Crystalline forms of compounds, methods of their preparation, drug substances, compositions, and uses

Abstract

The present application relates to the field of pharmacy, and provides a crystal form B of a compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, which can meet the pharmaceutical requirements such as production, processing, transportation and storage convenience. The present application also relates to a preparation method of the crystal form B of the compound, a bulk drug and a composition containing the same, and a use of the crystal form B in preparation of drugs for treating angina, hypertension, coronary heart disease and / or arrhythmia.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmacy, in particular to a crystal form of a specific compound, a preparation method, a drug substance or a composition and / or its use in the preparation of a drug for treating diseases. BACKGROUND

[0002] Diltiazem is a calcium channel blocker, which reduces myocardial oxygen consumption, dilates coronary artery and peripheral blood vessels, reduces blood pressure, and reduces cardiac load by inhibiting calcium ions from entering vascular smooth muscle cells and myocardial cells. Diltiazem The compound has two chiral centers, which 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)-ketone hydrochloride, also known as diltiazem hydrochloride , is a compound with clinical use, which is widely used in the treatment of heart disease, angina pectoris, etc. SUMMARY

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

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

[0005] According to a first aspect of the present application, there is provided a crystal form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride, which has characteristic diffraction peaks of X-ray powder diffraction pattern expressed in 2θ value ±0.2° including 4.35, 8.53, 16.93, 19.55, 29.29 using Cu-Kα radiation.

[0006] According to a second aspect of the present application, there is provided a drug substance comprising the crystal form B of the compound according to the first aspect of the present application.

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

[0008] According to a fourth aspect of the present application, there is provided the use of the crystalline form B of the compound of the first aspect of the present application or the drug substance of the second aspect of the present application or the composition of the third aspect of the present application in the preparation of a medicament for the treatment of a disease selected from the group consisting of angina, hypertension, coronary heart disease, and / or arrhythmia.

[0009] According to a fifth aspect of the present application, there is provided a method for preparing the crystalline form B of the compound of the first aspect of the present application, comprising the following steps: dissolving the compound of the first aspect of the present application in a mixed solvent comprising a first solvent, a second solvent and a third solvent, cooling the solution, and crystallizing the compound of the first aspect of the present application.

[0010] According to a fifth aspect of the present application, there is provided a method for preparing the crystalline form B of the compound of the first aspect of the present application, comprising the following steps: dissolving the compound of the first aspect of the present application in a mixed solvent comprising a first solvent, a second solvent and a third solvent, cooling the solution, and crystallizing the compound of the first aspect of the present application. The crystalline form B of the compound of the first aspect of the present application has excellent optical rotation, hygroscopicity and stability, and also has improved processing and production advantages; and the preparation process and crystallization reagents are easy to obtain and low in price, suitable for industrial scale-up and commercialization. Therefore, using the drug substance comprising the crystalline form of the compound of the present application can effectively prolong the storage period of the drug product, and can meet the pharmaceutical requirements of production, processing, transportation and storage. BRIEF DESCRIPTION OF DRAWINGS

[0011] Figure 1 is the compound of the first aspect of the present application, and the X-ray powder diffraction pattern of the crystalline form A of the compound of the first aspect of the present application is shown in FIG. 1. In FIG. 1, the abscissa is 2θ (°), and the ordinate is intensity (counts). is the compound of the first aspect of the present application, and the X-ray powder diffraction pattern of the crystalline form A of the compound of the first aspect of the present application is shown in FIG. 1. In FIG. 1, the abscissa is 2θ (°), and the ordinate is intensity (counts).

[0012] Figure 2 is the compound of the first aspect of the present application, and the X-ray powder diffraction pattern of the crystalline form A of the compound of the first aspect of the present application is shown in FIG. 1. In FIG. 1, the abscissa is 2θ (°), and the ordinate is intensity (counts). is the compound of the first aspect of the present application, and the X-ray powder diffraction pattern of the crystalline form A of the compound of the first aspect of the present application is shown in FIG. 1. In FIG. 1, the abscissa is 2θ (°), and the ordinate is intensity (counts).​

[0013] Figure 3 It is 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 It is 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 It is 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 It is 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 It is 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 It is 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 herein, the term "polymorph" refers to crystalline forms of the same molecule and as a result of the arrangement or conformation of the molecule in the crystal lattice; or, to crystal structures in which the molecules can crystallize in different crystal packings and all have the same elemental composition.

[0021] In a first aspect of the application, there is provided a crystalline 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 -4(5H)-ketone hydrochloride having characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, comprising 4.35, 8.53, 16.93, 19.55, 29.29.

[0022] In a particular embodiment, the crystalline form B has characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, further comprising any one or more of 20.64, 27.65, 29.73, 38.47.

[0023] In a particular embodiment, the crystalline form B has characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, further comprising any one or more of 20.64, 27.65, 29.73, 38.47.

[0024] In a particular embodiment, the crystalline form B has characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, further comprising any one or more of 20.64, 27.65, 29.73, 38.47.

[0025] In a particular embodiment, the crystalline form B has characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, further comprising any one or more of 20.64, 27.65, 29.73, 38.47.

