CN115181046A - Eutectic crystal of vitamin D3 and L-menthol and preparation method and application thereof - Google Patents

Eutectic crystal of vitamin D3 and L-menthol and preparation method and application thereof Download PDF

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CN115181046A
CN115181046A CN202210884097.1A CN202210884097A CN115181046A CN 115181046 A CN115181046 A CN 115181046A CN 202210884097 A CN202210884097 A CN 202210884097A CN 115181046 A CN115181046 A CN 115181046A
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menthol
vitamin
crystal
eutectic
powder
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CN115181046B (en
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梅雪锋
刘立宇
王建荣
陆鹂烨
张在永
丁翘策
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
    • C07C35/12—Menthol
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

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Abstract

The invention relates to vitamin D 3 A co-crystal with L-menthol, a preparation method and application thereof. In the co-crystal, vitamin D 3 The molar ratio of L-menthol to water molecules is 1. Vitamin D is analyzed by means of X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry and the like 3 The eutectic crystal with L-menthol is comprehensively characterized, and the vitamin D can be obviously improved by the eutectic crystal 3 Can be absorbed in vivo. In addition, after the eutectic is formed, the melting point of the eutectic is improved by 28 ℃ compared with that of the L-menthol, and the volatility of the L-menthol is also obviously reduced. The stability results show that the storage stability of the L-menthol in the cocrystal is improved to a certain extent compared with the raw material.

Description

Eutectic crystal of vitamin D3 and L-menthol and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry and crystallization processes, in particular to vitamin D 3 Eutectic crystal with L-menthol and preparation method and application thereof.
Background
Vitamin D 3 (Vitamin D 3 ) The chemical name is: 9, 10-secocholest-5, 7,10 (19) -trien-3-ol, molecular formula C 27 H 44 And O. The structure is as follows:
Figure BDA0003765303420000011
vitamin D is a group of fat-soluble vitamins essential to sustain higher animal life: vitamin D and its metabolite can regulate calcium and phosphorus balance in higher animal body, and is favorable to formation and calcification of new bone; vitamin D is also a good selective immunomodulator, and shows potential clinical application value in the treatment fields of cancers, immunotherapy, cardiovascular diseases, metabolic syndrome and the like. Of the vitamin D compounds, vitamin D 3 Is considered to have the highest physiological effect. Vitamin D 3 After entering into the body, the vitamin D is converted into 1, 25-dihydroxy vitamin D under the action of liver, kidney and mitochondrial hydroxylase 3 (calcifediol), bioactive, and calcifediol water in plasma is routinely used to assess whether vitamin D is deficient in vivo. When the level of calcifediol in serum is more than or equal to 30ng/mL, which reflects better intake or synthesis of vitamin D and can reduce the risk of fracture, many people must take more than 1000IU (25 mug) of vitamin D per day to achieve this level of vitamin D; the osteoporosis association of canada recommends that adults should consume at least 800IU per day; the chinese resident dietary guideline (version 2013) raised the upper limit from the previous version 800IU to 2000IU. Therefore, the vitamin D has wide prospect in the pharmaceutical industry, the food additive industry and the feed industry.
However, the requirement of the calcifediol and the vitamin in the clinical use at presentElement D 3 The combination is used for improving the level of vitamin D in the body and achieving the purpose of treating osteoporosis. But vitamin D 3 And different specifications of ossifying glycol are difficult to match and use, and the compliance of patients is poor. In addition, the exposure to light, oxygen, temperature, and other environmental factors can cause vitamin D 3 And degradation impurities are generated, and the components cannot achieve the treatment effect but cause side effects to damage the organism to a certain extent.
L-Menthol (L-Menthol), chemical name: (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexanol having a molecular formula of C 10 H 20 And (O). The structure is as follows:
Figure BDA0003765303420000021
l-menthol is an edible spice which is allowed to be used by China, has special cool fragrance or aroma, can play the roles of easing pain, relieving itching and sterilizing, and is widely applied to the industries of medicines, tobaccos, foods and daily chemicals. It can be extracted from Mentha haplocalyx of Labiatae, and the market for synthetic menthol is increasing year by year. The L-menthol is colorless needle crystal, has high volatility (vapor pressure of 5.48Pa at 25 ℃) and low melting point (41-43 ℃), is easy to lose in the production and storage process, and affects the product quality.
At present, microcapsule technology or embedding method is mainly adopted to improve the stability of the L-menthol (for example, in the prior art, CN111885920A adopts cyclodextrin for embedding; CN101296627A adopts polyvinyl acetate, and CN111992153A adopts modified starch and lipid for encapsulation). However, the above methods need to be improved in terms of loading and embedding rate, and have a limited application range: for example, cyclodextrin inclusion compound can escape to a certain extent at about 40 deg.C, and the stability of the embedded product of water-soluble inclusion material (such as maltodextrin, acacia, modified starch, etc.) can be rapidly reduced under the condition of more than 50% of relative humidity. The adsorption reported in CN104152267A and the eutectic reported in CN101677926A have certain difficulties in quality control.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
One of the objectives of the present invention is to provide a vitamin D 3 Co-crystal with L-menthol.
The second purpose of the invention is to provide the vitamin D 3 A method for preparing a co-crystal with L-menthol.
The third object of the present invention is to provide a composition containing vitamin D 3 A product of co-crystals with L-menthol.
