having the same stereochemistry, such as, for example, D-α-tocopherol and D-α-tocopherol acetate. A combination of at least one of the propionate, palmitate, and stearate esters of D-α-tocopherol with at least one of D-α-tocopherol or D-α-tocopherol acetate can also be an active material. Each arrangement of the molecules mentioned above is possible and represents one embodiment of "at least two different molecules".

[0043] Active substances can also be mixtures of different stereoisomers of molecules with defined molecular weights, such as DL-α-tocopherol having a variable number of stereoisomers ranging from 2 to 8, or racemic α-tocopherol having eight stereoisomers. This meaning is also encompassed by the phrase "at least two different molecules".

[0044] An active substance can also be a mixture of at least one different stereoisomer of a molecule having a defined molecular weight with a mixture of different molecules having the same stereochemistry. An example would be D-α-tocopherol palmitate in combination with D-α-tocopherol and D-α-tocopherol stearate. Again, this definition falls within the scope of the term "at least two different molecules".

[0045] Finally, the active substance can be a mixture of different stereoisomers of molecules, wherein at least one molecule has a defined molecular weight. An example would be RRR-tocopherol acetate, RSS-tocopherol acetate, and D-α-tocopherol stearate. This is a further definition, which is covered by the phrase "at least two different molecules".

[0046] The crystallizing agent (2) is any compound that satisfies all the conditions, is suitable for forming an ion and contains an H-bond acceptor, and is suitable for forming a zwitterionic structure and has a molecular weight in the range of 100 g / mol to 135 g / mol. It may also or alternatively contain an H-bond donor. Preferably, the crystallizing agent (2) is any dietaryly acceptable compound that is suitable for forming an ion and contains an H-bond acceptor, and is suitable for forming a zwitterionic structure and has a molecular weight in the range of 100 g / mol to 135 g / mol and / or contains an H-bond donor.

[0047] H-bond acceptors are groups containing electronegative elements that have free electron pairs capable of participating in hydrogen bonds, such as O in C=O and N in NH2.

[0048] The H-bond donor is a group containing an electronegative element (e.g., O in the form of OH, N in the form of NH or NH2), to which a hydrogen atom is covalently attached.

[0049] The applicant tested the ability of a total of 60 compounds to be used as crystallizing agents, two of which (2) showed the ability to form multicomponent crystals with the active substance of formula (1), namely racemic α-tocopherol.

[0050] An exemplary co-crystallizing agent (2) is betaine of formula (2a).

[0051] ,

[0052] Nicotinic acid of formula (2h)

[0053] ,

[0054] Nicotinamide of formula (2i)

[0055] ,

[0056] N-methylaminopropionic acid of formula (2b)

[0057] ,

[0058] Succinic acid of formula (2k)

[0059] ,

[0060] Malic acid of formula (2m)

[0061]

[0062] Of these exemplary compounds, only two (2) show the ability to form multicomponent crystals with the active material of the present invention.

[0063] Compounds (2b), (2h), and (2i) can vary between their zwitterionic and nonionic forms. This is reflected in compound (2b) by indicating their meso compound.

[0064] However, proline of formula (2z) can also be used as a crystallizing agent.

[0065]

[0066] This is neither an exemplary crystallizer nor a crystallizer of the present invention.

[0067] The highly preferred crystallizing agent (2) is selected from the group consisting of betaine (2a) and N-methylaminopropionic acid (2b).

[0068] In another embodiment of the invention, a multi-component crystal is defined.

[0069] - The active substance is a mixture of at least three different molecules of formula (1), preferably a mixture of at least four different molecules of formula (1), more preferably a mixture of at least five different molecules of formula (1), even more preferably a mixture of at least six different molecules of formula (1), even more preferably a mixture of at least seven different molecules of formula (1), and most preferably a mixture of at least eight different molecules of formula (1).

[0070] and

[0071] In equation (1), R is selected from at least one of the groups consisting of H and COCH3.

[0072] and

[0073] - The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization;

[0074]

[0075] N-methylaminopropionic acid of formula (2b)

[0076] .

[0077] When betaine is used as a crystallizing agent of formula (2a), the advantages of claim 1, namely better flowability, stability, hygroscopicity, storage stability, bioavailability, purity, and purification behavior, are even improved, as can be seen below. This means that the solid form of the multi-component crystals has better flowability, lower hygroscopicity, better storage stability, higher bioavailability, less variability in bioavailability, higher purity, and better purification performance.

[0078] In a further developed embodiment of the multi-component crystal of the present invention,

[0079] -The active substance is D / L-α-tocopherol of formula (3).

[0080]

[0081] The methyl groups at positions 2', 4', and 8' have either S- or R-configurations, including racemic α-tocopherol.

[0082] and

[0083] - The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization;

[0084]

[0085] N-methylaminopropionic acid of formula (2b)

[0086] .

[0087] Stabilizing D / L-α-tocopherol or racemic α-tocopherol through esterification to reduce its susceptibility to oxidation also reduces its ability to act as an antioxidant and its bioavailability to some extent. This minor, however present drawback can be overcome by using D / L-α-tocopherol of formula (3) that is synonymous with DL-α-tocopherol of formula (3), including racemic α-tocopherol, because in these entities there is free access to the OH- group at position 6 of formula (3). However, this is not detrimental because the molecule of formula (3) is part of a multicomponent crystal.

[0088] If an excessive amount of active ingredient is used, not all of the active ingredient can be incorporated into the multicomponent crystal. On the other hand, a lack of active ingredient will reduce its deliverable amount, for example, in dietary supplements, and thus reduce the amount that is bioavailable to the body. This can be avoided with the multicomponent crystal of the present invention, which exhibits a molar ratio of active ingredient to crystallizer (2) in the range of 3:1 to 1:3, preferably 2.1:1 to 1.9:1 or 2:1 to 1:2, including molar ratios of 1:1 and 1:1.1, and more preferably 2:1. This can be avoided with the multicomponent crystal of the present invention, which exhibits a molar ratio of active ingredient to crystallizer (2a), (2b) in the range of 3:1 to 1:3, preferably 2.1:1 to 1.9:1 or 2:1 to 1:2, including molar ratios of 1:1 and 1:1.1, and more preferably 2:1.

[0089] When betaine of formula (2a) is used as crystallizing agent (2), the multicomponent crystal of the present invention has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from peaks located at 5.5, 7.4, 9.2, 12.9, 16.7, and 20.4; preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation). The powder X-ray diffraction (PXRD) pattern has at least three characteristic peaks selected from those located at 5.5, 7.4, 9.2, 12.9, 16.7, and 20.4; more preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks located at 5.5, 7.4, 9.2, 12.9, 16.7, and 20.4, expressed in °2θ ± 0.2°2θ (CuKα radiation).

[0090] It was observed that the peaks of the highly crystalline multicomponent crystals of the present invention, containing the active substance and betaine (2a), differed from those of the cocrystal of D-α-tocopherol and betaine (2a) disclosed in Comparative Example 13, such as... Figure 12 As shown in the figure. This is also due to the high decomposition temperature T of 200°C. D Example 1 and Figure 2 The results are supported by thermogravimetric analysis (TGA) and are supported by examples such as Example 1 and Figure 3 The high initial temperature T of 98℃ is given in the text. O The peak temperature T is 103℃. P The high enthalpy of phase change ΔH of 82 J / g supports this, all of which indicate a well-packed, highly structured multicomponent crystal that can only be decomposed at high temperatures and with an increased amount of energy. As shown by HPLC analysis, the multicomponent crystal contains all eight stereoisomers in the same proportions observed in racemic α-tocopherol (refer to Example 5). Figure 7 ).

[0091] When betaine of formula (2a) is used as crystallizing agent (2), a further improved embodiment of the multicomponent crystal of the present invention has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from 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 with at least three characteristic peaks expressed in °2θ ± 0.2°2θ (CuKα radiation). The at least three characteristic peaks are selected from those 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; more preferably, it has a powder X-ray diffraction (PXRD) pattern with characteristic 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, expressed in °2θ ± 0.2°2θ (CuKα radiation).

[0092] It was observed that the peaks of the highly crystalline multicomponent crystals of the present invention containing D / L-α-tocopherol and betaine (2a) differed from those of the cocrystal of D-α-tocopherol and betaine (2a) disclosed in Comparative Example 13, such as... Figure 12As shown in the figure. This is also due to the high decomposition temperature T of 200°C. D Example 1 and Figure 2 The results are supported by thermogravimetric analysis (TGA) and are supported by examples such as Example 1 and Figure 3 The high initial temperature T of 98℃ is given in the text. O The peak temperature T is 103℃. P The high enthalpy of phase change ΔH of 82 J / g supports this, all of which indicate a well-packed, highly structured multicomponent crystal that can only be decomposed at high temperatures with an increased amount of energy. Similarly, the overall recovery and identical redistribution of the different stereoisomers in the multicomponent crystals compared to pure D / L-α-tocopherol reveal the highly ordered and poorly soluble structure of the multicomponent crystals of the present invention. As shown by HPLC analysis, the multicomponent crystals contain all eight stereoisomers in the same proportions observed in racemic α-tocopherol (refer to Example 5). Figure 7 ).

