WO2020104353A1 - 7-dehydrocholesterol-hemimethanolate - Google Patents
7-dehydrocholesterol-hemimethanolateInfo
- Publication number
- WO2020104353A1 WO2020104353A1 PCT/EP2019/081599 EP2019081599W WO2020104353A1 WO 2020104353 A1 WO2020104353 A1 WO 2020104353A1 EP 2019081599 W EP2019081599 W EP 2019081599W WO 2020104353 A1 WO2020104353 A1 WO 2020104353A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dehydrocholesterol
- methanol
- hemimethanolate
- xrd
- range
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the problem to be solved by the present invention is to increase the storage stability of 7-dehydrocholesterol, respectively to decrease the degra- dation of 7-dehydrocholesterol upon storage. It has been, surprisingly, found that 7-dehydrocholesterol-hemimethanolate shows polymorphism. 7-Dehydrocholeste- rol-hemimethanolate offers a solution to this problem. 7-Dehydrocholesterol-hemi- methanolate can be easily formed from 7-dehydrocholesterol. Furthermore, 7-de hydrocholesterol can easily be regenerated in high yields from 7-dehydrocholes- terol-hemimethanolate. It has been found that 7-dehydrocholesterol-hemimetha- nolate shows significantly increased storage stability, respectively shows a significant decrease in the degradation.
- polymorphism The ability of a substance to exist in more than one crystalline form is generally referred to as polymorphism and these different crystalline forms are usually named "polymorphs" and may be referred to by certain analytical proper ties such their X-ray powder diffraction (XRD) patterns.
- polymorphism reflects the ability of a molecule to change its conformation or to form different intermolecular and intramolecular interactions. This can result in different atom arrangements that are reflected in the crystal lattices of different polymorphs.
- polymorphism is not a universal feature of solids, since some molecules can exist in one or more crystal forms while other molecules cannot. Therefore, the existence or extent of polymorphism for a given compound is unpredictable.
- those properties can affect positively or negatively the stability, dissolution and bioavailability of a solid-state formulation, which subsequently affects suitability or efficacy of such formulations in treating disease.
- the physical properties of a polymorphic form may also affect the further processability of a compound.
- An individual polymorph having one or more desirable properties can be suitable for the development of a pharmaceutical formulation having desired property(properties).
- Existence of a compound with a polymorphic form(s) having undesirable properties can impede or prevent development of the polymorphic form as a pharmaceutical agent.
- 7-dehydrocholesterol shows polymor phism.
- 7-dehydrocholesterol-hemimethanolate is a specific polymorph of 7-dehydrocholesterol.
- 7-Dehydrocholesterol-hemi- methanolate is a crystalline compound in which methanol is stoichiometrically bound to 7-dehydrocholesterol.
- 7-dehydrocholesterol-hemimethanolate comprises one molecule of methanol (- 'bound methanol”) per two molecules of 7- dehydrocholesterol in its crystalline structure.
- 7-Dehydrocholesterol-hemimethanolate can be represented by formula (I)
- the X-ray powder diffraction (XRD) has been measured in the reflection mode at 295 K using CuKal as radiation source. The measurement has been carried out in the range of 2 - 50° 2Q.
- the exact intensity (in counts per second) of the maxima mentioned above may vary between the individual XRD measurements. However, the intensity (in counts per second) of the 2 theta maxima can be used for further characterization of 7-dehydrocholesterol-hemimethanolate.
- the intensity (in counts per second) of the 2 theta maximum in the range of 12.46 - 12.76° is typically at least 10 %, preferably at least 20 %, of the intensity (in counts per second) of the 2 theta maximum in the range of 4.98 - 5.28 °.
- the structure of 7-dehydrocholesterol-hemimethanolate has been further characterized by X-ray diffraction of single crystals of 7-dehydrocholesterol-hemi- methanolate at 123 K. These measurements show that 7-dehydrocholesterol- hemimethanolate crystallizes triclinic, in the space group P1 and that four molecules of 7-dehydrocholesterol are present in an asymmetric unit alongside with two molecules of methanol. Particularly, the following crystal parameters have been found:
- the 7-dehydrocholesterol-hemi- methanolate can be prepared by a process comprising the following steps:
- step b) removing methanol from the mixture of step a) to an extend that a
- the amounts of DHC are determined by High-Performance Liquid Chromatography (HPLC) using a HPLC Agilent 1200 with a HPLC column Supelcosil ABZ+/Sigma of 250 mm length, 4.6 mm internal diameter, 5 micrometre particle size, measured at 30°C, using a detector DAD at wavelength of 212 nm, 270 nm and 300nm.
- HPLC High-Performance Liquid Chromatography
- the 7-dehydrocholesterol-hemi- methanolate dissociates into the 7-dehydrocholesterol and methanol.
- Said initial composition is composed of crystals wetted by methanol.
- step a) the molar ratio of 7-dehydrocholesterol to methanol as determined by HPLC resp. GC, as mentioned before is between 1.8:1 and 0.1 :1. This corresponds to a weight fraction of methanol of between 4.4 and 45 % by weight.
- the unbound methanol is then removed in step b).
- step b) the unbound methanol is removed from 7-dehydrocholesterol- hemimethanolate.
- the methanol in the crystal structure of 7-dehydrocholesterol- hemimethanolate is bound (- 'bound methanol") by hydrogen bonds within the crystal lattice.
- the level of binding force of methanol to the 7-dehydro- cholesterol in the 7-dehydrocholesterol-hemimethanolate is limited. It is important to note that, for the purpose of this invention, it is exactly this reversibility of binding of methanol to DHC which is important.
- the removal of excess (i.e. unbound) methanol is preferably removed under very mild removal conditions to avoid removal of bound methanol.
- the removal of methanol can be by simple drying, i.e. expo sure to air at ambient pressure. This is typically performed by blowing a gas mix ture, particularly air, over the crystals. The removal can be accelerated by using warm gas respectively air.
- the step b) of methanol removal can be performed by drying the crystals after filtration of the crystals on the filter paper, or on a Nutsche filter (Biichner funnel) or on a glass frit (sintered glass) filter.
- the methanol is removed by heating under reduced pressure.
- the methanol is removed by heating to a temperature of bet ween 50 and 80°C, particularly of between 60 and 70°C, and a pressure of bet ween 0.1 and 15 mbara, particularly of between 1 and 10 mbara.
- step b) it is essential that the removal of methanol in step b) is done so that the excess of methanol (i.e. the unbound methanol, i.e. methanol wetting the crystals) is removed but not more, so that the amount of the molar ratio of 7-dehydrocholesterol and methanol, determined as indicated above by HPLC and GC, is between 2.1 :1 and 1.9:1 , particularly between 2.05 : 1 and 1.95 : 1 , preferably 2.0:1.0.
