CN113039192A - 7-dehydrocholesterol-hemihydrate - Google Patents
7-dehydrocholesterol-hemihydrate Download PDFInfo
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Abstract
The present invention relates to 7-dehydrocholesterol-hemihydrate. It has been found that the formation of 7-dehydrocholesterol-hemihydrate provides an effective means of increasing the storage stability of 7-dehydrocholesterol, or reducing degradation of 7-dehydrocholesterol on storage.
Description
Technical Field
The present invention relates to the field of 7-dehydrocholesterol.
Background
7-dehydrocholesterol is a key intermediate used in the synthesis of cholecalciferol (═ vitamin D3).
However, 7-dehydrocholesterol has limited storage stability and degrades during prolonged storage.
Disclosure of Invention
Therefore, the problem to be solved by the present invention is to increase the storage stability of 7-dehydrocholesterol, or to reduce the degradation of 7-dehydrocholesterol upon storage. Surprisingly it has been found that 7-dehydrocholesterol-hemihydrate shows polymorphism. 7-dehydrocholesterol-hemihydrate provides a solution to this problem. 7-dehydrocholesterol-hemihydrate can be readily formed from 7-dehydrocholesterol. In addition, 7-dehydrocholesterol can be easily regenerated from 7-dehydrocholesterol-hemihydrate in high yield. It has been found that 7-dehydrocholesterol-hemihydrate shows significantly increased storage stability, or shows significantly reduced degradation.
Other aspects of the invention are the subject of other independent claims. Particularly preferred embodiments are the subject of the dependent claims.
Detailed Description
In a first aspect, the present invention relates to 7-dehydrocholesterol-hemihydrate.
The ability of a substance to exist in more than one crystalline form is often referred to as polymorphism, and these different crystalline forms are often referred to as "polymorphs" and can be referenced by certain analytical properties, such as their X-ray powder diffraction (XRD) patterns. Generally, polymorphisms reflect the ability of a molecule to change its conformation or form different intermolecular and intramolecular interactions. This may result in different atomic arrangements, which are reflected in different polymorphic crystal lattices. However, polymorphisms are not a common feature of solids, as some molecules can exist in one or more crystal forms, while others cannot. Thus, the presence or extent of polymorphism of a given compound is unpredictable.
Different polymorphic forms of a substance exhibit different lattice energies, and thus each polymorphic form typically exhibits one or more different physical properties in the solid state, such as density, melting point, color, stability, dissolution rate, flowability, compatibility with grinding, granulation, and compaction, and/or uniformity of distribution [ see, e.g., p. The ability of any given compound to occur in one or more crystalline forms (i.e., polymorphs) is unpredictable, as is the physical properties of any single crystalline form. The physical properties of polymorphs may affect their suitability for use in pharmaceutical formulations. For example, these properties may positively or negatively affect the stability, dissolution and bioavailability of solid formulations, which in turn affects the suitability or efficacy of such formulations in treating disease. Likewise, the physical properties of the polymorph may also affect the processability of the compound.
Individual polymorphs having one or more desired properties may be suitable for use in the development of pharmaceutical formulations having one or more desired properties. The presence of polymorphic forms of a compound with undesirable properties may hinder or prevent the development of the polymorphic form as a pharmaceutical agent.
It has been found for the first time that 7-dehydrocholesterol (═ DHC) shows polymorphism. In particular, it has been found that 7-dehydrocholesterol-hemihydrate is a specific polymorph of 7-dehydrocholesterol. 7-dehydrocholesterol-hemihydrate is a crystalline compound in which water is combined with 7-dehydrocholesterol in stoichiometric amounts. In fact, 7-dehydrocholesterol-hemihydrate contains one water molecule (═ bound water ") per two molecules of 7-dehydrocholesterol in its crystalline structure. The person skilled in the art also refers to bound water as "crystal water" or "water of hydration".
The 7-dehydrocholesterol-hemihydrate can be represented by formula (I)
It has been found that 7-dehydrocholesterol-hemihydrate exhibits a maximum in intensity (in counts per second) in the following 2 theta (2 theta) range when measured using X-ray powder diffraction (XRD)
3.07-3.15°、
6.26-6.34°、
6.52-6.60°、
13.10-13.18°、
16.23-16.31°、
18.95-19.03 °, and
19.40-19.48°。
the X-ray powder diffraction (XRD) was measured in reflection mode at 295K using CuK α 1 as a radiation source. The measurement was performed in the 2 theta range of 2-50 deg..
The most important feature of the maximum is its location, not the intensity value. Therefore, the maximum value is hereinafter referred to as a 2 θ maximum value.
The exact intensity of the above maximum (in counts per second) can be varied between each individual XRD measurement. However, the intensity of the 2 θ maximum (in counts per second) can be used to further characterize 7-dehydrocholesterol-hemihydrate.
