Pharmaceutical composition comprising neptinib or salt thereof and method for controlling impurity thereof

Abstract

A pharmaceutical composition including neptinib is provided. The composition includes neptinib or a pharmaceutically acceptable salt thereof, and an excipient at a low risk of compatibleness. Furthermore, the pharmaceutical composition of the present invention may also include pharmaceutically acceptable organic acid or inorganic acid as a stabilizer. The content of impurity A maintains a non-significant increase in the long-term and accelerated stability investigation for the pharmaceutical composition.

Claims

1. A pharmaceutical composition comprising neptinib, comprising the following components by weight: Neptinib or a pharmaceutically acceptable salt thereof 0.1%-7% Lactose and mannitol combination 70-96% Crospovidone 1-10% Colloidal silica 0.5-3% Glyceryl behenate 0.5-3% Stabilizer 0.1-15%, wherein the stabilizer is selected from the group consisting of benzoic acid, citric acid, tartaric acid, malic acid, edetic acid, and lactic acid.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of neptinib comprises neptinib dihydrochloride, neptinib dimaleate or neptinib xylenesulfonate.

3. The pharmaceutical composition according to claim 2, wherein the neptinib xylenesulfonate is a hydrate of neptinib xylenesulfonate.

4. The pharmaceutical composition according to claim 3, wherein the hydrate of neptinib xylenesulfonate comprises 1.0-1.5% crystal water in the neptinib xylenesulfonate molecule.

5. The pharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of citric acid, tartaric acid and malic acid.

6. A preparation comprising the pharmaceutical composition of claim 1, wherein its dosage form is selected from the group consisting of tablet, capsule, granule, and powder.

7. A preparation comprising the pharmaceutical composition of claim 1, wherein its dosage form is tablet coated with HPMC film.

Description

DETAILED DESCRIPTION

Examples

(1) The following examples are intended to facilitate the person skilled in the art to fully understand the technical solution and the intent of the invention, in stead of limiting the scope of the invention. The active ingredient (API, neptinib xylenesulfonate) used in Examples 1-3 was synthesized in pilot-scale by the inventors according to the methods described in Chinese Patent No. ZL201410822395.3 and ZL 201410826075.5, with the content of 99.8%-100.3% and moisture of 3.0-3.1% (determined by Karl Fischer method). Other related excipients are commercially available products.