- the amount of the molar ratio of 7- dehydrocholesterol and methanol, determined as indicated above by HPLC and GC, is between 2.0:1 and 1.9:1 , particularly between 2.0 : 1 and 1.95 : 1 , preferable 2.0:1.0.
- the difference between DHC20 W and DHCo is due to a degradation of DHC during the storage.
- the invention relates to a composition which is obtained from the removal of methanol from an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and methanol,
- 7-dehydrocholesterol-hemimethanolate shows an increased storage stability, respectively a decrease degradation, as compared to 7-dehydrocholesterol. Therefore, it is very advantageous to store and to transport 7-dehydrocho- lesterol-hemimethanolate rather than 7-dehydrocholesterol.
- the "packaging” in German “Verpackung", as defined in this document, also referred as “containment”, is the physical object which has an inner hollow space which serves to take up a packaged good and is a physical barrier towards the outer space of the packaging and the environment around the packaging respectively the package.
- a “transport packaging” is any packaging which is suitable for transport purposes.
- the invention relates to a package (1 ) consisting of a transport packaging (2) and 7-dehydrocholesterol-hemimethano- late, as already described above in great detail, as a packaged good (3) or part of the packaged good (3), which is localized in the inner space of the transport packaging (2).
- intercontinental transports It is particularly also very advantageous for transports of several days to months, particularly in or through tropic climate zones.
- the increased storage stability, respectively decreased degradation, can be particularly advantageous in that the needs of special conditions for transport such as cooling may be strongly reduced or even removed when the method of the present invention is used.
- This invention offers also a very efficient and economical way for the synthesis of vitamin D3 where the key intermediate 7-dehydrocholesterol is produced in a different place to where the 7-dehydrocholesterol is used for further chemical reactions.
- the invention allows particularly a transport between production sites without significant degradation during transport or storage.
- Figure 8a shows a schematic representation of a transport packaging (2) of figure 8, which has an inner space (4).
- the inner space (4) can be filled at least partially with the packaging good, i.e. 7-dehydrocholesterol-hemimethanolate, to form a package (1 ) as shown in figure 8.
- Figure 9a shows a schematic representation of such a transport packaging (2) of figure 9.
- the sealable container (6) has an opening through which the packaged good (3), i.e. 7-dehydrocholesterol-hemimethanolate, can be put into the inner space (4) of the sealable container (6). After a partially filling of the cavity, i.e. the inner space (4), the seal (5) can be put onto the opening of the sealable container (6) to seal the packing and to form a package (1 ) as shown in figure 9.
- the packaged good (3) i.e. 7-dehydrocholesterol-hemimethanolate
- Methanol in a sample has been determined by Gas Chromatography using a GC Agilent Technologies 1890, with a GC column Rtx-1 , Restek, of 30 m length, 0.32 mm inner diameter, 5 micrometre film thickness, using hydrogen as carrier gas and a constant flow of 2.5 ml/min, injector 300°C, split injection mode (ratio 1/40) , injection volume of 1 microliter, using a FID detector at 250°C, a nitrogen flow rate of 20 mL/min flow rate, and a calibration with N-Methyl-2- pyrrolidone (NMP).
- the oven temperature is initially 40°C, held for 2 minutes, increased to 140°C over 12.5 minutes, then increased to 220°C over 1.6 minutes and held for 10 minutes.
- 7-dehydrocholesterol has been dissolved in a mixture of hexane and methanol under stirring and heating to 40°C. Then the solution was cooled to 0°C over several hours under stirring so that white crystals have been precipitated. These crystals have been filtered over a Nutsche filter.
- Figure 5 shows a graphic representation of the molar ratio of MeOH to DHC versus the ratio of DHC20 W to DHCo. In this representation the stability effect, respectively the impact on degradation, can be visualized very clearly.
- the 7-dehydrocholesterol-hemimethanolate and the 7-dehydrocholesterol ansolvate ( Ref.4 ) have been investigated by XRD before storage.
- the X-ray powder diffractogram (XRD) has been measured in the reflection mode at 295 K using CuKal as radiation source. The measurement has been carried out in the range of 2 - 50° 2Q.
- the diffractograms are shown in figure 1 and figure 3 for 7- dehydrocholesterol-hemimethanolate and in figure 2 and figure 4 for 7- dehydrocholesterol ansolvate.
- Figure 6 shows the representation of the unit cell of 7-dehydrocholesterol- hemimethanolate showing the chains formed by hydrogen bonds.
- the unit cell is, in the case of the space group P1 , identical to the asymmetric unit.
- table 4 the atoms near acceptors (A) and donors (D) are listed with the respective bond lengths and angles.
- the D...A distances are between 2.656(2) and 2.695(2) Angstrom.
- the D-FI...A angles are, as expected for this kind of classical hydrogen bonds, between 169.0(20) and 177(2) degrees and can I be regarded as directional. Details about the hydrogen bond patterns can be seen in table 4, while figure 7 show the two chains built by the hydrogen bonds one by one. Particularly, the positioning of the methanol (see 057 and 0115) in the crystal system is shown.
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Abstract
The present invention relates to 7-dehydrocholesterol-hemimethanolate. It has been found that the formation of 7-dehydrocholesterol-hemimethanolate offers an efficient method of increasing the storage stability of 7-dehydrocholesterol, respectively of decreasing the degradation upon storage of 7-dehydrocholesterol.
Description
7-DEHYDROCHOLESTEROL-HEMIMETHANOLATE
Technical Field
The present invention relates to the field of 7-dehydrocholesterol.
Background of the invention
7-Dehydrocholesterol is a key intermediate used in the synthesis for cholecalciferol (=vitamin D3).
7-Dehydrocholesterol, however, has limited storage stability and degrades during extended storage.
Summary of the invention
Therefore, the problem to be solved by the present invention is to increase the storage stability of 7-dehydrocholesterol, respectively to decrease the degra- dation of 7-dehydrocholesterol upon storage. It has been, surprisingly, found that 7-dehydrocholesterol-hemimethanolate shows polymorphism. 7-Dehydrocholeste- rol-hemimethanolate offers a solution to this problem. 7-Dehydrocholesterol-hemi- methanolate can be easily formed from 7-dehydrocholesterol. Furthermore, 7-de hydrocholesterol can easily be regenerated in high yields from 7-dehydrocholes- terol-hemimethanolate. It has been found that 7-dehydrocholesterol-hemimetha- nolate shows significantly increased storage stability, respectively shows a significant decrease in the degradation.
Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.
Detailed description of the invention
In a first aspect, the present invention relates to 7-dehydrocholesterol- hemimethanolate.
