CN118908900B - A minoxidil lactate crystal form and its preparation method and application - Google Patents
A minoxidil lactate crystal form and its preparation method and application Download PDFInfo
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- CN118908900B CN118908900B CN202411408549.4A CN202411408549A CN118908900B CN 118908900 B CN118908900 B CN 118908900B CN 202411408549 A CN202411408549 A CN 202411408549A CN 118908900 B CN118908900 B CN 118908900B
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- 229960003632 minoxidil Drugs 0.000 title claims abstract description 121
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 title claims abstract description 114
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 title claims abstract description 68
- 239000013078 crystal Substances 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 230000035699 permeability Effects 0.000 claims abstract description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 34
- 239000007787 solid Substances 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000004310 lactic acid Substances 0.000 claims description 17
- 235000014655 lactic acid Nutrition 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 9
- 201000004384 Alopecia Diseases 0.000 claims description 4
- 231100000360 alopecia Toxicity 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- -1 minoxidil cations Chemical class 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- XHQZJYCNDZAGLW-UHFFFAOYSA-N 3-methoxybenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1 XHQZJYCNDZAGLW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
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- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZIMGGGWCDYVHOY-UHFFFAOYSA-N 3-hydroxy-2-imino-6-(1-piperidinyl)-4-pyrimidinamine Chemical compound N=C1N(O)C(N)=CC(N2CCCCC2)=N1 ZIMGGGWCDYVHOY-UHFFFAOYSA-N 0.000 description 1
- 241000125205 Anethum Species 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000845082 Panama Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 238000007872 degassing Methods 0.000 description 1
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- 210000004207 dermis Anatomy 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 210000000442 hair follicle cell Anatomy 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000008338 local blood flow Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
- C07C59/08—Lactic acid
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种米诺地尔乳酸盐晶型及其制备方法和应用，涉及药物晶型技术领域。所述米诺地尔乳酸盐晶型在衍射角2θ=6.505°、15.67°、18.805°、23.189°、10.165°、19.425°、20.779°、25.657°和30.449°处有XRPD特征峰。本发明将米诺地尔制成米诺地尔乳酸盐的特定晶型，该晶型可以显著提高其水溶性、稳定性和渗透性。
The invention discloses a minoxidil lactate crystal form and a preparation method and application thereof, and relates to the technical field of drug crystal forms. The minoxidil lactate crystal form has XRPD characteristic peaks at diffraction angles 2θ=6.505°, 15.67°, 18.805°, 23.189°, 10.165°, 19.425°, 20.779°, 25.657° and 30.449°. The invention prepares minoxidil into a specific crystal form of minoxidil lactate, and the crystal form can significantly improve its water solubility, stability and permeability.
Description
Technical Field
The invention relates to the technical field of medicine crystal forms, in particular to a minoxidil lactate crystal form, and a preparation method and application thereof.
Background
The crystal engineering means is used for carrying out crystal modification on the active ingredients of the medicine to obtain the dominant crystal form which is more suitable for production, has better physicochemical properties and better biological activity, and is a new 'shortcut' for medicine research and development. Drug salification is one of the modes of modifying the crystal forms of drugs, and compared with modification means such as forming eutectic or solvate, the drug salification requires that each salifying reagent has ionizable sites and different ionic electricity, and the interaction strength of the formed ionic bond is far greater than non-covalent interactions such as hydrogen bonds. Therefore, the salt formation of the medicine can change the protonation state of the active ingredients of the medicine, has great influence on the spatial arrangement of medicine molecules, further changes the physicochemical properties of the medicine, such as solubility, stability, pharmacokinetics and other parameters, changes the combination mode of the medicine and a target point, influences the interaction strength and selectivity of the medicine and the target point, and leads the treatment effect to be obviously changed.
