CN113603706A - Crystal form of delamasil, active drug and pharmaceutical composition containing the crystal form - Google Patents
Crystal form of delamasil, active drug and pharmaceutical composition containing the crystal form Download PDFInfo
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- CN113603706A CN113603706A CN202110892848.XA CN202110892848A CN113603706A CN 113603706 A CN113603706 A CN 113603706A CN 202110892848 A CN202110892848 A CN 202110892848A CN 113603706 A CN113603706 A CN 113603706A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- 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 a crystal form of delamanib, an active medicine containing the crystal form and a pharmaceutical composition. The Delamani crystal form alpha has characteristic peaks at diffraction angles 2 theta of 2.5 degrees +/-0.1 degrees, 4.8 degrees +/-0.1 degrees, 7.2 degrees +/-0.1 degrees, 9.6 degrees +/-0.1 degrees, 12.0 degrees +/-0.1 degrees, 14.4 degrees +/-0.1 degrees, 19.2 degrees +/-0.1 degrees, 21.6 degrees +/-0.1 degrees, 21.9 degrees +/-0.1 degrees, 24.1 degrees +/-0.1 degrees, 26.5 degrees +/-0.1 degrees, 29.0 degrees +/-0.1 degrees and 31.4 degrees +/-0.1 degrees in an X-ray powder diffraction pattern measured by using Cu-K alpha rays. The Delamani crystal form beta has characteristic peaks at diffraction angles 2 theta of 2.4 degrees +/-0.1 degrees, 4.7 degrees +/-0.1 degrees, 7.0 degrees +/-0.1 degrees, 9.4 degrees +/-0.1 degrees, 11.7 degrees +/-0.1 degrees, 14.1 degrees +/-0.1 degrees, 18.8 degrees +/-0.1 degrees, 23.5 degrees +/-0.1 degrees, 28.3 degrees +/-0.1 degrees and 30.7 degrees +/-0.1 degrees in an X-ray powder diffraction pattern measured by using Cu-K alpha rays. The invention provides two crystal forms of delaunay, which have higher apparent solubility in aqueous solution compared with delaunay; the crystal form has higher apparent solubility in an organic solvent or a combined solvent, is favorable for dissolution and absorption in a human body, and has larger application prospect due to good dissolution characteristics.
Description
The technical field is as follows:
the invention relates to the field of drug crystal forms, in particular to a crystal form of delamanib, an active drug containing the crystal form and a pharmaceutical composition.
Background art:
delamani, chemical name (2R) -2, 3-dihydro-2-methyl-6-nitro-2- [ [4- [4- [4- (trifluoromethoxy) phenoxy ] methyl ester]-1-piperidinyl group]Phenoxy radical]Methyl radical]Imidazo [2,1-B]An oxazole having the formula:
delamanit is an antitubercular drug and can be used in combination therapy for the treatment of multi-drug resistant and broad-spectrum drug resistant tuberculosis. It can effectively improve the treatment effect of drug-resistant tuberculosis and reduce the death rate. However, the therapeutic window of drug-resistant tuberculosis is narrow, and the bioavailability of delaunay is not high, the oral bioavailability of delaunay is about 25% -47%, and the food effect can increase the bioavailability by 2.7 times, which is greatly related to the poor solubility of delaunay.
Currently, no particular method is expectable to obtain a particular crystalline form. There is a need in the art for continued improvements in the crystalline form of delamanib to enhance its solubility and thus oral bioavailability.
The invention content is as follows:
the present invention is directed to solving at least one of the problems of the prior art. For this purpose, the invention proposes two crystal forms of delamanib. These crystalline forms have higher apparent solubility in aqueous solutions; the crystal form has higher apparent solubility in organic solvents or combined solvents, and active medicaments can be efficiently formed by utilizing the two crystal forms.
In a first aspect of the present invention, a delamanit crystal form α is provided, which has characteristic diffraction peaks at diffraction angles 2 θ of 2.5 ° ± 0.1 °, 4.8 ° ± 0.1 °, 7.2 ° ± 0.1 °, 9.6 ° ± 0.1 °, 12.0 ° ± 0.1 °, 14.4 ° ± 0.1 °, 19.2 ° ± 0.1 °, 21.6 ° ± 0.1 °, 21.9 ° ± 0.1 °, 24.1 ° ± 0.1 °, 26.5 ° ± 0.1 °, 29.0 ° ± 0.1 ° and 31.4 ° ± 0.1 ° in an X-ray powder diffraction pattern obtained by measurement using Cu-K α rays, and has endothermic peaks at 43 to 49 ℃ (peak value) using differential scanning calorimetry.