[0093] The existing eutectic still contains free D / L-α-tocopherol as an amorphous substance, as shown in Comparative Example 9. The amorphous substance can be any active material of formula (1) or formula (3) that cannot be suitably located within the ordered structure of the crystal, or is amorphously adhered to its surface and / or to the pores, gaps, or voids of a less ordered or partially amorphous crystal. This also contributes to making the crystal less homogeneous and less structured, as in… Figure 10 As can be seen in the powder X-ray diffraction (PXRD) pattern, it is similar to... Figure 1 and Figure 4 compared to, Figure 10 This displays a larger background, especially in the middle of the image.

[0094] In contrast, when betaine of formula (2a) is used as a crystallizing agent (2), the multi-component crystal of the present invention contains less than 45% by weight of uncrystallized material, preferably less than 30% by weight, more preferably less than 20% by weight, even more preferably less than 10% by weight, and highly preferably less than 5% by weight, including 1% by weight and 0% by weight.

[0095] As already mentioned, the higher crystallinity of this implementation provides better stability, better flowability, and lower hygroscopicity.

[0096] As previously mentioned, the multi-component crystals of the present invention exhibit a highly ordered structure and contain only a small amount to no excess or unequal amounts of active material. Only in this way can the elevated onset temperature T be observed. o Peak temperature T p And the enthalpy of phase transition ΔH.

[0097] This is reflected in another embodiment of the invention, wherein when betaine of formula (2a) is used as a crystallizing agent (2), the multicomponent crystal exhibits a phase transition having the following characteristics:

[0098] - Such as an initial temperature T of at least 72°C as measured by differential scanning calorimetry (DSC). o ,

[0099] and

[0100] - A peak temperature T of at least 75°C as measured by differential scanning calorimetry (DSC). p ,

[0101] as well as

[0102] - Such as a phase transition enthalpy ΔH of at least 50 J / g as measured by differential scanning calorimetry (DSC).

[0103] Preferably

[0104] - Such as an initial temperature T of at least 85°C as measured by differential scanning calorimetry (DSC). o ,

[0105] and

[0106] -A peak temperature T of at least 89°C as measured by differential scanning calorimetry (DSC). p ,

[0107] And - such as a phase transition enthalpy ΔH of at least 60 J / g as measured by differential scanning calorimetry (DSC),

[0108] and further optimization

[0109] - Such as an initial temperature T of at least 98°C as measured by differential scanning calorimetry (DSC). o ,

[0110] and

[0111] - A peak temperature T of at least 103°C as measured by differential scanning calorimetry (DSC). p ,

[0112] And - such as a phase transition enthalpy ΔH of at least 82 J / g as measured by differential scanning calorimetry (DSC).

[0113] In the context of this disclosure, such as the initial temperature T obtained by differential scanning calorimetry (DSC) o The melting point is defined as the melting point of the multicomponent crystal or any other compound being analyzed, while the peak temperature T, as measured by differential scanning calorimetry (DSC), is the temperature at which the melting point is determined. p It is defined as the point in which the corresponding peak in the DSC chart shows its highest or lowest value.

[0114] The highly ordered structure of the multi-component crystals of this invention, and the presence of only small amounts to no excess or unequal amounts of active substances, also contribute to its high decomposition temperature T. d To reveal.

[0115] This is reflected in another embodiment of the multicomponent crystal of the present invention, in which, when betaine of formula (2a) is used as a crystallizing agent (2), the multicomponent crystal exhibits a decomposition temperature T of at least 175°C, preferably at least 180°C, more preferably at least 185°C, even more preferably at least 190°C, and even more preferably at 195°C or higher, as measured by thermogravimetric analysis (TGA). d .

[0116] During the search for additional candidates suitable for use as crystallizing agents (2) for active substances of formula (1), particularly active substances of formula (3) (including racemic α-tocopherol), the compound N-methylaminopropionic acid of formula (2b)

[0117]

[0118] In compounds identified as capable of forming two different multicomponent crystal types (C1) and (C2), the two different multicomponent crystal types are synonymous with two different crystal variants (C1) and (C2).

[0119] When N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern in the crystal variant (C1) with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from 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, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation). The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from peaks located at 5.1, 6.8, 8.5, 10.2, and 20.4. More preferably, the multicomponent crystal has a PXRD pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from peaks located at 3.4, 5.1, 6.8, 8.5, 10.2, and 20.4. The multicomponent crystal has peaks at 3.6, 16.0, 16.9, 18.7, 19.2, 20.4, 22.2, and 27.4. More preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks expressed in °2θ ± 0.2°2θ (CuKα radiation), selected from peaks located at 5.1, 6.8, 8.5, 10.2, and 20.4. Even more preferably, the multicomponent crystal has peaks with the following characteristics expressed in °2θ ± 0.2°2θ (CuKα radiation). The powder X-ray diffraction (PXRD) pattern of the characteristic peaks is shown, located at 5.1, 6.8, 8.5, 10.2, and 20.4; and further preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with the characteristic peaks shown in °2θ±0.2°2θ (CuKα radiation) 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.

[0120] The PXRD pattern was not structured as it was obtained with crystallizing agent (2a). However, as indicated above and Figure 13 As demonstrated in Examples 14 to 16 of the present invention, individualized peaks can be observed, indicating crystal formation.

[0121] Further thermodynamic data revealed that when N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal exhibits the following phase transition for crystal transformation (C1):

[0122] - Such as an initial temperature T of at least 47°C as measured by differential scanning calorimetry (DSC). o ,

[0123] and

[0124] - A peak temperature T of at least 54°C as measured by differential scanning calorimetry (DSC). p ,

[0125] And - such as a phase transition enthalpy ΔH of at least 37 J / g as measured by differential scanning calorimetry (DSC),

[0126] And a decomposition temperature T of at least 80°C, as measured by thermogravimetric analysis (TGA). d .

[0127] These data show that the crystal variant (C1) of the multicomponent crystal is less stable than the eutectic of betaine including formula (2a). This is in addition to the initial temperature T of 47°C. o And the peak temperature T of 54℃ p In addition to the related phase transition, a second abrupt phase transition was also observed at 72 °C (see reference). Figure 15 ).

[0128] This reveals the different properties of multicomponent crystals formed using different crystallizing agents of the present invention. These multicomponent crystals have different degrees of crystallinity and therefore exhibit different thermodynamic properties. The idea is that the more thermodynamically stable the multicomponent crystal, the better, which can be achieved by using a higher onset temperature T. o Higher peak temperature T p And a higher enthalpy of transformation ΔH is used to show this. The idea is achieved to varying degrees by different crystallizing agents, and some of these crystallizing agents do not crystallize at all. Some crystallizing agents may form multicomponent crystals with monomolecule D-α-tocopherol, but not with the active substances of formula (1), and not even with the active substances of formula (3) (including racemic α-tocopherol), or only provide multicomponent crystals that have decomposed at room temperature.

[0129] This also reveals that by combining the teachings of one prior art document with the teachings of another prior art document, it is impossible to predict what the result will be and how multicomponent crystals will look after formation.

[0130] With this in mind, it is surprising that N-methylaminopropionic acid of formula (2b) forms a second type of multicomponent crystal (C2) when combined with the active substance of formula (1).

[0131] The N-methylaminopropionic acid of formula (2b), when combined with the active substance of formula (1), particularly with the active substance of formula (3) (including racemic α-tocopherol), provides a second type of multicomponent crystal (C2). When the N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern in crystal variant (C2) with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), the at least one characteristic peak being selected from 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, the multicomponent crystal has a peak expressed in °2θ ± 0.2°2θ (CuKα radiation). A powder X-ray diffraction (PXRD) pattern having at least one characteristic peak represented by 2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from peaks located at 7.4, 12.9, 15.7, 16.9, and 28.1; more preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern having at least three characteristic peaks represented by 2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from peaks located at 3.7, 5.5, 7.4, 11.1, 12. The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks at 7.4, 12.9, 15.7, 16.9, 17.8, 20.4, 21.7, and 28.1°; more preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks expressed in °2θ ± 0.2°2θ (CuKα radiation), the at least three characteristic peaks being selected from peaks located at 7.4, 12.9, 15.7, 16.9, and 28.1°; and even more preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks expressed in °2θ ± 0.2°2θ (CuKα radiation). The powder X-ray diffraction (PXRD) pattern of the characteristic peaks (represented by CuKα radiation) located at 7.4, 12.9, 15.7, 16.9, and 28.1; and further preferably, the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks (represented by CuKα radiation) 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.