Minoxidil has the chemical name of 6- (1-piperidinyl) -2, 4-pyrimidinediamine-3-oxide, the molecular formula of C 9H15N5 O, and the structural formula is as follows:
。
Minoxidil can be used for treating hypertension by oral administration and alopecia by external application. Minoxidil plays a role in promoting hair growth by improving the local blood circulation of the scalp and stimulating proliferation and differentiation of hair follicle cells. Minoxidil is a poorly water-soluble drug, limiting its use in water-soluble formulations. Most of the commercially available minoxidil external preparations are tinctures, and usually have various side effects such as allergy, itching, skin flushing, edema of lower limbs, acceleration of heartbeat and the like.
Chinese patent CN113336710a discloses a minoxidil-3-methoxybenzoate crystal form for treating alopecia and a preparation method thereof, wherein the minoxidil-3-methoxybenzoate crystal form is formed by combining 2 minoxidil cations and 2 3-methoxybenzoate anions through ionic bond interaction, the crystal structure belongs to a monoclinic crystal system, and the crystal form has powder diffraction peaks at diffraction angles 2θ= 7.025 °, 8.006 °, 11.168 °, 18.001 °, 20.001 °, 22.170 ° and 22.780 °. The minoxidil crystal form has better therapeutic effect than the original medicine, and also improves the solubility to a certain extent. However, 3-methoxybenzoic acid is more irritating when used during the preparation.
At present, the novel crystal form of minoxidil is still deficient, the crystal form of minoxidil is modified by lactic acid, and the structural formula of the lactic acid is as follows:
。
according to the invention, minoxidil is prepared into a specific crystal form of minoxidil lactate, and the crystal form can remarkably improve water solubility, stability and permeability.
Disclosure of Invention
The invention aims to provide a minoxidil lactate crystal form, a preparation method and application thereof, and a basic structural unit of the minoxidil lactate crystal form is formed by combining 1 minoxidil cation and 1 lactic acid anion through ionic bond interaction, so that the solubility can be improved, and the solid stability, the solution stability and the permeability of an aqueous solution can be obviously improved.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
In one aspect, the invention provides a minoxidil lactate crystal form, wherein XRPD characteristic peaks exist at diffraction angles 2θ= 6.505 °, 15.67 °, 18.805 °, 23.189 °, 10.165 °, 19.425 °, 20.779 °, 25.657 ° and 30.449 °, and the error range of the diffraction angle 2θ value is-0.30 ° to 0.30 °.
Preferably, the minoxidil lactate crystal form has a main peak at diffraction angles 2θ= 6.505 °, 15.67 °, 18.805 ° and 23.189 °, the relative intensity of the main peak being 30% -100%, and a secondary peak at diffraction angles 2θ= 10.165 °, 19.425 °, 20.779 °, 25.657 ° and 30.449 °, the relative intensity of the secondary peak being 10% -30%.
Further preferably, the minoxidil lactate crystal form further has at least one other diffraction peak selected from the group consisting of diffraction angles 2θ=12.88 °, 15.013 °, 16.923 °, 20.275 °, 26.839 °, 27.606 °, 31.496 °, 32.305 °, 33.256 °.
Still more preferably, the relative intensity of the other diffraction peaks is less than 10%.
Still more preferably, the minoxidil lactate crystalline form has XRPD feature peaks at diffraction angles 2θ=6.505°、15.67°、18.805°、23.189°、10.165°、19.425°、20.779°、25.657°、30.449°、12.88°、15.013°、16.923°、20.275°、26.839°、27.606°、31.496°、32.305° and 33.256 °.
Preferably, the minoxidil lactate salt crystalline form has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 2.
Preferably, the minoxidil lactate crystalline form has a thermogravimetric analysis (TGA) profile substantially as shown in figure 3.
Preferably, the minoxidil lactate salt crystalline form has a nuclear magnetic resonance hydrogen spectrum (1 H-NMR) with a chemical environment substantially as shown in fig. 4.