[0026] In a particular embodiment, the crystalline form B has characteristic diffraction peaks of an X-ray powder diffraction pattern, expressed in terms of 2-theta values ± 0.2° using Cu-Ka radiation, further comprising any one or more of 20.64, 27.65, 29.73, 38.47.

[0027] In one specific embodiment, the crystal form B is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ values ​​is essentially as follows: Figure 2 As shown.

[0028] In this invention, "having substantially as Figure 2 The term "substantially" used in the X-ray powder diffraction patterns shown refers to the precise location of the peaks in the figures and should not be interpreted as absolute values. This is because, as those skilled in the art will recognize, the 2θ values ​​of X-ray powder diffraction patterns can be erroneous due to different measurement conditions (such as the equipment and instruments used) and different samples (such as different batches of samples). Measurement errors in the diffraction angles of X-ray powder diffraction patterns are typically 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 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 patterns are substantially the same as those disclosed herein is within the scope 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 composition of the present application can be in the form of tablets, granules and capsules.

[0034] In one embodiment, examples of suitable excipients for the composition or solid dosage form according to the present application include fillers, disintegrants, binders, lubricants, glidants, and the like or mixtures thereof.

[0035] In one embodiment, the filler of the present application includes lactose, such as spray dried lactose, a-lactose, β-lactose, lactose monohydrate, anhydrous lactose; dextrin, starch or modified starch, which can include potato starch, corn starch, and rice starch, and the like.

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

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

[0038] In one embodiment, the binder of the present application includes sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, pectin, polyethylene glycol 6000, povidone K30, pregelatinized starch, and the like.

[0039] In one embodiment, the lubricant of the present application includes stearic acid, magnesium stearate, calcium stearate or other metal stearate, talc, waxes and glycerides, light mineral oil, glyceryl behenate, colloidal silicon dioxide, and the like.

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

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

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

[0043] In one embodiment, the weight percent of the lubricant in the composition is 0-5%, for example, the weight percent of the lubricant in the composition is selected from any one of the following values or a range between any two of the following values: 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, preferably the weight percent of the lubricant in the composition is 0-3%.

[0044] In one embodiment, the weight percent of the lubricant in the composition is 0-5%, for example, the weight percent of the lubricant in the composition is selected from any one of the following values or a range between any two of the following values: 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, preferably the weight percent of the lubricant in the composition is 0-3%.

[0045] In one embodiment, the weight ratio of the filler:(adhesive + hydrogenated castor oil) in the composition is in the range of 3.5:1-4.5:1, for example, the weight ratio of the filler:(adhesive + hydrogenated castor oil) in the composition is selected from any one of the following values or a range between any two of the following values: 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 embodiment, the composition,

[0047] includes active ingredient in an amount of 9-30% by weight;

[0048] includes filler in an amount of 35-85% by weight;

[0049] includes hydrogenated castor oil in an amount of 5-20% by weight;

[0050] includes adhesive in an amount of 1-12% by weight; and / or

[0051] includes lubricant in an amount of 0-3% by weight.

[0052] In one embodiment, the composition,

[0053] includes active ingredient in an amount of 9-30% by weight;

[0054] includes lactose in an amount of 35-85% by weight;

[0055] includes hydrogenated castor oil in an amount of 5-20% by weight;

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

[0057] including 0-3% by weight of magnesium stearate.

[0058] In one embodiment, the composition of the application 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 Form B per dose.

[0059] In one embodiment, the composition of the application is a tablet comprising:

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

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

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

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

[0064] In one embodiment, the composition of the application is a stable pharmaceutical composition.

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

[0066] The physiologically acceptable / excipient with which Compound Form B of the present application is mixed to form a pharmaceutical composition can depend on the intended method of administering the pharmaceutical composition.

[0067] For these routes of administration, Compound Form B of the present application can be administered in a suitable administration form.

[0068] In a fourth aspect of the present application, there is provided a use of crystalline form B of the compound of the first aspect of the present application, the drug substance of the second aspect of the present application, or the composition of the third aspect of the present application in the manufacture of a medicament for the treatment of a disease selected from the group consisting of angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

[0069] The term "angina pectoris" generally refers to a clinical syndrome caused by acute, temporary ischemia and hypoxia of myocardium due to insufficient blood supply of coronary artery caused by coronary atherosclerosis stenosis, with episodic chest pain or chest discomfort as the main manifestation. It is usually a feeling of compression, tightness, and burning, rather than sharp pain. It is often found in the posterior sternum and can radiate to the precordial region, left shoulder, left arm, and other parts. It includes stable angina pectoris, unstable angina pectoris, and variant angina pectoris.

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

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

[0072] The term "arrhythmia" generally refers to an abnormality in the frequency and / or rhythm of the heartbeats due to abnormalities in the origin and / or conduction of the heart activity. It includes supraventricular arrhythmia, tachycardia, atrial flutter, atrioventricular block, sinoatrial block, etc.

[0073] The term "supraventricular arrhythmia" originates from the upper part of the heart, i.e., the area near the atrium or atrioventricular node. Common supraventricular arrhythmias include sinus tachycardia, sinus nodal reentrant tachycardia, and atrial premature beats.

[0074] The term "tachycardia" generally refers to a condition where the heart rate exceeds 100 beats per minute in adults. It can be divided into physiological and pathological types.

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

[0076] The term "atrioventricular block" generally refers to an abnormality in the electrical activation conduction between the atria and the ventricles, which can lead to arrhythmias, causing the heart to not contract and pump blood normally.

[0077] The term "sinoatrial block" generally refers to a pathological change in the tissue around the sinoatrial node, which causes the activation transmitted by the sinoatrial node to the atria to be delayed or not transmitted, resulting in atrial ventricular arrest.

[0078] In a fifth aspect of the present application, a preparation method of the crystal form B of the compound hydrochloride salt of the first aspect of the present application is provided, which comprises 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 crystallized by cooling, and optionally dried to obtain the crystal form B.

[0080] As used herein, the term "high temperature dissolution" in the art refers to heating the solvent containing the product to be purified to a dissolved and clear state, specifically, the high temperature is generally higher than room temperature; preferably higher than 30°C, more preferably higher than 40°C; and lower than the boiling point of the mixed solvent. Optionally, high temperature dissolution can include stirring, shaking and the like. The term "cooling crystallization" in the art refers to the step of cooling the clear solution dissolving the sample to be purified to precipitate solids. 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 comprises water. Preferably, purified water.

[0085] In particular, 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, third solvent can be a ratio formed from any point value selected from the numerical ranges described above, for example, if the volume ratio of the first solvent, second solvent, third solvent is (1-10):(1-30):(1-10), then the volume ratio of the three solvents can be any point value from 1-10 of 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) to any point value from 1-30 of the second solvent (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 point value from 1-10 of the third 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). In particular, the volume ratio of the first solvent, second solvent, 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] In particular, 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] In particular, the first solvent and / or the second solvent is selected from one or more of methanol, absolute ethanol, propanol, isopropanol, acetonitrile, and acetone.

[0088] In particular, the first solvent is selected from methanol and the second solvent is selected from absolute ethanol.

[0089] In one particular embodiment, the "high temperature dissolution" further comprises the step of filtering after the addition of activated carbon.

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

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

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

[0093] The embodiments or different levels of preference mentioned in the present application can be combined arbitrarily, unless otherwise specified.

[0094] The present application is illustrated by the following examples, but it should not be construed that the scope of the subject matter of the present application is limited to the following examples. Any technology realized based on the above description of the present application falls within the scope of the present application. The compounds or reagents used in the following examples can be purchased commercially 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 commercially.

[0095] Preparation of the hydrochloride salt of the compound of Example 1

[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 acetic anhydride 500 ml for 1-2 h. The excess acetic anhydride was distilled off under reduced pressure, the residue was dissolved in 2-butanone and hydrochloric acid in ethanol was added to prepare 29.0 g of solid of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3- acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (yield 80.5%). -4(5H)-one hydrochloride (yield 80.5%).

[0097] Example 2: Crystal form screening

[0098] In this example, crystal form screening was performed by solvent evaporation method, 5°C suspension, 50°C suspension, binary solvent counter-dropping method, cooling crystallization and the like.

[0099] 2.1 Solvent evaporation method

[0100] About 15 mg of the product of Example 1 was weighed into a glass vial, the corresponding solvent was added to just dissolve, and the vial was left open at room temperature until the solvent was completely evaporated to obtain a solid. The obtained solid was subjected to XRPD detection. The experimental results are shown in Table 1. The results show that the crystal form A is obtained by solvent evaporation screening.

[0101] Table 1. Results of evaporation experiments

[0102] Example Solvent Phenomenon Crystal form 2-1 Ethanol Solid obtained after evaporation Crystal form A 2-2 Acetone Solid obtained after evaporation Crystal form A 2-3 Acetonitrile Solid obtained after evaporation Crystal form A 2-4 Ethanol / diethyl ether (9:1) Solid obtained after evaporation Crystal form A 2-5 Isopropanol Solid obtained after evaporation Crystal form A 2-6 Dichloromethane / methanol (1:1) Solid obtained after evaporation Crystal form A 2-7 Dichloromethane Solid obtained after evaporation Crystal form A 2-8 Ethyl acetate / methanol (3:1) Solid obtained after evaporation Crystal form A 2-9 n-Heptane / methanol (3:1) Solid obtained after evaporation Crystal form A 2-10 Isopropyl acetate (IPAc) No solid obtained after evaporation / 2-11 Methyl tert-butyl ether (MTBE) No solid obtained after evaporation /

[0103] 2.2 Suspension at 5°C

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

[0105] Table 2. Results of 5°C suspension experiments

[0106]

[0107] 2.3 Suspension at 50°C

[0108] About 30 mg of the product of Example 1 was weighed into a glass vial, the corresponding solvent was added, and a suspension was obtained by stirring at 50°C. After 1-2 days, the solid was separated by centrifugation and dried, and then subjected to XRPD detection. The experimental results are shown in Table 3. The results show that the crystal form A is obtained by 50°C suspension screening.

[0109] Table 3. Results of 50°C suspension experiments

[0110]

[0111]

[0112] 2.4 Anti-dropping method with binary solvent

[0113] About 50 mg of the product of Example 1 was weighed into a glass vial, and the corresponding good solvent was added to just dissolve after magnetic stirring at room temperature to obtain a clear solution. The corresponding anti-solvent (0.1-0.3 mL per time) was added to the above glass vial until a solid appeared or the total volume of the solvent reached 1.2 mL. The experimental results are shown in Table 4.

[0114] Table 4. Results of anti-solvent addition experiments

[0115]

[0116] 2.5 Cooling crystallization

[0117] About 50 mg of the product of Example 1 was weighed into a vial, the corresponding solvent was added, and the system was made into a suspension under stirring at 25°C. After stirring at high temperature until the solution was clear, the system was cooled to precipitate crystals. The solid obtained was characterized by XRPD, and the results are shown in Table 5.

[0118] Table 5. Results of cooling crystallization experiments

[0119]

[0120]

[0121] Identification of the crystal form of Example 3

[0122] X-ray powder diffraction data of the samples were collected under ambient conditions using a Malvern Panalytical Aeris X-ray powder diffractometer with a scan range of 3.5°-40°, a scan step of 0.02°, a voltage of 40 KV, and a current of 15 mA. The X-ray tube used a Cu target,

[0123] The differential scanning calorimeter was a TA Instruments DSC250. 4-5 mg of sample was accurately weighed into a pin-holed DSC aluminum sample pan and heated at a rate of 10°C / min to a final temperature with a nitrogen purge of 50 mL / min in the furnace.

[0124] The thermal gravimetric analyzer was a TA Instruments TGA500. 4-5 mg of sample was placed into an open aluminum sample pan that was equilibrated in the TGA furnace. The sample was heated at a rate of 10°C / min to a final temperature with a nitrogen purge of 25 mL / min.

[0125] The XRPD diffraction peak data of the crystal form A in Example 1 and the crystal form screening example were detected, as shown in Table 6, and it was found that the crystal form A was the same crystal form as the crystal form described in Crystal Data of Diltiazem Hydrochloride C 22 H 26 N2O4S·HCl; Powder Diffraction, Vol. 5, No. 3, September 1990. Figure 1

[0126] Table 6. XRPD diffraction peak data of the crystal form A of the compound according to the present application

[0127]

[0128] ​

[0129]

[0130] In the above characteristic diffraction peaks, the main characteristic diffraction peaks of the crystal form A include 9.96, 10.60, 15.26, 18.12, 19.54, 20.56.

[0131] The diffraction peak position of the crystal form B of the compound of the present application is shown in Table 7, and the XRPD spectrum is shown in Figure 2 .

[0132] Table 7 XRPD diffraction peak data of the crystal form B of the compound of the present application

[0133]

[0134]

[0135] In the above characteristic diffraction peaks, the main characteristic diffraction peaks of the crystal form B include 4.35, 8.53, 16.93, 19.55, 29.29; any one or more of 20.64, 27.65, 29.73, 38.47 can also be included; the main characteristic peaks can include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, 38.47; any one or more of 4.35, 8.53, 16.93, 19.55, 20.64, 27.65, 29.29, 29.73, 38.47 can also be included; any one or more of 10.74, 21.81, 23.32 can also be included; any one or more of 12.72, 15.36, 18.22, 21.16, 25.42, 26.04, 27.30, 32.88 can also be included.

[0136] Conclusion: Compared with the crystal form A, the crystal form B of the present application has obviously distinguished characteristic diffraction peaks, and can be determined as a crystal form different from the crystal form A.

[0137] In addition, the DSC spectrum and the TGA spectrum of the crystal form B of the compound of the present application are shown in Figure 3 . The DSC shows that the sample phase transition starting point temperature is 213.92℃, and the TGA result shows that the weight loss before 213.92℃ is 0.86%, and the sample continuously loses weight during the heating process, and has an endothermic peak at the peak value of 216.27℃.

[0138] Example 4 Scale-up preparation and stability test

[0139] According to the above crystal form screening experiment, the laboratory scale-up preparation of the crystal form A and the crystal form B is carried out, and the preparation process is as follows.

[0140] Example 4-1 Preparation of Form A on a large scale

[0141] The 3000 mg of the cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3- acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride prepared in Example 1 was dissolved in a mixed solvent of methanol and acetone (9 ml of acetone / 3 ml of methanol) by heating and stirring, and a solid was precipitated upon cooling. After drying, 2815 mg of a white solid was obtained, which was Form A.

[0142] Example 4-2 Preparation of Form B on a large scale

[0143] The 3000 mg of the cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3- acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride prepared in Example 1 was dissolved in a mixed solvent of methanol, anhydrous ethanol and water (2 ml of methanol / 7 ml of anhydrous ethanol / 1 ml of water) by heating and stirring, and a solid was precipitated upon cooling. After drying, 2820 mg of a white solid was obtained, which was Form B.

[0144] The hygroscopicity and stability of the Form A and Form B prepared on a large scale as described above were tested, and the results are shown in Table 8.

[0145] Hygroscopicity test method:

[0146] 1. A dry stoppered glass weighing bottle (50 mm in outer diameter and 15 mm in height) was placed in a suitable constant temperature and humidity chamber (lower part was filled with a saturated solution of ammonium chloride or ammonium sulfate) or an artificial climate chamber (set temperature: 25°C ± 1 °C, relative humidity: 80% ± 2%) at 1 day before the test, and the weight (m1) was accurately measured.

[0147] 2. An appropriate amount of the test sample was spread in the above weighing bottle, and the weight (m2) was accurately measured. The thickness of the test sample was generally about 1 mm.

[0148] 3. The weighing bottle was left open, and the cap was placed in the above constant temperature and humidity chamber for 24 hours.

[0149] 4. The cap of the weighing bottle was closed, and the weight (m3) was accurately measured.

[0150] Weight gain percentage = (m3 - m2) / (m2 - m1) x 100%

[0151] 5. Hygroscopicity characteristic description and definition of hygroscopicity weight gain

[0152] Deliquescence: Absorbs sufficient amount of moisture to form a liquid. ​​

[0153] Very hygroscopic: hygroscopic weight gain not less than 15%.

[0154] Hygroscopic: hygroscopic weight gain less than 15% but not less than 2%.

[0155] Slightly hygroscopic: hygroscopic weight gain less than 2% but not less than 0.2%.

[0156] Non- or almost non-hygroscopic: hygroscopic weight gain less than 0.2%.

[0157] Stability test method for the above amplified preparation of crystal form A and crystal form B: stability study under high temperature (60℃), high humidity (25℃ / 92.5% RH), light (25℃ / 4500Lux), accelerated (40℃ / 75% RH) conditions, sampling at 0 days and 30 days for XRPD, total impurity content and optical rotation characterization.

[0158] Total impurity content analysis method:

[0159] According to the method of high performance liquid chromatography in Chinese Pharmacopoeia 2020 edition volume IV general rules 0512.

[0160] The chromatographic conditions are as follows:

[0161] High performance liquid chromatograph: Dionex: UltiMate3000;

[0162] Chromatographic column: XDB-C18 column, 4.6mm x 150mm;

[0163] Mobile phase: acetate buffer (take d-camphorsulfonic acid 1.16g, dissolve and dilute to 1000ml with 0.1mol / L sodium acetate solution, adjust pH value to 6.2 with 0.1mol / L sodium hydroxide solution)-acetonitrile-methanol (50:25:25);

[0164] Flow rate: 1.0mL / min;

[0165] Detection wavelength: 240nm;

[0166] Column temperature: 25℃;

[0167] Injection volume: 20μL;

[0168] System suitability solution: take diltiazem hydrochloride Appropriate amount, dissolve and dilute with ethanol to prepare a solution containing about 0.1mg per 1ml, take 5ml, add 2 drops of 0.1mol / L sodium hydroxide solution, shake thoroughly for 1 minute, add 2 drops of 0.1mol / L hydrochloric acid solution, shake well.

[0169] The test solution was prepared by dissolving and diluting the sample under different conditions with the mobile phase to obtain a solution containing about 1 mg per 1 ml.

[0170] The control solution was prepared by accurately measuring an appropriate amount of the test solution and quantitatively diluting it with the mobile phase to obtain a solution containing about 5 μg per 1 ml.

[0171] The test solution and the control solution were accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded to 2 times the retention time of the main component peak.

[0172] Optical rotation test method:

[0173] 0.2 g of the sample under different conditions was accurately weighed, dissolved and quantitatively diluted with water (20 mL) to obtain a solution containing about 10 mg of the sample per 1 ml, which was determined according to the Optical Rotation Determination Method of Chinese Pharmacopoeia 2020 Edition Part IV 0621.

[0174] Table 8 Results of hygroscopicity and stability studies

[0175]

[0176]

[0177] Conclusion: The test results show that the optical rotation of Form A at 0 days is 115.0°, slightly hygroscopic, stable under high temperature, high humidity, light, and accelerated conditions for 30 days, and no crystal form conversion occurs; but Form A appears surface yellowing after 30 days of light, the impurity content increases, and the optical rotation is unstable, ranging from 97.6° to 115.0°; long-term storage requires brown bottle low-temperature storage (2-10°C). The optical rotation of Form B at 0 days is 117.8°, almost non-hygroscopic, stable under high temperature, high humidity, light, and accelerated conditions for 30 days, and no crystal form conversion occurs; and Form B is stable under high temperature and light conditions, the impurity is stable, and the optical rotation is maintained between 115.1° and 117.8°, with better stability.

[0178] Therapeutically active diltiazem hydrochloride The optical rotation is between 110° and 120°, more preferably 115 to 120°, Form A and Form B meet the requirements of pharmaceuticals, but Form A is slightly hygroscopic and the purity and optical rotation are unstable under light conditions, and Form B can meet the requirements of convenient transportation, storage, and drug preparation.

[0179] Example 5 Scale-up production of crystal forms

[0180] 5.1 Scale-up production of Form A

[0181] Into a 30 L decolorization kettle, add 4 kg of the cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine hydrochloride prepared according to the scale-up of Example 1, 1.2 L of methanol, 4.2 L of absolute ethanol, 600 ml of purified water, and stir to dissolve. Add 30 g of activated carbon to the system, stir, and then filter while hot. After slowly cooling, the solid is precipitated, and a sample is taken and subjected to polarized light microscopy. The PLM microscope shows a single crystal form of platelets. The filter cake is rinsed with absolute ethanol, and after a drying process, 3.76 kg of white solid is obtained, with a yield of 94.0% and a purity of 99.95%. XRPD characterization shows that it is Form B, and the crystals exhibit platelets, as shown in Figure 2. -4(5H)-ketone hydrochloride, 2 L of methanol, 6 L of acetone, and stir to dissolve while warming. Add 30 g of activated carbon to the system, stir, and then filter while hot. After slowly cooling, the solid is precipitated, and a sample is taken and subjected to polarized light microscopy. The PLM microscope shows fine, crushed crystals. The filter cake is rinsed with absolute ethanol, and after a drying process, 3.62 kg of white solid is obtained, with a yield of 90.5% and a purity of 99.94%. XRPD characterization shows that it is Form A, and the crystals exhibit fine, crushed crystal agglomerates, as shown in Figure 1. Figure 4- Figure 5

[0182] 5.2 Scale-up production of Form B

[0183] Into a 30 L decolorization kettle, add 4 kg of the cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine hydrochloride prepared according to the scale-up of Example 1, 1.2 L of methanol, 4.2 L of absolute ethanol, 600 ml of purified water, and stir to dissolve. Add 30 g of activated carbon to the system, stir, and then filter while hot. After slowly cooling, the solid is precipitated, and a sample is taken and subjected to polarized light microscopy. The PLM microscope shows a single crystal form of platelets. The filter cake is rinsed with absolute ethanol, and after a drying process, 3.76 kg of white solid is obtained, with a yield of 94.0% and a purity of 99.95%. XRPD characterization shows that it is Form B, and the crystals exhibit platelets, as shown in Figure 2. Figure 6- Figure 7

[0184] Applicants 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 habit of the crystal form (Table 9): the drying time of Form B (2 h) is significantly lower than that of Form A (8 h). This is because Form B has a platelet form and can uniformly and quickly remove the solvent in the drying equipment; while Form A is a fine, crushed crystal, which has a small particle size and is easy to agglomerate, and the drying process is easy to agglomerate into balls (as shown in Figure 1 ), which causes the inside of the agglomerated balls to not be fully dried, and the agglomerated balls need to be manually kneaded and then dried. Figure 8

[0185] Table 9 Scale-up production process of different crystal forms

[0186]

[0187] ​​​​In summary, the crystal form B has better optical rotation, hygroscopicity and stability, and also has improved processing and production advantages, which can be dried faster than the crystal form A, has a significant positive impact on operating costs; and the preparation process and crystallization reagent are easy to obtain and low in price, suitable for industrial scale-up and commercialization. Therefore, using the drug substance containing the crystal form B of the compound of the present application can effectively prolong the storage period of the drug product, and can meet the pharmaceutical requirements of convenient production, processing, transportation and storage.

[0188] Preparation of Formulation 6

[0189] 6.1 Preparation of Tablets

[0190] According to the prescription composition of Table 10, the drug substances of the crystal form A and the crystal form B prepared in the examples of the present application are used to prepare Formulation 1 and Formulation 2, respectively, according to the following process. Among them, Formulation 1-2 only differs in the crystal form of the drug substance, and the rest of the excipients and preparation process are the same.

[0191] (1) The drug substance (crystal form A or crystal form B), polyethylene glycol 6000 (commercially available from Nanjing Well Pharmaceutical Group Co., Ltd.) and lactose (commercially available from Merck KGaA, Germany) were weighed, crushed, sieved to obtain fine powder of each raw material with a particle size of 0.074 mm, and then each raw material fine powder was mixed with hydrogenated vegetable oil (commercially available from JRS Pharma LP) for 5 min to obtain a mixed drug powder;

[0192] (2) The mixed drug powder was granulated using a high-speed stirring granulator with a heating temperature of 90°C, a side knife speed of 3000 rpm and a stirring speed of 250 rpm, and the granule temperature was heated to 85°C; then the granules were sucked into a fluidized bed granulator in a vacuum feeding mode, all the granules were blown up with normal temperature gas and cooled to 40°C, sieved to obtain granules with a particle size of 0.8 mm;

[0193] (3) The granules were mixed uniformly with magnesium stearate (commercially available from Hunan Erkang Pharmaceutical Co., Ltd.), and a high-speed rotary tablet press was used to press the tablets, and the tablets with a specification of 30 mg / tablet and a total amount of 500 tablets were obtained.

[0194] Table 10 Formulation 1-Formulation 2 Prescription

[0195]

[0196] Results: Formulation 2 prepared using the crystal form B has better compressibility, and there is no phenomenon of sticking or powder adhesion during the tabletting process, and the tablet surface finish is relatively better. Compared with Formulation 2, Formulation 1 (crystal form A) has relatively poor compressibility, has powder adhesion phenomenon, and the tablet surface finish is relatively worse than Formulation 2.

[0197] 6.2 Formulation 3-Formulation 7

[0198] The present application continues to study the formulation comprising the crystal form B and investigate the effect of the formulation, including the study of the hardening oil and the filler. The tablets are prepared according to the prescription composition of Table 11, referring to the process of the 6.1 section. The crystal form B raw material prepared in the present application is used in the formulation 3-7, and the auxiliary materials such as polyethylene glycol 6000, magnesium stearate, etc. of the formulation 3-7 are the same as the auxiliary materials used in the process of the 6.1 section; the hardening oil of the formulation 3 uses hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP), the hardening oil of the formulation 4 uses hydrogenated palm oil (commercially available, purchased from Jiangxi Alpha Gaoke Pharmaceutical Co., Ltd.), and the hardening oil of the formulation 5-7 uses hydrogenated castor oil (commercially available, purchased from BASF (China) Co., Ltd.). The filler of the formulation 5 uses microcrystalline cellulose (commercially available, purchased from Asahi Kasei Corporation), and the filler of the formulation 6 uses calcium carbonate (commercially available, purchased from SUDEEP PHARMA PVT. LTD)

[0199] Table 11 Formulation 3-7 prescription

[0200]

[0201] The formulations 3-7 have good compressibility in the tabletting process, without sticking or powder adhesion phenomenon; however, the tablet surface brightness of the formulation 5 and the formulation 6 is poor, and further research shows that the addition of microcrystalline cellulose has an adverse effect on the dissolution of the formulation, therefore, the formulation composition of the present application does not include microcrystalline cellulose, calcium carbonate.

[0202] The tablet surface of the formulation 2-4 and the formulation 7 is complete and smooth, and the color is uniform, and the hardness of the formulation is tested according to the following method.

[0203] Hardness test: 10 tablets are randomly taken from the formulation to be tested, and the radial crushing force is tested using a hardness tester, and the data displayed by the tablet fracture hardness tester is the hardness of the tablet, and the hardness of the tablets of each formulation is recorded, and the average hardness is calculated as the hardness of the formulation.

[0204] The test results are as follows:

[0205] Inspection item Control index Formulation 2 Formulation 3 Formulation 4 Formulation 7 Characteristics White tablet Pass Pass Pass Pass Appearance Tablet surface smooth Pass Pass Pass Pass Hardness > 4 kg 3.88 3.91 3.90 Pass

[0206] 6.3 Formulation 8-Formulation 13

[0207] The tablets are prepared according to the prescription composition of Table 12, referring to the process of the 6.1 section. The crystal form B raw material prepared in the present application is used in the formulation 8-13, and the auxiliary materials such as lactose, polyethylene glycol 6000, magnesium stearate, etc. of the formulation 8-13 are the same as the auxiliary materials used in the process of the 6.1 section; the auxiliary material hydrogenated castor oil is the same as that of the formulation 6-7.

[0208] Table 12 Formulation 8-13 prescription

[0209]

[0210]

[0211] Formulation 12 has a specification of 60 mg / tablet, and formulation 13 has a specification of 20 mg / tablet.

[0212] Results: Formulations 8-13 have good compressibility during tabletting, and the tablet faces are smooth.

[0213] 6.4 Quality investigation of the formulations

[0214] Hardness test: 10 tablets were randomly taken from each of the formulations to be tested, and the radial breaking force was tested using a hardness tester. The data displayed by the tablet breaking hardness tester was the hardness of the tablet, and the hardness of each formulation was recorded, and the average hardness was calculated as the hardness of the formulation to be tested.

[0215] Tablet weight test: 20 tablets were randomly taken from each of the formulations to be tested, and the total weight was accurately weighed. After obtaining the average tablet weight, the weight of each tablet was accurately weighed again, and compared with the average tablet weight. The tablet weight difference % = 100% * (single tablet weight - average tablet weight) / average tablet weight was calculated. The tablet weight difference of the present application was not more than ± 5%. The number of tablets exceeding the weight difference limit was recorded. More than 2 tablets exceeded the weight difference limit; or although not more than 2 tablets exceeded the weight difference limit, 1 tablet exceeded the limit by 1 times, which were all judged as unqualified. Results: The hardness of formulations 7-13 meets the control index requirements. Formulations 8 and 11 have the problems of over-weight or under-weight tablets, and unstable tablet weight. The test results are shown in Table 13.

[0216] Table 13 Test results of the formulations

[0217]

[0218] Tablet quality and stability test

[0219] The dissolution, related substances and accelerated stability of formulations 7 and 10 were detected.

[0220] Dissolution test: Tablets were taken from the formulations, and the second method of Chinese Pharmacopoeia 2020 edition four general rules 0931 was used to determine the dissolution medium of 900 ml water, the rotation speed was 75 revolutions per minute, 10 ml of dissolution liquid was taken at 30 minutes and 180 minutes, and the same temperature and volume of dissolution medium was immediately added to the operation container.

[0221] Related substance test: The test sample solution was prepared according to the high performance liquid chromatography method (general rule 0512) of Chinese Pharmacopoeia. The test sample solution contained about 0.5 mg of diltiazem hydrochloride per 1 ml of ethanol. 1 mg solution, filter and take the filtrate. Take the test solution by pipette, and dilute with ethanol to prepare a solution containing 1 mg of diltiazem hydrochloride per 1 ml. 5 μg of the solution.

[0222] If there are impurity peaks in the chromatogram of the test solution of the preparation to be tested, the area of a single impurity peak should not be greater than that of the main peak of the control solution (0.5%), and the sum of the areas of all impurity peaks should not be greater than twice the area of the main peak of the control solution (1.0%).

[0223] Accelerated stability test:

[0224] Formulation 7 and formulation 10 were subjected to accelerated stability testing, with properties, related substances, dissolution, and content as the investigation items. The accelerated test was conducted 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%;

[0225] Table 14 Test data of formulation 7 and formulation 10

[0226]

[0227] The dissolution and related substance content of the formulation of the present application all meet the standards, and under the conditions of accelerated stability testing, there is no obvious change in each investigation item, all of which meet the requirements of the quality standards. The stability of the formulation of the present application is good.

[0228] In summary, the crystalline form B of the present application has better processability, and the composition containing the crystalline form B has good compressibility, and there is no phenomenon such as sticking, powder adhesion, etc. in the tabletting process. Moreover, the composition containing the crystalline form B of the present application, the filler and hydrogenated castor oil also has excellent hardness, tablet weight and dissolution properties, and the properties of the composition are stable.

[0229] The above specific embodiments further illustrate the purpose, technical solutions and beneficial effects of the present application, and it should be understood that the above description is only for specific embodiments of the present application, and is not used to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and main idea of the present application should be included in the protection scope of the present application.

Claims

1. The crystal form B of compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazide-4(5H)-one 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, 21.16, 21.42, 29.29, and 38.

47.

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, and 29.

73.

3. The crystal form B according to claim 1, 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, 21.16, 21.42, 27.65, 29.29, and 38.

47.

4. 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 10.74, 21.81, 23.32, 34.71, and 36.

32.

5. The crystal form B according to claim 1, characterized in that, The crystal form B has an endothermic peak at a peak temperature of 216.27 °C.

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

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

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 a lubricant; The total weight of all components in the composition is 100%.

12. The composition according to claim 11, characterized in that, The composition comprises 55-85% by weight of filler. The composition comprises 5-18% by weight of hydrogenated castor oil, and / or The composition includes 2-12% by weight of an adhesive.

13. 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; The total weight of all components in the composition is 100%.

14. The composition according to claim 13, characterized in that, The composition comprises 55-85% lactose by weight; The composition comprises 5-18% by weight of hydrogenated castor oil; and / or The composition comprises 2-12% by weight of polyethylene glycol 6000.

15. 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.

16. A composition, 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 a lubricant; The weight ratio of the filler (binder + hydrogenated castor oil) ranges from 3.5:1 to 4.5:1; The total weight of all components in the composition is 100%. The active ingredient comprises crystalline form B of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine-4(5H)-one hydrochloride. The characteristic diffraction peaks of crystalline form B, expressed as 2θ ± 0.2° using Cu-Kα radiation, include 4.35, 8.53, 16.93, 19.55, 21.16, 21.42, 29.29, and 38.

47.

17. The composition of claim 16, characterized in that, The composition comprises 55-85% by weight of filler; The composition comprises 5-18% by weight of hydrogenated castor oil; and / or The composition includes 2-12% by weight of an adhesive.

18. 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.

19. The composition according to claim 7, 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.

20. The use of the compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine-4(5H)-one hydrochloride, as described in any one of claims 1-5, in the preparation of a medicament for treating diseases selected from: angina pectoris, hypertension, coronary heart disease, and / or arrhythmia.

21. A method for preparing crystal form B of cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine-4(5H)-one hydrochloride according to any one of claims 1-5, characterized in that, Includes the following steps: The compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazazepine-4(5H)-one hydrochloride was added to a mixed solvent containing 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; wherein the first solvent and the second solvent are organic solvents, the second solvent is different from the first solvent, and the third solvent includes water.

22. The preparation method according to claim 21, characterized in that, The first solvent and / or the second solvent are selected from one or more of methanol, anhydrous ethanol, propanol, isopropanol, acetonitrile and acetone; the volume ratio of the first solvent: the second solvent: the third solvent is in the range of (1-10):(1-30):(1-10).

23. The preparation method according to claim 21, characterized in that, The temperature of the "high-temperature dissolution" is higher than 30°C; the cooling temperature of the "cooling crystallization" is -10°C to 30°C.

24. The preparation method according to claim 21, characterized in that, The "high-temperature dissolution" also includes the step of adding activated carbon and then filtering.

Images