WO2018045889A1 - Crystal form of oritavancin diphosphate, and preparation method and use thereof - Google Patents

Abstract

Provided are a crystal form A of oritavancin diphosphate, and a preparation method and use thereof. The crystal form has excellent properties in the aspects of dissolution time, biological release, chemical stability, and processing adaptability.

Description

Crystal form of oritavancin diphosphate, preparation method and use thereof Technical field

The present invention relates to the field of chemical pharmaceuticals. More particularly, the present invention relates to novel crystalline forms of oritavancin diphosphate and methods of making the crystalline forms and their pharmaceutical use.

technical background

On August 7, 2014, the FDA approved the antibiotic Orbactiv (oritavancin, oritavancin, IV) injection, the active ingredient of oritavancin bisphosphate, used by sensitive Gram-positive bacteria (including methicillin-resistant) Treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by Staphylococcus aureus, MRSA). Orbactiv is the first and only single-dose treatment approved by the FDA for the treatment of ABSSSIs. The patient received only one Orbactiv infusion and the entire treatment plan was over. The approval of Orbactiv also represents a significant advancement in the treatment of bacterial skin and skin structure infections far beyond current clinical standards. Currently, patients often require multiple intravenous infusions of antibiotics, and the Orbactiv single-dose regimen will significantly reduce the patient's dose burden. Currently available in the United States by HaoeyouPharmacy on the shelves.

Orbactiv was approved based on data from SOLOI and SOLOII studies, both of which were randomized, double-blind, multicenter clinical trials evaluating single-dose Orbactiv (1200 mg, IV, IV) treatment regimens for 1987 ABSSSI The patient was treated and a large subset of patients (n = 405) with MRSA infection were evaluated. These experiments demonstrated that only one injection of Orbactiv (1200 mg, IV) and 7-10 days of daily injection of vancomycin (1 g or 15 mg/kg body weight) were non-inferiority at both the primary and secondary endpoints.

Orbactiv is suitable for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive strains, including: Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains) ), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus angina (including S. anginosus, S. intermedius and S. constellatus) and Enterococcus faecalis (vancomycin-sensitive strains only).

The structural formula of oritavancin bisphosphate is as follows:

For drugs, crystalline and amorphous may have different physicochemical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, etc., and these physical properties directly determine a particular crystal form. Or whether amorphous can be used as a medicine, and they affect the quality of the drug substance and preparation. Nowadays, there is no patent document that discloses a crystal form of oritavancin bisphosphate. Therefore, it is necessary to develop a new crystal form which has different properties from amorphous and has excellent application prospects to meet the stringent demand as a medicine. .

Summary of the invention

One of the objects of the present invention is to provide an oritavancin bisphosphate crystal form A which is excellent in chemical and physical stability. The crystal form has excellent properties in terms of dissolution time, biological release, chemical stability, and processing (filtration, drying, tableting) adaptability.

The X-ray powder diffraction (XRPD) pattern of the oritavancin bisphosphate crystal form A of the present invention has characteristic peaks at the following diffraction angle 2θ: 5.9 ± 0.2°, 7.0 ± 0.2°, 8.7 ± 0.2°, 9.4 ±0.2°, 12.1±0.2°, 17.8±0.2°, 18.2±0.2°.

Further, the X-ray powder diffraction pattern of the oritavancin bisphosphate crystal form A There are characteristic peaks at 2θ: 5.9±0.2°, 7.0±0.2°, 7.6±0.2°, 8.7±0.2°, 9.4±0.2°, 12.1±0.2°, 13.8±0.2°, 17.8±0.2°, 18.2± 0.2°, 19.8±0.2°, 21.2±0.2°, 23.0±0.2°, 24.5±0.2°.

Further, the X-ray powder diffraction pattern of the oritavancin bisphosphate crystal form A of the present invention has 2θ, d and relative intensity data as shown in Table 1 below:

Table 1

Without limitation, the oritavancin diphosphate crystal form A of the present invention has an X-ray powder diffraction pattern as shown in FIG.

Further, the oritavancin bisphosphate crystal form A of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting at about 3406.26 cm ^-1 , 1654.98 cm ^-1 , 1505.65 cm ^-1 , 1387.79 cm ^{- 1} , 1334.94cm ^-1 , 1231.79cm ^-1 , 1132.41cm ^-1 , 1066.73cm ^-1 , 1026.52cm ^-1 , 906.30cm ^-1 , 817.17cm ^-1 , 711.34cm ^-1 , 553.40cm ^-1 .

Without limitation, the oritavancin diphosphate crystal form A of the present invention has an infrared spectrum as shown in FIG.

The microscopic spectrum of the oritavancin bisphosphate crystal form A of the present invention is shown as needle crystals.

Without limitation, the oritavancin diphosphate crystal form A of the present invention has a microscopic spectrum as shown in FIG.

Without limitation, the oritavancin diphosphate crystal form A of the present invention has a TGA spectrum as shown in FIG.

Another object of the present invention is to provide a method for preparing the oritavancin bisphosphate crystal form A, the method comprising:

(1) adding oritavancin bisphosphonate to a water/alcohol mixed solvent to dissolve to dissolve;

(2) Crystallization at 0-40 ° C, filtration, to obtain oritavancin bisphosphate crystal form A.

among them,

The alcohol in the step (1) is preferably a C1-C4 alcohol, more preferably methanol, ethanol, isopropanol or n-butanol.

Wherein the volume ratio of water to alcohol (v/v) is preferably 1:2.5-20.

The weight-to-volume ratio of the oritavancin diphosphate to the water/alcohol mixed solvent is preferably from 1:5 to 100, more preferably from 1:10 to 40, the weight of the oritavancin diphosphate and the corresponding solvent. The unit of the volume ratio may be g/ml or Kg/L, etc., depending on the specific operation scale.

The crystallization temperature is preferably 5 to 25 °C.

The crystallization time is preferably from 10 to 48 hours, more preferably from 24 to 36 hours.

The oritavancin bisphosphonate raw material used in the method of the present invention is an oritavancin bisphosphonate obtained by a phosphate salt formation reaction according to the method described in Example 4 of the patent document US Pat. No. 5,840,684. The literature is incorporated herein by reference. The solvent to be used in the present invention is not particularly limited, and a commercially available conventional solvent may be employed. For example, the isopropanol may be commercially available isopropanol, including industrial isopropanol, analytically pure isopropanol, and the like.

Another aspect of the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of oritavancin bisphosphate crystal form A as an active ingredient. The pharmaceutical composition includes, but is not limited to, administration in a general dosage form, such as an oral dosage form and an injection dosage form, including capsules, tablets, powders, cachets, suspensions, and solutions, preferably in an injection form. . The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient/additive, including but not limited to non-toxic compatible fillers, binders , disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, thickeners, colorants, emulsifiers, and the like.

The invention also provides the use of oritavancin bisphosphate crystal form A or a pharmaceutical composition thereof for preparing an anti-infective drug, and the oritavancin bisphosphate injection is suitable for the following Gram-positive bacteria sensitive strain Treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs), including: Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, lactating chain Cocci, angina streptococcus (including S. anginosus, S. intermedius, and S. constellatus) and Enterococcus faecalis (vancomycin-sensitive strains).

Unless otherwise indicated, the "stirring" described in the process of the present invention may be carried out by conventional methods in the art, such as agitation including magnetic stirring, mechanical agitation, and a stirring speed of 50-300 rpm/min, preferably 120-250 rpm/min.

Unless otherwise stated, the "volume ratio of water to alcohol" as described in the process of the present invention is the ratio of the same volume unit.

The X-ray powder diffraction apparatus and test conditions according to the present invention are: X-diffraction instrument model Rigaku D/max-2200Cu target

Operation method: scanning temperature 25 ° C, scanning speed 4 ° / min, scanning step width 0.01 °.

The infrared spectrophotometer and the test conditions of the invention are: infrared spectrophotometer model: BRWKER VECTOR 22; operation method: KBr tableting method, scanning range 400-4000 cm ^-1 .

The microscope spectrum of the invention is as follows: the microscope model is: OLYMPUS CX31; operation method: a small amount of precipitated crystal is placed on the glass slide, the cover glass is covered, and then the sample is placed on the stage at 100 The morphology of the sample was observed at a magnification of multiples and photographed.

The TGA test conditions involved in the present invention are: TGA detector model: PerkinElmer TGA400; operation method: heating rate 10 ° C / min, temperature range: 30-280 ° C.

The liquid phase (HPLC) test conditions of the present invention are: Acchrom Xcharge C18, 5 μm,

Mobile phase A: 2 ‰ phosphoric acid aqueous solution; mobile phase B: acetonitrile; detection wavelength: 230 nm; flow rate: 1 ml/min; injection amount: 10 μl; column temperature: 65 ° C, liquid phase conditions are shown in Table 2:

Table 2

t(min)	A (%)	B (%)
0	95	5
10	89	11
40	88	12

It should be emphasized that the numerical or numerical endpoints referred to in the technical solutions of the present invention are not limited to the number itself, and those skilled in the art can understand that they include those which have been widely used in the field. Acceptable allowable error ranges, such as experimental errors, measurement errors, statistical errors, and random errors, etc., are all included within the scope of the present invention.

The inventors of the present invention have discovered a large amount of oritavancin bisphosphate new crystal form A, which has good solubility, simple crystallization process, easy operation, low pollution, and industrial production, and the crystalline drug of the present invention is simultaneously It has the advantages of high product purity, excellent physicochemical properties, good chemical stability, and reproducibility of processing (filtration, drying, dissolution and tableting); In addition, in contrast to amorphous, the oritavancin bisphosphate crystal form A of the present invention has low hygroscopicity and good stability, and is advantageous for sample storage.

DRAWINGS

1 is an X-ray powder diffraction pattern of oritavancin bisphosphate crystal form A obtained in Example 1.

2 is an infrared absorption spectrum of oritavancin diphosphate crystal form A obtained in Example 1.

3 is a microscopic view of crystal form A of oritavancin diphosphate obtained in Example 1.

4 is a TGA pattern of oritavancin diphosphate crystal form A obtained in Example 1.

Figure 5 is an amorphous X-ray powder diffraction pattern of oritavancin diphosphate obtained in Preparation Example 1.

Figure 6 is a microscopic view of the amorphous form of oritavancin diphosphate obtained in Preparation Example 1.

Specific embodiment

The following examples are intended to illustrate the invention, but they are not intended to limit or limit the scope of the invention.

Example 1

2 g of oritavancin bisphosphonate raw material (HPLC purity: 98%) was dissolved in 40 ml of a mixed solution of water and isopropanol at room temperature (the volume ratio of water to isopropanol was 1:20; Propyl alcohol content>99.5%), stirring and dissolving, controlling the stirring speed to 200 rpm/min; stirring and crystallization at 25 ° C, crystallization time 48 h, filtration, vacuum drying at 30 ° C, 450 mg crystals, HPLC purity 99.6 %.

The X-ray powder diffraction, infrared, microscopic, and TGA spectra of this crystal form are detailed in Figures 1-4, which are designated as oritavancin bisphosphate crystal form A in the present invention.

Example 2

1 g of oritavancin bisphosphate raw material (HPLC purity 98%) at room temperature Dissolved in 100ml water and ethanol mixed solution (water to ethanol volume ratio of 1:20; used ethanol content >99.5%), stirred and dissolved, controlled stirring speed of 200rpm / min; stirred at 20 ° C conditions Crystals, crystallization time 12 h, filtration, vacuum drying at 30 ° C, 300 mg of crystals were obtained, HPLC purity was 99.4%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 3

5 g of oritavancin bisphosphate raw material (HPLC purity: 98%) was dissolved in 25 ml of a mixed solution of water and isopropanol at room temperature (the volume ratio of water to isopropanol was 1:2.5; Propyl alcohol content>99.5%), stirring and dissolving, controlling the stirring speed to 200 rpm/min; stirring and crystallization at 25 ° C, crystallization time 10 h, filtration, vacuum drying at 30 ° C, 1.2 g crystals, HPLC purity 99.2%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 4

2 g of oritavancin bisphosphonate raw material (HPLC purity: 98%) was dissolved in 30 ml of a mixed solution of water and methanol at room temperature (the volume ratio of water to methanol was 1:5; the methanol content used was >99.5%). ), stirring and dissolving, controlling the stirring speed to 200 rpm / min; stirring and crystallization at 20 ° C, crystallization time 48 h, filtration, vacuum drying at 30 ° C, to obtain 100 mg of crystals, HPLC purity of 99.2%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 5

1 g of oritavancin bisphosphonate raw material (HPLC purity: 98%) was dissolved in 50 ml of a mixed solution of water and ethanol at room temperature (the volume ratio of water to ethanol was 1:2.5; the ethanol content used was >99.5%). ), stirring and dissolving, controlling the stirring speed to 200 rpm / min; stirring and crystallization at 20 ° C, crystallization time 36 h, filtration, vacuum drying at 30 ° C, to obtain 250 mg of crystals, HPLC purity of 99.6%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 6

2 g of oritavancin bisphosphonate raw material (HPLC purity: 98%) was dissolved in 40 ml of a mixed solution of water and isopropanol at room temperature (the volume ratio of water to isopropanol was 1:5; Propyl alcohol content>99.5%), stirring and dissolving, controlling the stirring speed to 200 rpm/min; stirring and crystallization at 5 ° C, crystallization time 12 h, filtration, vacuum drying at 30 ° C, 320 mg of crystals, HPLC purity of 99.1 %. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 7

2 g of oritavancin bisphosphonate raw material (HPLC purity: 98%) was dissolved in 40 ml of water and n-butanol mixed solution at room temperature (the volume ratio of water to n-butanol was 1:4; Alcohol content>99.5%), stirred and dissolved, controlled stirring speed is 200rpm/min; stirred and crystallized at 25°C, crystallization time is 10h, filtered, vacuum dried at 30°C to obtain 220mg crystal, HPLC purity is 99.4% . The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 8

2 g of oritavancin bisphosphate raw material (HPLC purity: 98%) was dissolved in 40 ml of a mixed solution of water and methanol at room temperature (the volume ratio of water to methanol was 1:10; the methanol content used was >99.5%). ), stirring and dissolving, controlling the stirring speed to 200 rpm / min; stirring and crystallization at 20 ° C, crystallization time 24 h, filtration, vacuum drying at 30 ° C, to obtain 180 mg of crystals, HPLC purity of 99.3%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 9

2 g of oritavancin bisphosphonate raw material (HPLC purity 98%) was dissolved in 65 ml of water and isopropanol mixed solution at room temperature (the volume ratio of water to isopropanol was 1:10; Propyl alcohol content>99.5%), stirring and dissolving, controlling the stirring speed to 200 rpm/min; stirring and crystallization at 40 ° C, crystallization time 36 h, filtration, vacuum drying at 30 ° C, 100 mg of crystals with an HPLC purity of 99.3%. The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

Example 10

2 g of oritavancin bisphosphonate raw material (HPLC purity 98%) was dissolved in 40 ml of water and n-butanol mixed solution at room temperature (the volume ratio of water to isopropanol was 1:15; the isopropyl group used) Alcohol content>99.5%), stirred and dissolved, controlled stirring speed is 200rpm/min; stirred and crystallized at 30°C, crystallization time is 24h, filtered, vacuum dried at 30°C to obtain 140mg crystal, HPLC purity is 99.2% . The X-ray powder diffraction pattern (XRPD) was measured and confirmed to be Form A.

The X-ray powder diffraction patterns of the products obtained in Examples 2 to 10 were the same as in Example 1, and are not repeated here.

Preparation Example 1

Preparation of oritavancin bisphosphonate raw material

Orivin is prepared according to the method described in Example 4 of the patent document US Pat. No. 5,840,684, and the obtained oritavancin is purified by a preparative column (filler AQ-C18), and eluted into a salt with a 5% phosphoric acid water buffer solution. The collected stream was deliquored and subjected to nanofiltration to obtain a filtrate. Ethanol was added to the obtained filtrate to control the ethanol concentration at 50% (V/V), and crystallized at 25 ° C to obtain oritavancin bisphosphate raw material, and the HPLC purity was 98.26. %. The X-ray powder diffraction pattern (XRPD) was measured to confirm that the obtained oritavancin bisphosphate raw material was amorphous. The amorphous X-ray powder diffraction and microscopic spectra are detailed in Figures 5-6.

Comparative Example 1: Hygroscopicity comparison experiment

The amorphous form prepared in Preparation Example 1 and the crystalline form A obtained in Example 1 of the present invention were subjected to a hygroscopicity comparison test at 75% RH at 25 ° C for an equilibrium time of 24 hours. The results are shown in Table 3.

table 3

sample	Hygroscopicity
Amorphous	17.61%
Crystal form A	10.11%

It can be seen from Table 3 that the hygroscopicity of Form A is significantly lower than that of amorphous, and the hygroscopicity is low for the storage of the sample.

Comparative Example 2: Accelerated stability test

The amorphous form prepared in Preparation Example 1 and the crystalline form A obtained in Example 1 of the present invention were subjected to a stability test at 40 ° C for 5 days and 10 days, and the HPLC purity of the compound before and after the standing was examined. Table 4.

Table 4

It can be seen from the results of the accelerated stability test in Table 4 that the stability of the crystal form A is better than that of the amorphous one.

Claims (10)

1. An oritavancin diphosphate crystal form A characterized in that its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angle 2θ: 5.9 ± 0.2°, 7.0 ± 0.2°, 8.7 ± 0.2°, 9.4 ±0.2°, 12.1±0.2°, 17.8±0.2°, 18.2±0.2°.
2. The oritavancin diphosphate crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has characteristic peaks at the following diffraction angle 2θ: 7.6 ± 0.2°, 13.8 ± 0.2°, 19.8 ± 0.2 °, 21.2 ± 0.2 °, 23.0 ± 0.2 °, 24.5 ± 0.2 °.
3. A method of preparing oritavancin bisphosphate crystal form A according to any one of claims 1 to 2, the method comprising the steps of:

   (1) adding oritavancin bisphosphonate to a water/alcohol mixed solvent to dissolve to dissolve;

   (2) Crystallization at 0-40 ° C, filtration, to obtain oritavancin bisphosphate crystal form A.
4. A process for the preparation of crystal form A of oritavancin diphosphate according to claim 3, wherein the alcohol is a C1-C4 alcohol, preferably methanol, ethanol, isopropanol or n-butanol.
5. The method for producing oritavancin diphosphate crystal form A according to claim 3 or 4, wherein a volume ratio of water to alcohol in the water/alcohol mixed solvent is 1:2.5-20.
6. The method for preparing oritavancin bisphosphate crystal form A according to claim 3 or 4, wherein the weight ratio of the oritavancin bisphosphate to the water/alcohol mixed solvent is 1:5 to 100, It is preferably 1:10-40 and its unit is g/mL or Kg/L.
7. The method for producing oritavancin diphosphate crystal form A according to claim 3 or 4, wherein the crystallization temperature is 5 to 25 °C.
8. The process for producing oritavancin diphosphate crystal form A according to claim 3 or 4, wherein the crystallization time is from 10 to 48 hours, preferably from 24 to 36 hours.
9. A pharmaceutical composition comprising the oritavancin bisphosphate crystal form A of claim 1 or 2.
10. Use of oritavancin bisphosphate crystal form A according to claim 1 or 2, or a pharmaceutical composition according to claim 9 for the preparation of an anti-infective agent, wherein said infection is preferably made of golden yellow grapes Caused by cocci, S. pyogenes, Streptococcus agalactiae, Streptococcus dysgalactia, Streptococcus angina and Enterococcus faecalis.

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