The 2 theta maximum in the range of 16.23 to 16.31 deg. has, inter alia, the highest intensity (in counts per second) in the measured overall powder X-ray diffraction pattern (XRD) of the composition.
Furthermore, the intensity (in counts per second) of said 2 θ maximum in the range of 3.07-3.15 ° is typically at least 10%, in particular at least 20%, of the intensity (in counts per second) of said 2 θ maximum in the range of 16.23-16.31 °.
Furthermore, the intensity (in counts per second) of said 2 θ maximum in the range of 19.40-19.48 ° is at least 10%, preferably at least 20%, more preferably 55-75% of the intensity (in counts per second) of said 2 θ maximum in the range of 3.07-3.15 °.
The powder X-ray diffraction pattern (XRD) of the measured 7-dehydrocholesterol-hemihydrate is shown in fig. 1. See the experimental section for further details.
7-dehydrocholesterol-hemihydrate is especially formed from 7-dehydrocholesterol. Specifically, it may be formed by crystallization or precipitation from an aqueous 7-dehydrocholesterol solution. In particular, 7-dehydrocholesterol-hemihydrate is obtained by crystallization from a solution of 7-dehydrocholesterol in a suitable hydrocarbon (in particular an alkane, preferably hexane or heptane) and water. Crystallization is specifically achieved by cooling a hot (i.e., in the range between 35 ℃ to 60 ℃) solution of 7-dehydrocholesterol in heptane or hexane and water.
More specifically, 7-dehydrocholesterol-hemihydrate is obtained by crystallization from a solution of 7-dehydrocholesterol in a suitable polar solvent (in particular acetone or methyl ethyl ketone) having a boiling point significantly lower than 80 ℃ and water. Crystallization is specifically achieved by cooling a hot (i.e., in the range of between 35 ℃ to 55 ℃) solution of 7-dehydrocholesterol in acetone and water.
It has been found that 7-dehydrocholesterol-hemihydrate is formed even in excess water. In particular, it has been observed that, in all the condition variants of the experiments carried out, no 7-dehydrocholesterol-hydrate (DHC · H) was observed2O) (corresponding to DHC/water molecular ratio of 1: 1).
Despite the fact that 7-dehydrocholesterol-hemihydrate is formed even in excess water, it is very advantageous to remove excess water to obtain 7-dehydrocholesterol-hemihydrate without excess (i.e. unbound) water.
In particular, it has been observed that 7-dehydrocholesterol-hemihydrate can be prepared by a process comprising the steps of:
a) providing an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and water, wherein the molar ratio of 7-dehydrocholesterol to water is between 1.8:1 and 0.1:1
b) Removing water from said mixture of step a) to such an extent that a composition is formed in which the molar ratio of 7-dehydrocholesterol to water is strictly between 2.1:1 and 1.9:1, preferably 2: 1.
Any amount of 7-dehydrocholesterol referred to in this document is determined by High Performance Liquid Chromatography (HPLC).
Specifically, the amount of DHC was determined by High Performance Liquid Chromatography (HPLC) using HPLC Agilent 1200 having an HPLC column Supelcosil ABZ +/Sigma with a length of 250mm, an internal diameter of 4.6mm, a particle size of 5 microns, measured at 30 ℃ using detector DAD at wavelengths of 212nm, 270nm and 300 nm. The eluent was acetonitrile (a)/methyl tertiary butyl ether (B) in the following gradient procedure:
0min A/B＝70/30 1ml/min
25min A/B＝50/50 1ml/min
28min A/B＝90/10 1ml/min
30min A/B＝90/10 1ml/min
calibration was performed by dissolving 5 precisely weighed samples of crystals ranging from 1mg to 20mg in a solvent consisting of acetonitrile/methyl-t-butyl ether 60/40.
Under the above measurement conditions, 7-dehydrocholesterol-hemihydrate dissociates into 7-dehydrocholesterol and water.
Any amount of water mentioned in this document is determined by karl fischer titration. Specifically, a Metrohm 874/Metrohm 851 and Hydranal Medium K titration solution using a Metrohm platinum bipolar electrode was used.
The initial composition consists of crystals wetted by water. By "wetted" herein is meant that some free liquid water is observed at the crystal surface (═ unbound water).
Thus, in step a), the molar ratio of 7-dehydrocholesterol to water, as determined by HPLC or karl fischer titration as described previously, is between 1.8:1 and 0.1: 1. This corresponds to a weight fraction of water between 2.5 and 32 wt.%.
Unbound water is then removed in step b).
