Crystalline form of the compound, its manufacturing method and use

Abstract

To provide a crystal form of a compound, and a preparation method therefor and use thereof.SOLUTION: The present invention discloses a crystal form A of a compound, where the compound is S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine, and an X-ray powder diffraction pattern of the crystal form A includes three or more 2θ values selected from the group consisting of: 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.171±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0.2°, 24.391±0.2°, and 25.321±0.2°. The crystal form A of the compound of the present invention does not contain water and a solvent, has high stability and low hygroscopicity, and is suitable for pharmaceuticals.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] This invention relates to the field of medicinal chemistry, and more specifically to the crystalline form of a compound, its manufacturing method, and its use. Regarding. [Background technology]

[0002] Patent Document 1 describes S-(-)-2,3-methylenedioxy-5,8,13,13a-te Trahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazine α 1A -AR A method for producing the antagonist is disclosed. [ka]

[0003] Benign prostatic hyperplasia (BPH) is a common physiological condition in middle-aged and older men, affecting half of men over 50 worldwide. More than a certain number of men suffer from prostate lesions, making it one of the leading diseases of the urinary tract in older adults. Currently, several 5α-reductase inhibitors and α1-adrenergic receptor (α1-A) are being used. R) Antagonists are used to treat benign prostatic hyperplasia, but these drugs have efficacy and safety aspects. There are some issues that need to be resolved, including side effects such as sexual dysfunction and postural hypotension. Therefore, the therapeutic effects of these drugs were greatly limited. Consequently, safer and The development of effective new drugs is of great importance in meeting the clinical medication requirements for BPH patients. I have it.

[0004] The various crystalline forms of pharmaceuticals affect their dissolution and absorption in the body, and thus the pharmaceuticals This may have some effect on the clinical therapeutic efficacy and safety of the product, especially poorly soluble oral solids. Alternatively, in the case of semi-solid dosage forms, the influence of the crystalline form becomes even greater.

[0005] Therefore, it was necessary to develop a crystal form of a compound that has high stability, low hygroscopicity, and is easy to process. There was.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The present invention aims to provide a crystal form of a compound of Formula 1 that has high stability, low hygroscopicity, and is easy to process. To do.

Means for Solving the Problems

[0008] The present invention provides Crystal Form A of the compound of Formula 1.

Chemical

[0009] The powder X-ray diffraction pattern of Crystal Form A is the following group: 12.21 ± 0.2°, 13.381 ± 0.2°, 15.181 ± 0.2°, 16.1 71 ± 0.2°, 17.101 ± 0.2°, 19.801 ± 0.2°, 21.511 ± 0 .2°, 24.391 ± 0.2°, 25.321 ± 0.2° and includes three or more 2 θ values.

[0010] Furthermore, the powder X-ray diffraction pattern of Crystal Form A is the following group: 12.21 ± 0.2°, 13.381 ± 0.2°, 15.181 ± 0.2°, 16.1 71 ± 0.2°, 17.101 ± 0.2°, 19.801 ± 0.2°, 21.511 ± 0 Includes a 2θ value selected from 0.2°, 24.391±0.2°, and 25.321±0.2°. .

[0011] Furthermore, the powder X-ray diffraction patterns of crystal form A belong to the following groups: 12.21±0.1°, 13.381±0.1°, 15.181±0.1°, 16.1 71±0.1°, 17.101±0.1°, 19.801±0.1°, 21.511±0 Three or more 2°s selected from 0.1°, 24.391±0.1°, and 25.321±0.1°. Includes the θ value.

[0012] Furthermore, the relative intensities corresponding to the peak positions of the aforementioned 2θ values ​​are as follows: [Table 1]

[0013] Furthermore, crystal form A is divided into the following groups: 7.2 Å ± 0.2 Å, 6.6 Å ± 0.2 Å, and 5.8 Å. ±0.2Å, 5.5ű0.2Å, 5.2ű0.2Å, 4.5ű0.2Å, 4.1Å Three or more lattice planes selected from ±0.2 Å, 3.6 Å ± 0.2 Å, and 3.5 Å ± 0.2 Å. Includes characteristic peaks with interval d values.

[0014] Furthermore, crystal form A basically has the XRPD pattern shown in Figure 2, or crystal form The powder X-ray diffraction pattern of A is basically as shown in Table 1. The characteristic peak at the 2θ value... The 2θ values ​​of each peak of the curve selectively have an error range of ±0.2°, preferably ±0.1°. It has a difference in width.