On the other hand, the invention provides a preparation method of the minoxidil lactate crystal form, which comprises the following steps of mixing minoxidil and lactic acid with a solvent 1 to dissolve out solids, adding a solvent 2 to precipitate solids, and separating the solids to obtain the minoxidil lactate crystal form;
Wherein the solvent 1 is at least one selected from acetone, ethanol, isopropanol, methanol, 1, 4-dioxane, tetrahydrofuran and N, N-dimethylamide, and the solvent 2 is at least one selected from ethyl acetate, isopropyl acetate, methyl tertiary butyl ether, N-heptane and acetonitrile.
Preferably, the molar ratio of minoxidil to lactic acid is 1:1-2.
Preferably, the solids are dissolved at a temperature of 20-30 ℃, more preferably 25 ℃.
The preparation method of the minoxidil lactate crystal form comprises the following steps of mixing minoxidil and lactic acid with a solvent 1, carrying out ultrasonic treatment or magnetic stirring at 25 ℃ to dissolve solids, adding a solvent 2 while stirring, magnetically stirring at room temperature for 1-2h or overnight to precipitate solids, and separating the solids to obtain the minoxidil lactate crystal form.
On the other hand, the invention provides a preparation method of the minoxidil lactate crystal form, which comprises the following steps of mixing minoxidil and lactic acid with a solvent, reacting, separating out solids, and separating the solids to obtain the minoxidil lactate crystal form;
Wherein the solvent is at least one selected from acetone, ethyl acetate, acetonitrile, isopropyl acetate isopropyl isopropoxide and methyl ethyl ketone.
Preferably, the molar ratio of minoxidil to lactic acid is 1:1-2.
Finally, the invention provides application of the minoxidil lactate crystal form in preparing a medicament for treating alopecia.
The beneficial effects of the invention are as follows:
The solubility of the specific minoxidil lactate crystal form prepared by the invention is improved, the solid stability and the solution stability are both obviously improved, and the permeability of minoxidil lactate aqueous solution is also improved.
Drawings
Fig. 1 is an XRPD pattern of minoxidil lactate crystalline form of example 1 of the present invention.
FIG. 2 is a DSC profile of the minoxidil lactate crystal form of example 1 of the present invention.
FIG. 3 is a TGA spectrum of minoxidil lactate crystal form of example 1 of the present invention.
FIG. 4 shows the result of 1 H-NMR of minoxidil lactate crystal form according to example 1 of the present invention.
Fig. 5 is an XRPD pattern of minoxidil lactate crystalline form obtained by the method described in experiment No. 1.
FIG. 6 is an XRPD pattern for minoxidil lactate crystals obtained as described in experiment No. 2.
FIG. 7 is an XRPD pattern for minoxidil lactate crystals obtained as described in experiment No. 3.
Fig. 8 is an XRPD pattern of minoxidil lactate crystalline form obtained by the method described in experiment No. 4.
Fig. 9 is an XRPD pattern of minoxidil lactate crystalline form obtained by the method described in experiment No. 5.
Fig. 10 is an XRPD pattern of minoxidil lactate crystalline form obtained by the method described in experiment No. 6.
FIG. 11 is an XRPD pattern for minoxidil lactate crystals obtained as described in experiment No. 7.
Fig. 12 is an enlarged XRPD pattern of minoxidil lactate crystalline form.
Fig. 13 is a graph comparing minoxidil lactate salt form and minoxidil pH dependent solubility.
Fig. 14 shows the results of minoxidil lactate crystal form and minoxidil IVPT.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which should be construed to fall within the scope of the invention as claimed.
The invention is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified. Unless otherwise specified, the contents are mass contents in the following. Unless otherwise indicated, it is understood that it is carried out at room temperature.
In the embodiments described in the following description of the embodiments,
Powder X-ray diffraction (XRPD) powder X-ray diffraction patterns of minoxidil lactate crystals were measured and the patterns of minoxidil as a drug substance and the resulting crystals were compared to confirm the uniqueness of the crystals. The brand of equipment used is Bruker model D8 ADVANCE.