The fourth object of the present invention is to provide the vitamin D 3 Use of co-crystals with L-menthol.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
pharmaceutical co-crystals refer to the association of a pharmaceutically active ingredient (API) in the same crystal lattice with other physiologically acceptable ligands (CCF), such as acids, bases, salts, molecules of non-ionic compounds, etc., linked by hydrogen bonds, pi-pi stacking, van der waals forces and other non-covalent bonds. The design of molecular self-assembly based on intermolecular interaction force can realize the improvement of physicochemical properties (such as stability, dissolution property, bioavailability, mechanical properties, etc.) of the drug. For vitamin D without an ionization center 3 And L-menthol molecules, the eutectic design based on cyclohexanol hydrogen bond supramolecular synthon is an effective means for improving the physicochemical properties of the L-menthol molecules.
The inventors aimed at clinical use of vitamin D 3 The problems of difficult rapid reaching of the therapeutic level and poor stability of the L-menthol in the production and storage processes are solved, and the vitamin D is synthesized by a eutectic technical means 3 And a water molecule molar ratio of 1 3 The bioavailability is effectively improved, and the storage stability of the L-menthol is obviously enhanced.
In a first aspect, the present invention provides a vitamin D 3 Co-crystals with L-menthol in which vitamin D is present 3 The molar ratio of L-menthol to water molecules is 1. In particular, the vitamin D 3 Co-crystals with L-menthol have an X-ray powder diffraction pattern at least at 2 theta diffraction anglesCharacteristic peaks are arranged at 4.5 +/-0.2 degrees, 6.5 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.7 +/-0.2 degrees, 21.7 +/-0.2 degrees.
Preferably, said vitamin D 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol further has characteristic peaks at least at 2 theta diffraction angles of 11.9 + -0.2 DEG, 13.2 + -0.2 DEG, and 19.6 + -0.2 deg.
More preferably, the vitamin D 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol further has characteristic peaks at least at 2 theta diffraction angles of 11.4 + -0.2 DEG, 13.7 + -0.2 DEG, 17.5 + -0.2 DEG, and 18.2 + -0.2 deg.
In a specific embodiment, the vitamin D 3 The X-ray powder diffraction pattern of the eutectic with L-menthol has at least the characteristic peaks at 2 theta diffraction angles of 4.5 +/-0.2 degrees, 6.5 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.2 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.4 +/-0.2 degrees, 11.9 +/-0.2 degrees, 13.2 +/-0.2 degrees, 13.7 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.6 +/-0.2 degrees, 23.6 +/-0.2 degrees, 24.5 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.9 +/-0.2 degrees, 27.2 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.6 +/-0.2 degrees, 2.2 degrees, 9 +/-0.2.2 degrees, 2 degrees, and 29.2 degrees.
In a specific embodiment, the vitamin D 3 The co-crystal with L-menthol has an X-ray powder diffraction pattern substantially as shown in figure 2.
The 2 theta angle and relative intensity of each peak on an X-ray powder diffraction (XRPD) pattern will vary depending on the measurement conditions, typically the 2 theta angle will vary within 0.2 °, but can also slightly exceed this range, as will be appreciated by those skilled in the art, the relative intensity of diffraction may depend, for example, on the sample formulation or the equipment used.
Preferably, vitamin D of the present invention 3 The eutectic crystal with L-menthol is monoclinic system, and the space group is P2 1 The unit cell parameters are:
Figure BDA0003765303420000031
α =90 °; β =103.318 (4) °; γ =90 °; cell volume of
Figure BDA0003765303420000032
It should be noted that the parentheses indicate the deviation of the last bit calculated by the cell parameter program, for example, 15.569 (2) indicates 15.569 ± 0.002.
In particular, the vitamin D 3 During the process that the eutectic crystal with the L-menthol is heated to 400 ℃ from the room temperature of 25 +/-0.2 ℃ at the heating rate of 10 ℃/min, the weight loss is 31 percent when the eutectic crystal is heated to 196.1 +/-0.2 ℃, and the weight loss is 99 percent when the eutectic crystal is continuously heated to 400 +/-0.2 ℃. More particularly, said vitamin D 3 The co-crystal with L-menthol has a thermogravimetric analysis substantially as shown in figure 3.
In particular, the vitamin D 3 The Differential Scanning Calorimetry (DSC) spectrum of the eutectic crystal with the L-menthol has an endothermic peak at 53.1-78.0 ℃, the peak temperature is 70.9 +/-0.2 ℃, and the temperature T is onset The value (initial temperature) was 68.9. + -. 0.2 ℃. More particularly, said vitamin D 3 The co-crystal with L-menthol has a differential scanning calorimetry spectrum substantially as shown in figure 4.
In a second aspect, the invention relates to a simple, practical, easily scalable and reproducible vitamin D 3 A method for preparing co-crystal with L-menthol comprises adding vitamin D 3 Contacting with L-menthol in a molecular state and then crystallizing.
Contacting in a molecular state may include, but is not limited to, a solution crystallization method, a solid-state milling method, and the like. The solution crystallization method refers to the synthesis of the co-crystal in solution, and comprises slow volatilization, cooling crystallization, anti-solvent crystallization, suspension crystallization and the like. In the solution crystallization method, a main drug and ligand molecules can form new non-covalent interaction in a proper solution system to obtain eutectic molecules; the solution reaction system comprises starting materials and eutectic molecules, and the eutectic molecules are precipitated by means of evaporation, cooling and addition of an anti-solvent when reaching supersaturation degree in the solvent system, and meanwhile, the starting material molecules are promoted to continuously interact to form eutectic precipitation; in a suspension crystallization system, undissolved starting materials exist in the system, each component has solid-liquid phase dynamic balance, the balance can be pushed to move towards one direction by the formation of eutectic, and in the process of establishing new balance, raw materials are continuously dissolved and the eutectic is continuously separated out. The solid-state grinding method mainly comprises solid dry grinding and solvent-assisted grinding. The dry grinding is to grind the mixture of the main drug and the ligand to obtain the eutectic product, and the solution-assisted grinding is to improve the grinding efficiency by adding a small amount of solvent in the grinding process. Means of solid state milling may include, but are not limited to, ball milling or high speed shearing.