Example 1: Selection of Excipients

(2) TABLE-US-00001 TABLE 1 Results of API and excipients compatibility study Day 10 Illumination Day 0 RH75% 5% RH92.5% 5% 60 C. 2 C. (4500 5001x) Maximum Maximum Maximum Maximum Maximum API/ single Total single Total single Total single Total single Total excipient impurity impurity impurity impurity impurity impurity impurity impurity impurity impurity Name ratio (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) API / 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.04 0.12 0.14 RRT1.21 RRT1.21 RRT1.22 RRT1.21 RRT0.93 Lactose 1:10 0.02 0.02 0.02 0.02 0.02 0.06 0.04 0.06 0.16 0.26 RRT1.22 RRT1.21 RRT1.21 RRT0.51 RRT0.93 Microcrystalline 1:10 0.02 0.02 0.05 0.08 0.04 0.08 1.19 1.21 0.13 0.20 cellulose RRT1.22 RRT0.93 RRT0.51 RRT0.51 RRT0.93 Microcrystalline 1:10 0.02 0.02 0.05 0.07 0.04 0.07 0.20 0.22 0.14 0.17 cellulose-lactose RRT1.22 RRT0.93 RRT0.93 RRT0.51 RRT0.93 compound Mannitol 1:10 0.02 0.02 0.02 0.02 0.01 0.04 0.04 0.04 0.14 0.23 RRT1.22 RRT0.93 RRT0.52 RRT0.51 RRT0.93 Pregelatinized 1:10 0.02 0.02 0.10 0.14 0.14 0.19 0.86 0.88 0.11 0.14 starch RRT1.22 RRT0.51 RRT0.51 RRT0.51 RRT0.93 Starch 1:10 0.02 0.02 0.18 0.22 0.14 0.16 2.53 2.55 0.12 0.22 RRT1.22 RRT0.51 RRT0.51 RRT0.51 RRT0.93 Starch-lactose 1:10 0.02 0.02 0.02 0.03 0.03 0.05 0.02 0.05 0.14 0.19 compound RRT1.21 RRT1.21 RRT0.52 RRT0.52 RRT0.94 Crospovidone 1:10 0.02 0.03 0.08 0.14 0.06 0.12 0.11 0.15 0.15 0.26 RRT1.22 RRT0.33 RRT0.32 RRT0.51 RRT0.93 Sodium 1:10 0.02 0.02 0.48 0.59 0.67 0.74 0.35 0.37 0.15 0.33 carboxymethyl RRT1.22 RRT0.51 RRT0.51 RRT0.51 RRT0.93 starch Cross-linked 1:10 0.02 0.02 0.10 0.19 0.05 0.14 0.12 0.14 0.16 0.32 CMCNa RRT1.22 RRT0.51 RRT 0.81 RRT0.51 RRT0.93 L-HPC 1:10 0.02 0.02 0.13 0.20 0.11 0.14 2.45 2.76 0.14 0.29 RRT1.22 RRT0.51 RRT0.51 RRT0.52 RRT0.93 Tartaric acid 1:10 0.02 0.02 0.02 0.02 0.02 0.05 0.04 0.06 0.12 0.21 RRT1.22 RRT0.93 RRT1.21 RRT0.51 RRT0.93 Citric acid 1:10 0.02 0.02 0.02 0.02 0.02 0.04 0.08 0.10 0.14 0.24 RRT1.22 RRT1.21 RRT1.21 RRT0.51 RRT0.93 Malic acid 1:10 0.02 0.02 0.04 0.04 0.05 0.06 0.12 0.14 0.11 0.20 RRT1.22 RRT1.21 RRT1.21 RRT0.51 RRT0.93 Magnesium 1:10 0.07 0.22 0.04 0.08 0.14 0.23 0.48 0.53 0.11 0.32 stearate RRT0.66 RRT0.81 RRT0.51 RRT0.51 RRT0.93 Sodium stearyl 1:10 0.06 0.13 0.08 0.14 0.55 0.65 18.35 18.69 0.10 0.34 fumarate RRT0.51 RRT0.51 RRT0.51 RRT0.52 RRT0.93 Glyceryl 1:10 0.02 0.02 0.02 0.02 0.02 0.04 0.02 0.02 0.34 0.45 behenate RRT1.22 RRT0.93 RRT0.51 RRT0.51 RRT1.39 Povidone 1:10 0.04 0.07 0.05 0.15 0.08 0.35 0.78 0.99 0.13 0.40 RRT0.51 RRT2.53 RRT0.32 RRT0.51 RRT0.93 Colloidal 1:5 0.01 0.01 0.04 0.06 0.02 0.03 0.10 0.10 0.17 0.22 silica RRT0.93 RRT0.29 RRT0.93 RRT0.51 RRT0.93 Empty gelatin 1:10 0.02 0.02 0.02 0.03 0.02 0.03 0.38 0.40 0.04 0.06 capsule RRT1.21 RRT1.21 RRT1.21 RRT0.52 RRT0.94 HPMC 1:10 0.02 0.02 0.02 0.02 0.02 0.04 0.03 0.07 0.07 0.09 capsule RBT1.21 RRT1.21 RRT1.21 RRT0.20 RRT0.94 API-PVA 1:10 0.03 0.08 0.50 0.61 0.63 0.74 6.04 6.21 0.12 0.30 RRT0.51 RRT0.51 RRT0.51 RRT0.93 API -HPMC 1:10 0.03 0.07 0.06 0.12 0.08 0.13 0.91 0.96 0.10 0.14 RRT0.51 RRT0.51 RRT0.51 RRT0.94 API- 1:10 0.12 0.19 0.10 0.18 0.12 0.20 0.10 0.18 0.11 0.23 Triacetin RRT0.22 RRT0.22 RRT0.22 RRT0.22 Drug-TiO.sub.2 1:10 0.03 0.09 0.04 0.09 0.06 0.12 0.96 1.80 0.47 1.25 RRT0.51 RRT0.51 RRT0.51 RRT0.32 Core tablet - 24.4 0.03 0.09 0.19 0.29 0.32 0.48 1.39 1.45 0.20 0.36 PVA .sup.g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94 Core tablet - 24.4 0.03 0.07 0.07 0.13 0.12 0.31 0.82 0.87 0.15 0.15 HPMC .sup.g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94 Core tablet - 24.4 0.13 0.20 0.13 0.18 0.13 0.18 0.13 0.22 0.30 0.63 Triacetin .sup.g:15 g RRT0.22 RRT0.22 RRT0.22 RRT1.46 Core tablet - 24.4 0.03 0.06 0.04 0.06 0.04 0.09 0.71 0.87 0.13 0.32 TiO.sub.2 .sup.g:15 g RRT0.51 RRT0.51 RRT0.51 RRT0.94

(3) Table 1 shows the results of the impurity content changes in the mixed powder of the active ingredient and the excipients after 10 days of stress testing, and the corresponding risk levels are classified according to the following criteria:

(4) Level 1 (low risk): maximum single impurity is less than 0.1% and total impurity is less than 0.2%;

(5) Level 2 (medium risk): maximum single impurity is 0.1-0.2% or total impurity is 0.2%-0.4%;

(6) Level 3 (high risk): maximum single impurity is more than 0.2% or total impurity is more than 0.4%.

(7) TABLE-US-00002 TABLE 2 Risk assessment of the API and excipients compatibility API/excipient Risk level assessment value Excipient Type Excipient Name ratio RH75% RH92.5% 60 C. Illumination Total Filler Lactose 1:10 1 1 1 2 5 Microcrystalline 1:10 1 1 3 2 7 cellulose Microcrystalline 1:10 1 1 2 2 6 cellulose-lactose compound Mannitol 1:10 1 1 1 2 5 Pregelatinized starch 1:10 2 2 3 2 9 Starch 1:10 2 2 3 2 9 Starch-lactose 1:10 1 1 1 2 5 compound Stabilizer Tartaric acid 1:10 1 1 1 2 5 Citric acid 1:10 1 1 1 2 5 Malic acid 1:10 1 1 2 2 6 Disintegrant Crospovidone 1:10 1 1 2 2 6 Sodium 1:10 3 3 3 2 11 carboxymethyl starch Cross-linked sodium 1:10 2 1 2 2 7 carboxymethyl cellulose L-HPC 1:10 2 2 3 2 9 Lubricant Magnesium stearate 1:10 1 2 3 2 8 Sodium stearyl 1:10 1 3 3 2 9 fumarate Glyceryl behenate 1:10 1 1 1 3 6 Adhesive Povidone K29/32 1:10 1 1 3 2 7 Glidant Colloidal silica 1:5 1 1 1 2 5 Empty Empty gelatin Packing 1 1 3 1 6 capsule capsule Empty HPMC Packing 1 1 1 1 4 capsule Coating PVA 1:10 3 3 3 2 11 powder HPMC 1:10 1 1 3 2 7 ingredient Triacetin 1:10 2 2 2 2 8 TiO.sub.2 1:10 1 1 3 3 8 API Neptinib 1 1 1 2 5 xylenesulfonate

(8) From the risk assessment results in Table 2 it is clear that the compositions comprising one or more ingredients of starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, L-HPC, magnesium stearate, sodium stearyl fumarate and PVA present a higher risk. While the compositions with one or several ingredients selected from lactose, mannitol, microcrystalline cellulose-lactose compound, starch-lactose compound, tartaric acid, citric acid, crospovidone, colloidal silica, and glyceryl behenate were identified low risks of compatibility.

Example 2: Preparation of Dosage Forms

(9) The following examples show a method of preparing the dosage forms comprising neptinib xylenesulfonate as the active ingredient.