Thermogravimetric analysis (TGA) the thermal stability of the crystalline form was determined by thermogravimetric analysis. The equipment used was of model PERKIN ELMER TGA 4000.
Differential Scanning Calorimeter (DSC) melting point and thermal behavior of the crystalline form are determined by differential scanning calorimeter analysis. The equipment brand used is PERKIN ELMER model DSC 4000.
Nuclear Magnetic Resonance (NMR) analysis was performed to confirm the chemical environmental change of minoxidil lactate crystal form. The equipment used was of the type Bruker Biospin GmbH.
The crystalline form is most often characterized by XRPD. The XRPD pattern of diffraction (peaks) is generally considered to be a fingerprint of a particular crystal form. The term "peak" refers to a reflection having a relative intensity of at least about 3% of the maximum peak intensity.
DSC, TGA related temperature readings may vary by about + -4 ℃ depending on the instrument, specific setup, sample preparation, etc.
Minoxidil was purchased from Start the Eastern Mountain, lot number MN-202201501.
Example 1
The minoxidil lactate crystal form was prepared by weighing 150mg minoxidil and 130mg lactic acid, adding 0.4mL acetone, sonicating for 1min to completely dissolve the solid, adding 2mL ethyl acetate, magnetically stirring for a period of time to precipitate a white solid, magnetically stirring overnight at room temperature, and separating the solid by centrifugation.
The X-ray powder diffraction pattern of Cu ka radiation is shown in fig. 1, and the peak list is as follows:
Table 1.
The DSC spectrum of the minoxidil lactate crystal form is shown in figure 2, and absorbs heat at 105-140 ℃.
The TGA spectrum of the minoxidil lactate crystal form is shown in fig. 3.
The 1 H-NMR results of the minoxidil lactate crystalline form are shown in FIG. 4. From the nuclear magnetic results, the molar ratio of minoxidil to lactic acid in minoxidil lactate was 1:1.
EXAMPLE 2 preparation of different minoxidil lactate salt crystalline forms
2.1 Reactive crystallization process
Weighing a certain amount of minoxidil and lactic acid, adding a proper amount of solvent, and magnetically stirring at room temperature overnight to enable minoxidil and lactic acid to react with each other. The solids were separated by centrifugation and the dried solids were characterized under the following experimental conditions:
Table 2.
Characterization results are shown in fig. 5-7.
From the characterization results, the crystalline forms of minoxidil lactate shown in fig. 5, 6, and 7 are consistent, wherein the diffraction peak of minoxidil lactate prepared in fig. 6, i.e., experiment No. 2, is stronger and the crystallinity is higher.
2.2 Antisolvent crystallization
Weighing a certain amount of minoxidil and lactic acid, adding a proper amount of solvent, dissolving the solid at room temperature, precipitating the solid by adding an antisolvent or concentrating and then adding the antisolvent (namely a solvent with smaller solubility), magnetically stirring at room temperature overnight, separating the solid by a centrifugal or filtering mode, and characterizing the dried solid, wherein the specific experimental conditions are as follows:
Table 3.
The characterization results are shown in FIGS. 8-11.
From the characterization results, the crystal forms shown in fig. 8-11 are all the same crystal form of minoxidil lactate, and compared with fig. 9, 10 and 11, fig. 8 shows two more diffraction peaks belonging to minoxidil at 16.64 degrees and 19.80 degrees, which indicates that the reaction of the number 4 is incomplete.
