Disclosure of Invention
The invention aims to provide a novel crystal form of a compound shown in a formula (I) which is easy to prepare and high in stability so as to meet the requirements of pharmaceutical research and industrial production.
In a first aspect of the invention, there is provided a crystalline form of a compound of formula (I): the crystal form comprises a crystal form CM-I, a crystal form CM-II, a crystal form CM-III, a crystal form CM-IV, a crystal form CM-V, a crystal form CM-VI, a crystal form CM-VII and/or a crystal form CM-VIII.
Preferably, the crystalline form is selected from the group consisting of: crystal form CM-I, crystal form CM-II, crystal form CM-III;
wherein the XRPD pattern of said crystalline form CM-I comprises 2 or more than 2 values selected from the group consisting of: 7.7 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 15.5 degrees +/-0.2 degrees and 17.8 degrees +/-0.2 degrees;
the XRPD of crystalline form CM-II comprises 3 or more than 3 2 Θ values selected from the group consisting of: 10.7 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees and 22.8 degrees +/-0.2 degrees;
the XRPD pattern of the crystalline form CM-III comprises 3 or more than 3 2 Θ values selected from the group consisting of: 7.9 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees and 18.9 degrees +/-0.2 degrees.
Preferably, the crystalline form is crystalline form CM-I, wherein the XRPD pattern of the crystalline form CM-I comprises 2 or more (e.g., 2, 3, 4) 2 θ values selected from the group consisting of: 7.7 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 15.5 degrees +/-0.2 degrees and 17.8 degrees +/-0.2 degrees.
Preferably, the crystalline form is crystalline form CM-II, wherein the XRPD of the crystalline form CM-II comprises 3 or more (e.g., 3, 4, 5) 2 Θ values selected from the group consisting of: 10.7 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees and 22.8 degrees +/-0.2 degrees.
Preferably, the crystalline form is crystalline form CM-III, wherein the XRPD pattern of the crystalline form CM-III comprises 3 or more (e.g., 3, 4, 5) 2 Θ values selected from the group consisting of: 7.9 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees and 18.9 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-I has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-I comprises 6 or more (e.g. 6,7, 8, 9, 10) 2 Θ values selected from the group consisting of: 3.9 degrees +/-0.2 degrees, 7.7 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 11.3 degrees +/-0.2 degrees, 14.3 degrees +/-0.2 degrees, 15.5 degrees +/-0.2 degrees, 17.8 degrees +/-0.2 degrees, 20.0 degrees +/-0.2 degrees, 22.7 degrees +/-0.2 degrees, 23.3 degrees +/-0.2 degrees, 25.1 degrees +/-0.2 degrees and 28.9 degrees +/-0.2 degrees.
2) The crystalline form CM-I has an XRPD pattern substantially as shown in figure 1;
3) the crystalline form CM-I has a TGA profile substantially as shown in figure 2;
4) said crystalline form CM-I having a DSC profile substantially as shown in figure 3;
5) said crystalline form CM-I having a structure substantially as shown in FIG. 41H NMR spectrum.
Preferably, the crystalline form CM-II has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-II comprises 6 or more (e.g., 6,7, 8, 9, 10) 2 Θ values selected from the group consisting of: 6.2 degrees +/-0.2 degrees, 8.8 degrees +/-0.2 degrees, 10.7 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.5 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 20.2 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.3 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 24.5 degrees +/-0.2 degrees, 26.8 degrees +/-0.2 degrees, 27.0 degrees +/-0.2 degrees and 27.5 degrees +/-0.2 degrees.
2) The crystalline form CM-II has an XRPD pattern substantially as shown in figure 6;
3) the crystalline form CM-II has a TGA profile substantially as shown in figure 7;
4) said crystalline form CM-II having a DSC profile substantially as shown in figure 8;
5) said crystalline form CM-II having a structure substantially as shown in FIG. 91H NMR spectrum.
Preferably, the crystalline form CM-III has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-III comprises 6 or more (e.g., 6,7, 8, 9, 10) 2 Θ values selected from the group consisting of: 6.5 degrees +/-0.2 degrees, 7.9 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 9.7 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 18.8 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 21.1 degrees +/-0.2 degrees, 23.3 degrees +/-0.2 degrees, 23.8 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees and 28.9 degrees +/-0.2 degrees.
2) The crystalline form CM-III has an XRPD pattern substantially as shown in figure 13;
3) the crystalline form CM-III has a TGA profile substantially as shown in figure 14;
4) the crystalline form CM-III has a DSC profile substantially as shown in figure 15;
5) the crystalline form CM-III has a structure substantially as shown in figure 161H NMR spectrum.
Preferably, the crystalline form is crystalline form CM-IV, wherein the XRPD pattern of the crystalline form CM-IV comprises 2 or more (e.g., 2, 3, 4) 2 θ values selected from the group consisting of: 7.1 degrees +/-0.2 degrees, 19.6 degrees +/-0.2 degrees, 21.5 degrees +/-0.2 degrees and 28.9 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-IV has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of crystalline form CM-IV comprises 4 or more than 4 (e.g. 5, 6,7, 8) 2 Θ values selected from the group consisting of: 7.1 ° ± 0.2 °, 9.7 ° ± 0.2 °, 18.6 ° ± 0.2 °, 19.6 ° ± 0.2 °, 21.5 ° ± 0.2 °, 28.9 ° ± 0.2 °;
2) the crystalline form CM-IV has an XRPD pattern substantially as shown in figure 18.
