Polymorph of compound, preparation method therefor, active pharmaceutical ingredient, composition, and use

Abstract

The present invention relates to the field of pharmaceuticals, and provides a polymorph B of a compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, which can meet the pharmaceutical requirements of convenient production, processing, transportation, storage and the like. The present invention also relates to a preparation method for the polymorph B of the compound, an active pharmaceutical ingredient containing the polymorph B, a composition containing the polymorph B and a use of the polymorph B in the preparation of medicines for treating diseases such as angina pectoris, hypertension, coronary heart disease and / or arrhythmia.

Description

Crystal forms of compounds, their preparation methods, active pharmaceutical ingredients, compositions, and uses Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a crystal form of a particular compound, its preparation method, active pharmaceutical ingredient or composition, and / or its use in the preparation of medicaments for treating diseases. Background Technology

[0002] Dilsulfuron It is a calcium channel blocker that reduces myocardial oxygen consumption, dilates coronary and peripheral blood vessels, lowers blood pressure, and reduces cardiac workload by inhibiting the entry of calcium ions into vascular smooth muscle cells and cardiomyocytes. (diltiazem) The compound has two chiral centers, which can produce four chiral isomers. The compound is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. -4(5H)-keto hydrochloride, also known as diltiazem hydrochloride These are compounds with clinical applications, widely used to treat heart disease, angina, and other conditions. Summary of the Invention

[0003] The inventors' research found that existing diltiazem hydrochloride The crystal form has drawbacks such as high processing and storage costs. For example, according to the literature Crystal Data of Diltiazem Hydrochloride C 22 H 26 The method described in N2O4S·HCl; Powder Diffraction, Vol.5, No.3, September 1990 can obtain crystal form A. However, the inventors have found that it has disadvantages such as poor stability, poor processability, inconvenient storage and / or high storage cost.

[0004] In view of the above-mentioned problems in the prior art, the present invention provides a technical solution to solve the above problems.

[0005] According to a first aspect of the invention, the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide is provided. The characteristic diffraction peaks of the X-ray powder diffraction pattern of 4(5H)-keto hydrochloride, crystal form B, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include 4.35, 8.53, 16.93, 19.55, and 29.29.

[0006] According to a second aspect of the present invention, a pharmaceutical ingredient is provided comprising crystal form B of the compound described in the first aspect of the present invention.

[0007] According to a third aspect of the invention, a composition is provided comprising crystal form B of the compound of the first aspect of the invention and one or more physiologically acceptable / pharmaceutical excipients.

[0008] According to a fourth aspect of the invention, the use of crystal form B of the compound of the first aspect of the invention, or the active pharmaceutical ingredient of the second aspect of the invention, or the composition of the third aspect of the invention, in the preparation of a medicament for treating diseases selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia is provided.

[0009] According to a fifth aspect of the invention, the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide of the first aspect of the invention is provided. A method for preparing crystal form B of -4(5H)-ketone hydrochloride includes the following steps: adding the compound hydrochloride to a mixed solvent containing a first solvent, a second solvent and a third solvent, dissolving it at high temperature, then cooling to crystallize, and optionally drying to obtain crystal form B; wherein the first solvent and the second solvent are organic solvents, and the third solvent includes water.

[0010] In this invention, the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiaza Crystal form B of the -4(5H)-keto hydrochloride exhibits excellent optical rotation, hygroscopicity, and stability, and also offers advantages in improved processing and production. Furthermore, the preparation process and crystallization reagents are readily available and inexpensive, making it suitable for industrial scale-up and commercialization. Therefore, using active pharmaceutical ingredients containing the crystal form of the compounds of this invention can effectively extend the shelf life of pharmaceutical products and meet the pharmaceutical requirements for production, processing, transportation, and storage. Attached Figure Description

[0011] Figure 1 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. X-ray powder diffraction pattern of crystalline form A of 4(5H)-keto hydrochloride. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count).

[0012] Figure 2 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. X-ray powder diffraction pattern of 4(5H)-keto hydrochloride crystal form B. The horizontal axis represents 2θ (°), and the vertical axis represents intensity (count).

[0013] Figure 3 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of crystal form B of 4(5H)-keto hydrochloride;

[0014] Figure 4 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Physiological diagram of crystal form A of 4(5H)-keto hydrochloride;

[0015] Figure 5 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Polarized light microscopy (PLM) pattern of crystal form A of 4(5H)-keto hydrochloride;

[0016] Figure 6 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Physiological diagram of crystal form B of 4(5H)-keto hydrochloride;

[0017] Figure 7 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Polarized light microscopy (PLM) pattern of crystal form B of 4(5H)-keto hydrochloride.

[0018] Figure 8 shows the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Image of the drying process of crystal form A of -4(5H)-keto hydrochloride. Detailed Implementation

[0019] The term "crystal form" refers to the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. A single crystal form or a mixture of two of the -4(5H)-keto hydrochloride (referred to as "the compound of the present invention" in the context of this invention).

[0020] As used in this invention, the term "polymorphism" refers to the crystalline form of identical molecules and is the result of the arrangement or conformation of molecules in a crystal lattice; or, it refers to a crystal structure in which molecules can be arranged in different crystal packages and all have the same elemental composition.

[0021] In a first aspect of the invention, the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine is provided. The characteristic diffraction peaks of the X-ray powder diffraction pattern of 4(5H)-keto hydrochloride, crystal form B, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include 4.35, 8.53, 16.93, 19.55, and 29.29.

[0022] In one specific embodiment, the crystal form B uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values ​​± 0.2°, also include any one or more of 20.64, 27.65, 29.73, and 38.47.

[0023] In one specific embodiment, using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values ​​± 0.2°, include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, and 38.47.

[0024] Specifically, the characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form B, expressed as 2θ value ± 0.2°, using Cu-Kα radiation, also include any one or more of 10.74, 21.81, and 23.32.

[0025] Specifically, the characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form B using Cu-Kα radiation, expressed in 2θ values ​​± 0.2°, include 4.35, 8.53, 10.74, 16.93, 19.55, 20.64, 21.81, 23.32, 27.65, 29.29, 29.73, and 38.47.