(10) 2.1 Preparation of Capsules and Powder Dosage Form of Neptinib Xylenesulfonate

(11) TABLE-US-00003 TABLE 3 The contents and compositions for preparation of capsules and powder dosage form of neptinib xylenesulfonate Specification Specification Specification Specification Component 1 2 3 4 Neptinib 1.78 mg 5.33 mg 8.88 mg 17.76 mg xylenesulfonate (1 mg (3 mg (5 mg (10 mg (calculated on neptinib) neptinib) neptinib) neptinib) the anhydrous basis) Mannitol 120.78 mg 138.12 mg 236.12 mg 276.24 mg Colloidal silica 1.25 mg 1.5 mg 2.5 mg 3.0 Glyceryl 1.25 mg 1.5 mg 2.5 mg 3.0 mg behenate Total weight 125 mg 150 mg 250 mg 300 mg

(12) Preparation method: according to the contents and compositions shown in Table 3, the active ingredient neptinib xylenesulfonate was first passed through a 60-100 mesh sieve, and then mixed with mannitol, colloidal silica, glyceryl behenate and passed through a 40-60 mesh sieve together, yielding the final blending material. The finial blending material was directly placed in an automatic capsule filling machine, and filled to empty gelatin capsules of sizes 4#, 3# or 2# based on the weight of the contents.

(13) 2.2 Preparation of Granule Dosage Form of Neptinib Xylenesulfonate

(14) TABLE-US-00004 TABLE 4 The contents and compositions for preparation of granule dosage form of neptinib xylenesulfonate Component Specification 1 Specification 2 Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg 5.33 8 88 mg 17.76 mg (calculated on the (1 mg (3 mg (5 mg (10 mg anhydrous basis) neptinib) neptinib) neptinib) neptinib) Lactose monohydrate 120.78 mg 138.12 mg 236.12 mg 276.24 mg Colloidal silica 1.25 mg 1.5 mg 2.5 mg 3.0 Glyceryl behenate 1.25 mg 1.5 mg 2.5 mg 3.0 mg Total weight 125 mg 150 mg 250 mg 300 mg

(15) Preparation method: According to the contents and compositions shown in Table 4, the active ingredient neptinib xylenesulfonate was first passed through a 60-100 mesh sieve, and then was mixed with lactose monohydrate in a high-speed shear granulator. Purified water was added for granulation, and then was dried at 50-60 C. The dried granules were finally blended with colloidal silica and glyceryl behenate and filled into composite film bags.

(16) 2.3 Preparation of Tablets of Neptinib Xylenesulfonate

(17) 2.3.1

(18) TABLE-US-00005 TABLE 5 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Specification 2 Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg 5.33 mg 8.88 mg 17.76 mg (calculated on the (1 mg (3 mg (5 mg (10 mg anhydrous basis) neptinib) neptinib) neptinib) neptinib) Lactose monohydrate 31.1 mg 37.8 mg 44.5 mg 89.0 mg Mannitol 62.12 mg 75.62 mg 89.12 mg 178.24 mg Crospovidone 3.0 mg 3.75 mg 4.5 mg 9 mg Colloidal silica 1.0 mg 1.25 mg 1.5 mg 3 mg Glyceryl behenate 1.0 mg 1.25 mg 1.5 mg 3 mg Opadry coating powder 4 mg 5 mg 6 mg 12 mg Total weight 104 mg 130 mg 156.0 mg 312.0

(19) Preparation method: according to the contents and compositions shown in Table 5, the active ingredient neptinib xylenesulfonate was first passed through a 60-100 mesh sieve, the other excipients were passed through a 40-60 mesh sieve. Then they were subjected to final blending and compressing, and compressed into core tablets with diameter of 6 mm, 6 mm, 7 mm and 9 mm respectively, according to the specifications 1-4. The coating material (HPMC, triacetin or titanium dioxide) was sprayed on the core tablets. The surface temperature of the tablets was controlled in the range of 40-55 C. during film coating.

(20) 2.3.2

(21) TABLE-US-00006 TABLE 6 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Neptinib xylenesulfonate (calculated 8.88 mg on the anhydrous basis) (5 mg neptinib) Lactose monohydrate 44.5 mg Microcrystalline cellulose 89.12 mg Crospovidone 4.5 mg Colloidal silica 1.5 mg Magnesium stearate 1.5 mg Opadry coating powder 6 mg Total weight 156.0 mg

(22) Preparation method: same as in Example 2.3.1.