The ability of a substance to exist in more than one crystalline form is generally referred to as polymorphism and these different crystalline forms are usually named "polymorphs" and may be referred to by certain analytical proper ties such their X-ray powder diffraction (XRD) patterns. In general, polymorphism reflects the ability of a molecule to change its conformation or to form different intermolecular and intramolecular interactions. This can result in different atom
arrangements that are reflected in the crystal lattices of different polymorphs. However, polymorphism is not a universal feature of solids, since some molecules can exist in one or more crystal forms while other molecules cannot. Therefore, the existence or extent of polymorphism for a given compound is unpredictable.
The different polymorphs of a substance show different crystal lattice energies and thus each polymorph typically shows one or more different physical properties in the solid state, such as density, melting point, colour, stability, dissolution rate, flowability, compatibility with milling, granulation and compacting and/or uniformity of distribution [See, e.g., P. DiMartino, et al., J. Thermal Anal. 48:447-458 (1997)]. The capacity of any given compound to occur in one or more crystalline forms (i.e. polymorphs) is unpredictable as are the physical properties of any single crystalline form. The physical properties of a polymorphic form may affect its suitability in pharmaceutical formulations. For example, those properties can affect positively or negatively the stability, dissolution and bioavailability of a solid-state formulation, which subsequently affects suitability or efficacy of such formulations in treating disease. Likewise, the physical properties of a polymorphic form may also affect the further processability of a compound.
An individual polymorph having one or more desirable properties can be suitable for the development of a pharmaceutical formulation having desired property(properties). Existence of a compound with a polymorphic form(s) having undesirable properties can impede or prevent development of the polymorphic form as a pharmaceutical agent.
It has been first found that 7-dehydrocholesterol (=DHC) shows polymor phism. Particularly, it has been found that 7-dehydrocholesterol-hemimethanolate is a specific polymorph of 7-dehydrocholesterol. 7-Dehydrocholesterol-hemi- methanolate is a crystalline compound in which methanol is stoichiometrically bound to 7-dehydrocholesterol. In fact, 7-dehydrocholesterol-hemimethanolate comprises one molecule of methanol (- 'bound methanol") per two molecules of 7- dehydrocholesterol in its crystalline structure.
7-Dehydrocholesterol-hemimethanolate can be represented by formula (I)
It has been found that 7-dehydrocholesterol-hemimethanolate exhibits maxima of the intensities (in counts per second) measured using X-ray powder diffraction (XRD) in the 2 theta (2Q) range of
4.98 - 5.28 °,
8.93 - 9.23°,
10.14 - 10.44°,
12.46 - 12.76°, and
16.78 - 17.28°.
The X-ray powder diffraction (XRD) has been measured in the reflection mode at 295 K using CuKal as radiation source. The measurement has been carried out in the range of 2 - 50° 2Q.
The most important feature of the maxima is their position, and not the value of the intensity. Therefore, the maxima are referred to as 2 theta maxima in the following.
The exact intensity (in counts per second) of the maxima mentioned above may vary between the individual XRD measurements. However, the intensity (in counts per second) of the 2 theta maxima can be used for further characterization of 7-dehydrocholesterol-hemimethanolate.
The 2 theta maximum in the range of 16.78 - 17.28° has particularly the highest intensity (in counts per second) in the whole measured powder X-ray diffractogram (XRD) of the composition.
Furthermore, the intensity (in counts per second) of the 2 theta maximum in the range 4.98 - 5.28 ° is typically at least 10 %, particularly at least 20 %, of the intensity (in counts per second) of the 2 theta maximum in the range of 16.78 - 17.28°.
Furthermore, the intensity (in counts per second) of the 2 theta maximum in the range of 12.46 - 12.76° is typically at least 10 %, preferably at least 20 %, of the intensity (in counts per second) of the 2 theta maximum in the range of 4.98 - 5.28 °.
The powder X-ray diffractogram (XRD) of 7-dehydrocholesterol- hemimethanolate as measured is shown in figure 1. See the experimental part for further details.
The structure of 7-dehydrocholesterol-hemimethanolate has been further characterized by X-ray diffraction of single crystals of 7-dehydrocholesterol-hemi- methanolate at 123 K. These measurements show that 7-dehydrocholesterol- hemimethanolate crystallizes triclinic, in the space group P1 and that four molecules of 7-dehydrocholesterol are present in an asymmetric unit alongside with two molecules of methanol. Particularly, the following crystal parameters have been found:
a 6.3895(5) A
b 20.3567(15) A
c 20.5862(15) A
a 110.584(3)°
b 94.222(3)°
g 97.884(3)°
V 2461.5(3) A3
7-Dehydrocholesterol-hemimethanolate can be particularly formed from 7- dehydrocholesterol. Particularly, it can be formed by crystallization or precipita- tions from solutions of 7-dehydrocholesterol containing methanol. Particularly 7- dehydrocholesterol-hemimethanolate is obtained by crystallization from a solution 7-dehydrocholesterol in a suitable hydrocarbon, particularly an alkane, preferably hexane or heptane, and methanol. The crystallization is particularly realized by
cooling a hot (i.e. in the range of between 35°C to 60°C) solution of 7- dehydrocholesterol in heptane or hexane and methanol.
It has been found that 7-dehydrocholesterol-hemimethanolate is formed even in an excess of methanol. Particularly, it has been observed that under all variations of conditions of the experiments undertaken, no formation of 7-dehydro- cholesterol-methanolate (DHC · CH3OH) (corresponding to a molecular ratio of DHC/methanol = 1 :1 ) has been ever observed.
Despite the fact that 7-dehydrocholesterol-hemimethanolate is formed even in an excess of methanol, it is very advantageous to remove the excess of methanol to obtain 7-dehydrocholesterol-hemimethanolate which is void of excess (i.e. unbound) methanol.
Particularly, it has been observed that the 7-dehydrocholesterol-hemi- methanolate can be prepared by a process comprising the following steps:
a) providing an initial composition consisting essentially of a mixture of 7- dehydrocholesterol and methanol wherein the molar ratio of 7-dehydro- cholesterol to methanol is between 1.8:1 and 0.1 :1
b) removing methanol from the mixture of step a) to an extend that a
composition is formed in which the molar ratio of 7-dehydrocholesterol and methanol is strictly between 2.1 :1 and 1.9:1 , preferably 2:1.
Any amounts of 7-dehydrocholesterol mentioned in this document are determined by High-Performance Liquid Chromatography (HPLC).
Specifically, the amounts of DHC are determined by High-Performance Liquid Chromatography (HPLC) using a HPLC Agilent 1200 with a HPLC column Supelcosil ABZ+/Sigma of 250 mm length, 4.6 mm internal diameter, 5 micrometre particle size, measured at 30°C, using a detector DAD at wavelength of 212 nm, 270 nm and 300nm. The eluent was acetonitrile (A) / methyl tert. -butyl ether (B) in a gradient program:
0 min A/B= 70/30 1 ml/m in
25 min A/B= 50/50 I ml/min
28 min A/B= 90/10 1 ml/min
30 min A/B= 90/10 1 ml/min
The calibration has been performed by dissolving 5 exactly weighed samples of the crystal in the range of 1 to 20 mg in a solvent consisting of acetonitrile / methyl tert. -butyl ether 60/40.
