CN112062751A

CN112062751A - Novel crystal of lenalidomide and pharmaceutical composition thereof

Info

Publication number: CN112062751A
Application number: CN202010856246.4A
Authority: CN
Inventors: 高策; 程兴栋; 张爱明; 夏春光; 张喜全; 杨玉雷; 朱雪焱
Original assignee: Shanghai Institute of Pharmaceutical Industry; Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Shanghai Institute of Pharmaceutical Industry; Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2017-08-04
Filing date: 2017-08-04
Publication date: 2020-12-11
Also published as: CN107400115A

Abstract

The present application relates to a novel crystal of lenalidomide and a pharmaceutical composition thereof. Also relates to a crystal composition containing the new crystal of lenalidomide, a pharmaceutical composition thereof and application thereof. The lenalidomide new crystal provided by the application has the advantages of high purity, high crystallinity, good stability and small particle size change.

Description

Novel crystal of lenalidomide and pharmaceutical composition thereof

The application is a divisional application of Chinese patent application with the application number of 201710658382.0, the application date of 2017, 8 and 4, and the invention name of 'a new crystal of lenalidomide and a pharmaceutical composition thereof'.

Technical Field

The application belongs to the field of pharmaceutical chemistry, and particularly relates to a novel crystal of lenalidomide, a crystal composition containing the crystal, a pharmaceutical composition containing the crystal or the crystal composition, and applications of the crystal and the pharmaceutical composition.

Background

Lenalidomide (lenalidomide) is chemically 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-diketone and has a structure shown in a formula I.

It was developed by celgene corporation and is a thalidomide analog that is an immunomodulatory drug. One of the therapies FDA approved lenalidomide capsules for the treatment of myelodysplastic syndrome, multiple myeloma in combination with dexamethasone, and mantle cell lymphoma that recurs or develops further after two rounds of treatment is the use of bortezomib.

WO2005023192 discloses various crystals of lenalidomide. Further, other crystals of lenalidomide are disclosed in the following documents: WO2010061209, CN101696205, CN102060842, CN102127054, CN101817813, CN102453020, WO2011111053, etc.

Since lenalidomide crystals having different physical properties and the like have important effects on clinical medication, research is continuously required to develop new crystals of lenalidomide suitable for pharmaceutical preparations.

Disclosure of Invention

In one aspect, the present application provides a crystal of lenalidomide having an X-ray diffraction pattern with diffraction peaks with a 2 Θ of 8.18, 12.33, 14.68, 16.10, and 20.91 ± 0.2 °.

In some embodiments of the present application, the crystalline lenalidomide has an X-ray diffraction pattern having diffraction peaks with a 2 Θ of 8.18, 12.33, 14.68, 16.10, 17.94, 20.91, 24.09, and 24.41 ± 0.2 °.

In some embodiments of the present application, the crystal of lenalidomide has an X-ray diffraction pattern having diffraction peaks with a 2 Θ of 8.18, 11.59, 12.33, 14.68, 16.10, 16.54, 17.94, 20.91, 21.20, 22.42, 24.09, 24.41, 25.58, 26.35, 28.61, and 32.91 ± 0.2 °.

In some embodiments of the present application, the crystalline lenalidomide has an X-ray diffraction pattern characterized by:

serial number	2θ±0.2(°)	Relative Strength (%)	Serial number	2θ±0.2(°)	Relative Strength (%)
						1	8.18	40.4％	19	20.47	3.8％
2	8.38	1.3％	20	20.91	29.9％
						3	10.54	2.7％	21	21.20	10.5％
4	10.95	1.3％	22	21.65	1.0％
						5	11.59	5.0％	23	22.42	7.7％
6	12.33	31.3％	24	22.88	2.4％
						7	13.43	1.3％	25	24.09	17.7％
8	14.18	3.0％	26	24.41	18.6％
						9	14.68	100.0％	27	24.80	1.2％
10	15.08	3.3％	28	25.14	1.1％
						11	15.54	2.7％	29	25.58	9.6％
12	16.10	49.5％	30	26.35	7.3％
						13	16.54	7.6％	31	26.93	4.8％
14	17.94	11.3％	32	27.81	2.0％
						15	18.34	1.2％	33	28.61	8.3％
16	18.72	0.7％	34	29.29	5.5％
						17	19.44	1.8％	35	29.56	3.2％
18	19.86	1.9％

in some embodiments of the present application, the crystalline lenalidomide has an X-ray diffraction pattern as shown in figure 1.

Wherein the above-mentioned crystallization of lenalidomide is a crystallization substantially free of crystallization water and/or other solvents.

Note that the present application includes not only crystals in which the diffraction angles of the peaks in the X-ray powder diffraction are completely uniform or ± 0.2 °, but also crystals in which the diffraction angles are uniform with an error of ± 0.2 °.

The present application further provides a method for preparing the above lenalidomide crystal, comprising the steps of:

1) dissolving lenalidomide in 90% ethanol, and heating to dissolve the lenalidomide clearly; and

2) devitrification and optionally filtration, washing and/or drying.