[0132] The PXRD pattern obtained for the crystal variant (C2) of the multi-component crystal of the present invention again reveals less structured structure than the PXRD pattern obtained using betaine as a crystallizing agent (2a). However, it appears to be more structured than the pattern obtained for the crystal variant (C1) (see reference). Figure 16 ).

[0133] This more ordered structure is confirmed by thermodynamic data, namely, by a higher onset temperature T obtained through differential scanning calorimetry (DSC). oHigher peak temperature T p And a higher phase transition enthalpy ΔH. Additionally, the decomposition temperature T obtained by thermogravimetric analysis... d The ratio is higher than that for crystal variant (C1). When N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal exhibits the following phase transition for crystal variant (C2).

[0134] - Such as an initial temperature T of at least 53°C as measured by differential scanning calorimetry (DSC). o ,

[0135] and

[0136] - A peak temperature T of at least 58°C as measured by differential scanning calorimetry (DSC). p ,

[0137] as well as

[0138] - Such as a phase transition enthalpy ΔH of at least 44 J / g as measured by differential scanning calorimetry (DSC).

[0139] And - such as a decomposition temperature T of at least 150°C as measured by thermogravimetric analysis (TGA) d .

[0140] In addition to the phase transition observed at 53 °C, a further phase transition was observed at 161 °C (see reference). Figure 17 ).

[0141] The obtained thermodynamic data show that the multicomponent crystal (C2) has a higher onset temperature T than the multicomponent crystal (C1). o Higher peak temperature T p Higher transformation enthalpy ΔH and higher decomposition temperature T d The current research focuses on whether even more stable multicomponent crystal variants can be obtained.

[0142] A method for preparing the multi-component crystal of the present invention from at least two solids or from at least one solid and at least one liquid includes the following steps:

[0143] i) Provide an active substance, said active substance being a mixture of at least two different molecules of formula (1).

[0144]

[0145] - Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3

[0146] -The methyl groups at positions 2', 4', and 8' have either S-configuration or R-configuration, respectively.

[0147] ii) Add crystallizing agent (2) to the active substance of step i), wherein the crystallizing agent (2) exhibits the following properties:

[0148] ii.i) - suitable for forming ions, and

[0149] - Contains H-bond receptors, and

[0150] -Suitable for forming zwitterionic structures, and

[0151] - Having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or

[0152] ii.ii) - Contains H-bond donors,

[0153] iii) Mix the active substance and crystallizing agent (2) to obtain a mixture.

[0154] iv) Optionally, the mixture from step iii) may be concentrated, or a solvent and / or anti-solvent may be added to the mixture from step iii) while stirring.

[0155] v) Cool the mixture from step iii) or step iv) for crystallization.

[0156] and / or stirring the mixture from step iii) or step iv) for crystallization,

[0157] vi) Incubate the mixture from step v) to allow the formed multicomponent crystals to settle.

[0158] vii) Remove the supernatant formed in step vi) by decantation, evaporation, or filtration.

[0159] viii) Optionally wash the multicomponent crystals formed in step vii) with a solvent and / or with an antisolvent.

[0160] ix) and drying the multi-component crystals formed in step vii) or viii).

[0161] The condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this method.

[0162] The method for obtaining the multicomponent crystals of the present invention is straightforward, as all method steps can be performed within hours and require overnight operation only in exceptional cases. Highly trained personnel are not required, as each method step is self-explanatory. The active material and crystallizing agents (2a) and (2b) are harmless when handled with ordinary laboratory skills. This is further applicable when, in the preferred embodiment, both the active material and crystallizing agents (2a) and (2b) have GRAS status, meaning they are generally considered preserved by the FDA. The method provides for the use of the active material and crystallizing agent (2) as is or diluted. All method steps are safe to perform and are harmless. It will be apparent to those skilled in the art that the method steps are not expensive. The manner in which the method is performed is readily achievable. By the method of the present invention, twice the molar amount of active material relative to the crystallizing agent (2) and even more can become an integral part of the new multicomponent crystal, i.e., a properly allocated portion. As explained above, the presence of unequalized material, or even entirely unequalized material, as part of the multicomponent crystal can be largely avoided. Another advantage of the method of the present invention is that it provides the multi-component crystals of the present invention as fine powder, which can be directly further processed.

[0163] As understood in the phrase “the condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this method,” tocopherol refers to both natural and synthetic tocopherols. Natural tocopherols include two types of tocopherols and tocotrienols, and comprise eight classes of compounds: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. Synthetic tocopherols refer to α-tocopherol and have at least one, two, three, four, five, six, seven, or eight optical isomers: RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR.

[0164] As understood in the phrase “the condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this method,” proline (2z) means that proline (2z) includes D-proline or L-proline or a racemic mixture of both.

[0165] The terms “active substance,” “crystallizing agent,” “H-bond acceptor,” and “H-bond donor” used in the methods of the present invention have the same meanings as given above for the multi-component crystals of the present invention.

[0166] The solvent should be understood as any solvent that dissolves at least the active substance, and also the active substance and the crystallizing agent (2). Suitable solvents are selected from the group consisting of methanol, ethanol, isopropanol, heptane, acetonitrile and ethyl acetate, and mixtures thereof.

[0167] Antisolvents are those solvents that reduce the amount of the solubilized active substance and / or the solubilized crystallizing agent (2) or completely prevent the solubilization of the active substance and / or crystallizing agent (2). They should also be understood as solvents that prevent the solubilization of multicomponent crystals. Antisolvents should be understood as solvents that cause precipitation when added to a solution or another solvent. Nitromethane or water is used as an antisolvent.

[0168] The warming in step vi) means bringing the mixture of step v) to a lower temperature, preferably the temperature at which it was cooled in step v), with or without stirring, or bringing the mixture of step v) to the temperature at which it was stirred in step v), with or without stirring.

[0169] The supernatant of step vii) should be understood as the liquid remaining above the multi-component crystals formed in this invention.

[0170] Filtration in step vii) should be understood as any measure that can remove the supernatant from the multicomponent crystals. Therefore, filtration includes any filtration means used without pressure or under pressure. It also includes removing the supernatant by transferring the settled multicomponent crystals onto at least one of one or more sheets of filter paper and tissue paper and immersing the supernatant in the filter paper and / or tissue paper.

[0171] As can be seen from the examples below, it is sometimes difficult to operate with the active substance and crystallizing agents (2a), (2b), especially if the amount of the active substance is increased relative to the amount of crystallizing agents (2a), (2b). This is solved by extending the method of the present invention, wherein...

[0172] - Before providing the active substance in step i) of the method of the present invention, the active substance is diluted with or dissolved in an active substance solubilizing solvent.

[0173] or

[0174] Before adding the crystallizing agent (2) in step ii) of the method of the present invention, the crystallizing agent is diluted with or dissolved in an active substance solubilizing solvent.

[0175] or

[0176] - Before mixing the active substance and the crystallizing agent (2) in step iii) of the method of the present invention, the active substance and the crystallizing agent are diluted with or dissolved in an active substance solubilizing solvent.

[0177] And / or

[0178] - After step ii) or iii) of the method of the present invention, at least one of the group consisting of the active substance and the crystallizing agent (2) is added back in one or more parts.

[0179] The active substance solubilizing solvent is a solvent that solubilizes the active substance or the crystallizing agent (2) or both. A particular characteristic of the active substance solubilizing solvent is that it is used before step i) of the method of the present invention to solubilize the active substance, or it is used before step ii) of the method of the present invention to solubilize the crystallizing agent (2), or it is used before step iii) to solubilize both the active substance and the crystallizing agent (2).

[0180] If at least one of the group consisting of the active substance and the crystallizing agent (2) is re-added in several parts after step ii) or step iii) of the method of the present invention, then before adding one or several parts of the active substance or the crystallizing agent (2) after step ii) or step iii) of the method of the present invention, an active substance solubilizing solvent may be used but it is not necessary to use an active substance solubilizing solvent for solubilizing at least one of the active substance or the crystallizing agent.

[0181] Suitable solubilizing solvents for active substances are selected from the group consisting of methanol, ethanol, isopropanol, heptane, acetonitrile, ethyl acetate, and mixtures thereof.

[0182] Instead of first solubilizing the active substance and then the crystallizing agent (2), the alternative implementation scheme of the method of the present invention is as follows:

[0183] The method embodiment for preparing the multi-component crystal of the present invention from at least two solids or from at least one solid and at least one liquid includes the following steps:

[0184] i) Provide an active substance, said active substance being a mixture of at least two different molecules of formula (1).

[0185]

[0186] - Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3

[0187] -The methyl groups at positions 2', 4', and 8' have either S-configuration or R-configuration, respectively.

[0188] ii) Provide a crystallizing agent (2) that exhibits the following properties:

[0189] ii.i) - suitable for forming ions, and

[0190] - Contains H-bond receptors, and

[0191] -Suitable for forming zwitterionic structures, and

[0192] - Having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or

[0193] ii.ii) - Contains H-bond donors,

[0194] iii) Dissolve the crystallizing agent (2) in the active substance solubilizing solvent.