The Delamani crystal form alpha of the invention at least has the following beneficial effects:
experimental research shows that the crystal form alpha of the Delamanib has higher solubility in an aqueous solution, is beneficial to dissolution and absorption in a human body, and has larger application prospect due to good dissolution characteristic.
In another aspect of the present invention, a method for preparing the delamanib crystal form α is provided, which comprises the following steps:
(1) dissolving Delamanil in 1-methyl-2-pyrrolidone;
(2) stirring and volatilizing the 1-methyl-2-pyrrolidone to obtain the Delamanib crystal form alpha.
In some embodiments of the invention, in step (1), the mass-to-volume ratio of delamanide to 1-methyl-2-pyrrolidone is 1:2 to 1:30, and the unit of the mass-to-volume ratio is mg/. mu.L, and most preferably 1:5 to 1: 10.
In some embodiments of the present invention, in the step (2), the crystallization temperature is 10 to 70 ℃, and most preferably 25 to 50 ℃.
In another aspect of the present invention, there is provided a crystalline form β of deramanic acid having characteristic diffraction peaks at diffraction angles 2 θ of 2.4 ° ± 0.1 °, 4.7 ° ± 0.1 °, 7.0 ° ± 0.1 °, 9.4 ° ± 0.1 °, 11.7 ° ± 0.1 °, 14.1 ° ± 0.1 °, 18.8 ° ± 0.1 °, 23.5 ° ± 0.1 °, 28.3 ° ± 0.1 ° and 30.7 ° ± 0.1 ° in an X-ray powder diffraction pattern measured using Cu-K α rays, and having endothermic peaks at 66 to 72 ℃ (peak value) using differential calorimetry scanning.
The Delamani crystal form beta of the invention at least has the following beneficial effects:
experimental research shows that the Delamani crystal form beta has higher solubility in an aqueous solution, is beneficial to dissolution and absorption in a human body, and has larger application prospect due to good dissolution characteristic.
In another aspect of the present invention, a method for preparing the delamanib crystal form β is provided, which comprises the following steps:
(1) dissolving Delamani in N, N-dimethylformamide;
(2) stirring to volatilize the N, N-dimethylformamide, and preparing the Delamanib crystal form beta.
In some embodiments of the invention, in step (1), the mass-to-volume ratio of Delamani and N, N-dimethylformamide is 1:5 to 1:30, and the unit of the mass-to-volume ratio is mg/. mu.L, and most preferably 1: 10.
In some embodiments of the present invention, in the step (2), the crystallization temperature is 10 to 70 ℃, and most preferably 25 to 50 ℃.
In a third aspect of the invention, an active pharmaceutical is provided, comprising delamanic form α, form β or their polymers as active ingredient. The invention improves the solubility of the delamanic in the organic solvent by changing the crystal structure so as to improve the industrialized production efficiency of the subsequent active medicament, namely, the yield is high, the solvent consumption is low, and a foundation is provided for improving the oral bioavailability.
The "polymer" in the present invention refers to a high molecular material which is non-toxic, non-antigenic and has good biocompatibility.
In some embodiments of the invention, the polymer is selected from at least one of polyvinylpyrrolidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, and methyl cellulose acetate phthalate; preferably, the mass fraction of the active ingredients in the active medicine is 10-40%.
In some embodiments of the invention, a solution is formed from a starting material comprising an active ingredient and a polymer dissolved in a solvent and the solution is spin-evaporated, spray-dried or lyophilized.
In some embodiments of the invention, the temperature of the rotary evaporation water bath is 30-60 ℃.
In some embodiments of the present invention, the solvent is acetone or a mixed solvent of ethanol and acetone. Ethanol and acetone are three solvents (the limit of solvent residue is 0.5 percent), meet the requirement of solubility and have the characteristics of low toxicity and low boiling point.
In a fourth aspect of the present invention, a pharmaceutical composition is provided, which comprises ingredients and the above active drug, wherein the ingredients are adjuvants or pharmaceutically acceptable carriers.