The preparation method of the 90% ethanol comprises the following steps: 90mL of ethanol and 12mL of water were prepared to obtain 100mL of 90% ethanol.

In some embodiments of the present application, the amount of 90% ethanol used per 1g lenalidomide is selected from 50 to 200g, preferably from 80 to 150g, most preferably from 90 to 120g, for example 100 g. Naturally cooling and crystallizing, wherein the crystallization time can be 3-8h, preferably 5 h.

In a specific embodiment of the present application, the method for preparing the lenalidomide crystal comprises: dissolving lenalidomide 1g in 90% ethanol 100g, heating to dissolve, naturally cooling, crystallizing for 5 hr, and filtering. Further drying at room temperature is possible.

In another aspect, the present application provides a crystalline composition comprising the above-described lenalidomide crystal. In some embodiments of the present application, the lenalidomide crystals comprise 50% or more, or 80% or more, or 90% or more, or 95% or more, or 99% or more, or 99.5% or more of the crystalline composition by weight. The crystalline composition may contain other crystalline or amorphous forms of lenalidomide.

The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline lenalidomide or the crystalline composition described above. In addition, the pharmaceutical composition may or may not contain one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

In some embodiments of the present application, the pharmaceutical composition may be in the form of a capsule formulation, and may comprise crystalline lenalidomide or the crystalline composition described above, lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate. The preparation process can be as follows: sieving lenalidomide crystal or the above crystal composition, lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate for pretreatment, adding into a hopper mixer, mixing, and filling with a capsule filling machine.

Further, the present application provides a use of the above-mentioned crystal of lenalidomide, or the above-mentioned crystal composition or the above-mentioned pharmaceutical composition for the preparation of a medicament for treating or preventing cancer.

In some embodiments of the present application, the cancer is preferably a solid tumor or a hematological tumor, such as myelodysplastic syndrome, multiple myeloma or multiple myeloma treated with dexamethasone, mantle cell lymphoma, or the like.

In the present application, the X-ray diffraction pattern is determined by the following method: using an X-ray powder diffractometer of D8 ADVANCE, taking a proper amount of the sample, and determining according to the operating procedure of X-ray powder diffraction method (Q/SOP ZL075-04), wherein the X-ray powder diffraction spectrum of the sample (the blind area of the X-ray diffractometer should not be more than 3 degrees, and the measuring range is 3-40 degrees)

It is noted that in X-ray diffraction spectroscopy, the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. In addition, there may be slight errors in the position of the peaks for any given crystalline form, which is also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, movement of the sample, calibration of the instrument, or the like, and the measurement error of the 2 θ value may be about ± 0.2 °. Therefore, this error should be taken into account when determining each type of structure. The peak position is usually expressed in the XRPD pattern as 2 θ angle or crystal plane distance d, with a simple conversion between the two: d ═ λ/2sin θ, where d represents the interplanar spacing, λ denotes the wavelength of the incident X-rays, and θ denotes the diffraction angle. For the same crystal form of the same compound, the peak positions of the XRPD spectrum have similarity on the whole, and the relative intensity error can be larger.

Drawings

Figure 1 the X-ray powder diffraction (XRPD) pattern of lenalidomide crystals prepared in example 1.

Detailed Description

The following examples further illustrate the present invention in non-limiting detail. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. The solvents, reagents, raw materials and the like used in the present application are all commercially available chemically pure or analytically pure products.

Example 1 preparation of novel crystals of lenalidomide

Adding 100g of 90% ethanol into a reaction bottle, magnetically stirring, heating to reflux, adding 1g of lenalidomide, dissolving and cleaning, decoloring with active carbon for 15min, filtering, naturally cooling and crystallizing for 5h, filtering, washing a filter cake with a small amount of ethanol, and drying at room temperature to obtain the crystal of the lenalidomide. The XRPD pattern is shown in figure 1 after detection.

Example 2 preparation of novel crystals of lenalidomide

Adding 100g of 90% ethanol into a reaction bottle, magnetically stirring, heating to reflux, adding 1g of lenalidomide, dissolving and cleaning, decoloring with active carbon for 15min, filtering, naturally cooling and crystallizing for 5h, filtering, washing a filter cake with a small amount of ethanol, and drying at room temperature to obtain the crystal of the lenalidomide. The XRPD pattern was determined to be substantially in accordance with figure 1.

Example 3 particle size investigation of New Lenalidomide crystals

The lenalidomide crystals obtained in example 1 were taken and subjected to air-jet pulverization. The crushed lenalidomide crystals are used as samples and placed under certain investigation conditions, and the particle sizes of the lenalidomide crystals are detected at 0 month, 3 months, 6 months and 36 months respectively. The corresponding specific results are shown in table 1.

Wherein, certain investigation conditions are as follows: 25 +/-2 ℃ and RH 60% +/-5%; the samples were packed using pharmaceutical low density polyethylene bags.

The particle size detection method comprises the following steps: taking a proper amount (20-80 mg) of a corresponding sample, applying a RODOS/M type laser particle size analyzer of New Partach, Germany, selecting an R2 lens, wherein the dispersion pressure is 3-5 bar, and checking according to a particle size and particle size distribution determination method (0982 third method in the 2015 edition of Chinese pharmacopoeia).