[0195] iv) Add the active substance to the solubilized crystallizing agent (2) and mix to obtain a mixture.

[0196] v) Optionally, concentrate the mixture from step iv), or add a solvent and / or anti-solvent to the mixture from step iv) while stirring.

[0197] vi) Cool the mixture from step iv) or step v) for crystallization.

[0198] and / or stirring the mixture from step iv) or step v) for crystallization,

[0199] vii) Incubate the mixture in step vi) to allow the formed multi-component crystals to settle.

[0200] viii) The supernatant formed in step vii) is removed by decanting, evaporation, or filtration.

[0201] ix) Optionally wash the multicomponent crystals formed in step viii) with a solvent and / or an antisolvent.

[0202] x) and drying the multi-component crystals formed in step viii) or ix).

[0203] The condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of this method.

[0204] In the previously mentioned implementation scheme, the active substance added in step iv) is added in solid form or is solubilized in an active substance solubilizing solvent.

[0205] The meanings of terms used in the previously disclosed embodiments, such as filtering, are the same as those in the method embodiments disclosed above.

[0206] Further embodiments of the method of the present invention are provided.

[0207] - The active substance is a mixture of at least three different molecules of formula (1), preferably a mixture of at least four different molecules of formula (1), more preferably a mixture of at least five different molecules of formula (1), even more preferably a mixture of at least six different molecules of formula (1), even more preferably a mixture of at least seven different molecules of formula (1), and most preferably a mixture of at least eight different molecules of formula (1).

[0208] and

[0209] -R is selected from at least one of the groups consisting of H and COCH3.

[0210] and

[0211] - The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization;

[0212]

[0213] N-methylaminopropionic acid of formula (2b)

[0214] .

[0215] After using the methods described above, highly stable multicomponent crystals are obtained.

[0216] This is further highlighted by the following improvements to the method of the present invention, which defines the method of the present invention.

[0217] -The active substance is D / L-α-tocopherol of formula (3).

[0218]

[0219] The methyl groups at positions 2', 4', and 8' have either S- or R-configurations, including racemic α-tocopherol.

[0220] and

[0221] - The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization;

[0222]

[0223] N-methylaminopropionic acid of formula (2b)

[0224] .

[0225] In an alternative, the multi-component crystals according to the invention can be used directly in the form of powder, granules, or suspension.

[0226] In another alternative, it can be combined with the ingredients by mixing multi-component crystals with other dietaryly or pharmaceutically acceptable ingredients to obtain a mixture, optionally finely grinding the mixture, and then filling it into capsules. The capsules can be made of, for example, hard gelatin or soft gelatin.

[0227] Part of the invention is also a composition comprising a multi-component crystal as defined in at least one of the embodiments mentioned above or as obtained in at least one method embodiment as previously defined, and at least one dietaryally acceptable ingredient.

[0228] In one embodiment, the composition is a dietary supplement.

[0229] In another embodiment, the composition is a pharmaceutical composition, preferably a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier, and / or at least one diluent, and / or additional ingredients, and / or at least one pharmaceutical excipient.

[0230] In one extension, the composition is a pre-formulation, an oral formulation, a solid formulation such as a powder, capsule, tablet, pill, lozenge, or liquid suspension.

[0231] Another important aspect of the invention is the use of multi-component crystals as previously defined or obtained as identified in the methods described above, or the use of the compositions disclosed above in food or feed formulations or in pharmaceutical preparations.

[0232] The invention is further illustrated below by way of specific embodiments as disclosed in the examples and with reference to the accompanying drawings. However, the detailed descriptions and examples described herein should not be construed as limiting the scope of the invention. They are merely intended to illustrate the invention in more detail.

[0233] abbreviation

[0234] HPLC (High-Performance Liquid Chromatography)

[0235] ATR-IR attenuated total reflectance infrared spectrum

[0236] MeOH methanol

[0237] NMR nuclear magnetic resonance

[0238] TG / TGA thermogravimetric analysis

[0239] relative humidity (rh, air, unless otherwise specified)

[0240] w% weight%

[0241] v / v volume ratio

[0242] PXRD Powder X-ray Diffraction

[0243] DSC differential scanning calorimetry Attached Figure Description

[0244] Figure 1 PXRD pattern of racemic α-tocopherol-betaine (2a) eutectic crystal from MeOH, in which the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1; Cu Kα radiation.

[0245] Figure 2 TGA data from a racemic α-tocopherol-betaine (2a) eutectic crystallized in MeOH, wherein the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1, and the heating rate is 10 °C / min.

[0246] Figure 3 DSC data from a racemic α-tocopherol-betaine (2a) eutectic crystallized in MeOH, where the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal was 2:1, the heating rate was 10 °C / min, and the exothermic phase transition during heating was recorded.

[0247] Figure 4 PXRD pattern of racemic α-tocopherol-betaine (2a) eutectic crystal from MeOH, in which the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1; Cu Kα radiation.

[0248] Figure 5 PXRD pattern of racemic α-tocopherol-betaine (2a) eutectic crystal from MeOH, in which the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1; Cu Kα radiation.

[0249] Figure 6 ATR-IR spectrum of racemic α-tocopherol-betaine (2a) eutectic crystal from MeOH, wherein the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1.

[0250] Figure 7 HPLC data of racemic α-tocopherol-betaine (2a) cocrystals crystallized in MeOH, wherein the molar ratio of racemic α-tocopherol to betaine (2a) in the crystals is 2:1, 295 nm.

[0251] Figure 8 TGA data from a racemic α-tocopherol-L-proline (2z) cocrystal crystallized in MeOH, wherein the molar ratio of racemic α-tocopherol to L-proline (2z) in the crystal is 2:1, and the heating rate is 10 °C / min.

[0252] Figure 9 DSC data from a racemic α-tocopherol-L-proline (2z) cocrystal crystallized in MeOH, wherein the molar ratio of racemic α-tocopherol to L-proline (2z) in the crystal was 2:1, the heating rate was 10 °C / min, and the exothermic phase transition during heating was recorded.

[0253] Figure 10 PXRD pattern of racemic α-tocopherol-L-proline (2z) cocrystal crystallized from MeOH:nitromethane (1:1 v / v), wherein the molar ratio of racemic α-tocopherol to L-proline (2z) in the crystal is 2:1; Cu Kα radiation.

[0254] Figure 11 PXRD pattern of D-α-tocopherol-betaine (2a) eutectic crystal from MeOH, in which the molar ratio of D-α-tocopherol to betaine (2a) in the crystal is 2:1; Cu Kα radiation.

[0255] Figure 12 Racemic α-tocopherol-betaine (2a) eutectic 2:1 (bottom, Example 1 and Figure 1 ) and from Example 13 and Figure 11 PXRD plot of D-α-tocopherol-betaine (2a) eutectic (top; count +500) compared to Cu Kα radiation.

[0256] Figure 13 PXRD pattern of racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C1), in which the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) was 1:1.1 in the experiment; Cu Kα radiation.

[0257] Figure 14 TGA data for racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C1), wherein the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) was 1:1.1 and the heating rate was 10 °C / min.

[0258] Figure 15DSC data for racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C1), in which the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) was 1:1.1, the heating rate was 10 °C / min, and the exothermic phase transition during heating was recorded.

[0259] Figure 16 PXRD pattern of racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C2), in which the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) in the crystal is 2:1; Cu Kα radiation.

[0260] Figure 17 DSC data for racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C2), in which the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) in the crystal is 2:1, the heating rate is 10 °C / min, and the exothermic phase transition during heating is recorded.

[0261] Figure 18 TGA data for racemic α-tocopherol-N-methylaminopropionic acid (2b) eutectic form (C2), in which the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) in the crystal is 2:1, and the heating rate is 10 °C / min.

[0262] Figure 19 PXRD pattern of racemic α-tocopherol-betaine (2a) eutectic crystal from MeOH, as given in Example 19, wherein the molar ratio of racemic α-tocopherol to betaine (2a) in the crystal is 2:1; Cu Kα radiation.

[0263] Figure 20 : Racemic α-tocopherol-betaine (2a) cocrystal 2:1 (as in Example 19, Figure 19 The obtained bottom) and the racemic α-tocopherol-betaine (2a) cocrystal 2:1 (as from Example 1, Figure 1 The obtained top; count +5000) PXRD plot compared to Cu Kα radiation. Example

[0264] Wherever indicated, in the following text, room temperature describes a temperature in the range of 22°C to 25°C, ambient temperature is defined as 25°C ± 10°C, and unless otherwise stated, percentages are given by weight.