In particular, vitamin D 3 The method for preparing the co-crystal with L-menthol may be one of the following methods:
the method comprises the following steps: vitamin D 3 Cooling and crystallizing with L-menthol in organic solvent or mixed solvent of organic solvent and water to obtain vitamin D 3 Co-crystal with L-menthol.
In particular, the first method comprises the following steps:
(a1) Separately weighing vitamin D 3 And powder of L-menthol;
(b1) Dissolving the powder obtained in step (a 1) in an organic solvent or a mixed solvent of an organic solvent and water at a relatively high temperature to form vitamin D 3 And an unsaturated solution of L-menthol;
(c1) Cooling the unsaturated solution obtained in the step (b 1) from a higher temperature to a lower temperature to precipitate vitamin D 3 And L-menthol;
(d1) Separating to obtain vitamin D 3 Co-crystals with L-menthol;
in particular, vitamin D in step (a 1) 3 And the molar ratio of L-menthol powder fluctuates within a range having no effect on the quality of the co-crystal, which is 1;
specifically, the organic solvent in step (b 1) is selected from one or more of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, diethyl ether and n-hexane;
specifically, the volume ratio of the organic solvent to the water in the mixed solvent of the organic solvent and the water in the step (b 1) is 8;
specifically, the higher temperature in the step (b 1) is 70-room temperature;
specifically, the water used is purified water;
in particular, a lower temperature in step (c 1) means a temperature lower than the higher temperature, preferably between room temperature and-20 ℃;
specifically, the separation of step (d 1) comprises: filtration, or, centrifugation and filtration;
specifically, the separated liquid solution can be further evaporated to dryness after separation to obtain vitamin D 3 Co-crystals with L-menthol.
The second method comprises the following steps: vitamin D 3 Crystallizing with L-menthol in organic solvent or mixed solvent of organic solvent and water to obtain vitamin D 3 Co-crystal with L-menthol.
In particular, method two comprises the following steps:
(a2) Separately weighing vitamin D 3 And powder of L-menthol;
(b2) Dissolving the powder obtained in the step (a 2) in a good solvent until the solid is completely dissolved to form vitamin D 3 And an unsaturated solution of L-menthol;
(c2) Dropwise adding a poor solvent into the unsaturated solution obtained in the step (b 2) until precipitates are separated out;
(d2) Separating the precipitate to obtain vitamin D 3 Co-crystals with L-menthol;
in particular, vitamin D in step (a 2) 3 And the molar ratio of L-menthol powder fluctuates within a range having no effect on the quality of the co-crystal, which is 1;
specifically, the good solvent of step (b 2) comprises menthol and vitamin D 3 An organic solvent or a mixed solvent of an organic solvent and water, the solubility of which is 5mg/mL or more; the organic solvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, diethyl ether, n-hexane and n-heptane; mixed solution of organic solvent and waterWhen the agent is used as a good solvent, the volume ratio of the organic solvent to water is 8;
specifically, the poor solvent of step (c 2) is selected from water, nitromethane, ethylene glycol or vitamin D 3 And a corresponding solvent having a solubility of L-menthol lower than that of the good solvent selected in step (b 2), e.g., a corresponding solvent having a water content ratio higher than that of the aqueous mixed solvent used in step (b 2);
specifically, the water used is purified water;
specifically, the separating of step (d 2) comprises: filtration, or, centrifugation and filtration;
specifically, the separated liquid solution can be further volatilized to obtain vitamin D 3 Co-crystals with L-menthol.
The third method comprises the following steps: mixing vitamin D 3 Performing mechanochemical reaction with L-menthol to obtain vitamin D 3 And co-crystals of L-menthol.
Mechanochemical reaction (Mechanochemistry) is that components interact with each other in molecules during grinding or mechanical mixing, and the components exist in a fixed stoichiometric ratio in a crystal lattice, so that a eutectic is obtained.
In particular, method three comprises the following steps:
(a3) Separately weighing vitamin D 3 And powder of L-menthol;
(b3) Adding the powder obtained in the step (a 3) into a mechanical grinding device, fully contacting the powder through mechanical force, and obtaining the vitamin D after all reactions 3 Co-crystal with L-menthol.
In particular, vitamin D in step (a 3) 3 1 to L-menthol powder in a molar ratio of 1;
specifically, the mechanical milling apparatus of step (b 3) is selected from one of a ball mill, a pulverizer, a mixer, and a stirring device. Preferably, a ball mill is adopted, an auxiliary solvent can be added in the ball milling process, and the auxiliary solvent is a mixed solvent of water and one or more of the following solvents: acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, n-heptane, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, ethanol, isopropanol, n-propanol and isoamyl alcohol. Preferably, the oscillation frequency is 5 to 60Hz, preferably 30Hz, and the oscillation time is 10 to 180 minutes, preferably 30 to 180 minutes.