Example 3 amplification reaction
(1) Weighing 2000mg minoxidil, adding 45mL of methanol for ultrasonic dissolution to obtain a methanol solution of minoxidil;
(2) Weighing 1.78g of lactic acid, adding 5mL of methanol for dilution to obtain a methanol solution of lactic acid, gradually dropwise adding the methanol solution of minoxidil into the methanol solution of minoxidil under stirring, uniformly stirring, removing most of the methanol to 1-2mL of the solution by rotary evaporation, adding 20mL of ethyl acetate, magnetically stirring at room temperature, gradually precipitating white solid after about 10min, magnetically stirring overnight to obtain a white suspension, separating the solid by suction filtration, rinsing a filter cake twice with 10mL of ethyl acetate, removing redundant lactic acid, drying the filter cake, and obtaining the solid which is minoxidil lactate crystal form. The characterization results are shown in FIG. 12.
Test case
1. Solubility test
(1) Minoxidil solubility test method 5mg minoxidil sample was weighed into each glass vial, 50 μl of solvent was added each time at room temperature for shaking or sonication, visual inspection of whether the solids were clear, and when the solvent was added to about 1mL, 1mL of solvent was added each time, optionally with the amount of solvent added up to 5mL, when there was still significant solids remaining. The minimum volume to dissolve the solid and the previous insoluble volume were recorded and the approximate solubility calculated. The results are shown in the table below.
Table 4.
The results show that minoxidil is slightly soluble in methanol and ethanol, slightly soluble in isopropanol, and less soluble in other organic solvents.
(2) The minoxidil lactate crystal form in example 3 was examined for solubility (24 hours) at pH2-pH6 in synchronization with minoxidil, 500mg of minoxidil and minoxidil lactate were weighed each, 5mL of buffer solutions of pH=2, pH=3, pH=4, pH=5, and pH=6 were added respectively, and the phenomenon was observed, and minoxidil or minoxidil lactate was added to the buffer solution if there was a clear solution until a suspension state was maintained, and the solubility was measured after shaking at room temperature for 24 hours.
The results were as follows:
Table 5.
It can be seen that the minoxidil lactate crystal form was close to minoxidil in solubility at ph=2 and ph=5, and that the minoxidil lactate crystal form was significantly higher in solubility at ph=3 and ph=4 than minoxidil in solubility at Yu Minuo dill.
2. Stability test
Test methods minoxidil lactate in example 3 was examined for its solids and solution stability in synchronization with minoxidil.
Stability at room temperature for 0 day, 40 ℃ for 1 week, 40 ℃ for 2 weeks, 60 ℃ for 1 week, 60 ℃ for 2 weeks was examined, respectively, and the results were as follows:
Table 6.
From the solid stability results, minoxidil lactate was lower than minoxidil in both total and maximum single impurities.
Solution stability mainly the stability of the ph=4 and ph=8 solutions in 40% ethanol solvent system, and the stability of the samples placed at 40 ℃ and 60 ℃, formulation recipe and stability results are shown in fig. 13 and table below:
Table 7.
In the table, q.s. represents up to 100%.
From the results of the substances related to the solution stability, comparing prescription 1 with prescription 3, prescription 2 and prescription 4, the stability of minoxidil lactate crystal form is better than that of minoxidil.
In conclusion, minoxidil lactate has a solubility of Yu Minuo dil at pH3.0-pH4.0, and both solid and solution stability are superior to minoxidil.
3. IVPT (in vitro permeation) experiment
(1) Preparation of test samples
Minoxidil and minoxidil lactate were each formulated as 2mg/mL (in minoxidil) in water.
(2) The testing method comprises the following steps:
The skin of the used percutaneous animal is abdomen skin and back skin of male Panama fragrant pig of 1 month old, and the average thickness is 0.8mm-1mm.
