CN112939945A - Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms - Google Patents
Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms Download PDFInfo
- Publication number
- CN112939945A CN112939945A CN202110208115.XA CN202110208115A CN112939945A CN 112939945 A CN112939945 A CN 112939945A CN 202110208115 A CN202110208115 A CN 202110208115A CN 112939945 A CN112939945 A CN 112939945A
- Authority
- CN
- China
- Prior art keywords
- nilotinib
- crystalline form
- active
- methylpyrrolidone
- prepared
- 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.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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 nilotinib crystal form, which has characteristic peaks at diffraction angles 2 theta of 5.0 degrees +/-0.2 degrees, 5.4 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 11.6 degrees +/-0.2 degrees and 13.8 degrees +/-0.2 degrees in an X-ray powder diffraction pattern obtained by Cu-K alpha ray measurement. The nilotinib crystal form provided by the invention is a new crystal form, has good solubility in an aqueous solution with a pH value of 1 and an organic solvent, and has good application prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a nilotinib crystal form, an active medicine prepared from the nilotinib crystal form and a pharmaceutical composition.
Background
Nilotinib, chemical name 4-methyl-N- [3- (4-methylimidazol-1-yl) -5- (trifluoromethyl) phenyl]-3- [ (4-pyridin-3-ylpyrimidin-2-yl) amino group]Benzamide, having the formula:
nilotinib is useful for the treatment of philadelphia chromosome positive chronic myeloid leukemia. It is selective for tumor cells compared to traditional cytotoxic chemotherapy, thus drastically altering the modality of cancer treatment. However, the bioavailability of nilotinib is not high and there is a food effect, which is strongly correlated with the poor solubility of nilotinib.
There is a need in the art for continued improvements in crystalline forms of nilotinib, enhancing its solubility, and thereby increasing oral bioavailability.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. To this end, the invention provides a crystalline form of nilotinib, an active drug and a pharmaceutical composition prepared using the crystalline form. The crystal form is a new crystal form, and has higher solubility or faster dissolution speed in water/ethanol solution and hydrochloric acid aqueous solution with the pH value of 1; the crystal form has higher solubility in an organic solvent or a combined solvent, and an active medicament formed by utilizing the new crystal form has good solubility.
In a first aspect of the invention, a crystalline form of nilotinib is provided, which has characteristic peaks at diffraction angles 2 θ of 5.0 ° ± 0.2 °, 5.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.6 ° ± 0.2 ° and 13.8 ° ± 0.2 ° in an X-ray powder diffraction pattern obtained by measurement using Cu-K α rays.
The crystalline form of nilotinib according to embodiments of the present invention has at least the following beneficial effects:
the embodiment of the invention prepares a new crystal form of nilotinib, and experimental research shows that the new crystal form has better solubility in water/ethanol solution and faster dissolution speed in hydrochloric acid aqueous solution with pH of 1, is beneficial to dissolution and absorption in human body, and has better dissolution characteristics so that the new crystal form has a wider application prospect.
In some preferred embodiments of the invention, the crystalline form also has characteristic peaks at diffraction angles 2 θ of 8.4 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.7 ° ± 0.2 °, 19.6 ° ± 0.2 ° and 20.9 ° ± 0.2 ° in an X-ray powder diffraction pattern measured using Cu-K α radiation.
In some more preferred embodiments of the invention, the crystalline form further has characteristic peaks at diffraction angles 2 θ of 8.8 ° ± 0.2 °, 9.1 ° ± 0.2 °, 16.0 ± 0.2 °,17.8 ° ± 0.2 °, 18.8 ° ± 0.2 °, 25.7 ° ± 0.2 ° in an X-ray powder diffraction pattern measured using Cu-K α radiation.
In a second aspect of the present invention, a preparation method of the above crystalline form of nilotinib is provided, which comprises the following steps:
(1) mixing nilotinib with N-methylpyrrolidone, and stirring and dissolving at 10-40 ℃;
(2) and then adding water, and continuously stirring at 0-40 ℃ to obtain the nilotinib crystal form.
The preparation method of the nilotinib crystal form provided by the embodiment of the invention has at least the following beneficial effects:
according to the embodiment of the invention, nilotinib is dissolved by N-methylpyrrolidone, then water is added to crystallize nilotinib, nilotinib with a new crystal form is successfully prepared by matching N-methylpyrrolidone and water, the obtained nilotinib crystal has high purity, the purity can reach more than 99% by HPLC (high performance liquid chromatography) detection, and the maximum single impurity content is extremely low.