The method four comprises the following steps: suspending vitamin D3 and L-menthol in organic solvent or mixed solvent of organic solvent and water for crystallization to obtain vitamin D 3 And co-crystals of L-menthol.
In particular, method four comprises the following steps:
(a4) Separately weighing vitamin D 3 And powder of L-menthol;
(b4) Suspending and balancing the powder in the step (a 4) in a glass vial in an organic solvent or a mixed solvent of the organic solvent and water for 8-36 hours;
(c4) Separating the suspended solid to obtain vitamin D 3 Co-crystals with L-menthol.
In particular, vitamin D in step (a 4) 3 And the molar ratio of L-menthol powder fluctuates within a range from 1;
specifically, the organic solvent in step (b 4) is selected from one or more of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, diethyl ether, n-hexane, n-heptane, nitromethane, cyclohexane and ethylene glycol;
specifically, the volume ratio of the organic solvent to water in step (b 4) is 4;
specifically, the water used is purified water;
specifically, the separating of step (c 4) comprises: filtration, or, centrifugation and filtration.
Specifically, the separated liquid solution can be further volatilized to obtain vitamin D 3 Co-crystals with L-menthol.
It should be noted that the water content of the monohydrate eutectic is low, at 3.2%, and that when the eutectic is prepared in large quantities by milling, a small amount of water is added (for example, when the eutectic is prepared by milling 2.7g, the water content is 0.09g, i.e., 90 μ L). In the case of the solution method or milligram-scale sample preparation, the hydrated eutectic can be obtained without adding extra water under the condition that the solvent contains a little water or under the condition of proper humidity.
In a third aspect, the present invention relates to a product, such as a nutraceutical, food, cosmetic, pharmaceutical, pharmaceutic adjuvant or feed, comprising vitamin D as described above 3 Co-crystals with L-menthol.
Other suitable materials required for the product may also be included in the product, for example, food products may include food ingredients and food acceptable edible food additives such as sweeteners, flavors, preservatives, flavoring agents, colorants, and the like; the cosmetic may contain cosmetically acceptable major ingredients and additives such as solvents, fragrances, preservatives, perfumes, colorants, and the like; the medicine can contain medicinal active ingredients and pharmaceutically acceptable auxiliary materials, such as carriers, diluents, adjuvants, coloring agents and the like; the feed may contain feed main materials such as soybean meal, hay, etc., and feed auxiliary materials acceptable in the feed such as sweeteners, flavors, preservatives, fragrances, colorants, etc., but the present invention is not limited thereto.
In a fourth aspect, the present invention relates to a vitamin D as described above 3 The eutectic crystal with L-menthol can be applied to health products, foods, cosmetics, medicines, pharmaceutic adjuvants or feeds.
Advantageous effects
The invention converts vitamin D into vitamin D 3 Vitamin D is synthesized by the technical means of eutectic crystal with L-menthol 3 The molar ratio of the L-menthol to the water molecule is 1 3 Bioavailability, and stability of L-menthol. Vitamin D 3 The eutectic crystallinity of the L-menthol crystal is higher, and the preparation method is simple, easy to amplify and good in repeatability.
The animal experiment results show that the vitamin D 3 The co-crystal with L-menthol can obviously improve vitamin D 3 The in vivo absorption of (2); compared with vitamin D 3 Raw materials for vitamin D 3 The in vivo blood concentration of the eutectic crystal with the L-menthol is higher, so the eutectic crystal has strong clinical application value. In addition, the method can be used for producing a composite materialAfter the eutectic is formed, the volatility of the L-menthol is obviously reduced, the melting point is improved, and the melting point of the eutectic is improved by 28 ℃ compared with that of the L-menthol. The long-term stability test and the accelerated stability test result show that the stability of the L-menthol in the eutectic is improved to a certain extent compared with the raw material. Thus, the present invention provides such vitamin D 3 The co-crystal with the L-menthol not only has the clinical application value of improving the treatment effect of vitamin D deficiency, but also can obviously improve the stability of the L-menthol in the production and storage processes.
The present invention has been described in detail hereinabove, but the above embodiments are merely illustrative in nature and are not intended to limit the present invention. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary or the following examples.
Unless expressly stated otherwise, a numerical range throughout this specification includes any sub-range therein and any numerical value incremented by the smallest sub-unit within a given value. Unless expressly stated otherwise, numerical values throughout this specification represent approximate measures or limitations to the extent that such deviations from the given values, as well as embodiments having approximately the stated values and having the exact values stated, are included. Other than in the operating examples provided at the end of the detailed description, all numbers expressing quantities or conditions of parameters (e.g., quantities or conditions) used in the specification (including the appended claims) are to be understood as being modified in all instances by the term "about" whether or not "about" actually appears before the number. "about" means that the numerical value so stated is allowed to be somewhat imprecise (with some approach to exactness in that value; about or reasonably close to that value; approximately). As used herein, "about" refers to at least variations that can be produced by ordinary methods of measuring and using such parameters, provided that the imprecision provided by "about" is not otherwise understood in the art with this ordinary meaning. For example, "about" can include variations of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%.
