TWI664172B - Crystal form of lenalidomide, preparation method and application thereof - Google Patents

Abstract

The invention relates to a new crystalline form J of lenalidomide and a preparation method thereof, as well as a composition containing the crystalline form J and a medical use thereof.

Description

Crystal form of lenalidomide, preparation method and application thereof

The invention relates to the field of chemistry and pharmacy, in particular to a new crystalline form J of lenalidomide, a preparation method thereof, a pharmaceutical composition containing the crystalline form J, and a medicinal use thereof.

Lenalidomide is a TNF-α inhibitor developed by Celgene. In December 2005, the FDA approved Celgene's lenalidomide capsule formulation revlimid for the treatment of myelodysplastic syndrome. In June 2006, the FDA approved lenalidomide in combination with dexamethasone to treat multiple myeloma. The product was approved for sale in China in June 2013 under the trade name Ruifumei. The chemical name of lenalidomide: 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione, its structure The formula is as follows: [Chemical Formula 1]

CN101838261B discloses the crystalline forms A, B, C, D, E, F, G, and H of lenalidomide. These eight forms are prepared in the future by using lenalidomide in water or organic solvents such as hexane, Toluene, acetone, acetonitrile, methanol, ethyl acetate) are heated to dissolve, and then the crystals are precipitated at a lower temperature, or the solid-liquid two-phase slurry system is stirred and converted for a long time.

CN101696205A discloses three new crystalline forms I, II, III of lenalidomide. WO2011111053A discloses another new crystalline form I. WO2010129636A discloses a new crystalline form 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 and chemical properties directly determine a specific Whether the crystalline form can be used in the preparation of pharmaceutical preparations and affects the quality of the drug substance and preparation. Therefore, although some crystalline forms of lenalidomide have been disclosed in the prior art, it is still necessary to develop new crystalline forms with stable performance and excellent application prospects to meet the needs of the industrial production of drugs.

Therefore, the object of the present invention is to provide a lenalidomide crystal form J, which can overcome the disadvantages of the foregoing prior art.

Therefore, the lenalidomide form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 2θ expressed in degrees are 12.0 ± 0.2 °, 13.6 ± 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 at 2θ between 13.0-14.0 °.

Another object of the present invention is to provide a method for preparing crystal form J of lenalidomide, which method comprises crystallizing lenalidomide from an aqueous phosphoric acid solution to obtain crystal form J of lenalidomide.

Another object of the present invention is to provide a method for preparing lenalidomide crystal form J. The method includes the following steps: (1) adding lenalidomide to an aqueous phosphoric acid solution, heating and stirring to dissolve it, and obtaining A solution of phosphoric acid of nalidamine; (2) optionally, filtering the solution obtained in step (1); (3) cooling the solution obtained in step (1) or (2) to -5 to 5 ° C, and crystallizing; (4) Crystalline form J of lenalidomide was isolated.

Another object of the present invention is to provide a pharmaceutical composition containing 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 mixed with one or more pharmaceutically acceptable solid or liquid diluents and / or excipients and made into a galenic formulation. In one embodiment, the invention provides a pharmaceutical composition comprising lenalidomide Form J of the invention, and one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide a crystalline form J of lenalidomide for use in preparing an antitumor medicament.

The following will describe the content of the present invention in detail:

In a specific embodiment, the lenalidomide crystal form J according to the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 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 ° 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 crystal form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 2θ expressed in degrees is 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, the lenalidomide crystal form J is characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG. 1.

In another embodiment, the lenalidomide crystal form J is characterized in that its DSC spectrum has a first endothermic peak at 110-117 ° C and a second endothermic peak at 266-271 ° C.

In yet another embodiment, the lenalidomide crystal form J is characterized in that its DSC pattern is substantially as shown in FIG. 3.

In one embodiment, the lenalidomide crystal form J is a dihydrate crystal form.

In a specific embodiment, the weight-volume ratio of lenalidomide to the aqueous phosphoric acid solution according to the present invention is 1: 20-1: 500 (g / mL), preferably 1: 30-1: 60 (g / mL).

In a specific embodiment, the concentration of the phosphoric acid aqueous solution according to the present invention is 0.1% -50% (mL / mL), preferably 1% -5% (mL / mL).

In a specific embodiment, in step (3), the solution is cooled to -5 ° C, 0 ° C, or 5 ° C to crystallize.