In step b), unbound water is removed from the 7-dehydrocholesterol-hemihydrate. Water in the crystal structure of 7-dehydrocholesterol-hemihydrate binds by hydrogen bonds within the crystal lattice (═ bound water "or" crystal water "). However, in 7-dehydrocholesterol-hemihydrate, the level of binding of water to 7-dehydrocholesterol is limited. It is important to note that it is this reversibility of water binding to DHC that is important for the purposes of the present invention. Thus, for best results, removal of excess (i.e., unbound) water is preferably removed under very mild removal conditions to avoid removal of bound water.
For example, water may be removed by simple drying, i.e., exposure to air at ambient pressure. This is usually performed by blowing a gas mixture, in particular air, over the crystal. Removal can be accelerated by using hot gas or air. In particular, the water removal step b) can be performed by drying the crystals after filtration on filter paper, or on Nutsche filter (buchner funnel) or on frit (sintered glass) filter.
In another embodiment, the water is removed by heating under reduced pressure.
Typically, the water is removed by heating to a temperature between 50 ℃ and 80 ℃, in particular between 60 ℃ and 70 ℃, and a pressure between 0.1 mbar and 15 mbar, in particular between 1 mbar and 10 mbar.
It is important to emphasize that care needs to be taken to ensure that the water removal operation does not result in too much water (i.e. bound water, a part of the water of crystallization) being removed, especially when performed at elevated temperatures and/or reduced pressure. It is therefore crucial that the removal of water in step b) is carried out to such an extent that excess water (i.e. unbound water, i.e. water wetting the crystals) is removed, but no more water is removed, so that the amount of molar ratio of 7-dehydrocholesterol to water, as determined by HPLC and karl fischer titration as described above, is between 2.1:1 and 1.9:1, in particular between 2.05:1 and 1.95:1, preferably 2.0: 1.0. This corresponds to a weight fraction of water of between 0.022 and 0.024, in particular between 0.0223 and 0.0234, preferably 0.0228.
In a further embodiment, the amount of molar ratio of 7-dehydrocholesterol to water, as determined by HPLC and karl fischer titration as described above, is between 2.0:1 and 1.9:1, in particular between 2.0:1 and 1.95:1, preferably 2.0: 1.0. This corresponds to a weight fraction of water of between 0.0228 and 0.024, in particular between 0.0028 and 0.023, preferably 0.0228.
It has been observed that when the ratio of 7-dehydrocholesterol to water is higher than 2.1, the storage stability is greatly reduced. In other words, when the ratio of 7-dehydrocholesterol to water is higher than 2.1, the degradation during storage is strongly increased, i.e. the 7-dehydrocholesterol is significantly degraded into degradation products. The decomposition of 7-dehydrocholesterol-hemihydrate can be evidenced by changes in the powder X-ray diffraction pattern (XRD).
In the present invention it has been observed that the formation of 7-dehydrocholesterol-hemihydrate is a very effective way to reduce the degradation of 7-dehydrocholesterol upon storage, or to increase the storage stability of 7-dehydrocholesterol.
The formation of 7-dehydrocholesterol-hemihydrate is described in detail above.
The term "stabilized" in this application is understood in this document as 7-dehydrocholesterol being stabilized against degradation during storage. In other words, low degradation results in high stability and vice versa. This is reflected in an increase in storage stability, or a decrease in degradation on storage, which is characterized by a weight ratio of DHC20w/DHC0Greater than 0.80, in particular greater than 0.90. The term DHC20wIs the amount of 7-dehydrocholesterol after storage in contact with air, the term DHC0Is the amount of 7-dehydrocholesterol in the same sample prior to storage.
DHC20wAnd DHC0The difference between is due to degradation of DHC during storage. Thus, weight ratio DHC20w/DHC0The higher the amount of any degradation products formed during storage time and thus the higher the storage stability.
Particularly useful is the determination of the said weight ratio DHC of a sample stored for 20 weeks in contact with air at 4 ℃20w/DHC0To assess degradation or storage stability on storage.
The amount of 7-dehydrocholesterol was determined by HPLC as described previously.
Thus, in another aspect, the invention relates to a method of reducing the degradation of 7-dehydrocholesterol after storage for at least 1 week, said method comprising the steps of
α) forming 7-dehydrocholesterol-hemihydrate;
β) storing the 7-dehydrocholesterol-hemihydrate for an extended period of at least 1 week, preferably at least 4 weeks, more preferably at least 20 weeks, before releasing the 7-dehydrocholesterol from the 7-dehydrocholesterol-hemihydrate.
In particular, it has been observed that the stability drops significantly when more than the amount of unbound water is removed. When any unbound and bound water is substantially completely removed, anhydrous 7-dehydrocholesterol (anhydrous DHC) is obtained, which has been shown to be very unstable and susceptible to chemical degradation. The anhydrous 7-dehydrocholesterol has a powder X-ray diffraction pattern (XRD) with a distinct crystalline structure, as evidenced by a distinct powder X-ray diffraction pattern (XRD).
