CN114436823A - Fenbufen pharmaceutical co-crystal and preparation method thereof - Google Patents
Fenbufen pharmaceutical co-crystal and preparation method thereof Download PDFInfo
- Publication number
- CN114436823A CN114436823A CN202210097252.5A CN202210097252A CN114436823A CN 114436823 A CN114436823 A CN 114436823A CN 202210097252 A CN202210097252 A CN 202210097252A CN 114436823 A CN114436823 A CN 114436823A
- Authority
- CN
- China
- Prior art keywords
- fenbufen
- pharmaceutical
- crystal
- nicotinamide
- crystal according
- 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
- 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
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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
Abstract
The invention discloses two fenbufen pharmaceutical co-crystals and a preparation method thereof, wherein the two fenbufen pharmaceutical co-crystals both take fenbufen as a pharmaceutical active ingredient and respectively take isonicotinamide or nicotinamide as a co-crystal former. The two eutectic crystals are prepared by a solvent volatilization method. The obtained co-crystals were characterized by differential scanning calorimetry, powder X-ray diffraction and single crystal X-ray diffraction, demonstrating the formation of new crystalline forms. The solubility of the fenbufen medicament and two eutectics thereof in water and simulated duodenal solution is investigated, and the two medicament eutectics are found to obviously improve the solubility of the fenbufen medicament and improve the bioavailability of the fenbufen medicament.
Description
Technical Field
The invention belongs to the field of organic pharmaceutical co-crystals, and particularly relates to a fenbufen pharmaceutical co-crystal and a preparation method thereof.
Background
The solid forms of the drug generally include salts, polymorphs, hydrates, solvates, amorphous forms and co-crystals, and the crystal form drugs are often selected because of their advantages in terms of stability and operability, and thus have great and profound significance in the research of the drug crystal form. Meanwhile, the research of pharmaceutical co-crystals is an important component of the research of pharmaceutical crystal forms.
Pharmaceutical co-crystals are a novel solid form of a pharmaceutically active ingredient formed with a co-crystal agent by intermolecular forces, such as hydrogen bonding. The pharmaceutical cocrystal can greatly affect the physicochemical properties of active ingredients of the drugs without changing the covalent structure of the drugs, thereby improving the bioavailability of the drugs, enhancing the curative effect of the drugs and reducing the toxic and side effects of the drugs, so the research on the pharmaceutical cocrystal has become a hot spot in the pharmaceutical field in recent years.
Fenbufen (fenbufen), chemical name is 4- (4-biphenyl) -4-oxobutyric acid, molecular formula is C16H14O3The structural formula is shown as follows. Fenbufen is a long-acting non-steroidal anti-inflammatory analgesic, and is suitable for rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout and the like, and is also used for toothache, traumatic pain and postoperative pain. However, the fenbufen belongs to BCSII medicines, and the dissolution performance is poor, so that the bioavailability effect of the fenbufen in a human body is poor, and therefore, the improvement of the dissolution performance of the fenbufen and the improvement of the absorption effect of the fenbufen in the human body have important research significance.
Solutions to the problem of poor water Solubility of Hydrochlorothiazide by pharmaceutical co-crystals are disclosed in the literature (P.Sanphui, V.K.Devi, D.Clara, N.Mallviya, S.Ganguly, G.R.Desiraju (2015) crystals of Hydrochlorothiazide: solublility and Diffusion/Permeability Enhancings through sodium-modifier Interactions, No.12, 1615. sub.1622, DOI: 10.1021/acs.molpharmaceut.5b 00020.). Five cocrystals of hydrochlorothiazide with nicotinic acid, nicotinamide, 4-aminobenzoic acid, succinamide and resorcinol were prepared and the solubility of hydrochlorothiazide and its five drug cocrystals in a buffer at pH 7.4 was investigated. The solubility of hydrochlorothiazide is found to be obviously increased after the hydrochlorothiazide forms eutectic with nicotinamide, 4-aminobenzoic acid and resorcinol. After the hydrochlorothiazide, the nicotinic acid and the succinamide form the eutectic, the solubility of the drug eutectic is obviously lower than that of the hydrochlorothiazide drug. The drug may also be poorly soluble after co-crystallization.
In the method, the structure of the medicament is changed by adding the eutectic forming substance, so that the solubility of the medicament is changed. Although pharmaceutical co-crystals have significant advantages in improving the solubility of drugs, the solubility of drugs is not improved after the drug forms co-crystals, and some drugs have reduced solubility after the drug forms co-crystals. Therefore, there is still uncertainty as to whether the drug can improve its solubility after forming a cocrystal.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide two novel fenbufen pharmaceutical co-crystals, and the solubility and bioavailability of the fenbufen serving as a raw material are obviously improved after the co-crystals are formed.
The invention also aims to solve the technical problem of providing a preparation method of fenbufen eutectic, which is simple in process and low in cost.
The technical scheme is as follows: the invention provides a fenbufen pharmaceutical co-crystal which takes fenbufen as a pharmaceutical active ingredient and pyridine carboxamide micromolecules as a co-crystal former.
Wherein the mol ratio of the fenbufen to the pyridine carboxamide micromolecules is 1: 1.
Wherein the pyridine carboxamide micromolecules are isonicotinamide or nicotinamide.
When the pyridine carboxamide micromolecules are isonicotinamide, the basic structural unit of the fenbufen pharmaceutical co-crystal consists of a fenbufen molecule and an isonicotinamide molecule which are connected through intermolecular hydrogen bonds, the co-crystal is a triclinic system, and the space group is
Axial length:
the included angle is as follows: 84.335(4), 86.495(4), 80.888(4),
Z＝2。
the powder X-ray diffraction characteristic peak of the fenbufen pharmaceutical co-crystal appears at 2 theta of 5.8 degrees, 8.9 degrees, 12.0 degrees, 17.9 degrees, 19.6 degrees, 20.9 degrees, 21.6 degrees, 23.9 degrees, 25.8 degrees, 27.1 degrees, 30.1 degrees, 36.3 degrees and 46.0 degrees.
Wherein, when the pyridine carboxamide micromolecules are nicotinamide, the basic structural unit of the fenbufen pharmaceutical co-crystal consists of a fenbufen molecule and a nicotinamide molecule.
The powder X-ray diffraction characteristic peak of the fenbufen pharmaceutical co-crystal appears at 2 theta of 8.8 degrees, 14.4 degrees, 18.7 degrees, 19.2 degrees, 21.8 degrees, 22.6 degrees, 24.4 degrees, 26.9 degrees, 28.4 degrees, 32.5 degrees, 39.3 degrees and 48.1 degrees.
The invention also comprises a preparation method of the fenbufen pharmaceutical co-crystal, which comprises the following steps: weighing fenbufen and pyridine carboxamide micromolecules according to the mol ratio of 2: 1-1: 5, dissolving the fenbufen and the pyridine carboxamide micromolecules in a volatile organic solvent, carrying out ultrasonic treatment for 30-120 min, slowly cooling, filtering the obtained suspension to obtain a clear solution, placing the clear solution in a constant-temperature incubator at 15-35 ℃ for constant-temperature culture, and obtaining the fenbufen pharmaceutical co-crystal after 7-15 days.
Wherein the volume ratio of the total mass of the fenbufen and the pyridine carboxamide micromolecules to the solvent is 1: 15-1: 120 g/mL.
Wherein the volatile organic solvent is any one or a combination of methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, 2-butanone, ethyl acetate, cyclohexane, n-hexane and chloroform.
Wherein, when the two solvents are used, the volume ratio is 4: 1-1: 6.
The invention designs and prepares the pharmaceutical co-crystal which has good stability and can effectively improve the solubility of the fenbufen, and is of great importance for solving the problem of poor solubility of the fenbufen. Meanwhile, the method provides wider prospect for the subsequent clinical application of the fenbufen.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the invention adopts fenbufen, nicotinamide and isonicotinamide as raw materials by a pharmaceutical co-crystal technology to prepare two fenbufen pharmaceutical novel co-crystals, which obviously improves the solubility and bioavailability and provides a basis for improving the oral absorption rate of fenbufen.
(2) The method for preparing the fenbufen pharmaceutical co-crystal is simple and convenient in process flow and low in cost, and is beneficial to further production.
Drawings
Fig. 1 is a schematic diagram of a structural unit of a fenbufen-isonicotinamide eutectic crystal.
FIG. 2 is a DSC of fenbufen, isonicotinamide and fenbufen-isonicotinamide co-crystal, wherein F/I represents fenbufen-isonicotinamide co-crystal.
FIG. 3 is a PXRD diagram of fenbufen, isonicotinamide and a fenbufen-isonicotinamide eutectic crystal, wherein F/I represents the fenbufen-isonicotinamide eutectic crystal.
FIG. 4 is a DSC of fenbufen, nicotinamide and the co-crystal of fenbufen-nicotinamide, in which F/N represents the co-crystal of fenbufen-nicotinamide.
FIG. 5 is a PXRD diagram of fenbufen, nicotinamide and a fenbufen-nicotinamide eutectic, wherein F/N represents the fenbufen-nicotinamide eutectic.
Fig. 6 is a graph comparing the solubility of fenbufen, fenbufen-isonicotinamide co-crystal and fenbufen-nicotinamide co-crystal in water.
Fig. 7 is a graph comparing the solubility of fenbufen, fenbufen-isonicotinamide co-crystal and fenbufen-nicotinamide co-crystal in simulated duodenum.
Detailed Description
The invention is further described below with reference to the figures and examples.
Example 1:
weighing 254.2mg of fenbufen and 122.2mg of isonicotinamide, dissolving in 10ml of mixed solvent of acetone and cyclohexane with the volume ratio of 1:1, carrying out ultrasonic treatment for 50min, slowly cooling, filtering the obtained suspension, placing the obtained clear solution in a constant-temperature incubator at 35 ℃ for constant-temperature culture, and obtaining the fenbufen-isonicotinamide eutectic after 7 days. The crystal is characterized and analyzed by SXRD, the obtained fenbufen-isonicotinamide crystal structure is shown in figure 1, the crystal structure belongs to a triclinic system, and the space group is
Axial length:
the included angle is as follows: 84.335(4), 86.495(4), 80.888(4),
Z＝2。
example 2:
weighing 127.1mg of fenbufen and 122.2mg of isonicotinamide, dissolving in 12ml of mixed solvent of acetonitrile and chloroform with the volume ratio of 2:1, carrying out ultrasonic treatment for 80min, slowly cooling, filtering the obtained suspension, placing the obtained clear solution in a constant-temperature incubator at 30 ℃ for constant-temperature culture, and obtaining the fenbufen-isonicotinamide eutectic after 10 days. The crystals were characterized by differential scanning calorimetry, and the fenbufen-isonicotinamide co-crystal had an absorption peak at 143.31 ℃, and the DSC diagram is shown in figure 2.
Example 3:
weighing 254.2mg of fenbufen and 61.1mg of isonicotinamide, dissolving in 15ml of a mixed solvent of ethanol and acetone in a volume ratio of 4:1, carrying out ultrasonic treatment for 120min, slowly cooling, filtering the obtained suspension, placing the obtained clear solution in a constant-temperature incubator at 25 ℃ for constant-temperature culture, and obtaining the fenbufen-isonicotinamide eutectic crystal after 15 days. The obtained crystals were characterized by PXRD, and the fenbufen-isonicotinamide co-crystal had characteristic peaks at 2 θ ═ 5.8 °, 8.9 °, 12.0 °, 17.9 °, 19.6 °, 20.9 °, 21.6 °, 23.9 °, 25.8 °, 27.1 °, 30.1 °, 36.3 °, and 46.0 °, as shown in fig. 3.
Example 4:
weighing 127.1mg of fenbufen and 61.1mg of nicotinamide, dissolving in 8mL of a mixed solvent of methanol and acetone with the volume ratio of 1:1, carrying out ultrasonic reaction for 30min, slowly cooling, filtering the obtained suspension, placing the obtained clear solution in a constant-temperature incubator at 35 ℃ for constant-temperature culture, and obtaining the fenbufen-nicotinamide eutectic crystal after 7 days. The crystals were characterized by differential scanning calorimetry, and the fenbufen-nicotinamide eutectic has an absorption peak at 147.10 ℃, and the DSC chart is shown in figure 4.
Example 5:
weighing 50.8mg of fenbufen and 122.2mg of nicotinamide, dissolving in 14mL of a mixed solvent of methanol and chloroform with the volume ratio of 1:6, carrying out ultrasonic reaction for 90min, slowly cooling, filtering the obtained suspension, placing the obtained clear solution in a constant-temperature incubator at 15 ℃ for constant-temperature culture, and obtaining the fenbufen-nicotinamide eutectic crystal after 12 days. The crystals obtained were characterized using PXRD, and the fenbufen-nicotinamide eutectic had characteristic peaks at 2 θ ═ 8.8 °, 14.4 °, 18.7 °, 19.2 °, 21.8 °, 22.6 °, 24.4 °, 26.9 °, 28.4 °, 32.5 °, 39.3 °, and 48.1 °. The characteristic curve is shown in figure 5.
Example 6:
the solubility of the excess fenbufen, the fenbufen-isonicotinamide eutectic prepared in example 1, and the fenbufen-nicotinamide eutectic prepared in example 4, each 200mg, was measured by dissolving them in 5mL of water and 5mL of simulated duodenal fluid, and the results are shown in fig. 6 and 7.
By combining the results of the above items, the fenbufen-isonicotinamide and the fenbufen-nicotinamide eutectic are successfully prepared, and the solubility of the fenbufen drug can be effectively improved.
Claims (10)
1. The fenbufen pharmaceutical co-crystal is characterized in that fenbufen is used as a pharmaceutical active ingredient, and a pyridine carboxamide micromolecule is used as a co-crystal former.
2. Fenbufen pharmaceutical co-crystal according to claim 1, wherein the pyridine carboxamide small molecule is isonicotinamide or nicotinamide.
3. Fenbufen pharmaceutical co-crystal according to claim 2, characterized in that the essential of the fenbufen pharmaceutical co-crystal is when the picolinamide type small molecule is isonicotinamideThe structural unit consists of a fenbufen molecule and an isonicotinamide molecule which are connected through intermolecular hydrogen bonds, the eutectic is a triclinic system, and the space group is P
The axial length is as follows: a/a =5.9823(9), b/a =10.9257(17), c/a =29.798(4), included angle: α/° =84.335 (4), β/° =86.495(4), γ/° =80.888 (4), Volume/a 3=1911.60(49), Z = 2.
4. The fenbufen pharmaceutical co-crystal according to claim 3, wherein characteristic peaks of powder X-ray diffraction of the fenbufen pharmaceutical co-crystal appear at 2 θ = 5.8 °, 8.9 °, 12.0 °, 17.9 °, 19.6 °, 20.9 °, 21.6 °, 23.9 °, 25.8 °, 27.1 °, 30.1 °, 36.3 °, 46.0 °.
5. The fenbufen pharmaceutical co-crystal according to claim 2, wherein when said pyridine carboxamide small molecule is nicotinamide, the basic building block of said fenbufen pharmaceutical co-crystal consists of one fenbufen molecule and one nicotinamide molecule.
6. The fenbufen pharmaceutical co-crystal according to claim 5, wherein a characteristic peak of the fenbufen pharmaceutical co-crystal in powder X-ray diffraction appears at 2 θ = 8.8 °, 14.4 °, 18.7 °, 19.2 °, 21.8 °, 22.6 °, 24.4 °, 26.9 °, 28.4 °, 32.5 °, 39.3 °, and 48.1 °.
7. A process for the preparation of fenbufen pharmaceutical co-crystal according to any one of claims 1 to 6, comprising the steps of: weighing fenbufen and pyridine carboxamide micromolecules according to a molar ratio of 2: 1-1: 5, dissolving the fenbufen and the pyridine carboxamide micromolecules in a volatile organic solvent, carrying out ultrasonic treatment for 30-120 min, slowly cooling, filtering the obtained suspension to obtain a clear solution, placing the clear solution in a constant-temperature incubator at 15-35 ℃ for constant-temperature culture, and obtaining the fenbufen pharmaceutical co-crystal after 7-15 days.
8. The preparation method of the fenbufen pharmaceutical co-crystal according to claim 7, wherein the volume ratio of the total mass of fenbufen and picolinamide small molecules to the volatile organic solvent is 1: 15-1: 120 g/mL.