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

In a further aspect, the present invention also provides a method for treating a tumor disease, the method comprising administering an effective amount of lenalidomide, Form J to an individual in need.

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

The present invention will be further described with reference to the following examples, but it should be understood that these examples are for illustrative purposes only and should not be construed as limiting the implementation of the present invention.

General definitions and terms

Unless stated otherwise, 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. In case of 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 value and a preferred lower numerical value, it should be understood that it is equivalent to specifically revealing that the Any range combined with any lower range limit or preferred value, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

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

The expression "comprising" or similar expressions "including," "containing," and "having" are open-ended, and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of" excludes any element, step, or ingredient not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps or ingredients, plus elements, steps or ingredients that are optionally present and do not substantially affect the basic and new characteristics of the claimed subject matter. It should be understood that the expression "comprising" covers the expressions "consisting essentially of" and "consisting of".

The term "optional" or "optionally" as used herein refers to an event or situation described later that may or may not occur, and the description includes the occurrence or non-occurrence of the event or situation. For example, in the method for preparing the crystalline form J of lenalidomide, "optional, filtering ..." means that filtering may or may not be performed.

Unless stated otherwise, percentages, parts, etc. herein are by weight.

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

As used herein, the term "amorphous" refers to any solid matter that is unordered in three dimensions.

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

As used herein, the term "X-ray powder diffraction (XRPD) pattern" refers to a diffraction pattern observed experimentally or a parameter, data, or value derived therefrom. XRPD patterns are usually characterized by peak position (abscissa) and / or peak intensity (ordinate).

As used herein, the term "2θ" refers to a peak position expressed in degrees (°) based on an X-ray diffraction experiment set, and is generally an abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms a θ angle with a lattice plane, the experimental setup needs to record the reflected beam at a 2θ angle. It should be understood that the specific 2θ value of the specific crystal form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, Cu-Kα (Kα1 is 1.5418Å) is used as the radiation source. XRPD patterns herein can be acquired, for example, on a Rigaku D / max-2200 X-ray powder diffraction analyzer. An exemplary test condition may be a scanning speed of 4 ° / min and a scanning step width of 0.01 °.

As used herein, the term "substantially" for X-ray diffraction peaks means taking into account representative peak positions and intensity variations. For example, those with ordinary knowledge in the technical field to which the present invention pertains will understand that the peak position (2θ) will show some changes, usually as much as 0.1-0.2 degrees (± 0.1 to ± 0.2 degrees), and the instrument used to measure diffraction will also cause Some changes. In addition, those with ordinary knowledge in the technical field to which the present invention pertains will understand that the relative peak intensities will vary due to differences between instruments and the degree of crystallinity, preferred orientation, prepared sample surface, and other known to those with ordinary knowledge in the technical field to which the present invention pertains. Factors, and should be considered as qualitative measurements only.

As used herein, differential scanning calorimetry (DSC) determines the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the thermal transition temperature and melting point error are typically within about 5 ° C in continuous analysis. When a compound is described to have a given DSC peak or melting point, it means that the DSC peak or melting point is ± 5 ° C. "Basically" also takes this temperature change into account. DSC provides an auxiliary method to distinguish different crystal forms. Different crystal morphologies can be identified based on their different transition temperature characteristics. It should be pointed out that the DSC peak or melting point of the mixture may vary within a larger range. In addition, since the decomposition is accompanied by the melting process of the substance, the melting temperature is related to the heating rate. The DSC pattern can be measured, for example, on an instrument of the model NETZSCH DSC200 F3 Jaia, for example. Exemplary test conditions are a heating rate of 10 ° C / min, and a temperature range: 25-300 ° C.

As used herein, infrared absorption spectroscopy (FTIR) can be used to study the structure and chemical bonds of a molecule, and it can also be used as a method to characterize and identify chemical species. In this paper, FTIR is used to characterize the molecular structure and crystal form of lenalidomide Form J. Compounds in solid form can usually be measured by KBr tableting. FTIR can be acquired, for example, on an infrared spectrophotometer model BRUKER VECTOR 22. An exemplary test condition is the KBr compression method with a scanning range of 400-4000 cm ^-1 .

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

Crystal form of lenalidomide J

In one embodiment, the present invention provides crystalline form J of lenalidomide, using X-ray powder diffraction (XRPD) spectra of Cu-Kα radiation, with 2θ in degrees 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 2θ has only one diffraction peak between 13.0-14.0 °.