The powder X-ray diffraction pattern (XRD) of anhydrous DHC is shown in figure 2. For more details see the experimental section.
The anhydrous 7-dehydrocholesterol exhibits a characteristic 2 theta maximum in the following range
2.63-2.93°
5.45-5.75 °, and
16.11-16.41°。
the 2 theta maximum in the 2.63-2.93 ° range has the highest intensity (in counts per second) in the overall powder X-ray diffraction pattern (XRD) of anhydrous 7-dehydrocholesterol. The X-ray powder diffraction (XRD) was measured in the 2 theta range of 2-50 ° using CuK α 1 as a radiation source in reflection mode at 295K.
Thus, in another aspect, the invention relates to a composition obtained by removing water from an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and water,
wherein the mixture of 7-dehydrocholesterol and water has an initial molar ratio of 7-dehydrocholesterol to water of 1.8:1 and 0.1:1,
removing water until the final molar ratio of 7-dehydrocholesterol to water is between 2.1:1 and 1.9:1, preferably 2:1
Wherein the amount of 7-dehydrocholesterol is determined by High Performance Liquid Chromatography (HPLC) and the amount of water is determined by Karl Fischer titration, characterized in that the composition has a powder X-ray diffraction pattern (XRD) showing 2 theta maxima in the following ranges
3.07-3.15°、
6.26-6.34°、
6.52-6.60°、
13.10-13.18°、
16.23-16.31°、
18.95-19.03 °, and
19.40-19.48°。
the X-ray powder diffraction (XRD) was measured in the 2 theta range of 2-50 ° using CuK α 1 as a radiation source in reflection mode at 295K.
All details of 7-dehydrocholesterol-hemihydrate formation have been discussed above in great detail.
The composition is particularly free of anhydrous 7-dehydrocholesterol. Thus, in the powder X-ray diffraction pattern (XRD) of the composition, in particular, in the following rangesIs not provided withA significant 2 theta maximum, preferably no 2 theta maximum
2.63-2.93 deg. and
5.45-5.75°
is detected.
As described above, 7-dehydrocholesterol-hemihydrate shows increased storage stability, or reduced degradation, compared to 7-dehydrocholesterol.
Therefore, it is very advantageous to store and transport 7-dehydrocholesterol-hemihydrate instead of 7-dehydrocholesterol.
A "package" (in german, "Packung") as defined in this document is a combined physical object consisting of a package and packaged goods.
A "package" (in german, "Verpackung"), also known as a "container," as defined in this document, is a physical object having an interior hollow space for containing packaged goods and being a physical barrier towards the exterior space of the package and the environment surrounding the package or package. A "shipping package" is any package suitable for shipping purposes.
As defined in this document, "packaged goods" (in german, "Packgut") refers to materials stored in the hollow space of a package.
Thus, in another aspect, the invention relates to a package (1) consisting of a transport package (2) and 7-dehydrocholesterol-hemihydrate as already described in great detail above as a packaged good (3) or as part of a packaged good (3), the packaged good (3) being positioned in the inner space of the transport package (2).
A shipping package is any package used for shipping. Examples of such packages are bags, sacks, cartridges, jars, drums, jars, bottles, containers, reservoirs. The transport package is preferably sealed, more preferably made of plastic or metal or a composite material, especially a metallized polymer material (e.g. foil or paper or cardboard coated with a metal or plastic film).
In one embodiment, the shipping package consists of a sealable package (i.e., it has at least one opening) and a seal. The seal may be part of a sealable package, for example connected by a flexible part, or a separate part. The sealable package is filled with the packaged goods and then a seal seals the opening in the sealable package. After the package has been transported to a different location, the seal is removed and the package goods may be partially or completely removed from the package. Preferably, the seal can be used again to seal the package. Non-limiting examples of seals are caps, lids, valves, cover plates or adhesive foils.
One particular example of such a preferred embodiment is a bottle ("sealable package") having a cap ("seal"). The 7-dehydrocholesterol-hemihydrate may be filled into the opening of the bottle, into the interior of the bottle. The cap is applied, preferably screwed, to the bottle so that the bottle is completely sealed. After transporting (e.g., shipping) the sealed bottles ("packages") filled with 7-dehydrocholesterol-hemihydrate to a different location, the lid may be removed and the 7-dehydrocholesterol-hemihydrate may be removed from the bottles as packaged goods. The opened bottle can be closed again by applying the cap to the opened bottle again.
In another embodiment, the 7-dehydrocholesterol-hemihydrate is placed into the package through a temporary opening as a packaged good and then sealed for shipping, for example by welding or gluing. After the package has been transported to a different location, the package is ruptured and the packaged goods can be partially or completely removed from the package.
A specific example of such a preferred embodiment is a bag with an opening. The 7-dehydrocholesterol-hemihydrate may be filled into an opening of the bag, which may be closed, for example, by thermoplastic welding, to seal the package. After transporting (e.g., shipping) the sealed bag filled with 7-dehydrocholesterol-hemihydrate ("package") to a different location, the bag may be opened, for example, by a knife, so that the 7-dehydrocholesterol-hemihydrate may be removed from the bag as a packaged good.
Prior to shipping, the 7-dehydrocholesterol-hemihydrate is placed in a package. Typically, the cavity, i.e., the interior space of the shipping package, is not completely filled with 7-dehydrocholesterol-hemihydrate. Thus, typically, a portion (e.g., up to 10 vol%, and sometimes up to 20 vol%) of the volume of the interior space of the shipping package is filled with air.
The package is suitable for transportation.
Transportation is typically by car, truck, boat or airplane. The invention is very advantageous for long distance transportation such as intercontinental transportation. It is also particularly advantageous for transport over several days to several months, especially in or across tropical climate zones.
Increased storage stability or reduced degradation can be particularly advantageous when using the method of the invention, since the special condition requirements for transportation (e.g. cooling) can be greatly reduced or even eliminated.
It is important to recognize that when 7-dehydrocholesterol-hemihydrate is dissolved in the corresponding solvent, the crystals dissolve and dissociate into 7-dehydrocholesterol and water, and thus release 7-dehydrocholesterol. Any solvent in which 7-dehydrocholesterol or 7-dehydrocholesterol-hemihydrate is soluble or solubilized at ambient or elevated temperatures, typically up to 100 ℃, can be used as the corresponding solvent.
Preferably, the respective solvent is selected from the group consisting of: linear, branched or cyclic alcohols, preferably having less than 10 carbon atoms, acetone, methyl ethyl ketone, Tetrahydrofuran (THF), methyl tetrahydrofuran (2-MTHF), cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), C of acetic acid1-4Alkyl esters, chlorobenzene, alkanes, and mixtures thereof. Particularly preferred are solvents selected from the group consisting of: isopropyl alcohol, butyl alcohol, chlorobenzene and mixtures thereofA compound (I) is provided.
Thus, 7-dehydrocholesterol is again available for further reaction. Thus, a method of stabilizing or reducing the degradation of 7-dehydrocholesterol by forming 7-dehydrocholesterol-hemihydrate is a very efficient way and also a method of regenerating the starting material, i.e. 7-dehydrocholesterol-hemihydrate, very easily as required. Thus, 7-dehydrocholesterol can be easily stored without significant degradation over an extended period of time and can be further converted to other compounds, such as vitamin D3, only later (if needed) upon irradiation of the 7-dehydrocholesterol.
Therefore, the method as described above preferably comprises a step γ), which is performed after step β).
γ) release of 7-dehydrocholesterol from 7-dehydrocholesterol-hemihydrate.
The preferred method of releasing 7-dehydrocholesterol from 7-dehydrocholesterol-hemihydrate is to add a solvent suitable for dissolving or solubilizing the 7-dehydrocholesterol-hemihydrate, so as to dissociate the 7-dehydrocholesterol-hemihydrate into 7-dehydrocholesterol and water, and thereby release the 7-dehydrocholesterol. Examples of such suitable solvents for release are given above in this document.
The present invention also provides a very efficient and economical way for the synthesis of vitamin D3, wherein the key intermediate 7-dehydrocholesterol is produced at a different site than 7-dehydrocholesterol for further chemical reactions. The invention particularly allows transport between production sites without significant degradation during transport or storage.
In a preferred embodiment, an additional step α ') is performed between steps α) and β), and an additional step β ' is performed in step β) after storage and before release of 7-dehydrocholesterol from the 7-dehydrocholesterol-hemihydrate '
α') preparing a package (1) consisting of a transport package (2) and 7-dehydrocholesterol-hemihydrate as a packaged good (3) or part of the packaged good (3), the packaged good (3) being located in the inner space of the transport package (2)
β 'iii') opening the package (1) and removing the 7-dehydrocholesterol-hemihydrate from the inner space of the transport package (2).
The details of the features of these steps and preferred embodiments have been discussed in great detail above.
Drawings
Figure 1 shows XRD of 7-dehydrocholesterol-hemihydrate.
Figure 2 shows XRD of anhydrous 7-dehydrocholesterol.
Figure 3 shows XRD of 7-dehydrocholesterol-hemihydrate. Fig. 3 is the same as fig. 1, enlarged in the 2 θ range of 2-20 °.
Figure 4 shows XRD of anhydrous 7-dehydrocholesterol. Fig. 4 is the same as fig. 2, enlarged in the 2 θ range of 2-20 °.
FIG. 5 shows a ratio DHC12w/DHC0Relative to H before storage2Schematic representation of O/DHC (see examples).
Fig. 6 shows a schematic view of a package (1) consisting of a transport package (2) and a packaged goods (3).
The packaged goods (3), i.e. 7-dehydrocholesterol-hemihydrate, are positioned in the inner space of the transport package (2). The interior space is not completely filled with 7-dehydrocholesterol-hemihydrate. The remaining volume is filled with air.
Fig. 6a shows a schematic view of the transport package (2) of fig. 6, having an inner space (4). The inner space (4) may be at least partially filled with a packaged good, i.e. 7-dehydrocholesterol-hemihydrate, to form a package (1) as shown in fig. 6.
Fig. 7 shows a schematic view of an embodiment of a package (1) consisting of a transport package (2) and a packaged goods (3). The transport package consists of a sealable container (6) and a seal (5).
The packaged goods (3), i.e. 7-dehydrocholesterol-hemihydrate, are positioned in the inner space of the transport package (2). The interior space is not completely filled with 7-dehydrocholesterol-hemihydrate. The remaining volume is filled with air.
Fig. 7a shows a schematic view of such a transport package (2) of fig. 7. The sealable container (6) has an opening through which the packaged goods (3), i.e. 7-dehydrocholesterol-hemihydrate, can be placed into the interior space (4) of the sealable container (6). After partial filling of the cavity, i.e. the inner space (4), a seal (5) may be placed over the opening of the sealable container (6) to seal the package and form a package (1) as shown in fig. 7.
List of reference numerals
1 packaging piece (German: Packung)
2 transport package (German: Verpackung)
3 packaged goods (German: Packgut)
4 inner space of transport package (2)
5 sealing element (German: Verschluss)
6 sealable Container (German;. VerschliessBarer)
)
Examples
The invention is further illustrated by the following experiments.
Determination of 7-dehydrocholesterol-hemihydrate
The amount of 7-dehydrocholesterol in the sample has been determined by high performance liquid chromatography using HPLC Agilent 1200 having an HPLC column Supelcosil ABZ +/Sigma with a length of 250mm, an internal diameter of 4.6mm and a particle size of 5 microns, measured at 30 ℃ using detector DAD at wavelengths of 212nm, 270nm and 300 nm. The eluent was acetonitrile (a)/methyl tertiary butyl ether (B) in the following gradient procedure:
0min A/B＝70/30 1ml/min
25min A/B＝50/50 1ml/min
28min A/B＝90/10 1ml/min
30min A/B＝90/10 1ml/min
calibration has been performed by dissolving a sample of crystals in the range of 5 accurately weighed 1mg to 20mg in a solvent consisting of acetonitrile/methyl tertiary-butyl ether 60/40.
Determination of Water
The water in the samples has been determined by Karl Fischer titration with the aid of Metrohm 874/Metrohm 851 using a Metrohm platinum bipolar electrode and Hydranal Medium K titration solution.
Formation of 7-dehydrocholesterol-hemihydrate
8.8g of 7-dehydrocholesterol were dissolved in a mixture of 221g of acetone and 11g of water with stirring and heating to 50 ℃. The solution was then cooled to 0 ℃ over several hours with stirring, whereby white crystals precipitated. These crystals were filtered through Nutsche filter.
The filter cake had a moist appearance due to the excess water. Thus, some air was passed through the filter cake to remove most of the excess water, resulting in visually dry 7-dehydrocholesterol-hemihydrate crystals.
The filter cake had a moist appearance due to the excess water. Thus, some air was passed through the filter cake to remove most of the excess water, resulting in visually dry 7-dehydrocholesterol-hemihydrate crystals.
Drying
The crystals from the filter cake were then placed in a round bottom flask and exposed to a vacuum of 5 mbar at a heating temperature of 60 ℃. After different specific drying times, a separate sample (2, ref.1-2) was taken and the amount of 7-Dehydrocholesterol (DHC) was determined according to the method described above0) And the amount of water.
Storing
For storage testing, all samples (1ml) were filled into 10ml brown glass vials, which were then closed with plastic caps. The samples were then stored in vials at a temperature of 4 ℃ in contact with air for 12 cycles. The amount of 7-Dehydrocholesterol (DHC) was then determined using the method described above12w)。
The results are compiled in table 1.
| 1 | 2 | |
|
|
| Drying time [ h] | 1 | 2 | 4 | |
| DHC/H2O[mol/mol] | 1.87 | 1.95 | 4.73 | 8.21 |
| H2O/DHC[mol/mol] | 0.535 | 0.513 | 0.211 | 0.122 |
| DHC12w/DHC0[％] | 98 | 98 | 33 | 16 |
Table 1: storage stability or degradation of 7-dehydrocholesterol-hemihydrate.
It is important to emphasize that samples 1 and 2 were observed to exhibit a DHC/H of 2.0 after storage2And (3) the molar ratio of O. This corresponds exactly to DHC/H of 7-dehydrocholesterol-hemihydrate2And (3) the molar ratio of O. Thus, it can be concluded that in sample 1 and sample 2, the excess hydrates have been completely removed during storage to form storage stable 7-dehydrocholesterol-hemihydrate.
FIG. 5 shows H2Molar ratio of O to DHC compared to DHC12wAnd DHC0A graphical representation of the ratio of (a). In this representation, the stability effect or the influence on degradation can be visualized very clearly.
It clearly shows that 7-dehydrocholesterol-hemihydrate is very storage stable, while a ratio H significantly below 0.5 is obtained2The stability is very strongly reduced with O/DHC.
This means that 7-dehydrocholesterol-hemihydrate has very low degradation, while the degradation increases very strongly when a ratio MeOH/DHC significantly below 0.5 is obtained.
H2Anhydrous 7-dehydrocholesterol having an O/DHC ratio of 0 is very unstable, i.e. after 12 weeks of storage in contact with air at 4 ℃, only about 16% of the amount of DHC present before storage remains, i.e. about 84% of DHC has been degraded. DHC, i.e. in the form of unsolvated 7-dehydrocholesterol, shows a very high degradation.
Crystal structure
7-dehydrocholesterol-hemihydrate and anhydrous 7-dehydrocholesterol have been studied by XRD prior to storage. The X-ray powder diffraction pattern (XRD) was measured in reflection mode at 295K using CuK α 1 as a radiation source. The measurements were performed in the 2 theta range of 2-50 deg..
The diffractograms of 7-dehydrocholesterol-hemihydrate are shown in fig. 1 and 3, and the diffractograms of anhydrous 7-dehydrocholesterol are shown in fig. 2 and 4.
| 2 theta maximum value [ ° [)] | Intensity [ cps ]] |
| 3.11 | 404 |
| 6.30 | 185 |
| 6.56 | 203 |
| 13.14 | 320 |
| 16.27 | 1320 |
| 18.99 | 110 |
| 19.45 | 262 |
Table 2.7-characteristic maxima of XRD of dehydrocholesterol-hemihydrate.
| 2 theta maximum value [ ° [)] | Intensity [ cps ]] |
| 2.78 | 44'093 |
| 3.02 | 16'858 |
| 5.6 | 2'033 |
| 16.26 | 13'351 |
TABLE 3 characteristic maxima of XRD for anhydrous 7-dehydrocholesterol.
The XRD of 7-dehydrocholesterol-hemihydrate remained unchanged after storage.
Claims (15)
1.7-dehydrocholesterol-hemihydrate.
2. A method of reducing degradation of 7-dehydrocholesterol after storage for at least 1 week, the method comprising the steps of
α) forming 7-dehydrocholesterol-hemihydrate;
β) storing the 7-dehydrocholesterol-hemihydrate for an extended period of at least 1 week, preferably at least 4 weeks, more preferably at least 20 weeks, before releasing the 7-dehydrocholesterol from the 7-dehydrocholesterol-hemihydrate.
3. 7-dehydrocholesterol-hemihydrate according to claim 1 or a process according to claim 2, characterized in that the 7-dehydrocholesterol-hemihydrate shows a maximum of intensity (in counts per second) in the following 2 theta (2 Θ) range when measured using X-ray powder diffraction (XRD)
3.07-3.15°、
6.26-6.34°、
6.52-6.60°、
13.10-13.18°、
16.23-16.31°、
18.95-19.03 °, and
19.40-19.48°；
whereas the X-ray powder diffraction (XRD) was measured in reflection mode at 295K using CuK α 1 as a radiation source.
4. 7-dehydrocholesterol-hemihydrate of claim 3 or a process of claim 3, characterized in that the 2 θ maximum in the range of 16.23-16.31 ° has the highest intensity (in counts per second) in the measured overall powder X-ray diffraction pattern (XRD) of the composition.
5. Method according to any of the preceding claims 2-4, characterized in that the formation of 7-dehydrocholesterol-hemihydrate in step a is performed by
a) Providing an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and water, wherein the molar ratio of 7-dehydrocholesterol to water is between 1.8:1 and 0.1:1
b) Removing water from the mixture of step a) to such an extent that a composition is formed in which the molar ratio of 7-dehydrocholesterol to water is strictly between 2.1:1 and 1.9:1, preferably 2: 1;
wherein the amount of 7-dehydrocholesterol is determined by High Performance Liquid Chromatography (HPLC) and the amount of water is determined by Karl Fischer titration.
6. The method of claim 5, wherein the degradation of 7-dehydrocholesterol is characterized by a weight ratio of DHC12w/DHC0Greater than 0.80, particularly greater than 0.90,
wherein
DHC12wIs 7-takes offAmount of 7-dehydrocholesterol after 20 weeks of storage at 4 ℃;
and DHC0Is the amount of 7-dehydrocholesterol prior to storage.
7. Method according to claim 5 or 6, characterized in that the water is removed by heating under reduced pressure.
8. Method according to any one of the preceding claims 5-7, characterized in that the water is removed by heating to a temperature between 50 ℃ and 80 ℃, in particular between 60 ℃ and 70 ℃, and a pressure between 0.1 mbar and 15 mbar, in particular between 1 mbar and 10 mbar.
9. Method according to any one of the preceding claims 1 to 8, characterized in that the method comprises a step γ) performed after step β)
γ) release of 7-dehydrocholesterol from 7-dehydrocholesterol-hemihydrate.
10. A composition obtained by removing water from an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and water,
wherein the mixture of 7-dehydrocholesterol and water has an initial molar ratio of 7-dehydrocholesterol to water of 1.8:1 and 0.1:1,
removing water until the final molar ratio of 7-dehydrocholesterol to water is between 2.1:1 and 1.9:1, preferably 2: 1;
wherein the amount of 7-dehydrocholesterol is determined by High Performance Liquid Chromatography (HPLC) and the amount of water is determined by Karl Fischer titration, characterized in that the composition has a powder X-ray diffraction pattern (XRD) showing 2 theta maxima in the following ranges
3.07-3.15°、
6.26-6.34°、
6.52-6.60°、
13.10-13.18°、
16.23-16.31°、
18.95-19.03 °, and
19.40-19.48°；
and the powder X-ray diffraction pattern (XRD) was measured in reflection mode at 295K using CuK α 1 as a radiation source.
11. The composition according to claim 10, characterized in that the 2 Θ maximum in the range of 16.23-16.31 ° has the highest intensity (in counts per second) in the measured overall powder X-ray diffraction pattern (XRD) of the composition.
12. Composition according to claim 10 or 11, characterized in that the intensity (in counts per second) of the 2 Θ maximum in the range of 3.07-3.15 ° is at least 10%, in particular at least 20%, of the intensity (in counts per second) of the 2 Θ maximum in the range of 16.23-16.31 °.
13. Composition according to claim 10 or 11 or 12, characterized in that the intensity (in counts per second) of the 2 Θ maximum in the range 19.40-19.48 ° is at least 10%, preferably at least 20%, more preferably 55-75% of the intensity (in counts per second) of the 2 Θ maximum in the range 3.07-3.15 °.
14. Composition according to any one of the preceding claims 10 to 13, characterized in that the water is removed by heating to a temperature of between 50 ℃ and 80 ℃, in particular between 60 ℃ and 70 ℃, and a pressure of between 0.1 mbar and 15 mbar, in particular between 1 mbar and 10 mbar.
15. A package (1) consisting of a transport package (2) and 7-dehydrocholesterol-hemihydrate according to any of the preceding claims 1-4 as a packaged good (3) or as part of the packaged good (3), the packaged good (3) being located in the inner space of the transport package (2).
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| PCT/EP2019/081605 WO2020104356A1 (en) | 2018-11-19 | 2019-11-18 | 7-dehydrocholesterol-hemihydrate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2434015A (en) * | 1942-11-21 | 1948-01-06 | Du Pont | Stable provitamin d composition |
| US2568025A (en) * | 1949-03-24 | 1951-09-18 | Peboc Ltd | Process for the production of 7-halogenosterols |
| US3100783A (en) * | 1958-06-26 | 1963-08-13 | Philips Corp | Method of stabilizing crystalline compounds against oxidation |
-
2019
- 2019-11-18 WO PCT/EP2019/081605 patent/WO2020104356A1/en active Application Filing
- 2019-11-18 CN CN201980075399.0A patent/CN113039192A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2434015A (en) * | 1942-11-21 | 1948-01-06 | Du Pont | Stable provitamin d composition |
| US2568025A (en) * | 1949-03-24 | 1951-09-18 | Peboc Ltd | Process for the production of 7-halogenosterols |
| US3100783A (en) * | 1958-06-26 | 1963-08-13 | Philips Corp | Method of stabilizing crystalline compounds against oxidation |
Non-Patent Citations (2)
| Title |
|---|
| GEORGE J. SCHROEPFER等: ""Conversion of △-Cholestenol-4-C14 and 7-Dehydrocholesterol-4-C14 to Cholesterol" * |
| WOLFGANG HUBER等: "The Absorption Spectra of the Vitamins and Provitamins D" * |
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