A compound crystal form and its preparation method and application

Abstract

The invention discloses a crystalline form A of a compound, wherein 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 spectrum of the crystalline form A includes 3 or more 2θ values ​​selected from the following group: 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 crystalline form A of the compound of the invention does not contain water and solvent, has high stability and low hygroscopicity, and is suitable for drug formulation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a compound crystal form and a preparation method and application thereof. Background Art

[0002] S-(-)-2,3-Methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine α 1A -AR antagonist, the preparation method of which is disclosed in WO2018041112A1.

[0003]

[0004] Prostatic hyperplasia is a common physiological disease in middle-aged and elderly men. More than half of men over 50 years old worldwide suffer from prostatic diseases, which has become one of the main diseases of the elderly urinary system. Although there are some 5α-reductase inhibitors and α1-adrenergic receptor (α1-AR) antagonists for the treatment of prostatic hyperplasia, there are still some unresolved issues in the efficacy and safety of these drugs. Side effects such as sexual dysfunction and orthostatic hypotension have largely limited the efficacy of these drugs. Therefore, the development of new, safer and more effective drugs is of great significance to meet the clinical medication needs of BPH patients.

[0005] Different crystal forms of drugs may affect their dissolution and absorption in the body, which in turn may affect the clinical efficacy and safety of the drugs to a certain extent, especially for some poorly soluble oral solid or semisolid preparations, where the impact of the crystal form will be greater.

[0006] Therefore, it is necessary to develop a compound crystal form with high stability, low hygroscopicity and convenient processing. Summary of the invention

[0007] The object of the present invention is to provide a crystalline form of a compound of formula I which has high stability, low hygroscopicity and is easy to process.

[0008] In view of this, the present invention provides a crystalline form A of a compound of formula I,

[0009]

[0010] The X-ray powder diffraction pattern of the crystalline form A includes 3 or more 2θ values ​​selected from the following group:

[0011] 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°, 25.321±0.2°.

[0012] Further, the X-ray powder diffraction pattern of the crystalline form A includes a 2θ value selected from the following group:

[0013] 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°, 25.321±0.2°.

[0014] Furthermore, the X-ray powder diffraction pattern of the crystalline form A includes 3 or more 2θ values ​​selected from the following group:

[0015] 12.21±0.1°, 13.381±0.1°, 15.181±0.1°, 16.171±0.1°, 17.101±0.1°, 19.801±0.1°, 21.511±0.1°, 24.391±0.1°, 25.321±0.1°.

[0016] Furthermore, the relative intensity corresponding to the aforementioned 2θ value position peak is:

[0017]

[0018]

[0019] Furthermore, the crystalline form A comprises characteristic peaks at 3 or more interplanar spacing d values ​​selected from the following group:

[0020] Further, the crystalline form A has substantially Figure 2 The XRPD pattern shown, or the X-ray powder diffraction pattern of the crystalline form A is basically as shown in Table 1; the 2θ value of each peak of the characteristic peak at the 2θ value optionally has an error margin of ±0.2°, or preferably has an error margin of ±0.1°.

[0021] Furthermore, the crystalline form A has one or more characteristics selected from the following group:

[0022] 1) The TGA graph of the crystalline form A shows no weight loss before the decomposition of the compound of formula I;

[0023] 2) The DSC graph of the crystalline form A has a characteristic absorption peak at a peak value of 172±5°C (or ±3°C, or ±1°C);

[0024] 3) The crystalline form A has a moisture absorption weight gain of ≤1% at a relative humidity of 0-95%, preferably 0.4%±0.3%.

[0025] In another preferred embodiment, the IR spectrum of the crystal form A includes 3 or more of the following characteristic absorption peaks represented by wavelength λ: 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±2cm -1 、995±2cm -1 、926±2cm -1 、856±2cm -1 Preferably, each characteristic absorption peak exists within ±1cm -1 margin of error.

[0026] Furthermore, the crystalline form A has one or more characteristics selected from the following group:

[0027] 1) The crystalline form A has substantially Figure 3 TGA graph shown;

[0028] 2) The crystalline form A has substantially Figure 4 DSC graph shown;

[0029] 3) The crystalline form A has substantially Figure 5 The DVS diagram shown;

[0030] 4) The crystalline form A has substantially Figure 6 IR diagram shown.

[0031] The present invention also provides a crystalline composition, which comprises the crystalline form A as described above.

[0032] In another preferred embodiment, based on the total weight of the crystalline composition, the weight percentage of Form A is 60-99.999%, preferably 80-99.999%, and more preferably 90-99.999%.

[0033] In another preferred embodiment, the crystal form combination further includes: amorphous form A of the compound of formula I crystal or amorphous form of the compound of formula I.

[0034] The present invention also provides a method for preparing the above-mentioned crystal form A, the method comprising the following steps:

[0035] The compound of formula I is suspended in an inert solvent, stirred, and filtered to obtain the crystalline form A;

[0036] In another preferred embodiment, the inert solvent is selected from isopropanol or n-hexane.

[0037] In another preferred embodiment, the weight-to-volume ratio of the compound of formula I in the inert solvent is 10-100 mg / mL, preferably 15-50 mg / mL, and more preferably 20-40 mg / mL.

[0038] In another preferred embodiment, the stirring has one or more characteristics selected from the following group:

[0039] (1) The stirring time is 12-48 hours, preferably 18-36 hours.

[0040] (2) The stirring temperature is 25±5°C.

[0041] The present invention also provides a use of any of the above-mentioned crystal form A or the above-mentioned crystal form composition, which can be used to prepare a drug for preventing and / or treating prostate hyperplasia.

[0042] The present invention also provides a drug comprising any of the above-mentioned crystal form A or the above-mentioned crystal form combination and a pharmaceutically acceptable carrier.

[0043] In another preferred embodiment, the carrier is selected from the following group: a filler, a disintegrant, a lubricant, or a combination thereof.

[0044] In another preferred embodiment, the filler is selected from the following group: pregelatinized starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, or a combination thereof.

[0045] In another preferred embodiment, the disintegrant is selected from the following group: carboxymethyl cellulose and its salts, cross-linked carboxymethyl cellulose and its salts, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or a combination thereof.

[0046] In another preferred embodiment, the lubricant is selected from the following group: magnesium stearate, calcium stearate, or a combination thereof.

[0047] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is a polarizing microscope photograph of Form A of Example 1.

[0049] Figure 2 This is the X-ray powder diffraction (XRPD) pattern of Form A of Example 1.

[0050] Figure 3 This is the thermal gravimetric analysis (TGA) diagram of Form A of Example 1.

[0051] Figure 4 This is a differential scanning calorimetry (DSC) diagram of Form A of Example 1.

[0052] Figure 5 This is a dynamic vapor sorption (DVS) diagram of Form A of Example 1.

[0053] Figure 6 This is the infrared spectrum (IR) of Form A of Example 1.

[0054] Figure 7 This is the X-ray powder diffraction (XRPD) pattern of Form B of Comparative Example 1.

[0055] Figure 8 This is the X-ray powder diffraction (XRPD) pattern of Form C of Comparative Example 2.

[0056] Fig. 9 This is the X-ray powder diffraction (XRPD) pattern of Form D of Comparative Example 3. DETAILED DESCRIPTION

[0057] After extensive and in-depth research, a large number of screenings and tests, the inventors have provided a crystalline form A of a compound of formula I, which contains no water or solvent, has high stability and low hygroscopicity, is easy to process, and is suitable for drug production. On this basis, the present invention was completed.

[0058] the term

[0059] 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.

[0060] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0061] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0062] As used herein, the terms "compound of Formula I", "S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine" are used interchangeably.

[0063] As used herein, the term "n or more" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), wherein the upper limit Nup is the number of all values ​​in the group. For example, "1 or more" not only includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... each positive integer of the upper limit Nup, but also includes "2 or more", "3 or more", "4 or more", "5 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", etc. ranges. For example, "3 or more" not only includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ... the upper limit Nup, each positive integer, but also includes "4 or more", "5 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" and other ranges.

[0064] As used herein, the term "inert solvent" refers to a solvent that does not react with the compound of formula I of the present invention. Preferably, the solvents used in the preparation method of Form A of the present invention do not react with the compound of formula I.

[0065] Unless otherwise specified, the term "room temperature" or "normal temperature" refers to a temperature of 4-32°C, preferably 25±5°C.

[0066] Polymorph

[0067] Solids exist in either amorphous or crystalline form. In the case of crystalline form, the molecules are positioned in a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing mode, fluidity and / or solid state stability.

[0068] As used herein, "Form A", "Form A of the compound of Formula I", "Form A of the present invention", and "Form A of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine" can be used interchangeably.

[0069] Crystalline Form A

[0070] The present invention provides a crystalline form A of a compound of formula I,

[0071]

[0072] The X-ray powder diffraction pattern of the crystalline form A includes 3 or more 2θ values ​​selected from the following group:

[0073] 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°, 25.321±0.2°.

[0074] Furthermore, the X-ray powder diffraction pattern of the crystalline form A includes 3 or more 2θ values ​​selected from the following group:

[0075] 12.21±0.1°, 13.381±0.1°, 15.181±0.1°, 16.171±0.1°, 17.101±0.1°, 19.801±0.1°, 21.511±0.1°, 24.391±0.1°, 25.321±0.1°.

[0076] Furthermore, the relative intensity corresponding to the aforementioned 2θ value position peak is:

[0077] 2θ angle Relative Strength 12.21±0.2° 100 13.381±0.2° 2.5±0.5 15.181±0.2° 4.48±0.5 16.171±0.2° 7.05±0.5 17.101±0.2° 17.79±0.5 19.801±0.2° 14.02±0.5 21.511±0.2° 6.47±0.5 24.391±0.2° 6.56±0.5 25.321±0.2° 5.44±0.5

[0078] Furthermore, the crystalline form A comprises characteristic peaks at 3 or more interplanar spacing d values ​​selected from the following group:

[0079] Further, the crystalline form A has substantially Figure 2 The XRPD pattern shown, or the X-ray powder diffraction pattern of the crystalline form A is substantially as shown in Table 1. Characteristic peaks at 2θ values ​​The 2θ value of each peak optionally has an error margin of ±0.2°, or preferably has an error margin of ±0.1°.

[0080] Furthermore, the crystalline form A has one or more characteristics selected from the following group:

[0081] 1) The TGA graph of the crystalline form A shows no weight loss before the decomposition of the compound of formula I;

[0082] 2) The DSC graph of the crystalline form A has a characteristic absorption peak at a peak value of 172±5°C (or ±3°C, or ±1°C);

[0083] 3) The crystalline form A has a moisture absorption weight gain of ≤1% at a relative humidity of 0-95%, preferably 0.4%±0.3%.

[0084] In another preferred embodiment, the IR spectrum of the crystal form A includes 3 or more of the following characteristic absorption peaks represented by wavelength λ: 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±2cm -1 、995±2cm -1 、926±2cm -1 、856±2cm -1 Preferably, each characteristic absorption peak exists within ±1cm -1 margin of error.

[0085] Furthermore, the crystalline form A has one or more characteristics selected from the following group:

[0086] 1) The crystalline form A has substantially Figure 3 TGA graph shown;

[0087] 2) The crystalline form A has substantially Figure 4 DSC graph shown;

[0088] 3) The crystalline form A has substantially Figure 5 The DVS diagram shown;

[0089] 4) The crystalline form A has substantially Figure 6 IR diagram shown.

[0090] Crystal composition

[0091] The present invention also provides a crystalline composition, which comprises the crystalline form A described in the first aspect of the present invention.

[0092] In another preferred embodiment, based on the total weight of the crystalline composition, the weight percentage of Form A is 60-99.999%, preferably 80-99.999%, and more preferably 90-99.999%.

[0093] In another preferred embodiment, the crystal form combination further includes: amorphous form A of the compound of formula I crystal or amorphous form of the compound of formula I.

[0094] crystallization

[0095] Can be through the operation solution, make the solubility limit of target compound be exceeded, thereby complete production scale crystallization.This can be accomplished through many methods, for example, dissolve compound under relatively high temperature, then cool solution to below saturation limit.Or reduce liquid volume through boiling, atmospheric evaporation, vacuum drying or through some other methods.Can reduce the solubility of interested compound by adding anti-solvent or compound has solvent or such solvent mixture with low solubility therein.Another optional method is to adjust pH value to reduce solubility.

[0096] If it is desired that salt formation and crystallization occur simultaneously, the addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting materials. Likewise, completion of the synthesis reaction in a medium in which the final desired form is less soluble than the reactants may result in direct crystallization of the final product.

[0097] Optimization of crystallization can include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest 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 just below the saturation level. At this point, seeds of the desired form can be added (while maintaining the integrity of the seeds), and the system is cooled to complete crystallization.

[0098] Preparation method of crystal form A

[0099] The present invention also provides a method for preparing the above-mentioned crystal form A, the method comprising the following steps:

[0100] The compound of formula I is suspended in an inert solvent, stirred, and filtered to obtain the crystalline form A;

[0101] In another preferred embodiment, the inert solvent is selected from isopropanol or n-hexane.

[0102] In another preferred embodiment, the weight-to-volume ratio of the compound of formula I in the inert solvent is 10-100 mg / mL, preferably 15-50 mg / mL, and more preferably 20-40 mg / mL.

[0103] In another preferred embodiment, the stirring has one or more characteristics selected from the following group:

[0104] (1) The stirring time is 12-48 hours, preferably 18-36 hours.

[0105] (2) The stirring temperature is 25±5°C.

[0106] Preferably, the starting material for the above-mentioned various preparation methods is the compound of formula I in amorphous form.

[0107] Typically, the crystal form A obtained by the above-mentioned various preparation methods can be filtered, dried, etc. by conventional methods in the art as needed.

[0108] Preferably, the filtration can be selected from (but not limited to): filtration after centrifugation, filter pressing or vacuum filtration. The drying can be selected from (but not limited to): vacuum drying or oven drying.

[0109] Pharmaceutical compositions and applications

[0110] The pharmaceutical composition of the present invention comprises a safe and effective amount of the crystal form A of the compound of formula I and a pharmaceutically acceptable carrier.

[0111] The "active ingredient" of the present invention refers to the compound of formula I described in the present invention, preferably, refers to the crystalline form A of the present invention.

[0112] Typically, based on the total weight of the active ingredient, the weight percentage of Form A is 60-99.999%, preferably 80-99.999%, and more preferably 90-99.999%.

[0113] The crystal form A, crystal composition and pharmaceutical composition of the present invention can be used to prevent and / or treat prostate hyperplasia.

[0114] The "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the crystal form A of the present invention per dose, and more preferably, contains 10-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is one capsule or tablet.

[0115] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0116] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0117] The general range of the therapeutically effective dose of the crystalline form A of the present invention will be: about 1-2000mg / day, about 10-1000mg / day, about 10-500mg / day, about 10-250mg / day, about 10-100mg / day, or about 10-50mg / day. The therapeutically effective dose will be given with one or more doses. However, it should be understood that the specific dose of the compounds of the present invention for any particular patient will depend on multiple factors, for example, the age, sex, body weight, general health, diet, individual response of the patient to be treated, the activity, dosage form, application mode and concomitant drug of the specific compound of the time, the severity of the disease to be treated, the administration. The therapeutically effective amount of a given situation can be determined with routine experiments, and within the scope of clinician or physician's ability and judgment. In any case, the compound or composition will be given with multiple doses based on the individual situation of the patient and in a manner that allows the delivery of a therapeutically effective amount.

[0118] The main advantages of the present invention include:

[0119] (1) The crystalline form A of the compound of formula I of the present invention does not contain water and solvent, has high stability and low hygroscopicity, and is very suitable for drug formulation.

[0120] (2) The crystalline form A of the compound of formula I of the present invention is not easy to be blown up during the pharmaceutical manufacturing process such as packaging, and is easy to collect and not easy to cause waste, and is helpful to protect the health of operators.

[0121] (3) The preparation method of the crystalline form A of the compound of formula I of the present invention is simple and convenient, and is suitable for large-scale industrial production.

[0122] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0123] Detection Methods

[0124] X-ray diffraction analysis (XRD) is a method of structural analysis of the spatial distribution of atoms inside a substance using X-ray diffraction formed by crystals. When X-rays with a certain wavelength are irradiated onto a crystalline substance, the X-rays are scattered by atoms or ions arranged regularly in the crystal, and the phase of the scattered X-rays is enhanced in certain directions, thereby showing a unique diffraction phenomenon corresponding to the crystal structure.

[0125] In the present invention, the test parameters of XRD are as follows: instrument model: Bruker D8advance; target: Cu-Kα (40 kV, 40 mA); distance from sample to detector: 30 cm; scanning range: 3° to 40° (2 theta value); scanning step: 0.1 s.

[0126] Thermo Gravimetric Analysis (TGA) is an analytical technique that measures the mass of a substance as it changes with temperature under programmed temperature control. Thermogravimetric analysis can obtain the heat generated by the thermal change of the sample, and is suitable for checking the loss of crystallization solvent or crystal water molecules in crystalline substances or the process and value of sample sublimation and decomposition. It can also effectively distinguish whether a substance contains crystallization solvent or crystal water components.

[0127] In the present invention, the test parameters of TGA are as follows: instrument model: Netzsch TG 209F3; temperature range: 30-400° C.; scanning rate: 10 K / min; purge gas: 25 mL / min; protective gas: 15 mL / min.

[0128] Differential Scanning Calorimeter (DSC) is a technique that uses program-controlled heating or cooling to measure the heat difference between a sample and an inert reference material (usually α-Al2O3) as it changes with temperature. DSC detection is suitable for analyzing the melting and decomposition state, mixed crystal state, and crystal transformation state of a sample.

[0129] In the present invention, the test parameters of DSC are as follows: instrument model: Perkin Elmer DSC8500; nitrogen flow rate: 20 mL / min; temperature range: 50-200° C., scanning rate: 10° C. / min.

[0130] Infra-red Spectrometry (IR) is the earliest analytical method used for the identification and authentication of crystalline substances. Since the electrical environment of the covalent bonds of different crystalline molecules is different, the strength of the covalent bonds may also change. The change in the strength of the covalent bonds will inevitably lead to different IR spectra of different crystalline forms.

[0131] In the present invention, the IR test parameters are as follows: Instrument model: Nicolet 6700 Fourier transform infrared spectrometer; single-point ATR method, resolution 4.0 cm -1 .

[0132] Dynamic Vapor Sorption (DVS) Testing / Hygroscopicity Testing is a rapid measurement of the increase and loss of water in a sample caused by a flowing carrier gas at a set relative humidity (RH). The sample is placed on a highly sensitive, high stability digital microbalance in a self-suspended state. The adsorption / desorption of water vapor is then detected by measuring the increase / decrease in material mass, thereby determining the hygroscopicity of the sample.

[0133] In the present invention, the test parameters of DVS are as follows: instrument model: SMS DVS Intrinsic, 0-95% RH, temperature: 25°C.

[0134] Polarizing microscope

[0135] In the present invention, the polarizing microscope instrument model is: XPV-400E.

[0136] Example 1

[0137] Preparation of Form A of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine crystals:

[0138] Dissolve 15 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine in 1 mL of isopropanol, stir at room temperature at 25°C, and equilibrate for at least 24 hours. Filter, place the resulting solid material in a vacuum drying oven, and vacuum dry to obtain S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine Form A crystals.

[0139] The crystal form A obtained in Example 1 was subjected to polarizing microscope imaging, XRPD, TGA, DSC, DVS, IR and Raman tests, and the characterization results are as follows: Figure 1-Figure 7 .

[0140] Figure 1 This is a polarizing microscope photo of Form A. Figure 1 It can be seen that form A is a block crystal.

[0141] Figure 2 This is the XRPD pattern of Form A (peak table is shown in Table 1).

[0142] Table 1 X-ray powder diffraction peaks of Form A

[0143]

[0144]

[0145] Figure 3 It is the TGA diagram of Form A. Figure 3 It can be seen that Form A has no weight loss phenomenon before the compound decomposes, indicating that Form A does not contain water or other solvents.

[0146] Figure 4 It is the differential scanning calorimetry (DSC) diagram of Form A. Figure 4 It can be seen that the DSC corresponding to Form A shows a oneset of about 170.3°C and a melting peak temperature of 172.5°C.

[0147] Figure 5 It is the dynamic vapor adsorption (DVS) diagram of Form A. Figure 5 It can be seen that within the range of 0-95% relative humidity, the hygroscopicity of Form A changes very little, about 0.6%, and the weight changes little, indicating that Form A has low hygroscopicity.

[0148] Figure 6 It is the infrared spectrum (IR) figure of crystal form A. Figure 6 It can be seen that the crystal form A is at 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±2cm -1 、995±2cm -1 、926±2cm -1 、856±2cm -1 There is a characteristic absorption peak.

[0149] Example 2

[0150] Preparation of Form A of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine crystals:

[0151] 215 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine was dissolved in 1 mL of n-hexane, stirred at room temperature at 25°C, and equilibrated for at least 24 hours. Filtered, the obtained solid material was placed in a vacuum drying oven, and vacuum dried to obtain S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine Form A crystals.

[0152] The XRPD results of the obtained product are basically the same as those in Example 1.

[0153] Comparative Example 1

[0154] Preparation of Form B of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine crystals:

[0155] Dissolve 15 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine in 1 mL of methanol, stir at room temperature at 25°C, and balance for at least 24 hours. Filter, place the obtained solid material in a vacuum drying oven, and vacuum dry to obtain Form B.

[0156] The XRPD results of the obtained product are shown in Figure 7 .

[0157] Comparative Example 2

[0158] Preparation of Form C of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine crystals:

[0159] Take about 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine and dissolve it in 200 μl of ethanol and 100 μl of n-hexane, mix well, dissolve, and slowly evaporate to dryness at 25°C to obtain Form C.

[0160] The XRPD results of the obtained product are shown in Figure 8 .

[0161] Comparative Example 3

[0162] Preparation of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine crystal form D:

[0163] Take about 3 mg of S-(-)-2,3-methylenedioxy-5,8,13,13a-tetrahydro-10,11-dimethoxy-6H-dibenzo[a,g]quinolizine and dissolve it in 200 μl of isopropanol and 600 μl of chloroform, mix well, dissolve, and slowly evaporate to dryness at 25° C. to obtain Form D.

[0164] The XRPD results of the obtained product are shown in Fig. 9 .

[0165] Transformation experiment between crystal forms

[0166] Four crystal forms, Form A, Form B, Form C, and Form D, were used for mutual transformation experiments. The experimental conditions and results are as follows:

[0167] Table 2 Comparison of crystal stability

[0168] Starting sample Heating temperature(℃) Heating time (min) Product crystal form FormA 120 40 FormA FormB 120 40 FormA FormC 120 40 FormA FormD 120 40 FormA

[0169] Take 5 mg of each sample and stir it with 1 ml of solvent at 25°C. The experimental conditions and results are as follows:

[0170] Table 3 Comparison of crystal stability (suspension equilibrium)

[0171] Starting sample mixture Suspension solvent composition Suspension time (days) Product crystal form FormA+FormB Isopropyl alcohol 2 FormA FormA+FormC Isopropyl alcohol 2 FormA FormA+FormD Isopropyl alcohol 2 FormA FormB+FormC Isopropyl alcohol 2 FormA FormB+FormD Isopropyl alcohol 2 FormA FormC+FormD Isopropyl alcohol 2 FormA

[0172] From the results of the crystal transformation, it can be seen that Form A is the most stable crystal form.

[0173] Hygroscopicity study

[0174] The dynamic water sorption instrument (DVS) was used to examine the adsorption and desorption of water by the samples at a temperature of 25°C and a relative humidity of 0-95% to determine the moisture absorption properties of different crystal forms. The experimental results are as follows:

[0175] Table 4 Comparison of hygroscopicity of crystal forms

[0176]

[0177]

[0178] Preparation and stability study of pharmaceutical compositions

[0179] 1. Prescription of drug composition:

[0180] Element Dosage API (crystal form A / B / C / D) 1 serving sucrose 24 servings lactose 24 servings Cross-linked polyvinylpyrrolidone (CL-M) 0.3 parts Povidone K30 0.3 parts

[0181] 2. Preparation process:

[0182] ① According to the prescription, weigh povidone K30 and dissolve it in 80% ethanol to prepare an adhesive.

[0183] ② Evenly mix the API (crystal form A / B / C / D) and excipients sucrose / lactose / cross-linked polyvinylpyrrolidone (CL-M), and add adhesive to make a soft material.

[0184] ③ Granulate through 20 mesh sieve.

[0185] ④Dry at 50℃ and control the moisture content to less than 2.0%.

[0186] ⑤ Use a 20-mesh sieve to size the particles and a 80-mesh sieve to remove fine powder.

[0187] ⑥Collect particles.

[0188] ⑦Inner packaging.

[0189] 3. Stability study data:

[0190] Four batches of pilot-scale samples were prepared according to the above process, namely sample A, sample B, sample C and sample D. According to the Guidance on Stability Tests for APIs and Drug Preparations in Appendix XIXC of Part II of the 2015 edition of the Chinese Pharmacopoeia, accelerated stability tests were conducted on the above four batches of samples.

[0191] Conditions of accelerated stability test: The above samples were packaged with polyester / aluminum / polyethylene composite films for pharmaceutical packaging and placed at a temperature of 40°C and a relative humidity of 75% for 6 months. Samples were taken once at the 0th, 1st, 3rd and 6th month during the test and inspected according to the stability investigation items.

[0192] Table 5 Accelerated test results

[0193]

[0194] The results showed that the stability of granules prepared from crystal form A was better than that of granules prepared from other crystal forms, and the solubility was also significantly higher than that of granules prepared from other crystal forms. In addition, the changes in related substances in granules of crystal form A were much smaller than those of other crystal forms.

[0195] It can be seen that the crystal form A of the present invention does not contain water or solvent, is a columnar crystal, has good physical stability, and has very low hygroscopicity at a relative humidity of 0-95%, and is very suitable for processing into medicines. In addition, the crystal form A of the present invention is not easy to be blown up during the drug manufacturing process such as packaging, is easy to collect, is not easy to cause waste, and helps to protect the health of operators.

[0196] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A crystalline form A of a compound of formula I, characterized in that: The X-ray powder diffraction pattern of the crystalline form A includes 2θ values ​​selected from the following group: 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°、25.321±0.2°。 2. The crystalline form A according to claim 1, characterized in that The relative intensity corresponding to the 2θ value position peak is: 。 3. The crystalline form A according to claim 1, characterized in that The crystalline form A comprises characteristic peaks at 3 or more interplanar spacing d values ​​selected from the following group: 7.2ű0.2Å, 6.6ű0.2Å, 5.8ű0.2Å, 5.5ű0.2Å, 5.2ű0.2Å, 4.5ű0.2Å, 4.1ű0.2Å, 3.6ű0.2Å, and 3.5ű0.2Å.

4. The crystalline form A according to claim 1, characterized in that The crystalline form A has an XRPD pattern as shown in FIG2 .

5. The crystalline form A according to claim 1, characterized in that The crystalline form A has one or more characteristics selected from the following group: 1) The TGA graph of the crystalline form A shows no weight loss before the decomposition of the compound of formula I; 2) The DSC graph of the crystal form A has a characteristic absorption peak at a peak value of 172±5°C; 3) The crystalline form A absorbs moisture and gains weight by 0.4%±0.3% at a relative humidity of 0-95%.

6. The crystalline form A according to claim 1, characterized in that The crystalline form A has one or more characteristics selected from the following group: 1) The crystal form A has a TGA graph as shown in FIG3 ; 2) the crystal form A has a DSC graph as shown in FIG4 ; 3) the crystal form A has a DVS diagram as shown in FIG5 ; 4) The crystalline form A has an IR graph as shown in FIG6 .

7. A crystalline composition, comprising the crystalline form A according to any one of claims 1 to 6.

8. A method for preparing the crystalline form A according to any one of claims 1 to 6, characterized in that: The method comprises: Suspending the compound of formula I in an inert solvent, stirring, and filtering to obtain the crystalline form A; Wherein, the inert solvent is selected from isopropanol or n-hexane.

9. Use of the crystalline form A according to any one of claims 1 to 6 or the crystalline composition according to claim 7, characterized in that: Used for preparing medicines for preventing or treating prostate hyperplasia.

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