Under the above measuring conditions, the 7-dehydrocholesterol-hemi- methanolate dissociates into the 7-dehydrocholesterol and methanol.
Any amounts of methanol mentioned in this document are determined by Gas Chromatography (GC).
Specifically, the amounts of methanol are determined by Gas Chromatog raphy using a GC Agilent Technologies 1890, with a GC column Rtx-1 , Restek, of 30 m length, 0.32 mm inner diameter, 5 micrometre film thickness, using hydrogen as carrier gas and a constant flow of 2.5 ml/min, injector 300°C split injection mode (ratio 1/40) , injection volume of 1 microliter, using a FID detector at 250°C, a nitrogen flow rate of 20 mL/min flow rate, and a calibration with N-Methyl-2- pyrrolidone (NMP). The oven temperature is initially 40°C, held for 2 minutes, increased to 140°C over 12.5 minutes, then increased to 220°C over 1.6 minutes and held for 10 minutes.
Said initial composition is composed of crystals wetted by methanol.
"Wetted" in this context means that at the surface of the crystal some free, liquid methanol (- 'unbound methanol") is observable.
Therefore, in step a) the molar ratio of 7-dehydrocholesterol to methanol as determined by HPLC resp. GC, as mentioned before is between 1.8:1 and 0.1 :1. This corresponds to a weight fraction of methanol of between 4.4 and 45 % by weight.
The unbound methanol is then removed in step b).
In step b) the unbound methanol is removed from 7-dehydrocholesterol- hemimethanolate. The methanol in the crystal structure of 7-dehydrocholesterol- hemimethanolate is bound (- 'bound methanol") by hydrogen bonds within the
crystal lattice. However, the level of binding force of methanol to the 7-dehydro- cholesterol in the 7-dehydrocholesterol-hemimethanolate is limited. It is important to note that, for the purpose of this invention, it is exactly this reversibility of binding of methanol to DHC which is important. Hence, for obtaining optimal results the removal of excess (i.e. unbound) methanol is preferably removed under very mild removal conditions to avoid removal of bound methanol.
For example, the removal of methanol can be by simple drying, i.e. expo sure to air at ambient pressure. This is typically performed by blowing a gas mix ture, particularly air, over the crystals. The removal can be accelerated by using warm gas respectively air. Particularly, the step b) of methanol removal can be performed by drying the crystals after filtration of the crystals on the filter paper, or on a Nutsche filter (Biichner funnel) or on a glass frit (sintered glass) filter.
In another embodiment, the methanol is removed by heating under reduced pressure.
Typically, the methanol is removed by heating to a temperature of bet ween 50 and 80°C, particularly of between 60 and 70°C, and a pressure of bet ween 0.1 and 15 mbara, particularly of between 1 and 10 mbara.
It is important to stress, that, particularly when performed under elevated temperature and/or reduced pressure, care needs to be taken to assure that the removal is not performed so that too much methanol (i.e. also part of the bound methanol) is removed. Therefore, it is essential that the removal of methanol in step b) is done so that the excess of methanol (i.e. the unbound methanol, i.e. methanol wetting the crystals) is removed but not more, so that the amount of the molar ratio of 7-dehydrocholesterol and methanol, determined as indicated above by HPLC and GC, is between 2.1 :1 and 1.9:1 , particularly between 2.05 : 1 and 1.95 : 1 , preferably 2.0:1.0. This corresponds to a weight fraction of methanol of between 0.038 and 0.042, particularly between 0.039 and 0.041 , preferably of 0.040.
In an even further embodiment, the amount of the molar ratio of 7- dehydrocholesterol and methanol, determined as indicated above by HPLC and GC, is between 2.0:1 and 1.9:1 , particularly between 2.0 : 1 and 1.95 : 1 ,
preferable 2.0:1.0. This corresponds to a weight fraction of methanol of between 0.040 and 0.042, particularly between 0.040 and 0.041 , preferably of 0.040.
It has been observed, that when the ratio of 7-dehydrocholesterol to methanol is higher than 2.1 , the storage stability strongly decreases. In other words, when the ratio of 7-dehydrocholesterol to methanol is higher than 2.1 , the degradation during storage strongly increases, i.e. 7-dehydrocholesterol is degraded significantly into degradation products. The decomposition of 7-dehydro- cholesterol-hemimethanolate can be evidenced by changes in the powder X-ray diffractogram (XRD).
It has been observed in the present invention that the formation of 7-de- hydrocholesterol-hemimethanolate is a very efficient method of decreasing the degradation of 7-dehydrocholesterol upon storage, respectively of increasing the storage stability of 7-dehydrocholesterol.
The formation of the of 7-dehydrocholesterol-hemimethanolate has been described above in great detail.
The term "stabilization" in this application is understood in this document, 7-dehydrocholesterol is stabilized towards degradation during storage. In other words, a low degradation leads to high stabilization and vice versa. This is reflected in that the increase of the storage stability, respectively the decrease of degradation upon storage, is characterized in that the weight ratio DHC20w/DHCo is more than 0.80, particularly more than 0.90. The term DHC20W is the amount of 7-dehydrocholesterol after storage of 7-dehydrocholesterol in contact with air and the term DHCo is the amount of 7-dehydrocholesterol in the same sample before storage.
The difference between DHC20W and DHCo is due to a degradation of DHC during the storage. Hence, the higher the weight ratio DHC20wl DHCo is, the lower is the amount of any degradation products being formed during the time of storage and, hence, the higher the storage stability is.
It has been particularly useful that the degradation upon storage, respectively the storage stability, is assessed by determining said weight ratio DHC20W / DHCo for a sample being stored at 4°C in contact with air for 20 weeks.
The amount of 7-dehydrocholesterol is determined by HPLC as mentioned before.
Hence, in a further aspect, the present invention related to a method of decreasing the degradation of 7-dehydrocholesterol upon storage of at least 1 week, said method comprises the steps
a) forming 7-dehydrocholesterol-hemimethanolate;
b) storing 7-dehydrocholesterol-hemimethanolate for an extended time
period which is at least 1 week, preferably at least 4 weeks, more preferably at least 20 weeks, before releasing 7-dehydrcncholesterol from 7-dehydrocholesterol-hemimethanolate.