[0026] Specifically, the characteristic diffraction peaks of the X-ray powder diffraction pattern of crystal form B, expressed as 2θ value ± 0.2°, using Cu-Kα radiation, include 4.35, 8.53, 10.74, 12.72, 15.36, 16.93, 18.22, 19.55, 20.64, 21.16, 21.81, 23.32, 25.42, 26.04, 27.30, 27.65, 29.29, 29.73, 32.88, and 38.47.

[0027] In one specific implementation, the crystal form B is irradiated with Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ values ​​is essentially as shown in Figure 2.

[0028] In this invention, the term "substantially" used in the phrase "having an X-ray powder diffraction pattern substantially as shown in Figure 2" means that the precise location of the peaks in the figure should not be interpreted as an absolute value. This is because, as those skilled in the art will recognize, the 2θ values ​​of an X-ray powder diffraction pattern can be erroneous due to different measurement conditions (such as the equipment and instruments used) and different samples (such as different batches of samples). The measurement error of the diffraction angle of an X-ray powder diffraction pattern is 5% or less, and generally, a difference of ±0.2° for a given value is considered appropriate. It should also be understood that the relative intensity of the peaks can fluctuate with experimental conditions and sample preparation, such as the preferred orientation of particles in the sample. The use of automated or fixed divergence slits will also affect the calculation of relative intensity. The intensities shown in the XRD curves included herein are merely exemplary and should not be used for absolute comparison, and any crystalline form whose powder diffraction pattern is substantially the same as those disclosed herein is within the scope of protection of this invention.

[0029] In a second aspect of the invention, a pharmaceutical ingredient is provided comprising crystal form B of the compound described in the first aspect of the invention.

[0030] As used in this invention, the term "active pharmaceutical ingredient" refers to the active pharmaceutical ingredient used in the production of various formulations. It is the active ingredient in the formulation, also known as the active component. It is a substance prepared by chemical synthesis or biotechnology and is used as a medicine in the form of powder, crystals, etc., but cannot be directly taken by the subject.

[0031] In one specific embodiment, the crystal form B of the compound of the present invention constitutes 90.0-100% by weight in the active pharmaceutical ingredient, for example, 90.0%, 91.0%, 92.0%, 93.0%, 94.0%, 95.0%, 96.0%, 97.0%, 98.0%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%. The active pharmaceutical ingredient may also include, in addition to the crystal form B of the compound of the first aspect of the present invention, amorphous forms of the compound, other crystal forms, water, or other substances within the permissible range of quality standards, such as impurities or solvent residues. Specifically, the crystal form B of the compound of the present invention is as defined above.

[0032] In a third aspect of the invention, a composition is provided comprising crystal form B of the compound of the first aspect of the invention and one or more physiologically acceptable / pharmaceutical excipients.

[0033] The pharmaceutical compositions of the present invention may be in the form of tablets, granules, and capsules.

[0034] In one specific embodiment, examples of suitable excipients for the composition or solid dosage form according to the invention include fillers, disintegrants, binders, lubricants, flow aids, and mixtures thereof.

[0035] In one specific embodiment, the filler of the present invention includes lactose, such as spray-dried lactose, α-lactose, β-lactose, lactose monohydrate, anhydrous lactose; dextrin, starch or modified starch, wherein the modified starch may include potato starch, corn starch, and rice starch, etc.

[0036] In one specific implementation, the present invention does not use microcrystalline cellulose.

[0037] In one specific implementation, the present invention does not use calcium carbonate.

[0038] In one specific embodiment, the adhesive of the present invention includes sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, pectin, polyethylene glycol 6000, povidone K30, pregelatinized starch, etc.

[0039] In one specific embodiment, the lubricant of the present invention includes stearic acid, magnesium stearate, calcium stearate or other metal stearate salts, talc, wax and glycerol esters, light mineral oil, glycerol betaine esters, colloidal silica, etc.

[0040] In one specific embodiment, the physiologically acceptable / pharmaceutical excipient of the present invention further includes hydrogenated castor oil. The hydrogenated castor oil of the present invention is present in a weight percentage of 5-20% in the composition, for example, the weight percentage of the hydrogenated castor oil in the composition is selected from any one or a range between any two values ​​of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0041] In one specific embodiment, the crystal form B of the compound of the present invention is 5%-85% by weight in the composition. In some embodiments, the crystal form B of the compound of the present invention is 9%-30% by weight in the composition. In some embodiments, the crystal form B of the compound of the present invention is preferably 40%-85% by weight in the composition. Specifically, the crystal form B of the compound of the present invention is as defined above.

[0042] In one specific embodiment, the filler of the present invention is present in the composition at a weight percentage of 35%-85%, preferably 55-85%, and most preferably 55-75%.

[0043] In one specific embodiment, the adhesive of the present invention is present in the composition at a weight percentage of 1%-12%. For example, the weight percentage of the adhesive of the present invention in the composition is selected from any one value or a range between any two values ​​of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12%, preferably 1-10%, and most preferably 1-8%.

[0044] In one specific embodiment, the weight percentage of the lubricant of the present invention in the composition is 0%-5%. For example, the weight percentage of the lubricant of the present invention in the composition is selected from any one or any two values ​​of 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%. Preferably, the weight percentage of the lubricant of the present invention in the composition is 0-3%.

[0045] In one specific embodiment, the weight ratio of the filler (adhesive + hydrogenated castor oil) of the present invention is in the range of 3.5:1 to 4.5:1. For example, the weight ratio of the filler (adhesive + hydrogenated castor oil) of the present invention is selected from any one value or a range between any two values ​​of 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1.

[0046] In one specific implementation, the composition...

[0047] Includes active ingredients at a weight percentage of 9%-30%;

[0048] Includes fillers ranging from 35% to 85% by weight;

[0049] Includes 5%-20% hydrogenated castor oil by weight;

[0050] Includes 1%-12% by weight of adhesives; and / or

[0051] Includes lubricants in the form of 0%-3% by weight.

[0052] In one specific implementation, the composition...

[0053] Includes active ingredients at a weight percentage of 9%-30%;

[0054] Includes lactose in a weight percentage of 35%-85%;

[0055] Includes 5%-20% hydrogenated castor oil by weight;

[0056] Includes 1%-12% by weight of polyethylene glycol 6000; and / or

[0057] Includes magnesium stearate in a weight percentage of 0%-3%.

[0058] In one specific embodiment, each dose of the composition of the present invention comprises about 20 mg, or about 30 mg, or about 50 mg, or about 60 mg, or about 90 mg, or about 120 mg, or about 180 mg, or about 240 mg, or about 300 mg, or about 360 mg of compound crystal form B.

[0059] In one specific embodiment, the composition is a tablet comprising the following components:

[0060] a) 30mg of compound crystal form B, 100-200mg of lactose, 15-30mg of hydrogenated castor oil, 8-15mg of polyethylene glycol 6000, and 1-4mg of magnesium stearate; or

[0061] b) 60mg of compound crystal form B, 100-300mg of lactose, 15-60mg of hydrogenated castor oil, 8-30mg of polyethylene glycol 6000, and 1-8mg of magnesium stearate; or

[0062] c) 90mg of compound crystal form B, 100-600mg of lactose, 15-90mg of hydrogenated castor oil, 8-45mg of polyethylene glycol 6000, and 1-12mg of magnesium stearate.

[0063] In one specific embodiment, the composition is a capsule comprising the following components: 90 mg of compound crystal form B, 16-60 mg of sucrose, 8-40 mg of talc and / or corn starch, 1-10 mg of povidone, and 3-25 mg of ethyl cellulose.

[0064] In one specific embodiment, the composition of the present invention is a stable pharmaceutical composition.

[0065] As used in this invention, the term "physiologically acceptable / pharmaceutical excipient" refers to an excipient that does not cause significant irritation to an organism and does not impair the biological activity and properties of the given active ingredient.

[0066] The physiologically acceptable / pharmaceutical excipients that can be mixed with crystal form B of the compounds described in this invention to form a pharmaceutical composition may depend on the intended method of administering the pharmaceutical composition.

[0067] For these routes of administration, crystal form B of the compound described in this invention can be administered in a suitable form.

[0068] In a fourth aspect of the invention, the use of crystal form B of the compound of the first aspect of the invention, the active pharmaceutical ingredient of the second aspect of the invention, or the composition of the third aspect of the invention in the preparation of a medicament for treating diseases selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia is provided.

[0069] The term "angina pectoris" generally refers to a clinical syndrome caused by insufficient blood supply to the coronary arteries due to coronary atherosclerosis and narrowing, resulting in acute and temporary myocardial ischemia and hypoxia. The main symptom is paroxysmal chest pain or discomfort, often described as a pressing, constricting, or burning sensation rather than a sharp, stabbing pain. It is commonly located behind the sternum and can radiate to the precordial region, left shoulder, left arm, etc. It includes stable angina, unstable angina, and variant angina.

[0070] The term "hypertension" generally refers to a systolic blood pressure ≥140 mmHg and / or a diastolic blood pressure ≥90 mmHg measured on three separate days without the use of antihypertensive medication. Systolic blood pressure ≥140 mmHg and diastolic blood pressure <90 mmHg is considered isolated systolic hypertension. Even if a patient has a history of hypertension and is currently using antihypertensive medication, their blood pressure should still be diagnosed as hypertension, even if it is below 140 / 90 mmHg. This includes mild to moderate hypertension, and is particularly applicable to hypertension accompanied by angina. Injectable formulations are also used for hypertensive emergencies and the emergency treatment of abnormal hypertension during surgery.

[0071] The term "coronary artery disease" (CAD) generally refers to heart disease caused by reduced blood flow to the coronary arteries, with atherosclerosis being the most common cause. When the heart fails to receive enough oxygen-rich blood, symptoms such as angina and shortness of breath may occur, while complete blockage of blood flow can lead to a heart attack. Clinical manifestations of CAD include asymptomatic myocardial ischemia, angina, acute coronary syndrome, and sudden cardiac death.

[0072] The term "cardiac arrhythmia" generally refers to abnormalities in the frequency and / or rhythm of heartbeats caused by disorders in the origin and / or conduction of cardiac activity. These include supraventricular arrhythmias, tachycardia, atrial flutter, atrioventricular block, and sinoatrial block.

[0073] The term "supraventricular arrhythmia" refers to a group of arrhythmias originating in the upper part of the heart, specifically in the atria or near the atrioventricular node. Common supraventricular rhythms include sinus tachycardia, sinoatrial nodal reentrant tachycardia, and premature atrial contractions.

[0074] The term "tachycardia" generally refers to a heart rate exceeding 100 beats per minute in adults, and it can be divided into physiological and pathological types.

[0075] The term "atrial flutter" is a rapid and regular atrial arrhythmia, usually caused by atrial enlargement. The typical electrocardiographic feature of atrial flutter is the appearance of sawtooth-shaped flutter waves (F waves), with an atrial rate typically exceeding 250 beats per minute, and sometimes reaching up to 320 beats per minute. Because the conduction ratio of the atrioventricular node is usually 2:1, the ventricular rate is generally between 120 and 160 beats per minute, with a most typical ventricular rate of 150 beats per minute.

[0076] The term "atrioventricular block" generally refers to an abnormality in the conduction of electrical impulses between the atria and ventricles during the conduction of cardiac electrical impulses, which can lead to arrhythmias and prevent the heart from contracting and pumping blood normally.

[0077] The term "sinoatrial block" generally refers to a condition caused by lesions in the tissues surrounding the sinoatrial node, which prolongs the time it takes for the excitation from the sinoatrial node to reach the atrium or prevents it from reaching the atrium, leading to atrial and ventricular arrest.

[0078] In a fifth aspect, the present invention provides a method for preparing crystal form B of the hydrochloride salt of the compound described in the first aspect of the present invention, comprising the following steps:

[0079] The compound hydrochloride salt is added to a mixed solvent comprising a first solvent, a second solvent, and a third solvent, dissolved at high temperature, then cooled to crystallize, and optionally dried to obtain the crystal form B.

[0080] As used in this invention, the term "high-temperature dissolution" in the art refers to heating a solvent containing the product to be purified until it is dissolved and clear. Specifically, the high temperature is generally above room temperature; preferably above 30°C, more preferably above 40°C; and below the boiling point of the mixed solvent. Optionally, high-temperature dissolution may include stirring, shaking, or other operations. The term "cooling crystallization" in the art refers to the step of cooling the clear solution of the dissolved sample to precipitate a solid. Specifically, the cooling temperature is in the range of -10°C to 30°C, preferably in the range of -5°C to 20°C, and more preferably in the range of 0°C to 15°C.

[0081] Specifically, the first solvent is an organic solvent, preferably one or more of C1-C6 alcohols, acetone, and acetonitrile.

[0082] Specifically, the first solvent is an organic solvent, preferably one or more of C1-C4 alcohols, acetone, and acetonitrile.

[0083] Specifically, the second solvent is different from the first solvent; the second solvent is an organic solvent, preferably one or more of C1-C6 alcohols, acetone and acetonitrile.

[0084] Specifically, the third solvent includes water. Purified water is preferred.

[0085] Specifically, the volume ratio of the first solvent: second solvent: third solvent ranges from (1-10):(1-30):(1-10). The volume ratio of the first solvent, second solvent, and third solvent can be any value selected from the numerical range described above. For example, if the volume ratio of the first solvent, second solvent, and third solvent is (1-10):(1-30):(1-10), then the volume ratio of the three solvents can be any value from 1-10 for the first solvent (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10) and the volume ratio of the second solvent... The ratio formed by any value in -30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) and any point value in the third solvent 1-10 (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10). Specifically, the volume ratio of the first solvent, the second solvent, and the third solvent can be 1:10:1, 1:8:1, 1:7:1, 2:10:1, 2:9:1, 2:8:1, 2:7:1, 1:10:2, etc.

[0086] Specifically, the ratio of the total volume of the first solvent and the second solvent to the volume of the third solvent is in the range of 1:1 to 50:1, for example, 1:1, 5:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1. 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1; preferably in the range of 5:1 to 40:1.

[0087] Specifically, the first solvent and / or the second solvent are selected from one or more of methanol, anhydrous ethanol, propanol, isopropanol, acetonitrile, and acetone.

[0088] Specifically, the first solvent is selected from methanol and the second solvent is selected from anhydrous ethanol.

[0089] In one specific implementation, the "high-temperature dissolution" also includes the step of adding activated carbon and then filtering.

[0090] In one specific embodiment, the "cooling crystallization" further includes the step of rinsing the precipitated solids with a first solvent and / or a second solvent.

[0091] In one specific implementation, the "cooling crystallization" further includes the step of drying the precipitated solid.

[0092] Specifically, the drying process may be vacuum drying, freeze drying, forced-air drying, or double-cone drying; and / or, the drying temperature is in the range of 30°C to 80°C, preferably in the range of 40°C to 70°C, and more preferably in the range of 50°C to 60°C.

[0093] Unless otherwise stated, the various embodiments or different preferred levels of the present invention can be combined arbitrarily.

[0094] The present invention is illustrated below by way of examples, but should not be construed as limiting the scope of the invention to the following examples. All technologies implemented based on the above description of the present invention fall within the scope of the present invention. The compounds or reagents used in the following examples are commercially available or prepared by conventional methods known to those skilled in the art or by methods disclosed in the prior art; the experimental instruments used are commercially available.

[0095] Example 1: Preparation of the compound hydrochloride

[0096] (2S,3S)-5-(2-(dimethylamino)ethyl)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazazepine-4(5H)-one (CAS 42399-40-6; 30 g, 80 mmol) was heated to 90-100 °C for 1-2 h in 500 mL of acetic anhydride. Excess acetic anhydride was removed by vacuum distillation. The residue was dissolved in 2-butanone and then added to hydrochloric acid-ethanol solution to prepare 29.0 g of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine -4(5H)-keto hydrochloride solid (yield 80.5%).

[0097] Example 2 Crystal form screening

[0098] In this embodiment, crystal form screening was carried out using methods such as solvent evaporation, suspension at 5°C, suspension at 50°C, binary solvent back-dropping, and cooling crystallization.

[0099] 2.1 Solvent Evaporation Method

[0100] Approximately 15 mg of the product from Example 1 was weighed into a glass vial, and the corresponding solvent was added until just dissolved. The vial was left to stand open at room temperature until the solvent completely evaporated, yielding a solid. The obtained solid was analyzed by XRPD. The experimental results are shown in Table 1. The results indicate that all samples obtained through solvent evaporation screening were of crystal form A.

[0101] Table 1. Results of the volatilization experiment

[0102] 2.2 5℃ suspension

[0103] 30 mg of the product from Example 1 was weighed into a vial, and the appropriate solvent was added. The mixture was stirred to obtain a suspension. The system was kept at 5°C with stirring for 2-3 days. After centrifugation, the solid was separated and XRPD analysis was performed. The experimental results are shown in Table 2. The results show that all samples obtained by room temperature suspension screening were of crystal form A.

[0104] Table 2 Results of suspension experiment at 5℃

[0105] 2.3 Suspension at 50℃

[0106] 30 mg of the product from Example 1 was weighed into a glass vial, and the appropriate solvent was added. The mixture was stirred at 50 °C to obtain a suspension. After 1-2 days, the solid was separated by centrifugation, dried, and then subjected to XRPD analysis. The experimental results are shown in Table 3. The results show that all samples obtained by suspension screening at 50 °C were of crystal form A.

[0107] Table 3 Results of suspension experiment at 50℃

[0108] 2.4 Binary Solvent Back-Dipping Method

[0109] Approximately 50 mg of the product from Example 1 was weighed into a glass vial. A suitable good solvent was added, and the solution was stirred magnetically at room temperature until it dissolved just completely, yielding a clear solution. The appropriate antisolvent was then added to the vial (0.1-0.3 mL each time) until a solid appeared or the total volume of solvent reached 1.2 mL. The experimental results are shown in Table 4.

[0110] Table 4. Experimental results of antisolvent addition

[0111] 2.5 Cooling and Crystallization

[0112] Approximately 50 mg of the product from Example 1 was weighed into a vial, and the appropriate solvent was added. The system was stirred at 25°C to form a suspension. After stirring at high temperature until the solution became clear, it was cooled to crystallize. The final solid was characterized by XPRD, and the experimental results are shown in Table 5.

[0113] Table 5 Results of Cooling Crystallization Experiment

[0114] Example 3: Identification of Crystal Form

[0115] X-ray powder diffraction data of the samples were collected under ambient conditions using an Malvern Panalytical Aeris X-ray powder diffractometer. The scanning range was 3.5°–40°, the scanning step size was 0.02°, the voltage was 40 kV, and the current was 15 mA. A Cu target was used in the X-ray tube.

[0116] The differential scanning calorimeter used was a TA Instruments DSC250. 4-5 mg of sample was accurately weighed and placed in a perforated aluminum sample pan of the DSC. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 50 mL / min.

[0117] The thermogravimetric analyzer used was a TA Instruments TGA500. 4-5 mg of sample was placed in a pre-equilibrated open aluminum sample pan and automatically weighed inside the TGA furnace. The sample was heated to the final temperature at a rate of 10 °C / min, with nitrogen purging at a rate of 25 mL / min.

[0118] The XRPD diffraction peak data of crystal form A in Example 1 and the crystal form screening example are shown in Table 6. It was found that crystal form A is similar to that in the literature Crystal Data of Diltiazem Hydrochloride C 22 H 26 The crystal form described in N2O4S·HCl; Powder Diffraction, Vol. 5, No. 3, September 1990 is the same. Table 6 shows the XRPD diffraction peak data of crystal form A of the compound described in this invention, and the XRPD pattern is shown in Figure 1.

[0119] Table 6. XRPD diffraction peak data of crystal form A of the compound described in this invention.

[0120] Among the aforementioned characteristic diffraction peaks, the main characteristic diffraction peaks of crystal form A include 9.96, 10.60, 15.26, 18.12, 19.54, and 20.56.

[0121] The diffraction peak positions of crystal form B of the compound described in this invention are shown in Table 7, and the XRPD pattern is shown in Figure 2.

[0122] Table 7. XRPD diffraction peak data of crystal form B of the compound described in this invention.

[0123] Among the aforementioned characteristic diffraction peaks, the main characteristic diffraction peaks of crystal form B include 4.35, 8.53, 16.93, 19.55, and 29.29; and may also include any one or more of 20.64, 27.65, 29.73, and 38.47; the main characteristic peaks may include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, and 38.47; and may also include 4. 35, 8.53, 16.93, 19.55, 20.64, 27.65, 29.29, 29.73, 38.47; may also include any one or more of 10.74, 21.81, 23.32; may still include any one or more of 12.72, 15.36, 18.22, 21.16, 25.42, 26.04, 27.30, 32.88.

[0124] Conclusion: Compared with crystal form A, crystal form B of the present invention has significantly different characteristic diffraction peaks, and it can be determined that crystal form B is a crystal form different from crystal form A.

[0125] Furthermore, the DSC and TGA spectra of crystal form B of the compound described in this invention are shown in Figure 3. The DSC shows that the phase transition initiation temperature of the sample is 213.92℃, and the TGA results show that the weight loss is 0.86% before 213.92℃. The sample continues to lose weight during heating, and there is an endothermic peak at 216.27℃.

[0126] Example 4: Scale-up preparation and stability test

[0127] Based on the above crystal form screening experiments, crystal form A and crystal form B were prepared at the laboratory level. The preparation process is as follows.

[0128] Example 4-1 Scaled-up preparation of crystal form A

[0129] 3000 mg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide prepared in Example 1 was used. -4(5H)-keto hydrochloride was added to a mixed solvent of methanol and acetone (9 ml acetone / 3 ml methanol), heated and stirred until completely dissolved, cooled and precipitated as a solid. After drying, 2815 mg of white solid was obtained, which is crystal form A.

[0130] Example 4-2 Scale-up Preparation of Crystal Form B

[0131] 3000 mg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide prepared in Example 1 was used. -4(5H)-keto hydrochloride was added to a mixed solvent of methanol, anhydrous ethanol and water (2 ml methanol / 7 ml anhydrous ethanol / 1 ml water), heated and stirred until completely dissolved, cooled and precipitated as a solid, and dried to obtain 2820 mg of white solid, which is crystal form B.

[0132] The hygroscopicity and stability of the crystal forms A and B prepared above were tested, and the results are shown in Table 8.

[0133] Hygroscopicity test method:

[0134] 1. Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a suitable 25℃±1℃ constant temperature desiccator (with ammonium chloride or ammonium sulfate saturated solution at the bottom) or artificial climate chamber (set temperature 25℃±1℃, relative humidity 80%±2%) one day before the test, and accurately weigh it (m1).

[0135] 2. Take an appropriate amount of the test sample and spread it evenly in the weighing bottle mentioned above. The thickness of the test sample is generally about 1 mm. Accurately weigh the sample (m2).

[0136] 3. Leave the weighing bottle open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0137] 4. Close the weighing bottle cap and accurately weigh the contents (m3).

[0138] Weight gain percentage = (m3-m2) / (m2-m1)×100%

[0139] 5. Description of hygroscopic characteristics and definition of hygroscopic weight gain

[0140] Deliquescence: The process of absorbing sufficient water to form a liquid.

[0141] Extremely hygroscopic: the weight gain due to moisture absorption is not less than 15%.

[0142] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0143] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0144] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0145] The stability of the crystal forms A and B prepared by the above scale-up was tested by the following methods: stability studies were conducted under high temperature (60℃), high humidity (25℃ / 92.5% RH), light irradiation (25℃ / 4500Lux), and accelerated conditions (40℃ / 75% RH), respectively. Samples were taken at 0 days and 30 days to characterize XRPD, total impurity content, and optical rotation.

[0146] Total impurity content analysis method:

[0147] The determination was performed according to the high performance liquid chromatography method in General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0148] The chromatographic conditions are as follows:

[0149] High Performance Liquid Chromatography (HPLC): Dionex: UltiMate 3000;

[0150] Chromatographic column: XDB-C18 column, 4.6mm × 150mm;

[0151] Mobile phase: acetate buffer (1.16 g of d-camphorsulfonic acid was dissolved in 0.1 mol / L sodium acetate solution and diluted to 1000 ml, and the pH was adjusted to 6.2 with 0.1 mol / L sodium hydroxide solution) - acetonitrile - methanol (50:25:25);

[0152] Flow rate: 1.0 mL / min;

[0153] Detection wavelength: 240nm;

[0154] Column temperature: 25℃;

[0155] Injection volume: 20 μL;

[0156] System suitability solution: Take diltiazem hydrochloride Dissolve and dilute an appropriate amount of sodium hydroxide solution in ethanol to prepare a solution containing approximately 0.1 mg per ml. Take 5 ml of the solution, add 2 drops of 0.1 mol / L sodium hydroxide solution, shake thoroughly for 1 minute, add 2 drops of 0.1 mol / L hydrochloric acid solution, and shake well.

[0157] Test solution: Take samples under different conditions, dissolve and dilute them with the mobile phase to prepare a solution containing approximately 1 mg per 1 ml.

[0158] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to prepare a solution containing approximately 5 μg per ml.

[0159] Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms up to twice the retention time of the main component peak.

[0160] Optical rotation test method:

[0161] Accurately weigh 0.2g of the sample under different conditions, dissolve it in water and dilute it quantitatively (20mL) to prepare a solution containing approximately 10mg of the sample per 1ml. The optical rotation was determined according to the General Chapter 0621 of the 2020 edition of the Chinese Pharmacopoeia.

[0162] Table 8 Results of Hygroscopicity and Stability Studies

[0163] Conclusion: The test results show that crystal form A has an optical rotation of 115.0° on day 0, is slightly hygroscopic, and remains stable for 30 days under high temperature, high humidity, light, and accelerated conditions without undergoing a crystal form transformation. However, after 30 days of light exposure, crystal form A exhibits surface yellowing, increased impurity content, and unstable optical rotation, ranging from 97.6° to 115.0°. Long-term storage requires low-temperature conditions (2-10°C) in brown bottles. Crystal form B has an optical rotation of 117.8° on day 0, is almost non-hygroscopic, and remains stable for 30 days under high temperature, high humidity, light, and accelerated conditions without undergoing a crystal form transformation. Furthermore, crystal form B is stable under high temperature and light conditions, with stable impurities, and its optical rotation remains between 115.1° and 117.8°, demonstrating superior stability.

[0164] Diltiazem hydrochloride with therapeutic activity The optical rotation is between 110° and 120°, more preferably between 115° and 120°. Crystal form A and crystal form B meet the pharmaceutical requirements, but crystal form A is slightly hygroscopic and its purity and optical rotation are unstable under light conditions. Crystal form B can meet the requirements for convenient transportation, storage and drug preparation.

[0165] Example 5: Scale-up production of the crystal form

[0166] 5.1 Scale-up production of crystal form A

[0167] Add 4 kg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide, prepared according to Example 1, to a 30L decolorization reactor. -4(5H)-keto hydrochloride, 2L methanol, and 6L acetone were dissolved by heating and stirring. Then, 30g of activated carbon was added to the system, stirred, and filtered while hot. After slow cooling, a solid precipitated, and a sample was taken for polarized light microscopy examination. The PLM microscope showed fine crystals. The filter cake was washed with anhydrous ethanol and dried to obtain 3.62kg of white solid, with a yield of 90.5% and a purity of 99.94%. XRPD characterization showed it as crystal form A, with the crystals exhibiting fine crystal aggregation, as shown in Figures 4-5.

[0168] 5.2 Scale-up production of crystal form B

[0169] Add 4 kg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide, prepared according to Example 1, to a 30L decolorization reactor. -4(5H)-keto hydrochloride, 1.2 L methanol, 4.2 L anhydrous ethanol, and 600 ml purified water were heated and stirred until dissolved. Then, 30 g of activated carbon was added to the system, stirred, and filtered while hot. After slow cooling, a solid precipitated, and a sample was taken for polarized light microscopy examination. The PLM microscope showed a plate-like single crystal form. The filter cake was washed with anhydrous ethanol and dried to obtain 3.76 kg of white solid, with a yield of 94.0% and a purity of 99.95%. XRPD characterization showed it as crystal form B, with plate-like crystals, as shown in Figures 6-7.

[0170] The applicant discovered through scale-up production studies that different crystal forms have a significant impact on scale-up production, especially the drying process. Drying time and efficiency are directly related to the characteristics of the crystal form (Table 9): the drying time for crystal form B (2 hours) is significantly shorter than that for crystal form A (8 hours). This is because crystal form B has a plate-like structure, allowing for uniform and rapid solvent removal in the drying equipment; while crystal form A consists of fine, fragmented crystals with a small particle size that easily agglomerates. During the drying process, these crystals readily adsorb and agglomerate into spheres (as shown in Figure 8), resulting in insufficient drying of the interior of the agglomerated spheres. This necessitates manual crushing of the agglomerated spheres before further drying.

[0171] Table 9. Scale-up Production Processes for Different Crystal Forms

[0172] In summary, the crystal form B described in this invention possesses superior optical rotation, hygroscopicity, and stability, and also offers advantages in improved processing and production. Compared to crystal form A, it dries faster, significantly impacting operating costs. Furthermore, the preparation process and crystallization reagents are readily available and inexpensive, making it suitable for industrial scale-up and commercialization. Therefore, using a pharmaceutical raw material containing crystal form B of the compound of this invention can effectively extend the shelf life of the drug and meet the pharmaceutical requirements for convenient production, processing, transportation, and storage.

[0173] Example 6 Formulation Study

[0174] 6.1 Tablet Preparation

[0175] According to the formulation composition in Table 10, active pharmaceutical ingredients of crystal form A and crystal form B were prepared using the embodiments of the present invention to prepare formulation 1 and formulation 2 respectively according to the following process. Among them, formulations 1 and 2 differ only in the crystal form of the active pharmaceutical ingredient; all other excipients and preparation processes are the same.

[0176] (1) Weigh the raw materials (crystal form A or crystal form B), polyethylene glycol 6000 (commercially available, purchased from Nanjing Well Pharmaceutical Group Co., Ltd.) and lactose (commercially available, purchased from German company Metformin), pulverize them, and sieve them to obtain fine powder of each raw material with a particle size of 0.074 mm. Then mix each raw material fine powder with hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP) for 5 min to obtain mixed powder.

[0177] (2) The mixed powder is granulated using a high-speed stirring granulator. The heating temperature of the high-speed stirring granulator is 90°C, the side blade speed is 3000 rpm, the stirring speed is 250 rpm, and the temperature of the granules is heated to 85°C. Then the granules are attracted to the fluidized bed granulator by vacuum feeding, and all the granules are blown up and cooled to 40°C by room temperature gas. After sieving, granules with a particle size of 0.8 mm are obtained.

[0178] (3) After mixing the granules with magnesium stearate (commercially available, purchased from Hunan Ercon Pharmaceutical Co., Ltd.), the granules are compressed into tablets using a high-speed rotary tablet press to obtain the tablets, with a specification of 30mg / tablet and a total quantity of 500 tablets.

[0179] Table 10 Formulations 1-2

[0180] Results: Formulation 2, prepared using crystal form B, exhibited better compressibility, with no sticking or powder adhesion during tableting, and a relatively better tablet surface finish. Compared to formulation 2, formulation 1 (crystal form A) showed relatively poor compressibility, exhibited powder adhesion, and had a worse tablet surface finish.

[0181] 6.2 Formulation 3-Formulation 7

[0182] This invention, based on crystal form B, further studies formulations containing it and examines the effects of said formulations, including research on the hardened oil and fillers. Tablets were prepared according to the formulation composition in Table 11, referring to the process described in section 6.1. Formulations 3-7 all use the crystal form B active pharmaceutical ingredient prepared in the examples of this invention, and the excipients such as polyethylene glycol 6000 and magnesium stearate in formulations 3-7 are the same as those used in the process described in section 6.1; the hardened oil used in formulation 3 is hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP), the hardened oil used in formulation 4 is hydrogenated palm oil (commercially available, purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.), and the hardened oil used in formulations 5-7 is hydrogenated castor oil (commercially available, purchased from BASF (China) Co., Ltd.). The filler used in formulation 5 is microcrystalline cellulose (commercially available, purchased from Asahi Kasei Corporation), and the filler used in formulation 6 is calcium carbonate (commercially available, purchased from SUDEEP PHARMAPVT.LTD).

[0183] Table 11 Formulation 3-7 Prescription

[0184] Formulations 3-7 all exhibit good compressibility during the tableting process, with no sticking or powder adhesion. However, formulations 5 and 6 have poor tablet gloss, and further research has revealed that the addition of microcrystalline cellulose has an adverse effect on the dissolution of the formulations. Therefore, the formulation compositions of this invention do not include microcrystalline cellulose or calcium carbonate.

[0185] Formulations 2-4 and 7 have intact, smooth surfaces and uniform color. The hardness of the formulations is tested according to the following method.

[0186] Hardness test: Randomly select 10 tablets from the preparation to be tested and use a hardness tester to test their radial breaking force. The data displayed by the tablet fracture hardness tester is the hardness of the tablet. Record the tablet hardness of each preparation and calculate the average hardness as the hardness of the preparation.

[0187] The test results are as follows:

[0188] 6.3 Formulation 8 - Formulation 13

[0189] Tablets were prepared according to the formulation composition in Table 12 and the process described in section 6.1. Formulations 8-13 all used the crystalline form B active pharmaceutical ingredient prepared in the embodiments of the present invention, and the excipients such as lactose, polyethylene glycol 6000, and magnesium stearate in formulations 8-13 were the same as those used in the process described in section 6.1; the excipient hydrogenated castor oil was the same as that in formulations 6-7.

[0190] Table 12 Preparations 8-13 Prescriptions

[0191] *Formulation 12 is available in 60mg / tablet form, and formulation 13 is available in 20mg / tablet form.

[0192] Results: Formulations 8-13 showed good compressibility during the tableting process and produced smooth tablets.

[0193] 6.4 Formulation quality assessment

[0194] Hardness test: Randomly select 10 tablets from each of the preparations to be tested, and use a hardness tester to test their radial breaking force. The data displayed by the tablet fracture hardness tester is the hardness of the tablet. Record the tablet hardness of each preparation and calculate the average hardness. Use the average hardness as the hardness of the preparation to be tested.

[0195] Tablet weight test: 20 tablets were randomly selected from each of the tested formulations, and the total weight was accurately measured. After obtaining the average tablet weight, the weight of each individual tablet was accurately measured. The weight difference of each tablet was compared with the average tablet weight, and the tablet weight difference % was calculated as follows: Tablet weight difference % = 100% * (weight of individual tablet - average tablet weight) / average tablet weight. This invention controls the tablet weight difference to be no higher than ±5%. The number of tablets exceeding the weight difference limit was recorded. If more than 2 tablets exceeded the weight difference limit, or if no more than 2 tablets exceeded the weight difference limit but one tablet exceeded the limit by more than double, they were all judged as unqualified. Results: The hardness of formulations 7-13 all met the control index requirements. The tablets in formulations 8 and 11 were either too heavy or too light, and the tablet weight was unstable. The test results are shown in Table 13.

[0196] Table 13. Results of Formulation Testing

[0197] Tablet quality and stability test

[0198] Dissolution, related substances, and accelerated stability of formulations 7 and 10 were tested.

[0199] Dissolution test: Take tablets from the formulation and test according to Method 2 of General Chapter 0931 of Part IV of the 2020 Chinese Pharmacopoeia. Use 900ml of water as the dissolution medium and rotate at 75 revolutions per minute. Take 10ml of the dissolution solution after 30 minutes and 180 minutes respectively for testing. Immediately replenish the same volume of dissolution medium at the same temperature in the operating container.

[0200] Related substances detection: According to the high performance liquid chromatography method (General Chapter 0512) in the Chinese Pharmacopoeia, the test solution contains approximately diltiazem hydrochloride per 1 ml of ethanol. 1 mg solution, filter and collect the filtrate. For the control solution, accurately measure an appropriate amount of the test solution and quantitatively dilute with ethanol to prepare a solution containing diltiazem hydrochloride per 1 ml. A 5 μg solution.

[0201] If there are impurity peaks in the chromatogram of the test solution of the test preparation, the area of ​​a single impurity peak shall not be greater than the area of ​​the main peak of the control solution (0.5%), and the sum of the areas of all impurity peaks shall not be greater than twice the area of ​​the main peak of the control solution (1.0%).

[0202] Accelerated stability testing:

[0203] Accelerated stability tests were conducted on formulations 7 and 10, focusing on appearance, related substances, dissolution, and content. The tests were performed in a stability test chamber for 1 month and 3 months, respectively, according to the Chinese Pharmacopoeia 2020 edition. Test conditions: Temperature: 40℃±2℃, Humidity: 75%±5%.

[0204] Table 14 Test data for formulations 7 and 10

[0205] The dissolution and related substance content of the formulation of this invention meet the standards, and under accelerated stability test conditions, there are no significant changes in any of the tested items, all of which meet the quality standard requirements. The formulation of this invention has excellent stability.

[0206] In summary, the crystalline form B active pharmaceutical ingredient of the present invention has superior processability, and the composition containing crystalline form B of the present invention has good compressibility, with no sticking or powder adhesion during the tableting process. Furthermore, the composition containing the crystalline form B active pharmaceutical ingredient, filler, and hydrogenated castor oil of the present invention also has excellent hardness, tablet weight, and dissolution properties, and the composition is stable.

[0207] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and purpose of the present invention should be included within the scope of protection of the present invention.

Claims

1. The compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide Crystal form B of -4(5H)-keto hydrochloride, characterized in that, Characteristic diffraction peaks in the X-ray powder diffraction pattern, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include 4.35, 8.53, 16.93, 19.55, and 29.

29.

2. The crystal form B according to claim 1, characterized in that, The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values ​​± 0.2° using Cu-Kα radiation, also include any one or more of 20.64, 27.65, 29.73, and 38.

47.

3. Crystal form B according to claim 1 or 2, characterized in that, Characteristic diffraction peaks in the X-ray powder diffraction pattern, expressed as 2θ values ​​± 0.2° using Cu-Kα radiation, include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, and 38.

47.

4. Crystal form B according to claim 1 or 2, characterized in that, The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values ​​± 0.2° using Cu-Kα radiation, also include any one or more of 10.74, 21.81, and 23.

32.

5. The crystal form B according to claim 1, characterized in that, It has an X-ray powder diffraction pattern that is essentially as shown in Figure 2.

6. A pharmaceutical raw material, characterized in that, The compound comprising any one of claims 1-5 is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide. Crystal form B of -4(5H)-keto hydrochloride.

7. A composition, characterized in that, It comprises an active ingredient and one or more physiologically acceptable / pharmaceutical excipients, said active ingredient comprising the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide according to any one of claims 1-5. Crystal form B of -4(5H)-keto hydrochloride.

8. The composition according to claim 7, characterized in that, The physiologically acceptable / pharmaceutical excipients include one or more of fillers, binders, disintegrants, lubricants, and flow aids.

9. The composition according to claim 7, characterized in that, The composition is selected from tablets, granules and capsules.

10. The composition according to claim 8, characterized in that, Physiologically acceptable / pharmaceutical excipients also include hydrogenated castor oil.

11. The composition according to claim 10, characterized in that, The composition comprises 9%-30% by weight of an active ingredient; The composition comprises 35%-85% by weight of filler; The composition comprises 5%-20% hydrogenated castor oil by weight; The composition comprises 1%-12% by weight of an adhesive; and / or The composition comprises 0%-3% by weight of lubricant.

12. The composition according to claim 10, characterized in that, The composition comprises 9%-30% by weight of an active ingredient; The composition comprises 35%-85% lactose by weight; The composition comprises 5%-20% hydrogenated castor oil by weight; The composition comprises 1%-12% by weight of polyethylene glycol 6000; and / or The composition comprises 0%-3% magnesium stearate by weight.

13. The composition according to claim 10, characterized in that, The weight ratio of the filler (binder + hydrogenated castor oil) is in the range of 3.5:1 to 4.5:

1.

14. The composition according to claim 10, characterized in that, The composition comprises: a) 30mg of compound crystal form B, 100-200mg of lactose, 15-30mg of hydrogenated castor oil, 8-15mg of polyethylene glycol 6000, and 1-4mg of magnesium stearate; or b) 60mg of compound crystal form B, 100-300mg of lactose, 15-60mg of hydrogenated castor oil, 8-30mg of polyethylene glycol 6000, and 1-8mg of magnesium stearate; or c) 90mg of compound crystal form B, 100-600mg of lactose, 15-90mg of hydrogenated castor oil, 8-45mg of polyethylene glycol 6000, and 1-12mg of magnesium stearate.

15. The composition according to claim 9, characterized in that, The composition is a capsule containing the following components: 90mg of compound crystal form B, 16-60mg of sucrose, 8-40mg of talc and / or corn starch, 1-10mg of povidone, and 3-25mg of ethyl cellulose.

16. The compound according to any one of claims 1-5, cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide The use of the crystalline form B of -4(5H)-keto hydrochloride, the active pharmaceutical ingredient of claim 6, or the composition of any one of claims 7-15 in the preparation of a medicament for treating the following diseases selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

17. A compound according to any one of claims 1-5, cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide The method for preparing crystal form B of -4(5H)-keto hydrochloride is characterized by, The process includes the following steps: adding the compound hydrochloride salt to a mixed solvent containing a first solvent, a second solvent, and a third solvent, dissolving it at high temperature, then cooling to crystallize, and optionally drying it to obtain the crystal form B; wherein the first solvent and the second solvent are organic solvents, and the third solvent includes water.

18. The preparation method according to claim 17, characterized in that, The first solvent is different from the second solvent; the first solvent is one or more of C1-C6 alcohols, acetone and acetonitrile; the second solvent is one or more of C1-C6 alcohols, acetone and acetonitrile.

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