In a specific embodiment, the lenalidomide crystal form J according to the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 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 ° 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 crystal form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 2θ expressed in degrees is 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 crystal form J of the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern, 2θ expressed in degrees is 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 °, 34.7 ± 0.2 °, and there is only one diffraction peak at 2θ between 13.0-14.0 °.

In a further embodiment, the lenalidomide crystal form J according to the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern has a 2θ value, a d value, and a relative intensity (L / L ₀ ): [Table 1]

In a further embodiment, the lenalidomide crystal form J according to the present invention has a peak at a diffraction angle (2θ) substantially the same as that shown in FIG. 1. In another embodiment, Form J has an X-ray powder diffraction spectrum substantially as shown in FIG. 1.

In a further embodiment, the lenalidomide crystal form J according to the present invention has a peak at the same diffraction angle (2θ) as shown in FIG. 1. In another embodiment, Form J has an X-ray powder diffraction spectrum as shown in FIG. 1.

In another embodiment, lenalidomide the present invention is an amine Form J, with a KBr tablet infrared absorption spectra measured at about ^{3448.7 cm -1, 3356.7 cm -1,} 3267.8 cm -1, 3057.0 cm - ^{1, 2852.7 cm -1, 1738.9 cm} -1, 1690.4 cm -1, 1638.4 cm -1, 1492.6 cm -1, 1460.4 cm -1, 1446.0cm -1, 1422.6 cm -1, 1367.1 cm -1, 1351.7 cm - ^{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 , 470.6 cm ^-1 and 420.4 cm ^-1 .

In a specific embodiment, lenalidomide according to the present invention an amine Form J, with a KBr tablet infrared absorption spectrum was measured at about ^{3448.7 cm -1, 3356.7 cm -1,} 3267.8 cm -1, 3057.0cm - ^{1, 2852.7 cm -1, 1738.9 cm} -1, 1690.4 cm -1, 1638.4 cm -1, 1492.6 cm -1, 1460.4 cm -1, 1446.0 cm -1, 1422.6 cm -1, 1367.1 cm -1, 1351.7 cm - ^{1, 1302.0 cm -1, 1261.7 cm} -1, 1234.6 cm -1, 1207.0 cm -1, 1179.3 cm -1, 1089.9 cm -1, 1055.7 cm -1, 997.0 cm -1, 920.2 cm -1, 894.4 cm - ^{1, 833.3 cm -1, 814.4 cm} -1, 790.4 cm -1, 759.4 cm -1, 699.0 cm -1, 607.6 cm -1, 558.1 cm -1, 488.0 cm -1, 470.6 cm -1, 420.4 cm - There are characteristic peaks at ^one place.

In a preferred embodiment, the crystalline form J of lenalidomide according to the present invention has a characteristic peak at a peak position substantially the same as that shown in FIG. 2. In a further embodiment, the crystalline form J of lenalidomide has an infrared absorption spectrum substantially as shown in FIG. 2.

In a further embodiment, the crystalline form J of lenalidomide has a characteristic peak at the same peak position as shown in FIG. 2. In a further embodiment, Form J has an infrared absorption spectrum as shown in FIG. 2.

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

In a preferred embodiment, the lenalidomide crystal form J according to the present invention has a characteristic peak at a temperature substantially the same as that shown in FIG. 3. In another embodiment, the crystalline form J of lenalidomide has a DSC pattern substantially as shown in FIG. 3.

In a further preferred embodiment, the lenalidomide crystal form J according to the present invention has a characteristic peak at the same temperature as shown in FIG. 3. In a further embodiment, the crystalline form J of lenalidomide has a DSC pattern as shown in FIG. 3.

In one embodiment, the crystalline form J of lenalidomide according to the invention has a weight loss curve substantially the same as that shown in FIG. 4. In a preferred embodiment, the crystalline form J of lenalidomide has a TGA pattern substantially as shown in FIG. 4.

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

Crystal form of lenalidomide J Preparation method

The present invention also provides a method for preparing the crystalline form J of lenalidomide, which comprises crystallizing nalidonium from an aqueous phosphoric acid solution in order to obtain the crystalline form J of lenalidomide.

In a preferred embodiment, the present invention provides a method for preparing the crystalline form J of lenalidomide, which method comprises the following steps: (1) adding lenalidomide to an aqueous phosphoric acid solution, heating and stirring to dissolve it to obtain A solution of lenalidomide in phosphoric acid; (2) optionally, filtering the solution obtained in step (1); (3) cooling the solution obtained in step (1) or (2) to -5 to 5 ° C, and crystallizing; (4) ) The lenalidomide crystal form J was isolated.

