CN113683654A - Preparation and application of progesterone eutectic - Google Patents
Preparation and application of progesterone eutectic Download PDFInfo
- Publication number
- CN113683654A CN113683654A CN202111153647.4A CN202111153647A CN113683654A CN 113683654 A CN113683654 A CN 113683654A CN 202111153647 A CN202111153647 A CN 202111153647A CN 113683654 A CN113683654 A CN 113683654A
- Authority
- CN
- China
- Prior art keywords
- progesterone
- acid
- eutectic
- degrees
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/14—Monocyclic dicarboxylic acids
- C07C63/15—Monocyclic dicarboxylic acids all carboxyl groups bound to carbon atoms of the six-membered aromatic ring
- C07C63/16—1,2 - Benzenedicarboxylic acid
- C07C63/20—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to the preparation of progesterone cocrystals and uses thereof. The invention discloses a eutectic crystal, wherein the active ingredient of the eutectic crystal is progesterone, the eutectic crystal formation of the eutectic crystal is a benzoic acid derivative, and the benzoic acid derivative comprises p-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid or phthalic acid. The invention provides a preparation method of the eutectic.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to preparation and application of a progesterone eutectic.
Background
Progesterone (Progesterone, C)21H30O2) Is a bioactive primary progestin secreted by the ovary. The progesterone can not only induce the transformation of endometrium to secretion period and increase the receptivity of endometrium so as to be beneficial to implantation of fertilized eggs, but also act on the part of uterus so as to provide good internal environment for the maintenance of pregnancy. Because of the poor solubility of progesterone, progesterone oily injections are often administered clinically. Its advantages are sure curative effect, low cost and the following disadvantages: the pain and stimulation of the injection part are easy to form local induration, and the absorption and recovery of the local induration and the aseptic abscess require a long time, which belong to the normal phenomenon of injecting progesterone by muscle, and no special effective treatment method exists. In addition, intramuscular injection of progesterone requires daily injections.
The pharmaceutical co-crystal is a supermolecule which is formed by acting force between molecules such as hydrogen bonds and the like between drug molecules and a co-crystal reagent and has a fixed composition and a single melting point. The existing research results show that the pharmaceutical cocrystal is formed by using a cocrystal reagent with better water solubility and an insoluble drug, so that the water solubility and the bioavailability of the insoluble drug can be obviously improved under the condition of not changing the molecular structure of the drug, and the cocrystal is the latest key technology for improving the physicochemical properties of the drug such as water solubility, permeability, stability and the like. By screening the eutectic formation of the progesterone, the invention discovers that the benzoic acid derivative eutectic can increase the solubility of the progesterone so as to achieve the purpose of reducing the irritation and adverse reaction of the progesterone.
Disclosure of Invention
The object of the present invention is to provide a new progesterone cocrystal that should have one or more improved properties, such as good stability, high bioavailability, etc. The invention relates to a preparation method of the eutectic crystal, a pharmaceutical composition and application thereof. The development of the pharmaceutical co-crystal is just started as a novel pharmaceutical solid form, the preparation method of the co-crystal is still mainly in a repeated experiment stage at present, and whether the co-crystal can be formed among different systems or not and whether the formed co-crystal has improved physicochemical properties or not are unpredictable. The inventors have surprisingly obtained progesterone co-crystals with improved properties by varying the system and reaction conditions through a large number of experiments.
According to the purpose of the invention, the first aspect of the invention provides a eutectic crystal, wherein the active ingredient of the eutectic crystal is progesterone, and the eutectic crystal formation product of the eutectic crystal is a benzoic acid derivative, wherein the benzoic acid derivative comprises p-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid or phthalic acid.
When the benzoic acid derivative is p-aminobenzoic acid, the experimental formula of the obtained progesterone-p-aminobenzoic acid eutectic is C28H37NO4。
As a preferred embodiment, the X-ray powder diffraction pattern of the progesterone-p-aminobenzoic acid co-crystal expressed in 2 Θ angles using Cu-ka radiation has characteristic peaks at 13.519 °, 13.878 °, 17.86 °, 20.56 °, 27.142 °, wherein the error range of 2 Θ for each characteristic peak is ± 0.2 °.
As a more preferred embodiment, the X-ray powder diffraction pattern of the progesterone-p-aminobenzoic acid co-crystal expressed in 2 Θ angles using Cu-ka radiation also has characteristic peaks at 7.001 °, 8.521 °, 9.719 °, 14.44 °, 16.04 °, 16.995 °, 18.242 °, 18.596 °, 19.175 °, 19.913 °, 22.12 °, 23.42 °, 23.699 °, 24.016 °, 25.12 °, 25.816 °, 26.577 °, 27.396 °, 30.518 °, wherein the error range of 2 Θ per characteristic peak is ± 0.2 °. Without limitation, the progesterone-p-aminobenzoic acid co-crystal has an X-ray powder diffraction pattern as shown in fig. 1.
When the benzoic acid derivative is o-methylbenzoic acid, the laboratory of the obtained progesterone-o-methylbenzoic acid eutectic is C29H38O4。
Early stageAs a preferred embodiment, the progesterone-o-methyl group is irradiated with Cu-KaAn X-ray powder diffraction pattern of the benzoic acid eutectic expressed by 2 theta angles has characteristic peaks at 9.38 degrees, 10.818 degrees, 12.421 degrees, 12.962 degrees, 13.22 degrees, 14.02 degrees, 14.941 degrees, 15.741 degrees, 17.041 degrees, 18.38 degrees, 21.08 degrees, 21.561 degrees, 26.76 degrees and 28.001 degrees, wherein the error range of 2 theta of each characteristic peak is +/-0.2 degrees.
As a more preferred embodiment, the progesterone-o-methylbenzoic acid co-crystal further has characteristic peaks at 7.142 °, 11.597 °, 16.441 °, 18.799 °, 19.36 °, 20.378 °, 22.42 °, 22.74 °, 23.04 °, 23.725 °, 24.742 °, 25.96 °, 27.164 °, 28.561 °, 29.939 ° in an X-ray powder diffraction pattern expressed in 2 θ degrees using Cu-ka radiation, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °. Without limitation, the progesterone-o-methylbenzoic acid co-crystal has an X-ray powder diffraction pattern as shown in fig. 10.
When the benzoic acid derivative is p-methylbenzoic acid, the experimental formula of the obtained progesterone-p-methylbenzoic acid eutectic is C50H68O6。
As a preferred embodiment, the progesterone-p-toluic acid co-crystal has characteristic peaks at 12.958 °, 13.922 °, 14.256 °, 18.103 °, 18.501 °, 20.261 °, 20.942 °, 24.158 °, 26.921 ° in an X-ray powder diffraction pattern expressed in 2 θ degrees using Cu-ka radiation, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °.
As a more preferred embodiment, the X-ray powder diffraction pattern of the progesterone-p-toluic acid eutectic expressed by 2 θ angles using Cu-ka radiation also has characteristic peaks at 6.967 °, 8.343 °, 9.256 °, 12.3 °, 14.723 °, 16.2 °, 16.964 °, 17.324 °, 17.895 °, 19.283 °, 19.818 °, 24.423 °, 24.782 °, 25.062 °, 26.081 °, 26.662 °, 27.303 °, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °. Without limitation, the progesterone-p-methylbenzoic acid co-crystal has an X-ray powder diffraction pattern as shown in fig. 19.
When the benzoic acid derivative is m-methoxybenzoic acid, the obtained progesterone-m-methoxybenzoic acidThe experimental formula of the acid eutectic is C29H38O5。
As a preferred embodiment, the progesterone-m-methoxybenzoic acid eutectic has characteristic peaks at 10.635 °, 12.358 °, 12.739 °, 13.34 °, 14.583 °, 15.415 °, 16.116 °, 16.844 °, 17.017 °, 17.941 °, 18.176 °, 20.695 °, 21.16 °, 21.361 °, 26.814 °, 27.519 °, 33.122 °, 39.736 ° in an X-ray powder diffraction pattern expressed by 2 θ angles using Cu-ka radiation, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °.
As a more preferred embodiment, the progesterone-m-methoxybenzoic acid co-crystal has an X-ray powder diffraction pattern expressed in 2 θ angles with Cu-ka radiation also having characteristic peaks at 10.422 °, 11.22 °, 13.702 °, 22.237 °, 23.525 °, 23.701 °, 24.021 °, 24.171 °, 25.466 °, 25.696 °, 26.339 °, 37.575 °, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °. Without limitation, the progesterone-m-methoxybenzoic acid co-crystal has an X-ray powder diffraction pattern as shown in fig. 28.
