WO2018036557A1 - Lenalidomide crystal form, preparation method therefor, and application thereof - Google Patents

Abstract

The present invention relates to a new lenalidomide crystal form J, a preparation method therefor, and a composition containing the crystal form J and a pharmaceutical application thereof.

Description

Crystal form of lenalidomide, preparation method and use thereof Technical field

The invention belongs to the field of chemical pharmacy. In particular, the present invention relates to a novel crystalline form J of lenalidomide and a process for the preparation thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.

technical background

Lenalidomide is a TNF-α inhibitor developed by celgene. In December 2005, FDA approved celgene's lenalidomide capsule formulation revlimid for the treatment of myelodysplastic syndrome. In June 2006, the FDA approved the combination of lenalidomide and dexamethasone for the treatment of multiple myeloma. The product was approved for listing in China in June 2013 and the product name is Ruifumei. The chemical name of lenalidomide is 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, and its structural formula is as follows Shown as follows:

CN101838261B discloses crystal forms A, B, C, D, E, F, G, H of lenalidomide, which are prepared by using lenalidomide in water or an organic solvent (eg hexane). , toluene, acetone, acetonitrile, methanol, ethyl acetate) heated to dissolve, and then cooled to precipitate crystals or in a solid-liquid two-phase slurry system for a long time to stir and crystallize.

CN101696205A discloses three new crystal forms I, II, III of lenalidomide. Another new crystal form I is disclosed in WO2011111053A. WO2010129636A discloses a new crystalline Form 1 of lenalidomide. WO2012127493A discloses a new crystalline form H1 of lenalidomide.

For polymorphic drugs, different crystal forms have different physical and chemical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, etc., and these physical properties directly determine a specific Whether the crystal form can be used to prepare a pharmaceutical preparation affects the quality of the drug substance and the preparation. Therefore, although some crystal forms of lenalidomide have been disclosed in the prior art, it is still necessary to develop a new crystal form which is stable in performance and has a promising application prospect of the formulation to meet the industrial production demand of the drug.

Summary of the invention

In one aspect, the invention relates to a lenalidomide crystal form J, using Cu-K alpha radiation, having an X-ray powder diffraction (XRPD) pattern, expressed as 2θ at 12.0 ± 0.2 °, 13.6 ± 0.2 °, 24.1±0.2°, 24.7±0.2°, 25.4±0.2°, There are characteristic peaks at 26.7±0.2° and 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.

In a specific embodiment, the lenalidomide Form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed as 2θ at 12.0 ± 0.2°, 13.6 ± 0.2°. 15.3±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2° There are characteristic peaks at 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.

In a more specific embodiment, the lenalidomide Form J of the present invention uses Cu-Kα radiation with an X-ray powder diffraction pattern, expressed as 2θ at 12.0 ± 0.2°, 12.6 ± 0.2°, 13.6±0.2°, 15.3±0.2°, 17.5±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, 28.7±0.2°, 29.9±0.2°, 30.5±0.2°, 32.0±0.2°, 34.7±0.2° There are characteristic peaks and there is only one diffraction peak between 2θ and 13.0-14.0°.

In one embodiment, lenalidomide Form J is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. In another embodiment, lenalidomide Form J is characterized by a DSC pattern having a first endothermic peak at 110-117 ° C and a second endothermic peak at 266-271 ° C. In yet another embodiment, the lenalidomide form J is characterized by a DSC pattern substantially as shown in FIG.

In one embodiment, lenalidomide Form J is a dihydrate crystalline form.

In another aspect, the present invention is directed to a method of preparing lenalidomide Form J, characterized in that the method comprises crystallizing a lenalidomide from an aqueous phosphoric acid to obtain a crystalline form of the lenalidomide. J.

In yet another aspect, the present invention is directed to a method of preparing lenalidomide Form J, the method comprising the steps of:

(1) In the future, the lenalidomide is added to an aqueous solution of phosphoric acid, heated and stirred to dissolve, and an aqueous solution of lenalidomide in phosphoric acid is obtained;

(2) optionally, filtering the solution obtained in the step (1);

(3) cooling the solution obtained in the step (1) or (2) to -5 to 5 ° C, crystallization;

(4) The lenalidomide crystal form J is isolated.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of lenalidomide Form J as an active ingredient. Preferably, in the pharmaceutical composition, the crystalline form J of lenalidomide can be combined with one or more pharmaceutically acceptable solid or liquid diluents and/or excipients and made into a galen preparation.

In still another aspect, the invention provides the use of crystalline form J of lenalidomide for the preparation of an anti-tumor drug.

In a further aspect, the invention also relates to crystalline form J of lenalidomide for use in the treatment of neoplastic diseases.