Preferably, the crystalline form is crystalline form CM-V, wherein the XRPD pattern of the crystalline form CM-V comprises 2 or more (e.g., 2, 3, 4) 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 21.0 degrees +/-0.2 degrees, 21.5 degrees +/-0.2 degrees and 28.1 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-V has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-V comprises 6 or more (e.g. 6,7, 8, 9) 2 Θ values selected from the group consisting of: 6.9 degrees +/-0.2 degrees, 9.4 degrees +/-0.2 degrees, 21.0 degrees +/-0.2 degrees, 21.5 degrees +/-0.2 degrees, 23.2 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 28.1 degrees +/-0.2 degrees and 28.8 degrees +/-0.2 degrees;
2) the crystalline form CM-V has an XRPD pattern substantially as shown in figure 19.
Preferably, the crystalline form is crystalline form CM-VI, wherein the XRPD pattern of the crystalline form CM-VI comprises 2 or more (e.g., 2, 3, 4) 2 θ values selected from the group consisting of: 7.4 degrees +/-0.2 degrees, 9.0 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees and 22.5 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-VI has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-VI comprises 4 or more than 4 (e.g. 5, 6,7, 8) 2 Θ values selected from the group consisting of: 7.4 degrees +/-0.2 degrees, 9.0 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 15.1 degrees +/-0.2 degrees, 18.2 degrees +/-0.2 degrees, 22.5 degrees +/-0.2 degrees and 30.7 degrees +/-0.2 degrees;
2) the crystalline form CM-VI has an XRPD pattern substantially as shown in figure 20.
Preferably, the crystalline form is crystalline form CM-VII, wherein the XRPD pattern of the crystalline form CM-VII comprises 3 or more than 3 (e.g., 3, 4, 5) 2 Θ values selected from the group consisting of: 8.4 degrees +/-0.2 degrees, 13.6 degrees +/-0.2 degrees, 15.3 degrees +/-0.2 degrees, 16.8 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-VII has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-VII comprises 6 or more (e.g., 6,7, 8, 9) 2-theta values selected from the group consisting of: 8.4 ° ± 0.2 °, 13.6 ° ± 0.2 °, 15.3 ° ± 0.2 °, 16.5 ° ± 0.2 °, 16.8 ° ± 0.2 °, 17.3 ° ± 0.2 °, 18.0 ° ± 0.2 °, 18.9 ° ± 0.2 °, 19.8 ° ± 0.2 °, 21.2 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23.9 ° ± 0.2 °, 26.9 ° ± 0.2 °;
2) the crystalline form CM-VII has an XRPD pattern substantially as shown in figure 21;
3) the crystalline form CM-VII has a TGA profile substantially as shown in figure 22.
Preferably, the crystalline form is crystalline form CM-VIII, wherein the XRPD pattern of crystalline form CM-VIII comprises 2 or more (e.g., 2, 3, 4) 2 θ values selected from the group consisting of: 7.4 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees and 10.4 degrees +/-0.2 degrees.
Preferably, the crystalline form CM-VIII has one or more characteristics selected from the group consisting of:
1) the XRPD pattern of the crystalline form CM-VIII comprises 4 or more than 4 (e.g., 5, 6, 7) 2 θ values selected from the group consisting of: 7.4 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees, 10.4 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 18.3 degrees +/-0.2 degrees and 25.2 degrees +/-0.2 degrees;
2) the crystalline form CM-VIII has an XRPD pattern substantially as shown in figure 26.
In a second aspect of the present invention, there is provided a process for preparing the crystalline form of the first aspect, comprising the steps of: crystallizing a compound of formula (I) in an inert solvent, or treating a solid form of a compound of formula (I) to obtain said crystalline form, wherein said treating comprises one or more steps of the group consisting of: stirring, heating, and standing under certain temperature and humidity conditions.
Preferably, the preparation method comprises the steps of: a) providing a solution of a compound raw material shown in the formula (I) in a first solvent, adding a second solvent into the solution for crystallization, and collecting precipitated solids to obtain the crystal form.
Preferably, the step a) includes: dissolving the compound raw material shown in the formula (I) in a first solvent, filtering, adding a second solvent into the obtained filtrate for crystallization, and collecting precipitated solids to obtain the crystal form.
Preferably, in step a), the addition is dropwise or slow.
Preferably, in step a), the crystallization comprises stirring crystallization or standing crystallization.
Preferably, the preparation method comprises the steps of: b) providing a solution of a compound raw material shown in the formula (I) in a first solvent, adding the solution into a second solvent for crystallization, and collecting precipitated solids to obtain the crystal form.
Preferably, the step b) includes: dissolving the compound raw material shown in the formula (I) in a first solvent, filtering, adding the obtained filtrate into a second solvent for crystallization, and collecting precipitated solids to obtain the crystal form.
Preferably, in step b), the addition is dropwise or slow.
Preferably, in step b), the crystallization comprises stirring crystallization or standing crystallization.
Preferably, the preparation method comprises the steps of: c) providing a solution or crystal slurry of a compound raw material shown in a formula (I) in a first solvent, treating the solution or crystal slurry to obtain a solid, and collecting the obtained solid to obtain the crystal form; wherein the treatment comprises stirring or volatilizing.
Preferably, the preparation method comprises the steps of: d) providing a solid form of a compound of formula (I) starting material, and processing the solid form to obtain the crystalline form; wherein the solid form is crystalline or amorphous, and the treatment comprises one or more steps of: heating, and standing under certain temperature and humidity conditions.
Preferably, the first solvent includes an alcohol solvent, a ketone solvent, an amide solvent, an ester solvent, an ether solvent, an acid solvent, a nitrile, water, or a combination thereof.
Preferably, the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, or combinations thereof.
Preferably, the ketone solvent is selected from the group consisting of: acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.
Preferably, the amide-based solvent is selected from the group consisting of: n, N-dimethylformamide, N-dimethylacetamide, or a combination thereof.
Preferably, the ester solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, or a combination thereof.
Preferably, the ethereal solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, or a combination thereof.
Preferably, the acid solvent is selected from the group consisting of: formic acid, acetic acid, lactic acid, or a combination thereof.
Preferably, the nitrile solvent is selected from the group consisting of: and (3) acetonitrile.
Preferably, the second solvent comprises hydrocarbons, esters, water, or combinations thereof.
Preferably, the hydrocarbon solvent is selected from the group consisting of: chloroform, dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, or combinations thereof.
Preferably, the ester solvent is selected from the group consisting of: butyl acetate, n-propyl acetate, or combinations thereof.
In the step a) or the step b), after the precipitated solid is collected, the solid is processed to obtain the crystal form, wherein the processing comprises vacuum drying.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
1) a crystalline form as described in the first aspect; 2) a pharmaceutically acceptable carrier.
In a fourth aspect of the invention, there is provided a use of a pharmaceutical composition according to the third aspect for the manufacture of a medicament for the treatment of NSCLC patients carrying an ALK, ROS1 or NTRK oncogene rearrangement.
In a fifth aspect of the invention, there is provided a use of the crystalline form of the first aspect, the use comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a medicament for treating NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement.
In a fifth aspect of the invention, there is provided a use of the crystalline form of the first aspect, comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) for the preparation of a medicament for the treatment of NSCLC patients carrying an ALK, ROS1 or NTRK oncogene rearrangement.
Compared with the prior art, the invention has the advantages that:
(1) the crystal form of the invention has good stability and mechanical stability, thereby reducing the risk of crystal transformation in the preparation processing process, reducing the risk of changing the dissolution rate and bioavailability of the drug due to crystal form change, and being beneficial to the crystal form control in the crystallization and preparation processes.
(2) The crystal form of the invention has low hygroscopicity, does not have strict requirements on packaging and storage conditions, does not need special drying conditions in the preparation process, simplifies the preparation and post-treatment processes of the medicament, is beneficial to industrial production, and obviously reduces the cost of medicament production, transportation and storage.
(3) The preparation method of the crystal form provided by the invention is safe and reliable. Meanwhile, the method is simple and easy to operate, low in cost and suitable for drug research and development and industrial production.
(4) The crystal form provided by the invention has good solubility and high bioavailability, and can reduce the dosage of the medicine while ensuring the curative effect of the medicine, thereby reducing the side effect of the medicine and improving the safety of the medicine.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors of the present invention have surprisingly discovered a series of novel crystalline forms of the compound of formula (I) during the course of their research. The crystal forms are simple to prepare and low in cost, have advantages in the aspects of crystal form stability, solubility, hygroscopicity, tabletting stability, mechanical stability, preparation stability, process developability, powder processability and the like, and have important significance for the optimization and development of the medicine. And after the crystal form and pharmaceutically acceptable auxiliary materials are used for preparing tablets, the tablets do not stick to punch when being pressed, so the tablets prepared by the crystal form have excellent tabletting stability.
Term(s) for
In this context, each abbreviation is used in the conventional sense understood by those skilled in the art, unless otherwise specified.
As used herein, unless otherwise specified, the term "starting compound of formula (I)" refers to the amorphous form and/or various crystalline forms of the compound of formula (I) (including the various crystalline forms mentioned herein and the crystalline forms or amorphous forms mentioned in various documents or patents, published or unpublished, e.g., form 1 of the compound of formula (I) prepared according to the methods described in WO 2017007759.
As used herein, "crystalline form of the invention" refers to crystalline form CM-I, crystalline form CM-II, crystalline form CM-III, crystalline form CM-IV, crystalline form CM-V, crystalline form CM-VI, crystalline form CM-VII, and crystalline form CM-VIII as described herein.