When the benzoic acid derivative is phthalic acid, the experimental formula of the obtained progesterone-phthalic acid eutectic is C29H36O6。
As a preferred embodiment, the progesterone-phthalic acid co-crystal has characteristic peaks in the X-ray powder diffraction pattern expressed in 2 θ angles at 10.853 °, 12.883 °, 13.254 °, 14.175 °, 15.559 °, 16.319 °, 16.956 °, 17.159 °, 17.519 °, 18.523 °, 19.86 °, 20.363 °, 21.063 °, 23.774 °, 25.363 ° using Cu-ka radiation, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °.
As a more preferred embodiment, the progesterone-phthalic acid co-crystal has an X-ray powder diffraction pattern expressed in 2 θ angles using Cu-ka radiation also having characteristic peaks at 9.998 °, 10.557 °, 12.275 °, 13.598 °, 13.781 °, 14.744 °, 15.017 °, 18.024 °, 19.281 °, 21.583 °, 21.973 °, 23.461 °, 24.961 °, 26.378 °, 26.8 °, 27.042 °, 28.117 °, 37.761 °, wherein the error range of 2 θ for each characteristic peak is ± 0.2 °. Without limitation, the progesterone-phthalic acid co-crystal has an X-ray powder diffraction pattern as shown in fig. 37.
The co-crystals of the present invention are pure, single, and substantially free of any other crystalline, or amorphous state. "substantially free" means that less than 20% by weight, more specifically less than 10% by weight, especially less than 5% by weight, and especially less than 1% by weight, of other crystalline, crystalline or amorphous forms are present therein.
In the present invention, the crystal form of the "co-crystal" is confirmed by the shown X-ray powder diffraction pattern characterization. The structure of the "eutectic" is confirmed by the structural diagram obtained by diffraction from the shown X-ray single crystal. It is well known to those skilled in the art that experimental errors in X-ray powder diffraction patterns depend on instrument conditions, sample preparation and sample purity. X-ray powder diffraction pattern spectra typically vary with instrument conditions; the relative intensities of the peaks may vary with experimental conditions, so the order of peak intensities cannot be considered as the sole or determining factor; experimental errors in peak angle should also be taken into account, typically allowing an error of ± 0.2 °; the influence of experimental factors such as sample height can cause an overall shift in peak angle, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that any adduct of progesterone and a co-crystal former according to the first aspect of the invention, such as a crystalline form having characteristic peaks identical or similar to the X-ray powder diffraction pattern of the invention, falls within the scope of the present invention.
In one embodiment of the invention, the infrared spectrum of the progesterone-p-aminobenzoic acid eutectic is 3425.84cm-1、3346.40cm-1、3235.75cm-1、2940.83cm-1、2870.37cm-1、1693.62cm-1、1596.26cm-1、1569.84cm-1、1447.10cm-1、1414.77cm-1、1351.21cm-1、1316.64cm-1、1248.65cm-1、954.82cm-1、852.33cm-1、778.88cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
As a preferred embodiment, the progesterone-P-aminobenzoic acid eutectic is in the orthorhombic system, P2 12121Space group, cell parameter of
α is 90 °, β is 90 °, γ is 90 °, Z is 8, and the unit cell volume is
In one embodiment of the invention, the infrared spectrum of the progesterone-o-methylbenzoic acid eutectic is 2937.7cm-1、2558.2cm-1、2145.2cm-1、2014.3cm-1、1671.9cm-1、1446.8cm-1、1353.5cm-1、1272.5cm-1、1223.0cm-1、1085.1cm-1、939.8cm-1、874.1cm-1、749.1cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
As a preferred embodiment, the progesterone-o-methylbenzoic acid eutectic is a triclinic system, P1 space group and unit cell parameters are
A is 79.362(4), β is 81.464(4), γ is 75.860(5), and Z is 2, and the unit cell volume is
In one embodiment of the invention, the infrared spectrum of the progesterone-p-methylbenzoic acid eutectic is 2934.08cm-1、2882.59cm-1、2862.62cm-1、1705.61cm-1、1693.01cm-1、1643.71cm-1、1606.91cm-1、1413.16cm-1、1272.60cm-1、1176.18cm-1、1069.73cm-1、946.52cm-1、924.88cm-1、893.11cm-1、828.59cm-1、809.64cm-1、759.40cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
As a preferred embodiment, the progesterone-P-methylbenzoic acid eutectic is a triclinic system, P1 space group and unit cell parameters are
A is 104.300(5) °, β is 94.717(5) °, γ is 103.307(5) °, Z is 1, and unit cell volume is
In one embodiment of the invention, the infrared spectrum of the progesterone-m-methoxybenzoic acid eutectic is 2932.3cm-1、2579.1cm-1、2164.8cm-1、2031.5cm-1、1724.4cm-1、1693.5cm-1、1639.9cm-1、1588.7cm-1、1488.5cm-1、1464.7cm-1、1429.7cm-1、1355.9cm-1、1315.8cm-1、1292.3cm-1、1239.0cm-1、1210.4cm-1、1178.4cm-1、1161.2cm-1、1042.0cm-1、939.3cm-1、887.6cm-1、870.7cm-1、818.3cm-1、759.9cm-1、736.9cm-1、682.3cm-1Absorption peaks exist at the wavelength, wherein the error range of each absorption peak is +/-2 cm < -1 >;
as a preferred embodiment, the progesterone-m-methoxybenzoic acid eutectic is in an orthorhombic system, P2 12121Space group, cell parameter of
α is 90.00 °, β is 90.00 °, γ is 90.00 °, Z is 4, and the unit cell volume is
In one embodiment of the invention, the progesterone-phthalic acid co-crystal has an infrared spectrum of 1730.0cm-1、1472.9cm-1、1439.2cm-1、1384.9cm-1、1329.3cm-1、1278.0cm-1、1162.5cm-1、1145.1cm-1、1119.3cm-1、1070.1cm-1、948.5cm-1、870.6cm-1、778.9cm-1The wavelength has absorption peaks, wherein the error range of each absorption peak is +/-2 cm < -1 >.
As a preferred embodiment, the infrared spectrum of the progesterone-phthalic acid eutectic crystal is 2969.2cm-1、2940.7cm-1、2925.1cm-1、2851.9cm-1、1699.9cm-1、1666.4cm-1、1615.8cm-1、1356.9cm-1、1228.4cm-1、1205.2cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1。
As a preferred embodiment, the progesterone-phthalic acid co-crystal is of monoclinic system, P21Space group, cell parameter of
Alpha is 90.00 degree, beta is 92.380(2 degree), gamma is 90.00 degree, Z is 4, unit cell volume is
According to a second aspect of the present invention there is provided a pharmaceutical composition comprising a co-crystal according to the first aspect of the present invention. As a preferred embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant. The pharmaceutical composition typically comprises from about 1% to about 99% by weight of the co-crystals of the invention, and from about 99% to about 1% by weight of at least one pharmaceutically acceptable suitable carrier or adjuvant. In addition, the pharmaceutical composition may also contain crystalline or amorphous forms, or co-crystals, of other pharmaceutically acceptable salts, solvates, hydrates of progesterone. Optionally, the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
The pharmaceutical composition can be prepared into solid, semi-solid or liquid dosage forms, solid oral dosage forms, such as tablets, capsules, granules, pills and powders; liquid oral dosage forms, including, for example, solutions, syrups, suspensions, dispersions, and emulsions; injectable preparations include, for example, solutions, dispersions and lyophilized powders formulated as solutions. The formulations may be adapted for immediate, sustained or controlled release of the pharmaceutically active ingredient and may be conventional, dispersible, chewable, mouth dissolving or fast melting formulations. The administration route includes oral administration, intravenous injection, subcutaneous injection, transdermal administration, rectal administration, nasal drop administration, etc. To maintain the co-crystals of the present invention when prepared, the pharmaceutical compositions of the present invention are preferably solid oral dosage forms, including tablets, capsules, granules, pills and powders.