In a still further aspect, the present invention also provides a method of treating a neoplastic disease, the method comprising administering to a subject in need thereof an effective amount of Form J of lenalidomide.

Such tumors include, but are not limited to, multiple myeloma and mantle cell lymphoma.

BRIEF DESCRIPTION OF THE DRAWINGS:

1 is an X-ray powder diffraction pattern of lenalidomide crystal form J obtained in Example 1.

2 is an infrared absorption spectrum of lenalidomide crystal form J obtained in Example 1.

3 is a DSC chart of lenalidomide crystal form J obtained in Example 1.

4 is a TGA pattern of lenalidomide crystal form J obtained in Example 1.

Fig. 5 is an X-ray diffraction chart of the lenalidomide crystal form J obtained in Example 1 after 10 days of stability at 60 °C.

Fig. 6 is a DSC chart of the stability of the lenalidomide crystal form J obtained in Example 1 after 10 days of stability at 60 °C.

Figure 7 is an X-ray diffraction pattern of lenalidomide Form J obtained in Example 1 after 10 days at a relative humidity of 75 ± 5%.

Figure 8 is a DSC chart of the lenalidomide Form J obtained in Example 1 after 10 days at a relative humidity of 75 ± 5%.

Figure 9 is a TGA chart of lenalidomide Form J obtained in Example 1 after 10 days at a relative humidity of 75 ± 5%.

Figure 10 is a comparison chart of the hygroscopicity test curves of Form J and Form E, wherein

Representative crystal form J,

Represents Form E.

Figure 11 is a DSC chart after the transformation of Form E stability.

Fig. 12 is a DSC chart obtained by oscillating and mixing crystal form E and form J in a 1:1 ratio.

Figure 13 is a comparison chart of the dissolution profiles of Form J and Form E, wherein

Representative crystal form J,

Represents Form E.

detailed description

The invention is further described in detail below, and it is to be understood that the terms are not intended to limit the invention.

General definitions and terms

The technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise indicated. In the event of a conflict, the definition provided in this application shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is specifically disclosed by the upper limit or preferred value of any pair of ranges. Any range combined with any lower limit or preferred value of any range, regardless of whether the range is specifically disclosed. Ranges of values recited herein are intended to include the endpoints of the range and all integers and fractions (fractions) within the range, unless otherwise stated.

The terms "about" and "approximately" when used in conjunction with a numerical variable, generally mean that the value of that variable and all values of that variable are within experimental error (for example, within a 95% confidence interval for the mean) or ±10 of the specified value. Within %, or a wider range.

The expressions "including", "comprising", "having", and the like, are meant to be inclusive, and do not exclude additional elements, steps, or components. The expression "consisting of" excludes any element, step or ingredient that is not specified. The expression "consisting essentially of" means that the scope is limited to the specified element, step or ingredient, plus The elements, steps or components that are present are not essential to the basic and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expression "consisting essentially of" and "consisting of."

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, in the method of preparing Form L of lenalidomide, "optional, filtration..." means that filtration may or may not be carried out.

Unless otherwise indicated, percentages, parts, and the like herein are by weight.

As used herein, the term "crystal form" or "crystal" refers to any solid material that exhibits a three-dimensional order, as opposed to an amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.

As used herein, the term "amorphous" refers to any solid material that is not ordered in three dimensions.

As used herein, the term "hydrate" describes a solvate comprising a drug with a stoichiometric or non-stoichiometric amount of water.

As used herein, the term "X-ray powder diffraction (XRPD) map" refers to an experimentally observed diffraction pattern or parameters, data or values derived therefrom. The XRPD pattern is usually characterized by a peak position (abscissa) and/or a peak intensity (ordinate).

As used herein, the term "2θ" refers to a peak position expressed in degrees (°) set in an X-ray diffraction experiment, and is generally an abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at a 2θ angle. It will be understood that the particular 2 theta value of a particular crystalline form referred to herein is intended to mean a 2 theta value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-Kα is used (Kα1 is

) as a source of radiation. The XRPD pattern herein can be acquired, for example, on a Rigaku D/max-2200 X-ray powder diffraction analyzer. An exemplary test condition may be a scan speed of 4°/min and a scan step width of 0.01°.

As used herein, the term "substantially" for an X-ray diffraction peak means taking into account representative peak position and intensity variations. For example, those skilled in the art will appreciate that the peak position (2θ) will show some variation, typically as much as 0.1-0.2 degrees (±0.1 to ±0.2 degrees), and instruments used to measure diffraction will also cause some changes. Additionally, those skilled in the art will appreciate that the relative peak intensities may vary due to differences between the instruments and the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered as only For qualitative measurements.

As used herein, differential scanning calorimetry (DSC) measures the transition temperature when a crystal absorbs or releases heat due to changes in its crystal structure or crystal melting. For the same crystalline form of the same compound, the thermal transition temperature and melting point error is typically within about 5 °C in a continuous analysis. When a compound is described as having a given DSC peak or melting point, it refers to the DSC peak or melting point ± 5 °C. "Basic" also takes into account this temperature change. DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range. In addition, the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance. The DSC map can be, for example, in the model number NETZSCH DSC200 F3 Jaia Measured on the instrument. Exemplary test conditions are a heating rate of 10 ° C/min and a temperature range of 25-300 ° C.

As used herein, infrared absorption spectroscopy (FTIR) can be used to study the structure and chemical bonds of molecules, as well as methods for characterizing and identifying chemical species. Herein, FTIR is used to characterize the molecular structure and crystal form of lenalidomide crystal form J. Compounds in solid form can generally be assayed by KBr tableting. The FTIR can be collected, for example, on an infrared spectrophotometer model BRWKER JECTOR 22. An exemplary test condition is the KBr tableting method with a scan range of 400-4000 cm ^-1 .

As used herein, thermogravimetric analysis (TGA) is a common method for determining the thermal stability of a compound. In this context, TGA is also used to determine the hydration state of a compound. The rate of temperature rise during the test will have a certain effect on the map. For example, an excessively high rate of temperature rise is not conducive to the measurement of intermediate products. The TGA map can be measured, for example, on an instrument such as the PerkinElmer TGA400. Exemplary test conditions are a heating rate of 10 ° C/min and a temperature range of 30-300 ° C.

Lenalidomide crystal form J

In one embodiment, the invention provides Form J of lenalidomide, using Cu-K alpha radiation, an X-ray powder diffraction (XRPD) pattern, expressed as 2θ at 12.0 ± 0.2 °, 13.6 ± 0.2 ° There are characteristic peaks at 24.1±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.

In a specific embodiment, the lenalidomide Form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, expressed as 2θ at 12.0 ± 0.2°, 13.6 ± 0.2°. 15.3±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2° There are characteristic peaks at 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.

In a more specific embodiment, the lenalidomide Form J of the present invention uses Cu-Kα radiation with an X-ray powder diffraction pattern, expressed as 2θ at 12.0 ± 0.2°, 12.6 ± 0.2°, 13.6±0.2°, 15.3±0.2°, 17.5±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, 28.7±0.2°, 29.9±0.2°, 30.5±0.2°, 32.0±0.2°, 34.7±0.2° There are characteristic peaks and there is only one diffraction peak between 2θ and 13.0-14.0°.

In a more specific embodiment, the lenalidomide Form J of the present invention uses Cu-Kα radiation with an X-ray powder diffraction pattern, expressed as 2θ at 12.0 ± 0.2°, 12.6 ± 0.2°, 13.6±0.2°, 15.3±0.2°, 17.5±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2°, 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, 28.7±0.2°, 29.9±0.2°, 30.5±0.2°, 32.0±0.2°, 33.1±0.2°, There are characteristic peaks at 33.6 ± 0.2 °, 34.2 ± 0.2 °, and 34.7 ± 0.2 °, and there is only one diffraction peak between 2θ and 13.0-14.0 °.

In a further embodiment, the lenalidomide Form J of the present invention, using Cu-Kα radiation, has an X-ray powder diffraction pattern having 2θ values, d values, and relative intensities as shown in Table 1 below (L) /L ₀ ):

Table 1

In a further embodiment, the lenalidomide form J of the present invention has a peak at substantially the same diffraction angle (2 theta) as shown in FIG. In another embodiment, Form J has an X-ray powder diffraction pattern substantially as shown in FIG.

In a further embodiment, the lenalidomide form J of the present invention has a peak at the same diffraction angle (2 theta) as shown in FIG. In another embodiment, Form J has an X-ray powder diffraction pattern as shown in FIG.

In another embodiment, the lenalidomide form J of the present invention has an infrared absorption spectrum measured by KBr tableting at about 3448.7 cm ^-1 , 3356.7 cm ^-1 , 3267.8 cm ^-1 , 3057.0 cm ^{- 1} , 2852.7cm ^-1 , 1738.9cm ^-1 , 1690.4cm ^-1 , 1638.4cm ^-1 , 1492.6cm ^-1 , 1460.4cm ^-1 , 1446.0cm ^-1 , 1422.6cm ^-1 , 1367.1cm ^-1 , 1351.7cm ^{- 1} , 1302.0 cm ^-1 , 1234.6 cm ^-1 , 1207.0 cm ^-1 , 1179.3 cm ^-1 , 1055.7 cm ^-1 , 920.2 cm ^-1 , 894.4 cm ^-1 , 790.4 cm ^-1 , 759.4 cm ^-1 , 607.6 cm ^- There are absorption peaks at ¹ , 470.6cm ^-1 and 420.4cm ^-1 .

In a specific embodiment, the lenalidomide crystal form J of the present invention has an infrared absorption spectrum measured by KBr tableting at about 3448.7 cm ^-1 , 3356.7 cm ^-1 , 3267.8 cm ^-1 , 3057.0 cm . ^-1 , 2852.7cm ^-1 , 1738.9cm ^-1 , 1690.4cm ^-1 , 1638.4cm ^-1 , 1492.6cm ^-1 , 1460.4cm ^-1 , 1446.0cm ^-1 , 1422.6cm ^-1 , 1367.1em ^-1 , 1351.7cm ^-1 , 1302.0cm ^-1 , 1261.7cm ^-1 , 1234.6cm ^-1 , 1207.0cm ^-1 , 1179.3cm ^-1 , 1089.9cm ^-1 , 1055.7cm ^-1 , 997.0cm ^-1 , 920.2cm ^-1 , 894.4cm ^-1 , 833.3cm ^-1 , 814.4cm ^-1 , 790.4cm ^-1 , 759.4cm ^-1 , 699.0cm ^-1 , 607.6cm ^-1 , 558.1em ^-1 , 488.0cm ^-1 , 470.6cm ^-1 , 420.4cm There are characteristic peaks at ^-1 .

In a preferred embodiment, the crystalline form J of lenalidomide of the present invention has characteristic peaks at substantially the same peak position as shown in FIG. In a further embodiment, the crystalline form J of lenalidomide has an infrared absorption spectrum substantially as shown in FIG.

In a further embodiment, the crystalline form J of lenalidomide has a characteristic peak at the same peak position as shown in FIG. In a still further embodiment, Form J has an infrared absorption spectrum as shown in FIG.

In one embodiment, the differential scanning calorimetry (DSC) pattern of lenalidomide Form J of the present invention has a first endothermic peak at 110-117 ° C and a second endothermic at 266-271 ° C. peak.

In a preferred embodiment, the lenalidomide form J of the present invention has a characteristic peak at substantially the same temperature as shown in FIG. In another embodiment, the crystalline form J of lenalidomide has a DSC pattern substantially as shown in FIG.

In a further preferred embodiment, the lenalidomide form J of the present invention has a characteristic peak at the same temperature as shown in FIG. In a still further embodiment, the crystalline form J of lenalidomide has a DSC pattern as shown in FIG.

In one embodiment, the crystalline form J of lenalidomide of the present invention has substantially the same weight loss profile as shown in FIG. In a preferred embodiment, Form J of lenalidomide has a TGA profile substantially as shown in Figure 4.

In a more preferred embodiment, the lenalidomide form J of the present invention has the same weight loss curve as shown in FIG. In a further preferred embodiment, the crystalline form J of lenalidomide has a TGA pattern as shown in FIG. According to the TGA spectrum of Fig. 4, the crystal form J of lenalidomide is a dihydrate crystal form.

Method for preparing crystalline form J of lenalidomide

The present invention also provides a process for preparing crystalline form J of lenalidomide which comprises crystallizing lenalidomide from an aqueous phosphoric acid to obtain crystalline form J of said lenalidomide.

In a preferred embodiment, the invention provides a method of preparing crystalline form J of lenalidomide, the method comprising the steps of:

(1) In the future, the lenalidomide is added to an aqueous solution of phosphoric acid, heated and stirred to dissolve, and an aqueous solution of lenalidomide in phosphoric acid is obtained;

(2) optionally, filtering the solution obtained in the step (1);

(3) cooling the solution obtained in the step (1) or (2) to -5 to 5 ° C, crystallization;

(4) The lenalidomide crystal form J is isolated.

In a preferred embodiment, the weight to volume ratio (g/ml) of lenalidomide to aqueous phosphoric acid is from 1:20 to 1:500, preferably from 1:30 to 1:60. Such a choice allows the process of the invention to achieve excellent yields in the preparation of Form J.

In a preferred embodiment, the aqueous phosphoric acid solution has a concentration of from 0.1% to 50% (ml/ml), preferably from 1% to 5% (ml/ml).

Unless otherwise indicated, "heating" in the preparation process is to promote dissolution of the compound. The temperature of the heating is not particularly limited as long as it is lower than the boiling point of the crystallization solvent. The preferred heating temperature is from room temperature to 90 ° C, more preferably from 60 to 90 ° C, such as from 60 ° C, 70 ° C, 80 ° C, 85 ° C, 90 ° C.

Unless otherwise specified, the speed and time of "stirring" in the step of adding lenalidomide to the crystallization solvent are not particularly limited as long as the amine can be completely dissolved in the future. A preferred agitation time is from 20 to 40 min, more preferably 30 min.

The crystallization temperature in the preparation method should be such that Form J of lenalidomide can be formed. The preferred crystallization temperature is -10 ° C to 5 ° C, preferably -5 ° C to 5 ° C, such as -8 ° C, -6 ° C, -5 ° C, -3 ° C, 0 ° C, 3 ° C, 5 ° C.

Unless otherwise specified, "crystallization" in the preparation process can also be carried out during the stirring process. The crystallization can be carried out for about 6-60 h, for example about 48 h, 36 h, 24 h, 12 h.

The prepared crystalline form is separated and recovered by a method including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid separation under pressure or under reduced pressure, preferably filtration or centrifugation. Separation. The separated Form J can optionally be dried. Drying can be carried out at a temperature of about 60 ° C or less, about 50 ° C or less, about 45 ° C or less, about 40 ° C or less, about 35 ° C or less, about 20 ° C or less, or any other suitable temperature. Drying can be carried out, for example, for about 1 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, or any other suitable time.

Pharmaceutical composition and administration

In one embodiment, the invention provides a pharmaceutical composition comprising lenalidomide Form J, and one or more pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable carrier" as used herein refers to a solid or liquid diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is within the scope of sound medical judgment. Tissue suitable for contact with humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications corresponding to reasonable benefits/risks.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as soybean oil, peanut oil, minerals. Oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerin, propylene glycol, water, ethanol, and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, cellulose, sodium saccharin, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

The compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection, intraarterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration; or by oral, nasal, buccal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.

For these routes of administration, the compositions of the invention may be administered in a suitable dosage form. The dosage forms include, but are not limited to, tablets, pills, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, aqueous suspensions, injections, elixirs, syrups Agent.

The pharmaceutical compositions of the present invention can be prepared by any method well known in the art, for example by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, and the like. The term "therapeutically effective amount" as used herein refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., amphibians, reptiles, birds) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (e.g., dogs, cats). , sheep, cows, pigs, etc.).

Beneficial effect

The lenalidomide new crystal form J of the invention has good solubility, simple crystallization process, convenient operation, small pollution, and real Now it is industrialized, and the crystalline drug of the invention has high product purity, excellent physical and chemical properties, high temperature/high humidity, good chemical and physical stability, excellent processing (filtration, drying, dissolution and tableting), and can be reproduced. The advantages, but also good solubility, dissolution, dissolution time and biological release, have a good market application prospects.

Example

The invention is further illustrated by the following examples, which are intended to provide a better understanding of the invention, and are not intended to limit or limit the scope of the invention.

Preparation and characterization of lenalidomide crystal form J

The crude lenalidomide used in the preparation method of lenalidomide crystal form J in the embodiment of the present invention is not particularly limited and may be commercially available, or according to a known method, for example, the method described in the patent document US5635517A. Prepared.

The lenalidomide crystal form B and the crystal form E described in the examples of the present invention can be prepared according to the method disclosed in CN101838261B. The patent documents and non-patent documents mentioned in the present invention are incorporated herein by reference.

Test instrument information and methods

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 speed 4 ° / min, scanning step width 0.01 °.

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

The DSC test conditions involved in the present invention are: DSC detector model: NETZSCH DSC200 F3 Jaia; operation method: heating rate 10 ° C / min, temperature range: 25-300 ° C.

The TGA test conditions involved in the present invention are: TGA detector model: PerkinElmer TGA400; operating method: heating rate 10 ° C / min, temperature range: 30-300 ° C.

The present invention relates to high performance liquid chromatography (HPLC) test conditions: column is Agilent Zorbax SB-CN; 4.6 × 250mm, 5μm or equivalent column; mobile phase: buffer (take sodium octane sulfonate 2.16g, add water 1000ml to dissolve, add 1ml of phosphoric acid, mix, adjust the pH value to 2.50 with 0.1mol / L sodium hydroxide: acetonitrile = 92:8; detection wavelength: 210nm; flow rate: 1.0ml / min; injection volume: 10μl; Column temperature: 25 ° C.

The ion chromatographic test conditions of the present invention are: lonpac AG11; 4.0×50 mm, Guard lonpac AS11-HC5 μm; 4.0×250 mm; mobile phase: 30 mmol sodium hydroxide solution; diluent: 30 mmol sodium hydroxide solution Detection wavelength: 210 nm; flow rate: 1.5 ml/min; injection amount: 25 μl; column temperature: 30 °C.

The dissolution test method according to the present invention is: a dissolution apparatus model Agilent 708-DS; the method is a slurry method, a rotation speed of 50 rpm, a pH of 6.8, and a temperature of 37 °C.

Example 1

In the future, 10 g of crude lenalidomide (HPLC purity = 98%) was added to 200 ml of 50% (ml/ml) aqueous phosphoric acid solution. The temperature was raised to 60 ° C by heating, stirring was continued for 30 min, and dissolved to clear to obtain a lenalidomide solution. The obtained solution was cooled to 5 ° C, and stirred and crystallized at 5 ° C for 48 h, filtered, and dried under vacuum at 20 ° C to obtain 8.1 g of crystals. The purity was 99.8% by HPLC, and the ion chromatography showed that the phosphate ion was: 20 ppm. The X-ray powder diffraction pattern, the infrared absorption spectrum, the DSC spectrum, and the TGA spectrum of the crystal form are shown in Figures 1-4, respectively, and are defined as lenalidomide crystal form J. According to the TGA spectrum, the crystal form J is a dihydrate.

Example 2

In the future, 10 g of crude lenalidomide (HPLC purity = 98%) was added to 5 L of a 0.1% (ml/ml) aqueous phosphoric acid solution, and the mixture was heated to 90 ° C with heating, stirring was continued for 30 min, and dissolved to obtain a lenalidomide solution. The obtained solution was cooled to 0 ° C, and allowed to stand at 0 ° C for 48 h, filtered, and dried under vacuum at 35 ° C to obtain 7.1 g of crystals. The purity was 99.7% by HPLC, and X-ray powder diffraction detection showed that For the new crystal form J.

Example 3

In the future, 10 g of crude lenalidomide (HPLC purity = 98%) was added to 600 ml of a 1% (ml/ml) aqueous phosphoric acid solution, and the mixture was heated to 85 ° C with heating, stirring was continued for 30 min, and dissolved to clearness to obtain a lenalidomide solution. Filtration, the filtrate was cooled to -5 ° C, and stirred for precipitation at -5 ° C for 36 h, filtered, and dried under vacuum at 45 ° C to obtain 7.8 g of crystals. The purity was 99.9% by HPLC, X-ray powder diffraction detection It is indicated as a new crystal form J.

Example 4

In the future, 10 g of crude lenalidomide (HPLC purity = 98%) was added to 600 ml of a 1% (ml/ml) aqueous phosphoric acid solution, and the mixture was heated to 80 ° C with heating, stirring was continued for 30 min, and dissolved to clearness to obtain a lenalidomide solution. Filtration, the filtrate was cooled to 0 ° C, and stirred for crystallization at 0 ° C for 24 h, filtered, and dried under vacuum at 50 ° C to give 7.8 g of crystals. The purity was 99.8% by HPLC. X-ray powder diffraction detection showed For the new crystal form J.

Example 5

In the future, 10 g of crude lenalidomide (HPLC purity = 98%) was added to 300 ml of a 5% (ml/ml) aqueous phosphoric acid solution, and the mixture was heated to 70 ° C with heating, stirring was continued for 30 minutes, and dissolved to clearness to obtain a lenalidomide solution. Filtration, the filtrate was cooled to 0 ° C, and stirred at 0 ° C for 12 h, filtered, and dried under vacuum at 40 ° C to obtain 8.8 g of crystals. The purity was 99.8% by HPLC. X-ray powder diffraction detection showed For the new crystal form J.

Stability test

High temperature experiment

The lenalidomide crystal form J prepared in Example 1 was placed in a sealed clean glass bottle, placed in a 60 ° C constant temperature oven, and sampled at 5 and 10 days, respectively, and compared with the results of 0 days. The results are shown in Table 2. Table 2 shows that the appearance, melting point and Form J content of Form L of lenalidomide were substantially the same as those of Day 0 after 5 days and 10 days of standing. The crystal form J after 10 days of investigation at 60 ° C was tested. The X-ray diffraction pattern is shown in Fig. 5, the XRPD data is shown in Table 3, and the DSC spectrum is shown in Fig. 6. The DSC spectrum has a first endothermic peak at 110-117 ° C, at 266-271 There is a second endothermic peak at °C. The XRPD pattern, data and DSC spectrum of lenalidomide Form J after standing at 60 ° C for 10 days were substantially the same as those of 0 days, showing good high temperature stability.

Table 2

table 3

High humidity experiment

The lenalidomide crystal form J and the crystal form E prepared in Example 1 were uniformly distributed into an open petri dish, the thickness was ≤ 5 mm, and then placed at room temperature (25 ° C), and the relative humidity was 75 ± 5%. In the constant humidity incubator, the samples were taken on the 5th and 10th day, respectively, and compared with the results of 0 days. Among them, the hygroscopicity of lenalidomide crystal form J is shown in Table 4. It can be seen that after 5 days and 10 days, Form J has only a slight moisture absorption and weight gain, appearance, melting point and content of Form J with 0 days. The samples are basically the same. The X-ray diffraction pattern of Form J is shown in Figure 7 after 10 days of relative humidity of 75 ± 5% and room temperature (25 ° C). The XRPD data is shown in Table 5, the DSC chart is shown in Figure 8, and the TGA chart is shown in Figure 9. . The DSC plot shows a first endothermic peak at 110-117 °C and a second endothermic peak at 266-271 °C. The XRPD pattern, data, DSC pattern and TGA curve of lenalidomide crystal form J after 10 days in a high-humidity environment were substantially the same as those of day 0, showing good high-humidity stability.

Table 4

table 5

The experimental results of the hygroscopicity of lenalidomide crystal form J and lenalidomide crystal form E are shown in Fig. 10. As can be seen from Fig. 10, the hygroscopicity of lenalidomide crystal form J is significantly lower than that of the known crystal form E. , indicating that Form J has higher stability.

Crystalline stability test

Sample retention conditions: The prepared Form B, Form E, and Form J were sealed and stored at 25 ° C for 6 months to examine the change in crystal form.

Table 6

As can be seen from Table 6, the crystal form J has excellent stability. The DSC spectra of Form B and Form J after 6 months of retention were almost unchanged from those before the sample was taken. The crystal form E is unstable, and the DSC spectrum after the crystal form E transition is shown in Fig. 11, which is significantly different from the DSC pattern before the sample retention.

Crystal contrast test

After crystal form E and crystal form J were shake-mixed in a ratio of 1:1, the crystal form of the mixture was observed.

Figure 12 shows the DSC spectrum measured after the combination of Form E and Form J. The DSC spectrum of the mixture is inconsistent with the DSC spectrum of Form J (Fig. 3), and the independent endothermic peaks of Form E and Form J can be seen from the figure, further demonstrating that Form E and Form J are not The same crystal form.

Solubility test

The method for determining the solubility is as follows:

Column: Agilent ZORBAX SB-C18 250mm × 4.6mm 5μm

Detection wavelength: 215 nm, flow rate: 1.0 ml/min, injection amount: 10 μl, column temperature: 25 ° C

Running time: 14 minutes.

Diluent: Thinner 1: Acetonitrile: Water = 40: 60, Diluent 2: 0.01 NHCl

Mobile phase: Buffer (take 4.33 g of sodium octane-1-sulfonate in 1 L of water, add 1 ml of phosphoric acid and mix, filter): methanol = 70:30, mix, and sonicate.

Preparation of the reference solution: accurately weigh about 25mg of lenalidomide reference in a 50ml volumetric flask, dissolve with diluent 1 and dilute to the mark, and mix. Precision transfer from 5.0 ml to 25 ml volumetric flask, dilute to the mark with diluent 2, and mix to obtain a reference solution (containing lenalidomide 0.1 mg/ml).

Sample solution: Take appropriate amount of test sample (about 0.3g) to 25ml volumetric flask, add 5ml solvent (pH=1.2, pH=2, pH=4.5, pH=6.8, pH=7.5), mix and set at 37 °C water bath After shaking for 24 hours, the mixture was immediately filtered, and after 1-2 ml of the initial filtrate was discarded, the filtrate was collected, and the appropriate amount of the filtrate was accurately transferred and diluted with a diluent 2 to a solution of about 0.1 mg/ml.

Table 7

As can be seen from Table 7, the solubility of Form J is better than that of Form B.

Dissolution test

The dissolution of Form J of lenalidomide was determined using the capsule form of lenalidomide Form J.

Prescription of lenalidomide crystal form J capsule:

Table 8

ingredient	weight
Lenalidomide crystal form J	10mg
lactose	300mg
Microcrystalline cellulose	50mg
Croscone sodium	15mg
Magnesium stearate	3mg

Preparation method of lenalidomide crystal form J capsule:

Taking the prescribed amount of the lenalidomide crystal form J, lactose, microcrystalline cellulose, croscarmellose sodium, made of soft material with 95% ethanol solution, sifted, blast at 50-60 ° C Dry, sift through the whole grain, add magnesium stearate and mix and fill the capsule.

Prescription of lenalidomide crystal form E capsule:

Table 9

ingredient	weight
Lenalidomide Form E	10mg
lactose	300mg
Microcrystalline cellulose	50mg
Croscone sodium	15mg
Magnesium stearate	3mg

Preparation method of lenalidomide crystal form E capsule:

Take the prescribed amount of lenalidomide crystal form E, lactose, microcrystalline cellulose, croscarmellose sodium, make soft material with 95% ethanol solution, sift through, blast dry at 50-60 °C, The whole granules are sieved, and magnesium stearate is added and mixed to fill the capsules.

Lenalidomide dissolution test method:

Test equipment: stirring paddle, vessel, settling basket, motor.

Experimental procedure:

(1) Debug the instrument so that the bottom of the stirring paddle is 25 mm ± 2 mm from the bottom of the dissolution cup;

(2) The sample was taken, and 900 ml of the degassed treatment, 0.01 N hydrochloric acid solution was placed in a dissolution cup, and the lenalidomide capsule was charged;

(3) start the instrument, the speed is controlled at 50 rpm;

(4) Measure the dissolution rate.

A comparison of the dissolution profiles of lenalidomide Form J and Form E is shown in Figure 13. The results of the dissolution test of lenalidomide crystal form J and form E are shown in Table 10:

Table 10

From the results of the dissolution test, the lenalidomide crystal form J of the present invention has a better dissolution rate than the known crystal form E, and is more suitable for formulation application.

Those skilled in the art can understand that the numerical values or numerical endpoints involved in the technical solutions of the present invention are not limited to the numbers themselves, and they include those allowable errors that have been widely accepted in the art. Ranges such as experimental errors, measurement errors, statistical errors, and random errors, etc., are all included in the scope of the present invention.

Many modifications and variations of the present invention will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only and are not intended to be limiting in any way. The true scope and spirit of the invention are shown by the appended claims, and the description and embodiments are merely exemplary.

Claims (13)

1. A lenalidomide crystal form J characterized by using an X-ray powder diffraction pattern of Cu-Kα radiation, in terms of degrees 2θ at 12.0±0.2°, 13.6±0.2°, 24.1±0.2°, 24.7 There are characteristic peaks at ±0.2°, 25.4±0.2°, 26.7±0.2°, 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.
2. The lenalidomide crystal form J according to claim 1, wherein an X-ray powder diffraction pattern of Cu-Kα radiation is used, and the 2θ expressed in degrees is 12.0±0.2°, 13.6±0.2°, 15.3. ±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2°, 24.1±0.2°, 24.7±0.2°, 25.4 There are characteristic peaks at ±0.2°, 26.7±0.2°, 27.5±0.2°, and there is only one diffraction peak between 2θ and 13.0-14.0°.
3. The lenalidomide crystal form J according to claim 1 or 2, wherein an X-ray powder diffraction pattern of Cu-Kα radiation is used, and the 2θ expressed in degrees is 12.0±0.2° and 12.6±0.2°. 13.6±0.2°, 15.3±0.2°, 17.5±0.2°, 18.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.5±0.2°, 22.1±0.2°, 22.6±0.2°, 23.2±0.2° , 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.4 ± 0.2 °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, 28.7 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, 32.0 ± 0.2 °, 34.7 ± 0.2 ° There is a characteristic peak, and there is only one diffraction peak between 2θ and 13.0-14.0°.
4. The lenalidomide crystal form J according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern is substantially as shown in Fig. 1.
5. The lenalidomide crystal form J according to any one of claims 1 to 4, wherein the DSC spectrum has a first endothermic peak at 110-117 ° C and a second endothermic at 266-271 ° C. peak.
6. The lenalidomide crystal form J according to any one of claims 1 to 5, wherein the DSC pattern is substantially as shown in FIG.
7. The lenalidomide crystal form J according to any one of claims 1 to 6, which is a dihydrate crystal form.
8. A method of preparing lenalidomide crystal form J according to any one of claims 1 to 7, wherein the method comprises crystallizing lenalidomide from an aqueous phosphoric acid solution to obtain the enamel Form J of the amine.
9. A method of preparing lenalidomide crystal form J according to any one of claims 1-7, the method comprising The following steps:

   (1) In the future, the lenalidomide is added to an aqueous solution of phosphoric acid, heated and stirred to dissolve, and an aqueous solution of lenalidomide in phosphoric acid is obtained;

   (2) optionally, filtering the solution obtained in the step (1);

   (3) cooling the solution obtained in the step (1) or (2) to -5 to 5 ° C, crystallization;

   (4) The lenalidomide crystal form J is isolated.
10. The method according to claim 8 or 9, wherein the weight ratio of the lenalidomide to the aqueous phosphoric acid solution is from 1:20 to 1:500 (g/ml), preferably from 1:30 to 1:60. (g/ml).
11. The method according to any one of claims 8 to 10, characterized in that the concentration of the aqueous phosphoric acid solution is from 0.1% to 50% (ml/ml), preferably from 1% to 5% (ml/ml).
12. The method according to any one of claims 9-11, characterized in that in step (3) the solution is cooled to -5 ° C, 0 ° C or 5 ° C for crystallization.
13. The use of lenalidomide Form J according to any one of claims 1 to 7 for the preparation of a medicament for antitumor.

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