Drawings
FIG. 1 shows vitamin D of example 4 3 Single crystal structure (SC-XRD) pattern of co-crystals with L-menthol;
FIG. 2 shows vitamin D of example 1 3 An X-ray powder diffraction (XRPD) pattern of co-crystals with L-menthol;
FIG. 3 shows vitamin D of example 1 3 Thermogravimetric analysis (TG) of co-crystals with L-menthol;
FIG. 4 shows vitamin D of example 1 3 Differential Scanning Calorimetry (DSC) profile of co-crystals with L-menthol;
FIG. 5 shows vitamin D of example 1 3 Co-crystals with L-menthol and drug concentration profiles of L-menthol in blood at different times after oral administration (96 μ g/kg) in rats;
FIG. 6 shows L-menthol starting material and vitamin D of example 1 during isothermal thermogravimetric analysis 3 Weight loss curve of cocrystal with L-menthol (25 ℃);
FIG. 7 shows L-menthol starting material and vitamin D of example 1 during isothermal thermogravimetric analysis 3 Weight loss curve of cocrystal with L-menthol (40 ℃);
FIG. 8 shows L-menthol starting material and vitamin D of example 1 3 The retention rate of L-menthol in the eutectic crystal with L-menthol is 1 month and 2 months when the eutectic crystal is stored at 40 ℃ and 75% relative humidity under the condition of aluminum-plastic packaging.
Detailed Description
The present invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention.
Detection instrument and method
X-ray powder diffraction (XRPD) the instrument used was a Bruker D8 Advance diffractometer using Cu-Ka radiation
Figure BDA0003765303420000081
The voltage was 40 kv and the current was 40 ma. The instrument is used before using and the standard sample carried by the instrument is used for correcting peakA bit. The acquisition software used a Diffrac Plus XRD Commander and the analysis software used MDI Jade 6.0. The samples were placed on slides and tested at room temperature under the following detailed test conditions: 2 θ angular range: 3-40 degrees; step length: 0.02 degree; speed: 0.1 sec/step.
The X-ray single crystal diffractometer (SCXRD) is Bruker D8 VENTURE X-ray single crystal diffractometer adopting Mo-K alpha rays
Figure BDA0003765303420000082
The voltage was 50 kv and the current was 30 ma. The reduction and the structural analysis of the single crystal structural data are completed by two programs of SAINT-5.0 and SHELX-2014, and the SADABS program completes absorption correction. The coordinate of the non-hydrogen atom is obtained by a difference function method and a least square method, and the hydrogen atom is added at a proper position by theoretical calculation.
Thermogravimetric Analysis (TGA) data were collected from model TG20F3, a Tissus scientific instruments, germany, using NETZSCH-Proteus-6 as instrument control software and Proteus Analysis as Analysis software. The sample was warmed from room temperature to 400 ℃ at a warm-up rate of 10 ℃/min under the protection of 50mL/min dry nitrogen, and the weight change of the sample during the warm-up was recorded by the software.
Differential Scanning Calorimetry (DSC) data were collected from a TA instruments DSC Q2000 differential scanning calorimeter, thermal Advantage was used for instrument control software, and Universal Analysis was used for Analysis software. The sample was warmed from room temperature to 120 ℃ at a temperature ramp rate of 10 ℃/min under the protection of 50mL/min dry nitrogen, while the TA software recorded the thermal change of the sample during the warming process.
The reagents such as methanol are analytically pure and provided by the national chemical group chemical reagent company Limited, and the used reagents and solvents are not specially treated except for special instructions. Vitamin D 3 The raw material medicaments are purchased from Zhejiang garden pharmaceutical industry, and the purity is more than 99 percent; l-menthol was purchased from Aladdin reagent and was greater than 99% pure. All temperatures are expressed in degrees Celsius (C.), room temperature is 20-25 ℃.
The experimental methods used are conventional methods unless otherwise specified.
Example 1
Weighing vitamin D 3 Powder (1.92 g) and L-menthol powder (0.78 g) were charged to a 50mL ball mill pot, 80 μ L of acetone: water (1 3 Co-crystals with L-menthol.
For the prepared vitamin D 3 The co-crystals with L-menthol were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG) and Differential Scanning Calorimetry (DSC).
The results of the X-ray powder diffraction pattern analysis are shown in fig. 2, in which the position, relative intensity, peak height and full width at half maximum of characteristic XRPD peaks are summarized in table a below; the thermogravimetric analysis results are shown in FIG. 3, and the differential scanning calorimetry analysis results are shown in FIG. 4.
Table a. Vitamin D 3 And the molar ratio of L-menthol to water molecules is 1
Figure BDA0003765303420000091
Figure BDA0003765303420000101
Example 2 grinding method
Weighing vitamin D 3 The powder (384mg, 1mmol) and L-menthol powder (156mg, 1mmol) were charged to a 4mL ball mill jar and 80 μ L of acetone: a water (1 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
Example 3 anti-solvent Process
Respectively weighing vitamin D at room temperature 3 The powder (384mg, 1mmol) and L-menthol powder (156mg, 1mmol) were completely dissolved in 5.4mL of ethanol solution to obtain a clear solution. Dropwise adding in the stirring process4.7mL of purified water, white solid is separated out; filtering the suspension to obtain white crystalline solid as vitamin D 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
EXAMPLE 4 Cooling method
Cooling the filtrate obtained in example 3 at 4 deg.C, precipitating needle crystal with high crystallinity after 48 hr, and obtaining vitamin D with X-ray powder diffraction pattern substantially the same as that of figure 2 3 The needle-shaped crystal obtained by the solution method has higher crystallinity than the white crystalline solid obtained by the grinding and anti-solvent method, and can be used for single crystal analysis, and the analysis result of X-ray single crystal diffraction (SCXRD) test is shown in figure 1.