[0265] instrument :

[0266] Powder X-ray diffraction :

[0267] Measurements were performed using Cu Kα radiation with Bragg-Brentano reflection geometry, either with a Panalytical X'Pert Pro diffractometer (manufacturer: Panalytical) or a MiniFlex 600 X-ray diffractometer (manufacturer: Rigaku). Generally, 2θ values ​​are accurate within ±0.1° to 0.2° of error. Relative peak intensities can vary considerably for different samples of the same crystal form due to different preferred orientations of the crystal. Samples were prepared without any special treatment except by applying slight pressure to obtain a flat surface. A silicon single-crystal sample holder with a depth of 0.2 mm was typically used. The tube voltage and current were 45 kV and 40 mA, respectively. Diffraction patterns were recorded in increments of 0.0167° to 0.02° within the range of 2θ = 3° to 40°. The sample was rotated during the measurement.

[0268] Thermogravimetric analysis :

[0269] TGA data were recorded using a TG / DTA 7200 (SII Nano Technology Inc.). Samples were placed in platinum standard trays. Sample volumes ranged from 2 mg to 15 mg in each case. Heating rates were 10 °C / min. Samples were purged with synthetic air streams during the experiments.

[0270] Differential scanning calorimetry (DSC) :

[0271] DSC data were recorded using a Mettler Toledo DSC 823e / 700 / 229 module. Samples were placed in an aluminum standard pan. Sample volumes ranged from 1 mg to 10 mg in each case. The heating rate was 10 °C / min. Samples were purged with a nitrogen stream during the experiment. The onset of the endothermic event was reported as the melting point.

[0272] 1 H-NMR :

[0273] Recording with deuterated solvents on a Bruker AVN-600 spectrometer 1 H-NMR spectrum.

[0274] ATR-IR spectrum :

[0275] ATR-IR spectra were measured at room temperature using a Nicolet iS50_2 device. At 4000 cm⁻¹ -1 Up to 400cm -1 The measurement resolution is 4cm within the range. -1 32 scans.

[0276] HPLC :

[0277] Approximately 10 mg of solid material was dissolved in approximately 8 g of isopropanol. The solution was directly used for analysis by HPLC on an Agilent 1200 system equipped with a DAD1 UV detector (evaluated at 295 nm) and a G1313A sampler. Chromatograms were recorded and chromatographic parameters were calculated using Chromeleon 7.2.8 software. Gradient elution was achieved using CHIRALPAK IG-3, 150*2.1 mm, 3 µm, Daicel (solvent A: ACN + 0.1% formic acid / solvent B: water + 0.1% formic acid, gradient as described below). The injection volume was set to 5 µL using an auto-injector. Analysis was performed at a flow rate of 0.5 mL / min.

[0278] gradient

[0279] time Solvent A% Solvent B% 0.0 45 55 23.0 30 70 35.0 20 80 35.1 0 100 40.0 0 100 40.1 45 55 51.0 45 55

[0280] Solvent: Use standard grade solvents for all experiments. Example

[0281] Example 1: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0282] The racemic α-tocopherol-betaine cocrystal 2:1 was prepared from racemic α-tocopherol and betaine (2a).

[0283] PXRD plot shows Figure 1 Characteristic PXRD peaks (expressed as °2θ ± 0.2°2θ; Cu Kα radiation) were 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. ATR-IR data are presented in... Figure 6 In the middle. At 2953cm -1 2897cm -1 1647cm -1 1639cm -1 1223cm -1 1029cm -1 and 721cm -1 A characteristic peak was observed at that location.

[0284] Example 1a: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol-betaine) (The molar ratio of glycophenol to betaine is 2:1) :

[0285] At 60 °C, 431 mg of racemic α-tocopherol (1 mmol) and 117 mg of betaine (2a) (1 mmol) (ratio 1:1) were dissolved in 4 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated multicomponent crystals were filtered and vacuum dried at room temperature. The solid material showed the following characteristics: Figure 1 The PXRD pattern in the image has characteristic PXRD peaks as shown in Example 1 (denoted as °2θ±0.2°2θ; Cu Kα radiation). 1 ¹H-NMR spectroscopy indicated a molar ratio of racemic α-tocopherol to betaine (2a) of approximately 2:1. TGA data showed no significant weight loss prior to reaching the melting peak and above, with the first significant weight loss observed around 200 °C (reference). Figure 2 DSC data shows the melting point, starting at 98°C and peaking at 103°C, and the transformation enthalpy ΔH is 82 J / g (reference). Figure 3 ).

[0286] The enthalpy of transformation is almost twice that obtained for the racemic α-tocopherol-L-proline cocrystal shown in Comparative Example 8. Similarly, the onset of 98°C and the peak peak of 103°C are approximately 30°C higher than those obtained for the cocrystal of Comparative Example 8. Significant weight loss begins at approximately 200°C, which is approximately 30°C higher than the values ​​obtained for the racemic α-tocopherol-L-proline cocrystal shown in Comparative Example 8. These observations demonstrate that significantly more energy is required to decompose the multicomponent crystal of Example 1a, which is only possible if the crystal is much more structured and therefore has a higher crystallinity compared to the cocrystal of Comparative Example 8.

[0287] Example 2: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0288] At 60 °C, 431 mg of racemic α-tocopherol (1 mmol) and 117 mg of betaine (2a) (1 mmol) (ratio 1:1) were dissolved in 4 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated multicomponent crystals were filtered and vacuum dried at room temperature to obtain 303 mg of racemic α-tocopherol-betaine cocrystals. PXRD pattern and... Figure 1 The diagram presented is quite similar.

[0289] Example 3: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0290] At 60 °C, 1725 mg of racemic α-tocopherol (4 mmol) and 235 mg of betaine (2a) (2 mmol) (ratio 2:1) were dissolved in 4 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated multicomponent crystals were filtered and vacuum dried at room temperature to obtain 1093 mg of racemic α-tocopherol-betaine cocrystal. PXRD pattern and... Figure 1 The diagram presented is quite similar.

[0291] Example 4: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0292] At 60 °C, 6.9 g of racemic α-tocopherol (16 mmol) and 0.94 g of betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 200 rpm). The precipitated multicomponent crystals were filtered and vacuum dried at room temperature to obtain 5.0 g of racemic α-tocopherol-betaine cocrystals. PXRD pattern and... Figure 1 The graph presented is quite similar. DSC data shows the melting point, with an initial temperature of 98°C and a peak temperature of 104°C, and an enthalpy ΔH of 70 J / g.

[0293] Example 5: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0294] At 60 °C, 6.9 g of racemic α-tocopherol (16 mmol) and 0.94 g of betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 200 rpm). The precipitated multicomponent crystals were filtered, washed with 5 mL of methanol, and dried under vacuum at room temperature to obtain 4.4 g of racemic α-tocopherol-betaine cocrystals. The PXRD pattern is shown below. Figure 5 DSC data shows the melting point, with an initial temperature of 100°C and a peak temperature of 104°C (72 J / g). ATR-IR spectra show... Figure 6 HPLC measurement results Figure 7As shown in the figure. The chiral HPLC method did not separate all eight isomers of racemic α-tocopherol, but the ratio of 1 (12.12 area%):3 (37.57 area%):1 (12.74 area%):2 (25.16 area%):1 (12.41 area%) was the same as in racemic α-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 racemic α-tocopherol isomers were incorporated into the cocrystal.

[0295] Example 6: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0296] At 60 °C, 6.9 g of racemic α-tocopherol (16 mmol) and 0.94 g of betaine (2a) (8 mmol) (ratio 2:1) were dissolved in 16 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 200 rpm). The precipitated multicomponent crystals were filtered, washed with 5 mL of nitromethane, and dried under vacuum at room temperature to obtain 4.8 g of racemic α-tocopherol-betaine cocrystals. The solid material shows as follows: Figure 4 The PXRD plot is shown in the image. The DSC data shows the melting point, with an initial temperature of 101°C and a peak temperature of 103°C, and an enthalpy ΔH of 60 J / g.

[0297] Example 7: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol) (The molar ratio of phenol to betaine is 2:1) :

[0298] At 60 °C, 6.9 g (16 mmol) of racemic α-tocopherol and 0.94 g (8 mmol) of betaine (2a) (ratio 2:1) were dissolved in 16 mL of MeOH. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 200 rpm). The precipitate was filtered, washed with 5 mL of heptane, and dried under vacuum at room temperature to give 2.8 g of racemic α-tocopherol-betaine cocrystal. PXRD pattern and... Figure 1 The graph presented is quite similar. The DSC data shows the melting point, with an initial temperature of 101°C and a peak temperature of 105°C, and an enthalpy ΔH of 81 J / g.