In the case of solid dosage forms, the pharmaceutically acceptable carriers or adjuvants of the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and the like; disintegrants, such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, and the like; glidants such as colloidal silicon dioxide and the like; complex-forming agents, such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl methacrylate, waxes, and the like. Other pharmaceutically acceptable carriers or adjuvants that may be used include, but are not limited to, film forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.
The pharmaceutical compositions may be prepared using methods well known to those skilled in the art. The co-crystals of progesterone and benzoic acid derivatives of the present invention are prepared by mixing with one or more pharmaceutically acceptable carriers or adjuvants, optionally with one or more other active ingredients. The solid preparation can be prepared by direct mixing, granulation and the like.
According to an object of the invention, a third aspect of the invention provides a use as described in any one of the following:
(1) use of a pharmaceutical composition according to the second aspect of the invention in the manufacture of a medicament for maintaining pregnancy;
(2) the pharmaceutical composition according to the second aspect of the present invention is used for preparing a medicament for treating gynecological diseases.
The gynecological diseases include but are not limited to spontaneous premature birth, corpus luteum insufficiency, secondary amenorrhea, premenstrual syndrome.
According to a fourth aspect of the invention there is provided a method of preparing a co-crystal according to the first aspect of the invention, the method comprising the steps of:
1) crushing progesterone and benzoic acid derivative to obtain white powder sample,
2) adding a white powder sample into an organic solvent for dissolving, and volatilizing to obtain a colorless massive crystal;
the benzoic acid derivative is selected from p-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid or phthalic acid,
preferably, the molar ratio of progesterone to said benzoic acid derivative is 1: 1.
Preferably, the organic solvent comprises C1-C4 alcohol, ethyl acetate or acetone, more preferably, the organic solvent is C1-C4 alcohol, preferably, the C1-C4 alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or isobutanol, more preferably, the C1-C4 alcohol is methanol.
Preferably, the progesterone and the benzoic acid derivative are pulverized using a ball mill.
According to an object of the present invention, there is provided a method of maintaining pregnancy or treating gynaecological disorders, said method comprising administering to a patient in need thereof a therapeutically effective amount of a co-crystal according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention; the patient refers to mammals including human beings. In some embodiments, the dosage may range from about 0.01 mg to about 100mg per kg of body weight per day, and convenient daily dosage regimens may be employed. The dosage may be adjusted depending on the type and extent of the condition, the general health of the patient, the nature of the formulation, and the route of administration, among other things.
The gynecological diseases include but are not limited to spontaneous premature birth, corpus luteum insufficiency, secondary amenorrhea, premenstrual syndrome.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of progesterone-p-aminobenzoic acid;
FIG. 2 is a TGA/DSC graph of progesterone-p-aminobenzoic acid;
FIG. 3 is a diagram of an infrared absorption spectrum of progesterone-p-aminobenzoic acid;
FIG. 4 is a scanning electron micrograph of progesterone-p-aminobenzoic acid at different magnifications, wherein the magnification of Panel A is 500 and the magnification of Panel B is 5000;
FIG. 5 is a preparation of progesterone-p-aminobenzoic acid1H-NMR nuclear magnetic resonance spectrum;
FIG. 6 is an X-ray single crystal diffractogram of progesterone-p-aminobenzoic acid;
FIG. 7 is a graph of stability tests for progesterone-p-aminobenzoic acid;
FIG. 8 is a graph of the solubility assay of progesterone-p-aminobenzoic acid;
figure 9 is a graph of the bioavailability of progesterone-p-aminobenzoic acid;
FIG. 10 is an X-ray powder diffraction pattern of progesterone-o-methylbenzoic acid;
FIG. 11 is a TGA/DSC graph of progesterone-o-methylbenzoic acid;
FIG. 12 is a graph of the infrared absorption spectrum of progesterone-o-methylbenzoic acid;
FIG. 13 is a scanning electron micrograph of progesterone-o-methylbenzoic acid taken at different magnifications, wherein the magnification of Panel A is 500 and the magnification of Panel B is 5000;
FIG. 14 is a preparation of progesterone-o-methylbenzoic acid1H-NMR nuclear magnetic resonance spectrum;
FIG. 15 is an X-ray single crystal diffractogram of progesterone-o-methylbenzoic acid;
FIG. 16 is a graph of stability experiments for progesterone-o-methylbenzoic acid;
FIG. 17 is a graph of the solubility experiment for progesterone-o-methylbenzoic acid;
figure 18 is a graph of the bioavailability of progesterone-o-methylbenzoic acid;
FIG. 19 is an X-ray powder diffraction pattern of progesterone-p-methylbenzoic acid;
FIG. 20 is a TGA/DSC of progesterone-p-methylbenzoic acid;
FIG. 21 is a chart of the infrared absorption spectrum of progesterone-p-methylbenzoic acid;
FIG. 22 is a scanning electron micrograph of progesterone-p-methylbenzoic acid at different magnifications, wherein the magnification of Panel A is 500 and the magnification of Panel B is 5000;
FIG. 23 is of progesterone-p-methylbenzoic acid1H-NMR nuclear magnetic resonance spectrum;
FIG. 24 is an X-ray single crystal diffractogram of progesterone-p-methylbenzoic acid;
FIG. 25 is a graph of stability tests for progesterone-p-methylbenzoic acid;
FIG. 26 is a graph of the solubility assay of progesterone-p-methylbenzoic acid;
figure 27 is a graph of the bioavailability of progesterone-p-methylbenzoic acid;
FIG. 28 is an X-ray powder diffraction pattern of progesterone-m-methoxybenzoic acid;
FIG. 29 is a TGA/DSC of progesterone-m-methoxybenzoic acid;
FIG. 30 is a chart of the infrared absorption spectrum of progesterone-m-methoxybenzoic acid;
FIG. 31 is a scanning electron micrograph of progesterone-m-methoxybenzoic acid at different magnifications, wherein the magnification of Panel A is 500 and the magnification of Panel B is 5000;
FIG. 32 is a preparation of progesterone-m-methoxybenzoic acid1H-NMR nuclear magnetic resonance spectrum;
FIG. 33 is an X-ray single crystal diffractogram of progesterone-m-methoxybenzoic acid;
FIG. 34 is a graph of stability tests for progesterone-m-methoxybenzoic acid;
FIG. 35 is a graph of the solubility assay of progesterone-m-methoxybenzoic acid;
figure 36 is a graph of the bioavailability of progesterone-m-methoxybenzoic acid;
figure 37 is an X-ray powder diffraction pattern of progesterone-phthalic acid;
figure 38 is a TGA/DSC diagram of progesterone-phthalic acid;
FIG. 39 is a graph of the infrared absorption spectrum of progesterone-phthalic acid;
FIG. 40 is a scanning electron micrograph of progesterone-phthalic acid at different magnifications, wherein the magnification of Panel A is 500 and the magnification of Panel B is 5000;
FIG. 41 is a progesterone-phthalic acid solution1H-NMR nuclear magnetic resonance spectrum;
FIG. 42 is an X-ray single crystal diffractogram of progesterone-phthalic acid;
FIG. 43 is a graph of progesterone-phthalic acid stability assays;
figure 44 is a graph of the solubility assay of progesterone-phthalic acid;
figure 45 is a graph of the bioavailability of progesterone-phthalic acid.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental procedures, in which specific conditions are not specified in the examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
EXAMPLE 1 preparation of Progesterone Co-crystals
First, experimental material
Progesterone: zhejiang Xianju pharmaceutical Co Ltd (purity > 99%)
P-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid, phthalic acid: shanghai Bide pharmaceutical science and technology Limited (purity > 99%)
Ethyl acetate: beijing chemical plant (analytical pure)
Second, Experimental methods
1. The sample preparation method comprises the following steps: 943.4mg (3.0mmol) of progesterone, 411.4mg (3.0mmol) of p-aminobenzoic acid, 408.5mg (3.0mmol) of o-methylbenzoic acid, 408.5mg (3.0mmol) of p-methylbenzoic acid, 456.5mg (3.0mmol) of m-methoxybenzoic acid and 798.4mg (3.0mmol) of phthalic acid are weighed and added into a ball mill (planetary ball mill, Nanjing Chinshun scientific and technological development Co., Ltd.) to be ball-milled for 40min at 28Hz without solvent, and then a white powder sample is obtained.
2. The single crystal culture method comprises the following steps: taking 100mg of the powder sample, adding 15mL of methanol for dissolving, slowly volatilizing the solvent, and obtaining colorless massive crystals after about 1 week.
