CN118146216A

CN118146216A - Polymorphs of Ceralasertib salts and methods of making the same

Info

Publication number: CN118146216A
Application number: CN202211549815.6A
Authority: CN
Inventors: 张凤杰; 杨建章; 徐忠民
Original assignee: Pharmaresources Shanghai Co ltd
Current assignee: Pharmaresources Shanghai Co ltd
Priority date: 2022-12-05
Filing date: 2022-12-05
Publication date: 2024-06-07

Abstract

The present invention provides polymorphs of the salt of Ceralasertib and methods for their preparation. Specifically, the present invention provides polymorphs of 4- {4- [ (3R) -3-methylmorpholin-4-yl ] -6- [1- ((R) -S-methylsulfonylamino) cyclopropyl ] pyrimidin-2-yl } -1H-pyrrolo [2,3-b ] pyridine, pharmaceutically acceptable salts thereof, and methods for the preparation thereof. More particularly, the invention provides a crystal form PR-1 of Ceralasertib salt formed by maleic acid and a preparation method thereof. The crystal form provided by the invention has high stability, large solubility, better compressibility and simple preparation method, and is suitable for subsequent preparation research and development and industrial production.

Description

Polymorphs of Ceralasertib salts and methods of making the same

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a polymorph of a pharmaceutically acceptable salt of 4- {4- [ (3R) -3-methylmorpholine-4-yl ] -6- [1- ((R) -S-methylsulfonamidyl) cyclopropyl ] pyrimidine-2-yl } -1H-pyrrolo [2,3-b ] pyridine and a preparation method thereof.

Background

ATR is a member of the phosphatidylinositol 3-kinase related kinase (PIKK) family of serine/threonine protein kinases. The N-terminus of ATR contains the binding site for ATR interacting protein (ATRIP), regulating the localization of ATR at sites of replication stress and DNA damage. ATR is activated by a single stranded DNA structure, which, once activated, acts through its downstream targets to promote DNA repair, stabilization, restarting of the arrested replication fork, and transient cell cycle arrest. Most kinase inhibitors can bind to the activation site of the enzyme, exhibit ATP competitiveness, and ATR inhibitors have been developed based on this. At present, ATR targets have no marketed medicines, and most of the ATR targets are in clinical or preclinical stages. Ceralasertib (code AZD 6738) is an oral ATR kinase inhibitor, which can inhibit ataxia telangiectasia and Rad3 related proteins, and is the main regulator of DNA Damage Response (DDR). Ceralasertib preclinical studies showed that ATR was inhibited in vitro at a half inhibition rate (IC 50) of 0.001 μm/L and that half inhibition rates were as high as 0.3-1.0 μm/L after phosphorylation of ATR substrate CHK1Ser 345.

Clinical outcome of single drug treatment at CeralasertibI: 46 patients were enrolled and received at least 1 dose Ceralasertib,24 patients completed ≡1 cycle (28 days) during the up-dosing phase and 20 patients started treatment during the expansion phase. The duration of Stable Disease (SD) in subjects with 5/24 dose escalation (21%) and 5/20 dose escalation (25%) was ≡4 cycles (16 weeks). 17/26 (65%) patients had ≡3 treatment-related adverse events (TRAEs) at both the dose escalation and 7/20 (35%) at the dose expansion. The best overall response was 3 (7%) subjects confirmed Partial Responses (PR), 1 (2%) unconfirmed Partial Responses (PR).

Phase Ceralasertib I clinical trial was performed to explore the safety, tolerability and clinical efficacy of Ceralasertib in combination with the drug resistance You Shan (durvalumab) in previously treated patients with Advanced Gastric Cancer (AGC). Clinical trials were enrolled in 31 patients showing median Progression Free Survival (PFS) and total survival (OS) of 3.0 months and 6.7 months, respectively. A subset of patients with Ataxia Telangiectasia Mutated (ATM) expression deficiency and/or a high mutation profile due to homologous repair deficiency (sig. Hrd) exhibited significantly longer progression free survival (5.60 vs1.65 months) compared to patients with a low proportion of intact Ataxia Telangiectasia Mutated (ATM) and homologous repair deficiency (sig. Hrd), and it was seen that Ceralasertib and Durvalumab combined exhibited good anti-tumor activity with a persistent response in refractory advanced gastric cancer patients.

Ceralasertib under the chemical name 4- {4- [ (3R) -3-methylmorpholin-4-yl ] -6- [1- ((R) -S-methylsulfonamidyl) cyclopropyl ] pyrimidin-2-yl } -1H-pyrrolo [2,3-b ] pyridine, the molecular structural formula of which is shown below:

Patent document WO2011154737A1 reports that the crude product gives by crystallization a preparation of the compound of formula I as a white solid, but does not disclose a preparation of a pharmaceutically acceptable salt of the compound of formula I. The crystalline forms FormA and FormB of the free base of the compound of formula I are disclosed in patent document WO2022200251A1, but no study of any relevant crystalline forms with respect to stability, solubility, powder properties etc. of some physicochemical properties that are of importance for product development is disclosed.

Drug salification is one of the usual and effective means for improving bioavailability for drug development, and research into polymorphs of salts of compounds is also critical in the progress of drug development. The different crystal forms can cause the difference of solubility, stability, fluidity and the like of the medicine, thereby influencing the safety and effectiveness of the medicine and further causing the difference of clinical effects.

Therefore, there is a need in the art to develop a study on polymorphs of pharmaceutically acceptable salts of the compounds of formula I to find dominant crystalline forms of salts that are highly stable, have greater solubility, and meet the needs of drug development, formulation preparation, and industrial production.

Disclosure of Invention

The invention aims to provide a polymorph of a pharmaceutically acceptable salt of a compound of the formula I, which has good stability under different conditions of temperature, humidity and mechanical force, low production cost and simple preparation method, and a preparation method thereof.

In order to achieve one of the above objects, the present invention provides a polymorph of Ceralasertib salt, which adopts the following technical scheme:

A polymorph of a salt of Ceralasertib, ceralasertib being a compound of formula I,

The salt of Ceralasertib refers to a pharmaceutically acceptable salt of the compound shown in formula I.

Preferably, wherein said pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, sulfate, phosphate, acetate, L-lactate, maleate, fumarate, succinate, malate, adipate, tartrate, hippurate, citrate, glycolate, D-glucuronate, benzoate, gentisate, mesylate, besylate, 2-hydroxyethanesulfonate and hydrobromide, or a combination of each of the materials within the group.

Preferably, the polymorph of a pharmaceutically acceptable salt of Ceralasertib is crystalline form PR-1 of the salt of a compound of formula I with maleic acid, the X-ray powder diffraction pattern of which comprises 3 or more 2 theta values selected from the group consisting of: 9.2 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.1 ° ± 0.2 °, 20.2 ° ± 0.2 °, 23.9 ° ± 0.2 °.

Preferably, the polymorph of Ceralasertib pharmaceutically acceptable salt is PR-1 which is a salt of a compound of formula I with maleic acid, and has an X-ray powder diffraction pattern comprising 6 or more 2 theta values selected from the group consisting of ：5.7°±0.2°、7.8°±0.2°、8.3°±0.2°、8.8°±0.2°、9.2°±0.2°、11.4°±0.2°、12.4°±0.2°、13.1°±0.2°、14.3°±0.2°、14.7°±0.2°、15.6°±0.2°、16.1°±0.2°、17.1°±0.2°、17.5°±0.2°、18.1°±0.2°、18.6°±0.2°、18.8°±0.2°、20.2°±0.2°、20.7°±0.2°、21.2°±0.2°、22.2°±0.2°、22.8°±0.2°、23.2°±0.2°、23.9°±0.2°、24.9°±0.2°、25.1°±0.2°、25.7°±0.2°、26.1°±0.2°、26.3°±0.2°、27.0°±0.2°、27.8°±0.2°、28.4°±0.2°、28.6°±0.2°、29.7°±0.2°、30.5°±0.2°、31.1°±0.2°、32.5°±0.2°、33.4°±0.2°、33.9°±0.2°、34.1°±0.2°、34.7°±0.2°、35.9°±0.2°、37.4°±0.2°、38.6°±0.2°、39.6°±0.2°、41.1°±0.2°.