[0015] Furthermore, crystal form A belongs to the following group: 1) The TGA diagram of crystal form A shows no weight loss before the decomposition of the compound in formula 1. 2) The DSC diagram of crystalline form A has a characteristic absorption peak at a peak value of 172 ± 5 °C (or ± 3 °C, or ± 1 °C) (pe ak), 3) The weight increase due to moisture absorption of crystalline form A at a relative humidity of 0 - 95% is ≦ 1%, preferably 0 .4% ± 0.3%, and has one or more characteristics selected therefrom.

[0016] In another preferred example, the IR diagram of crystalline form A includes three or more characteristic absorption peaks represented by the following wavelengths λ: 3599 ± 2 cm , 3001 ± 2 cm -1 , 2934 ± 2 cm -1 , 2835 ± 2 cm -1 , 2789 ± 2 cm -1 , 1611 ± 2 cm -1 , 1520 -1 ± 2 cm , 1485 ± 2 cm -1 , 1452 ± 2 cm -1 , 1348 ± 2 cm -1 , 1248 ± 2 cm -1 , 1217 ± 2 cm -1 , 1107 ± 2 cm -1 , 1030 ± 2 c -1 m , 995 ± 2 cm -1 , 926 ± 2 cm -1 , 856 ± 2 cm -1 . Preferably, there is an error range of ± 1 cm -1 for each characteristic absorption peak.

[0017]

[0017] Furthermore, crystalline form A has one or more characteristics selected from the following group: 1) Crystalline form A basically has the TGA diagram shown in Figure 3. 2) Crystalline form A basically has the DSC diagram shown in Figure 4. 3) Crystalline form A basically has the DVS diagram shown in Figure 5. 4) Crystalline form A basically has the IR diagram shown in Figure 6. and has one or more characteristics selected therefrom.

[0018] The present invention further provides a crystalline composition comprising any of the above-described crystalline forms A.

[0019] In another preferred example, the calculation based on the total weight of the crystalline composition is as follows: The percentage is 60-99.999%, preferably 80-99.999%, and more preferably 90-99.999%. It is 9.999%.

[0020] In another preferred example, the crystalline composition may further be a compound crystal of formula 1 in amorphous form A or non It contains the crystalline compound of formula 1.

[0021] The present invention further provides a method for producing the above-mentioned crystal form A, the method being: The process involves suspending the compound of formula 1 in an inert solvent, stirring, and filtering to obtain crystalline form A. Includes.

[0022] In another preferred example, the inert solvent is selected from isopropanol or n-hexane. It will be selected.

[0023] In another preferred example, the weight-to-volume ratio of the compound of formula 1 in an inert solvent is 10 to 1 The concentration is 00 mg / mL, preferably 15-50 mg / mL, and more preferably 20-40 mg / mL. It is mL.

[0024] In another preferred example, the stirring has one or more features selected from the following group. (1) The stirring time is 12 to 48 hours, preferably 18 to 36 hours. (2) The stirring temperature is 25±5℃.

[0025] The present invention further provides the use of any of the above-described crystalline form A or the above-described crystalline composition, These can be used to manufacture pharmaceuticals for the prevention and / or treatment of benign prostatic hyperplasia. can.

[0026] The present invention further includes any of the above-described crystalline forms A or the above-described crystalline compositions and pharmaceutically acceptable We provide pharmaceuticals containing a carrier.

[0027] In another preferred example, the carrier is selected from the following group: fillers, disintegrants, lubricants, Or a combination of those.

[0028] In another preferred example, the filler is selected from the following group: pregelatinized starch, milk Sugar, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate Mu, or a combination thereof.

[0029] In another preferred example, the disintegrant is selected from the following group: carboxymethylcellulose Croscarmellose and its salts, croscarmellose and its salts, crospovidone, starch glycolate Sodium hydroxypropylcellulose, low-substituted hydroxypropylcellulose, or a combination thereof.

[0030] In another preferred example, the lubricant is selected from the following group: Magnesium stearate M, calcium stearate, or a combination thereof.

[0031] Furthermore, within the scope of the present invention, the above-mentioned technical features of the present invention and the following (examples, etc.) The specific technical features described below can be combined with each other to create new or suitable technical solutions. It is important to understand that these can constitute a single entity. Due to space limitations, we will not discuss each one individually here. . [Brief explanation of the drawing]