The adjuvants are those conventionally used in pharmacy, and can be exemplified by colloidal silica, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film-forming polymers, antioxidants, light stabilizers, radical scavengers, surfactants, pH adjusters, drug complexing agents or stabilizers against microbial attack, or combinations thereof.
Pharmaceutically acceptable carriers are exemplified by sterile aqueous or non-aqueous solutions, dispersions, suspensions or creams, and sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). The active ingredient may be formulated with pharmaceutically acceptable carriers, diluents and any other known adjuvants or adjuvants according to conventional techniques disclosed.
The invention provides two crystal forms of delaunay, which have higher apparent solubility in aqueous solution compared with delaunay; the crystal form has higher apparent solubility in an organic solvent or a combined solvent, is favorable for dissolution and absorption in a human body, and has larger application prospect due to good dissolution characteristics.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 is an X-ray powder diffraction pattern of commercial Delamani used in an example of the present invention;
FIG. 2 is an X-ray powder diffraction pattern of Delamanib form α in example 1 of the present invention;
FIG. 3 is an X-ray powder diffraction pattern of Delamanil form β of example 2 of the present invention;
FIG. 4 is an X-ray powder diffraction pattern of an active drug containing 10% Delamanib prepared in example 5 of the present invention;
FIG. 5 is an X-ray powder diffraction pattern of an active drug containing 20% Delamanib prepared in example 6 of the present invention;
FIG. 6 is a thermogravimetric analysis of Delamanib crystalline form α in example 1 of the present invention;
FIG. 7 is a thermogravimetric analysis of crystalline form β of Delamanib in example 2 of the present invention;
FIG. 8 is a differential scanning calorimetry thermogram of commercial Delamanib used in an example of the present invention;
FIG. 9 is a differential scanning calorimetry thermogram of Delamanib form α in example 1 of the present invention;
FIG. 10 is a differential scanning calorimetry trace of Delamanib form β in example 2 of the present invention;
FIG. 11 is a Raman spectrum of a commercially available Delamani used in an example of the present invention;
FIG. 12 is a Raman spectrum of Delamani form α in example 1 of the present invention;
FIG. 13 is a Raman spectrum of Delamani form β according to example 2 of the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
In the following examples, the detection apparatus and methods involved are as follows:
x-ray powder diffraction (PXRD): x-ray powder diffraction was carried out using a pennace sharp-image X-ray powder diffractometer using Cu-K α radiation, wavelength
(ii) a The voltage of the X-ray light pipe is 45kV, the current of the X-ray light pipe is 40mA, the scanning range is 2-40 degrees (2 theta), the step size is 0.026 degrees, and the scanning time per step is 56.865 s. The samples were spread on sample trays for testing. Data viewing software HighScore Plus.
Differential Scanning Calorimetry (DSC): the thermal properties of the samples were analyzed using a differential scanning calorimeter Q2000 (American TA instruments). The detection was carried out with a sample chamber nitrogen purge flow of 50mL/min, equilibration at 25 deg.C, heating to 200 deg.C at a rate of 10 deg.C/min, and data Analysis software TA Universal Analysis (US TA instruments).
Thermogravimetric analysis (TGA): samples were analyzed for thermal properties using a thermogravimetric analyzer Q500 (us TA instrument). The detection is carried out by setting the nitrogen purge flow of a balance chamber to be 40mL/min and the nitrogen purge flow of a sample chamber to be 60mL/min, balancing at room temperature, heating to 400 ℃ at the heating rate of 10 ℃/min and using data Analysis software TA Universal Analysis (American TA instruments).
Raman spectroscopy: the Renysha inVia Raman micro spectrometer is provided with a near-infrared diode laser source and a Rencam Charge Coupled Device (CCD) silicon detector. Placing the sample on a microscope slide glass, carrying out focusing observation under a 20-time objective lens and carrying out Raman single-point detection under the following detection conditions: the detection wavelength is 785nm, and the detection range is 100cm-1-3600cm-1The laser intensity is 100%, the exposure time is 3s, and 2 times of accumulation are carried out; and data acquisition and analysis software wire 5.3.
The delamanit used in the following examples was purchased from pure pharmaceutical technology ltd, guangzhou, and its X-ray powder diffraction pattern, DSC test pattern, and raman test pattern were respectively shown in fig. 1, 8, and 11, respectively, by PXRD detection.
Example 1
This example prepared deramanic form α, according to the following steps:
about 30mg of delamasil was weighed into 150. mu.L of 1-methyl-2-pyrrolidone, and dissolved at room temperature. And after complete dissolution, stirring the volatile solvent at room temperature until a layer of crystals are separated out on the surface of the solution, then slightly and uniformly shaking the seal, and continuously standing the seal to volatilize the solvent until a large number of crystals are separated out.
The solid sample was filtered and subjected to PXRD detection, and the results are shown in FIG. 2. As can be seen from the figure, the delamanic crystal form α has characteristic peaks at diffraction angles 2 θ of about 2.5 °, about 4.8 °, about 7.2 °, about 9.6 °, about 12.0 °, about 14.4 °, about 19.2 °, about 21.6 °, about 21.9 °, about 24.1 °, about 26.5 °, about 29.0 °, and about 31.4 °, and belongs to a new crystal form. FIG. 6 is a thermogravimetric analysis of Delamanib crystalline form α. Figure 9 is a differential scanning calorimetry trace of delamanit form α. Fig. 12 is a raman spectrum of delamani form α.
Example 2
This example prepared deramanic form α, according to the following steps:
about 5mg of delamasil was weighed into 50. mu.L of 1-methyl-2-pyrrolidone, and dissolved at room temperature. After complete dissolution, heating to about 50 ℃, stirring to volatilize the solvent for 1h, then moving to room temperature to continuously volatilize the solvent until a layer of crystals are separated out on the surface of the solution, slightly and uniformly shaking the seal, and continuously volatilizing the solvent in an open manner until the crystals are separated out but the solvent is not completely volatilized.
PXRD detection of solid-like crystals was also performed with characteristic peaks at diffraction angles 2 θ of about 2.5 °, about 4.8 °, about 7.2 °, about 9.6 °, about 12.0 °, about 14.4 °, about 19.2 °, about 21.6 °, about 21.9 °, about 24.1 °, about 26.5 °, about 29.0 °, about 31.5 °, belonging to form α.
Example 3
This example prepared delamanic form β according to the following steps:
30mg of Delamanib was added to 300. mu. L N of N-dimethylformamide and dissolved at room temperature. And after complete dissolution, standing at room temperature to volatilize the solvent until a layer of crystals are separated out on the surface of the solution, then slightly and uniformly sealing, and continuously opening to volatilize the solvent until the crystals are separated out but the solvent is not volatilized completely.
PXRD detection was performed on solid-like crystals, and the results are shown in fig. 3. As can be seen from the figure, the delamanic form β has characteristic peaks at diffraction angles 2 θ of about 2.4 °, about 4.7 °, about 7.0 °, about 9.4 °, about 11.7 °, about 14.1 °, about 18.8 °, about 23.5 °, about 28.3 °, about 30.7 °, and belongs to a new crystalline form. Figure 7 is a thermogravimetric analysis of delamanic form β. Figure 10 is a differential scanning calorimetry trace of crystalline form β of delamanic. Fig. 13 shows a raman spectrum of the prepared delamanic form β.
Example 4
This example prepared delamanic form β according to the following steps:
5mg of Delamanib was added to 50. mu. L N of N-dimethylformamide and dissolved at room temperature. After complete dissolution, heating to about 50 ℃ to volatilize the solvent for 1h, then moving to room temperature to continuously volatilize the solvent until a layer of crystals are separated out on the surface of the solution, slightly and uniformly shaking the seal, and continuously volatilizing the solvent by opening until the crystals are separated out but the solvent is not completely volatilized.
PXRD detection of solid-like crystals was also performed, with characteristic peaks at diffraction angles 2 θ of about 2.4 °, about 4.7 °, about 7.0 °, about 9.4 °, about 11.7 °, about 14.1 °, about 18.8 °, about 23.5 °, about 28.3 °, about 30.7 °, belonging to crystalline form β.
Effect example 1
Apparent solubility tests were performed on the two de ramanib crystalline forms α and β prepared in example 1 and example 3.5 mg of the crystalline forms α and β obtained in example 1 and example 3 were weighed, respectively, and 5mg of commercially available delamanic was taken as a control.
The dissolution medium was 10mL of 0.1% SDS aqueous solution, the stirring rate was adjusted to 1000 rpm at room temperature, and the sample was taken 15 minutes after the addition of the substance to be measured, and the concentration was measured after the filtration, and the results are shown in Table 1. It can be seen that the apparent solubility of form α is highest in aqueous solution, and form β is second, both of which are higher than commercially available delamanic. The improvement of the apparent solubility and the dissolution speed is beneficial to the dissolution and absorption of the medicine in vivo, and the two crystal forms alpha and beta provided by the embodiment of the invention have greater application potential.
TABLE 1 apparent solubility of aqueous solution
| Sample (I) | Apparent solubility (. mu.g/mL) |
| Commercial Delamani | Not detected out |
| Crystal form alpha | 0.85 |
| Crystalline form beta | 0.28 |
Effect example 2
The two de ramanib crystalline forms α and β prepared in example 1 and example 3 were subjected to solubility tests in organic solvents. 5mg of the crystalline forms α and β obtained in example 1 and example 3 were weighed, 5mg of commercially available delamanine was used as a control, a mixed solvent of ethanol and acetone (1:1 by volume) was added at 25 ℃. + -. 2 ℃ in a predetermined volume, and the mixture was vigorously shaken for 30 seconds every 5 minutes, followed by observation of dissolution within 30 minutes, and complete dissolution was observed in the absence of a visible solid. When the Delamanib crystal forms alpha and beta are completely dissolved, the volumes of the added mixed solvent are 240 mu L and 290 mu L respectively. Compared with the commercial Delamani, when the same weight is taken and the volume of the added mixed solvent is 350 mu L under the same condition, the solubility of the crystal forms alpha and beta in the mixed solvent of ethanol and acetone (1:1 volume ratio) is greatly improved, and the solubility test results are shown in Table 2.
TABLE 2 apparent solubility test in ethanol and acetone (1:1 by volume)
| Sample (I) | Solubility (mg/mL) |
| Commercial Delamani | 14.9 |
| Crystal form alpha | 21.8 |
| Crystalline form beta | 20.6 |
As can be seen from effect example 2, compared with the existing crystal forms, the two crystal forms α and β provided by the embodiment of the present invention have higher solubility in an organic solvent, consume less solvent when used as an active ingredient to prepare an active drug with an equal concentration, and have higher application value in industrial production.
Example 5
The present embodiment provides an active drug, which is prepared from delaminib crystal form α and polyvinylpyrrolidone, and is specifically prepared according to the following steps:
10mg of Delamani crystal form alpha and 90mg of polyvinylpyrrolidone are added into a mixed solvent of ethanol and acetone (1:1 volume ratio) in a proper amount, dissolved at room temperature, and the dissolved solution is subjected to rotary evaporation at the water bath temperature of 50 ℃. The physical state of the solid active drug is determined by PXRD, and the result is shown in figure 4, a dispersion peak is shown, and a sharp diffraction peak is not shown, which indicates that the prepared active drug is amorphous.
Example 6
The embodiment provides an active drug, which is prepared from a delamanic crystal form α and hypromellose phthalate, and is specifically prepared according to the following steps:
adding 30mg of Delamani crystal form alpha and 120mg of hydroxypropyl methylcellulose phthalate into 10mL of acetone, dissolving at room temperature, and performing rotary evaporation on the dissolved solution at the water bath temperature of 50 ℃. The physical state of the solid active drug is determined by PXRD, and the result is shown in FIG. 5, in which FIG. 5 shows a dispersion peak and does not show a sharp diffraction peak, which indicates that the prepared active drug is amorphous.
It is understood that the auxiliary materials or pharmaceutically acceptable carriers commonly used by those skilled in the art can be easily combined with the active drug provided by the embodiments of the present invention by conventional preparation methods to prepare powder, capsule, tablet, etc. and to apply them to treat the related diseases.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (10)
1. A delamanit crystalline form α characterized by having characteristic peaks at diffraction angles 2 θ of 2.5 ° ± 0.1 °, 4.8 ° ± 0.1 °, 7.2 ° ± 0.1 °, 9.6 ° ± 0.1 °, 12.0 ° ± 0.1 °, 14.4 ° ± 0.1 °, 19.2 ° ± 0.1 °, 21.6 ° ± 0.1 °, 21.9 ° ± 0.1 °, 24.1 ° ± 0.1 °, 26.5 ° ± 0.1 °, 29.0 ° ± 0.1 ° and 31.4 ° ± 0.1 ° in an X-ray powder diffraction pattern measured using Cu-K α rays, and having endothermic peaks at 43 to 49 ℃ using differential scanning calorimetry.