9. The preparation method of fenbufen pharmaceutical co-crystal according to claim 7, wherein the volatile organic solvent is any one or a combination of methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, 2-butanone, ethyl acetate, cyclohexane, n-hexane and chloroform.
10. The preparation method of fenbufen pharmaceutical co-crystal according to claim 7, wherein when the two solvents are used, the volume ratio of the two solvents is 4: 1-1: 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210097252.5A CN114436823A (en) | 2022-01-26 | 2022-01-26 | Fenbufen pharmaceutical co-crystal and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210097252.5A CN114436823A (en) | 2022-01-26 | 2022-01-26 | Fenbufen pharmaceutical co-crystal and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114436823A true CN114436823A (en) | 2022-05-06 |
Family
ID=81370689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210097252.5A Pending CN114436823A (en) | 2022-01-26 | 2022-01-26 | Fenbufen pharmaceutical co-crystal and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114436823A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646195A (en) * | 2015-07-22 | 2016-06-08 | 黑龙江大学 | Fenbufen pharmaceutical co-crystal and preparing method thereof |
-
2022
- 2022-01-26 CN CN202210097252.5A patent/CN114436823A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646195A (en) * | 2015-07-22 | 2016-06-08 | 黑龙江大学 | Fenbufen pharmaceutical co-crystal and preparing method thereof |
Non-Patent Citations (2)
| Title |
|---|
| DAVID J. BERRY等: "Applying Hot-Stage Microscopy to Co-Crystal Screening: A Study of Nicotinamide with Seven Active Pharmaceutical Ingredients", 《CRYSTAL GROWTH & DESIGN》 * |
| 沈致名;谢闯;杜威;尹秋响;: "布洛芬-烟酰胺共晶制备及其溶解度测定", 化学工业与工程 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Dai et al. | Pharmaceutical cocrystallization: an effective approach to modulate the physicochemical properties of solid-state drugs | |
| CN110922403B (en) | Co-crystal formed by apixaban and carboxylic acid and preparation method thereof | |
| CN107501178B (en) | Naphthalimide derivative and preparation method and application thereof | |
| CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
| CN102276594B (en) | Iloperidone medicinal cocrystal and preparation method thereof | |
| CN114436823A (en) | Fenbufen pharmaceutical co-crystal and preparation method thereof | |
| CN103864683B (en) | Medicine eutectic of ciprofloxacin and salicylic acid and preparation process thereof | |
| CN107311915A (en) | A kind of salicylic acid organic pharmaceutical co-crystal and preparation method thereof | |
| KR20240019064A (en) | Crystalline forms of pyridine nitrogen oxide compounds and their uses | |
| CN109336823B (en) | Tinidazole pharmaceutical co-crystal and preparation method thereof | |
| CN107011261A (en) | A kind of nicotinic acid drugs eutectic and preparation method thereof | |
| CN103265483A (en) | Co-crystal of norfloxacin and phthalic acid and preparation method thereof | |
| CN114409560B (en) | Axoliti pharmaceutical co-crystal and preparation method thereof | |
| JP5442711B2 (en) | 2-Trifluoromethylnicotinamide derivatives as HDL-cholesterol raising agents | |
| CN105669543A (en) | Isoliquiritigenin nicotinamide eutectic crystal and preparation method thereof | |
| TWI241289B (en) | Suplatast tosilate crystals | |
| CN113402458B (en) | Enrofloxacin eutectic and preparation method thereof | |
| WO2004076460A1 (en) | Method for preparing polymorphism of irinotecan hydrochloride | |
| CN111909086B (en) | Aripiprazole-acetylsalicylate and preparation method thereof | |
| CN114409560A (en) | Actalli pharmaceutical co-crystal and preparation method thereof | |
| TWI378929B (en) | Crystalline 1h-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1h-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses | |
| CN113197865A (en) | Eutectic crystal of abiraterone acetate and trans-aconitic acid, preparation method thereof, pharmaceutical composition and application thereof | |
| CN114524769B (en) | Celecoxib-carbamazepine eutectic, preparation method, pharmaceutical composition and application | |
| CN111689947A (en) | Tegafur-L-proline eutectic and preparation method thereof | |
| CN117003769A (en) | Lornoxicam compound, lornoxicam-berberine eutectic crystal, preparation method and application 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 |