EXAMPLE 5 Cooling method
Respectively weighing vitamin D under heating at 50 deg.C 3 Powder (275mg, 0.72mmol) and L-menthol powder (112mg, 0.72mmol), completely dissolved in 5mL ethanol: in the mixed solvent of water (8 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is basically the same as that in fig. 2.
EXAMPLE 6 Cooling method
Respectively weighing vitamin D under heating at 70 deg.C 3 Powder (275mg, 0.72mmol) and L-menthol powder (112mg, 0.72mmol) were dissolved in 5mL ethanol: in the mixed solvent of water (2 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
EXAMPLE 7 volatilization method
Respectively weighing vitamin D at room temperature 3 Completely dissolving powder (30mg, 0.078mmol) and L-menthol powder (12mg, 0.078mmol) in 3mL acetonitrile, cooling the clear solution from room temperature to-20 deg.C, standing for 24 hours, centrifuging, filtering, slowly volatilizing the supernatant at room temperature to obtain needle-like crystals as vitamin D after 1 week 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
Note: when the preparation amount is small, the anhydrous solvent is volatilized at room temperature to obtain the monohydrate eutectic crystal.
Example 8 suspension Process
Weighing vitamin D at room temperature 3 Powder (77mg, 0.2mmol) and L-menthol powder (31mg, 0.2mmol) in a glass vial, 2mL ethanol: mixing the solvents with water (1 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
Example 9 suspension Process
Weighing vitamin D at room temperature 3 Powder (154mg, 0.4 mmol) and L-menthol powder (62mg, 0.4 mmol) were put in a glass vial, and 4mL of methanol: mixing the solvents with water (1 3 The X-ray powder diffraction pattern of the co-crystal with L-menthol is substantially the same as that of fig. 2.
Test example 1 vitamin D 3 And vitamin D 3 Pharmacokinetic characteristics in cocrystals with L-menthol
The source of the test sample: vitamin D purchased from Zhejiang garden 3 Starting material, vitamin D prepared as in example 1 3 Co-crystal with L-menthol.
The experimental method is as follows:
mixing vitamin D 3 Raw material and vitamin D 3 After being ground with the eutectic crystal of L-menthol, the mixture is sieved by a 60-mesh sieve. Preparing vitamin D from 0.5% sodium carboxymethylcellulose solution 3 Oral suspension (vitamin D) at a concentration of 20. Mu.g/mL 3 The Relative Standard Deviation (RSD) of the raw material suspension uniformity test is 6 percent, and the vitamin D 3 The suspension homogeneity RSD of the co-crystal group with L-menthol was 2%). Dividing 12 clean male SD rats with weight of 180-220 g into two groups, each group comprises 6 rats, feeding with diet free of vitamin D for one week, and respectively orally administering vitamin D24 hr before administration 3 Raw material suspension and vitamin D 3 Co-crystal group suspension with L-menthol, and administration dosage is vitamin D 3 The amount was measured to be 96. Mu.g/mL. Before (0 h) and after administration2,4,6,8,10,12,24,48 and 72h, blood is taken through orbital venous plexus and placed in a heparinized tube, and plasma is centrifugally separated under the centrifugal conditions of 12000 rpm and 5 minutes. Plasma was processed and analyzed for drug concentration by HPLC-MS.
The experimental results are as follows:
the results of the pharmacokinetic profile are shown in FIG. 5.
Vitamin D 3 Raw material and vitamin D 3 The pharmacokinetic parameters in cocrystals with L-menthol are shown in table 1:
TABLE 1 pharmacokinetic parameters
Figure BDA0003765303420000121
Vitamin D 3 The cocrystal group with L-menthol showed maximum blood concentration 24 hours after administration, faster than vitamin D 3 Raw material group (48 hours). Vitamin D 3 Maximum blood concentration (C) of cocrystallized group with L-menthol max ) Is vitamin D 3 1.9 times of the raw material group, area under blood concentration-time curve (AUC) 0-72h ) Is vitamin D 3 1.6 times of the raw material group.
Test example 2L-menthol starting Material and vitamin D 3 The mass loss rate and vapor pressure of the eutectic with L-menthol at 25 deg.C and 40 deg.C
The source of the test sample: l-menthol starting Material purchased from Allandine reagent, vitamin D prepared in example 1 3 Co-crystal with L-menthol.
The experimental method is as follows:
mixing L-menthol and vitamin D 3 After being ground with the eutectic crystal of L-menthol, the mixture is sieved by a 60-mesh sieve. Weighing a proper amount of powder sample, placing the powder sample in an aluminum disc with the inner diameter of 5mm for constant temperature thermogravimetric analysis: the weight change of the samples over time was recorded at constant temperature conditions of 25 ℃ and 40 ℃ respectively.
According to the formula:
P＝α -1 (dm/dt)(2πRT/M) 1/2
wherein-dm/dt is a weight loss per unit area (kg/s), and P is saturationVapor pressure (Pa), α is vaporization constant, T is absolute temperature (K), R is gas constant (J/(K · mol)), M is molecular mass of the vaporized substance (kg/mol), α is 1 under vacuum conditions, and α can be considered as a constant in the presence of a protector. During slow sublimation of the solid, the exposed area of the sample in the sample dish remains substantially unchanged. The thermal weight data of L-menthol with known vapor pressure can be used to calculate the L-menthol and vitamin D under the same experimental conditions 3 Saturated vapor pressure value of the eutectic.