2. A process for the preparation of delamanic form α according to claim 1, characterized in that it comprises the following steps:
(1) dissolving Delamanil in 1-methyl-2-pyrrolidone;
(2) stirring and volatilizing the 1-methyl-2-pyrrolidone to obtain the Delamanib crystal form alpha.
3. The method for preparing delamanic form α according to claim 2, wherein the ratio of delamanic to 1-methyl-2-pyrrolidone is 1:2 to 1:30 by mass/volume, and the unit of the ratio of mass to volume is mg/μ L.
4. The method for preparing delamanic form α according to claim 2, wherein in the step (2), the crystallization temperature is 10 to 70 ℃.
5. A crystalline form β of delamanit, characterized in that it has characteristic peaks at diffraction angles 2 θ of 2.4 ° ± 0.1 °, 4.7 ° ± 0.1 °, 7.0 ° ± 0.1 °, 9.4 ° ± 0.1 °, 11.7 ° Δ 0.1 °, 14.1 ° ± 0.1 °, 18.8 ° ± 0.1 °, 23.5 ° ± 0.1 °, 28.3 ° ± 0.1 ° and 30.7 ° ± 0.1 ° in an X-ray powder diffraction pattern measured using Cu-K α rays, and has an endothermic peak at a peak value of 66 to 72 ℃ using differential scanning calorimetry.
6. The process for the preparation of crystalline form β of delamanic acid according to claim 5, characterized in that it comprises the following steps:
(1) dissolving Delamani in N, N-dimethylformamide;
(2) stirring to volatilize the N, N-dimethylformamide, and preparing the Delamanib crystal form beta.
7. The method for preparing Delamani crystal form beta according to claim 6, wherein in step (1), the mass-to-volume ratio of Delamani and N, N-dimethylformamide is 1:5 to 1:30, and the unit of the mass-to-volume ratio is mg/μ L.
8. The method for preparing Delamani form beta according to claim 6, wherein in the step (2), the crystallization temperature is 10-70 ℃.
9. An active pharmaceutical agent comprising the delaunay form α of claim 1 or the delaunay form β of claim 5, or a polymer thereof selected from at least one of polyvinylpyrrolidone, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate phthalate and methylcellulose acetate phthalate.
10. A pharmaceutical composition comprising an active agent of claim 9 and an adjuvant or a pharmaceutically acceptable carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004033463A1 (en) * | 2002-10-11 | 2004-04-22 | Otsuka Pharmaceutical Co., Ltd. | 2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES |
| WO2016119706A1 (en) * | 2015-01-29 | 2016-08-04 | 南京明德新药研发股份有限公司 | Anti-pulmonary tuberculosis nitroimidazole derivative |
| CN110857294A (en) * | 2018-08-22 | 2020-03-03 | 华北制药集团新药研究开发有限责任公司 | Crystal form of diramanib intermediate and preparation method thereof |
-
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- 2021-08-04 CN CN202110892848.XA patent/CN113603706A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004033463A1 (en) * | 2002-10-11 | 2004-04-22 | Otsuka Pharmaceutical Co., Ltd. | 2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES |
| WO2016119706A1 (en) * | 2015-01-29 | 2016-08-04 | 南京明德新药研发股份有限公司 | Anti-pulmonary tuberculosis nitroimidazole derivative |
| CN110857294A (en) * | 2018-08-22 | 2020-03-03 | 华北制药集团新药研究开发有限责任公司 | Crystal form of diramanib intermediate and preparation method thereof |
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| Title |
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| HIROFUMI SASAKI: "Synthesis and Antituberculosis Activity of a Novel Series of Optically", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 张珊珊等: "德拉马尼治疗耐多药结核病的研究进展", 《实用心脑肺血管病杂志》 * |
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