[0299] Example 7b: (Complete racemic α-tocopherol-betaine cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol-betaine) (The molar ratio of glycophenol to betaine is 2:1) :

[0300] 139 g of racemic α-tocopherol (323 mmol) and 18 g of betaine (2a) (154 mmol) (ratio 2:1) were added to a 250 mL tall glass beaker cooled in an ice bath. The mixture was blended at 30,000 rpm for 40 seconds using a Polytron PT3100 D high-shear mixer equipped with a rotor-stator head. The mixture was then stirred via an IKAEurostar 20 stirrer equipped with a dissolver. The temperature was maintained below 50 °C. The mixture was stirred for 2.25 h. After 50 minutes, due to increased viscosity, the stirrer speed was gradually reduced from the initial 5,000 rpm. After 1 hour and 23 minutes, the stirrer speed was maintained at 1,000 rpm. Starting 30 minutes after the start of stirring, the material was periodically homogenized manually during the experiment, as the dissolver could not effectively agitate the entire reaction mixture. PXRD plots are shown below. Figure 1 The diagram presented is quite similar.

[0301] Comparative experiment

[0302] The racemic α-tocopherol-L-proline cocrystal is described in WO 2019 / 128175 A1 (corresponding to EP3733657 A1) with a PXRD pattern showing low crystallinity and amorphous content. Examples 8 to 13 below are improved examples from said WO2019 / 128175 A1.

[0303] Example 8: (Complete racemic α-tocopherol-L-proline cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol-L-proline) (The molar ratio of tocopherol to L-proline is 2:1) :

[0304] At 60 °C, 431 mg of racemic α-tocopherol (1 mmol) and 115 mg of L-proline (2 oz) (1 mmol) (ratio 1:1) were dissolved in 4 mL of methanol:nitromethane (1:1). After 1 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated cocrystal was filtered and dried under vacuum at room temperature to obtain a racemic α-tocopherol-L-proline cocrystal. The solid material showed the following characteristics: Figure 10 The difference PXRD plot is given in the image.

[0305] 1 H-NMR spectroscopy indicates that the molar ratio of racemic α-tocopherol to L-proline (2z) is approximately 2:1.

[0306] As described, the racemic α-tocopherol-L-proline cocrystal is presented in WO 2019 / 128175 A1 (corresponding to EP 3 733 657 A1). However, the presented stoichiometry is 1:1, which is the stoichiometry of the starting materials. Neither analytical methods nor any results are presented to determine the stoichiometry of racemic α-tocopherol and L-proline of formula (2z) in the cocrystal. The molar ratio of racemic α-tocopherol and L-proline of formula (2z) in the prior art cocrystal remains unclear.

[0307] TGA data showed no significant weight loss before reaching the melting peak and above, and the first significant weight loss was observed around 170°C (reference). Figure 8 The melting point is approximately 30°C lower than that obtained from the cocrystal of racemic α-tocopherol and betaine. DSC data show a melting point of 69°C onset and a peak value of 72°C (44 J / g), which is approximately 30°C and 40 J / g lower than the values ​​obtained for the cocrystal of racemic α-tocopherol and betaine.

[0308] These values ​​are lower than those in Example 1, indicating lower stability of the eutectic obtained in Comparative Example 8.

[0309] Example 9: (Complete racemic α-tocopherol-L-proline cocrystal, wherein the multi-component crystal contains complete racemic α-tocopherol-L-proline) (The molar ratio of tocopherol to L-proline is 2:1) :

[0310] At 60 °C, 473 mg of racemic α-tocopherol (1.1 mmol) and 127 mg of L-proline (2 oz) (1.1 mmol) (ratio 1:1) were dissolved in 4 mL of methanol:nitromethane (1:1). After 1 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated cocrystal was filtered and dried under vacuum at room temperature to obtain approximately 150 mg of racemic α-tocopherol-L-proline cocrystal. The PXRD pattern of the solid material is shown in [image missing]. Figure 10 middle.

[0311] Example 10: (Complete racemic α-tocopherol-L-proline cocrystal, wherein the multi-component crystal contains complete racemic α- (The molar ratio of tocopherol to L-proline is 2:1) :

[0312] At 60 °C, 529 mg of racemic α-tocopherol (1.2 mmol) and 71 mg of L-proline (2 oz) (0.6 mmol) (ratio 2:1) were dissolved in 4 mL of methanol:nitromethane (1:1). After 1 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated cocrystal was filtered and dried under vacuum at room temperature to obtain approximately 100 mg of racemic α-tocopherol-L-proline cocrystal. The solid material shows... Figure 10 The PXRD diagram in the image.

[0313] Example 11: (Complete racemic α-tocopherol-L-proline cocrystal, wherein the multi-component crystal contains complete racemic α- (The molar ratio of tocopherol to L-proline is 2:1) :

[0314] At 60 °C, 529 mg of racemic α-tocopherol (1.2 mmol) and 71 mg of L-proline (2 oz) (0.6 mmol) (ratio 2:1) were dissolved in 4 mL of MeOH. After 1 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated cocrystal was filtered and dried under vacuum at room temperature to obtain 9 mg of racemic α-tocopherol-L-proline cocrystal. The solid material shows... Figure 10 The PXRD diagram in the image.

[0315] Example 12: (Complete racemic α-tocopherol-L-proline cocrystal, wherein the multi-component crystal contains complete racemic α- (The molar ratio of tocopherol to L-proline is 2:1) :

[0316] At 60 °C, 473 mg of racemic α-tocopherol (1.1 mmol) and 127 mg of L-proline (2 oz) (1.1 mmol) (ratio 1:1) were dissolved in 4 mL of MeOH. After 1 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated cocrystal was filtered and dried under vacuum at room temperature to obtain 89 mg of racemic α-tocopherol-L-proline cocrystal. The solid material shows as follows: Figure 10 The PXRD diagram in the image.

[0317] The D-α-tocopherol-betaine cocrystal was described in *International Journal of Pharmaceutical Sciences* (Int. J. Pharm.) 592 (2021)120057. Experiments were replicated as much as possible. No dissolution was observed at room temperature. Therefore, the solid dissolved at 60°C before cooling began.

[0318] Example 13: (d-α-tocopherol-betaine cocrystal, wherein the molar ratio of d-α-tocopherol-betaine in the cocrystal is...) The ratio is 2:1. :

[0319] At 60 °C, 4.3 g d-αToc (10 mmol) and 0.585 g betaine (2a) (5 mmol) (ratio 2:1) were dissolved in 10 mL of methanol, and the solution was cooled to -20 °C (cooling rate -5 °C / h, stirring rate 1200 rpm). The powder was filtered and dried under vacuum at room temperature. The PXRD pattern of the solid material is shown in [image missing]. Figure 11 middle.

[0320] pass Figure 12 The superposition of the PXRD patterns of the racemic α-tocopherol-betaine multicomponent crystals 2:1 (bottom image, from Example 1) and the D-α-tocopherol-betaine cocrystal (top image, from Example 13) was compared.

[0321] Two things are clear: First, the bottom plot shows different signals that shift towards lower 2θ values ​​as the differences originating from different cell sizes increase when compared to the 2θ values ​​in the top plot. Furthermore, new signals appear in the bottom plot, while others disappear. All of this suggests the formation of a different type of crystal. Second, the bottom plot appears more uniform and does not exhibit a large background when compared to the top plot.

[0322] However, considering that the racemic α-tocopherol in the multicomponent crystal in the bottom diagram is a mixture of eight isomers, while the D-α-tocopherol in the cocrystal in the upper diagram is only a molecule that is more easily crystallized, it is more surprising that a multicomponent crystal is formed from racemic α-tocopherol and betaine (2a). Despite this fact, the racemic α-tocopherol-betaine multicomponent crystal of the present invention is more structured and thermodynamically more stable than the corresponding D-α-tocopherol-betaine cocrystal of the prior art.

[0323] Another embodiment of the present invention obtained using N-methylaminopropionic acid (2b) as a crystallizing agent.

[0324] Example 14: (Completely racemic α-tocopherol-N-methylaminopropionic acid cocrystal (C1)) :

[0325] 158 mg of racemic α-tocopherol (0.37 mmol) and 42 mg of N-methylaminopropionic acid (2b) (0.41 mmol) (ratio 1:1.1) were weighed into an Eppendorf cap and steel balls were added. The mixture was dissolved in 200 µL of acetone and the solvent was evaporated. Another 20 µL of acetone was added, and the mixture was milled at 20 Hz for 30 min using a ball mill (Retsch MM-301). The solvent was evaporated. 20 µL of ethanol was added, and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of ethyl acetate was added, and the mixture was milled at 20 Hz for 30 min. The obtained solid material (C1) showed the following characteristics: Figure 13 The PXRD diagram in the image.

[0326] Example 15: (Completely racemic α-tocopherol-N-methylaminopropionic acid cocrystal (C1)) :

[0327] 158 mg of racemic α-tocopherol (0.37 mmol) and 42 mg of N-methylaminopropionic acid (2b) (0.41 mmol) (ratio 1:1.1) were weighed into an Eppendorf cap and steel balls were added. The mixture was dissolved in 200 µL of acetone and the solvent was evaporated. 20 µL of acetone was added and the mixture was milled at 20 Hz for 30 min using a ball mill (Retsch MM-301). The solvent was evaporated. 20 µL of ethanol was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of ethyl acetate was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of toluene was added and the mixture was milled at 20 Hz for 30 min. The PXRD pattern of the obtained multicomponent crystalline material (C1) was compared with... Figure 13 The diagram presented in the middle is quite similar.

[0328] Example 16: (Completely racemic α-tocopherol-N-methylaminopropionic acid cocrystal (C1)) :

[0329] 158 mg of racemic α-tocopherol (0.37 mmol) and 42 mg of N-methylaminopropionic acid (2b) (0.41 mmol) (ratio 1:1.1) were weighed into an Eppendorf cap and steel balls were added. The mixture was dissolved in 200 µL of acetone and the solvent was evaporated. 20 µL of acetone was added and the mixture was milled at 20 Hz for 30 min using a ball mill (Retsch MM-301). The solvent was evaporated. 20 µL of ethanol was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of ethyl acetate was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of toluene was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. 20 µL of water was added and the mixture was milled at 20 Hz for 30 min. The solvent was evaporated. The PXRD pattern of the obtained crystalline material (C1) was compared with... Figure 13 The graph presented is quite similar. TGA data shows that at a decomposition temperature T of 80°C... d Previously there was almost no significant weight loss ( Figure 14 The DSC data shows the melting point, including the initial temperature T. o The temperature is 47℃, and the peak temperature T is... p 54℃ (strong leading edge trailing, reference) Figure 15 ), and the phase transition enthalpy ΔH is 37 J / g.

[0330] Example 17: (Completely racemic α-tocopherol-N-methylaminopropionic acid cocrystal (C2), wherein the cocrystal contains all...) The molar ratio of racemic α-tocopherol-N-methylaminopropionic acid is 2:1. :

[0331] At 60 °C, 1750 mg of racemic α-tocopherol (4 mmol) and 210 mg of N-methylaminopropionic acid (2b) (2 mmol) (ratio 2:1) were dissolved in 4 mL of methanol. After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated multicomponent crystals (C2) showed the following... Figure 16 The PXRD image presented in the image.

[0332] Example 18: (Completely racemic α-tocopherol-N-methylaminopropionic acid cocrystal (C2), wherein in this cocrystal d- The molar ratio of α-tocopherol to N-methylaminopropionic acid is 2:1. :

[0333] At 60 °C, 1750 mg of racemic α-tocopherol (4 mmol) and 210 mg of N-methylaminopropionic acid (2b) (2 mmol) (ratio 2:1) were dissolved in 4 mL of methanol:nitromethane (1:1). After 0.5 h, the solution was cooled to -10 °C (cooling rate -5 °C / h, stirring rate 120 rpm). The precipitated multicomponent crystals were filtered and dried under vacuum at room temperature to obtain 133 mg of racemic α-tocopherol-N-methylaminopropionic acid cocrystalline form (C2). The PXRD pattern is as follows. Figure 16 As presented in the document. 1 ¹H-NMR spectroscopy indicates that the molar ratio of racemic α-tocopherol to N-methylaminopropionic acid (2b) is approximately 2:1. DSC data show the melting point, with the onset temperature T0 being... o It is 53℃, of which the peak temperature T p The temperature is 58℃ (strong leading edge tail), and the phase transition enthalpy ΔH is 44 J / g. Figure 17 ), and the decomposition temperature T as measured by thermogravimetric analysis (TGA) d For at least 150℃ ( Figure 18 ).

[0334] As is evident in Examples 14 to 18, racemic α-tocopherol can form two multicomponent crystal variants (C1) and (C2), depending on stoichiometry and the preparation conditions applied. These multicomponent crystals (C1) and (C2) do not exhibit the unexpectedly high thermodynamic stability of multicomponent crystals obtained from racemic α-tocopherol and betaine of formula (2a). However, N-methylaminopropionic acid (2b) also appears to be a suitable crystallizing agent (2) for forming multicomponent crystals with racemic α-tocopherol.

[0335] Further embodiments of the invention demonstrating additional methods for forming multicomponent crystals of racemic α-tocopherol and betaine of formula (2a).

[0336] Example 19: (A racemic α-tocopherol-betaine cocrystal prepared at ambient temperature, comprising multiple components) The molar ratio of racemic α-tocopherol to betaine in the crystal is 2:1. :

[0337] At room temperature, 0.18 g of betaine (1.5 mmol) was dissolved in 1.6 g of methanol (50 mmol) in a 5 mL glass vial with stirring at 400 rpm for 5 min using a magnetic stir bar. 1.9 g (4.4 mmol) of racemic α-tocopherol was added to the solution. The resulting mixture was stirred with a magnetic stir bar at 400 rpm at room temperature for 24 h. The solid was separated from the solution by placing the formed precipitate on filter paper, folding it to obtain a sealed package, and wrapping the package with a tissue paper used as a tissue. The precipitate was pressure-dried by manually applying pressure to the wrapped package. After the pressure-drying process, the solid was further dried at ambient temperature. Approximately 50 mg of multicomponent crystals were obtained, and their PXRD patterns are shown in [insert PXRD pattern here]. Figure 19 As shown in the image. Its relationship with... Figure 1 The PXRD plots are quite similar, as in Figure 20 This can be seen in the diagram. This means that even when prepared in different ways, the multicomponent crystals of racemic α-tocopherol and betaine of formula (2a) show the same PXRD pattern and therefore have the same stoichiometry in the resulting multicomponent crystals.

[0338] Example 19 can also be achieved by first dissolving the active substance racemic α-tocopherol, and then adding betaine of crystallizing formula (2) to the solution.

[0339] Example 20: (A racemic α-tocopherol-betaine cocrystal prepared sequentially at ambient temperature, wherein multiple...) The molar ratio of racemic α-tocopherol to betaine in the component crystals is 2:1. :

[0340] At room temperature, 47.9 g of racemic α-tocopherol (111 mmol) and 3.6 g of betaine (30.7 mmol) were added to 46.1 g of methanol (1439 mmol) in a 100 mL glass bottle. The mixture was stirred at 400 rpm using a magnetic stir bar. The mixture of racemic α-tocopherol and betaine was added in two portions, one after stirring for 4 h and the other after stirring for a further 18 h. The two portions together produced a total of 8.8 g of racemic α-tocopherol (20.4 mmol) and 1.2 g of betaine (10.2 mmol). The mixture was stirred at 200 rpm for an additional 24 h. As explained in Example 19, the obtained solid was separated from the solution by pressure drying the precipitate between folded filter paper covered with a paper towel. The obtained solid was redispersed in 10 mL of acetonitrile at room temperature. The pressure drying and redispersion in acetonitrile process was repeated four times. Following the final pressure drying step, the solid was vacuum dried. 11.6 g of dried multicomponent crystals were obtained, exhibiting the following characteristics: Figure 19 The PXRD plot is given in the image.

Claims

1. A multi-component crystal, the multi-component crystal comprising... a) An active substance, said active substance being a mixture of at least two different molecules of formula (1). - Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3 -The methyl groups at positions 2', 4', and 8' have either S-configuration or R-configuration, respectively. and b) Crystallizing agent (2), which exhibits the following properties: b1)- is suitable for forming ions, and - Contains H-bond receptors, and -Suitable for forming zwitterionic structures, and - Having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or b2)- Contains an H-bond donor, The condition is that the combination of proline as a crystallizing agent of formula (2z) and tocopherol as an active substance is excluded from the teachings of claim 1.

2. The multi-component crystal according to claim 1, wherein... - The active substance is a mixture of at least three different molecules of formula (1), preferably a mixture of at least four different molecules of formula (1), more preferably a mixture of at least five different molecules of formula (1), even more preferably a mixture of at least six different molecules of formula (1), even more preferably a mixture of at least seven different molecules of formula (1), and most preferably a mixture of at least eight different molecules of formula (1). and -R is selected from at least one of the groups consisting of H and COCH3. and -The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization; N-methylaminopropionic acid of formula (2b) 。 3. The multi-component crystal according to claim 1 or 2, wherein... -The active substance is D / L-α-tocopherol of formula (3). The methyl groups at positions 2', 4', and 8' have either an S-configuration or an R-configuration, including racemic α-tocopherol. and -The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization; N-methylaminopropionic acid of formula (2b) 。 4. The multi-component crystal according to any one of claims 1 to 3, wherein The molar ratio of the active substance to the crystallizing agent (2) is in the range of 3:1 to 1:3, preferably 2.1:1 to 1.9:1 or 2:1 to 1:2, including molar ratios of 1:1 and 1:1.1, and more preferably 2:

1.

5. The multicomponent crystal according to any one of claims 1 to 4, wherein when betaine of formula (2a) is used as the crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), said at least one characteristic peak being selected from peaks located at 5.5, 7.4, 9.2, 12.9, 16.7, and 20.

4. Preferably The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those located at 5.5, 7.4, 9.2, 12.9, 16.7, and 20.

4. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 5.5, 7.4, 9.2, 12.9, 16.7 and 20.4, expressed as °2θ±0.2°2θ (CuKα radiation).

6. The multicomponent crystal according to any one of claims 1 to 4, wherein when betaine of formula (2a) is used as the crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), said at least one characteristic peak being selected from 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 The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those 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 optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks 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, expressed as °2θ ± 0.2°2θ (CuKα radiation).

7. The multi-component crystal according to any one of claims 1 to 6, wherein when betaine of formula (2a) is used as a crystallizing agent (2), the multi-component crystal contains less than 45% by weight of uncrystallized material, preferably less than 30% by weight, more preferably less than 20% by weight, even more preferably less than 10% by weight, and highly preferably less than 5% by weight, including 1% by weight and 0% by weight.

8. The multicomponent crystal according to any one of claims 1 to 7, wherein when betaine of formula (2a) is used as a crystallizing agent (2), the multicomponent crystal exhibits a phase transition having the following characteristics: - Such as an initial temperature T of at least 72°C as measured by differential scanning calorimetry (DSC). o , and - A peak temperature T of at least 75°C as measured by differential scanning calorimetry (DSC). p , as well as - Such as a phase transition enthalpy ΔH of at least 50 J / g as measured by differential scanning calorimetry (DSC). Preferably - Such as an initial temperature T of at least 85°C as measured by differential scanning calorimetry (DSC). o , and -A peak temperature T of at least 89°C as measured by differential scanning calorimetry (DSC). p , And - such as a phase transition enthalpy ΔH of at least 60 J / g as measured by differential scanning calorimetry (DSC), And further optimization - Such as an initial temperature T of at least 98°C as measured by differential scanning calorimetry (DSC). o , and - A peak temperature T of at least 103°C as measured by differential scanning calorimetry (DSC). p , And - such as a phase transition enthalpy ΔH of at least 82 J / g as measured by differential scanning calorimetry (DSC).

9. The multicomponent crystal according to any one of claims 1 to 8, wherein when betaine of formula (2a) is used as a crystallizing agent (2), the decomposition temperature T of the multicomponent crystal is as measured by thermogravimetric analysis (TGA). d The temperature is at least 175°C, preferably at least 180°C, more preferably at least 185°C, even more preferably at least 190°C, and even more preferably the decomposition temperature is 195°C or higher.

10. The multicomponent crystal according to any one of claims 1 to 4, wherein when N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern in the crystal variant (C1) with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), said at least one characteristic peak being selected from 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 The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from peaks located at 5.1, 6.8, 8.5, 10.2, and 20.

4. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those 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. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those located at 5.1, 6.8, 8.5, 10.2, and 20.

4. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 5.1, 6.8, 8.5, 10.2, and 20.4 Å, denoted as °2θ ± 0.2°2θ (CuKα radiation). Furthermore, further optimization was carried out. The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks 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, expressed in °2θ±0.2°2θ (CuKα radiation).

11. The multicomponent crystal according to claim 10, wherein when N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal exhibits the following phase transition for the crystal variant (C1): - Such as an initial temperature T of at least 47°C as measured by differential scanning calorimetry (DSC). o , and - A peak temperature T of at least 54°C as measured by differential scanning calorimetry (DSC). p , as well as - Such as a phase transition enthalpy ΔH of at least 37 J / g as measured by differential scanning calorimetry (DSC). And - such as a decomposition temperature T of at least 80°C as measured by thermogravimetric analysis (TGA) d .

12. The multicomponent crystal according to any one of claims 1 to 4, wherein when N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal has a powder X-ray diffraction (PXRD) pattern in crystal variant (C2) with at least one characteristic peak expressed in °2θ ± 0.2°2θ (CuKα radiation), said at least one characteristic peak being selected from 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 The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least one characteristic peak represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least one characteristic peak is selected from peaks located at 7.4, 12.9, 15.7, 16.9, and 28.

1. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those 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. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with at least three characteristic peaks represented by °2θ ± 0.2°2θ (CuKα radiation), wherein the at least three characteristic peaks are selected from those located at 7.4, 12.9, 15.7, 16.9, and 28.

1. Further optimization The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 7.4, 12.9, 15.7, 16.9, and 28.1 °C, denoted as °2θ ± 0.2°2θ (CuKα radiation). Furthermore, further optimization was carried out. The multicomponent crystal has a powder X-ray diffraction (PXRD) pattern with characteristic peaks at 3.7, 5.5, 7.4, 11.1, 12.9, 15.7, 16.9, 17.8, 20.4, 21.7 and 28.1, expressed in °2θ±0.2°2θ (CuKα radiation).

13. The multicomponent crystal according to claim 12, wherein when N-methylaminopropionic acid of formula (2b) is used as a crystallizing agent (2), the multicomponent crystal exhibits the following phase transition for the crystal variant (C2): - Such as an initial temperature T of at least 53°C as measured by differential scanning calorimetry (DSC). o , and - A peak temperature T of at least 58°C as measured by differential scanning calorimetry (DSC). p , as well as - Such as a phase transition enthalpy ΔH of at least 44 J / g as measured by differential scanning calorimetry (DSC). And - such as a decomposition temperature T of at least 150°C as measured by thermogravimetric analysis (TGA) d .

14. A method for preparing a multicomponent crystal according to any one of claims 1 to 13 from at least two solids or from at least one solid and at least one liquid, the method comprising the steps of: i) Provide an active substance, said active substance being a mixture of at least two different molecules of formula (1). - Where R is chosen from H, COCH3, COCH2CH3, and CO(CH2). 14 CH3, CO(CH2) 16 At least one of the groups consisting of CH3 -The methyl groups at positions 2', 4', and 8' have either an S-configuration or an R-configuration, respectively. ii) Add crystallizing agent (2) to the active substance of step i), wherein the crystallizing agent (2) exhibits the following properties: ii.i) - suitable for forming ions, and - Contains H-bond receptors, and -Suitable for forming zwitterionic structures, and - Having a molecular weight in the range of 100 g / mol to 135 g / mol, and / or ii.ii) - Contains H-bond donors, iii) Mix the active substance and the crystallizing agent (2) to obtain a mixture. iv) Optionally, the mixture from step iii) may be concentrated, or a solvent and / or anti-solvent may be added to the mixture from step iii) while stirring. v) Cool the mixture from step iii) or iv) for crystallization. and / or stirring the mixture in step iii) or step iv) for crystallization, vi) Incubate the mixture from step v) to allow the formed multicomponent crystals to settle. vii) Remove the supernatant formed in step vi) by decantation, evaporation, or filtration. viii) Optionally wash the multicomponent crystals formed in step vii) with the solvent and / or the antisolvent. ix) and drying the multi-component crystals formed in step vii) or viii). The condition is that the combination of proline as a crystallizing agent (2z) and tocopherol as an active substance is excluded from the teachings of claim 14.

15. The method of claim 14, wherein - Prior to providing the active substance in step i) of claim 14, the active substance is diluted with or dissolved in an active substance solubilizing solvent. or Before adding the crystallizing agent (2) in step ii) of claim 14, the crystallizing agent is diluted with or dissolved in an active substance solubilizing solvent. or - Before mixing the active substance and the crystallizing agent (2) in step iii) of claim 14, the active substance and the crystallizing agent are diluted with or dissolved in an active substance solubilizing solvent. And / or - After step ii) or iii) of claim 14, at least one of the group consisting of the active substance and the crystallizing agent (2) is added back in one or more parts.

16. The method according to claim 14 or 15, wherein - The active substance is a mixture of at least three different molecules of formula (1), preferably a mixture of at least four different molecules of formula (1), more preferably a mixture of at least five different molecules of formula (1), even more preferably a mixture of at least six different molecules of formula (1), even more preferably a mixture of at least seven different molecules of formula (1), and most preferably a mixture of at least eight different molecules of formula (1). and -R is selected from at least one of the groups consisting of H and COCH3. and -The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization; N-methylaminopropionic acid of formula (2b) 。 17. The method according to any one of claims 14 to 16, wherein -The active substance is D / L-α-tocopherol of formula (3). The methyl groups at positions 2', 4', and 8' have either an S-configuration or an R-configuration, including racemic α-tocopherol. and -The crystallizing agent (2) is selected from one of the following groups: betaine of formula (2a) in its ionic form used during crystallization; N-methylaminopropionic acid of formula (2b) 。 18. A composition comprising a multi-component crystal according to any one of claims 1 to 13 or a multi-component crystal obtained according to the method of any one of claims 14 to 17, and at least one dietaryally acceptable ingredient.

19. The use of a multi-component crystal according to any one of claims 1 to 13, or a multi-component crystal obtained by the method according to any one of claims 14 to 17, or a composition according to claim 18, in a food formulation or feed formulation or in a pharmaceutical preparation.

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