In some embodiments of the invention, in step (1), nilotinib: the mass-volume ratio of the N-methylpyrrolidone is 1: (5-30) the unit of the mass-volume ratio is kg/L.
In some embodiments of the present invention, the amount of water used in step (2) is 0.5 to 5 times the amount of N-methylpyrrolidone used by volume. In some preferred embodiments of the present invention, the temperature of the added water is 0 to 40 ℃.
In some embodiments of the present invention, the method further comprises a step of treating the crystalline form of nilotinib with a mixed solvent of N-methylpyrrolidone and water, and water.
In some preferred embodiments of the present invention, in the mixed solvent, the ratio of N-methylpyrrolidone: the volume ratio of water is 1: 3.
in some embodiments of the invention, the product of step (2) is filtered under reduced pressure before said purification and then treated with a mixed solvent and water.
In a third aspect of the present invention, an active pharmaceutical is provided, which is prepared from a raw material comprising an active ingredient and an acidic polymer, wherein the active ingredient is the crystalline form of nilotinib or a material prepared according to the above preparation method of the crystalline form of nilotinib. The invention improves the solubility of nilotinib in an organic solvent by changing the crystal structure so as to improve the industrialized production efficiency of subsequent active medicaments, and the active medicament prepared by the crystal has high purity, high yield, low solvent consumption and higher dissolution speed, thereby providing a basis for improving the oral bioavailability.
The "acidic polymer" in the present invention refers to an acidic polymer material which is non-toxic, non-antigenic and has good biocompatibility.
In some embodiments of the invention, the acidic polymer is selected from at least one of 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 20-50%.
In some embodiments of the invention, the solution is formed by dissolving a starting material comprising an active ingredient and an acidic polymer in a solvent and spray drying or lyophilizing the solution.
In some embodiments of the invention, the parameters of the spray drying are set as: the suction force is 500-800 kg/h, the inlet temperature is 50-100 ℃, the outlet temperature is 45-65 ℃, the sample injection rate is 0.2-1L/min, the atomized air flow is 500-800 kg/h, and the cooling temperature of the inert loop is-18 to-20 ℃.
In some preferred embodiments of the present invention, the solvent is a mixed solvent of tetrahydrofuran and ethanol, or a mixed solvent of methanol and acetone. Methanol is a second solvent (the limit of solvent residue is 0.3 percent), acetone is a third solvent (the limit of solvent residue is 0.5 percent), and the active ingredients and the acidic polymer can not be dissolved by selecting the third solvent alone.
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.
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 commercially available nilotinib form A used in examples of the present invention;
figure 2 is an X-ray powder diffraction pattern of nilotinib form B prepared according to patent CN 101228150B;
FIG. 3 is an X-ray powder diffraction pattern of nilotinib crystals of example 1 of the present invention;
FIG. 4 is a Raman spectrum of nilotinib crystals of example 1 according to the present invention;
FIG. 5 is a Raman spectrum of nilotinib crystals and HPMCP dissolved in a solution of example 3 according to the present invention;
FIG. 6 is an X-ray powder diffraction pattern of the active drug of example 3 of the present invention;
FIG. 7 is a polarizing microscope photograph of the active agent of example 3 of the present invention;
FIG. 8 is a Raman spectrum overlay of active drugs containing different nilotinib amounts prepared in example 7;
figure 9 is a graph of the dissolution of the active drug substance in effect example 6 versus commercially available nilotinib.
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 diffraction method (PXRD): x-ray powder diffraction was carried out using an Empyrean sharp X-ray powder diffractometer (PW3040/60) of the family Pynaudiaceae, the Netherlands, using Cu-Ka radiation at a wavelength of
A Ni filter; incident light path: a divergence slit FDS 1/8 degrees, a light shielding frame Mask 5mm degrees and an anti-divergence slit FDS 1/4 degrees; diffraction light path: 7.5 of the anti-scattering slit, 45kV of the voltage of the X-ray light pipe, 40mA of the current of the X-ray light pipe, 2-40 degrees (2 theta) of the scanning range, 0.0260 degree of step and 156.315s of scanning time of each step. The samples were spread on sample trays for testing. Data acquisition software X' Pert Data Collector, Data viewing software HighScore Plus.
Raman spectroscopy: raney's NiThe ShaoxinVia Raman micro spectrometer is provided with a near-infrared diode laser source and a Rencam Charge Coupled Device (CCD) silicon detector. Transversely cutting the preparation particles, placing the particles on a microscope glass slide, 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 200cm-1-1800cm-1The laser intensity is 100%, the exposure time is 3s, and the accumulated times are 2 times; and data acquisition and analysis software wire 4.3.