TABLE 1 results of particle size experiments on lenalidomide crystals obtained in example 1 at various times

Example 4 preparation of crystalline capsules of lenalidomide obtained in example 1

(1) 1.00kg of lenalidomide (namely, lenalidomide crystal after jet milling in example 3), 2.54kg of lactose and 240.0g of croscarmellose sodium are mixed and sieved by a 60-mesh sieve; then mixing with the rest 2.54kg of lactose and sieving with a 60-mesh sieve for later use;

(2) adding the pretreated raw and auxiliary materials, 1.64kg of microcrystalline cellulose and 40.0g of magnesium stearate into a hopper mixer for total mixing, and sampling to detect an intermediate product;

(3) after the intermediate product is qualified, filling the intermediate product by using a capsule filling machine according to the content of the intermediate product and the converted standard filling amount;

(4) the resulting 25mg size lenalidomide capsules were packaged using an automatic blister pack machine.

Example 5 dissolution test of lenalidomide capsules prepared in example 4

The lenalidomide capsules (six groups in total) prepared in example 4, which are 25mg in size, are packaged in double aluminum and placed at 25 ℃ +/-2 ℃ and 60% +/-5% relative humidity, and the dissolution rates of the lenalidomide capsules are respectively detected at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months and 36 months.

Dissolution rate: taking each group of samples, taking 900ml of 0.01mol/L hydrochloric acid solution as a dissolution medium according to a dissolution and release determination method (0931 second method of the four general rules of the Chinese pharmacopoeia 2015 edition), rotating at 50 revolutions per minute, taking 10ml of solution after 30 minutes, filtering, and taking a subsequent filtrate as a test solution; taking a proper amount of lenalidomide crystals obtained in the example 1 as a reference substance, precisely weighing, adding 0.1mol/L hydrochloric acid solution for dissolving and diluting to prepare a solution containing about 0.5mg of lenalidomide per 1ml, and taking the solution as a reference substance stock solution; an appropriate amount of the control stock solution was precisely measured and diluted with 0.01mol/L hydrochloric acid solution to prepare a solution of 25. mu.g (25mg standard) per 1ml as a control solution. Precisely measuring the sample solution and the reference solution each 100 μ l according to the chromatographic conditions under the content measurement item, respectively injecting into a liquid chromatograph, and recording the chromatogram. And calculating the dissolution amount of each particle by peak area according to an external standard method.

The content measurement is performed by high performance liquid chromatography (0512 in the four-part general regulation of 2015 edition of Chinese pharmacopoeia). Chromatographic conditions and system suitability test using octadecylsilane chemically bonded silica (Waters XTerra C18, 4.6 mm. times.150 mm, 5 μm or equivalent performance column) as filler; phosphate buffer solution-methanol-acetonitrile (90:9:1) is used as a mobile phase; the detection wavelength was 240 nm. The number of theoretical plates is not less than 2000 calculated according to the lenalidomide peak. Wherein the phosphate buffer solution: taking 1.36g of anhydrous potassium dihydrogen phosphate, adding water to dissolve and dilute the anhydrous potassium dihydrogen phosphate to 1000ml, and adjusting the pH value to 3.5 +/-0.05 by using phosphoric acid.

Table 2 dissolution test results of lenalidomide capsules prepared in example 4

Claims

1. A crystal of lenalidomide having an X-ray diffraction pattern with diffraction peaks with 2 Θ of 8.18, 12.33, 14.68, 16.10, and 20.91 ± 0.2 °.

2. The crystal of lenalidomide of claim 1, having an X-ray diffraction pattern with diffraction peaks, in terms of 2 Θ, at 8.18, 12.33, 14.68, 16.10, 17.94, 20.91, 24.09, and 24.41 ± 0.2 °.

3. The crystal of lenalidomide of claim 1, having an X-ray diffraction pattern with diffraction peaks, in terms of 2 Θ, at 8.18, 11.59, 12.33, 14.68, 16.10, 16.54, 17.94, 20.91, 21.20, 22.42, 24.09, 24.41, 25.58, 26.35, 28.61, and 32.91 ± 0.2 °.

4. The crystalline lenalidomide of claim 1 having an X-ray diffraction pattern characterized by,

。

5. The crystalline lenalidomide of claim 1 having an X-ray diffraction pattern characterized by,

6. the crystalline lenalidomide of claim 1 having an X-ray diffraction pattern as shown in figure 1.

7. A crystalline composition comprising the lenalidomide crystal according to claims 1-6, wherein the lenalidomide crystal accounts for 50% or more, or 80% or more, or 90% or more, or 95% or more, or 99% or more, or 99.5% or more of the crystalline composition by weight.

8. A pharmaceutical composition comprising a therapeutically effective amount of a crystal of lenalidomide according to claims 1-6, or a crystalline composition according to claim 7, and one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

9. The pharmaceutical composition of claim 8, which is in the form of a capsule formulation comprising lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate.

10. Use of the crystal of lenalidomide according to claims 1-6 or the crystalline composition according to claim 7 or the pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment of cancer.