Particularly, it has been observed that when more than the amount of unbound methanol is removed the stability significantly drops. When the removal of any unbound and bound methanol is essentially complete, 7-dehydrocholesterol ansolvate (DHC ansolvate) is obtained which has been shown to be very unstable and prone to chemical degradation. Said 7-dehydrocholesterol ansolvate has a powder X-ray diffractogram (XRD) which has a significantly different crystal structure as evidenced by significantly different powder X-ray diffractogram (XRD).
A powder X-ray diffractogram (XRD) of the DHC ansolvate is shown in figure 2. See the experimental part for more details.
Said 7-dehydrocholesterol ansolvate shows characteristic 2 theta maxima in the range of
2.61 - 2.91 °
4.55 - 4.85°,
9.19 - 9.49°,
12.37- 12.67°, and
16.33 - 16.63°.
The 2 theta maximum in the range of 16.33 - 16.63° has the highest intensity (in counts per second) in the whole powder X-ray diffractogram (XRD) of the 7-dehydrocholesterol ansolvate. The X-ray powder diffraction (XRD) has been measured in the reflection mode at 295 K using CuKcd as radiation source in the range 2-50 ° 2Q.
Therefore, in a further aspect, the invention relates to a composition which is obtained from the removal of methanol from an initial composition consisting essentially of a mixture of 7-dehydrocholesterol and methanol,
wherein the mixture of 7-dehydrocholesterol and methanol with an initial molar ratio of 7-dehydrocholesterol to methanol is 1.8:1 and 0.1 :1 , to a final molar ratio of 7-dehydrocholesterol to methanol of between 2.1 :1 and 1.9:1 , preferable 2:1
wherein the amounts of 7-dehydrocholesterol are determined by High- Performance Liquid Chromatography (HPLC) and the amounts of methanol are determined by Gas Chromatography (GC) characterized in that a powder X-ray diffractogram (XRD) of said composition shows 2 theta maxima in the range of 4.98 - 5.28 °,
8.93 - 9.23°,
10.14 - 10.44°,
12.46 - 12.76°, and
16.78 - 17.28°.
The X-ray powder diffraction (XRD) has been measured in the reflection mode at 295 K using CuKal as radiation source in the range 2-50 ° 2 theta.
All the details are already discussed above in great details for the formation of the 7-dehydrocholesterol-hemimethanolate.
Said composition is particularly free of 7-dehydrocholesterol ansolvate. Hence, in the powder X-ray diffractogram (XRD) of said composition particularly no significant, preferably no, 2 theta maxima in the range of
2.61 - 2.91 °,
4.55 - 4.85°,
9.19 - 9.49°, and
16.33 - 16.63°
are detected.
As mentioned above, 7-dehydrocholesterol-hemimethanolate shows an increased storage stability, respectively a decrease degradation, as compared to 7-dehydrocholesterol.
Therefore, it is very advantageous to store and to transport 7-dehydrocho- lesterol-hemimethanolate rather than 7-dehydrocholesterol.
A "package" (in German " Packung ") as defined in this document is the combined physical object consisting of a packaging and the packaged good.
The "packaging" (in German "Verpackung"), as defined in this document, also referred as "containment", is the physical object which has an inner hollow space which serves to take up a packaged good and is a physical barrier towards the outer space of the packaging and the environment around the packaging respectively the package. A "transport packaging" is any packaging which is suitable for transport purposes.
The "packaged good" (in German " Packgut ") as defined in this document is the material which is stored in the hollow space of the packaging.
Hence, in a further aspect, the invention relates to a package (1 ) consisting of a transport packaging (2) and 7-dehydrocholesterol-hemimethano- late, as already described above in great detail, as a packaged good (3) or part of the packaged good (3), which is localized in the inner space of the transport packaging (2).
The transport packaging is any packaging used for transport. Examples for such packaging are bags, big bags, barrels, canister, drums, cans, bottles, containers, tanks. The transport packaging is preferably sealed and more preferably made out of plastic or metal or of a composite material, particularly a metalized polymer material such as a foil or a paper or cardboard coated by metal or plastic film.
In one of the embodiments, the transport packaging consists of a sealable packaging, i.e. it has at least one opening, and a seal. The seal can be part of the sealable packaging, e.g. linked by a flexible part, or be a separate part. The sealable packaging is filled by the packaging good and then the seal is sealing the opening in the sealable packaging. After the transport of the package to a different location, the seal is removed and the packaging good can be partially or completely removed from the packaging. Preferably the seal can be re-used for sealing the packaging again. Non-limiting examples for seals are caps, lids, valves, cover plates or adhesive foils.
A specific example for such a preferred embodiment is a bottle ("sealable packaging") which a cap ("seal"). 7-dehydrocholesterol-hemimethanolate can be filled into the opening of the bottle into the inside of the bottle. A cap is put, preferable screwed, onto the bottle so that the bottle is completely sealed. After the transport, e.g. shipping, of the sealed bottle filled with 7-dehydrocholesterol- hemimethanolate ("package") to a different location, the cap can be removed, the 7-dehydrocholesterol-hemimethanolate can be taken out as packaged goof from the bottle. The open bottle can be closed again by putting the cap again onto the open bottle.
In another embodiment, 7-dehydrocholesterol-hemimethanolate is put as packaged good inside the packaging through a temporary opening and then sealed for transport, for example by welding or gluing. After the transport of the package to a different location, the package is broken and the packaging good can be partially or completely removed from the packaging.
A specific example for such a preferred embodiment is a bag which has an opening. 7-dehydrocholesterol-hemimethanolate can be filled into the opening of the bag which can be closed, e.g. by thermoplastic welding, to seal the packing. After transport, e.g. shipping, of the sealed bag filled with 7-dehydrocholesterol- hemimethanolate ("package") to a different location, bag can be opened, for example by a knife, so that 7-dehydrocholesterol-hemimethanolate can be taken out as packaged good from the bag.
The 7-dehydrocholesterol-hemimethanolate is placed inside the
packaging prior to the transport. Typically, the cavity, i.e. the inner space of the transport packaging, is not completely filled with 7-dehydrocholesterol-hemi- methanolate. Therefore, typically a part (e.g. up to 10 %, sometimes up to 20 % by volume) of the volume of the inner space of the transport packaging is filled up with air.
The packaging is suitable for transport.
The transport is typically a transport by car, truck, ship or plane. The invention is very advantageous for long distance transports such as
intercontinental transports. It is particularly also very advantageous for transports of several days to months, particularly in or through tropic climate zones.
The increased storage stability, respectively decreased degradation, can be particularly advantageous in that the needs of special conditions for transport such as cooling may be strongly reduced or even removed when the method of the present invention is used.
It is important to realize that when 7-dehydrocholesterol-hemimethanolate is dissolved in a respective solvent, the crystal dissolves and dissociates into 7- dehydrocholesterol and methanol, and, hence, 7-dehydrocholesterol is released. Any solvent in which 7-dehydrocholesterol, respectively 7-dehydrocholesterol- hemimethanolate, can be dissolved or solubilized at ambient or elevated temperatures, typically up to 100°C, can be used as respective solvent.
Preferably, the respective solvent is selected from the group consisting of water, linear, branched or cyclic alcohols, preferably with less than 10 carbon atoms, acetone, methyl ethyl ketone, tetrahydrofuran (THF), methyl
tetrahydrofuran (2-MTHF), cyclopentyl methyl ether (CPME), methyl tert - butyl ether (MTBE), C1-4 alkyl esters of acetic acid, chlorobenzene, alkanes and mixtures thereof. Particularly preferred is the solvent selected from the group consisting of water, isopropanol, butanol, chlorobenzene and the mixtures thereof.
Therefore, 7-dehydrocholesterol is again available for further reaction. Flence, the method of stabilization, respectively of decreasing the degradation, of 7-dehydrocholesterol by formation of 7-dehydrocholesterol-hemimethanolate is a very efficient manner and is a way of regenerating the starting material, i.e. 7- dehydrocholesterol-hemimethanolate, again on demand very easily. Therefore, 7- dehydrocholesterol can be easily stored without significant degradation also over an extended period of time and only later can be transformed if desired further to other compounds such as vitamin D3 upon irradiation of 7-dehydrocholesterol.
Flence the method as described above comprises preferably a step g) which is performed after step b)
g) releasing 7-dehydro_icholesterol from 7-dehydrocholesterol- hemimethanolate.
The preferred method of releasing 7-dehydro_,cholesterol from 7- dehydrocholesterol-hemimethanolate is adding a solvent which is suitable for dissolving or solubilizing 7-dehydrocholesterol-hemimethanolate in order to dissociate 7-dehydrocholesterol-hemimethanolate into 7-dehydrocholesterol and methanol, and, hence, to release 7-dehydrocholesterol. Examples for such suitable solvents for the release are given above in this document.
This invention offers also a very efficient and economical way for the synthesis of vitamin D3 where the key intermediate 7-dehydrocholesterol is produced in a different place to where the 7-dehydrocholesterol is used for further chemical reactions. The invention allows particularly a transport between production sites without significant degradation during transport or storage.
In a preferred embodiment, an additional step a') is performed between step a) and b) and an additional step b' is performed in step b) after storage and before the release of 7-dehydrcncholesterol from 7-dehydrocholesterol- hemimethanolate
a') preparing a package (1 ) consisting of a transport packaging (2) and 7-dehydro- cholesterol-hemimethanolate a as a packaged good (3) or part of the packaged good (3), which is localized in the inner space of the transport packaging (2) b'ίϋ') opening the package (1 ) and removing 7-dehydrocholesterol- hemimethanolate from the inner space of the transport packaging (2).
The details and preferred embodiments of the features of these steps have been discussed above in great detail.
Figures
Figure 1 shows a XRD of 7-dehydrocholesterol-hemimethanolate.
Figure 2 shows a XRD of of 7-dehydrocholesterol ansolvate.
Figure 3 shows a XRD of 7-dehydrocholesterol-hemimethanolate. Figure 3 is the same as figure 1 zoomed in the 2 theta range of 2-19°.
Figure 4 shows a XRD of of 7-dehydrocholesterol ansolvate. Figure 4 is the same as figure 2 zoomed in the 2 theta range of 2-19°.
Figure 5 shows a representation of the ratio DHC20w/DHCo versus MeOH/DHC before storage (see examples). Figure 6 shows the representation of the crystal structure of 7-dehydrocholesterol- hemimethanolate as determined by using X-ray diffraction.
Figure 7 shows details about the bond length and angles within the crystals of 7- dehydrocholesterol-hemimethanolate as determined by using X-ray diffraction.
Figure 8 shows a schematic representation of a package (1 ) which consists of a transport packaging (2) and a packaged good (3).
The packaged good (3), i.e. 7-dehydrocholesterol-hemimethanolate, is localized in the inner space of the transport packaging (2). The inner space is not completely filled with 7-dehydrocholesterol-hemimethanolate. The remaining volume is filled with air.
Figure 8a shows a schematic representation of a transport packaging (2) of figure 8, which has an inner space (4). The inner space (4) can be filled at least partially with the packaging good, i.e. 7-dehydrocholesterol-hemimethanolate, to form a package (1 ) as shown in figure 8.
Figure 9 shows a schematic representation of one embodiments of a package (1 ) which consists of a transport packaging (2) and a packaged good (3). The transport packaging consists of a sealable container (6) and a seal (5).
The packaged good (3), i.e. 7-dehydrocholesterol-hemimethanolate, is localized in the inner space of the transport packaging (2). The inner space is not completely filled with 7-dehydrocholesterol-hemimethanolate. The remaining volume is filled with air.
Figure 9a shows a schematic representation of such a transport packaging (2) of figure 9. The sealable container (6) has an opening through which the packaged good (3), i.e. 7-dehydrocholesterol-hemimethanolate, can be put into the inner space (4) of the sealable container (6). After a partially filling of the cavity, i.e. the inner space (4), the seal (5) can be put onto the opening of the sealable container (6) to seal the packing and to form a package (1 ) as shown in figure 9.
List of reference signs
1 Package (German: Packung)
2 Transport packaging (German: Verpackung)
3 Packaged good (German: Packgut )
4 Inner space of the transport packing (2)
5 Seal (German: Verschluss)
6 Sealable container (German: verschliessbarer Behalter)
Examples
The present invention is further illustrated by the following experiments.
Determination of 7-dehvdrocholesterol-hemimethanolate
The amount of 7-dehydrocholesterol in a sample has been determined by High-Performance Liquid Chromatography using a HPLC Agilent 1200 with a HPLC column Supelcosil ABZ+/Sigma of 250 mm length, 4.6 mm internal diameter, 5 micrometre particle size, measured at 30°C, using a detector DAD at wavelength of 212 nm, 270 nm and 300nm. The eluent was acetonitrile (A) / methyl tert. -butyl ether (B) in a gradient program:
0 min A/B= 70/30 1 ml/m in
25 min A/B= 50/50 1 ml/min
28 min A/B= 90/10 1 ml/min
30 min A/B= 90/10 1 ml/min
The calibration has been performed by dissolving 5 exactly weighed samples of the crystal in the range of 1 to 20 mg in a solvent consisting of acetonitrile / methyl tert. -butyl ether 60/40.