Example 2 structural characterization of progesterone cocrystals
First, experimental conditions
1. Thermal analysis (TG-DSC)
The instrument model is as follows: TGA/DSC 3 +; the heating rate is as follows: 10 ℃/min; temperature range: 40-400 ℃; gas atmosphere: nitrogen gas.
2. Infrared absorption Spectrum (IR)
The instrument model is as follows: bruker EQUINOX 55 FT-IR; the experimental method comprises the following steps: and taking a proper amount of sample, and placing the sample in the middle of a probe for testing.
3. 1H-NMR nuclear magnetic resonance spectrum
The instrument model is as follows: AVANCE III HD 400/500MHz type NMR spectrometer; solvent: d6-DMSO (TMS internal standard).
4. X-ray single crystal diffraction (SXRD)
The instrument model is as follows: rigaku AFC-10; the experimental method comprises the following steps: selecting colorless crystal of 0.31mm0.22mm0.18mm size, adopting graphite monochromatized Mo-K ray, radiating wavelength
Measuring temperature: 173.00(15) K. The structure resolution and refinement are done using the SHELL XT-14 and Olex2 programs. The atomic position is determined by a direct method, then all non-hydrogen atomic coordinates are obtained by a difference function method and a least square method, and the structure is corrected by the least square method.
5. Powder X-ray diffraction Spectrum (PXRD)
The instrument model is as follows: x-ray powder apparatus model D8ADVANCE of Bruker, germany. The measurement conditions were as follows: copper target, 40KV/40mA, initial angle 5 degree, end angle 40 degree/60 degree, step width 0.02 degree, scanning speed 17.7 seconds per step. Wavelength of light
A graphite monochromator.
6. Scanning electron microscope atlas
The instrument model is as follows: jeol JSM-6100
7. Stability test
The instrument model is as follows: comprehensive medicine stability test box (Shanghai-Hengscientific instruments Co., Ltd.)
The experimental method comprises the following steps: the stability experiment examines the stability and the transformation rule of the sample under the conditions of high temperature, high humidity and illumination. 100mg of test sample powder is filled into a weighing bottle, the opening of the sample is respectively placed under the conditions of high temperature (60 +/-2 ℃), high humidity (90% +/-5%) and illumination (4500 +/-500 lx) for 10 days, and samples are respectively taken on the 0 th day, the 5 th day and the 10 th day for powder X-ray diffraction analysis.
8. Solubility test
The instrument model is as follows: tiandatianfa RC806D dissolution tester
The experimental method comprises the following steps: sieving the sample with a 100-mesh sieve, weighing 2g of the sample, respectively adding into 1000mL of deionized water, stirring at 37 ℃ and 100rpm by a slurry method, respectively sampling 2mL at 5min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240min, 300min and 360min, filtering with a filter membrane, taking the filtrate as the sample, injecting 2 needles, and detecting by HPLC.
Liquid phase conditions: high performance liquid chromatograph: waters; chromatographic column of Waters Xbridge C184.6 × 150mm, 3.5 μm chromatographic column; mobile phase: acetonitrile and water 45: 55; the detection wavelength is 280 nm; flow rate: 0.8 mL/min; column temperature: 40 ℃; sample introduction amount: 20 mu L of the solution; operating time: and 15 min.
Second, experimental results
1. Progesterone-p-aminobenzoic acid eutectic crystal
(1)PXRD
The experimental results are shown in fig. 1 and table 1, and the X-ray powder diffraction pattern of progesterone-p-aminobenzoic acid has characteristic diffraction peaks corresponding to the corresponding positions of the 2 theta values.
TABLE 1 progesterone-p-aminobenzoic acid cocrystal X-powder diffraction Spectroscopy absorption peaks
| Serial number | 2θ/° | Relative intensity/%) | Serial number | 2θ/° | Relative intensity/%) |
| 1 | 7.001 | 9.2 | 13 | 19.913 | 3.3 |
| 2 | 8.521 | 3.9 | 14 | 20.56 | 100 |
| 3 | 9.719 | 4.5 | 15 | 22.12 | 11.5 |
| 4 | 13.519 | 53.7 | 16 | 23.42 | 7.9 |
| 5 | 13.878 | 25.7 | 17 | 23.699 | 5.4 |
| 6 | 14.44 | 10.3 | 18 | 24.016 | 3.1 |
| 7 | 16.04 | 8.1 | 19 | 25.12 | 8.2 |
| 8 | 16.995 | 7.2 | 20 | 25.816 | 3.9 |
| 9 | 17.86 | 31.7 | 21 | 26.577 | 4.1 |
| 10 | 18.242 | 5 | 22 | 27.142 | 25.4 |
| 11 | 18.596 | 5.5 | 23 | 27.396 | 12.3 |
| 12 | 19.175 | 5.6 | 24 | 30.518 | 5.3 |
(2)TG-DSC
The results are shown in fig. 2, which shows a Differential Scanning Calorimeter (DSC): the eutectic melting point was 158.3 ℃.
Thermogravimetric analysis (TGA) shows: decomposition of p-aminobenzoic acid and decomposition of progesterone were observed over the temperature range tested.
(3) Infrared absorption Spectrum (IR)
As shown in fig. 3 and table 2, the progesterone-p-aminobenzoic acid eutectic has an infrared absorption peak at the position shown in table 2.
TABLE 2 main IR absorption peaks of progesterone-p-aminobenzoic acid cocrystals
(4) Scanning electron microscope atlas
The test result is shown in fig. 4, and as can be seen from a scanning electron microscope image, the size of the eutectic particles is small, which is beneficial to improving the water solubility; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.
(5)1H-NMR nuclear magnetic resonance spectrum
The results are shown in FIG. 5, where the shift of the NMR spectrum is as follows:
1H-NMR(500MHz,d6-DMSO)δ＝11.94(s,1H),7.62(d,2H),6.53(d,2H),5.86(s,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25(m,1H),2.23(m,1H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H)。
(6) x-ray single crystal diffraction (SXRD)
As shown in fig. 6 and table 3, it is clear from the results of the single crystal structure analysis that the ratio of the progesterone-p-aminobenzoic acid eutectic molecules is 1:2, and the two are connected by a hydrogen bond.
TABLE 3 progesterone-p-aminobenzoic acid eutectic structures
(7) Stability test
The experimental results are shown in fig. 7, where the progesterone-p-aminobenzoic acid eutectic is stable under high temperature, high humidity, and light conditions.
(8) Solubility test
The experimental results, as shown in fig. 8, the formation of co-crystals significantly increased the water solubility of progesterone.
2. Progesterone-o-methylbenzoic acid eutectic
(1)PXRD
As shown in fig. 10 and table 4, the X-ray powder diffraction pattern of progesterone-o-methylbenzoic acid has characteristic diffraction peaks corresponding to the corresponding positions of the 2 theta values.
TABLE 4 absorption peaks of X-powder diffraction spectra of eutectic progesterone-o-methylbenzoic acid
| Serial number | 2θ/° | Relative intensity/%) | Serial number | 2θ/° | Relative intensity/%) |
| 1 | 7.142 | 7.7 | 16 | 20.378 | 8.2 |
| 2 | 9.38 | 27.6 | 17 | 21.08 | 62.4 |
| 3 | 10.818 | 22.2 | 18 | 21.561 | 82.1 |
| 4 | 11.597 | 14.2 | 19 | 22.42 | 15.5 |
| 5 | 12.421 | 26.8 | 20 | 22.74 | 8.3 |
| 6 | 12.962 | 40.5 | 21 | 23.04 | 15.6 |
| 7 | 13.22 | 100 | 22 | 23.725 | 7.8 |
| 8 | 14.02 | 36.6 | 23 | 24.742 | 13.8 |
| 9 | 14.941 | 25.7 | 24 | 25.96 | 8.5 |
| 10 | 15.741 | 48.7 | 25 | 26.76 | 38.1 |
| 11 | 16.441 | 14.7 | 26 | 27.164 | 8.9 |
| 12 | 17.041 | 51.2 | 27 | 28.001 | 32.1 |
| 13 | 18.38 | 34.7 | 28 | 28.561 | 14.5 |
| 14 | 18.799 | 19.5 | 29 | 29.939 | 8.1 |
| 15 | 19.36 | 10.9 |
(2)TG-DSC
The results are shown in fig. 11, which shows a Differential Scanning Calorimeter (DSC): the eutectic melting point was 88.68 ℃.
Thermogravimetric analysis (TGA) shows: decomposition of o-methylbenzoic acid and decomposition of progesterone were observed over the temperature range tested.
(3) Infrared absorption Spectrum (IR)
As shown in fig. 12 and table 5, the progesterone-o-methylbenzoic acid co-crystal exhibited infrared absorption peaks at the positions shown in table 5.
TABLE 5 Main Infrared absorption Peak of Progesterone-o-methylbenzoic acid Co-crystal
| Wave number v/cm-1 | Transmittance/%) |
| 2937.7 | 94.7 |
| 2558.2 | 98.1 |
| 2145.2 | 98.6 |
| 2014.3 | 98.7 |
| 1671.9 | 92.5 |
| 1446.8 | 97.8 |
| 1353.5 | 97.6 |
| 1272.5 | 96.2 |
| 1223 | 97.2 |
| 1085.1 | 98.6 |
| 939.8 | 97.6 |
| 874.1 | 98.4 |
| 749.1 | 98.4 |
(4) Scanning electron microscope atlas
The test result is shown in fig. 13, and as can be seen from a scanning electron microscope image, the size of the eutectic particles is small, which is beneficial to improving the water solubility; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.
(5)1H-NMR nuclear magnetic resonance spectrum
The results are shown in FIG. 14, where the shift of the NMR spectrum is as follows:
1H-NMR(400MHz,d6-DMSO)δ＝12.80(s,1H),7.82(d,1H),7.42(t,1H),7.30(d,2H),5.63(s,1H),2.58-2.56(t,1H),2.44-2.37(m,2H),2.36(s,3H),2.25-2.23(m,2H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H)。
(6) x-ray single crystal diffraction (SXRD)
As shown in fig. 15 and table 6, from the single crystal structure analysis results, it was found that the progesterone-o-methylbenzoic acid eutectic molecular ratio was 1:1, and the two were connected by a hydrogen bond.
TABLE 6 progesterone-o-methylbenzoic acid eutectic structures
(7) Stability test
The experimental results are shown in fig. 16, where the progesterone-o-methylbenzoic acid eutectic is stable under high temperature, high humidity, and light conditions.
(8) Solubility test
The results of the experiment are shown in fig. 17, and the formation of the co-crystal significantly increases the water solubility of progesterone.
3. Progesterone-p-methylbenzoic acid eutectic crystal
(1)PXRD
The experimental results are shown in fig. 19 and table 7, and the X-ray powder diffraction pattern of progesterone-p-methylbenzoic acid has characteristic diffraction peaks corresponding to the corresponding positions of the 2 theta values.
TABLE 7 eutectic X-powder diffraction spectra absorption peaks of progesterone-p-methylbenzoic acid
(2)TG-DSC
The results are shown in fig. 20, which shows a Differential Scanning Calorimeter (DSC): the eutectic melting point was 114.5 ℃.
Thermogravimetric analysis (TGA) shows: decomposition of p-toluic acid and decomposition of progesterone were observed in the temperature range tested.
(3) Infrared absorption Spectrum (IR)
As shown in fig. 21 and table 8, the progesterone-p-methylbenzoic acid eutectic has an infrared absorption peak at the position shown in table 8.
TABLE 8 main infrared absorption peaks of progesterone-p-methylbenzoic acid cocrystal
| Wave number v/cm-1 | Transmittance/%) |
| 2934.08 | 92.5 |
| 2882.59 | 95.9 |
| 2862.62 | 96.4 |
| 1705.61 | 88.3 |
| 1693.01 | 76.6 |
| 1643.71 | 91.1 |
| 1606.91 | 89.9 |
| 1413.16 | 95.5 |
| 1272.60 | 96.4 |
| 1176.18 | 88.5 |
| 1069.73 | 98.2 |
| 946.52 | 94.3 |
| 924.88 | 96.3 |
| 893.11 | 92.4 |
| 828.59 | 94.9 |
| 809.64 | 96.9 |
| 759.40 | 87.3 |
(4) Scanning electron microscope atlas
The test result is shown in fig. 22, and as can be seen from a scanning electron microscope image, the size of the eutectic particles is small, which is beneficial to improving the water solubility; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.
(5)1H-NMR nuclear magnetic resonance spectrum
The results are shown in FIG. 23, where the shifts of the NMR spectra are as follows:
1H-NMR(400MHz,d6-DMSO)δ＝12.81(s,1H),7.84(d,2H),7.31(d,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,4H),2.25-2.23(m,2H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H)。
(6) x-ray single crystal diffraction (SXRD)
As shown in fig. 24 and table 9, from the single crystal structure analysis results, it was found that the progesterone-p-methylbenzoic acid eutectic molecular ratio was 2:1, and the two were linked by a hydrogen bond.
TABLE 9 progesterone-p-methylbenzoic acid eutectic structure
(7) Stability test
The experimental results are shown in fig. 25, where the progesterone-p-methylbenzoic acid eutectic is stable under high temperature, high humidity, and light conditions.
(8) Solubility test
The experimental results, as shown in fig. 26, formation of the co-crystal significantly increased the water solubility of progesterone.
4. Progesterone-m-methoxybenzoic acid eutectic
(1)PXRD
The experimental results are shown in fig. 28 and table 10, and the X-ray powder diffraction pattern of progesterone-m-methoxybenzoic acid has characteristic diffraction peaks corresponding to the corresponding positions of the 2 theta values.
TABLE 10 eutectic X-powder diffraction spectra absorption peaks of progesterone-m-methoxybenzoic acid
| Serial number | 2θ/° | Relative intensity/%) | Serial number | 2θ/° | Relative intensity/%) |
| 1 | 10.422 | 8.5 | 16 | 21.16 | 87.6 |
| 2 | 10.635 | 25.5 | 17 | 21.361 | 35.4 |
| 3 | 11.22 | 11.4 | 18 | 22.237 | 15.8 |
| 4 | 12.358 | 20.4 | 19 | 23.525 | 5.4 |
| 5 | 12.739 | 41.4 | 20 | 23.701 | 12.4 |
| 6 | 13.34 | 64.1 | 21 | 24.021 | 11.9 |
| 7 | 13.702 | 5.4 | 22 | 24.171 | 13.6 |
| 8 | 14.583 | 27.3 | 23 | 25.466 | 9.5 |
| 9 | 15.415 | 100 | 24 | 25.696 | 8.3 |
| 10 | 16.116 | 49.7 | 25 | 26.339 | 17.3 |
| 11 | 16.844 | 64.3 | 26 | 26.814 | 22.3 |
| 12 | 17.017 | 78.6 | 27 | 27.519 | 46.5 |
| 13 | 17.941 | 24.7 | 28 | 33.122 | 30.8 |
| 14 | 18.176 | 71 | 29 | 37.575 | 19.5 |
| 15 | 20.695 | 31.6 | 30 | 39.736 | 31.9 |
(2)TG-DSC
The results are shown in fig. 29, which shows a Differential Scanning Calorimeter (DSC): the eutectic melting point was 77.19 ℃.
Thermogravimetric analysis (TGA) shows: decomposition of m-methoxybenzoic acid and decomposition of progesterone were observed over the temperature range tested.
(3) Infrared absorption Spectrum (IR)
As shown in fig. 30 and table 11, the progesterone-m-methoxybenzoic acid eutectic has an infrared absorption peak at the position shown in table 11.
TABLE 11 main infrared absorption peaks of progesterone-m-methoxybenzoic acid cocrystal
| Wave number v/cm-1 | Transmittance/%) |
| 2932.3 | 96.2 |
| 2579.1 | 97.8 |
| 2164.8 | 98.2 |
| 2031.5 | 98.4 |
| 1724.4 | 97.3 |
| 1693.5 | 94.6 |
| 1639.9 | 97.1 |
| 1588.7 | 97.4 |
| 1488.5 | 98.4 |
| 1464.7 | 97.2 |
| 1429.7 | 97.7 |
| 1355.9 | 98.2 |
| 1315.8 | 96.7 |
| 1292.3 | 96.5 |
| 1239 | 97.5 |
| 1210.4 | 96.5 |
| 1178.4 | 97.6 |
| 1161.2 | 98.1 |
| 1042 | 98.2 |
| 939.3 | 98.2 |
| 887.6 | 98 |
| 870.7 | 97.6 |
| 818.3 | 98.4 |
| 759.9 | 95.4 |
| 736.9 | 96.3 |
| 682.3 | 96.9 |
(4) Scanning electron microscope atlas
The test result is shown in fig. 31, and as can be seen from a scanning electron microscope image, the size of the eutectic particles is small, which is beneficial to improving the water solubility; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.
(5)1H-NMR nuclear magnetic resonance spectrum
The results are shown in FIG. 32, where the shifts of the NMR spectrum are as follows:
1H-NMR(500MHz,d6-DMSO)δ＝12.95(s,1H),7.54(d,1H),7.44(t,2H),7.20(d,1H),5.63(s,1H),3.80(s,3H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25-2.23(m,2H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H).
(6) x-ray single crystal diffraction (SXRD)
As shown in fig. 33 and table 12, it is clear from the single crystal structure analysis results that the progesterone-m-methoxybenzoic acid eutectic molecular ratio is 1:1, and the two are linked by a hydrogen bond.
TABLE 12 progesterone-m-methoxybenzoic acid eutectic structure
(7) Stability test
The experimental results are shown in fig. 34, where the progesterone-m-methoxybenzoic acid eutectic is stable under high temperature, high humidity, and light conditions.
(8) Solubility test
The results of the experiment are shown in fig. 35, and the formation of the co-crystal significantly increases the water solubility of progesterone.
5. Progesterone-phthalic acid cocrystal
(1)PXRD
As shown in fig. 37 and table 13, the X-ray powder diffraction pattern of progesterone-phthalic acid has characteristic diffraction peaks at corresponding positions of 2 θ.
TABLE 13 progesterone-phthalic acid cocrystal X-powder diffraction Spectrum absorption peaks
(2)TG-DSC
The results are shown in fig. 38, which shows a Differential Scanning Calorimeter (DSC): the eutectic melting point was 126.04 ℃.
Thermogravimetric analysis (TGA) shows: decomposition of phthalic acid and decomposition of progesterone were observed over the temperature range tested.
(3) Infrared absorption Spectrum (IR)
As shown in fig. 39 and table 14, the progesterone-phthalic acid co-crystal has an infrared absorption peak at the position shown in table 14.
TABLE 14 main infrared absorption peaks of progesterone-phthalic acid cocrystals
| Wave number v/cm-1 | Transmittance/%) |
| 2969.2 | 47.2 |
| 2940.7 | 44.1 |
| 2925.1 | 44.1 |
| 2851.9 | 53.6 |
| 1730 | 67.6 |
| 1699.9 | 52.4 |
| 1666.4 | 43.4 |
| 1615.8 | 55.9 |
| 1472.9 | 75.7 |
| 1439.2 | 66.2 |
| 1384.9 | 71.4 |
| 1356.9 | 52.5 |
| 1329.3 | 70.3 |
| 1278 | 67.5 |
| 1228.4 | 54.2 |
| 1205.2 | 57.8 |
| 1162.5 | 72.1 |
| 1145.1 | 76.9 |
| 1119.3 | 80 |
| 1070.1 | 83.6 |
| 948.5 | 71.5 |
| 870.6 | 74.7 |
| 778.9 | 83.9 |
(4) Scanning electron microscope atlas
The test result is shown in fig. 40, and as can be seen from a scanning electron microscope image, the size of the eutectic particles is small, which is beneficial to improving the water solubility; the eutectic particles are uniform, which shows that the preparation process is good and is very beneficial to industrial production and preparation.
(5)1H-NMR nuclear magnetic resonance spectrum
The results are shown in FIG. 41, where the shifts of the NMR spectrum are as follows:
1H-NMR(500MHz,d6-DMSO)δ＝13.15(s,2H),7.68(d,2H),7.59(d,2H),5.63(s,1H),2.57-2.55(t,1H),2.42-2.33(m,2H),2.25-2.23(m,2H),2.18-2.14(m,6H),1.77-1.64(d,1H),1.61-1.52(m,5H),1.43-1.38(m,2H),1.18-1.14(m,5H),0.96-0.93(m,2H),0.57(S,3H)。
(6) x-ray single crystal diffraction (SXRD)
As shown in fig. 42 and table 15, from the single crystal structure analysis results, it was found that the progesterone-phthalic acid eutectic molecular ratio was 1:1, and the two were linked by a hydrogen bond.
TABLE 15 progesterone-phthalic acid eutectic structures
(7) Stability test
As shown in fig. 43, the progesterone-phthalic acid co-crystal was stable under high temperature, high humidity, and light conditions.
(8) Solubility test
The results of the experiment are shown in fig. 44, and the formation of the co-crystal significantly increases the water solubility of progesterone.
Example 3 bioavailability assay of Progesterone Co-crystals
Firstly, testing:
1. animal(s) production
Healthy female SD rats (7-9 weeks old, weight 220 + -30 g, 5 per group) were purchased from Peking Wintolite laboratory animals technology, Inc.
2. Animal administration method
All animals were kept on a 12 hr/12 hr light/dark cycle, 5 animals per cage, with free diet. Progesterone and its eutectic crystal and PBS (phosphate buffered saline, containing 0.1% DMSO) are prepared into solution, the dosage is equivalent to 5.0mg/kg of progesterone, and intramuscular injection is used for administration.
3. Method for preparing biological sample
Samples of 50 μ L jugular venous blood were collected in batches at defined times (15, 30min and 1, 1.5, 2, 3, 5, 7, 12, 24, 48h) into heparinized tubes. The blood was then centrifuged for 15 min. Plasma samples were stored at-20 ℃. mu.L rat plasma, 5. mu.L methanol and 200. mu.L internal standard solution (buspirone, 5ng/mL) were added to 1mL methanol: acetonitrile (1:1, v/v). The plasma samples were vortexed for 1min, centrifuged at 4000rpm for 15min, and the plasma samples were vortexed with methanol: the supernatant was diluted 20 times with water (1:1, v/v, 0.1% trifluoroacetic acid) and injected.
4. Biological sample analysis method
LC-MS/MS instrument model: AB Sciex 5500; LC-MS/MS quantitative analysis software: 1.6.3; an ionization mode: electrospray positive ions; the scanning mode is as follows: multiple Reaction Monitoring (MRM); analyte MRM: EE-DNS, 530.4/171.0; internal standard MRM: buspirone, 386.2/122.2;
liquid phase conditions: shimadzu LC-30AD, ACE Excel 5C4(50mm × 2.1mm), sample size 10 μ L; mobile phase: a5 mM ammonium acetate (0.05% trifluoroacetic acid) and B acetonitrile (0.1% trifluoroacetic acid) at a flow rate of 0.8mL/min, and the gradients of mobile phases A and B are shown in the following table.
TABLE 16 gradient of mobile phases A and B
| Time (min) | A(％) | B(％) |
| 0.4-1.8 | 80.0 | 20.0 |
| 1.8-2.7 | 5.00 | 95.0 |
| 2.7-3.5 | 80.0 | 20.0 |
Second, test results
1. Progesterone-p-aminobenzoic acid eutectic crystal
As shown in fig. 9, the peak time of progesterone was 1h, the co-crystal peak time was 1.5h, and the co-crystal Cmax was 1.9 times that of progesterone.
2. Progesterone-o-methylbenzoic acid eutectic
As shown in fig. 18, the peak time of progesterone was 1h, the co-crystal peak time was 1.5h, and the co-crystal Cmax was 2.4 times that of progesterone.
3. Progesterone-p-methylbenzoic acid eutectic crystal
As shown in fig. 27, the peak time of progesterone was 1h, the co-crystal peak time was 1.5h, and the co-crystal Cmax was 2.2 times that of progesterone.
4. Progesterone-m-methoxybenzoic acid eutectic
As shown in fig. 36, the peak time of progesterone was 1h, the co-crystal peak time was 1.5h, and the co-crystal Cmax was 2.0 times that of progesterone.
5. Progesterone-phthalic acid cocrystal
As shown in fig. 45, the peak time of progesterone was 1h, the co-crystal peak time was 1.5h, and the co-crystal Cmax was 1.7 times that of progesterone.
The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.
Claims (10)
1. The eutectic crystal is characterized in that the active ingredient of the eutectic crystal is progesterone, the eutectic crystal formation of the eutectic crystal is a benzoic acid derivative, and the benzoic acid derivative comprises p-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid or phthalic acid,
when the benzoic acid derivative is p-aminobenzoic acid, the experimental formula of the obtained progesterone-p-aminobenzoic acid eutectic is C28H37NO4Preferably, the progesterone-p-aminobenzoic acid eutectic has an X-ray powder diffraction pattern expressed in 2 theta angles at 13.519 DEG, 13.878 DEG, using Cu-Ka radiation,Characteristic peaks at 17.86 °, 20.56 °, 27.142 °, wherein the error range of each characteristic peak 2 θ is ± 0.2 °, preferably, the X-ray powder diffraction pattern of the progesterone-p-aminobenzoic acid eutectic expressed in 2 θ angles also has characteristic peaks at 7.001 °, 8.521 °, 9.719 °, 14.44 °, 16.04 °, 16.995 °, 18.242 °, 18.596 °, 19.175 °, 19.913 °, 22.12 °, 23.42 °, 23.699 °, 24.016 °, 25.12 °, 25.816 °, 26.577 °, 27.396 °, 30.518 ° using Cu-ka radiation, wherein the error range of each characteristic peak 2 θ is ± 0.2 °;
when the benzoic acid derivative is o-methylbenzoic acid, the laboratory of the obtained progesterone-o-methylbenzoic acid eutectic is C29H38O4Preferably, the eutectic progesterone-o-methylbenzoic acid has characteristic peaks in the X-ray powder diffraction pattern of 2 theta angles using Cu-ka radiation at 9.38 °, 10.818 °, 12.421 °, 12.962 °, 13.22 °, 14.02 °, 14.941 °, 15.741 °, 17.041 °, 18.38 °, 21.08 °, 21.561 °, 26.76 °, 28.001 °, wherein the error range of 2 theta for each characteristic peak is ± 0.2 °, preferably, the eutectic progesterone-o-methylbenzoic acid also has characteristic peaks in the X-ray powder diffraction pattern of 2 theta angles using Cu-ka radiation at 7.142 °, 11.597 °, 16.441 °, 18.799 °, 19.36 °, 20.378 °, 22.42 °, 22.74 °, 23.04 °, 23.725 °, 24.742 °, 25.96 °, 27.164 °, 28.561 °, 29.939 °, wherein the error range of 2 theta for each characteristic peak is ± 0.2 °;
when the benzoic acid derivative is p-methylbenzoic acid, the experimental formula of the obtained progesterone-p-methylbenzoic acid eutectic is C50H68O6Preferably, Cu-Ka radiation is used, and the X-ray powder diffraction pattern of the progesterone-p-toluic acid eutectic expressed by the angle of 2 theta has characteristic peaks at 12.958 degrees, 13.922 degrees, 14.256 degrees, 18.103 degrees, 18.501 degrees, 20.261 degrees, 20.942 degrees, 24.158 degrees and 26.921 degrees, wherein the error range of 2 theta of each characteristic peak is +/-0.2 degrees, and preferably, Cu-Ka radiation is used, and the X-ray powder diffraction pattern of the progesterone-p-toluic acid eutectic expressed by the angle of 2 theta is also 6.967 degrees, 8.343 degrees, 9.256 degrees, 12.3 degrees and 14.723 degreesCharacteristic peaks are arranged at the positions of degree, 16.2 degrees, 16.964 degrees, 17.324 degrees, 17.895 degrees, 19.283 degrees, 19.818 degrees, 24.423 degrees, 24.782 degrees, 25.062 degrees, 26.081 degrees, 26.662 degrees and 27.303 degrees, wherein the error range of 2 theta of each characteristic peak is +/-0.2 degrees;
when the benzoic acid derivative is m-methoxybenzoic acid, the experimental formula of the obtained progesterone-m-methoxybenzoic acid eutectic is C29H38O5Preferably, with Cu-ka radiation, the X-ray powder diffraction pattern of the progesterone-m-anisic acid eutectic expressed by 2 θ angles has characteristic peaks at 10.635 °, 12.358 °, 12.739 °, 13.34 °, 14.583 °, 15.415 °, 16.116 °, 16.844 °, 17.017 °, 17.941 °, 18.176 °, 20.695 °, 21.16 °, 21.361 °, 26.814 °, 27.519 °, 33.122 °, 39.736 °, wherein the error range of 2 θ of each characteristic peak is ± 0.2 °, preferably, with Cu-ka radiation, the X-ray powder diffraction pattern of the progesterone-m-anisic acid eutectic expressed by 2 θ angles also has characteristic peaks at 10.422 °, 11.22 °, 13.702 °, 22.237 °, 23.525 °, 23.701 °, 24.021 °, 24.171 °, 25.466 °, 25.696 °, 26.339 °, 37.575 °, wherein the error range of 2 θ of each characteristic peak is ± 0.2 °;
when the benzoic acid derivative is phthalic acid, the experimental formula of the obtained progesterone-phthalic acid eutectic is C29H36O6Preferably, the progesterone-phthalic acid co-crystal has characteristic peaks in the X-ray powder diffraction pattern at 2 theta angles expressed by 10.853 °, 12.883 °, 13.254 °, 14.175 °, 15.559 °, 16.319 °, 16.956 °, 17.159 °, 17.519 °, 18.523 °, 19.86 °, 20.363 °, 21.063 °, 23.774 °, 25.363 ° using Cu-ka radiation, wherein the error range of 2 theta for each characteristic peak is ± 0.2 °, preferably, the progesterone-phthalic acid co-crystal also has characteristic peaks in the X-ray powder diffraction pattern at 2 theta angles expressed by 9.998 °, 10.557 °, 12.275 °, 13.598 °, 13.781 °, 14.744 °, 15.017 °, 18.024 °, 19.281 °, 21.583 °, 21.973 °, 23.461 °, 24.961 °, 26.378 °, 26.8 °, 27.042 °, 28.117 °, 37.761 °, wherein the error range of 2 theta for each characteristic peak is 2 thetaThe circumference is +/-0.2 degrees.
2. The co-crystal according to claim 1, characterized in that the infrared spectrum of said co-crystal of progesterone-p-aminobenzoic acid is 3425.84cm-1、3346.40cm-1、3235.75cm-1、2940.83cm-1、2870.37cm-1、1693.62cm-1、1596.26cm-1、1569.84cm-1、1447.10cm-1、1414.77cm-1、1351.21cm-1、1316.64cm-1、1248.65cm-1、954.82cm-1、852.33cm-1、778.88cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
Preferably, the progesterone-P-aminobenzoic acid eutectic is an orthorhombic system, P212121Space group, cell parameter of
α is 90 °, β is 90 °, γ is 90 °, Z is 8, and the unit cell volume is
3. The co-crystal of claim 1, wherein the progesterone-o-methylbenzoic acid co-crystal has an infrared spectrum of 2937.7cm-1、2558.2cm-1、2145.2cm-1、2014.3cm-1、1671.9cm-1、1446.8cm-1、1353.5cm-1、1272.5cm-1、1223.0cm-1、1085.1cm-1、939.8cm-1、874.1cm-1、749.1cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
Preferably, the progesterone-o-methylbenzoic acid eutectic is a triclinic system, P1 space group and unit cell parameters are
A is 79.362(4), β is 81.464(4), γ is 75.860(5), and Z is 2, and the unit cell volume is
4. The co-crystal of claim 1, wherein the progesterone-p-toluic acid co-crystal has an infrared spectrum of 2934.08cm-1、2882.59cm-1、2862.62cm-1、1705.61cm-1、1693.01cm-1、1643.71cm-1、1606.91cm-1、1413.16cm-1、1272.60cm-1、1176.18cm-1、1069.73cm-1、946.52cm-1、924.88cm-1、893.11cm-1、828.59cm-1、809.64cm-1、759.40cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
Preferably, the progesterone-P-methylbenzoic acid eutectic is a triclinic system, P1 space group and unit cell parameters are
A is 104.300(5) °, β is 94.717(5) °, γ is 103.307(5) °, Z is 1, and unit cell volume is
5. The co-crystal of claim 1, wherein the progesterone-m-methoxybenzoic acid co-crystal has an infrared spectrum of 2932.3cm-1、2579.1cm-1、2164.8cm-1、2031.5cm-1、1724.4cm-1、1693.5cm-1、1639.9cm-1、1588.7cm-1、1488.5cm-1、1464.7cm-1、1429.7cm-1、1355.9cm-1、1315.8cm-1、1292.3cm-1、1239.0cm-1、1210.4cm-1、1178.4cm-1、1161.2cm-1、1042.0cm-1、939.3cm-1、887.6cm-1、870.7cm-1、818.3cm-1、759.9cm-1、736.9cm-1、682.3cm-1Absorption peaks exist at the wavelength, wherein the error range of each absorption peak is +/-2 cm < -1 >;
preferably, the progesterone-m-methoxybenzoic acid eutectic is an orthorhombic system, P212121Space group, cell parameter of
α is 90.00 °, β is 90.00 °, γ is 90.00 °, Z is 4, and the unit cell volume is
6. The co-crystal of claim 1, wherein the progesterone-phthalic acid co-crystal has an infrared spectrum of 1730.0cm-1、1472.9cm-1、1439.2cm-1、1384.9cm-1、1329.3cm-1、1278.0cm-1、1162.5cm-1、1145.1cm-1、1119.3cm-1、1070.1cm-1、948.5cm-1、870.6cm-1、778.9cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1(ii) a Preferably, the infrared spectrum of the progesterone-phthalic acid eutectic crystal is 2969.2cm-1、2940.7cm-1、2925.1cm-1、2851.9cm-1、1699.9cm-1、1666.4cm-1、1615.8cm-1、1356.9cm-1、1228.4cm-1、1205.2cm-1Has absorption peaks at the wavelength, wherein the error range at each absorption peak is + -2 cm-1；
Preferably, the progesterone-phthalic acid eutectic is monoclinic system, P21Space group, cell parameter of
Alpha is 90.00 degree, beta is 92.380(2 degree), gamma is 90.00 degree, Z is 4, unit cell volume is
7. A pharmaceutical composition comprising the co-crystal of any one of claims 1 to 6, preferably further comprising a pharmaceutically acceptable carrier or adjuvant.
8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition comprises a solid, a semi-solid, a liquid, and a solid oral dosage form, preferably the dosage form is a solid oral dosage form, preferably the solid oral dosage form comprises a tablet, a capsule, a granule, a pill, or a powder.
9. Use according to any one of the following:
(1) use of a pharmaceutical composition according to claim 7 or 8 for the manufacture of a medicament for maintaining pregnancy;
(2) use of a pharmaceutical composition according to claim 7 or 8 for the manufacture of a medicament for the treatment of gynaecological disorders;
preferably, the gynecological diseases include spontaneous premature birth, corpus luteum insufficiency, secondary amenorrhea, premenstrual syndrome.
10. A method of making the co-crystal of claim 1, comprising the steps of:
1) crushing progesterone and benzoic acid derivative to obtain white powder sample,
2) adding a white powder sample into an organic solvent for dissolving, and volatilizing to obtain a colorless massive crystal;
the benzoic acid derivative comprises p-aminobenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, m-methoxybenzoic acid or phthalic acid,
preferably, the molar ratio of progesterone to said benzoic acid derivative is 1: 1;
preferably, the organic solvent comprises C1-C4 alcohol, ethyl acetate or acetone, preferably, the organic solvent is C1-C4 alcohol, preferably, the C1-C4 alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol or isobutanol, preferably, the C1-C4 alcohol is methanol;
preferably, the progesterone and the benzoic acid derivative are pulverized using a ball mill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111153647.4A CN113683654A (en) | 2021-09-29 | 2021-09-29 | Preparation and application of progesterone eutectic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111153647.4A CN113683654A (en) | 2021-09-29 | 2021-09-29 | Preparation and application of progesterone eutectic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113683654A true CN113683654A (en) | 2021-11-23 |
Family
ID=78587402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111153647.4A Pending CN113683654A (en) | 2021-09-29 | 2021-09-29 | Preparation and application of progesterone eutectic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113683654A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114292305A (en) * | 2022-01-25 | 2022-04-08 | 国家卫生健康委科学技术研究所 | Pharmaceutical co-crystal of progesterone and formic acid derivative and application thereof |
| CN114644669A (en) * | 2022-03-10 | 2022-06-21 | 华润紫竹药业有限公司 | Preparation method and application of progesterone eutectic |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130102781A1 (en) * | 2011-10-21 | 2013-04-25 | Aptuit (West Lafayette), Llc | Methods of making cocrystals |
| US20140235595A1 (en) * | 2012-09-05 | 2014-08-21 | Aptuit, Inc. | Cocrystals of progesterone |
| CN111303230A (en) * | 2020-03-09 | 2020-06-19 | 中国食品药品检定研究院 | Progesterone eutectic compound and preparation method and application thereof |
| CN113214337A (en) * | 2021-05-19 | 2021-08-06 | 国家卫生健康委科学技术研究所 | Pharmaceutical co-crystal of progesterone, pyridine and derivatives thereof |
-
2021
- 2021-09-29 CN CN202111153647.4A patent/CN113683654A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130102781A1 (en) * | 2011-10-21 | 2013-04-25 | Aptuit (West Lafayette), Llc | Methods of making cocrystals |
| US20140235595A1 (en) * | 2012-09-05 | 2014-08-21 | Aptuit, Inc. | Cocrystals of progesterone |
| US20170101433A1 (en) * | 2012-09-05 | 2017-04-13 | Amri Ssci, Llc | Cocrystals of progesterone |
| CN111303230A (en) * | 2020-03-09 | 2020-06-19 | 中国食品药品检定研究院 | Progesterone eutectic compound and preparation method and application thereof |
| CN113214337A (en) * | 2021-05-19 | 2021-08-06 | 国家卫生健康委科学技术研究所 | Pharmaceutical co-crystal of progesterone, pyridine and derivatives thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114292305A (en) * | 2022-01-25 | 2022-04-08 | 国家卫生健康委科学技术研究所 | Pharmaceutical co-crystal of progesterone and formic acid derivative and application thereof |
| CN114644669A (en) * | 2022-03-10 | 2022-06-21 | 华润紫竹药业有限公司 | Preparation method and application of progesterone eutectic |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113683654A (en) | Preparation and application of progesterone eutectic | |
| CN109641851B (en) | Crystal form of androgen receptor antagonist medicine and preparation method and application thereof | |
| US10703724B2 (en) | Crystalline forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino} acetic acid and processes for preparation thereof | |
| CN108794555B (en) | Ethinylestradiol pharmaceutical co-crystal and preparation method thereof | |
| WO2019242439A1 (en) | Crystal form of arn-509, preparation method therefor and use thereof | |
| WO2019062854A1 (en) | Co-crystals of ribociclib and co-crystals of ribociclib mono-succinate, preparation method therefor, compositions thereof, and uses thereof | |
| CN113817012B (en) | Progesterone eutectic crystal and preparation method and application thereof | |
| WO2020063939A1 (en) | Crystal form of upadacitinib and preparation method and use thereof | |
| US20230374030A1 (en) | Solid-state forms of relugolix | |
| WO2020156448A1 (en) | Crystal of diarylthiohydantoin compound | |
| CN113292621B (en) | Pharmaceutical crystal form of progesterone and application thereof | |
| CN113214337B (en) | Pharmaceutical co-crystal of progesterone, pyridine and derivatives thereof | |
| US9593117B2 (en) | Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN112159448A (en) | Ethinylestradiol pharmaceutical co-crystal and preparation method and application thereof | |
| US9598413B2 (en) | Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN110105417B (en) | Medicine eutectic and preparation method and application thereof | |
| US9593116B2 (en) | Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN113185564B (en) | Pharmaceutical co-crystal of progesterone, preparation method and application thereof | |
| CN110003122B (en) | Pharmaceutical cocrystal of ethinylestradiol and ligustrazine and application thereof | |
| US10221185B2 (en) | Crystal form of substituted aminopyran derivativek | |
| WO2022166774A1 (en) | Crystal form of 3-hydroxy-5-pregnane-20-one derivative, and preparation method therefor and use thereof | |
| CN114644669A (en) | Preparation method and application of progesterone eutectic | |
| CN114292305A (en) | Pharmaceutical co-crystal of progesterone and formic acid derivative and application thereof | |
| CN116239598A (en) | Ketorolac and piperazine eutectic and preparation method thereof | |
| JP2023532217A (en) | Crystal forms of SHP2 inhibitors, compositions thereof, methods of preparation and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |