Crystal form of compound, preparation method thereof, raw material, composition and use thereof

Abstract

The present invention relates to the pharmaceutical field, and provides a crystalline form B of a compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride, which can meet pharmaceutical requirements such as convenient production, processing, transportation, and storage. The present invention also relates to a preparation method of the crystalline form B of the compound, a raw material drug containing the same, a composition, and use thereof in preparing drugs for diseases such as angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a crystal form of a specific compound, a preparation method thereof, a raw material drug or a composition thereof and / or its use in preparing a drug for treating a disease. Background Art

[0002] Diltiazem is a calcium channel blocker that inhibits calcium ions from entering vascular smooth muscle cells and cardiomyocytes, thereby reducing myocardial oxygen consumption, dilating coronary arteries and peripheral blood vessels, lowering blood pressure, and alleviating cardiac load. Diltiazem compounds have two chiral centers and can produce four chiral isomers. The compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride, also known as diltiazem hydrochloride, is a compound with clinical uses and is widely used to treat heart disease, angina pectoris, etc. Summary of the invention

[0003] The inventors have found that the existing diltiazem hydrochloride crystals have defects such as high processing and storage costs. 22 H 26 N2O4S・HCl; PowderDiffraction, Vol. 5, No.3, September 1990. The method described in the invention can obtain the crystal form A. The inventors found that the crystal form A has the disadvantages of poor stability, poor processability, inconvenient storage and / or high storage cost.

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

[0005] According to the first aspect of the present invention, a crystalline form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride is provided, wherein the characteristic diffraction peaks of 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.

[0006] According to the second aspect of the present invention, a raw material drug is provided, which comprises the crystalline form B of the compound according to the first aspect of the present invention.

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

[0008] According to the fourth aspect of the present invention, provided is the use of Form B of the compound of the first aspect of the present invention, the API of the second aspect of the present invention, or the composition of the third aspect of the present invention in the preparation of a medicament for treating the following diseases, wherein the diseases are selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

[0009] According to a fifth aspect of the present invention, there is provided a method for preparing Form B of the hydrochloride salt of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one according to the first aspect of the present invention, comprising the following steps: adding the hydrochloride salt of the compound to a mixed solvent comprising a first solvent, a second solvent and a third solvent, dissolving the mixture at a high temperature, cooling the mixture for crystallization, and optionally drying the mixture to obtain Form B; wherein the first solvent and the second solvent are organic solvents, and the third solvent comprises water.

[0010] In the present invention, the crystalline form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride has excellent optical rotation, hygroscopicity and stability, and also has the advantages of improved processing and production; and the preparation process and crystallization reagents are easily available and inexpensive, suitable for industrial scale-up and commercialization. Therefore, the use of the raw material containing the crystalline form of the compound of the present invention can effectively extend the shelf life of the drug, and can meet the pharmaceutical requirements of production, processing, transportation and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 It is the X-ray powder diffraction pattern of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride crystal form A. Among them, the abscissa is 2θ(º) and the ordinate is intensity (count);

[0012] Figure 2 It is the X-ray powder diffraction pattern of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride crystal form B. Wherein, the abscissa is 2θ(°) and the ordinate is intensity (count);

[0013] Figure 3The differential scanning calorimetry (DSC) spectrum and thermogravimetric analysis (TGA) spectrum of Form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride;

[0014] Figure 4 is a property diagram of the crystal form A of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride;

[0015] Figure 5 It is a polarizing microscope PLM spectrum of the crystal form A of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride;

[0016] Figure 6 is a property diagram of Form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride;

[0017] Figure 7 It is a polarizing microscope PLM spectrum of the crystal form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride;

[0018] Figure 8 This is a picture of the drying process of Form A of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride. DETAILED DESCRIPTION

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

[0020] As used herein, the term "polymorph" refers to crystalline forms of the same molecule and is a result of the arrangement or conformation of the molecules in the crystal lattice; or, refers to a crystal structure in which molecules can crystallize in different crystal packing arrangements and all have the same elemental composition.

[0021] In the first aspect of the present invention, a crystalline form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride is provided, and the characteristic diffraction peaks of 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.

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

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

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

[0025] Specifically, the crystal form B uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 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 crystal form B uses Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​±0.2° 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 a specific embodiment, the crystalline form B uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ values ​​is substantially as follows Figure 2 shown.

[0028] In the present invention, "having substantially Figure 2The term "substantially" used in the "X-ray powder diffraction pattern shown" means that the exact position of the peak in the accompanying drawing should not be interpreted as an absolute value. Because it is known to those skilled in the art that the 2θ value of the X-ray powder diffraction pattern may produce errors due to different measurement conditions (such as the equipment and instruments used) and different samples (such as samples from different batches), the measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less, and generally, a difference of ±0.2° of a given value is considered appropriate. It should also be understood that the relative intensity of the peak may fluctuate with experimental conditions and sample preparation such as the preferred orientation of particles in the sample. The use of automatic or fixed divergence slits will also affect the calculation of relative intensities. The intensities shown in the XRD curves included here are only exemplary and cannot be used as absolute comparisons, and any crystalline form having a powder diffraction pattern that is substantially the same as those disclosed herein is within the scope of protection of the present invention.