As used herein, unless otherwise specified, the solvent or solution is added by direct pouring or by uniform addition, and the like.
As used herein, the manner of "slow addition" includes, but is not limited to: dropwise, slowly along the vessel wall, etc.
General procedure
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The solvents used in the present invention were all analytically pure and had a water content of about 0.1%. The compounds of formula (I) used as starting materials in the examples were all purchased commercially. All test methods of the invention are general methods, and the test parameters are as follows:
XRPD pattern determination method:
x-ray powder diffraction instrument: bruker D2 Phaser X-ray powder diffractometer; radiation source Cu
Generator (Generator) kv: 30 kv; generator (Generator) mA: 10 mA; initial 2 θ: 2.000 °, scan range: 2.0000-35.000 degrees, a scanning step size of 0.02 degrees and a scanning speed of 0.1 s/step.
TGA profile determination method:
thermogravimetric analysis (TGA) instrument: TGA55 from TA USA; heating rate: 10 ℃/min; nitrogen flow rate: 40 mL/min.
DSC chart measurement method:
differential Scanning Calorimetry (DSC) instrument: TA Q2000 by TA, USA; heating rate: 10 ℃/min, nitrogen flow rate: 50 mL/min.
Nuclear magnetic resonance hydrogen spectroscopy data (1H NMR) was taken from Bruker Avance II DMX 400M HZ NMR spectrometer. 2mg of the sample was weighed, dissolved in 0.6mL of deuterated dimethylsulfoxide, filtered, and the filtrate was added to a nuclear magnetic tube for testing.
DVS graph measurement method:
dynamic moisture sorption instrument (DVS) instrument: TA Q5000 SA from TA of America; temperature: 25 ℃; nitrogen flow rate: 50 mL/min; change in mass per unit time: 0.002%/min; relative humidity range: 0% RH to 90% RH.
Bulk density test:
particle and powder characterization analyzer: model FT-2000A/B from Ningbor-Reviei instruments Inc.
Tabletting:
single-punch manual tablet press, type: enderpac, mold:
and (4) a circle.
In the present invention, the method for drying is a conventional drying method in the art unless otherwise specified, for example, drying in the examples of the present invention means drying in vacuum or drying under normal pressure in a conventional drying oven. Generally, the drying is carried out for 0.1 to 50 hours or 1 to 30 hours.
Pharmaceutical compositions and methods of administration
Since the crystalline form of the present invention or the lopertinib (amorphous) prepared from the crystalline form of the present invention has an excellent therapeutic effect on NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement, the crystalline form of the present invention or the lopertinib (amorphous) prepared from the crystalline form of the present invention and the pharmaceutical composition comprising the crystalline form of the present invention or the lopertinib (amorphous) prepared from the crystalline form of the present invention as a main active ingredient can be used for treating cancer patients or NSCLC patients carrying ALK, ROS1 or NTRK oncogene rearrangement. Accordingly, the crystalline forms of the invention or lopinib prepared from the crystalline forms of the invention (amorphous form can be used for the preparation of a medicament for treating a patient with cancer (e.g., a patient with NSCLC harboring an ALK, ROS1 or NTRK oncogene rearrangement) can be prepared by methods commonly used in the art.
The pharmaceutical composition of the present invention comprises the crystalline form of the present invention or lopertinib (amorphous form) prepared from the crystalline form of the present invention in a safe and effective amount range, and a pharmaceutically acceptable excipient or carrier.
Wherein "safe and effective amount" means: the amount of the compound (either crystalline or amorphous) is sufficient to significantly ameliorate the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 to 2000mg of the crystalline form/dosage of the present invention, more preferably, 10 to 200mg of the crystalline form/dosage of the present invention. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the polymorphic forms of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The crystalline form of the invention or the lopertinib (amorphous) prepared from the crystalline form of the invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the crystal form of the invention or the lopertinib (amorphous form) prepared from the crystal form of the invention is suitable for mammals (such as human beings) needing treatment, wherein the administration dosage is a pharmaceutically-considered effective administration dosage, and for a human body with the weight of 60kg, the daily administration dosage is usually 1-2000mg, preferably 20-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention are:
(1) the crystal form stability and the mechanical stability are good. The crystalline form CM-I is stable for at least 30 days when left open at 25 ℃/60% RH. The crystal form CM-II and the crystal form CM-III are placed in an open atmosphere at 25 ℃/60% RH and 40 ℃/75% RH, and can be stabilized for at least 30 days. The crystal forms of the crystal form CM-II and the crystal form CM-III are unchanged before and after grinding, which shows that the crystal forms have better mechanical stability and can reduce the crystal transformation risk caused by crushing the raw material medicines in the preparation processing process. The crystal form CM-I, the crystal form CM-II and the crystal form CM-III are mixed with auxiliary materials and then tabletted, and the crystal forms are unchanged before and after tabletting, which shows that the crystal form CM-I, the crystal form CM-II and the crystal form CM-III have better tabletting stability. The better crystal form stability can reduce the risk of the change of the dissolution rate and the bioavailability of the medicine caused by the change of the crystal form, is beneficial to the crystal form control in the crystallization and preparation processes, and is also beneficial to the production and the storage of products.
(2) And the hygroscopicity is low. The crystal form CM-II has low hygroscopicity, and the weight gain of 40 percent RH-80 percent RH is 0.12 percent. The low hygroscopicity shows that the crystal form has no strict requirements on packaging and storage conditions, and special drying conditions are not needed in the preparation process, so that the preparation and post-treatment processes of the medicament are simplified, the industrial production is facilitated, and the production, transportation and storage costs of the medicament are obviously reduced.
(3) Compared with the prior art, the preparation method of the crystal form provided by the invention is safer and more reliable. Meanwhile, the method is simple and easy to operate, low in cost and suitable for drug research and development and industrial production. The crystal form provided by the invention can be prepared by using low-toxicity or non-toxicity solvents, such as ethanol, acetic acid, water and the like. Meanwhile, the preparation method is a conventional crystallization method capable of realizing industrial production, and the granularity, crystal habit, crystal form and the like can be controlled by controlling process parameters, so that a stable and high-quality product is obtained.
(4) Compared with the prior art, the crystal form provided by the invention has good solubility, and better solubility is beneficial to improving the absorption of the medicine in a human body, improving the bioavailability and enabling the medicine to play a better treatment role. In addition, the better dissolving performance can ensure the curative effect of the medicine and reduce the dosage of the medicine, thereby reducing the side effect of the medicine and improving the safety of the medicine.
(5) Compared with the prior art, the crystal form provided by the invention has better fluidity and is not sticky and dashing during tabletting. Is beneficial to the transportation and the transfer of the medicine and the development of the preparation process.
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Comparative example 1: form 1 in patent WO2017007759
According to the method described in patent WO2017007759, said form 1 is prepared as follows: 5.55g of the compound of formula (I) are weighed out and dissolved in ethyl acetate: dichloromethane: methanol (200:150:40) and the solution was concentrated to a volume of about 70mL, a white solid precipitated which was form 1 of patent WO2017007759, filtered and the resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 25.
Example 1: preparation of crystalline form CM-I
500mg of the compound of the formula (I) are weighed out, dissolved in 27mL of ethanol at 50 ℃ and filtered. The filtrate was added dropwise to 200mL of water at 20 deg.C, stirred for 2h, and filtered. And drying the wet filter cake for 24 hours in vacuum at 25 ℃, wherein the obtained solid is the crystal form CM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 1, and the XRPD pattern of which is shown in fig. 1; TGA test is carried out on the obtained solid, the spectrogram is shown in figure 2, and the weight loss is about 10.5% at 25-100 ℃; DSC test is carried out on the obtained solid, 2 endothermic peaks exist at 60-92 ℃,1 exothermic peak exists at 170-185 ℃, and the spectrogram is shown in figure 3; the obtained solid was subjected to 1H NMR measurement, the spectrum of which is shown in fig. 4, and the nuclear magnetic data:1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.81(d,J=6.7Hz,1H),8.58(d,J=7.6Hz,1H),8.04(s,1H),7.13(dd,J=9.5,3.0Hz,1H),7.00(ddd,J=10.9,8.5,3.8Hz,2H),6.36(d,J=7.6Hz,1H),5.75–5.35(m,1H),4.49(t,J=9.0Hz,1H),3.91(ddd,J=12.1,8.1,3.7Hz,1H),3.14(dd,J=11.5,8.6Hz,1H),2.50(s,6H),1.45(t,J=6.8Hz,6H)。
TABLE 1
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
3.8
|
1.1
|
20.0
|
2.9
|
7.7
|
8.8
|
22.7
|
1.4
|
8.9
|
100.0
|
22.7
|
1.1
|
11.3
|
3.7
|
23.3
|
1.1
|
14.3
|
0.8
|
25.1
|
3.0
|
15.5
|
1.8
|
28.9
|
1.4
|
17.8
|
5.7
|
|
|
Example 2: preparation of crystalline form CM-I
9mg of the compound of formula (I) are weighed out and dissolved in 0.4mL formic acid/water (4:1, v/v) at room temperature and filtered. The filtrate was added dropwise to 4mL of water at 28 deg.C, stirred for 2h, and filtered. And (3) drying the solid at 25 ℃ in vacuum for 24h to obtain the solid which is the crystal form CM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 2.
TABLE 2
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
3.7
|
1.9
|
17.6
|
4.2
|
7.5
|
11.4
|
20.0
|
3.2
|
8.7
|
100.0
|
24.9
|
2.4
|
11.1
|
3.8
|
28.7
|
1.7 |
Example 3: preparation of crystalline form CM-I
10mg of the compound of the formula (I) are weighed out, dissolved in 0.5mL of tetrahydrofuran at room temperature and filtered. 1mL of water was slowly dropped into the filtrate, and the mixture was stirred for 2 hours and filtered. And (3) drying the solid at 25 ℃ in vacuum for 24h to obtain the solid which is the crystal form CM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 3.
TABLE 3
Example 4: preparation of crystalline form CM-I
10mg of the compound of the formula (I) are weighed out, dissolved in 0.5mL of acetone at room temperature and filtered. 1mL of water was slowly dropped into the filtrate, and the mixture was stirred for 2 hours and filtered. And (3) drying the solid at 25 ℃ in vacuum for 24h to obtain the solid which is the crystal form CM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 4.
TABLE 4
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
7.5
|
4.4
|
17.6
|
4.0
|
8.7
|
100.0
|
19.8
|
2.1
|
11.1
|
2.3
|
24.8
|
1.3
|
14.1
|
0.5
|
28.7
|
0.7 |
Example 5: preparation of crystalline form CM-I
5mg of the compound of formula (I) are weighed out and dissolved in 5mL of acetonitrile at room temperature and filtered. And (3) volatilizing the filtrate at 23 ℃ in an open way, volatilizing the solvent to obtain a solid which is the crystal form CM-I of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 5.
TABLE 5
2θ(°)
|
Relative Strength (%)
|
7.6
|
14.5
|
8.9
|
100.0
|
15.3
|
3.0 |
Example 6: preparation of crystalline form CM-I
The crystalline form CM-II obtained in example 9 was placed in water and stirred at 5 ℃ for 1 day to give a solid which was the crystalline form CM-I of the compound of formula (I). The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 6.
TABLE 6
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
7.5
|
2.1
|
17.6
|
4.0
|
8.7
|
100.0
|
19.8
|
1.9
|
11.1
|
2.1
|
28.7
|
1.0 |
Example 7: preparation of crystalline form CM-I
The crystalline form CM-IV obtained in example 11 was placed in water and stirred for 1 day at 5 ℃ to give a solid which was the compound of formula (I) in crystalline form CM-I. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 7.
TABLE 7
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
7.5
|
2.6
|
17.6
|
2.6
|
8.7
|
100.0
|
19.8
|
1.2
|
11.1
|
1.4
|
|
|
Example 8: preparation of crystalline form CM-I
The crystalline form obtained in example 10 was left in water and stirred at 5 ℃ for 1 day to obtain a solid as the compound of formula (I) in crystalline form CM-I. The resulting solid was subjected to XRPD testing and the X-ray powder diffraction data are shown in table 8.
TABLE 8
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
7.5
|
11.1
|
17.7
|
3.2
|
8.8
|
100.0
|
19.8
|
1.4
|
11.1
|
3.2
|
22.7
|
0.7
|
14.2
|
0.9
|
24.9
|
1.1
|
15.3
|
1.1
|
|
|
Example 9: preparation of crystalline form CM-II
Weighing 12mg of the crystal form CM-I obtained in the step 1, heating the crystal form CM-I to 200 ℃ under the normal pressure under the protection of nitrogen, and obtaining a solid which is the crystal form CM-II of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 9, and the XRPD pattern of which is shown in fig. 6; TGA test is carried out on the obtained solid, the spectrogram is shown in figure 7, and the weight loss is about 0.8% at 25-100 ℃; the obtained solid is subjected to DSC test, and the spectrum is shown in figure 8; subjecting the obtained solid to1H NMR measurement, spectrum as shown in fig. 9, nuclear magnetic data:1H NMR(400MHz,DMSO-d6)δ9.82(d,J=6.3Hz,1H),8.81(d,J=6.7Hz,1H),8.58(d,J=7.6Hz,1H),8.04(s,1H),7.13(dd,J=9.5,3.0Hz,1H),7.06–6.91(m,2H),6.36(d,J=7.6Hz,1H),5.60–5.48(m,1H),4.54–4.43(m,1H),3.91(ddd,J=12.3,8.1,3.8Hz,1H),3.14(dd,J=11.3,8.5Hz,1H),1.45(t,J=6.9Hz,6H)。
TABLE 9
Example 10: preparation of crystalline form CM-III
8mg of the compound of the formula (I) are weighed out, dissolved in 0.4mL of acetic acid at room temperature, filtered, the filtrate is added dropwise to 4mL of water at 28 ℃, stirred for 2h and filtered. The solid was dried under vacuum at 25 ℃ for 24h to give the compound of formula (I) as crystalline form CM-III. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 10, and the XRPD pattern of which is shown in fig. 13; TGA test is carried out on the obtained solid, the spectrogram is shown in figure 14, and the weight loss is about 8.6% at 25-100 ℃; DSC test is carried out on the obtained solid, 2 endothermic peaks exist at 60-92 ℃,1 exothermic peak exists at 170-185 ℃, and the spectrogram is shown in figure 15; the obtained solid was subjected to 1H NMR measurement, and the spectrum thereof is shown in fig. 16, and the nuclear magnetic data: 1H NMR (400MHz, DMSO-d)6)δ9.81(d,J=6.6Hz,1H),8.80(d,J=6.7Hz,1H),8.58(d,J=7.6Hz,1H),8.04(s,1H),7.13(dd,J=9.5,3.1Hz,1H),7.08–6.91(m,2H),6.36(d,J=7.6Hz,1H),5.61–5.45(m,1H),4.54–4.43(m,1H),3.90(ddd,J=12.3,8.4,4.0Hz,1H),3.14(dd,J=11.4,8.5Hz,1H),1.45(t,J=7.0Hz,6H)。
Watch 10
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
6.5
|
33.4
|
20.3
|
11.9
|
7.9
|
46.8
|
21.1
|
15.9
|
9.1
|
100.0
|
23.3
|
12.2
|
9.7
|
40.8
|
23.8
|
10.3
|
15.3
|
8.4
|
26.1
|
5.7
|
18.8
|
25.2
|
28.9
|
6.1
|
18.9
|
29.1
|
|
|
Example 11: preparation of crystalline form CM-IV
196mg of the compound of the formula (I) are weighed out and dissolved in 8mL of 95% ethanol at room temperature, the solution is filtered, and the filtrate is dropped into 80mL of water, and a solid precipitates. The obtained solid is a compound of formula (I) in a crystal form CM-IV. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in Table 11, and the XRPD pattern of which is shown in FIG. 18.
TABLE 11
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
6.0
|
0.5
|
21.5
|
14.4
|
7.1
|
100.0
|
22.9
|
0.6
|
7.8
|
0.6
|
23.9
|
0.3
|
9.7
|
0.8
|
24.5
|
0.2
|
12.6
|
0.4
|
25.6
|
0.2
|
18.6
|
0.9
|
28.9
|
5.5
|
19.6
|
1.5
|
30.0
|
0.4
|
21.0
|
0.5
|
31.5
|
0.4 |
Example 12: preparation of crystalline form CM-V
12mg of the compound of formula (I) are weighed out and dissolved in 1mL1, 4-dioxane/water (1:1, v/v) at room temperature, filtered, the filtrate is put into a 10mL glass vial, 3mL water is slowly added, the vial is capped and left to stand at 25 ℃ until a solid precipitates. The obtained solid is a compound of formula (I) in a crystal form CM-V. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 12, and the XRPD pattern is shown in fig. 19.
TABLE 12
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
6.9
|
100.0
|
23.6
|
1.7
|
7.6
|
1.1
|
25.6
|
0.5
|
9.4
|
1.7
|
28.1
|
2.9
|
19.3
|
0.9
|
28.8
|
1.8
|
21.0
|
8.1
|
30.8
|
0.7
|
21.5
|
3.2
|
|
|
22.2
|
0.5
|
|
|
23.2
|
1.5
|
|
|
Example 13: preparation of crystalline form CM-VI
20mg of the compound of formula (I) are dissolved in 1mL of formic acid at room temperature, filtered and the filtrate is placed in a 10mL glass vial. 4mL of water was slowly added along the wall of the flask, the flask was capped and allowed to stand at 25 ℃ until a solid precipitated out. The obtained solid is the crystal form CM-VI. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 13, and the XRPD pattern is shown in fig. 20.
Watch 13
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
6.6
|
0.2
|
16.1
|
0.1
|
7.4
|
100.0
|
18.2
|
0.9
|
9.0
|
7.6
|
22.5
|
3.5
|
9.6
|
0.2
|
22.8
|
0.4
|
13.6
|
0.1
|
30.4
|
0.1
|
14.9
|
1.7
|
30.7
|
0.8
|
15.1
|
5.1
|
32.4
|
0.1 |
Example 14: preparation of crystalline form CM-VII
36mg of the compound of the formula (I) are dissolved in 0.2mL of N, N-dimethylacetamide at room temperature, filtered and the filtrate is added dropwise to 2mL of butyl acetate at 28 ℃. Stirring was continued until a solid precipitated. The obtained solid is the crystal form CM-VII. The resulting solid was subjected to XRPD testing, the X-ray powder diffraction data of which are shown in table 14, and the XRPD pattern of which is shown in fig. 21; the solid obtained was subjected to TGA test, and its spectrum is shown in fig. 22.
TABLE 14
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
6.8
|
1.6
|
20.6
|
4.4
|
7.7
|
1.1
|
21.2
|
17.1
|
8.4
|
100.0
|
21.6
|
5.1
|
9.4
|
2.0
|
22.1
|
4.9
|
10.6
|
2.0
|
22.6
|
7.1
|
11.8
|
4.1
|
23.0
|
14.1
|
12.9
|
1.5
|
23.5
|
3.9
|
13.3
|
2.7
|
23.9
|
10.3
|
13.6
|
6.7
|
24.8
|
9.1
|
13.9
|
4.4
|
25.4
|
2.4
|
14.2
|
3.1
|
25.7
|
7.7
|
14.5
|
2.2
|
26.9
|
11.6
|
15.3
|
15.5
|
28.0
|
2.8
|
16.5
|
7.5
|
28.5
|
4.7
|
16.8
|
30.4
|
29.0
|
6.6
|
17.3
|
8.0
|
29.6
|
6.7
|
18.0
|
12.0
|
30.7
|
3.7
|
18.9
|
41.5
|
31.0
|
3.3
|
19.8
|
6.9
|
|
|
Example 15: preparation of amorphous form
Weighing 15mg of the crystalline form CM-I obtained in the step 1, heating to 100 ℃ under the protection of nitrogen, and obtaining amorphous solid of the compound shown in the formula (I). The resulting solid was subjected to XRPD testing, the XRPD pattern of which is shown in figure 23.
Example 16: preparation of crystalline form CM-VIII
Weighing 15mg of the amorphous form obtained by the implementation of 15, and placing the amorphous form in an open state at 25 ℃/92.5% RH for 2 weeks to obtain a solid, namely the crystal form CM-VIII. The resulting solid was subjected to XRPD testing, and the X-ray powder diffraction data is shown in table 15, and the XRPD pattern is shown in fig. 26.
Watch 15
2θ(°)
|
Relative Strength (%)
|
2θ(°)
|
Relative Strength (%)
|
7.4
|
9.9
|
16.3
|
3.7
|
8.2
|
100.0
|
18.3
|
3.3
|
8.9
|
27.3
|
25.2
|
3.6
|
10.4
|
6.6
|
|
|
Test example
Test example 1: stability of crystal form
Respectively placing the crystal form CM-I and the crystal form CM-II prepared by the invention under different conditions for 30 days in an open environment, carrying out XRPD detection on the crystal forms before and after placement, and comparing XRPD patterns of the crystal forms before and after placement. The results are shown in Table 16.
As can be seen by comparing XRPD patterns before and after the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the invention are placed in an open environment for 30 days under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, and the crystal forms do not change, which shows that the crystal forms of the invention have good stability under different temperatures/humidities.
TABLE 16
Test example 2: mechanical stability
Respectively weighing 50mg of the crystal form CM-II and the crystal form CM-III, grinding the crystal forms CM-II and the crystal form CM-III in a mortar for 10min, respectively carrying out XRPD test on the ground solid, respectively showing comparison graphs of the crystal forms XRPD before and after grinding in the figures 11 and 17, and showing the grinding results in the table 17.
As can be seen by comparing XRPD patterns before and after grinding in the figures, the crystal forms of the crystal form CM-II and the crystal form CM-III provided by the invention do not change before and after grinding, which shows that the crystal forms of the crystal form CM-II and the crystal form CM-III provided by the invention have good mechanical stability.
TABLE 17
Test example 3: moisture-wicking property
About 20mg of the crystalline form CM-II obtained in example 9 of the present invention was measured for hygroscopicity by a dynamic moisture adsorption apparatus (DVS), and the DVS pattern is shown in FIG. 12. Additionally, the XRPD pattern of the solid before and after DVS testing is shown in fig. 27. The overall test results are shown in Table 18.
According to the DVS test result, the crystal form CM-II provided by the invention has lower hygroscopicity; as can be seen from the XRPD results, the crystal form did not change before and after DVS testing. Therefore, the crystal form CM-II has the capability of resisting high-humidity environment.
Watch 18
Test example 4: solubility in water
5mg of the crystalline form CM-I prepared in example 1 of the present invention, the crystalline form CM-II prepared in example 9, the crystalline form CM-III prepared in example 10, and the crystalline form of comparative example 1 (form 1 prepared by the method described in WO 2017007759) were stirred in solvents of different pH values at 37 ℃ for 24 hours, the dissolution phenomenon was observed, and the corresponding solubility was calculated, and the specific data are shown in Table 19.
Therefore, the solubility of the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the invention is greater than that of the crystal form 1 in the patent WO2017007759, and the crystal form CM-I, the crystal form CM-II and the crystal form CM-III have better solubility.
Watch 19
Test example 5: bulk density
Bulk densities of form 1 in form CM-I, form CM-III and WO2017007759 were tested and the specific data are shown in table 20. Therefore, the crystal form CM-I and the crystal form CM-III provided by the invention have better flowability than the form 1 in WO 2017007759.
Watch 20
Crystal form
|
Bulk density (g/mL)
|
Tap density (g/mL)
|
Hao-Si-Nabi
|
Form |
1
|
0.22
|
0.35
|
1.59
|
Crystal form CM-I
|
0.28
|
0.33
|
1.18
|
Crystal form CM-III
|
0.27
|
0.33
|
1.22 |
Test example 6: stability of tablets containing excipients
The tablet stability of the form 1 containing auxiliary materials in the crystal form CM-I, the crystal form CM-II, the crystal form CM-III and the WO2017007759 is tested, the pressure is 10kN, and the preparation formula is shown in Table 21. The crystal form change before and after tabletting is shown in Table 22. According to tabletting data, the crystal form CM-I, the crystal form CM-II and the crystal form CM-III provided by the invention have excellent tabletting stability when containing auxiliary materials. And no sticking phenomenon is caused during tabletting.
TABLE 21
Categories
|
mg/tablet
|
%(w/w)
|
The crystal form provided by the invention
|
30.0
|
30.0
|
Microcrystalline cellulose
|
50.0
|
50.0
|
Hydroxypropyl methylcellulose
|
9.0
|
9.0
|
Pregelatinized starch
|
9.0
|
9.0
|
Cross-linked polyvidone
|
1.0
|
1.0
|
Magnesium stearate
|
1.0
|
1.0 |
TABLE 22
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.