In a preferred embodiment, the weight-volume ratio (g / mL) of lenalidomide to the aqueous phosphoric acid solution is 1: 20-1: 500, preferably 1: 30-1: 60. Such selection can make the method of the present invention obtain an excellent yield when preparing the form J.

In a preferred embodiment, the concentration of the phosphoric acid aqueous solution is 0.1% -50% (mL / mL), preferably 1% -5% (mL / mL).

Unless specifically stated, "heating" in the preparation method is to promote the dissolution of the compound. The heating temperature 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 60-90 ° C, such as 60 ° C, 70 ° C, 80 ° C, 85 ° C, 90 ° C.

Unless specifically stated, the speed and time of "stirring" in the step of adding lenalidomide to the crystallization solvent is not particularly limited, as long as the lenalidomide can be completely dissolved in the future. The preferred stirring time is 20-40 minutes, and more preferably 30 minutes.

The crystallization temperature in the preparation method should be such that crystal 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 specifically stated, the "crystallization" in the preparation method may be performed during stirring or standing. Crystallization can be performed for about 6-60 hours, such as about 48 hours, 36 hours, 24 hours, and 12 hours.

The prepared crystal form is separated and recovered by methods 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 crystal form J may be optionally dried. Drying may be performed at a temperature of about 60 ° C or lower, about 50 ° C or lower, about 45 ° C or lower, about 40 ° C or lower, about 35 ° C or lower, or about 20 ° C or lower, or any other suitable temperature. Drying can be performed, 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 present 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 administered with a therapeutic agent, and it is within the scope of sound medical judgment Suitable for contact with human and / or other animal tissues without undue toxicity, irritation, allergic reactions 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, mineral oil Wait. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, especially for injections. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silicone, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerol, propylene glycol, water, ethanol, and the like. The composition may further contain a small amount of a wetting agent, an emulsifying agent, or a pH buffering agent as necessary. 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 described in Remington's Pharmaceutical Sciences (1990).

The composition according to the invention can act systematically and / or locally. To this end, they can be administered by a suitable route, such as by injection, intra-arterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal; orally, nasally, bucally, transmucosally, topically, It is administered in the form of an ophthalmic preparation or by inhalation.

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

The pharmaceutical composition 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 the amount of a compound that, when administered, will to some extent alleviate one or more symptoms of the condition being treated.

The dosing regimen can be adjusted to provide the best 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 a therapeutic situation. It is to be noted that the dose value may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time based on the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.

As used herein, unless otherwise stated, the term "treating" means reversing, alleviating, inhibiting the condition or condition to which such term is applied or the progression of one or more symptoms of such condition or condition, or preventing such condition Or a condition or one or more symptoms of such a condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease, such as a disease described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as amphibians, reptiles, birds) and mammals, such as non-human primates, domestic animals, and / or domesticated animals (such as dogs, cats, Sheep, dairy cows, pigs, etc.).

Beneficial effect

The lenalidomide new crystal form J of the present invention has good solubility, simple crystallization process, easy operation, low pollution, and can realize industrialized production. Moreover, the crystalline drug of the present invention also has high product purity, excellent physical and chemical properties, and high temperature / high Good wet and chemical and physical stability, excellent processing (filtration, drying, dissolution, and tableting), reproducible advantages, and good solubility, dissolution, dissolution time and biological release, it has a good market Application prospects.

<Example>

The following examples further explain the present invention, the purpose of which is only to better understand the content of the present invention, they do not constitute a limitation or limitation on the protection scope of the present invention.

Lenalidomide crystal form J Preparation and characterization

In the method for preparing lenalidomide crystal form J described in the examples of the present invention, there is no particular limitation on the crude lenalidomide used. It can be obtained commercially, or according to a known method, for example, a method described in patent document US5635517A. Prepared.

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

Test instrument information and methods

The X-ray powder diffraction apparatus and test conditions involved in the present invention are: X-ray diffraction model Rigaku D / max-2200 Cu target; operation method: scanning speed 4 ° / min, scanning step width 0.01 °.

The infrared spectrophotometer and test conditions involved in the present invention are: the infrared spectrophotometer model: BRUKER VECTOR 22; operation method: using KBr tablet method, scanning range 400-4000 cm ^-1 .

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

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

The high-performance liquid chromatography (HPLC) test conditions involved in the present invention are: the chromatographic column is an Agilent Zorbax SB-CN; 4.6 × 250 mm, 5 μm or an equivalent chromatographic column; Add 1000 mL of water to dissolve, add 1 mL of phosphoric acid, mix well, adjust the pH to 2.50 with 0.1 mol / L sodium hydroxide): acetonitrile = 92: 8; detection wavelength: 210 nm; flow rate: 1.0 mL / min; Sample volume: 10 µL; column temperature: 25 ° C.

The ion chromatography test conditions involved in the present invention are: chromatographic column is lonpac AG11; 4.0 × 50 mm, Guard lonpacAS11-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 volume: 25 µL; column temperature: 30 ° C.

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

Examples 1

In the future, 10 g of crude nalidamine (HPLC purity = 98%) is added to 200 mL of a 50% (mL / mL) phosphoric acid aqueous solution, heated to 60 ° C, continuously stirred for 30 minutes, and dissolved to clear to obtain lenalidomide. Solution. The resulting solution was cooled to 5 ° C., and stirred for crystallization 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% as measured by HPLC. At 20 ppm, the X-ray powder diffraction pattern, infrared absorption pattern, DSC pattern, and TGA pattern of this crystal form are shown in Figures 1-4, respectively, and they are defined as lenalidomide Form J. According to the TGA spectrum, it is known that the crystal form J is a dihydrate.

Examples 2

In the future, 10 g of crude nalidamine (HPLC purity = 98%) is added to 5 L of a 0.1% (mL / mL) phosphoric acid aqueous solution, heated to 90 ° C, continuously stirred for 30 minutes, and dissolved to obtain lenalidomide. Solution. The resulting solution was cooled to 0 ° C, and was left to stand for crystallization 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. X-ray powder diffraction detection showed that It is a new crystalline form J.

Examples 3

In the future, 10 g of crude nalidamine (HPLC purity = 98%) was added to 600 mL of a 1% (mL / mL) phosphoric acid aqueous solution, heated to 85 ° C, stirred continuously for 30 minutes, and dissolved to clear to obtain lenalidomide. Solution. After filtration, the obtained filtrate was cooled to -5 ° C, and was crystallized by stirring 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 showed that it was the new crystal form J.

Examples 4

In the future, 10 g of crude nalidamine (HPLC purity = 98%) is added to 600 mL of a 1% (mL / mL) phosphoric acid aqueous solution, heated to 80 ° C, continuously stirred for 30 minutes, and dissolved to clear to obtain lenalidomide. Solution. After filtration, the resulting filtrate was cooled to 0 ° C, and was stirred and crystallized at 0 ° C for 24 hours. The crystal was filtered and dried under vacuum at 50 ° C to obtain 7.8 g of crystals. The purity was 99.8% by HPLC. It is a new crystalline form J.

Examples 5

In the future, 10 g of crude nalidamine (HPLC purity = 98%) was added to 300 mL of a 5% (mL / mL) phosphoric acid aqueous solution, heated to 70 ° C, continuously stirred for 30 minutes, and dissolved to clear to obtain a lenalidomide solution. . After filtration, the obtained filtrate was cooled to 0 ° C, and was stirred and crystallized at 0 ° C for 12 hours. The crystals were 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 that It is a new crystalline form J.

Stability test

High temperature experiment

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

High humidity experiment

The lenalidomide crystal forms J and E prepared in Example 1 were evenly distributed to open petri dishes with a thickness of 5 mm or less, and then placed at room temperature (25 ° C) with a relative humidity of 75 ± 5%. In a constant temperature and humidity incubator, samples were taken on the 5th and 10th days for measurement and compared with the results on the 0th day. Among them, the hygroscopicity results of lenalidomide Form J are shown in Table 4. It can be seen that Form 5 has only a slight hygroscopic weight gain after 5 and 10 days. The appearance, melting point, and content of Form J are similar to those of Form J. The samples at day 0 were essentially the same. The X-ray diffraction pattern of Form J after standing at a relative humidity of 75 ± 5% at room temperature (25 ° C) for 10 days is shown in Figure 7, the XRPD data is shown in Table 5, the DSC picture is shown in Figure 8, and the TGA picture is shown Figure 9. The DSC chart 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 Form J after being left for 10 days in a high humidity environment are basically the same as those of 0 days, showing good high humidity stability. 【Table 4】 【table 5】

The experimental results of the comparative hygroscopicity of lenalidomide form J and lenalidomide form E are shown in FIG. 10. From FIG. 10, it can be seen that the hygroscopicity of lenalidomide form J is significantly lower than that of known crystals. Form E indicates that Form J has higher stability.

Crystal Form Stability Test

Sample retention conditions: The prepared Form B, Form E, and Form J are kept tightly closed and stored at 25 ° C for 6 months to examine the change of the crystal form. [Table 6]

As can be seen from Table 6, Form J has excellent stability. The DSC spectra of Form B and Form J after leaving the sample for 6 months showed almost no significant changes compared with those before the sample retention. Form E is unstable. The DSC spectrum after Form E transformation is shown in Figure 11, which is significantly different from the DSC spectrum before sample retention.

Crystal type comparison test

After Form E and Form J were mixed by shaking at a ratio of 1: 1, the state of the crystal form of the mixture was observed.

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

Solubility test

The method of measuring solubility is as follows:

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

Detection wavelength: 215 nm, flow rate: 1.0 mL / min, injection volume: 10 µL, column temperature: 25 ° C

Running time: 14 minutes

Thinner: Thinner 1 is acetonitrile: water = 40: 60, Thinner 2 is 0.01 N HCl

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

Preparation of reference solution: Weigh approximately 25 mg of lenalidomide reference into a 50 mL volumetric flask, dissolve with diluent 1 and dilute to the mark, and mix. Accurately transfer 5.0 mL to 25 mL volumetric flasks, dilute to the mark with Diluent 2 and mix to obtain a reference solution (containing lenalidomide 0.1 mg / mL).

Sample solution: Take an appropriate amount of the test product (approximately 0.3 g) to a 25 mL volumetric flask, add 5 mL of solvent (pH = 1.2, pH = 2, pH = 4.5, pH = 6.8, pH = 7.5) and mix, and place in a 37 ° C water bath After shaking for 24 hours, take out and immediately filter. After discarding 1-2ml of the initial filtrate, collect the continuous filtrate, and accurately transfer the appropriate amount of the continuous filtrate and dilute with 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 Form B.

Dissolution test

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

Formula of lenalidomide crystal J capsule: [Table 8]

Preparation method of lenalidomide crystal J capsule:

Take the formula of the lenalidomide crystal form J, lactose, microcrystalline cellulose, and croscarmellose sodium, make a soft material with 95% ethanol solution, sieve, blow at 50-60 ° C Dry, sieve the whole granules, mix with magnesium stearate and fill the capsules.

Formula of Lenalidomide Crystalline E Capsules: [Table 9]

Preparation method of lenalidomide crystal E capsule:

Take the formula amount of lenalidomide crystal form E, lactose, microcrystalline cellulose, croscarmellose sodium, make a soft material with 95% ethanol solution, sieve, blow dry at 50-60 ℃, The whole granules are sieved, mixed with magnesium stearate and filled with capsules.

Test method for lenalidomide dissolution:

Test equipment: stirring paddle, dissolution cup, sedimentation basket, electric motor.

Test procedure: (1) Debug the instrument so that the bottom of the stirring paddle is 25 mm ± 2 mm from the bottom of the dissolution vessel; (2) Sample injection, take 900 mL of degassed solution, 0.01 N hydrochloric acid solution and place it in the dissolution vessel. Lenalidomide capsules; (3) Start the instrument and control the speed 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 dissolution test results of lenalidomide Form J and Form E are shown in Table 10: [Table 10]

From the results of the dissolution experiment, it can be known that 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 applications.

Those with ordinary knowledge in the technical field to which the present invention belongs can understand that the meaning or intended protection range of the numerical values or numerical endpoints involved in the technical solution of the present invention is not limited to the number itself, and they include those that have been used by the present invention. The permissible error ranges widely accepted in the technical field, such as experimental errors, measurement errors, statistical errors, random errors, etc., are all included in the scope of the present invention.

However, the above are only examples of the present invention. When the scope of implementation of the present invention cannot be limited in this way, any simple equivalent changes and modifications made in accordance with the scope of the patent application and the content of the patent specification of the present invention are still Within the scope of the invention patent.

Other features and effects of the present invention will be clearly presented in the embodiment with reference to the drawings, in which: [Fig. 1] is an X-ray powder diffraction pattern of lenalidomide crystal form J obtained in Example 1 of the present invention; [Fig. 2] is an infrared absorption spectrum of lenalidomide crystal form J obtained in Example 1; [Fig. 3] is a DSC spectrum of lenalidomide crystal form J obtained in Example 1; [Fig. 4] is the implementation TGA spectrum of lenalidomide crystal form J obtained in Example 1; [Fig. 5] X-ray diffraction pattern of the stability of lenalidomide crystal form J obtained in Example 1 at 60 ° C for 10 days; 6] DSC chart of the lenalidomide crystal form J obtained in Example 1 at 60 ° C for 10 days; [Fig. 7] This is the lenalidomide crystal form J obtained in Example 1 at a relative humidity of X-ray diffraction pattern after 75 days at 75 ± 5%; [Figure 8] DSC pattern of lenalidomide Form J obtained in Example 1 after 10 days at a relative humidity of 75 ± 5%; 9] TGA diagram of lenalidomide crystal form J obtained in Example 1 after 10 days at a relative humidity of 75 ± 5%; [Fig. 10] Comparison of the hygroscopicity experimental curves of crystal form J and crystal form E Figure where Represents crystal form J, Represents Form E; [Fig. 11] is a DSC chart of Form E after leaving a sample; [Fig. 12] is a DSC chart obtained by mixing Form E and Form J in a 1: 1 ratio; and [Fig. 13] Comparison chart of the dissolution curves of Form J and Form E, where Represents crystal form J, Represents crystalline form E.

Claims (15)

A lenalidomide crystal form J, characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern, 2θ in degrees are 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 at 2θ between 13.0-14.0 °, where the lenalidomide crystal form J is dihydrate物 crystalline form. The lenalidomide crystal form J as described in claim 1, wherein the X-ray powder diffraction pattern of Cu-Kα radiation is 2θ in degrees 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 °, 25.4 ± 0.2 There are characteristic peaks at °, 26.7 ± 0.2 °, 27.5 ± 0.2 °, and there is only one diffraction peak at 2θ between 13.0-14.0 °. The lenalidomide crystal form J according to claim 1 or 2, wherein the X-ray powder diffraction pattern of Cu-Kα radiation is used, and 2θ expressed in degrees is 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 ° Characteristic peak, and 2θ has only one diffraction peak between 13.0-14.0 °. The lenalidomide crystal form J according to claim 1 or 2, wherein the X-ray powder diffraction pattern thereof is substantially as shown in FIG. The lenalidomide crystal form J according to claim 1 or 2, wherein the DSC spectrum has a first endothermic peak at 110-117 ° C and a second endothermic peak at 266-271 ° C. The lenalidomide crystal form J according to claim 1 or 2, wherein the DSC pattern thereof is basically as shown in FIG. 3. A method for preparing lenalidomide crystal form J according to any one of claims 1 to 6, wherein the method comprises crystallizing lenalidomide from an aqueous phosphoric acid solution in order to obtain the lenalidomide. Crystalline form of amine J. A method for preparing lenalidomide crystal form J according to any one of claims 1 to 6, the method comprising the following steps: (1) adding lenalidomide to an aqueous phosphoric acid solution, heating and stirring to dissolve it To obtain a phosphoric acid aqueous solution of lenalidomide; (2) optionally, filtering the solution obtained in step (1); (3) cooling the solution obtained in step (1) or (2) to -5 to 5 ° C, and crystallizing; And (4) lenalidomide crystal form J was isolated. The method according to claim 7 or 8, wherein the weight-volume ratio of the lenalidomide to the aqueous phosphoric acid solution is 1: 20-1: 500 (g / mL). The method according to claim 7 or 8, wherein the weight-volume ratio of the lenalidomide to the aqueous phosphoric acid solution is 1: 30-1: 60 (g / mL). The method according to claim 7 or 8, wherein the concentration of the phosphoric acid aqueous solution is 0.1% -50% (mL / mL). The method according to claim 7 or 8, wherein the concentration of the phosphoric acid aqueous solution is 1% -5% (mL / mL). The method according to claim 8, wherein in step (3), the solution is crystallized by lowering the temperature to -5 ° C, 0 ° C, or 5 ° C. A use of lenalidomide crystal form J according to any one of claims 1 to 6 in the preparation of an antitumor medicament. A pharmaceutical composition comprising the lenalidomide crystal form J according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers.