CN107445938B

CN107445938B - Crystalline form of eliglutacoside hemitartrate, process for its preparation and pharmaceutical compositions containing it

Info

Publication number: CN107445938B
Application number: CN201610375158.6A
Authority: CN
Inventors: 刘素云; 冯朴纯
Original assignee: Beijing Qihui Biomedical Co Ltd
Current assignee: Beijing Qihui Biomedical Co ltd
Priority date: 2016-05-31
Filing date: 2016-05-31
Publication date: 2020-04-03
Anticipated expiration: 2036-05-31
Also published as: CN107445938A

Abstract

The invention provides a crystalline form of eletriptan hemitartrate shown as a formula I (a), a preparation method thereof and a pharmaceutical composition containing the crystalline form, wherein X-ray powder diffraction of the crystalline form of the eletriptan hemitartrate has main characteristic peaks at the positions with 2 theta angles of 10.2 degrees, 12.4 degrees, 13.6 degrees, 14.9 degrees, 20.1 degrees and 22.1 degrees, a DSC (differential scanning calorimetry) spectrum shows that an endothermic peak exists at 161-162 ℃, the crystalline form of the eletriptan hemitartrate has the advantage of good stability, the prepared pharmaceutical composition has the advantage of good dissolution, and the crystal is suitable for being used as a raw material medicament for production and storage of pharmaceutical preparations.

Description

Crystalline form of eliglutacoside hemitartrate, process for its preparation and pharmaceutical compositions containing it

Technical Field

The invention relates to a crystalline form of eliglutacteostat hemitartrate, a preparation method, a pharmaceutical composition containing the crystalline form and application thereof, and belongs to the technical field of medicines.

Background

Eliglustat (Eliglustat), chemically N- [ (1R,2R) -1- (2, 3-dihydro-1, 4-benzodioxan-6-yl) -2-hydroxy-1- (1-pyrrolidinemethyl) ethyl ] octanamide, is the first small molecule compound used for treating specific type I gaucher disease, and has the structural formula shown in formula I:

the globally known rare diseases are 7000 kinds which account for 10% of human diseases, the Chinese found disease is 5781 kinds, more than ten million patients are suffering from Gaucher's disease, the most common genetic rare diseases of lysosomal storage diseases are β -glucocerebrosidase, the large deposition of glucocerebroside in the mononuclear macrophage system causes the massive proliferation of histiocytes, and the Gaucher's disease is classified into type I, type II and type III 3 according to the acute and slow onset, visceral involvement and nervous system symptoms of the Gaucher disease, wherein the type I disease is the most common type, which accounts for 94% of cerebral metabolic diseases of adults, the Gaucher disease can be developed by children and adults, the onset is more than that of preschool children, the onset is slow, the Gaucher disease is developed all over the world, the morbidity of different groups is greatly different, the northern Europe type northern Europe disease mainly affects people, but more than 50% of early onset renal failure of patients is discovered in time, the early onset of liver is found to 20% of patients, the early onset of the Gaucher disease is found by about 3 types of liver, the early onset of the liver dysfunction is found by 3632 types of the early onset, the early onset of the early onset, the liver dysfunction is found by about 3632 types of the early onset of the Gaucher disease, the early onset of.

Existing treatments for gaucher's disease include: symptomatic treatment, splenectomy, Enzyme Replacement Therapy (ERT) and hematopoietic stem cell transplantation therapy, wherein the Enzyme Replacement Therapy (ERT) is the most effective method for treating gaucher type I disease at present, but patients need to receive intravenous infusion periodically for life (once every 2 weeks) and the cost is very high, so that domestic patient families need to bear high treatment cost, and therefore most patients are still in a state of poor diagnosis and no medicine.

Eliaglucol is the first small molecule oral drug to treat gaucher's disease, used as a first line oral therapy for adult patients with specific type I gaucher disease. Eliglutacter is a potent, highly specific ceramide analogue inhibitor, targeting glucosylceramide synthase (GCS), and is able to reduce the production and accumulation of glucosylceramide. At present, the medicine is not on the market at home. As the first oral drug for treating the gaucher disease type I, the drug is convenient to apply clinically, completely subverts the market pattern of gaucher disease depending on injection drugs at present, and becomes a unique and very important new practical treatment option for gaucher disease type I groups. The medicine is developed and marketed in China, so that the tragic situation that patients suffering from gaucher disease are not provided with medicines at present can be fundamentally changed, the medicine becomes a revolutionary medicine for treating gaucher disease in China, and great social benefits and development necessity are achieved.

A crystalline form of eliglutacoside hemitartrate is disclosed in patent CN 201080061535. The existence of different crystalline forms of a single compound is called polymorphism, which is an important property of the compound, and for most compounds, polymorphism generally exists, while different crystalline forms of the same drug have important influence on the stability, uniformity, bioavailability, preparation production and the like of the drug. The polymorphs each have different physical properties, such as different solubility properties, different melting points, and/or different X-ray diffraction peaks. Therefore, when a drug has polymorphism, it is necessary to conduct intensive research on its crystal form.

Because the solubility of each polymorph can vary, it is important to identify the presence of pharmaceutical polymorphs to provide pharmaceutical compositions with predictable dissolution properties. It is desirable to study all solid state forms of the drug, including all polymorphs, pseudopolymorphs, and hydrates, and to determine the stability, solubility, and flowability of each polymorph. The discovery of new polymorphs of a pharmaceutically acceptable compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It expands the repertoire of materials that formulation scientists have available for designing, for example, pharmaceutical dosage forms of drugs with targeted release properties or other desired characteristics. Therefore, research and development of new crystal forms of the existing drugs to improve the preparation performance and exert the clinical advantages of the drugs are one of the ways of independent innovation in the pharmaceutical industry at present.

The invention provides a new crystalline form of the eletroUstat hemitartrate, the crystalline form has the advantages of good stability, no increase of related substances after long-term storage and no decrease of clarity, and the prepared pharmaceutical composition has the advantages of high bioavailability, good dissolution and the like, and is suitable for being used as a raw material medicament for production and storage of pharmaceutical preparations.

Disclosure of Invention

It is an object of the present invention to provide a novel crystalline form of eletriptan hemitartrate which is easy to manufacture and formulate, has good stability to light, moisture and heat, and is suitable for industrial production and storage.

It is another object of the present invention to provide a process for the preparation of the crystalline form of eliglutacoside hemitartrate.

It is a further object of the present invention to provide pharmaceutical compositions containing said crystalline forms.

These objects of the invention are achieved by the following idea:

the present invention provides a novel crystalline form of eliglutacoside hemitartrate represented by the following formula i (a), preferably having major X-ray powder diffraction peaks at 2 Θ angles of 10.2 °, 12.4 °, 13.6 °, 14.9 °, 20.1 °, 22.1 °.

According to the crystalline form of the hemitartrate salt of eliglutasistat according to the present invention, more preferably, the crystalline form has major X-ray powder diffraction peaks at 2 Θ angles of 7.4 °, 10.2 °, 12.4 °, 13.6 °, 14.9 °, 18.4 °, 19.0 °, 20.1 °, 20.8 °, 22.1 °.

The crystalline form of the hemitartrate salt of eliglutacter according to the invention, wherein the hemitartrate salt is L-hemitartrate.

Preferably, the DSC profile of said crystalline form shows an endothermic peak at 161 ℃ to 162 ℃.

The method for preparing the crystalline form of the eliglutacoside hemitartrate comprises the preferred steps of preparing a mixed solution, dissolving a certain amount of L-tartaric acid in a certain amount of the mixed solution, and heating until the solid is dissolved; dissolving a certain amount of eliglutacoside in another certain amount of mixed solution, dropwise adding the L-tartaric acid solution, stirring at room temperature for crystallization, filtering, and drying to obtain the compound.

Preferably, the mixed solution is selected from any two of methanol, acetone, water, ethanol and isopropanol.

Preferably, one of the mixed solutions is an acetone solution.

More preferably, the mixed solution is a mixed solution of water and acetone.

Preferably, the vacuum drying temperature is 50-70 ℃.

The invention also provides a pharmaceutical composition, which comprises the crystal and a pharmaceutically acceptable carrier. Pharmaceutical compositions may be formulated using conventional solid or liquid carriers or diluents and pharmaceutical additives of a type appropriate to the intended mode of administration.

The pharmaceutical composition comprising the crystalline form of eliglutaconate hemitartrate of the invention may further comprise one or more pharmaceutically acceptable excipients, preferably selected from fillers, buffers, glidants, flow agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners. Other excipients known in the art of pharmaceutical compositions may also be used. Furthermore, the pharmaceutical composition may further comprise 2 or more members also belonging to the above-mentioned group.

The crystalline form of eliglutacoside hemitartrate according to the invention is illustrated by the data below.

The X-ray powder diffraction spectrum of the crystalline eletriptan hemitartrate of example 3, measured using an X-ray powder diffractometer (Bruker D8-advance, Germany), a Cu target, a tube pressure of 40kv, and a tube flow of 40mA, expressed as 2 theta angles and interplanar spacings (D values), is shown in the attached FIG. 1, and the data is as follows:

angle (2 theta degree)	d value (Angel)	Relative Strength I (%)
			5.309	16.63236	10.2％
6.165	14.32367	16.9％
			7.407	11.92542	30.7％
10.174	8.68779	37.7％
			10.644	8.30512	5.9％
11.852	7.46073	5.1％
			12.400	7.12360	48.6％
13.566	6.52205	37.3％
			14.878	5.94978	48.0％
15.491	5.71556	16.7％
			15.898	5.57001	22.6％
16.295	5.43535	21.6％
			16.741	5.29138	9.2％
17.112	5.17744	12.7％
			17.608	5.03284	18.4％
17.989	4.92721	17.3％
			18.379	4.82333	27.2％
18.649	4.75409	17.9％
			18.985	4.67074	27.5％
19.456	4.55878	17.5％
			19.844	4.47052	18.7％
20.106	4.41278	34.4％
			20.442	4.34096	8.3％
20.838	4.25941	28.9％
			22.118	4.01568	99.5％
23.634	3.76146	11.1％
			23.898	3.72050	20.3％
24.168	3.67961	14.2％
			24.405	3.64437	8.8％
25.312	3.51586	10.0％
			25.838	3.44535	9.0％
30.363	2.94149	6.5％

The crystalline eletriptan hemitartrate of example 3 is taken and its Differential Scanning Curve (DSC) is shown in figure 2, the crystal has an endothermic transition at 161-162 ℃ and an endothermic onset temperature at 161 ℃.

The crystalline eletroglucasistat hemitartrate of example 3 was taken, disrupted at 105 ℃ for 10 days, and the obtained HPLC (detection conditions: Shimadzu liquid phase, mobile phase: Na₂HPO₄/H₃PO₄pH: 5, wavelength 210nm, flow rate 1.0ml/min, sample amount 10 mul) as shown in figure 3, and the data are shown in the following table, wherein the spectrum shows that the crystal content is still above 99.8%, the single impurity is less than 0.1%, and the number of impurities is 3.

HPLC attached data

Peak(s)	Retention time	Area%	Degree of separation
				1	3.949	0.013	0.000
2	8.302	0.029	19.179
				3	21.789	0.068	34.983
4	22.620	99.890	1.222
				Total of		100.000

3 batches of capsules containing the crystalline eliaglutistat hemitartrate of the present invention prepared in example 4 and a commercially available base (Eliglustat, trade name)

Manufacturer Genzyme Corporation), dissolution control tests were performed (conditions: the serous method, pH1.0 hydrochloric acid solution, the volume of the dissolution liquid is 900mL, the rotating speed is 75rpm, the sampling volume is 10mL, and the detection: 280nm, absorbance by uv spectrophotometer), the respective dissolution data are as follows:

the data show that the capsule prepared by using the crystalline eliglutacter hemitartrate of the invention has good dissolution rate, the dissolution rate reaches more than 95% in 15 minutes, and the capsule can be completely dissolved within 1 hour.

Drawings

FIG. 1: an X-ray powder diffraction pattern of the crystalline form of eliglutasistat hemitartrate of the invention;

FIG. 2: a DSC differential thermal scan of the crystalline form of eliglutasistat hemitartrate of the invention;

FIG. 3: HPLC (high performance liquid chromatography) images of the crystal of the isoglutacteostat hemitartrate disclosed by the invention after high-temperature damage.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 1: referring to the examples of patent CN201510703628.2, the synthesis of Elligusrostat includes the following steps.

1. Preparation of the Compound of formula (III)

A5L round bottom three-necked flask equipped with a drying tube was charged with the compound of formula (II) (278g, 1mol) and acetonitrile (2.8L), potassium carbonate (276g, 2mol) was added with stirring, a solution of Boc anhydride (327g, 1.5mol) in acetonitrile (300mL) was added dropwise at 10 ℃ in an external bath, and after completion of the addition, the reaction was continued for 3 hours, then water (3L) was added, extraction was carried out three times with ethyl acetate (800 mL. times.3), the organic phases were combined, washed with saturated brine (800mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 368g of a pale yellow oil with a yield of 97.6%.

2. Preparation of the Compound of formula (IV)

After dissolving the compound of formula (III) (302g, 0.8mol) and DMF (3.6L) in a 5L round bottom three-necked flask equipped with a drying tube with stirring, potassium carbonate (276g, 2mol), benzyl bromide (205g, 1.2mol) are added in turn, the reaction is continued for 7h at 160 ℃ in an external bath, the mixture is cooled, poured into water (20L), extracted with ethyl acetate (2 Lx 3) for three times, the organic phases are combined, washed with water (2 Lx 5) and saturated saline (2L) in turn, dried with anhydrous sodium sulfate, filtered and concentrated to obtain 318g of yellow oily matter with 85.1 percent yield.

3. Preparation of Compounds of formula (V)

After dissolving the compound of formula (IV) (280g, 0.6mol) and tetrahydrofuran (2.2L) in a 3L round-bottom three-necked flask equipped with a drying tube under stirring, 4N aqueous hydrochloric acid (300mL, 1.2mol) was added, the reaction was continued at room temperature for 2 hours, 2L of water was added, tetrahydrofuran was evaporated under reduced pressure, the mixture was extracted with ethyl acetate (500 mL. times.3) three times, the organic phases were combined, washed with water (500mL) and saturated brine (500mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 208g of a yellow oily substance with a yield of 94.2%.

4. Preparation of the Compound of formula (VI)

After dissolving the compound of formula (V) (184g, 0.5mol) and dichloromethane (1.8L) in a 3L round-bottom three-necked flask equipped with a drying tube with stirring, triethylamine (71g, 0.7mol) and octanoyl chloride (97g, 0.6mol) were added, the reaction was continued at room temperature for 28 hours, 2L of water was added, extraction was performed three times with ethyl acetate (500 mL. times.3), the organic phases were combined, washed with water (500mL) and saturated brine (500mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 199g of a yellow oil with a yield of 80.6%.

5. Preparation of Compounds of formula (I)

Adding a compound (VI) (198g, 0.4mol) and a 10% glacial acetic acid methanol solution (1.9L) into a 3L round-bottom three-mouth bottle, stirring to dissolve, adding 10% palladium-carbon (9.9g), hydrogenating at 50 ℃ internal temperature under normal pressure for 18h, filtering, concentrating the filtrate, adding water (2L), adjusting the pH to 9-10 with 2N sodium hydroxide, extracting with ethyl acetate (500mL × 3) for three times, combining the organic phases, washing with water (500mL) and saturated brine (500mL) in sequence, drying with anhydrous sodium sulfate, filtering and concentrating to obtain a yellow solid (the compound (I), namely the compound (Eiglurostat), dissolving with acetone (1.3L), adding L-tartaric acid (60g, 0.4mol), stirring for 16h, performing suction filtration, washing a filter cake with acetone, and drying in vacuum to obtain 139g of a white-like solid (Eiglurasirox tartrate) with the yield of 62.9%.

Example 2: preparation of crystalline eliglutacter hemitartrate

Elliguslat (10g/24.7mmol) from example 1 was dissolved in 140ml of methanol/acetone (v/v: 0.05:0.95) solution at room temperature. L-tartaric acid (1.84g/12.3mmol) was added to 60ml of a methanol/acetone (v/v: 0.05:0.95) solution, heated to 40 ℃ to dissolve the solid completely, and the solution was dropped into the former solution. Stirring for ten minutes at room temperature, slowly separating out a small amount of solid, separating out a large amount of solid after fifteen minutes, stirring for 3 hours, filtering, leaching a filter cake with 20ml of acetone by 2, and vacuum drying the solid at 50 ℃ for 16-20 hours to obtain 9.18g of off-white solid with the yield of 77.5%.

Example 3: preparation of crystalline eliglutacter hemitartrate

Elliguslat (10g/24.7mmol) prepared in example 1 was dissolved in 140ml of a water/acetone (v/v: 0.01:0.99) solution at room temperature. L-tartaric acid (1.84g/12.3mmol) was added to 60ml of a water/acetone (v/v: 0.01:0.99) solution, heated to 40 ℃ to dissolve the solid completely, and the solution was dropped into the former solution. Stirring for ten minutes at room temperature to rapidly separate out a large amount of solid, stirring for 3 hours, filtering, leaching with acetone 2 x 20ml, and vacuum drying the solid at 60 ℃ for 16-20 hours to obtain 9.78g of off-white solid with the yield of 82.5%.

Example 4: preparation of capsules containing the crystalline Eliguslata hemitartrate of the present invention (1000 capsules) 100g of the crystalline Eliguslata hemitartrate as obtained in example 3 were mixed with 44.6g of microcrystalline cellulose 101, 44.6g of lactose monohydrate, 8.1g of hydroxypropylmethylcellulose E50, passed through a 60 mesh sieve, mixed at high speed for 3 minutes in a wet granulator, added with an appropriate amount of water to prepare a soft mass, passed through a 20 mesh sieve using a rocking granulator to granulate, dried, added with 2.7g of glyceryl behenate, mixed for 5 minutes in a three-dimensional mixer, and filled into capsules using a capsule filling machine.

Claims

1. A crystalline form of the hemitartrate salt of Eliguslatus of formula I (a), wherein the crystalline form has major X-ray powder diffraction peaks at 2 θ angles of 10.2 °, 12.4 °, 13.6 °, 14.9 °, 20.1 °, 22.1 °,

the hemitartrate is L-hemitartrate.

2. The crystalline form of the hemitartrate salt of eliglutason of claim 1, wherein the crystalline form has major X-ray powder diffraction peaks at 2 Θ angles of 7.4 °, 10.2 °, 12.4 °, 13.6 °, 14.9 °, 18.4 °, 19.0 °, 20.1 °, 20.8 °, 22.1 °.

3. The crystalline form of eletroglucstat hemitartrate of claim 1, wherein the crystalline form exhibits a DSC profile exhibiting an endothermic peak at 161 ℃ -162 ℃.

4. A process for preparing the crystalline form of eliglutacoside hemitartrate as claimed in any one of claims 1 to 3, comprising the steps of preparing a mixed solution, dissolving a quantity of L-tartaric acid in a quantity of the mixed solution, and heating until the solid dissolves; dissolving a certain amount of eliglutacoside in another certain amount of mixed solution, dropwise adding the L-tartaric acid solution, stirring at room temperature for crystallization, filtering, and drying to obtain the compound preparation, wherein the mixed solution is selected from any two of methanol, acetone and water.

5. The method according to claim 4, wherein the mixed solution is a mixed solution of water and acetone.

6. The method according to claim 4, wherein the drying temperature is 50 to 70 ℃.

7. A pharmaceutical composition comprising a crystalline form of the hemitartrate salt of eliglutasonate selected from any one of claims 1 to 3, and a pharmaceutically acceptable carrier.