(23) 2.3.3

(24) TABLE-US-00007 TABLE 7 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Neptinib xylertesulfonate (calculated 8.88 mg on the anhydrous basis) (5 mg Neptinib) Lactose monohydrate 44.5 mg Pregelatinized starch 89.12 mg Crospovidone 4.5 mg Colloidal silica 1.5 mg Magnesium stearate 1.5 mg Opadry coating powder 6 mg Total weight 156.0 mg

(25) Preparation method: same as in Example 2.3.1.

(26) 2.3.4

(27) TABLE-US-00008 TABLE 8 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Neptinib xylenesulfonate (calculated 8.88 mg on the anhydrous basis) (5 mg Neptinib) Lactose monohydrate 44.5 mg Microcrystalline cellulose 89.12 mg Sodium carboxymethyl cellulose 4.5 mg Colloidal silica 1.5 mg Magnesium stearate 1.5 mg Opadry coating powder 6 mg Total weight 156.0 mg

(28) Preparation method: same as in Example 2.3.1.

(29) 2.3.5 Preparation of Neptinib Xylenesulfonate Tablets Containing a Stabilizer

(30) TABLE-US-00009 TABLE 9 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Specification 2 Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg 5.33 mg 8.88 mg 17.76 mg (calculated on the (1 mg (3 mg (5 mg (10 mg anhydrous basis) Neptinib) Neptinib) Neptinib) Neptinib) Lactose monohydrate 22.1 mg 26.6 mg 39.5 mg 79.1 mg Mannitol 44.12 mg 53.07 mg 79.12 mg 158.14 mg Crospovidone 2.4 mg 3.0 mg 4.5 mg 9 mg Colloidal silica 0.8 mg 1.0 mg 1.5 mg 3 mg Glyceryl behenate 0.8 mg 1.0 mg 1.5 mg 3 mg Tartaric acid 8 10 15 30 Opadry coating powder 3.2 mg 4 mg 6 mg 12 mg Total weight 83.2 mg 104 mg 156.0 mg 312.0

(31) Preparation method: The active ingredient neptinib xylenesulfonate was first passed through a 60-100 mesh sieve. Tartaric acid was crushed and then passed through an 80-120 mesh sieve. The sieved neptinib, tartaric acid and colloidal dioxide were pre-mixed, then subjected to final blending together with other excipients and compressing. The blending material was compressed into core tablets with diameter of 6 mm, 6 mm, 7 mm and 9 mm respectively, according to the specifications 1-4. The coating material (HPMC, triacetin or titanium dioxide) was sprayed on the core tablets. The surface temperature of the tablets was controlled in the range of 40-55 C. during film coating.

(32) 2.3.6 Preparation of Neptinib Xylenesulfonate Tablets Containing a Stabilizer

(33) TABLE-US-00010 TABLE 10 The contents and compositions for preparation of tablets of neptinib xylenesulfonate Component Specification 1 Specification 2 Specification 3 Specification 4 Neptinib xylenesulfonate 1.78 mg 5.33 mg 8.88 mg 17.76 mg (calculated on the anhydrous (1 mg Neptinib) (3 mg Neptinib) (5 mg Neptinib) (10 mg basis) Neptinib) Lactose monohydrate 22.1 mg 26.6 mg 39.5 mg 79.1 mg Mannitol 44.12 mg 53.07 mg 79.12 mg 158.14 mg Crospovidone 2.4 mg 3.0 ma 4.5 mg 9 mg Colloidal silica 0.8 mg 1.0 mg 1.5 mg 3 mg Glyceryl behenate 0.8 mg 1.0 mg 1.5 mg 3 mg Malic acid 8 10 15 30 Opadry coating powder 3.2 mg 4 mg 6 mg 12 mg Total weight 83.2 mg 104 mg 156.0 mg 312.0

(34) Preparation method: same as in Example 2.3.5.

Example 3: Detection of the Content of Impurity A

(35) Accelerated stability test was carried out on the 5 mg coated tablets prepared in Example 2.2 and Example 2.3. The method for detecting impurity A and total impurity was shown as follows:

(36) Equipment: Agilent 1260 series;

(37) Column: XBridge Shield RP18 column (1004.6 mm, 3.5 m);

(38) Mobile phase A: 0.05 mol/L potassium dihydrogen phosphate solution (adjusted to pH 7.2 with sodium hydroxide solution)-acetonitrile (20:80);

(39) Mobile phase B: 0.05 mol/L potassium dihydrogen phosphate solution (adjusted to pH 7.2 with sodium hydroxide solution)-acetonitrile (40:60);

(40) Linear gradient:

(41) TABLE-US-00011 Time (mm) Mobile phase A Mobile phase B 0 74 26 8 54 46 20 54 46 30 0 100 40 0 100 40.1 26 74 45 26 74

(42) Detection wavelength: 247 nm;

(43) Flow rate: 1.0 ml/min;

(44) Column temperature: 30 C.;

(45) Injection volume: 10 l;

(46) Solvent: acetonitrile-water (50:50).

(47) TABLE-US-00012 TABLE 11 Accelerated stability test results of Examples 2.3.1-2.3.4 Test time 0 month 1 month 1.5 months Total Total Total Impurity impurity Impurity impurity Impurity impurity Test condition A % % A % % A % % Example 2.3.1 ND 0.06 0.13 0.20 0.23 0.32 (specification 5 mg) 40 2 C., RH75 5% Example 2.3.2 ND 0.06 0.35 0.86 0.54 1.41 40 2 C., RH75 5% Example 2.3.3 ND 0.07 0.42 1.07 0.66 1.84 40 2 C., RH75 5% Example 2.3.4 ND 0.06 0.81 1.76 1.33 2.12 40 2 C., RH75 5%

(48) From the above accelerated stability test results, it was found that within 0-1.5 months, the contents of impurity A and total impurity in the drug product of Examples 2.3.2, 2.3.3 and 2.3.4 was much higher than that of Example 2.3.1, and the impurity growth was significant. Therefore, the low-risk composition presented in the invention can effectively reduce the generation rate of impurity A.

(49) TABLE-US-00013 TABLE 12 Accelerated stability test results of Example 2.3.1, Example 2.3.5 and Example 2.3.6 Test time 0 month 1 month 2 months 3 months 6 months Total Total Total Total Total Impurity impurity Impurity impurity Impurity impurity Impurity impurity Impurity impurity Test condition A % % A % % A % % A % % A % % Example 2.3.1 0.03 0.07 0.13 0.21 0.22 0.32 0.33 0.43 0.40 0.49 (specification 5 mg) 30 2 C., RH65 5% Example 2.3.1 0.03 0.07 0.16 0.23 0.34 0.43 0.49 0.58 0.94 1.08 (specification 5 mg) 40 2 C., RH75 5% Example 2.3.5 0.02 0.07 0.02 0.06 0.02 0.07 0.03 0.08 0.04 0.12 (specification 5 mg) 30 2 C., RH65 5% Example 2.3.5 0.02 0.07 0.03 0.11 0.03 0.1 0.04 0.15 0.05 0.17 (specification 5 mg) 40 2 C., RH75 5% Example 2.3.6 0.02 0.03 0.04 0.07 0.06 0.09 0.09 0.14 0.16 0.20 (specification 5 mg) 30 2 C., RH65 5% Example 2.3.6 0.02 0.03 0.05 0.08 0.07 0.12 0.10 0.14 0.17 0.22 (specification 5 mg) 40 2 C., RH75 5%

(50) As shown in the above accelerated test stability results, although the pharmaceutical excipients with relative low risks of compatibility was used in the drug product of Example 23.1, the content of the specific impurity A in the drug product still increased significantly when it was tested for six months under conditions of longer period of time and higher temperature of the accelerated tests. Based on the composition of Example 2.3.1, the acid according to the present invention was added to obtain the compositions of Examples 2.3.5 and 2.3.6. As demonstrated by the results of the accelerated tests in Example 2.3.5 and Example 2.3.6, these specific compositions presented in this invention can overcome the issue of the impurity A controlling, ensuring that the content of impurity A does not increase significantly.