[0029] In the second aspect of the present invention, a bulk drug is provided, which comprises the crystalline form B of the compound of the first aspect of the present invention.

[0030] As used in the present invention, the term "raw material drug" refers to the raw material drug used to produce various preparations. It is the effective ingredient in the preparation, also known as the active ingredient, which is prepared by chemical synthesis or biotechnology and other methods for use as a medicine in the form of powder, crystals, etc., but cannot be directly taken by the subject.

[0031] In a specific embodiment, the weight percentage of Form B of the compound of the present invention in the bulk drug is 90.0-100%, 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%. In addition to Form B of the compound of the first aspect of the present invention, the bulk drug may also include amorphous compounds, other crystal forms, water, or other substances such as impurities or solvent residues within the range allowed by the quality standard. Specifically, Form B of the compound of the present invention is as defined above.

[0032] In the third aspect of the present invention, a composition is provided, which comprises the crystalline form B of the compound according to the first aspect of the present invention and one or more physiologically acceptable / pharmaceutically acceptable excipients.

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

[0034] In a specific embodiment, examples of suitable excipients for the composition or solid dosage form according to the present invention include fillers, disintegrants, binders, lubricants, glidants, etc. or mixtures thereof.

[0035] In a 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, and the modified starch may include potato starch, corn starch, and rice starch.

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

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

[0038] In a specific embodiment, the binder of the present invention includes sodium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, pectin, polyethylene glycol 6000, povidone K30, pregelatinized starch and the like.

[0039] In a specific embodiment, the lubricant of the present invention includes stearic acid, magnesium stearate, calcium stearate or other metal stearate, talc, wax and glyceride, light mineral oil, glyceryl behenate, colloidal silicon dioxide and the like.

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

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

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

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

[0044] In a 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 of 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%, or a range between any two values. The weight percentage of the lubricant of the present invention in the composition is preferably 0-3%.

[0045] In a specific embodiment, the weight ratio of the filler of the present invention: (binder + hydrogenated castor oil) ranges from 3.5:1 to 4.5:1. For example, the weight ratio of the filler of the present invention: (binder + hydrogenated castor oil) ranges from 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, and 4.5:1 is selected from any one value or a range value between any two values.

[0046] In a specific embodiment, the composition,

[0047] The active ingredient comprises 9% to 30% by weight;

[0048] The invention comprises a filler in an amount of 35% to 85% by weight;

[0049] The invention comprises 5% to 20% by weight of hydrogenated castor oil;

[0050] comprising 1% to 12% by weight of an adhesive; and / or

[0051] The lubricant is included in an amount of 0% to 3% by weight.

[0052] In a specific embodiment, the composition,

[0053] The active ingredient comprises 9% to 30% by weight;

[0054] The invention comprises 35% to 85% by weight of lactose;

[0055] The invention comprises 5% to 20% by weight of hydrogenated castor oil;

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

[0057] The invention comprises 0% to 3% by weight of magnesium stearate.

[0058] In a specific embodiment, 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 Form B of the compound per dose.

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

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

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

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

[0063] In a specific embodiment, the composition is a capsule comprising the following components: 90 mg of the compound crystalline 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 a specific embodiment, the composition of the present invention is a stable pharmaceutical composition.

[0065] As used herein, the term "physiologically acceptable / pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered active ingredient.

[0066] The physiologically acceptable / pharmaceutically acceptable excipients mixed with the crystalline Form B of the compound of the present invention to form a pharmaceutical composition may depend on the intended method of administering the pharmaceutical composition.

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

[0068] In the fourth aspect of the present invention, provided is the use of Form B of the compound of the first aspect of the present invention, the API of the second aspect of the present invention, or the composition of the third aspect of the present invention in the preparation of a medicament for treating the following diseases, wherein the diseases are selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

[0069] The term "angina pectoris" generally refers to a clinical syndrome caused by acute and temporary myocardial ischemia and hypoxia due to insufficient blood supply to the coronary arteries caused by coronary atherosclerosis and stenosis, with paroxysmal chest pain or chest discomfort as the main manifestation. It is usually a sense of compression, tightening, and burning, rather than sharp stabbing pain. It is common behind the sternum and can radiate to the precordial area, left shoulder, left arm, etc. It includes stable angina pectoris, unstable angina pectoris, and variant angina pectoris.

[0070] The term "hypertension" generally refers to systolic blood pressure ≥140mmHg and / or diastolic blood pressure ≥90mmHg when blood pressure is measured three times on different days without taking antihypertensive drugs. Systolic blood pressure ≥140mmHg and diastolic blood pressure <90mmHg are isolated systolic hypertension. Patients with a history of hypertension who are currently taking antihypertensive drugs should still be diagnosed with hypertension even if their blood pressure is lower than 140 / 90mmHg. This includes mild to moderate hypertension, especially hypertension with angina pectoris. Injectable preparations are also used for emergency treatment of hypertensive emergencies and abnormal hypertension during surgery.

[0071] The term "coronary heart disease," also known as coronary artery disease (CAD), generally refers to heart disease caused by reduced blood flow in the coronary arteries, most commonly caused by atherosclerosis. When the heart does not receive enough oxygen-rich blood, symptoms such as angina and shortness of breath may occur, while a complete blockage of blood flow may cause a heart attack. Clinical manifestations of CAD include silent myocardial ischemia, angina, acute coronary syndrome, and sudden cardiac death.

[0072] The term "arrhythmia" generally refers to abnormal frequency and / or rhythm of heart beats caused by disturbances in the origin and / or conduction of cardiac activity, including supraventricular arrhythmia, tachycardia, atrial flutter, atrioventricular block, sinoatrial block, etc.

[0073] The term "supraventricular arrhythmias" refers to a group of arrhythmias that originate in the upper part of the heart, in the atria or near the atrioventricular node. Common supraventricular rhythms include sinus tachycardia, sinus node reentrant tachycardia, and atrial premature beats.

[0074] The term "tachycardia" generally refers to a heart rate of more than 100 beats per minute in an adult, which can be divided into physiological and pathological types.

[0075] The term "atrial flutter" refers to a rapid and regular atrial arrhythmia, usually due to atrial enlargement. The typical electrocardiographic feature of atrial flutter is the presence of sawtooth flutter waves (F waves), and the atrial rate is usually over 250 beats / minute, up to 320 beats / minute. Because the conduction ratio of the atrioventricular node is usually 2:1, the ventricular rate is generally between 120-160 beats / minute, with the most typical ventricular rate being 150 beats / minute.

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

[0077] The term "sinoatrial block" generally refers to the fact that due to lesions in the tissues surrounding the sinoatrial node, the time it takes for the excitation from the sinoatrial node to reach the atrium is prolonged or the excitation cannot be transmitted, leading to atrial and ventricular arrest.

[0078] In the fifth aspect of the present invention, there is provided a method for preparing the crystalline form B of the hydrochloride salt of the compound according to the first aspect of the present invention, comprising the following steps:

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

[0080] As used in the present invention, the term "high temperature dissolution" in the art refers to heating the solvent containing the product to be purified to a dissolved clear state. Specifically, the high temperature is generally higher than room temperature; preferably higher than 30°C, more preferably higher than 40°C; lower than the boiling point of the mixed solvent. Optionally, high temperature dissolution may include operations such as stirring and shaking. The term "cooling crystallization" in the art refers to the step of cooling the clear solution containing the sample to be purified 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 alcohol, acetone and acetonitrile.

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

[0084] Specifically, the third solvent includes water, preferably purified water.

[0085] Specifically, the volume ratio of the first solvent: the second solvent: the third solvent is in the range of (1-10): (1-30): (1-10). The volume ratio of the first solvent, the second solvent, and the third solvent can be a ratio formed by any point value selected from the above numerical range. For example, the volume ratio of the first solvent, the second solvent, and the third solvent is (1-10): (1-30): (1-10), and the volume ratio of the three solvents can be any value in the range of 1-10 (for example, 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) of the first solvent to the second solvent. The ratio of any value in the range of 1 to 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) to any value in the range of 1 to 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, and the like.

[0086] 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, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1 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 is 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 a specific embodiment, the "high temperature dissolution" further comprises the step of filtering after adding activated carbon.

[0090] In a specific embodiment, the "cooling crystallization" further comprises the step of eluting the precipitated solid using the first solvent and / or the second solvent.

[0091] In a specific embodiment, the "cooling crystallization" further comprises the step of drying the precipitated solid.

[0092] Specifically, the drying 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-70°C, more preferably in the range of 50°C-60°C.

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

[0094] The present invention is illustrated below by way of examples, but this should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. The compounds or reagents used in the following examples can be purchased from commercial sources, or prepared by conventional methods known to those skilled in the art or methods disclosed in the prior art; the experimental instruments used can be purchased from commercial sources.

[0095] Example 1 Preparation of Compound Hydrochloride

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

[0097] Example 2 Crystal form screening

[0098] In this embodiment, the crystal form screening was carried out by using solvent evaporation method, 5°C suspension, 50°C suspension, binary solvent back-drip method, cooling crystallization and the like.

[0099] 2.1 Solvent evaporation method

[0100] Weigh about 15 mg of the product of Example 1 in a glass vial, add the corresponding solvent until it is just dissolved, and leave it open at room temperature until the solvent is completely evaporated to obtain a solid. XRPD detection is performed on the obtained solid. The experimental results are shown in Table 1. The results show that all the crystals obtained by solvent evaporation screening are Form A.

[0101] Table 1 Volatilization test results

[0102]

[0103] 2.2 5℃ suspension

[0104] 30 mg of the product of Example 1 was weighed into a vial, and the corresponding solvent was added and stirred to obtain a suspension. The system was placed at 5°C for incubation and stirring, and the solid was separated by centrifugation after 2-3 days and subjected to XRPD detection. The experimental results are shown in Table 2. The results show that all the crystals obtained by room temperature suspension screening are Form A.

[0105] Table 2 Results of 5℃ suspension experiment

[0106]

[0107] 2.3 50℃ suspension

[0108] 30 mg of the product of Example 1 was weighed into a glass vial, and the corresponding solvent was added, and the suspension was obtained by stirring at 50° C. After 1-2 days, the solid was separated by centrifugation, and XRPD detection was performed after drying. The experimental results are shown in Table 3. The results show that all the crystals obtained by suspension screening at 50° C. are Form A.

[0109] Table 3 Results of 50℃ suspension test

[0110]

[0111] 2.4 Binary solvent back titration method

[0112] About 50 mg of the product of Example 1 was weighed into a glass vial, and the corresponding good solvent was added to the glass vial until it was just dissolved by magnetic stirring at room temperature to obtain a clear solution. The corresponding anti-solvent (0.1-0.3 mL / each time) was added to the glass vial until solid appeared or the total volume of the solvent reached 1.2 mL. The experimental results are shown in Table 4.

[0113] Table 4 Antisolvent addition experimental results

[0114]

[0115] 2.5 Cooling crystallization

[0116] About 50 mg of the product of Example 1 was weighed into a vial, and the corresponding solvent was added. The system was stirred at 25°C to form a suspension, stirred at high temperature until the solution was clear, and then cooled for crystallization. The solid finally obtained was characterized by XPRD, and the experimental results are shown in Table 5.

[0117] Table 5 Cooling crystallization test results

[0118]

[0119] Example 3 Identification of Crystal Form

[0120] The X-ray powder diffraction data of the sample were collected under ambient conditions using an Aeris X-ray powder diffractometer from Malvern Panalytical, with a scanning range of 3.5°-40°, a scanning step of 0.02°, a voltage of 40KV, and a current of 15mA. The X-ray tube used a Cu target with Kα1 = 1.5406 Å.

[0121] The model of the differential scanning calorimeter was TA Instruments DSC250. 4-5 mg of sample was accurately weighed and placed in a perforated DSC aluminum sample pan and heated to the final temperature at a rate of 10 °C / min, with a nitrogen purge rate of 50 mL / min in the furnace.

[0122] The thermogravimetric analyzer model is TA Instruments TGA500. 4-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10°C / min, and the nitrogen purge rate was 25 mL / min.

[0123] The XRPD diffraction peak data of Form A in Example 1 and the crystal screening example are shown in Table 6. It is found that Form A is consistent with the literature Crystal Data of Diltiazem Hydrochloride C 22 H 26 N2O4S・HCl; PowderDiffraction, Vol. 5, No.3, September 1990 is the same crystal form. Table 6 XRPD diffraction peak data of crystal form A of the compound of the present invention, XRPD spectrum is as follows Figure 1 shown.

[0124] Table 6 XRPD diffraction peak data of Form A of the compound of the present invention

[0125]

[0126] Among the above characteristic diffraction peaks, the main characteristic diffraction peaks of Form A include 9.96, 10.60, 15.26, 18.12, 19.54, and 20.56.

[0127] The diffraction peak positions of the crystalline form B of the compound of the present invention are shown in Table 7, and the XRPD spectrum is shown in Figure 2 shown.

[0128] Table 7 XRPD diffraction peak data of Form B of the compound of the present invention

[0129]

[0130] Among the above characteristic diffraction peaks, the main characteristic diffraction peaks of Form B include 4.35, 8.53, 16.93, 19.55, 29.29; and may also include any one or more of 20.64, 27.65, 29.73, 38.47; the main characteristic peaks may include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, 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; still may also include any one or more of 12.72, 15.36, 18.22, 21.16, 25.42, 26.04, 27.30, 32.88.

[0131] Conclusion: Compared with crystal form A, the crystal form B of the present invention has obviously different characteristic diffraction peaks, which can be determined that crystal form B is a crystal form different from crystal form A.

[0132] In addition, the DSC spectrum and TGA spectrum of the crystalline form B of the compound of the present invention are as follows: Figure 3 DSC shows that the starting point temperature of the phase change of the sample is 213.92 ℃, and TGA results show that the weight loss is 0.86% before 213.92 ℃. The sample continues to lose weight during the heating process and has an endothermic peak at a peak value of 216.27 ℃.

[0133] Example 4 Scale-up preparation and stability test

[0134] According to the above crystal screening experiments, the crystal forms A and B were prepared on a laboratory scale, and the preparation process is as follows.

[0135] Example 4-1 Scaled-up preparation of Form A

[0136] A mixed solvent of methanol and acetone (9 ml acetone / 3 ml methanol) was added to 3000 mg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride prepared in Example 1, and the mixture was heated and stirred to completely dissolve. After cooling, a solid was precipitated, and after drying, 2815 mg of a white solid was obtained, which was Form A.

[0137] Example 4-2 Scale-up preparation of Form B

[0138] A mixed solvent of methanol, anhydrous ethanol and water (2 ml methanol / 7 ml anhydrous ethanol / 1 ml water) was added to 3000 mg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride prepared in Example 1, and heated and stirred to completely dissolve it. After cooling, a solid was precipitated, and after drying, 2820 mg of a white solid was obtained, which was Form B.

[0139] The above-mentioned enlarged prepared crystal form A and crystal form B were subjected to hygroscopicity test and stability test, and the results are shown in Table 8.

[0140] Moisture absorption test method:

[0141] 1. Take a dry stoppered glass weighing bottle (outer diameter 50mm, height 15mm), place it in a suitable 25℃±1℃ constant temperature dryer (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or artificial climate box (set temperature at 25℃±1℃, relative humidity at 80%±2%) one day before the test, and accurately weigh the weight (m1).

[0142] 2. Take an appropriate amount of the test sample and spread it evenly in the above-mentioned weighing bottle. The thickness of the test sample is generally about 1mm. Accurately weigh the weight (m2).

[0143] 3. Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0144] 4. Close the lid of the weighing bottle and weigh the weight accurately (m3).

[0145] Weight gain percentage = (m3-m2) / (m2-m1) × 100%

[0146] 5. Description of hygroscopic characteristics and definition of hygroscopic weight gain

[0147] Deliquescent: Absorbs sufficient water to form a liquid.

[0148] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%.

[0149] Hygroscopic: Weight gain due to moisture absorption is less than 15% but not less than 2%.

[0150] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0151] No or almost no hygroscopicity: weight gain due to moisture absorption is less than 0.2%.

[0152] The stability test method for the above-mentioned scaled-up prepared Form A and Form B was carried out: stability studies were conducted under high temperature (60 ºC), high humidity (25 ºC / 92.5% RH), light (25 ºC / 4500 Lux), and accelerated (40 ºC / 75% RH) conditions, and samples were taken at 0 days and 30 days for characterization of XRPD, total impurity content and optical rotation.

[0153] Total impurity content analysis method:

[0154] The determination was carried out according to the high performance liquid chromatography method in General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0155] The chromatographic conditions were as follows:

[0156] High performance liquid chromatography: Dionex: UltiMate3000;

[0157] Chromatographic column: XDB-C18 column, 4.6mm×150mm;

[0158] Mobile phase: acetate buffer (take d-camphorsulfonic acid 1.16g, dissolve it with 0.1mol / L sodium acetate solution and dilute it to 1000ml, and adjust the pH value to 6.2 with 0.1mol / L sodium hydroxide solution)-acetonitrile-methanol (50:25:25);

[0159] Flow rate: 1.0 mL / min;

[0160] Detection wavelength: 240nm;

[0161] Column temperature: 25°C;

[0162] Injection volume: 20 μL;

[0163] System suitability solution: Take an appropriate amount of diltiazem hydrochloride, dissolve it in ethanol and dilute it to make a solution containing about 0.1 mg per 1 ml. Take 5 ml, 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.

[0164] Test solution Take samples under different conditions, add mobile phase to dissolve and dilute to make a solution containing about 1 mg per 1 ml.

[0165] For the control solution, accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to make a solution containing approximately 5 μg per 1 ml.

[0166] Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram until twice the retention time of the main component peak.

[0167] Optical rotation test method:

[0168] Take 0.2 g of the sample under different conditions, weigh it accurately, dissolve it in water and dilute it quantitatively (20 mL) to make a solution containing approximately 10 mg of the sample per 1 ml, and determine it according to the optical rotation method 0621 of the general rules of Part IV of the 2020 edition of the "Chinese Pharmacopoeia".

[0169] Table 8 Hygroscopicity and stability study results

[0170]

[0171] Conclusion: The test results show that the optical rotation of Form A on day 0 is 115.0°, which is slightly hygroscopic. It is stable for 30 days under high temperature, high humidity, light and accelerated conditions, and no crystal transformation occurs. However, after 30 days of light exposure, the surface of Form A turns yellow, the impurity content increases, and the optical rotation is unstable, ranging from 97.6° to 115.0°. For long-term storage, brown bottles must be stored at low temperatures (2-10°C). The optical rotation of Form B on day 0 is 117.8°, which is almost non-hygroscopic. It is stable for 30 days under high temperature, high humidity, light and accelerated conditions, and no crystal transformation occurs. In addition, Form B is stable in properties and impurities under high temperature and light conditions, and the optical rotation is maintained between 115.1° and 117.8°, which has better stability.

[0172] The optical rotation of therapeutically active diltiazem hydrochloride is between 110° and 120°, more preferably between 115° and 120°. Form A and Form B meet pharmaceutical requirements, but Form A is slightly hygroscopic and its purity and optical rotation are unstable under light conditions. Form B can meet the requirements of convenient transportation, storage and drug preparation.

[0173] Example 5 Scale-up production of crystal form

[0174] 5.1 Scale-up of Form A

[0175] To a 30L decolorizing kettle, add 4kg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride prepared on an enlarged scale according to Example 1, 2L of methanol, and 6L of acetone, and heat and stir to dissolve. Then add 30g of activated carbon to the system, filter while hot after stirring, slowly cool down to precipitate solid, take samples and examine under a polarized light microscope. PLM microscopy shows finely divided crystals, the filter cake is rinsed with anhydrous ethanol, and after a drying process, 3.62kg of white solid can be obtained, with a yield of 90.5% and a purity of 99.94%; XRPD characterization is form A, and the crystals appear as agglomerates of finely divided crystals, such as Figure 4-Figure 5 shown.

[0176] 5.2 Scale-up of Form B

[0177] To a 30L decolorizing kettle, add 4kg of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride prepared on an enlarged scale according to Example 1, 1.2L of methanol, 4.2L of anhydrous ethanol, and 600ml of purified water, and heat and stir to dissolve. Then add 30g of activated carbon to the system, filter while hot after stirring, slowly cool down to precipitate solid, take a sample and examine under a polarized light microscope. PLM microscopy shows a single flaky crystal. The filter cake is rinsed with anhydrous ethanol and dried to obtain 3.76kg of a white solid with a yield of 94.0% and a purity of 99.95%. XRPD characterization shows that it is Form B, and the crystals appear flaky, such as Figure 6-Figure 7 shown.

[0178] The applicant found through scale-up production research that different crystal forms have a significant impact on scale-up production, especially the drying process. The drying time and efficiency are directly related to the habits of the crystal form (Table 9): the drying time of crystal form B (2h) is significantly lower than that of crystal form A (8h). This is because crystal form B has a flaky form and can remove the solvent evenly and quickly in the drying equipment; while crystal form A is finely divided crystals with a small particle size and is easy to agglomerate. It is easy to adsorb and agglomerate into balls during the drying process (such as Figure 8 As shown in the figure, the inside of the agglomerated spheres cannot be fully dried, and the agglomerated spheres need to be manually crushed before drying.

[0179] Table 9 Scale-up production process of different crystal forms

[0180]

[0181] In summary, the crystal form B of the present invention has better optical rotation, hygroscopicity and stability, and also has the advantages of improved processing and production. It can be dried faster than the crystal form A, which has a significant positive impact on the operating cost; and the preparation process and crystallization reagents are easy to obtain and inexpensive, suitable for industrial scale-up and commercialization. Therefore, the use of the raw material containing the crystal form B of the compound of the present invention can effectively extend the shelf life of the drug, and can meet the pharmaceutical requirements of convenient production, processing, transportation and storage.

[0182] Example 6 Preparation Study

[0183] 6.1 Tablet preparation

[0184] According to the prescription composition in Table 10, the APIs of crystalline form A and crystalline form B prepared in the embodiments of the present invention were used to prepare preparations 1 and 2 according to the following processes. Among them, preparations 1-2 differ only in the crystalline form of the API, and the other excipients and preparation processes are the same.

[0185] (1) Weigh the API (crystalline form A or crystalline form B), polyethylene glycol 6000 (commercially available, purchased from Nanjing Well Pharmaceutical Group Co., Ltd.) and lactose (commercially available, purchased from Megler GmbH & Co. KG, Germany), grind them, and sieve them to obtain fine powders of each raw material with a particle size of 0.074 mm. Then, fully mix the fine powders of each raw material with hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP) for 5 minutes to obtain a mixed drug powder;

[0186] (2) The mixed drug powder is granulated using a high-speed stirring granulator, wherein the heating temperature of the high-speed stirring granulator is 90°C, the side knife speed is 3000 rpm, and the stirring speed is 250 rpm, and the granule temperature is heated to 85°C; then the granules are sucked into a fluidized bed granulator by vacuum feeding, all the granules are blown up by normal temperature gas and cooled to 40°C, and sieved to obtain granules with a particle size of 0.8 mm;

[0187] (3) The granules were mixed evenly with magnesium stearate (commercially available from Hunan Erkang Pharmaceutical Co., Ltd.), and then tableted using a high-speed rotary tablet press to obtain the tablets, with a specification of 30 mg / tablet and a total of 500 tablets.

[0188] Table 10 Formulation 1-Formulation 2

[0189]

[0190] Results: Preparation 2 prepared using crystal form B had better compressibility, no sticking or powder adhesion during tableting, and relatively better tablet surface finish. Compared with preparation 2, preparation 1 (crystal form A) had relatively poor compressibility, powder adhesion, and worse tablet surface finish than preparation 2.

[0191] 6.2 Formulations 3 to 7

[0192] Based on the crystal form B, the present invention continues to study the preparations containing it and investigate the effects of the preparations, including the study of hardened oil and fillers. Tablets are prepared according to the prescription composition of Table 11 and the process of Section 6.1. Preparations 3-7 all use the crystal form B API prepared in the embodiment of the present invention, and the excipients such as polyethylene glycol 6000 and magnesium stearate of preparations 3-7 are the same as the excipients used in the process of Section 6.1; the hardened oil of preparation 3 uses hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP), the hardened oil of preparation 4 uses hydrogenated palm oil (commercially available, purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.), and the hardened oil of preparations 5-7 uses hydrogenated castor oil (commercially available, purchased from BASF (China) Co., Ltd.). The filler of preparation 5 uses microcrystalline cellulose (commercially available, purchased from Asahi Kasei Corporation), and the filler of preparation 6 uses calcium carbonate (commercially available, purchased from SUDEEP PHARMA PVT. LTD)

[0193] Table 11 Prescription of Preparation 3-7

[0194]

[0195] Preparations 3-7 all had good compressibility during the tableting process, without sticking or powder adhesion; however, preparations 5 and 6 had poor tablet surface glossiness, and further studies found that the addition of microcrystalline cellulose had an adverse effect on the dissolution of the preparations. Therefore, the preparation composition of the present invention does not include microcrystalline cellulose and calcium carbonate.

[0196] The slices of preparations 2-4 and 7 were complete and smooth with uniform color. The hardness of the preparations was tested according to the following method.

[0197] Hardness test: Randomly select 10 tablets from the preparation to be tested and use a hardness tester to test their radial crushing 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.

[0198] The test results are as follows:

[0199]

[0200] 6.3 Formulations 8-13

[0201] Tablets were prepared according to the prescription composition in Table 12 and the process in Section 6.1. Preparations 8-13 all used the crystalline form B API prepared in the examples of the present invention, and the excipients such as lactose, polyethylene glycol 6000, and magnesium stearate in Preparations 8-13 were the same as those used in the process in Section 6.1; the excipient hydrogenated castor oil was the same as that in Preparations 6-7.

[0202] Table 12 Prescription of Preparations 8-13

[0203]

[0204] *The strength of preparation 12 is 60 mg / tablet, and the strength of preparation 13 is 20 mg / tablet.

[0205] Results: Preparations 8-13 had good compressibility during tableting and the tablet surface was smooth.

[0206] 6.4 Preparation Quality Assessment

[0207] Hardness test: Randomly select 10 tablets from each preparation to be tested, and use a hardness tester to test their radial crushing 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. The average hardness is used as the hardness of the preparation to be tested.

[0208] Tablet weight test: 20 tablets are randomly taken from the preparations to be tested, the total weight is accurately weighed, and the average tablet weight is obtained. Then, the weight of each tablet is accurately weighed, and each tablet is compared with the average tablet weight. The tablet weight difference %=100%*(single tablet weight-average tablet weight) / average tablet weight is calculated. The present invention controls the tablet weight difference to be no higher than ±5%, and records the number of tablets exceeding the weight difference limit. If there are more than 2 tablets exceeding the weight difference limit; or if there are no more than 2 tablets exceeding the weight difference limit, but one of them exceeds the limit by 1 times, they are all judged as unqualified. Results: The hardness of preparations 7-13 all meet the control index requirements. The tablets in preparations 8 and 11 are too heavy or too light, and the tablet weight is unstable. The test results are shown in Table 13.

[0209] Table 13 Preparation test results

[0210]

[0211] Tablet quality and stability test

[0212] The dissolution, related substances and accelerated stability of Formulations 7 and 10 were tested.

[0213] Dissolution test: Take tablets from the preparation separately and measure according to the second method of 0931 of the fourth part of the "Chinese Pharmacopoeia" 2020 edition, with 900 ml of water as the dissolution medium, the rotation speed is 75 revolutions per minute, and 10 ml of the dissolution solution is taken for measurement after 30 minutes and 180 minutes respectively, and the dissolution medium of the same temperature and volume is immediately added to the operating container.

[0214] Related substance detection: According to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia, the test solution is prepared to contain about 1 mg of diltiazem hydrochloride in 1 ml of ethanol, and the filtrate is filtered. For the control solution, accurately measure an appropriate amount of the test solution and quantitatively dilute it with ethanol to prepare a solution containing 5 μg of diltiazem hydrochloride in 1 ml.

[0215] If there are impurity peaks in the chromatogram of the test solution of the limit preparation, the area of ​​a single impurity peak shall not be greater than the main peak area of ​​the control solution (0.5%), and the sum of the areas of all impurity peaks shall not be greater than twice the main peak area of ​​the control solution (1.0%).

[0216] Accelerated stability test:

[0217] Preparation 7 and Preparation 10 were subjected to accelerated stability tests, with properties, related substances, dissolution, and content as the inspection items. Accelerated tests were carried out in a stability test chamber for 1 month and 3 months, and the inspection standard was the Chinese Pharmacopoeia 2020 edition. Test conditions: temperature: 40℃±2℃, humidity: 75%±5%;

[0218] Table 14 Test data of preparation 7 and preparation 10

[0219]

[0220] The dissolution and related substance content of the preparation of the present invention all meet the standards, and under the conditions of the accelerated stability test, there are no obvious changes in each inspection item, all meet the quality standard requirements, and the preparation of the present invention has good stability.

[0221] In summary, the crystal form B API of the present invention has better processability, the composition comprising the crystal form B of the present invention has good compressibility, and there is no sticking, powder adhesion and the like during tableting. In addition, the composition comprising the crystal form B API, filler and hydrogenated castor oil of the present invention also has excellent properties such as hardness, tablet weight and dissolution, and the composition is stable in nature.

[0222] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only 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 in the scope of protection of the present invention.

Claims

1. Form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride, characterized in that: Using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​±0.2° include 4.35, 8.53, 16.93, 19.55, 20.64, 27.65, 29.29, 29.73, and 38.

47.

2. According to the crystalline form B of claim 1, characterized in that Using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ​​±0.2° also include any one or more of 10.74, 21.16, 21.81, and 23.

32.

3. According to the crystalline form B of claim 1, characterized in that It has an X-ray powder diffraction pattern substantially as shown in FIG2 .

4. A bulk drug, characterized in that: A crystalline form B of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride comprising the compound described in any one of claims 1 to 3.

5. A composition, characterized in that The invention comprises an active ingredient and one or more physiologically acceptable / pharmaceutically usable excipients, wherein the active ingredient comprises the crystalline form B of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride of any one of claims 1 to 3.

6. The composition according to claim 5, characterized in that The physiologically acceptable / pharmaceutically acceptable excipients include one or more of fillers, binders, disintegrants, lubricants, and glidants.

7. The composition according to claim 5, characterized in that The composition is selected from one of tablets, granules and capsules.

8. The composition according to claim 7, characterized in that The physiologically acceptable / pharmaceutically acceptable excipients also include hydrogenated castor oil.

9. The composition according to claim 8, characterized in that The composition comprises 9% to 30% by weight of active ingredients; The composition comprises 35% to 85% by weight of a filler; The composition comprises 5% to 20% by weight of hydrogenated castor oil; The composition comprises 1% to 12% by weight of a binder; and / or The composition comprises 0%-3% by weight of a lubricant.

10. The composition according to claim 8, characterized in that The composition comprises 9% to 30% by weight of active ingredients; The composition comprises 35% to 85% by weight of lactose; The composition comprises 5% to 20% by weight of hydrogenated castor oil; The composition comprises 1% to 12% by weight of polyethylene glycol 6000; and / or The composition comprises 0%-3% by weight of magnesium stearate.

11. The composition according to claim 8, characterized in that The weight ratio of the filler:(binder+hydrogenated castor oil) is in the range of 3.5:1-4.5:

1.

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

13. The composition according to claim 7, characterized in that The composition is a capsule comprising the following components: 90 mg of compound crystalline 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.

14. Use of the crystalline form B of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride according to any one of claims 1 to 3, the raw material according to claim 4, or the composition according to any one of claims 5 to 13 in the preparation of a medicament for treating the following diseases, wherein the diseases are selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

15. A method for preparing the crystal form B of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: adding the compound hydrochloride to a mixed solvent comprising a first solvent, a second solvent and a third solvent, dissolving at high temperature, cooling and crystallizing, and optionally drying to obtain the crystalline form B; wherein the first solvent and the second solvent are organic solvents, and the third solvent comprises water; The first solvent is different from the second solvent; the first solvent is one or more of C1-C6 alcohol, acetone and acetonitrile; the second solvent is one or more of C1-C6 alcohol, acetone and acetonitrile.

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