It is a second object of the present invention to provide a process for the preparation of polymorphs of the salt of Ceralasertib comprising the following steps:

a. providing a solution or slurry of a compound of formula I in a first solvent or in a mixture of first and second solvents, and filtering;

b. Adding maleic acid into the solution of the first solvent or the first and second mixed solvents which are the same as those in the step a, and mixing the solution with the filtrate obtained in the step a;

c. and (3) stirring the solution obtained by mixing the step a and the step b at the temperature of 10-40 ℃ to obtain the polymorphic substance of the pharmaceutically acceptable salt of the compound shown in the formula I.

Preferably, the first solvent and the second solvent are each independently selected from the group consisting of: alcohol solvents, ester solvents, hydrocarbon solvents, ether solvents, water, or combinations of various solvents within a group.

Preferably, the alcoholic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination of the materials in the group.

Preferably, the ester solvent is selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, or a combination of the materials in the group.

Preferably, the hydrocarbon solvent is selected from the group consisting of: dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, n-hexane, or a combination of the materials within the group.

Preferably, the ether solvent is selected from the group consisting of: diethyl ether, anisole, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, cyclopentyl methyl ether, 1, 4-dioxane, 1, 3-dioxolane, or combinations of the individual materials within the group.

Preferably, in step c, the solution obtained by mixing the step a and the step b is stirred for 12-72 hours at 15-30 ℃.

It is a further object of the present invention to provide a pharmaceutical composition comprising: 1) Polymorphs of the above salts; and 2) a pharmaceutically acceptable carrier.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

The beneficial effects are that:

(1) The invention has good crystal form stability, and the crystal form PR-1 of the salt formed by the compound formula I and the maleic acid can be at least stable for 10 days when being placed at an opening of 25 ℃/92.5% RH and 40 ℃/75% RH. The crystal form PR-1 has no change before and after grinding and tabletting, which indicates that the crystal form PR-1 has better mechanical stability and tabletting stability, and can reduce the crystal transformation risk brought by crushing the bulk drug in the preparation processing process.

(2) Compared with the prior art, the compound shown in the formula I and the salt formed by maleic acid have better solubility in crystal form PR-1, so that the bioavailability is improved, and the clinical treatment effect is improved.

(3) The solvents used in the preparation process of the crystal form PR-1 of the salt formed by the compound formula I and the maleic acid are low-toxicity or nontoxic solvents, the cost is low, the preparation method is a conventional crystallization method capable of realizing industrial production, and the stable and high-quality product is obtained by controlling the process parameters, further controlling the granularity, the crystal habit, the crystal form and the like.

Drawings

The invention will be further described with reference to the drawings and examples.

FIG. 1 is an XRPD pattern for crystalline form PR-1 of the salt of a compound of formula I according to the invention with maleic acid.

FIG. 2 is a DSC of crystalline form PR-1 of the salt of a compound of formula I according to the present invention with maleic acid.

FIG. 3 is a TGA spectrum of crystalline form PR-1 of the salt of the compound of formula I according to the invention with maleic acid.

FIG. 4 is a 1HNMR spectrum of crystalline form PR-1 of the salt of the compound of formula I with maleic acid according to the present invention.

Fig. 5 is a graph showing XRPD contrast patterns of crystalline form PR-1 of the salt of the compound of formula I according to the invention with maleic acid, before and after 10 days of standing at 25 ℃/92.5% rh and 40 ℃/75% rh, respectively, from bottom to top.

FIG. 6 is a chart showing the XRPD patterns of crystalline form PR-1 of the compound of formula I of the present invention with maleic acid before and after milling, with the lower side being the XRPD pattern before milling and the upper side being the XRPD pattern after milling.

Fig. 7 is an XRPD pattern of crystalline form PR-1 of the salt of the compound of formula I of the invention with maleic acid before and after tabletting, with the lower side being the XRPD pattern before tabletting and the upper side being the XRPD pattern after tabletting.

Fig. 8 is an XRPD pattern of polymorph FormA reported in WO2022200251 A1.

Detailed Description

The present invention is explained in further detail below with reference to the drawings and the description of specific embodiments, but the following description of the embodiments is included only to enable one of ordinary skill in the art to which the present invention pertains to more clearly understand the principle and spirit of the present invention, and is not meant to limit the present invention in any way.

In this document, each abbreviation is in a conventional sense as understood by those skilled in the art unless otherwise indicated.

Terminology

As used herein, unless otherwise indicated, the term "compound of formula I" refers to the amorphous form and/or forms of the compound of formula I, including the various forms and amorphous forms mentioned herein, and the crystalline forms or amorphous forms mentioned in various documents or patents, whether disclosed or not.

As used herein, unless otherwise indicated, the solvent or solution is added by direct pouring, constant velocity addition, or slow dropping, etc.

Compounds of formula I

In the present invention, "compound of formula I" or "compound of formula I" may be used interchangeably and, unless otherwise indicated, generally refers to the free base form, not the salt-forming form, including the crystalline forms or amorphous forms mentioned in the various documents or patents, whether disclosed or not.

In the present invention, the compound of formula I is Ceralasertib, chemical name 4- {4- [ (3R) -3-methylmorpholin-4-yl ] -6- [1- ((R) -S-methylsulfonylamino) cyclopropyl ] pyrimidin-2-yl } -1H-pyrrolo [2,3-b ] pyridine.

Pharmaceutically acceptable salts of compounds of formula I

Selected from the group consisting of: hydrochloride, sulfate, phosphate, acetate, L-lactate, maleate, fumarate, succinate, malate, adipate, tartrate, hippurate, citrate, glycolate, D-glucuronate, benzoate, gentisate, mesylate, besylate, 2-hydroxyethanesulfonate and hydrobromide, or a combination of each of the materials within the group.

Polymorphs

The solid is present either in amorphous form or in crystalline form. In the case of the crystalline form, the molecules are positioned within the three-dimensional lattice sites. When a compound crystallizes out of solution or slurry, it can crystallize in a different spatial lattice arrangement (this property is known as "polymorphism") to form crystals having different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, stacking means, flowability and/or solid state stability.

According to a preferred embodiment of the present invention, a polymorph of a salt of Ceralasertib, ceralasertib is a compound of formula I, ceralasertib having the chemical name 4- {4- [ (3R) -3-methylmorpholin-4-yl ] -6- [1- ((R) -S-methylsulfonylamino) cyclopropyl ] pyrimidin-2-yl } -1H-pyrrolo [2,3-b ] pyridine;

The salt of the compound shown in the formula I is pharmaceutically acceptable salt of the compound shown in the formula I.

Crystallization

In the preparation method of the invention, the crystallization process is involved, and the solution can be operated so that the solubility limit of the required compound is exceeded, thereby completing the crystallization on a production scale. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature, and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method. The solubility of the desired compound may be reduced by adding an anti-solvent or mixture of solvents in which the compound has low solubility. An alternative is to adjust the pH to reduce the solubility. For a detailed description of crystallization see Crystallization, third edition, JWMullens, butterworth-HeinemanLtd.,1993,ISBN0750611294.

If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble in the reaction medium than the starting material, the addition of an appropriate acid or base can result in direct crystallization of the desired salt. Also, completion of the synthesis reaction may allow direct crystallization of the final product in a medium where the final desired form is less soluble than the reactants.

Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the desired compound in a solvent at an elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner to bring the system well below saturation level. At this point, the desired form of seed crystals (and maintaining the integrity of the seed crystals) may be added and the system cooled to complete crystallization.

Polymorphs of the present invention

As used herein, polymorphs of a pharmaceutically acceptable salt include polymorphs of a salt of a compound of formula I with a pharmaceutically acceptable acid.

As used herein, polymorphs of a salt refer to crystals after crystallization of a salt of a compound of formula I with an acid. Through extensive and intensive studies, the present inventors have surprisingly developed crystalline form PR-1 of the salt of the compound of formula I with maleic acid, by extensive screening.

Identification and Properties of polymorphs

The present invention, after preparing polymorphs of a pharmaceutically acceptable salt of a compound of formula I, has been studied for its properties by a number of means and instruments:

x-ray powder diffraction methods for determining the X-ray powder diffraction of crystalline forms are known in the art. For example, using an X-ray powder diffractometer model RigakuD/max2550VB/PC, a profile is obtained with a copper radiation target at a scan rate of 2 DEG per minute.

Polymorphs of pharmaceutically acceptable salts of the compounds of formula I of the present invention have specific crystalline forms with specific characteristic peaks in the X-ray powder diffraction (XRPD) pattern.

Differential scanning calorimeter analysis

Also known as "differential thermal scanning analysis" (DSC), is a technique that measures the relationship between the energy difference between a substance being measured and a reference substance and temperature during heating. The position, shape and number of peaks on a DSC profile are related to the nature of the substance and can therefore be used qualitatively to identify the substance. The method is commonly used in the art to detect various parameters such as the phase transition temperature, the glass transition temperature, the reaction heat and the like of a substance.

DSC measurement methods are known in the art. For example, a DSC scan pattern of the crystalline form can be obtained by heating from 25℃to 350℃at a heating rate of 10℃per minute using a DSC3+ type differential scanning calorimeter of METTLERTOLEDO.

Polymorphs of pharmaceutically acceptable salts of the compounds of formula I of the present invention have specific characteristic peaks in the differential thermal scanning analysis (DSC) pattern.

Pharmaceutical compositions and methods of administration

The pharmaceutical compositions of the present invention comprise Ceralasertib of or made from the crystalline forms of the present invention, and a pharmaceutically acceptable excipient or carrier, within a safe and effective amount.

Wherein, "safe and effective amount" means: the amount of the compound (either crystalline or amorphous) is sufficient to significantly improve the condition without serious side effects. Typically, the pharmaceutical composition contains 1 to 2000mg of the crystalline form/agent of the invention, more preferably 2.5 to 200mg of the crystalline form/agent of the invention. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. 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 sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiersWetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the polymorphs or pharmaceutical compositions 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.

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 used 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, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.

In addition to these inert diluents, the pharmaceutical compositions of the present invention can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredient, 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 substances, 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 excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of polymorphs of the present 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.

When the pharmaceutical composition is used, the safe and effective amount of the crystal form or Ceralasertib prepared from the crystal form is applied to the preparation of the medicine for treating non-small cell lung cancer and solid tumor. For the preparation of the resulting medicament for the treatment of non-small cell lung cancer and solid tumors, it is suitable for use in mammals (e.g. humans) in need of treatment, wherein the dosage at administration is a pharmaceutically effective dosage, typically 1 to 2000mg, preferably 2.5 to 500mg, per day for a human of 60kg body weight. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.

General method

The following experimental methods, which do not specify specific conditions in the following examples, were conducted based on the above embodiments, generally according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

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 methods and materials described herein are presented for illustrative purposes only.

The solvents used in the present invention were all analytically pure with a water content of about 0.1%. The compounds of the formula I used as starting materials in the examples were all obtained by purchase. All the test methods of the invention are universal methods, and the test parameters are as follows:

XRPD assay

X-ray powder diffractometer: brukerD2 PhaserX-ray powder diffractometer; radiation source CuGenerator (Generator) k4:30k4; generator (Generator) mA:10mA; starting 2θ:4.000 °, scan range: 4.0000-45.000 DEG, scanning step length 0.02 DEG, and scanning speed 0.1s/step.

TGA assay

Thermogravimetric analysis (TGA) instrument: TGA type 55 of TA company in the united states; heating rate: 10 ℃/min; nitrogen flow rate: 40mL/min.

DSC measurement method

Differential Scanning Calorimetry (DSC) instrument: DSC3+ form of METTLERTOLEDO, switzerland; heating rate: 10 ℃/min, nitrogen flow rate: 50mL/min.

Nuclear magnetic resonance hydrogen spectrum data (¹ HNMR) were obtained from a BrukerA4anceIIDMX400MHZ nuclear magnetic resonance spectrometer. 2.0mg of the sample was weighed, dissolved in 0.6mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a nuclear magnetic resonance tube for testing.

Single-punch manual tablet press, model: RETSCHPP and RETSCHPP.

In the present invention, unless otherwise specified, the method used for drying is a conventional drying method in the art, for example, drying in the examples of the present invention means vacuum drying or normal pressure drying in a conventional drying oven. Typically, the drying is carried out for 0.1 to 50 hours or 1 to 30 hours.

Example 1: preparation of crystalline PR-1

210Mg of the compound of formula I are weighed and dissolved in 6mL of tetrahydrofuran/isopropyl ether (1:1, v/v); separately, 65.7mg of maleic acid was weighed and dissolved in 6mL of tetrahydrofuran/isopropyl ether (1:1, v/v) at 40 ℃, the latter solution was added dropwise to the former solution and mixed well, and the precipitated solid was subjected to XRPD test with stirring at 25℃for 72 hours, and characterization data indicated that the obtained solid was crystalline PR-1 as a salt of the compound of formula I with maleic acid.

The X-ray powder diffraction data are shown in table 1 and the XRPD pattern is shown in figure 1;

DSC test is carried out on the obtained solid, and the result spectrum is shown in figure 2;

The obtained solid is subjected to TGA test, and the result spectrum is shown in figure 3;

The obtained solid was subjected to ¹ HNMR test, the result spectrum of which is shown in FIG. 4, and nuclear magnetic data ：¹HNMR(400MHz,DMSO-d6)δ11.80(s,1H),8.34(d,J＝5.0Hz,1H),7.95(d,J＝5.0Hz,1H),7.63–7.56(m,1H),7.22(dd,J＝3.2,1.9Hz,1H),7.00(s,1H),6.23(s,2H),4.58(s,1H),4.19(d,J＝13.4Hz,1H),3.99(d,J＝3.2Hz,1H),3.79(s,2H),3.65(d,J＝2.9Hz,1H),3.51–3.47(m,1H),3.31–3.27(m,1H),3.20(s,3H),1.76(dd,J＝12.6,8.3Hz,1H),1.61–1.48(m,3H),1.28(d,J＝6.7Hz,3H).

TABLE 1

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Example 2: preparation of crystalline PR-1

21Mg of the compound of formula I are weighed and dissolved in 0.6mL of ethyl acetate/toluene (1:1, v/v); 6.9mg of maleic acid was additionally weighed and dissolved in 0.6mL of ethyl acetate/toluene (1:1, v/v) at 25℃and the latter solution was added dropwise to the former solution and mixed well, and the precipitated solid was subjected to XRPD testing at 25℃with stirring for 48h, the X-ray diffraction data indicating that the solid obtained was crystalline PR-1 as a salt of the compound of formula I with maleic acid.

The X-ray powder diffraction data are shown in Table 2.

TABLE 2

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Example 3: preparation of crystalline PR-1

21Mg of the compound of formula I are weighed and dissolved in 0.3mL of ethanol/water (4:1, v/v); 6.7mg of maleic acid was additionally weighed and dissolved in 0.3mL of ethanol/water (4:1, v/v) at 25℃and the latter solution was added dropwise to the former solution and mixed well, and the precipitated solid was subjected to XRPD testing at 23℃with stirring for 72h, the X-ray diffraction data indicating that the solid obtained was crystalline PR-1 as a salt of the compound of formula I with maleic acid.

The X-ray powder diffraction data are shown in Table 3.

TABLE 3 Table 3

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Test example 1: stability of crystal form

The crystal forms PR-1 of the salt formed by the compound of the formula I and the maleic acid prepared by the method are respectively placed for 10 days under different conditions in an open mode, XRPD detection is carried out on the crystal forms before and after the placement, and XRPD patterns of the crystal forms before and after the placement are compared. The specific results are shown in Table 4.

As can be seen by comparing XRPD patterns before and after placement in each pattern (corresponding to the pattern 5, which is a pattern before placement, 25 ℃/92.5% RH and 40 ℃/75% RH from bottom to top respectively after placement for 10 days), the crystal form PR-1 of the salt formed by the compound of the formula I and the maleic acid provided by the invention is free from change after being placed in an open state under the conditions of 25 ℃/92.5% RH and 40 ℃/75% RH, and the crystal form of the salt is shown to have better stability under different temperatures and humidity.

TABLE 4 Table 4

Test example 2: mechanical stability

About 50mg of crystalline form PR-1 of the salt of the compound of formula I prepared according to the present invention with maleic acid was weighed, milled in an agate mortar for 5min, and the XRPD of the samples before and after milling was tested, with the results shown in Table 5. As can be seen by comparing the XRPD patterns before and after grinding (corresponding to FIG. 6, the lower side is the XRPD pattern before grinding, and the upper side is the XRPD pattern after grinding), the crystal form PR-1 of the salt formed by the compound of formula I and maleic acid provided by the invention has better mechanical stability.

Test example 3: solubility of

Taking a certain amount of the crystal form PR-1 prepared by the invention and the polymorph FormA reported in patent WO2022200251A1 respectively, putting the crystal form PR-1 and the polymorph FormA into a buffer solution with the pH value of 1.2 and a pure water solution with the pH value of 7.0, stirring the mixture at 37 ℃ for 24 hours, standing the mixture for 1 hour, observing the solid dissolution phenomenon, and calculating the corresponding solubility, wherein specific data are shown in Table 6.

TABLE 6

It can be seen from the combination of Table 6 that the solubility of the maleate salt form PR-1 of the present invention is greater than that of the polymorph FormA reported in WO2022200251A1, which significantly improves the water solubility.

Test example 4: tablet stability

About 100mg of crystalline form PR-1 of the salt of the compound of formula I with maleic acid was weighed and compressed into round flat-punch tablets using a pressure of 10kN, the XRPD of the samples were tested before and after compression and the results after compression are shown in Table 7.

TABLE 7

As can be seen from the comparison of the XRPD patterns before and after tabletting in the graph (corresponding to FIG. 7, the lower graph is the XRPD pattern before tabletting, and the upper graph is the XRPD pattern after tabletting), the crystal form PR-1 of the salt formed by the compound of the formula I and the maleic acid is unchanged before and after tabletting, which shows that the crystal form PR-1 of the salt formed by the compound of the formula I and the maleic acid provided by the invention has better tabletting stability.

The above-described preferred embodiments according to the present invention are intended to suggest that, in view of the above description, various changes and modifications may be made by the worker in question without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the description, but must be determined according to the scope of claims.

Claims

1. A polymorph of a salt of Ceralasertib, characterised in that Ceralasertib is a compound of formula I,

2. The polymorph of a salt of Ceralasertib of claim 1, wherein the salt of Ceralasertib is a pharmaceutically acceptable salt of a compound of formula I; wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, sulfate, phosphate, acetate, L-lactate, maleate, fumarate, succinate, malate, adipate, tartrate, hippurate, citrate, glycolate, D-glucuronate, benzoate, gentisate, mesylate, besylate, 2-hydroxyethanesulfonate and hydrobromide, or a combination of each of the materials within the group.

3. The polymorph of a salt of Ceralasertib as claimed in claim 1, wherein the polymorph of a pharmaceutically acceptable salt of a compound of formula I is form PR-1 of the salt of the compound of formula I with maleic acid, and the X-ray powder diffraction pattern comprises 3 or more 2-theta values selected from the group consisting of: 9.2 ° ± 0.2 °, 15.6 ° ± 0.2 °, 17.1 ° ± 0.2 °, 20.2 ° ± 0.2 °, 23.9 ° ± 0.2 °.

4. The polymorph of a salt of Ceralasertib as claimed in claim 1, wherein the polymorph of a pharmaceutically acceptable salt of a compound of formula I is form PR-1 of the salt of a compound of formula I with maleic acid, the X-ray powder diffraction pattern of which comprises 6 or more 2-theta values selected from the group consisting of ：5.7°±0.2°、7.8°±0.2°、8.3°±0.2°、8.8°±0.2°、9.2°±0.2°、11.4°±0.2°、12.4°±0.2°、13.1°±0.2°、14.3°±0.2°、14.7°±0.2°、15.6°±0.2°、16.1°±0.2°、17.1°±0.2°、17.5°±0.2°、18.1°±0.2°、18.6°±0.2°、18.8°±0.2°、20.2°±0.2°、20.7°±0.2°、21.2°±0.2°、22.2°±0.2°、22.8°±0.2°、23.2°±0.2°、23.9°±0.2°、24.9°±0.2°、25.1°±0.2°、25.7°±0.2°、26.1°±0.2°、26.3°±0.2°、27.0°±0.2°、27.8°±0.2°、28.4°±0.2°、28.6°±0.2°、29.7°±0.2°、30.5°±0.2°、31.1°±0.2°、32.5°±0.2°、33.4°±0.2°、33.9°±0.2°、34.1°±0.2°、34.7°±0.2°、35.9°±0.2°、37.4°±0.2°、38.6°±0.2°、39.6°±0.2°、41.1°±0.2°.

5. A process for the preparation of the polymorph of the salt of Ceralasertib according to claims 1-4, comprising the steps of:

6. The method according to claim 5, wherein,

The first solvent and the second solvent are each independently selected from the group consisting of: alcohol solvents, ester solvents, hydrocarbon solvents, ether solvents, water, or combinations of various solvents within a group.

7. The method according to claim 6, wherein,

The alcohol solvent is selected from the group consisting of: methanol, ethanol, isopropanol, or a combination of materials within a group;

The ester solvent is selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, or a combination of each of the materials in the group;

The hydrocarbon solvent is selected from the group consisting of: dichloromethane, nitromethane, n-heptane, cyclohexane, toluene, n-hexane, or a combination of the materials within the group;

The ether solvent is selected from the group consisting of: diethyl ether, anisole, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, cyclopentyl methyl ether, 1, 4-dioxane, 1, 3-dioxolane, or combinations of the individual materials within the group.

8. The method according to claim 5, wherein,

In the step c, the solution obtained by mixing the step a and the step b is stirred for 12-72 hours at 15-30 ℃ to obtain the polymorphic substance of the pharmaceutically acceptable salt of the compound shown in the formula I.

9. A pharmaceutical composition, the pharmaceutical composition comprising:

1) A polymorph of a salt according to any one of claims 1 to 4; and 2) a pharmaceutically acceptable carrier.