The experimental results are as follows:
l-menthol raw material and vitamin D in isothermal thermogravimetric analysis process 3 The weight change of the cocrystal with L-menthol is shown in FIGS. 6 (25 ℃ C.) and 7 (40 ℃ C.). From Table 2, it can be seen that L-menthol and vitamin D 3 Compared with the L-menthol raw material, the eutectic phase has the advantages that the mass loss rate at 25 ℃ and 40 ℃ is reduced by orders of magnitude, and the vapor pressure is obviously reduced. Lower vapor pressure means lower volatility and thus the eutectic approach can effectively reduce volatility and thereby improve its stability during processing and storage.
TABLE 2 constant temperature thermogravimetric analysis of mass loss rate and saturated vapor pressure
Figure BDA0003765303420000131
Test example 3L-menthol starting Material and vitamin D 3 Comparison with the stability of the cocrystal of L-menthol at 40 ℃/75% relative humidity
The source of the test sample is: l-menthol starting material purchased from Allandine reagent, vitamin D prepared in example 1 3 Co-crystal with L-menthol.
The experimental method is as follows:
mixing L-menthol and vitamin D 3 After being ground with the eutectic crystal of L-menthol, the mixture is sieved by a 60-mesh sieve. About 300mg of sample is weighed and packaged by aluminum plastic. The sample was placed in an accelerated stability chamber (40 ℃/75% relative humidity) and stored for a period of time before being sampled. Detecting the content of L-menthol in the two groups of samples by using a gas chromatography method.
Gas chromatography measurement conditions:
the instrument comprises the following steps: agilent 7890B;
a chromatographic column: agilent DB-WAXetr GC column (30 m.times.0.32mm, 0.25 μm);
a detector: a hydrogen ion flame detector (FID);
sample inlet temperature: 250 ℃; constant pressure 8psi; the flow splitting ratio is 10;
temperature of the column box: 120 ℃;
a detector: 250 ℃;
hydrogen flow rate is 30mL/min; the air flow is 400mL/min; tail blown gas (nitrogen) 30mL/min.
The experimental results are as follows:
vitamin D 3 The L-menthol retention (remaining percentage) compared to the co-crystal of L-menthol and L-menthol starting material is shown in fig. 8 (40 ℃/75% relative humidity).
As shown in Table 3, vitamin D prepared according to the present invention 3 Compared with the eutectic crystal of the L-menthol and the L-menthol raw material, the retention rate of the L-menthol of the eutectic group is obviously improved under the condition of 40 ℃/75% relative humidity by taking the conversion of the content of the L-menthol of a 0-day initial sample into 100% as a reference.
TABLE 3L-menthol stability test results (Retention)
Figure BDA0003765303420000141
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements that fall within the spirit and principles of the present invention are intended to be included therein.

Claims (10)

1. Vitamin D 3 Co-crystals with L-menthol, characterized in that in the co-crystals vitamin D is present 3 The molar ratio of L-menthol to water molecules is 1.
2. The method of claim 1Vitamin D 3 Co-crystal with L-menthol, characterized in that said vitamin D is 3 An X-ray powder diffraction pattern of the eutectic with the L-menthol has characteristic peaks at least at 2 theta diffraction angles of 4.5 +/-0.2 degrees, 6.5 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.7 +/-0.2 degrees, and 21.7 +/-0.2 degrees;
preferably, said vitamin D 3 The X-ray powder diffraction pattern of the eutectic with L-menthol further has characteristic peaks at least at 2 theta diffraction angles of 11.9 + -0.2 DEG, 13.2 + -0.2 DEG, and 19.6 + -0.2 DEG;
more preferably, the vitamin D 3 The X-ray powder diffraction pattern of the eutectic with L-menthol further has characteristic peaks at least at 2 theta diffraction angles of 11.4 + -0.2 DEG, 13.7 + -0.2 DEG, 17.5 + -0.2 DEG, and 18.2 + -0.2 DEG;
more particularly, said vitamin D 3 The co-crystal with L-menthol has an X-ray powder diffraction pattern substantially as shown in figure 2.
3. Vitamin D according to claim 1 or 2 3 Co-crystal with L-menthol, characterized in that said vitamin D is 3 The eutectic crystal with L-menthol is monoclinic system, and the space group is P2 1 The unit cell parameters are:
Figure FDA0003765303410000011
Figure FDA0003765303410000015
Figure FDA0003765303410000014
Figure FDA0003765303410000013
α =90 °; β =103.318 (4) °; γ =90 °; cell volume of
Figure FDA0003765303410000012
4. Vitamin D according to claim 1 or 2 3 Co-crystal with L-menthol, characterized in that said vitamin D is 3 Heating the eutectic with L-menthol to 400 ℃ from room temperature of 25 +/-0.2 ℃ at a heating rate of 10 ℃/min, wherein the weight loss is 31% when the eutectic is heated to 196.1 +/-0.2 ℃, and the weight loss is 99% when the eutectic is continuously heated to 400 +/-0.2 ℃;
more particularly, said vitamin D 3 The co-crystal with L-menthol has a thermogravimetric analysis substantially as shown in figure 3.
5. Vitamin D according to claim 1 or 2 3 Co-crystal with L-menthol, characterized in that said vitamin D is 3 The Differential Scanning Calorimetry (DSC) spectrogram of the eutectic crystal with the L-menthol has an endothermic peak at the temperature of 53.1-78.0 ℃, the peak temperature is 70.9 +/-0.2 ℃, and the temperature T is onset The value was 68.9. + -. 0.2 ℃;
more particularly, said vitamin D 3 The co-crystal with L-menthol has a differential scanning calorimetry spectrum substantially as shown in figure 4.
6. A process for the preparation of vitamin D as claimed in any one of claims 1 to 5 3 Method of co-crystallizing with L-menthol, characterized in that it comprises the following steps:
(a1) Separately weighing vitamin D 3 And powder of L-menthol;
(b1) Dissolving the powder obtained in step (a 1) in an organic solvent or a mixed solvent of an organic solvent and water at a relatively high temperature to form vitamin D 3 And an unsaturated solution of L-menthol;
(c1) Cooling the unsaturated solution obtained in the step (b 1) from a higher temperature to a lower temperature to precipitate vitamin D 3 And co-crystals of L-menthol;
(d1) Separating to obtain vitamin D 3 Co-crystal with L-menthol;
in particular, vitamin D in step (a 1) 3 And the molar ratio of L-menthol powder is 1;
particularly, the organic solvent in step (b 1) is selected from one or more of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, diethyl ether and n-hexane;
specifically, the volume ratio of the organic solvent to water in the mixed solvent of the organic solvent and water in step (b 1) is 8;
in particular, the higher temperature in step (b 1) is between 70 ℃ and room temperature;
in particular, a lower temperature in step (c 1) means a temperature lower than the higher temperature, preferably between room temperature and-20 ℃;
in particular, the separation of step (d 1) comprises: filtration, or, centrifugation and filtration;
particularly, the separated liquid solution is further evaporated to dryness after separation to obtain vitamin D 3 Co-crystal with L-menthol.
7. A process for the preparation of vitamin D as claimed in any one of claims 1 to 5 3 Method of co-crystallizing with L-menthol, characterized in that it comprises the following steps:
(a2) Separately weighing vitamin D 3 And powder of L-menthol;
(b2) Dissolving the powder of step (a 2) in a good solvent to form vitamin D 3 And an unsaturated solution of L-menthol;
(c2) Dropwise adding a poor solvent into the unsaturated solution obtained in the step (b 2) until precipitates are separated out;
(d2) Separating the precipitate to obtain vitamin D 3 Co-crystals with L-menthol;
in particular, vitamin D in step (a 2) 3 And the molar ratio of L-menthol powder is 1;
in particular, the good solvent of step (b 2) comprises menthol and vitamin D 3 An organic solvent or a mixed solvent of an organic solvent and water, the solubility of which is 5mg/mL or more; the organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, and methyl isopropyl alcoholOne or more of butyl ketone, diethyl ether, n-hexane and n-heptane; when a mixed solvent of an organic solvent and water is used as a good solvent, the volume ratio of the organic solvent to the water is from 8;
in particular, the poor solvent of step (c 2) is selected from water, nitromethane, ethylene glycol or vitamin D 3 And a corresponding solvent having a solubility for L-menthol lower than the good solvent selected in step (b 2);
in particular, the separation of step (d 2) comprises: filtration, or, centrifugation and filtration;
in particular, after separation, the separated liquid solution is further evaporated to dryness to obtain vitamin D 3 Co-crystals with L-menthol.
8. A process for the preparation of vitamin D as claimed in any one of claims 1 to 5 3 Method of co-crystallizing with L-menthol, characterized in that it comprises the following steps:
(a3) Separately weighing vitamin D 3 And powder of L-menthol;
(b3) Adding the powder obtained in the step (a 3) into a mechanical grinding device, fully contacting the powder through mechanical force, and obtaining the vitamin D after all reactions 3 Co-crystals with L-menthol;
in particular, vitamin D in step (a 3) 3 1 to L-menthol powder in a molar ratio of 1;
in particular, the mechanical milling device of step (b 3) is selected from one of a ball mill, a pulverizer, a blender and a stirring apparatus; preferably a ball mill; an auxiliary solvent can be added in the ball milling process, and the auxiliary solvent is a mixed solvent of water and one or more of the following solvents: acetone, methyl ethyl ketone, methyl isobutyl ketone, n-hexane, n-heptane, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, ethanol, isopropanol, n-propanol, and isoamyl alcohol; the preferred oscillation frequency of the ball milling is 5-60 Hz, preferably 30Hz, and the oscillation time is 10-180 minutes, preferably 30-180 minutes;
alternatively, the first and second electrodes may be,
the method comprises the following steps:
(a4) Separately weighing vitamin D 3 And L-mentholThe powder of (4);
(b4) Suspending and balancing the powder in the step (a 4) in a glass vial in an organic solvent or a mixed solvent of the organic solvent and water for 8-36 hours;
(c4) Separating the suspended solid to obtain vitamin D 3 Co-crystals with L-menthol;
in particular, vitamin D in step (a 4) 3 And the molar ratio of L-menthol powder is 1;
particularly, the organic solvent in step (b 4) is selected from one or more of methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, methyl isobutyl ketone, diethyl ether, n-hexane, n-heptane, nitromethane, cyclohexane and glycol;
in particular, the volume ratio of the organic solvent to water in step (b 4) is 4;
in particular, the separation of step (c 4) comprises: filtration, or, centrifugation and filtration;
particularly, the separated liquid solution is further volatilized after the separation to obtain vitamin D 3 Co-crystals with L-menthol.
9. Vitamin D 3 Product comprising vitamin D according to any of claims 1 to 5 3 Co-crystals with L-menthol.
10. Vitamin D according to any one of claims 1 to 5 3 The eutectic crystal with L-menthol can be applied to health products, foods, cosmetics, medicines, pharmaceutic adjuvants or feeds.
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