[0032] [Figure 1] This is a polarized light microscope image of crystal form A from Example 1. [Figure 2] This is the powder X-ray diffraction (XRPD) pattern of crystal form A from Example 1. [Figure 3] This is a thermogravimetric analysis (TGA) diagram of crystal form A of Example 1. [Figure 4] This is a differential scanning calorimetry (DSC) diagram of crystal form A in Example 1. [Figure 5] This is a dynamic water vapor adsorption (DVS) diagram of crystal form A from Example 1. [Figure 6] This is the infrared absorption (IR) spectrum of crystal form A from Example 1. [Figure 7] This is the powder X-ray diffraction (XRPD) pattern of crystal form B with a proportionality of 1. [Figure 8] This is the powder X-ray diffraction (XRPD) pattern of crystal form C with a proportionality of 2. [Figure 9] This is the powder X-ray diffraction (XRPD) pattern of crystal form D with a proportionality of 3. [Modes for carrying out the invention]

[0033] The inventors, after extensive and advanced research, numerous screenings and tests, have determined the compound of formula 1 We have now provided a crystalline form A of the substance. Crystalline form A does not contain water or solvent, and has high stability and low absorption. It is moist, easy to process, and suitable for pharmaceuticals. This invention was completed based on this.

[0034] term Unless otherwise defined, the meanings of all technical and scientific terms used herein are as defined herein. This is the same meaning as that generally understood by a person skilled in the art to which the invention belongs.

[0035] The term "approximately" as used herein is used in relation to the numbers specifically listed. If so, it means that the value deviates by 1% or less from the listed values. For example, The expression "approximately 100" used in the document refers to all values ​​between 99 and 101 (for example, 99 Includes .1, 99.2, 99.3, 99.4, etc.

[0036] As used herein, the terms “contains” or “includes” refer to open and semi-closed. It can be a chain type or a closed type. In other words, the term means "basically composed of ~". , or also includes "composed of ~".

[0037] The terms "compound of formula 1" and "S-(-)-2,3-methylenedioxy-" used herein are used to describe the compound of formula 1. 5,8,13,13a-Tetrahydro-10,11-dimethoxy-6H-dibenzo[a, The term "g]quinazine" is interchangeable and can be used as a substitute.

[0038] As used herein, the term “n or more” refers to n and any positive integer greater than n. (including n, n+1, ..., etc.), of which the upper limit Nup is all values ​​in that group. This is the number of items. For example, "one or more" is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... Upper limit Nup In addition to including each positive integer, it also includes "two or more", "three or more", "four or more", and "five or more". "6 or more", "7 or more", "8 or more", "9 or more", "10 or more", "11 or more", "12 or more", "13 or more", "14 or more", "15 or more", This also includes ranges such as 3, 4, 5, 6, 7, 8, 9, 10, 11. , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... each of the upper limits of Nup In addition to including positive integers, there are also "4 or more", "5 or more", "6 or more", and "7 or more". "8 or more", "9 or more", "10 or more", "11 or more", "12 or more", This includes ranges such as "13 or more," "14 or more," and "15 or more."

[0039] As used herein, the term "inert solvent" means a solvent that does not react with the compound of Formula 1 of the present invention. This refers to a solvent. In the method for producing crystalline form A of the present invention, the solvents used are all chemical compounds of formula 1. It is preferable that it does not react with other substances.

[0040] Unless otherwise specified, the term "room temperature" or "normal temperature" refers to a temperature between 4 and 32°C. This means that the temperature is preferably 25±5℃.

[0041] crystal polymorphism Solids exist in either amorphous or crystalline forms. In the crystalline form, molecules are three-dimensional crystalline structures. It is located within the child site. When the compound crystallizes from a solution or slurry, different spaces Crystallization occurs in an interlattice arrangement (this property is called "crystal polymorphism"), resulting in different crystal forms. It is possible to form crystals with various states, and these various crystalline forms are called "crystalline polymorphs." Different crystalline polymorphs of a substance have one or more physical attributes (solubility, dissolution rate, true specific gravity, crystal form). They may differ from one another in terms of state, deposition method, fluidity, and / or stability in the solid state.

[0042] As used herein, "crystal form A", "crystal form A of the compound of formula 1", and "crystal form of the present invention" A, S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro The term "crystal form A of -10,11-dimethoxy-6H-dibenzo[a,g]quinazine" It is used interchangeably.

[0043] Crystal form A This invention provides crystalline form A of the compound of formula 1. [ka]

[0044] The powder X-ray diffraction patterns of crystal form A belong to the following groups: 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.1 71±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0 Choose three or more 2°s from 0.2°, 24.391±0.2°, and 25.321±0.2°. Includes the θ value.

[0045] Furthermore, the powder X-ray diffraction patterns of crystal form A belong to the following groups: 12.21±0.1°, 13.381±0.1°, 15.181±0.1°, 16.1 71±0.1°, 17.101±0.1°, 19.801±0.1°, 21.511±0 Three or more 2°s selected from 0.1°, 24.391±0.1°, and 25.321±0.1°. Includes the θ value.

[0046] Furthermore, the relative intensities corresponding to the peak positions of the aforementioned 2θ values ​​are as follows: [Table 2]

[0047] Furthermore, crystal form A is divided into the following groups: 7.2 Å ± 0.2 Å, 6.6 Å ± 0.2 Å, and 5.8 Å. ±0.2Å, 5.5ű0.2Å, 5.2ű0.2Å, 4.5ű0.2Å, 4.1Å Three or more lattice planes selected from ±0.2 Å, 3.6 Å ± 0.2 Å, and 3.5 Å ± 0.2 Å. Includes characteristic peaks with interval d values.

[0048] Furthermore, crystal form A basically has the XRPD pattern shown in Figure 2, or crystal form The powder X-ray diffraction pattern of A is basically as shown in Table 1. The characteristic peak at the 2θ value... The 2θ values ​​of each peak of the curve selectively have an error range of ±0.2°, or preferably ±0. It has an error margin of 1°.

[0049] Furthermore, crystal form A belongs to the following group: 1) The TGA diagram of crystal form A shows no weight loss before the decomposition of the compound in formula 1. 2) The DSC diagram of crystal form A shows a peak value (pe) at 172±5℃ (or ±3℃ or ±1℃). It has a characteristic absorption peak at ak. 3) The increase in moisture-absorbing weight of crystalline form A at relative humidity 0-95% is ≤1%, preferably 0 It has one or more characteristics selected from being 0.4% ± 0.3%.

[0050] In another preferred example, the IR diagram of crystal form A is represented by three or more specific wavelengths λ. Including the peak absorption: 3599±2cm -1 , 3001±2cm -1 , 2934±2cm -1 , 2835±2cm -1 , 2789±2cm -1 , 1611±2cm -1 , 1520 ±2cm -1 , 1485±2cm -1 , 1452±2cm -1 , 1348±2cm -1 , 1248±2cm -1 , 1217±2cm -1 , 1107±2cm -1 , 1030±2c m -1 , 995±2cm -1 , 926±2cm -1 , 856±2cm -1 Preferably, each Characteristic absorption peaks are within ±1 cm. -1 There is a margin of error.

[0051] Furthermore, crystal form A belongs to the following group: 1) Crystal form A basically has the TGA diagram shown in Figure 3. 2) Crystal form A basically has the DSC diagram shown in Figure 4. 3) Crystal form A basically has the DVS diagram shown in Figure 5. 4) Crystal form A basically has the IR diagram shown in Figure 6, and one or more selected from the above. It has distinctive features.

[0052] Crystal composition The present invention further provides a crystalline composition, wherein the crystalline composition is of crystal form A as described in the first aspect of the present invention. Includes.

[0053] In another preferred example, the calculation based on the total weight of the crystalline composition is as follows: The percentage is 60-99.999%, preferably 80-99.999%, and more preferably 90-99.999%. It is 9.999%.

[0054] In another preferred example, the crystalline composition may further be a compound crystal of formula 1 in amorphous form A or non It contains the crystalline compound of formula 1.

[0055] crystal By manipulating the solution to exceed the solubility limit of the target compound, crystallization on a production scale can be achieved. This can be completed, for example, by dissolving the compound at a relatively high temperature, and then the solution This can be completed in various ways, such as cooling it to below the saturation limit. Alternatively, boiling, The volume of the liquid may be reduced by atmospheric pressure evaporation, vacuum drying, or several other methods. By adding a reverse solvent or compound to a solvent or a mixture containing such a solvent, the target compound can be obtained. It is possible to reduce the solubility of the substance. Another method is to adjust the pH value to reduce solubility. It is selectable.

[0056] For example, if we desire the simultaneous formation and crystallization of salt, and the solubility of the salt in the reaction medium is If the crystals are smaller than the raw materials, the desired salt can be directly crystallized by adding an appropriate amount of acid or alkali. This can be done. Similarly, in a medium where the solubility of the final desired form is lower than that of the reactants, The final product can be directly crystallized upon completion of the synthesis reaction.

[0057] To optimize crystallization, a crystal of the desired form is used as a seed crystal and inoculated into the crystal medium. It may include. Also, many crystallization methods use a combination of the above methods. One real As an example, the target compound is dissolved in a solvent at high temperature, and then an appropriate volume of reverse solvent is controlled. By adding it in the specified way, the system is brought below the saturation level. Here, a seed crystal of the desired form is added. By adding (while maintaining the integrity of the seed crystal) and cooling the system, crystallization is completed. It is possible.

[0058] Method for producing crystal form A The present invention further provides a method for producing the above-mentioned crystal form A, the method being: The process involves suspending the compound of formula 1 in an inert solvent, stirring, and filtering to obtain crystalline form A. Includes.

[0059] In another preferred example, the inert solvent is selected from isopropanol or n-hexane. It will be selected.

[0060] In another preferred example, the weight-to-volume ratio of the compound of formula 1 in an inert solvent is 10 to 1 The concentration is 00 mg / mL, preferably 15-50 mg / mL, and more preferably 20-40 mg / mL. It is mL.

[0061] In another preferred example, the stirring has one or more features selected from the following group. (1) The stirring time is 12 to 48 hours, preferably 18 to 36 hours. (2) The stirring temperature is 25±5℃.

[0062] Preferably, the raw materials for the various manufacturing methods described above are amorphous compounds of formula 1.

[0063] Typically, crystal form A obtained by the various manufacturing methods described above is obtained using methods that are common in this field, as needed. This allows for processes such as filtration and drying.

[0064] Preferably, filtration can be selected from filtration after centrifugation, pressure filtration, or vacuum filtration. (However, this is not limited to) drying can be selected from vacuum drying or drying in a dryer. (However, this is not limited to)

[0065] Pharmaceutical composition and use The pharmaceutical composition of the present invention contains a safe and effective amount of crystalline form A of the compound of formula 1 and is pharmaceutically acceptable. It contains a carrier.

[0066] In this invention, the "active ingredient" refers to the compound of formula 1 described in this invention, preferably the compound of formula 1 described in this invention. This refers to the crystalline form A of the invention.

[0067] Typically, when calculating based on the total weight of the active ingredient, the weight content of crystalline form A is 60-99.999%. This is a percentage, preferably 80-99.999%, and more preferably 90-99.999%.

[0068] The crystalline form A, crystalline composition, and pharmaceutical composition of the present invention are for the prevention and / or treatment of benign prostatic hyperplasia. It can be used for this purpose.

[0069] Here, "safe effective dose" refers to a dose sufficient to significantly improve the patient's condition but without serious side effects. This refers to the amount of compound that does not result in the occurrence of the disease. Typically, pharmaceutical compositions contain 1 to 2000 mg of the active ingredient. It contains the crystalline form A / agent of the present invention, and more preferably contains 10 to 500 mg of the compound / agent of the present invention. It contains. Preferably, the "agent" described above is a single capsule or tablet.

[0070] "Pharmacologically acceptable carrier" means one or more compatible solid or liquid fillers or gels. They are of good quality, suitable for human use, and possess sufficient purity and sufficiently low toxicity. It must be. Here, "compatibility" means that each component in the composition does not affect the pharmacological effect of the compound. This means that the compounds of the present invention, and the components themselves, can be miscible with each other without significantly reducing their quality. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., cellulose). (Sodium methylcellulose, sodium ethylcellulose, cellulose acetate, etc.), Latin, talc, solid lubricants (stearic acid, magnesium stearate, etc.), potassium sulfate Calcium, vegetable oil (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), Polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol) (e.g., sulfate), emulsifier (e.g., TWEEN®), humectant (e.g., sodium dodecyl sulfate), These include colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free water. .

[0071] There are no particular restrictions on the method of use of the compound or pharmaceutical composition of the present invention, and typical methods of use include Oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and local administration Includes (but not limited to) the given.

[0072] The general range of effective doses for the treatment of crystalline form A of the present invention is approximately 1 to 2000 mg / day. Approx. 10~1000mg / day, Approx. 10~500mg / day, Approx. 10~250mg / day, Approx. 10 The effective dose is approximately 100 mg / day, or about 10-50 mg / day. It is administered in a certain amount. However, the specific use of the compound of the present invention for any particular patient The dosage depends on the patient's age, sex, weight, general health, diet, individual response, and administration. Duration of administration, severity of the disease being treated, activity of the specific compound used, dosage form, method of administration, and Please understand that it depends on various factors, including concomitant medications. The effectiveness of treatment in a given situation. The quantity can be measured using standard tests and is within the scope of the competence and judgment of the clinician or physician. In any situation, the above-mentioned compounds or compositions may be used in multiple ways based on the individual patient's condition. It is administered in a dose and in a manner that allows for the delivery of an effective therapeutic dose.

[0073] The main advantages of this invention include the following: (1) The crystalline form A of the compound of formula 1 of the present invention does not contain water or solvent, and has high stability and low absorption It has moist properties and is very suitable for pharmaceuticals. (2) The crystalline form A of the compound of formula 1 of the present invention is used in pharmaceutical manufacturing processes such as individual packaging. It is less likely to get up, easy to collect, produces less waste, and contributes to protecting the operator's physical health. do. (3) The crystalline form A of the compound of Formula 1 of the present invention is easy to produce and suitable for large-scale industrial production Suitable for production. [Examples]

[0074] The present invention will be described in more detail below, along with specific examples. Please understand that this is merely to explain the invention and does not limit its scope. I would like to know. For test methods in the following examples where specific conditions are not specified, The product was manufactured in accordance with standard or conventional conditions, or the conditions recommended by the manufacturer. Unless otherwise stated, The percentages and quantities were calculated based on weight.

[0075] Testing method X-ray diffraction (XRD) is a process that is formed by crystals. By utilizing X-ray diffraction, structural analysis is performed on the spatial distribution of atoms within a material. This method involves irradiating a crystalline material with X-rays of a specific wavelength, and the X-rays then penetrate the crystal in a specific manner. Scattering occurs when X-rays collide with atoms or ions that are arranged in a regular pattern, and the scattered X-rays are directed in a specific direction. The phase is enhanced, which leads to the appearance of a specific diffraction phenomenon corresponding to the crystal structure.

[0076] In this invention, the XRD test parameters are as follows: Instrument model: Bruker D8advance, Target: Cu-Kα (40kV, 40mA), Sample to Inspector Distance to target: 30cm, scanning range: 3°~40° (2 theta values), scanning step size Iz: 0.1s.

[0077] Thermo Gravimetric Analysis (TGA) This measures the change in mass of a substance with respect to temperature under program-controlled conditions. It is one of the analytical techniques. Thermogravimetric analysis obtains the amount of heat generated by the thermal changes of a sample. This allows for the loss of crystalline solvent or crystalline water molecules in crystalline materials, as well as the sublimation and decomposition processes of the sample. It is suitable for testing values ​​and effectively determines whether a substance contains a crystalline solvent or crystalline water molecules. It is also possible to make that judgment.

[0078] In this invention, the test parameters for TGA are as follows: Instrument model: Netzsch TG 209F3, Temperature range: 30~400℃, Scanning speed: 10K / min, Purge gigger Flow rate: 25 mL / min, Shielding gas: 15 mL / min.

[0079] Differential Scanning Calorimetry The try, DSC) employs programmed control of heating or cooling, and the sample and inert reference substance ( Measure the temperature-dependent change in the enthalpy difference between α-Al2O3 and (α-Al2O3 is commonly used). It is a technology. DSC testing analyzes the melting and decomposition state of a sample, the mixed crystal state, the crystal transition state, etc. Suitable for analysis.

[0080] In this invention, the test parameters for DSC are as follows: Instrument model: Perkin Elmer DSC 8500, nitrogen gas flow rate: 20 mL / min, temperature range: 50°C to 2°F 0°C, scanning speed: 10°C / min.

[0081] Infrared spectrometry (IR) is the oldest method of measurement. This analytical method has been used for the identification and recognition of crystalline substances. Because the electrical environment is different in the bonded state, the strength of the covalent bond may also change, and the covalent bond Changes in intensity inevitably lead to differences in IR spectra for different crystal forms.

[0082] In this invention, the IR test parameters are as follows: Instrument model: Nicolet 6700 Type Fourier Transform Infrared Spectrometer, Single-Point ATR Method, Resolution 4.0c m -1 .

[0083] Dynamic water vapor adsorption (DVS) tests / hygroscopicity tests involve the flow of water vapor at a set relative humidity (RH). Rapid measurement of the increase or decrease in moisture content of a sample caused by a carrier gas, and high sensitivity measurement of the sample in a suspended state. • After placing the material on a highly stable micro-electronic balance, measure the increase / decrease in its mass. Therefore, the adsorption / desorption of water vapor is examined to determine the hygroscopicity of the sample.

[0084] In this invention, the test parameters for DVS are as follows: Instrument model: SMS DVS Intrinsic, 0~95%RH, temperature: 25℃.

[0085] Polarizing microscope In this invention, the instrument model of the polarizing microscope is the XPV-400E.

[0086] Example 1 S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 Crystal form A of 11-dimethoxy-6H-dibenzo[a,g]quinazine crystals was prepared.

[0087] 15 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydroxy Add 1 mL of isopropyl alcohol to dr-10,11-dimethoxy-6H-dibenzo[a,g]quinazine. Dissolve in panol, stir at room temperature under 25°C conditions, and allow to equilibrate for at least 24 hours. Filter. The obtained solid is then placed in a vacuum dryer and vacuum dried to obtain S-(-)-2,3-methylene Dioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibe A crystalline form A of nzzo[a,g]quinazine was obtained.

[0088] Crystal form A of the crystal prepared in Example 1 was obtained by polarized light microscopy imaging, XRPD, and TG. Tests were performed using A, DSC, DVS, IR, and Raman. The results of the characterization are shown in Figures 1-1. As shown in 7.

[0089] Figure 1 is a polarized light microscope image of crystal form A. From Figure 1, it can be seen that crystal form A is a massive crystal. You can see that.

[0090] Figure 2 shows the XRPD pattern of crystal form A (the peak table is as shown in Table 1).

[0091] [Table 3]

[0092] Figure 3 is a TGA diagram of crystal form A. From Figure 3, the weight of the compound before decomposition in crystal form A. The absence of loss indicates that crystal form A does not contain water or other solvents.

[0093] Figure 4 is a differential scanning calorimetry (DSC) diagram of crystal form A. From Figure 4, the crystal form A corresponds to The DSC shows a oneset temperature of approximately 170.3°C and a melting peak temperature of 172.5°C. It becomes clear that...

[0094] Figure 5 shows the dynamic water vapor adsorption (DVS) diagram for crystal form A. From Figure 5, it can be seen that crystal form A is relative humidity It is within the range of 0-95%, the change in hygroscopicity is small (approximately 0.6%), and the change in weight is small. This indicates that crystal form A has low hygroscopicity.

[0095] Figure 6 shows the infrared absorption (IR) spectrum of crystal form A. From Figure 6, it can be seen that crystal form A is 359 9±2cm -1 , 3001±2cm -1 , 2934±2cm -1 , 2835±2cm -1 , 2789±2cm -1 , 1611±2cm-1 , 1520±2cm -1 , 1485±2 cm -1 , 1452±2cm -1 , 1348±2cm -1 , 1248±2cm -1 , 12 17±2cm -1 , 1107±2cm -1 , 1030±2cm -1 , 995±2cm -1 , 926±2cm -1 , 856±2cm -1 It was found to have a characteristic absorption peak in that region. ru.

[0096] Example 2 S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 Crystal form A of 11-dimethoxy-6H-dibenzo[a,g]quinazine crystals was prepared.

[0097] 215 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetra Hydro-10,11-dimethoxy-6H-dibenzo[a,g]quinazine in a normal dose of 1 mL The solution was dissolved in hexane, stirred at room temperature under 25°C conditions, and allowed to equilibrate for at least 24 hours. The resulting solid was filtered, placed in a vacuum dryer, and vacuum dried to obtain S-(-)-2,3-methyl Dioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-di A crystalline form A of benzo[a,g]quinazine was obtained.

[0098] The XRPD results of the obtained product were essentially the same as those in Example 1.

[0099] Ratio 1 S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 Crystal form B of 11-dimethoxy-6H-dibenzo[a,g]quinazine crystals was prepared.

[0100] 15 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydroxy Add 1 mL of dr-10,11-dimethoxy-6H-dibenzo[a,g]quinazine to methanol. Dissolve in , stir at room temperature under 25°C conditions, and equilibrate for at least 24 hours. Filter, The obtained solid was placed in a vacuum dryer and vacuum dried to obtain crystal form B.

[0101] The XRPD results of the obtained product are shown in Figure 7.

[0102] Ratio Proportionality 2 S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 Crystal form C of 11-dimethoxy-6H-dibenzo[a,g]quinazine crystals was prepared.

[0103] 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro Ro-10,11-dimethoxy-6H-dibenzo[a,g]quinazine in 200 μL of ethanol Dissolve in 100 μL of n-hexane, mix and dissolve, and slowly infuse at 25°C. The material was evaporated and dried to obtain crystalline form C.

[0104] The XRPD results of the obtained products are shown in Figure 8.

[0105] Ratio Proportionality 3 S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10 Crystal form D of 11-dimethoxy-6H-dibenzo[a,g]quinazine crystals was prepared.

[0106] 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro Ro-10,11-dimethoxy-6H-dibenzo[a,g]quinazine in 200 μL of isopodium Dissolve in ropanol and 600 μL of chloroform, mix and dissolve, and slowly infuse at 25°C. It was then volatilized and dried to obtain crystalline form D.

[0107] The XRPD results of the obtained product are shown in Figure 9.

[0108] Crystal transformation experiments Four different crystal forms, Form A, Form B, Form C, and Form D, interchange. A substitution experiment was conducted. The experimental conditions and results are as follows. [Table 4]

[0109] 5 mg of each sample was taken and stirred with 1 ml of solvent under 25°C conditions. The experimental conditions and results are as follows: It is as follows: [Table 5]

[0110] From the results of this crystal form transformation, it can be seen that Form A is the most stable crystal form.

[0111] Observation of hygroscopicity Using a dynamic water vapor adsorption analyzer (DVS), at a temperature of 25°C, relative humidity was measured between 0 and 95%. By observing the adsorption and desorption of samples to moisture, the hygroscopic properties of different crystal forms are determined. The experimental results are as follows: [Table 6]

[0112] Research on the preparation and stability of pharmaceutical compositions

[0113] [Table 7]

[0114] 2, Preparation process (1) Weigh out polyvinylpyrrolidone K30 according to the prescription and dissolve it in 80% ethanol. It was obtained by preparing a binder. (2) Raw materials (crystalline forms A / B / C / D) are used as pharmaceutical additives saccharose / lactose / Mix uniformly with crospovidone (CL-M) and add a binder to create a soft material. Ta. (3) Granulated with a 20-mesh granule. (4) The samples were dried at 50°C, and the moisture content was controlled to less than 2.0%. (5) The grains were sized using a 20-mesh filter, and fine particles were removed using an 80-mesh filter. (6) The granules were collected. (7) Primary packaging was applied.

[0115] 3. Stability research data Following the process described above, four pilot scales of sample A, sample B, sample C, and sample D were prepared. Samples were prepared. Stability of raw materials and drug preparations from Appendix XIXC of Part 2 of the 2015 edition of the Chinese Pharmacopoeia. In accordance with the stability testing guidelines, accelerated stability tests and observations were performed on the samples from the four lots mentioned above. .

[0116] Conditions for accelerated stability testing: The above samples were tested on polyester / aluminum / polyethylene Packaged in a composite film for pharmaceutical packaging, and stored for 6 months under conditions of 40°C and 75% relative humidity. The samples were placed in a specific location, and sampling was performed once each at months 0, 1, 3, and 6 of the test period to observe the stability parameters. The examination was based on the eyes.

[0117] [Table 8]

[0118] The results showed that the stability of the granules prepared from crystal form A was greater than that of the granules prepared from other crystal forms. It also has superior properties, and its dissolution rate is significantly higher compared to granules prepared from other crystalline forms. Crystal form A indicates that the changes in granular material-related substances are much smaller than in other crystal forms. .

[0119] Thus, the crystal form A described in the present invention does not contain water or solvent, is a columnar crystal, and is good It has good physical stability, and crystal form A exhibits low hygroscopicity at relative humidity levels of 0-95%. It possesses and is therefore very suitable for processing into pharmaceuticals. Furthermore, the conclusion of the present invention Crystal form A is less likely to become airborne during pharmaceutical manufacturing processes such as individual packaging, is easy to collect, and is free of dust. It is less prone to causing damage and contributes to protecting the operator's physical health.

[0120] All documents referenced in this invention are cited separately, just as each document is cited independently for reference. This is cited as reference in this application. Furthermore, after reading the above description of the present invention, Manufacturers may make various changes or modifications to the present invention, and their equivalent forms are similar. Please understand that this application falls within the scope limited by the claims attached to this application.

Claims

1. The crystalline form A of the compound of formula 1, 【Chemistry 1】 The powder X-ray diffraction pattern of the aforementioned crystal form A includes 2θ values ​​of 12.21±0.2°, 13.381±0.2°, 15.181±0.2°, 16.171±0.2°, 17.101±0.2°, 19.801±0.2°, 21.511±0.2°, 24.391±0.2°, and 25.321±0.2°. The relative intensity corresponding to the peak position of the aforementioned 2θ value is, Table 1 And, The crystal form A of the compound of formula 1 is characterized by containing characteristic peaks having lattice plane spacing d values ​​of the following groups: 7.2 Å ± 0.2 Å, 6.6 Å ± 0.2 Å, 5.8 Å ± 0.2 Å, 5.5 Å ± 0.2 Å, 5.2 Å ± 0.2 Å, 4.5 Å ± 0.2 Å, 4.1 Å ± 0.2 Å, 3.6 Å ± 0.2 Å, and 3.5 Å ± 0.2 Å.

2. The aforementioned crystal form A is, 1) In the thermogravimetric analysis (TGA) test of the crystal form A, there is no weight loss before the decomposition of the compound of formula 1. 2) The crystalline form A has a characteristic absorption peak at a peak value of 172 ± 5°C in differential scanning calorimetry (DSC). 3) The crystal form A according to claim 1, characterized in that the increase in moisture-absorbing weight of the crystal form A at a relative humidity of 0 to 95% is ≤1%.

3. A crystalline composition comprising crystal form A as described in claim 1 or 2.

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