CN114195693A

CN114195693A - Crystal form of amide compound and preparation method thereof

Info

Publication number: CN114195693A
Application number: CN202111071989.1A
Authority: CN
Inventors: 张鹏伟; 叶辉青; 张�杰; 徐巾超; 陈勇; 罗忠华; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-09-17
Filing date: 2021-09-14
Publication date: 2022-03-18

Abstract

The invention mainly provides a crystal form of an amide compound and a preparation method thereof, belonging to the technical field of medicines. The crystal form provided by the invention has better stability, is easy to obtain, and can be applied to pharmaceutical preparations.

Description

Crystal form of amide compound and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a crystal form of an amide compound and a preparation method thereof.

Background

Aticaprant (CAS number: 1174130-61-0) is a central-permeable kappa opioid (k opioid) receptor antagonist currently in clinical trials for the treatment of major depressive disorder.

The Aticaprant structure is shown as follows:

because the crystal form of the drug has important influence on the preparation of the drug, the preparation of the drug preparation, the reservoir, the application, the dissolution, the bioavailability and the like, different crystal forms may have differences in various aspects, which may cause the problems of obvious difference in the drug effect, the safety and the application of the drug preparation or the possibility of not meeting the quality requirements, the crystal form of the drug needs to be researched. The inventor carries out related research on the crystal form of the Aticaprant and discovers a novel crystal form which can be applied.

Disclosure of Invention

Summary of The Invention

The present invention relates generally to novel crystalline forms of the compound atiaprant. The novel crystal form provided by the invention has the characteristics of stability and convenience for implementation and application.

On the other hand, the invention also provides a preparation method, a composition and the like of the novel crystal form.

Definition of terms

The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

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 to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form, when the intensity of the first strong peak is defined as 100%.

In the context of the present invention, the 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).

The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.

The crystal has an X-ray powder diffraction peak whose measure of the 2theta or diffraction peak of the X-ray powder diffraction pattern has experimental error which may differ slightly between one machine and another and between one sample and another, the value of the experimental error or difference may be +/-0.2 units or +/-0.1 units or +/-0.05 units, and thus the value of the 2theta or diffraction peak cannot be considered absolute.

The Differential Scanning Calorimetry (DSC) curve of the crystal has experimental errors, the position and peak value of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so that the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, the endothermic curve or the weight loss rate may slightly differ between one machine and another and between one sample and another, the numerical value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, and thus the thermogravimetric analysis curve or the weight loss rate thereof cannot be regarded as absolute.

In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "approximately" is used, and there may be +/-1%, +/-2%, or +/-5% differences in each number based on the original number. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.

By "room temperature" is meant a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.

The term "good solvent" may be a single solvent or a mixture of solvents, meaning that the solubility of the sample in the single solvent or mixture of solvents is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100 g/L. In some embodiments, the sample has greater solubility in the good solvent than the anti-solvent; in some embodiments, the difference in solubility of the good solvent and the anti-solvent for the sample is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, the good solvent is more soluble in the sample than the anti-solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

Detailed Description

The prior art such as patent application WO2009094260 discloses a preparation method of Aticaprant, but does not disclose relevant information of crystal forms. The inventor obtains products according to the methods disclosed, and through detection, two different crystal forms, namely a crystal form I and a crystal form II, can be obtained.

Form I thus obtained has X-ray powder diffraction patterns with diffraction peaks at positions 2theta (unit: degree, °) of 3.7, 4.4, 5.1, 6.1, 8.7, 10.2, 12.3, 14.2, 15.3, 15.7, 18.1, 18.3, 19.2 and 22.7.

The form I has an X-ray powder diffraction (XRPD) pattern as shown in figure 1.

The Differential Scanning Calorimetry (DSC) curve of the crystal form I has an endothermic peak at 65-80 ℃, the peak top value is 78 ℃, and the Differential Scanning Calorimetry (DSC) curve is shown in figure 2.

The re-analytical curve (TGA) of the crystal form I has weight loss at 50-125 ℃, the weight loss is 0.24%, and the thermogravimetric analysis curve (TGA) is shown in figure 3.

The obtained crystalline form II has diffraction peaks in its X-ray powder diffraction pattern at positions of 4.60, 7.85, 10.20, 11.80, 13.83, 15.11, 15.78, 17.63, 21.96, 6.80,15.36,18.41,18.77,19.26,19.88,20.34,20.60,22.86,24.11,25.15,26.80,27.60,28.00 and 34.41 in 2 θ (unit: degree, °) and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 4.

The Differential Scanning Calorimetry (DSC) curve of the crystal form II has an endothermic peak at 93-98 ℃, the peak top value is 97 ℃, and the Differential Scanning Calorimetry (DSC) curve is shown in figure 5.

The thermogravimetric analysis curve of the crystal form II sample has no obvious weight loss between 50 ℃ and 200 ℃, the weight loss is 0.12%, and the thermogravimetric analysis curve (TGA) is shown in figure 6.

Further research shows that the crystal form I can generate crystal transformation after being placed for 5 days at the temperature of 60 ℃ and the relative humidity of 75 percent, and the crystal form I is converted into the crystal form E of the invention. The crystal form II is relatively stable under the conditions of high temperature, high humidity or illumination, and is not easy to generate crystal form conversion, but the crystal form II has higher solubility or wettability to organic solvents, and is similar to the phenomenon that a compound is deliquesced by water, and the property brings adverse effects on the preparation of certain preparations, particularly long-acting or slow-release preparations are required to be achieved.

For the preparation which needs to achieve long-acting or slow release, the stable and certain solubility of the raw material medicine is favorable, and for the raw material medicine with polymorphism, the stable and relatively low solubility crystal form is more advantageous.

In view of the shortcomings of the crystal forms obtained in the prior art, the inventors have conducted intensive studies on the crystal forms of atiaprant. Through research, the inventors developed a new crystalline form of atiaprant.

In one aspect, the inventors have developed through research novel crystalline forms of atiaprant, including form D, form E, form F, form G, or form H.

A novel crystalline form of Aticaprant, designated form D, has an X-ray powder diffraction pattern having diffraction peaks at 2 θ (units: degrees, °) of 4.06, 4.79, 7.96, 10.33, 11.86, 13.99, 15.05, 15.77, 18.02, 18.96, 19.70, 20.63, and 22.70.

In some embodiments, form D has an X-ray powder diffraction pattern having diffraction peaks at positions 2 Θ (units: degrees, °) of 4.06, 4.79, 6.99, 7.96, 10.33, 11.86, 13.99, 15.05, 15.77, 17.70, 18.02, 18.96, 19.70, 20.63, 20.86, 22.39, 22.70, 24.29, 24.95, and 27.13.

In some embodiments, form D has an X-ray powder diffraction (XRPD) pattern as shown in figure 7.

The crystal form D also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve of the crystal form D has an endothermic peak at 95-104 ℃. In some embodiments, form D has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 97 ℃ to 104 ℃ with a peak top value of 101 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form D is shown in figure 8.

The crystal form D also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss between 50 ℃ and 200 ℃, and the weight loss is about 0.23%. In some embodiments, the thermogravimetric analysis curve (TGA) of form D is as shown in figure 9.

The research shows that the crystal form D is unstable under the high-temperature condition and is easy to generate crystal transformation, and the crystal form D is placed for 5 days under the conditions of 60 ℃ and 75% of relative humidity and is transformed into the crystal form II.

A novel crystalline form of atiaprant, designated form E, has an X-ray powder diffraction pattern having at least 3 diffraction peaks selected from 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 18.25, 19.06, 19.80, 20.83, 23.53, 24.09, 24.39, 26.29, and 26.98 in 2 Θ (units: degrees, °).

In some embodiments, the crystalline form E has an X-ray powder diffraction pattern having at least 6 or 9 or 12 diffraction peaks selected from 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 18.25, 19.06, 19.80, 20.83, 23.53, 24.09, 24.39, 26.29, and 26.98 in 2 Θ (units: degrees, °).

In some embodiments, form E has an X-ray powder diffraction pattern having diffraction peaks at positions 2 Θ (units: degrees, °) of 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 18.25, 19.06, 19.80, 20.83, 23.53, 24.09, 24.39, 26.29, and 26.98.

In some embodiments, form E has an X-ray powder diffraction pattern having diffraction peaks at positions 2 Θ (units: degrees, °) of 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 17.35, 18.25, 19.06, 19.80, 20.83, 21.65, 22.26, 22.68, 23.53, 24.09, 24.39, 25.50, 26.29, and 26.98.

In some embodiments, form E has an X-ray powder diffraction pattern having diffraction peaks at positions 2 Θ (units: degrees, °) of 3.20, 9.31, 11.87, 12.14, 12.96, 13.39, 14.64, 15.19, 16.73, 17.35, 18.05, 18.25, 18.64, 19.06, 19.80, 20.83, 21.41, 21.65, 22.26, 22.68, 23.10, 23.53, 24.09, 24.39, 24.83, 25.50, 26.29, 26.98, 28.77, 30.79, and 33.00.

In some embodiments, form E has an X-ray powder diffraction (XRPD) pattern as shown in figure 10.

The crystal form E also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve has an endothermic peak at 100-105 ℃, and the peak top value is 104 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form E is shown in figure 11.

The crystal form E also has the following characteristics that the thermogravimetric analysis curve (TGA) has no weight loss basically between 50 ℃ and 200 ℃, and the weight loss is about 0.05%.

In some embodiments, the thermogravimetric analysis curve (TGA) of form E is as shown in figure 12. Form E is considered to be a non-solvated form, free of water or other solvents, as determined by DSC and TGA measurements of form E.

The research shows that the crystal form E is a stable crystal form, is stable under the conditions of high temperature, high humidity and illumination, and does not generate crystal transformation.

A novel crystalline form of Aticaprant, designated form F, has an X-ray powder diffraction pattern having diffraction peaks at 4.12, 5.09, 6.01, 10.12, 11.25, 12.60, 14.83, 15.86, 16.19, 16.81, 18.27, 18.77, 19.13, 19.91 and 22.58 degrees 2 θ (units: degrees. °).

The crystalline form F has diffraction peaks in an X-ray powder diffraction pattern at positions 2 θ (units: degrees, °) of 4.12, 5.09, 6.01, 7.94, 8.17, 10.12, 11.25, 12.60, 14.83, 15.21, 15.86, 16.19, 16.81, 18.27, 18.77, 19.13, 19.91, 20.20, and 22.58.

The crystalline form F has an X-ray powder diffraction pattern having diffraction peaks at positions of 4.12, 5.09, 6.01, 7.94, 8.17, 9.52, 10.12, 11.25, 11.96, 12.60, 13.27, 14.83, 15.21, 15.86, 16.19, 16.81, 18.27, 18.77, 19.13, 19.91, 20.20, 21.46, 22.58, 22.97, 23.34, 25.60 and 29.98 in 2theta (units: degrees, °).

In some embodiments, an X-ray powder diffraction (XRPD) pattern of form F is shown in figure 13.

The crystal form F also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve of the crystal form F has an endothermic peak at 60-95 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F has an endothermic peak at 65 ℃ to 80 ℃ with a peak top value of 77 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F is shown in figure 14.

The crystal form F also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss between 50 ℃ and 100 ℃, and the weight loss is about 2.9%. In some embodiments, the thermogravimetric analysis curve (TGA) of form F is as shown in figure 15.

Researches show that the crystal form F is unstable to heat, is subjected to crystal transformation under the high-temperature condition, is placed for 5 days under the conditions of 60 ℃ and 75% of relative humidity, and is transformed into the crystal form E.

A novel crystalline form of Aticaprant, designated form G, has an X-ray powder diffraction pattern having diffraction peaks at 2 θ (units: degrees, °) of 4.69, 7.76, 10.15, 11.66, 13.83, 14.77, 18.05, 18.88, 20.90, and 22.41.

The crystalline form G has diffraction peaks in an X-ray powder diffraction pattern at positions of 4.69, 6.91, 7.76, 10.15, 11.66, 13.83, 14.77, 15.28, 15.54, 17.53, 18.05, 18.88, 20.28, 20.48, 20.90 and 22.41 in terms of 2theta (unit: degree, °).

The crystal form G has diffraction peaks in X-ray powder diffraction patterns at positions with 2theta (unit: degree, °) of 4.69, 6.91, 7.76, 10.15, 11.66, 12.51, 13.83, 14.77, 15.28, 15.54, 17.53, 18.05, 18.88, 19.45, 20.28, 20.48, 20.90, 22.41, 24.09, 25.32, 27.11 and 29.55.

In some embodiments, form G has an X-ray powder diffraction (XRPD) pattern as shown in figure 16.

The crystal form G also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has an endothermic peak at 90-110 ℃. In some embodiments, form G has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 95 ℃ to 105 ℃ with a peak top value of 102 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form G is shown in figure 17.

The crystal form G also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss between 50 ℃ and 120 ℃, and the weight loss is about 1.72%. In some embodiments, the thermogravimetric analysis curve (TGA) of form G is as shown in figure 18.

According to researches, the crystal form G is a metastable crystal form, has instability in high temperature, high humidity and strong light, is easy to generate crystal transformation, and is transformed into the crystal form II after being placed for 5 days at 60 ℃ and 75% of relative humidity, or placed for 5 days at 92.5% of relative humidity, or placed for 5 days under 4500Lx +/-500 Lx illumination.

A novel crystalline form of Aticaprant, designated form H, has a pattern by X-ray powder diffraction having peaks at 2 θ (units: degrees, °) of 4.43, 5.04, 9.55, 13.61, 13.98, 14.71, 15.08, 17.61, 18.34, 19.14, 22.26, and 21.43.

The crystalline form H has diffraction peaks in an X-ray powder diffraction pattern at positions of 4.43, 5.04, 7.54, 9.55,10.00, 12.82, 13.61, 13.98, 14.71, 15.08, 17.61, 18.34, 19.14, 20.22, 20.71, 21.43, 22.79, 24.76 and 27.82 in terms of 2 θ (units: degrees, °).

The crystal form H has diffraction peaks in X-ray powder diffraction patterns at positions with 2theta (unit: degree, °) of 4.43, 5.04, 7.54, 9.55,10.00, 12.56, 12.82, 13.61, 13.98, 14.71, 15.08, 16.03, 17.20, 17.61, 18.34, 19.14, 20.22, 20.71, 21.43, 22.26, 22.79, 23.92, 24.41, 24.76 and 27.82.

In some embodiments, form H has an X-ray powder diffraction (XRPD) pattern as shown in figure 19.

The crystal form H also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve of the crystal form H has an endothermic peak at 70-105 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form H has an endothermic peak at 80 ℃ to 100 ℃ with a peak top value of 95 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form H is shown in figure 20.

The crystal form H also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss of about 2.25% at 50-120 ℃. In some embodiments, the thermogravimetric analysis curve (TGA) of form H is as shown in figure 21.

The research shows that the crystal form H is a thermally unstable crystal form, can be subjected to crystal transformation under the high-temperature condition, is placed for 5 days under the conditions of 60 ℃ and 75% of relative humidity, and is subjected to crystal transformation to be transformed into the crystal form E.

Among the crystal forms, the crystal form E has better stability, is favorable for operation in storage, transfer and production processes, and can be prepared into a medicinal composition together with a pharmaceutically acceptable carrier. The crystal form E is powder with good appearance and fluidity, has good performances in the aspects of dissolution rate, fluidity and the like, and is favorable for being prepared into a medicinal composition with a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method for preparing the aforementioned crystalline form.

A method of preparing crystalline aticparant comprising: dissolving the compound Aticaprant in a good solvent, adding an anti-solvent, filtering and drying to obtain Aticaprant crystals; alternatively, the compound atiaprant is combined with a crystallization solvent, stirred, and the solvent removed to provide crystalline atiaprant, optionally with the addition of an inducer.

The good solvent is methyl isobutyl ketone and/or tert-butyl alcohol, and the anti-solvent is n-heptane, so as to obtain the crystal form I.

The good solvent is at least one of acetonitrile, methanol, ethanol, isopropanol and other water-soluble solvents, and the anti-solvent is water, so as to obtain the crystal form II. In some embodiments, the good solvent is ethanol or acetonitrile or a combination thereof and the anti-solvent is water to give form II.

The good solvent is at least one of ester solvents such as methyl acetate, ethyl acetate and ethyl formate, and the anti-solvent is alkane such as n-heptane, n-hexane and the like, so that the crystal form D is obtained.

In some embodiments, compound atiaprant is combined with a crystallization solvent, optionally with an inducer, stirred, and the solvent removed to provide form E as previously described. And the crystallization solvent is ethanol, and an inducer is optionally added to obtain the crystal form E. In some embodiments, the crystallization solvent is ethanol and the inducer is cinnamamide, resulting in form E. In some embodiments, the crystallization solvent is acetone and the inducer is piperazine or a hydrate thereof, resulting in form E.

The crystallization solvent is an ether solvent such as isopropyl ether to obtain the crystal form F.

And the crystallization solvent is toluene to obtain a crystal form G.

The good solvent is toluene, and the anti-solvent is cyclohexane, so that the crystal form H is obtained.

In some embodiments, the compound atiaprant is dissolved in a good solvent, an anti-solvent is added, the mixture is filtered and dried to obtain the crystalline form II of the compound atiaprant, wherein the good solvent is at least one of acetonitrile, methanol, ethanol and isopropanol, and the anti-solvent is water.

In some embodiments, the compound atiaprant is combined with ethanol, dissolved to dryness, and the solvent is removed by evaporation at room temperature to provide form E; or mixing the compound Aticaprant with cinnamamide and ethanol, stirring, filtering, and removing the solvent to obtain a crystal form E; or mixing the compound Aticaprant with piperazine or the hexahydrate thereof and acetone, stirring, filtering and removing the solvent to obtain the crystal form E.

In another aspect, the present invention also provides a composition.

A composition, comprising: at least one of the crystal form D, the crystal form E, the crystal form F, the crystal form G and the crystal form H and pharmaceutically acceptable auxiliary materials. In some embodiments, the composition comprises the aforementioned form E.

In some embodiments, the crystalline form is at least 90% of the aciaprant, by mass. In some embodiments, the crystalline form is at least 95% of the aciaprant, by mass. In some embodiments, the crystalline form is at least 97% of the aciaprant, by mass. In some embodiments, the crystalline form is at least 99% of the aciaprant, by mass.

In some embodiments, the crystalline form is at least 5% of atiaprant, by mass, in the composition. In some embodiments, the crystalline form is at least 1% of the atiaprant, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 0.5% of atiaprant, by mass.

In some embodiments, the crystalline form is no more than 10% by mass of the aciprant in the composition. In some embodiments, the crystalline form is no more than 6% by mass of the aciprant in the composition. In some embodiments, the crystalline form is no more than 5% by mass of the aciprant in the composition. In some embodiments, the crystalline form is no more than 3% by mass of the aciprant in the composition. In some embodiments, the crystalline form is no more than 1% by mass of the aciprant in the composition. In some embodiments, the crystalline form is no more than 0.5% by mass of the aciprant in the composition.

In some embodiments, the crystalline form is at least 0.05% to 95% or 1% to 95% of the total mass of the composition, calculated as a mass ratio.

In some embodiments, the composition comprises form E as described above, and may further comprise form II as described above.

In some embodiments, in the aforementioned composition, the crystalline form is form E.

The pharmaceutically acceptable auxiliary materials comprise a diluent, a disintegrating agent, an adhesive, a lubricant or the like.

In some embodiments, the aforementioned composition is a long acting formulation or a sustained release formulation. The long-acting preparation or the sustained-release preparation refers to: compared with a quick-release preparation, the preparation has the advantages that the administration times are reduced under the condition of the same total dose in the same treatment period; or a reduction in the total dose of the formulation compared to an immediate release formulation over the same treatment period.

Drawings

Figure 1 shows an X-ray powder diffraction pattern (XRPD) of form I;

FIG. 2 shows a Differential Scanning Calorimetry (DSC) curve of form I;

figure 3 shows a thermogravimetric analysis plot (TGA) of form I.

FIG. 4 shows an X-ray powder diffraction pattern of form II;

FIG. 5 shows a Differential Scanning Calorimetry (DSC) curve of form II;

figure 6 shows a thermogravimetric analysis plot (TGA) of form II.

FIG. 7 shows an X-ray powder diffraction pattern of form D;

FIG. 8 shows a Differential Scanning Calorimetry (DSC) curve of form D;

figure 9 shows a thermogravimetric analysis plot (TGA) of form D.

FIG. 10 shows an X-ray powder diffraction pattern of form E;

FIG. 11 shows a Differential Scanning Calorimetry (DSC) curve of form E;

figure 12 shows a thermogravimetric analysis plot (TGA) of form E.

FIG. 13 shows an X-ray powder diffraction pattern of form F;

FIG. 14 shows a Differential Scanning Calorimetry (DSC) curve of form F;

figure 15 shows a thermogravimetric analysis plot (TGA) of form F.

FIG. 16 shows an X-ray powder diffraction pattern of form G;

FIG. 17 shows a Differential Scanning Calorimetry (DSC) curve of form G;

figure 18 shows a thermogravimetric analysis plot (TGA) of form G.

FIG. 19 shows an X-ray powder diffraction pattern of form H;

FIG. 20 shows a Differential Scanning Calorimetry (DSC) curve of form H;

figure 21 shows a thermogravimetric analysis plot (TGA) of form H.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

In the present invention, mg means mg, mL means mL, rpm means rpm, h means hour, and RH means relative humidity.

Parameters of the instrument

All analyses below were performed at room temperature unless otherwise specified in the parameters.

Powder X-ray diffraction (XRPD) study

X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used was a source of radiation of (Cu, k α,

1.540598；

1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 6.6 mm.a theta-theta continuous scan mode is used to obtain an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.

Differential Scanning Calorimetry (DSC)

DSC measurements were performed in a TA instruments model Q2000 using a sealed tray apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data were collected between 30 ℃ and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.

Thermogravimetric analysis (TGA)

TGA data were collected on TA Instruments Q500. The temperature of the instrument was calibrated using certified nickel. Typically 8-12mg of sample is loaded onto a pre-weighed platinum crucible and heated from 30 ℃ to 300 ℃ at 10 ℃/min. A nitrogen purge of 60mL/min was maintained over the sample. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents Weight loss in percentage (Weight (%)).

Preparation of form I

The method comprises the following steps: adding 30mg of ticaprant into 0.15mL of methyl isobutyl ketone for dissolving, and then adding 0.2mL of n-heptane; white solid is generated in the system, stirred for 12h and filtered to obtain a product which is a crystal form I; x-ray powder diffraction, DSC and TGA were measured, and the results were shown in FIGS. 1 to 3.

The method 2 comprises the following steps: adding 80mg of ticaprant into 0.4mL of tert-butyl alcohol for dissolving, adding 0.8mL of n-heptane, placing the system in an open environment at 50 ℃, stirring and evaporating for 12 hours to obtain a solid, and detecting to confirm that the solid is crystal form I.

Preparation of form II

The method comprises the following steps: adding 20mg of the Aticaprant raw material into 0.5mL of acetonitrile for dissolving, and dropwise adding 0.2mL of purified water; then placing the system in an open environment at 50 ℃ to stir and evaporate for 12h to obtain a white crystalline substance; filtering, vacuum drying at 50 deg.C for 12h in a drying oven to obtain crystal form II, detecting, and performing X-ray powder diffraction, DSC and TGA to obtain the results shown in FIG. 4-FIG. 6.

The method 2 comprises the following steps: 50mg of Aticaprant is added into 0.15mL of ethanol to be dissolved, 0.25mL of purified water is added, a white solid is immediately generated, the mixture is stirred for 12 hours and filtered to obtain a solid, and the solid is detected and confirmed to be crystal form II.

EXAMPLE 1 preparation of form D

30mg of ticaprant is added into 0.15mL of ethyl acetate to be dissolved, 0.3mL of n-heptane is added to generate white solid, the mixture is stirred for 12 hours and filtered to obtain the product of crystal form D, and X-ray powder diffraction, DSC and TGA are detected, and the results are shown in figure 7-figure 9.

Example 2 preparation of form E

The method comprises the following steps: placing 20mg of the crystal form I of the ticaprant in a test box with the temperature of 60 ℃ and the relative humidity of 75% for 5 days to obtain a crystal form E; x-ray powder diffraction, DSC, TGA were measured, and the results were shown in FIGS. 10 to 12.

The method 2 comprises the following steps: adding 10mg of aticaprant into a glass tube, and then adding 0.1ml of ethanol, so that the raw materials are quickly dissolved; and opening the bottle cap, evaporating the solvent at room temperature for 12-24 hours to obtain a white solid, and detecting to confirm that the crystal form E is the crystal form E.

The method 3 comprises the following steps: weighing 10mg of ticaprant, adding into an EP tube, adding 3.7mg of cinnamamide, adding 0.1mL of ethanol for dissolving, uncovering, stirring at room temperature for 12 hours, filtering, drying the solid at room temperature, detecting, and confirming to obtain the crystal form E.

The method 4 comprises the following steps: weighing 20mg of ticaprant, adding into an EP tube, adding 9.7mg of piperazine hexahydrate, adding 0.5mL of acetone for dissolution, uncovering, stirring at room temperature for 12 hours, filtering, drying the solid at room temperature, detecting, and confirming to obtain the crystal form E.

Example 3 preparation of form F

80mg of ticaprant was added to 2mL of isopropyl ether and suspended, and stirred open for 12h to give a solid as form F, which was examined for X-ray powder diffraction, DSC, TGA and the results are shown in FIGS. 13-15.

EXAMPLE 4 preparation of form G

100mg of ticaprant is added into 1.5mL of toluene to be dissolved, the system is placed in an open environment at 50 ℃ and stirred and evaporated for 12h to obtain a crystal form G, and X-ray powder diffraction, DSC and TGA are detected, and the results are shown in figures 16-18.

EXAMPLE 5 preparation of form H

30mg of ticaprant was added to 0.3mL of toluene to dissolve it, followed by 0.6mL of cyclohexane and stirred overnight to give the product crystalline form G. The X-ray powder diffraction pattern of the compound is determined to be substantially consistent with that of figure 19, the DSC pattern of the compound is determined to be substantially consistent with that of figure 20, and the TGA pattern of the compound is determined to be substantially consistent with that of figure 21.

Example 6 stability testing

According to the guiding principle of the pharmaceutical preparation stability test, the sample is subjected to influence factor tests including a high temperature test, a high humidity test and a strong light irradiation test, the stability conditions of each crystal form under different conditions are inspected, and the results are shown in the following table 1.

The experimental conditions are as follows:

high-temperature test: respectively taking a proper amount of samples, flatly placing the samples in a weighing bottle, opening the bottle, placing the bottles in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH75 +/-5 percent, then taking about 10mg of the samples in 0, 5 and 15 days respectively, and testing the crystal form condition of the samples by adopting powder X-ray diffraction (XRPD) and Differential Scanning Calorimetry (DSC).

High humidity test: respectively taking a proper amount of samples, flatly placing the samples in a weighing bottle, opening the bottle, placing the bottles in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, then respectively taking about 10mg of the samples in 0, 5 and 15 days, and testing the crystal form condition of the samples by adopting powder X-ray diffraction (XRPD) and Differential Scanning Calorimetry (DSC).

And (3) illumination test: appropriate amount of samples are respectively taken, the samples are spread into a weighing bottle, the bottle is opened, the bottle is placed under the conditions of a constant temperature and humidity box (25 ℃, RH 60% +/-5%) with visible light 4500Lux +/-500 Lux (VIS) and ultraviolet light 1.7W X h/m2(UV), then about 10mg of the samples are respectively taken at 0 day, 5 days and 15 days, and the crystal form condition of the samples is tested by powder X-ray diffraction (XRPD) and Differential Scanning Calorimetry (DSC).

The experimental results are as follows: the results of the measurements for each sample are shown in Table 1.

Table 1: results of stability experiments

Example 7 solubility testing

10mg of the crystal form II and the crystal form E are respectively taken in 2 test tubes. 0.5mL of 1% SDS phosphate buffer was added to each tube. The tube was placed in a 37 ℃ constant temperature trap and stirred for 2 hours, and if the sample was not clear, 0.5mL of buffer was added to the tube and stirred for 2 hours again to observe the dissolution. When 4mL of buffer solution is added, the crystal form II sample is cleared; when 5mL of buffer solution was added, the crystal form E sample was cleared; the solubility of form II was calculated to be 2.5 mg/mL; form E solubility was calculated to be 2 mg/mL. According to the solubility data of the two crystal forms, the two crystal forms have close solubility and better stability, so that the crystal forms II and E have more preparation applicability compared with other crystal forms, and for a preparation needing long-acting or slow release, the crystal form E has more advantages due to the stability, relatively higher melting point and relatively lower solubility.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims

1. A crystalline form of aticarpant comprising: form E having an X-ray powder diffraction pattern having at least 3 diffraction peaks selected from 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 18.25, 19.06, 19.80, 20.83, 23.53, 24.09, 24.39, 26.29, and 26.98 degrees 2 Θ.

2. The crystalline form of claim 1, having an X-ray powder diffraction pattern with diffraction peaks, in terms of 2 Θ, at 9.31, 11.87, 12.96, 13.39, 14.64, 15.19, 17.35, 18.25, 19.06, 19.80, 20.83, 21.65, 22.26, 22.68, 23.53, 24.09, 24.39, 25.50, 26.29, and 26.98 degrees; or form E has diffraction peaks in the X-ray powder diffraction pattern at 3.20, 9.31, 11.87, 12.14, 12.96, 13.39, 14.64, 15.19, 16.73, 17.35, 18.05, 18.25, 18.64, 19.06, 19.80, 20.83, 21.41, 21.65, 22.26, 22.68, 23.10, 23.53, 24.09, 24.39, 24.83, 25.50, 26.29, 26.98, 28.77, 30.79 and 33.00 degrees 2 Θ; or the X-ray powder diffraction pattern of the crystal form E is shown as the attached figure 10.

3. The crystalline form of claim 1, wherein form E has an endothermic peak at 100 ℃ to 105 ℃ in a differential scanning calorimetry curve.

4. A composition comprising the crystalline form of any one of claims 1-3 and a pharmaceutically acceptable carrier.

5. The composition of claim 4, further comprising form II having an X-ray powder diffraction pattern with diffraction peaks at 4.60, 7.85, 10.20, 11.80, 13.83, 15.11, 15.78, 17.63, 21.96, 6.80,15.36,18.41,18.77,19.26,19.88,20.34,20.60,22.86,24.11,25.15,26.80,27.60,28.00, and 34.41 degrees 2 θ.

6. The composition of claim 4 or 5, wherein the crystalline form is at least 90% of the Aticaprant, or the crystalline form is at least 0.5% of the Aticaprant, or the crystalline form is no more than 10% of the Aticaprant, by mass ratio.

7. The composition of claim 5 or 6, wherein the crystalline form II is prepared by a process comprising: dissolving the compound Aticaprant in a good solvent, adding an anti-solvent, filtering and drying to obtain Aticaprant crystal form II; the good solvent is at least one of acetonitrile, methanol, ethanol and isopropanol, and the anti-solvent is water.

8. The composition of any one of claims 4-7, which is a depot or sustained release formulation.

9. A method of preparing the crystalline form of any one of claims 1-3, comprising: mixing the compound Aticaprant with a crystallization solvent, stirring, and removing the solvent to obtain an Aticaprant crystal form; wherein; the crystallization solvent is ethanol, and an inducer, namely cinnamamide, is optionally added to obtain a crystal form E; or the crystallization solvent is acetone, and the inducer is piperazine or a hydrate thereof, so as to obtain the crystal form E.

10. The process of claim 8, wherein the compound atiaprant is combined with ethanol, dissolved and the solvent is removed by evaporation at room temperature to provide form E; or mixing the compound Aticaprant with cinnamamide and ethanol, stirring, filtering, and removing the solvent to obtain a crystal form E; or mixing the compound Aticaprant with piperazine or the hexahydrate thereof and acetone, stirring, filtering and removing the solvent to obtain the crystal form E.