(1) Preparing a receiving solution (20% polyethylene glycol 400+phosphoric acid balance buffer salt solution, pH=7.4), and performing suction filtration and degassing treatment before a test;
(2) Permeation tests were performed using diffusion cells. Fixing Bama miniature pig skin between a receiving tank and a supply tank, fixing horny layer facing the supply tank with spring clamp, adding 8.3 mL receiving liquid preheated at 32deg.C, making dermis layer closely contact with the receiving liquid, discharging air bubbles, balancing 30: 30 min, and administering;
(3) 0.5mL of sample was added to the supply side of the diffusion cell, a constant temperature water bath at 32℃and stirred at a constant magnetic speed of 200 rpm/min;
(4) Accurately sucking 2mL of receiving liquid samples at 1,2, 4, 8 and 24 hours respectively, and then supplementing the blank receiving liquid with the same temperature and corresponding quantity and removing bubbles.
The results are shown in FIG. 14 and the following table:
Table 8.
IVPT the experimental results show that the penetrability of minoxidil lactate aqueous solution is obviously better than that of minoxidil aqueous solution.
Claims (10)
1. The preparation method of the minoxidil lactate crystal form is characterized by comprising the following steps of mixing minoxidil and lactic acid with a solvent, reacting, separating out solids, and separating the solids to obtain the minoxidil lactate crystal form;
The molar ratio of minoxidil to lactic acid is 1:2, and the solvent is ethyl acetate;
The XRPD pattern of the minoxidil lactate salt form is shown in fig. 6.
2. The process of claim 1, wherein the minoxidil lactate crystalline form has a primary peak at diffraction angles 2Θ = 6.505 °, 15.67 °, 18.805 ° and 23.189 °, the relative intensity of the primary peak being 30% -100%, and a secondary peak at diffraction angles 2Θ = 10.165 °, 19.425 °, 20.779 °, 25.657 ° and 30.449 °, the relative intensity of the secondary peak being 10% -30%.
3. The method of preparation of claim 2, wherein the minoxidil lactate crystal form further has at least one other diffraction peak selected from the group consisting of diffraction angles 2Θ = 12.88 °, 15.013 °, 16.923 °, 20.275 °, 26.839 °, 27.606 °, 31.496 °, 32.305 °, 33.256 °.
4. A method of preparation according to claim 3, wherein the relative intensity of the other diffraction peaks is less than 10%.
5. The method of claim 4, wherein the minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°、15.67°、18.805°、23.189°、10.165°、19.425°、20.779°、25.657°、30.449°、12.88°、15.013°、16.923°、20.275°、26.839°、27.606°、31.496°、32.305° and 33.256 °.
6. The application of minoxidil lactate crystal forms in preparing alopecia medicines with improved permeability is characterized in that the minoxidil lactate crystal forms have XRPD characteristic peaks at diffraction angles 2θ= 6.505 °, 15.67 °, 18.805 °, 23.189 °, 10.165 °, 19.425 °, 20.779 °, 25.657 ° and 30.449 °, and the error range of the diffraction angle 2θ value is-0.30 °.
7. The use according to claim 6, wherein the minoxidil lactate crystal form has a main peak at diffraction angles 2θ= 6.505 °, 15.67 °, 18.805 ° and 23.189 °, the relative intensity of the main peak being 30% -100%, and a secondary peak at diffraction angles 2θ= 10.165 °, 19.425 °, 20.779 °, 25.657 ° and 30.449 °, the relative intensity of the secondary peak being 10% -30%.
8. The use according to claim 6 or 7, characterized in that the minoxidil lactate crystal form further has at least one other diffraction peak selected from the group consisting of diffraction angles 2Θ = 12.88 °, 15.013 °, 16.923 °, 20.275 °, 26.839 °, 27.606 °, 31.496 °, 32.305 °, 33.256 °.
9. The use according to claim 8, wherein the relative intensity of the other diffraction peaks is less than 10%.
10. The use according to claim 9, characterized in that the minoxidil lactate crystalline form has XRPD characteristic peaks at diffraction angles 2θ=6.505°、15.67°、18.805°、23.189°、10.165°、19.425°、20.779°、25.657°、30.449°、12.88°、15.013°、16.923°、20.275°、26.839°、27.606°、31.496°、32.305° and 33.256 °.
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