High Performance Liquid Chromatography (HPLC): the high performance liquid chromatography measurement adopts Agilent 1260Infinity II high performance liquid chromatography, and the chromatographic column comprises:
t33 μm 4.6 × 100mm, column temperature: 40 ℃; flow rate: 0.8 mL/min; wavelength: 240 nm; sample introduction amount: 5 μ L, mobile phase: a is a 1.36g/L potassium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid, and B is acetonitrile.
Polarization microscopy (PLM): the particle size and morphology of the samples were observed using a Nikon diet microscope with crossed polarizing filters. Reflected light mode, Nikon DS-Fi1c camera, NIS-Elements 4.50 analysis software.
The term "dissolution clarification" below refers to dissolution clarification.
Nilotinib used in the following examples was purchased from pure pharmaceutical science and technology ltd, guangzhou, and its X-ray powder diffraction pattern, as detected by PXRD, is shown in fig. 1 and is consistent with form a in patent CN 101228150B.
The crystal form B used in the following examples was prepared according to the method of patent CN101228150B, and its X-ray powder diffraction pattern detected by PXRD is shown in fig. 2, and is consistent with the crystal form B in CN 101228150B.
Example 1
This example prepares a crystalline form of nilotinib, prepared according to the following steps:
under stirring, 3kg of nilotinib was added to 30L N-methylpyrrolidone, and dissolved at room temperature with stirring. After complete dissolution, 90L of purified water was added over 2 h. After the addition was completed, stirring was continued at room temperature for 2 hours, and crystals were precipitated by filtration under reduced pressure.
PXRD detection was performed on solid-like crystals, and the results are shown in fig. 3. As can be seen from the figure, the crystals of nilotinib have characteristic peaks at diffraction angles 2 θ of about 5.0 °, about 5.4 °, about 8.4 °, about 8.8 °, about 9.1 °, about 10.8 °, about 11.6 °, about 13.8 °, about 16.0 °, about 16.3, about 16.7 °, about 17.8 °, about 18.3 °, about 18.8 °, about 19.6 °, about 20.9 °, about 21.3 °, about 21.9 °, about 22.3 °, about 23.5 °, about 24.0 °, about 24.6 °, about 25.0 °, about 25.7 °, about 29.9 °, about 30.5 °, about 33.8 °, about 34.7 °, which is a new crystalline form. FIG. 4 shows the Raman spectrum of the prepared nilotinib crystals at about 213cm-1About 242cm-1About 260cm-1About 318cm-1About 619cm-1About 670cm-1About 711cm-1About 753cm-1About 793cm-1About 851cm-1About 926cm-1About 966cm-1About 992cm-1About 999cm-1About 1025cm-1About 1039cm-1About 1268cm-1About 1291cm-1About 1399cm-1About 1451cm-1About 1594cm-1About 1617cm-1About 1670cm-1Has characteristic peaks.
And (3) taking crystals precipitated after vacuum filtration, washing the crystals once by using a mixed solvent (1L) of N-methyl pyrrolidone and water (the volume ratio is 1:3), washing twice (2X 2L) by using purified water, and drying the crystals under reduced pressure at 50 ℃ and 0.1MPa to obtain 2.7kg of high-purity nilotinib crystals with the yield of 89.6%. The data obtained using HPLC are shown in table 1, and the experimental results show that nilotinib crystals are obtained with a purity of 99.81% and a maximum of 0.07% monohetic. Experimental results show that the nilotinib crystal with a new crystal form is prepared by the preparation method provided by the invention, and the purity of the nilotinib crystal is very high.
TABLE 1 HPLC profiling data
Example 2
This example provides a crystalline form of nilotinib, prepared according to the following steps:
under stirring, 5kg of nilotinib was added to 55L N-methylpyrrolidone, and dissolved at room temperature with stirring. After complete dissolution, 150L of purified water was added over 3 h. After the addition is finished, the mixed solution is cooled to 5 ℃, and the mixed solution is kept warm and stirred for 5 hours to precipitate crystals.
PXRD detection of solid-like crystals was also performed, with characteristic peaks at diffraction angles 2 θ of about 5.0 °, about 5.4 °, about 8.4 °, about 8.8 °, about 9.1 °, about 10.8 °, about 11.6 °, about 13.8 °, about 16.0 °, about 16.3, about 16.7 °, about 18.8 °, about 19.6 °, about 20.9 °, about 21.3 °, about 21.9 °, about 22.3 °, about 23.5 °, about 24.0 °, about 24.6 °, about 25.0 °, about 25.7 °, which is a new crystal form.