Determination of methanol
Methanol in a sample has been determined by Gas Chromatography using a GC Agilent Technologies 1890, with a GC column Rtx-1 , Restek, of 30 m length, 0.32 mm inner diameter, 5 micrometre film thickness, using hydrogen as carrier gas and a constant flow of 2.5 ml/min, injector 300°C, split injection mode (ratio 1/40) , injection volume of 1 microliter, using a FID detector at 250°C, a nitrogen flow rate of 20 mL/min flow rate, and a calibration with N-Methyl-2- pyrrolidone (NMP). The oven temperature is initially 40°C, held for 2 minutes,
increased to 140°C over 12.5 minutes, then increased to 220°C over 1.6 minutes and held for 10 minutes.
Formation of 7-dehvdrocholesterol-hemimethanolate
7-dehydrocholesterol has been dissolved in a mixture of hexane and methanol under stirring and heating to 40°C. Then the solution was cooled to 0°C over several hours under stirring so that white crystals have been precipitated. These crystals have been filtered over a Nutsche filter.
The filter cake had a wet appearance due to excess methanol. Hence, some air has been flowed through the filter cake to remove the majority of excess of methanol to yield visually dry 7-dehydrocholesterol-hemimethanolate crystals.
Drying
A sample 1 of the crystals has been isolated and its ratio of 7-dehydro cholesterol to methanol has been determined using the method shown above.
Then the crystals from the filter cake have been put in a round bottom flask and have been exposed to a vacuum of 5 mbara at a heating temperature of 60°C. After different specific times of drying, individual samples (Ref. 1-4) have been taken and the amounts of 7-dehydrocholesterol ( DHCo ) and methanol have been determined according the method shown above. Sample 2 has been exposed only for a very short time to these drying conditions.
Storage
For the storage test, all samples (1 ml) have then been filled into 10 ml brown glass vials which then have been closed by a plastic cap. The samples then have been stored during 20 weeks at a temperature of 4°C in contact with air in the vial. Then the amount of 7-dehydrocholesterol ( DHC20W ) has been determined using the method shown above.
The results are compiled in table 1.
Table 1 : Storage stability, resp. degradation, of 7-dehydrocholesterol- hemimethanolate.
1: no methanol can be detected.
It is important to stress that it was observed that the sample 1 showed a molar ratio of DHC/MeOH of 2.0 after storage. This corresponds exactly to the molar ration of DHC/MeOH of 7-dehydrocholesterol-hemimethanolate. Hence, it can be concluded that in sample 1 the excess of methanol has been completely removed during storage to form the storage stable of 7-dehydrocholesterol-hemi- methanolate.
Figure 5 shows a graphic representation of the molar ratio of MeOH to DHC versus the ratio of DHC20W to DHCo. In this representation the stability effect, respectively the impact on degradation, can be visualized very clearly.
It shows clearly that 7-dehydrocholesterol-hemimethanolate is very storage stable, whereas when a ratio of MeOH/DHC being significantly lower than 0.5 is obtained, the stability decreases very strongly. This means that 7- dehydrocholesterol-hemimethanolate has a very low degradation, whereas when a ratio of MeOH/DHC being significantly lower than 0.5 is obtained, the
degradation increases very strongly. The 7-dehydrocholesterol ansolvate having a MeOH/DHC-ratio of 0 is very unstable, i.e. after 20 weeks storage at 4°C in contact with air only about 10 % of the amount of DHC present before storage remains, i.e. about 90 % of the DHC has been degraded. DHC, i.e. in the form of the 7-dehydrocholesterol ansolvate, exhibits an extremely high degradation.
Crystal structures
The 7-dehydrocholesterol-hemimethanolate and the 7-dehydrocholesterol ansolvate ( Ref.4 ) have been investigated by XRD before storage. The X-ray powder diffractogram (XRD) has been measured in the reflection mode at 295 K
using CuKal as radiation source. The measurement has been carried out in the range of 2 - 50° 2Q.
The diffractograms are shown in figure 1 and figure 3 for 7- dehydrocholesterol-hemimethanolate and in figure 2 and figure 4 for 7- dehydrocholesterol ansolvate.
Table 2. Characteristic maxima of the XRD of 7-dehydrocholesterol- hemimethanolate.
Table 3. Characteristic maxima of the XRD of 7-dehydrocholesterol- ansolvate.
The XRD of 7-dehydrocholesterol-hemimethanolate remains unchanged after storage.
Single crystals of 7-dehydrocholesterol-hemimethanolate have been measured using X-ray diffraction at 123 K. These measurements show that 7- dehydrocholesterol-hemimethanolate crystallizes triclinically, in the space group P1 and that four molecules of 7-dehydrocholesterol are present in an asymmetric unit alongside with two molecules of methanol. Particularly, the following crystal parameters have been found:
a 6.3895(5) A
b 20.3567(15) A
c 20.5862(15) A
a 110.584(3)°
b 94.222(3)°
g 97.884(3)°
V 2461.5(3) A3
Figure 6 shows the representation of the unit cell of 7-dehydrocholesterol- hemimethanolate showing the chains formed by hydrogen bonds. The unit cell is, in the case of the space group P1 , identical to the asymmetric unit. In table 4 the atoms near acceptors (A) and donors (D) are listed with the respective bond lengths and angles. The D...A distances are between 2.656(2) and 2.695(2) Angstrom. The D-FI...A angles are, as expected for this kind of classical hydrogen bonds, between 169.0(20) and 177(2) degrees and can I be regarded as directional. Details about the hydrogen bond patterns can be seen in table 4, while figure 7 show the two chains built by the hydrogen bonds one by one. Particularly, the positioning of the methanol (see 057 and 0115) in the crystal system is shown.
Table 4. Bond distances and angles in the crystal of structure of 7- dehydrocholesterol-hemimethanolate Figure 7 shows a representation of the two chains being formed by the hydrogen bonds in the structure of 7-dehydrocholesterol-hemimethanolate crystals.
Claims
1. 7-Dehydrocholesterol-hemimethanolate.
2. Method of decreasing the degradation of 7-dehydrocholesterol upon storage of at least 1 week, said method comprises the steps
a) forming 7-dehydrocholesterol-hemimethanolate;
b) storing 7-dehydrocholesterol-hemimethanolate for an extended time
period which is at least 1 week, preferably at least 4 weeks, more preferably at least 20 weeks, before releasing 7-dehydrcncholesterol from 7-dehydrocholesterol-hemimethanolate.
3. The 7-dehydrocholesterol-hemimethanolate according to claim 1 or the
method according to claim 2, characterized in that the 7-dehydrocholesterol- hemimethanolate exhibits maxima of the intensities (in counts per second) measured using X-ray powder diffraction (XRD) in the 2 theta (2Q) range of
4.98 - 5.28 °,
8.93 - 9.23°,
10.14 - 10.44°,
12.46 - 12.76°, and
16.78 - 17.28°;
whereas the X-ray powder diffraction (XRD) has been measured in the reflection mode at 295 K using CuKal as radiation source.
4. The 7-dehydrocholesterol-hemimethanolate according to claim 3 or the
method according to claim 3, characterized in that the 2 theta maximum in the range of 16.78 - 17.28° has the highest intensity (in counts per second) in the whole measured powder X-ray diffractogram (XRD) of the composition.
5. Method according to anyone of the preceding claims 2-4 characterized in that the formation of 7-dehydrocholesterol-hemimethanolate in step a is performed by the subsequent steps
a) providing an initial composition consisting essentially of a mixture of 7- dehydrocholesterol and methanol wherein the molar ratio of 7- dehydrocholesterol to methanol is between 1.8:1 and 0.1 :1
b) removing methanol from the mixture of step a) to an extend that a composition is formed in which the molar ratio of 7-dehydrocholesterol and methanol is strictly between 2.1 :1 and 1.9:1 , preferably 2:1 ;
wherein the amounts of 7-dehydrocholesterol are determined by High- Performance Liquid Chromatography (HPLC) and the amounts of methanol are determined by Gas Chromatography (GC).
6. Method according to claim 5 characterized in that the degradation of 7- dehydrocholesterol is characterized in that the weight ratio DHC20wl DHCo is more than 0.80, particularly more than 0.90,
wherein
DHC20W is the amount of 7-dehydrocholesterol after storage of 7- dehydrocholesterol for 20 weeks;
and DHCo is the amount of 7-dehydrocholesterol before storage.
7. Method according to claim 5 or 6, characterized in that the methanol is
removed by heating under reduced pressure.
8. Method according to anyone of the preceding claims 5-7, characterized in that the methanol is removed by heating to a temperature of between 50 and
80°C, particularly of between 60 and 70°C, and a pressure of between 0.1 and 15 mbara, particularly of between 1 and 10 mbara.
9. Method according to anyone of the preceding claims 1 -8, characterized in that the method comprises a step g) which is performed after step b) g) releasing 7-dehydro_icholesterol from 7-dehydrocholesterol- hemimethanolate.
10. Composition obtained from the removing of methanol from an initial
composition consisting essentially of a mixture of 7-dehydrocholesterol and methanol,
wherein the mixture of 7-dehydrocholesterol and methanol with an initial molar ratio of 7-dehydrocholesterol to methanol is 1.8:1 and 0.1 :1 , to a final molar ratio of 7-dehydrocholesterol to methanol of between 2.1 :1 and 1.9:1 , preferable 2:1 ;
wherein the amounts of 7-dehydrocholesterol are determined by High-Perfor mance Liquid Chromatography (HPLC) and the amounts of methanol are de termined by Gas Chromatography (GC) characterized in that a powder X-ray diffractogram (XRD) of said composition shows 2 theta maxima in the range of 4.98 - 5.28 °,
8.93 - 9.23°,
10.14 - 10.44°,
12.46 - 12.76°, and
16.78 - 17.28°;
whereas the powder X-ray diffractogram (XRD) has been measured in the reflection mode at 295 K using CuKcd as radiation source.
11. Composition according to claim 10 characterized in that the 2 theta
maximum in the range of 16.78 - 17.28° has the highest intensity (in counts per second) in the whole measured powder X-ray diffractogram (XRD) of the composition.
12. Composition according to claim 10 or 11 characterized in that the intensity (in counts per second) of the 2 theta maximum in the range 4.98 - 5.28 ° is at least 10 %, particularly at least 20 %, of the intensity (in counts per second) of the 2 theta maximum in the range of 16.78 - 17.28°.
13. Composition according to claim 10 or 11 or 12, characterized in that the
intensity (in counts per second) of the 2 theta maximum in the range of 12.46 - 12.76° at least 10 %, preferably at least 20 %, of the intensity (in counts per second) of the 2 theta maximum in the range of 4.98 - 5.28 °.
14. Composition according to anyone of the preceding claims 10 - 13, characteri zed in that the methanol is removed by heating to a temperature of between 50 and 80°C, particularly of between 60 and 70°C, and a pressure of between 0.1 and 15 mbara, particularly of between 1 and 10 mbara.
15. Package (1 ) consisting of a transport packaging (2) and 7-dehydro- cholesterol-hemimethanolate according to any one of the preceding claims 1 - 4) as a packaged good (3) or part of the packaged good (3), which is localized in the inner space of the transport packaging (2).
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| CN201980075502.1A CN113015739A (en) | 2018-11-19 | 2019-11-18 | 7-dehydrocholesterol-hemimethanolic compounds |
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| EP18206891 | 2018-11-19 | ||
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2434015A (en) * | 1942-11-21 | 1948-01-06 | Du Pont | Stable provitamin d composition |
| GB834773A (en) * | 1957-11-29 | 1960-05-11 | Nopco Chem Co | Purification of irradiated 7-dehydrocholesterol |
| US3100783A (en) * | 1958-06-26 | 1963-08-13 | Philips Corp | Method of stabilizing crystalline compounds against oxidation |
| US3367950A (en) * | 1964-12-19 | 1968-02-06 | Salwa Henryk Stanislaw | Process for the isolation of cholecalciferol from a mixture obtained on irradiation of 7-dehydrocholesterol |
| CN104017042A (en) * | 2014-05-19 | 2014-09-03 | 河南利伟生物药业股份有限公司 | Separation purification method for 7-dehydrocholesterol |
| WO2015170341A1 (en) * | 2014-05-06 | 2015-11-12 | Fermenta Biotech Limited | Process for preparation of 7-dehydrocholesterol |
-
2019
- 2019-11-18 WO PCT/EP2019/081599 patent/WO2020104353A1/en active Application Filing
- 2019-11-18 CN CN201980075502.1A patent/CN113015739A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2434015A (en) * | 1942-11-21 | 1948-01-06 | Du Pont | Stable provitamin d composition |
| GB834773A (en) * | 1957-11-29 | 1960-05-11 | Nopco Chem Co | Purification of irradiated 7-dehydrocholesterol |
| US3100783A (en) * | 1958-06-26 | 1963-08-13 | Philips Corp | Method of stabilizing crystalline compounds against oxidation |
| US3367950A (en) * | 1964-12-19 | 1968-02-06 | Salwa Henryk Stanislaw | Process for the isolation of cholecalciferol from a mixture obtained on irradiation of 7-dehydrocholesterol |
| WO2015170341A1 (en) * | 2014-05-06 | 2015-11-12 | Fermenta Biotech Limited | Process for preparation of 7-dehydrocholesterol |
| CN104017042A (en) * | 2014-05-19 | 2014-09-03 | 河南利伟生物药业股份有限公司 | Separation purification method for 7-dehydrocholesterol |
Non-Patent Citations (1)
| Title |
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| P. DIMARTINO ET AL., J. THERMAL ANAL., vol. 48, 1997, pages 447 - 458 |
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