The precipitated crystals were filtered, washed once with a mixed solvent (1.5L) of N-methylpyrrolidone and water (volume ratio 1:3), twice (3 × 2L) with purified water, and dried under reduced pressure at 50 ℃ and-0.1 MPa to obtain 4.6kg of high-purity nilotinib crystals with a yield of 92.5%.
Effect example 1
The nilotinib new form prepared in example 1 was subjected to instantaneous solubility determination using a dissolution apparatus. 50mg of the new crystal form prepared in example 1 was weighed, 50mg of each of the crystal form A and the crystal form B was taken as a control group, and 2 groups of solids were sieved through a 100-mesh sieve.
The dissolution medium was 500mL of 0.1N hydrochloric acid solution with pH 1, the temperature was maintained at 37 ℃. + -. 0.5 ℃, the stirring speed was adjusted to 100 rpm, 5mL of the dissolution medium was sampled at 5, 10, 15, 20, and 30 minutes from the time when the measured substance was added to the dissolution cup, and 5mL of the dissolution medium was added, and the concentration was measured in the liquid phase after filtration, and the results are shown in Table 2. It can be seen that the instantaneous solubility of the new form in 0.1N hydrochloric acid solution at pH 1 is higher than that of forms a and B at any sampling time point for 30 minutes. The improvement of the dissolution speed is beneficial to the dissolution and absorption of the medicine in vivo, and the new crystal form provided by the embodiment of the invention has greater application potential.
TABLE 2 instantaneous solubility of the New Crystal form (. mu.g/mL)
| 5 |
10 |
15 |
20 |
30 minutes | |
| Novel crystalline forms | 40.3 | 56.7 | 70.7 | 75.5 | 80.7 |
| Crystal form A | 10.3 | 15.2 | 30.3 | 42.2 | 50.4 |
| Crystal form B | 12.9 | 21.6 | 35.2 | 45.5 | 52.4 |
Effect example 2
The nilotinib crystal prepared in example 1 was subjected to an approximate solubility test, and a mixed solvent of water and ethanol was used as a solvent for solubility test, wherein ethanol was used for solubilization, which is beneficial to eliminating the result error caused by an excessively small measurement value, and the specific test method is as follows: 100mg of a sample to be tested is weighed and added into 2mL of water/ethanol (volume ratio is 1:1) mixed solvent, stirred and balanced for 24h at 25 +/-0.5 ℃, and then filtered. The concentration of the saturated liquid in liquid phase detection is 190 mug/mL, compared with the crystal form A and the crystal form B in the patent CN101228150B, the concentration of the saturated liquid is 71 mug/mL and 74 mug/mL respectively. As can be seen by comparison, the novel crystal form prepared by the embodiment of the invention has improved solubility in water/ethanol (1:1), and is beneficial to the dissolution and absorption of the drug in vivo.
Effect example 3
The nilotinib crystal prepared in example 1 is subjected to an apparent solubility test, which is a solubility test method determined in the four exceptional cases fifteen in the 2020 edition of the Chinese pharmacopoeia: sieving the crystal powder with a 100-mesh sieve, weighing 1g of the crystal powder in a triangular flask, adding a certain volume of mixed solvent of methanol and acetone (1:2 volume ratio) at 25 +/-2 ℃, shaking strongly for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes, and completely dissolving the crystal powder when no visible solid exists. When the solution is completely dissolved, the volume of the mixed solvent is 100 mL. Compared with the crystal form A and the crystal form B in the patent CN101228150B, when the same weight is taken and the volumes of the added mixed solvent are respectively 320mL and 300mL under the same condition, the solubility of the new crystal form in the mixed solvent of methanol and acetone (1:2 volume ratio) is greatly improved.
Effect example 4
The nilotinib crystal prepared in example 1 is subjected to an apparent solubility test, which is a solubility test method determined in the four exceptional cases fifteen in the 2020 edition of the Chinese pharmacopoeia: sieving the crystal powder with a 100-mesh sieve, weighing 1g of the crystal powder in a triangular flask, adding a certain volume of mixed solvent of tetrahydrofuran and ethanol (1:5 volume ratio) at 25 +/-2 ℃, shaking strongly for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes, and completely dissolving the crystal powder when no visible solute particles exist. When the solution is completely dissolved, the volume of the mixed solvent is 110 mL. Compared with the crystal form A and the crystal form B in the patent CN101228150B, when the same weight is taken and the volumes of the added mixed solvent are 440mL and 410mL respectively under the same condition, the solubility of the novel crystal form in the mixed solvent of tetrahydrofuran and ethanol (1:5 volume ratio) is greatly improved.
Effect example 5
The nilotinib crystal prepared in example 1 is subjected to an apparent solubility test, which is a solubility test method determined in the four exceptional cases fifteen in the 2020 edition of the Chinese pharmacopoeia: sieving the crystal powder with a 100-mesh sieve, weighing 1g of the crystal powder in a triangular flask, adding a certain volume of benzyl alcohol at 25 +/-2 ℃, shaking strongly for 30 seconds every 5 minutes, observing the dissolution condition within 30 minutes, and completely dissolving the crystal powder when no visible solid exists. When the solution was completely dissolved, 40mL of the mixed solvent was added. Compared with the crystal form A and the crystal form B in the patent CN101228150B, when the same weight is taken and the volumes of the added mixed solvent are respectively 70mL and 65mL under the same condition, the solubility of the new crystal form in the benzyl alcohol is greatly improved.
As can be seen from effect examples 3-5, compared with the existing crystal form, the new crystal form provided by the embodiment of the present invention has higher solubility in organic solvents, consumes less solvent when used as an active ingredient to prepare an active drug with an equal concentration, and has higher application value in industrial production.
Example 3
This example provides an active agent prepared from nilotinib crystals and an acidic polymer, wherein the acidic polymer used in this example is hydroxypropylmethylcellulose phthalate (HPMCP), prepared by the following steps:
0.9kg of HPMCP was added to 80L of a mixed solvent of methanol and acetone (1:1 volume ratio) with stirring and dissolved at room temperature, and then 0.6kg of nilotinib crystals prepared in example 1 was added and stirred at room temperature, and FIG. 5 shows a Raman spectrum of the solution after stirring and dissolution, and after confirming dissolution by Raman monitoring, the dissolved solution was spray-dried under nitrogen protection. The parameter settings for the spray-drying process are shown in table 3.
Table 3 parameter settings for spray drying
And after spray drying, drying the product at 50 ℃ under reduced pressure under-0.1 MPa to remove the redundant solvent, thus obtaining the active medicine containing 40% of nilotinib (mass ratio). The physical state of the solid active drug is determined by PXRD, and the result is shown in FIG. 6, which shows a dispersion peak in FIG. 6 and does not show a sharp diffraction peak, indicating that the prepared active drug is amorphous. Fig. 7 shows a spectrum of the active drug observed under a polarization microscope, showing that the particle size of the active drug is about 1 to 10 μm, and is a fine particle, not a nanoparticle. In this example, the active agent prepared by spray drying weighed 1.4kg, the yield was 93.3%, the purity was 99.72% by HPLC, and the maximum amount of single impurity was 0.17%.
Example 4
This example provides an active agent prepared from nilotinib crystals and an acidic polymer, wherein the acidic polymer used in this example is hydroxypropylmethylcellulose phthalate (HPMCP), prepared by the following steps:
0.3kg of HPMCP was added to 22L of a mixed solvent of methanol and acetone (1:2 by volume) with stirring to dissolve the HPMCP at room temperature, 0.2kg of nilotinib crystals prepared in example 1 was added to the dissolved HPMCP, the mixture was further stirred at room temperature to confirm the dissolution, and the dissolved solution was spray-dried under nitrogen protection. The parameter settings for the spray-drying process are shown in table 4.
Table 4 parameter settings for spray drying
And after spray drying, drying the product under reduced pressure at 50 ℃ under-0.1 MPa to remove redundant solvent to obtain the active medicine containing 40% of nilotinib. The physical state of the solid active drug is determined by PXRD, and the result shows that the dispersion peak is similar to that of figure 6, and no sharp diffraction peak is shown, which indicates that the prepared active drug is amorphous. The polarization micrograph of the active drug of this example also shows a particle size of about 1 μm to 10 μm, being a fine particle, not a nanoparticle. The active drug produced by spray drying in this example weighed 0.46kg, with a yield of 92%.
Example 5
This example provides an active agent prepared from nilotinib crystals and an acidic polymer, wherein the acidic polymer used in this example is hydroxypropylmethylcellulose phthalate (HPMCP), prepared by the following steps:
0.6kg of HPMCP was added to 50L of a mixed solvent of tetrahydrofuran and ethanol (1:5 by volume) under stirring, and dissolved by stirring at room temperature, and then 0.4kg of nilotinib crystals obtained in example 2 was added thereto, and stirring was continued at room temperature, and after confirming the dissolution, the dissolved solution was spray-dried under nitrogen protection. The parameter settings for the spray-drying process are shown in table 5.
Table 5 parameter settings for spray drying
| Parameter(s) | Set value |
| Suction force | 800kg/ |
| Inlet temperature | |
| 100℃ | |
| Outlet temperature | 65℃ |
| Sample introduction rate | 1L/min |
| Atomized gas flow | 800kg/h |
| Inert loop cooling temperature | ﹣20℃ |
And after spray drying, drying the product under reduced pressure at 50 ℃ under-0.1 MPa to remove redundant solvent to obtain the active medicine containing 40% of nilotinib. The active drug prepared by spray drying in this example weighed 0.94kg, with a yield of 94%.
Example 6
This example provides an active agent prepared from nilotinib crystals and an acidic polymer, wherein the acidic polymer used in this example is hydroxypropylmethylcellulose phthalate (HPMCP), prepared by the following steps:
0.3g of HPMCP and 0.2g of nilotinib crystals prepared in example 1 were added to 20mL of benzyl alcohol with stirring, dissolved at room temperature to give a solution, and lyophilized.
The process of lyophilization comprises:
(1) freezing: cooling to-30 deg.C, and pre-freezing for 3 hr; continuously cooling to-45 deg.C, and maintaining at the temperature for 6 h;
(2) sublimation drying: heating to-30 deg.C, and maintaining under vacuum for 16 h;
(3) and (3) resolving and drying: the temperature was adjusted to 35 ℃ and kept under vacuum for 8 h.
This example obtained 0.47g of amorphous active drug containing 40% nilotinib (mass ratio) in 94% yield by lyophilization.
Example 7
This example provides a series of active agents, and with reference to the method of example 3, 30% physical mixture of nilotinib (mass ratio) and HPMCP, 35% physical mixture of nilotinib (mass ratio) and HPMCP, 45% physical mixture of nilotinib (mass ratio) and HPMCP, and 50% physical mixture of nilotinib (mass ratio) and HPMCP were each dissolved in a mixed solvent of tetrahydrofuran and ethanol, then spray-drying to obtain amorphous solid, separating the solid and performing Raman spectrum detection, as shown in FIG. 8, in fig. 8, the active drug containing 30% nilotinib crystals, 35% nilotinib crystals, 45% nilotinib crystals, and 50% nilotinib crystals are shown in that order from top to bottom in the direction of the arrows. A linear model can be established by using a partial least square method according to the maps corresponding to the compositions with different mass ratios. In the subsequent production, a product spectrum is rapidly obtained by using Raman online monitoring, and the product content can be calculated after the product spectrum is substituted into the linear model.
Effect example 6
Using the active drug substance prepared in example 3, dissolution comparison tests were performed with commercially available nilotinib under the conditions shown in table 6:
table 6 test conditions of dissolution comparison test
62.5mg of active drug (containing nilotinib 25mg) and 25mg of commercially available nilotinib were put into a dissolution cup, and then samples were taken at 5, 10, 15, and 30 minutes after the start of the measurement, and the dissolution rates were calculated by the peak area using HPLC, and the dissolution comparison chart is shown in FIG. 9. It can be seen that the dissolution of the active drug prepared by the novel crystal form is greatly improved, and a basis is provided for improving the oral bioavailability.
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 (11)
1. A crystalline form of nilotinib having characteristic peaks at diffraction angles, 2 Θ, of 5.0 ° ± 0.2 °, 5.4 ° ± 0.2 °, 10.8 ° ± 0.2 °, 11.6 ° ± 0.2 ° and 13.8 ° ± 0.2 ° in an X-ray powder diffraction pattern measured using Cu-K α radiation.
2. A crystalline form of nilotinib according to claim 1, characterized in that it further has characteristic peaks in the X-ray powder diffraction pattern measured using Cu-ka radiation at diffraction angles 2 Θ of 8.4 ° ± 0.2 °, 16.3 ° ± 0.2 °, 16.7 ° ± 0.2 °, 19.6 ° ± 0.2 ° and 20.9 ° ± 0.2 °.
3. A crystalline form of nilotinib according to claim 1 or 2, characterized in that it further has characteristic peaks in the X-ray powder diffraction pattern measured using Cu-ka radiation at diffraction angles 2 Θ of 8.8 ° ± 0.2 °, 9.1 ° ± 0.2 °, 16.0 ° ± 0.2 °,17.8 ° ± 0.2 °, 18.8 ° ± 0.2 °, 25.7 ° ± 0.2 °.
4. A process for preparing a crystalline form of nilotinib according to any one of claims 1 to 3, comprising the steps of:
(1) mixing nilotinib with N-methylpyrrolidone, and stirring and dissolving at 10-40 ℃;
(2) and then adding water, and continuously stirring at 0-40 ℃ to obtain the nilotinib crystal form.
5. The process for preparing a crystalline form of nilotinib according to claim 4, wherein in step (1), nilotinib: the mass-volume ratio of the N-methylpyrrolidone is 1: (5-30) the unit of the mass-volume ratio is kg/L.
6. The method for preparing nilotinib in crystalline form according to claim 4, wherein in step (2), the amount of water used is 0.5 to 5 times the amount of N-methylpyrrolidone used by volume; preferably, the temperature of the added water is 0-40 ℃.
7. The method for preparing the crystalline form of nilotinib according to claim 4, further comprising the step of treating the crystalline form of nilotinib with a mixed solvent of N-methylpyrrolidone and water; preferably, in the mixed solvent, the ratio of N-methylpyrrolidone: the volume ratio of water is 1: 3.
8. active pharmaceutical, characterized in that it is prepared from a starting material comprising an active ingredient and an acidic polymer, said active ingredient being a material obtained by a process for the preparation of a crystalline form of nilotinib according to any one of claims 1 to 3 or a crystalline form of nilotinib according to any one of claims 4 to 7.
9. The active agent of claim 8, wherein the acidic polymer is selected from at least one of 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 20-50%.
10. The active agent according to claim 8, wherein the active agent is prepared by dissolving a starting material comprising the active ingredient and the acidic polymer in a solvent to form a solution and spray-drying or lyophilizing the solution.
11. A pharmaceutical composition comprising an active agent according to any one of claims 8 to 10 and an adjuvant or a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110208115.XA CN112939945B (en) | 2021-02-25 | 2021-02-25 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110208115.XA CN112939945B (en) | 2021-02-25 | 2021-02-25 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112939945A true CN112939945A (en) | 2021-06-11 |
| CN112939945B CN112939945B (en) | 2022-06-03 |
Family
ID=76245986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110208115.XA Active CN112939945B (en) | 2021-02-25 | 2021-02-25 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112939945B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116102540A (en) * | 2023-01-05 | 2023-05-12 | 浙江工业大学 | Novel two nilotinib free base crystal forms and preparation method thereof |
| CN117100715A (en) * | 2023-09-05 | 2023-11-24 | 深圳市泰力生物医药有限公司 | Capsule containing amorphous nilotinib and preparation method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130210847A1 (en) * | 2012-02-15 | 2013-08-15 | Natco Pharma Limited | Process for the preparation of nilotinib |
| CN106496193A (en) * | 2016-09-13 | 2017-03-15 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of high-purity nilotinib |
| CN108586431A (en) * | 2018-07-09 | 2018-09-28 | 威海云睿信息科技有限公司 | A kind of purification process of small grain size nilotinib |
| CN108640904A (en) * | 2018-07-09 | 2018-10-12 | 威海云睿信息科技有限公司 | A kind of purification process of small grain size nilotinib |
| CN108864051A (en) * | 2017-05-16 | 2018-11-23 | 意大利合成制造有限公司 | The method for being used to prepare pure nilotinib and its salt |
| CN109020954A (en) * | 2018-07-09 | 2018-12-18 | 威海云睿信息科技有限公司 | A kind of nilotinib novel crystal forms |
| CN108530364B (en) * | 2018-04-10 | 2020-01-21 | 江苏创诺制药有限公司 | Crystal form of 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline monohydrochloride and application thereof |
| CN112294971A (en) * | 2020-02-20 | 2021-02-02 | 深圳市泰力生物医药有限公司 | Nilotinib compositions having improved solubility |
-
2021
- 2021-02-25 CN CN202110208115.XA patent/CN112939945B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130210847A1 (en) * | 2012-02-15 | 2013-08-15 | Natco Pharma Limited | Process for the preparation of nilotinib |
| CN106496193A (en) * | 2016-09-13 | 2017-03-15 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of high-purity nilotinib |
| CN108864051A (en) * | 2017-05-16 | 2018-11-23 | 意大利合成制造有限公司 | The method for being used to prepare pure nilotinib and its salt |
| CN108530364B (en) * | 2018-04-10 | 2020-01-21 | 江苏创诺制药有限公司 | Crystal form of 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline monohydrochloride and application thereof |
| CN108586431A (en) * | 2018-07-09 | 2018-09-28 | 威海云睿信息科技有限公司 | A kind of purification process of small grain size nilotinib |
| CN108640904A (en) * | 2018-07-09 | 2018-10-12 | 威海云睿信息科技有限公司 | A kind of purification process of small grain size nilotinib |
| CN109020954A (en) * | 2018-07-09 | 2018-12-18 | 威海云睿信息科技有限公司 | A kind of nilotinib novel crystal forms |
| CN112294971A (en) * | 2020-02-20 | 2021-02-02 | 深圳市泰力生物医药有限公司 | Nilotinib compositions having improved solubility |
Non-Patent Citations (3)
| Title |
|---|
| 禹艳坤: "尼洛替尼的合成", 《中国优秀博硕士学位论文全文数据库（硕士） 医药卫生科技辑》 * |
| 陈永江 等: "尼罗替尼的合成", 《中国医药工业杂志》 * |
| 高朔漠 等: "新型抗癌药物尼洛替尼的合成工艺研究", 《西北大学学报（自然科学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116102540A (en) * | 2023-01-05 | 2023-05-12 | 浙江工业大学 | Novel two nilotinib free base crystal forms and preparation method thereof |
| CN117100715A (en) * | 2023-09-05 | 2023-11-24 | 深圳市泰力生物医药有限公司 | Capsule containing amorphous nilotinib and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112939945B (en) | 2022-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112939945B (en) | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms | |
| Ziaee et al. | Spray drying ternary amorphous solid dispersions of ibuprofen–An investigation into critical formulation and processing parameters | |
| JP2020513023A (en) | Amorphous Form and Solid Dispersion of Lumateperone p-Tosylate | |
| KR20150092354A (en) | Polymorphic forms st-246 and methods of preparation | |
| MX2007010433A (en) | Tadalafil having a large particle size and a process for preparation thereof. | |
| CN108276478B (en) | Crystal of cyclic peptide compound and preparation method and application thereof | |
| WO2009084023A2 (en) | Amorphous ramelteon and process for the preparation thereof | |
| JP2019518058A (en) | Solid state form of spiro-oxindole compounds | |
| JP2023539298A (en) | Cariprazine pharmaceutical composition, manufacturing method and application | |
| CN106397298A (en) | A pharmaceutical composition containing indobufen and uses thereof | |
| KR20190137116A (en) | EOC315 MOD. I crystalline compound and preparation method thereof | |
| WO2016193994A1 (en) | Amorphous selexipag and process for preparation thereof | |
| CN109432016B (en) | Enzalutamide ternary solid preparation and preparation method thereof | |
| Keraliya et al. | Formulation and Physical characterization of microcrystals for dissolution rate enhancement of Tolbutamide | |
| CN112469413A (en) | Monohydrate and crystalline forms of6- [ (3S,4S) -4-methyl-1- (pyrimidin-2-ylmethyl) pyrrolidin-3-yl ] -3-tetrahydropyran-4-yl-7H-imidazo [1,5-a ] pyrazin-8-one | |
| JP5823484B2 (en) | α-Ketoamide derivative solid dispersion | |
| JP6437004B2 (en) | Crystal powder of cyclopeptide compound and its production method and use | |
| JP4376628B2 (en) | Amorphous materials of tricyclic triazolobenzazepine derivatives. | |
| CN113603706A (en) | Crystal form of delamasil, active drug and pharmaceutical composition containing the crystal form | |
| JP2012515753A (en) | Method for isolating tigecycline | |
| US20220251111A1 (en) | Process for the preparation of amorphous midostaurin with a low content of residual organic solvent | |
| Liu et al. | Quercetin-phospholipids complex solid dispersion and quercetin solid dispersion: preparation and evaluation. | |
| JP2022540275A (en) | Crystal form, preparation method and use of tetramethylpyrazine nitrone | |
| Boukhris et al. | NOVEL ORAL FORMULATION OF CYCLOSPORINE-SPRAY-DRIED DISPERSION USING CYCLODEXTRIN COPOLYMERS. | |
| CN115181046B (en) | Eutectic crystal of vitamin D3 and L-menthol as well as 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |