中国药学杂志

Compound	Lot.	Purity/%
Gefitinib	420019-201902	99.8
Impurity A	420045-201701	100
Impurity Ⅲ	20191428	96.5
Impurity Ⅳ	GTFN-223-180901	99.8
Impurity V	9011461N1DYS	99.5
Impurity Ⅵ	XS120711-01	96.7
Impurity Ⅶ	LS50U72	99.58
Impurity Ⅷ	2-0-GFNB-191	97.30
Impurity Ⅸ	GTFN-227-180901	99.7
Impurity Ⅹ	XS150206-01	97.9
Impurity Ⅺ	20190614	96.4
Impurity Ⅻ	562-3201	98.25
Impurity B	20190523-1	96.3
Impurity ⅩⅢ	20190617	96.3
Impurity ⅩⅣ	XS120625-01	98.2
Impurity ⅩⅤ	200203-5D-C09	99.70
Impurity ⅩⅥ	RRW757	96
Impurity ⅩⅦ	200301-8D-133	98.36

Compound	Lot.	Purity/%
Gefitinib	420019-201902	99.8
Impurity A	420045-201701	100
Impurity Ⅲ	20191428	96.5
Impurity Ⅳ	GTFN-223-180901	99.8
Impurity V	9011461N1DYS	99.5
Impurity Ⅵ	XS120711-01	96.7
Impurity Ⅶ	LS50U72	99.58
Impurity Ⅷ	2-0-GFNB-191	97.30
Impurity Ⅸ	GTFN-227-180901	99.7
Impurity Ⅹ	XS150206-01	97.9
Impurity Ⅺ	20190614	96.4
Impurity Ⅻ	562-3201	98.25
Impurity B	20190523-1	96.3
Impurity ⅩⅢ	20190617	96.3
Impurity ⅩⅣ	XS120625-01	98.2
Impurity ⅩⅤ	200203-5D-C09	99.70
Impurity ⅩⅥ	RRW757	96
Impurity ⅩⅦ	200301-8D-133	98.36

Compound	LOQ	LOD
Gefitinib	0.61	0.003	0.12	0.001
Impurity A	0.88	0.004	0.20	0.001
ImpurityⅢ	0.93	0.005	0.24	0.001
Impurity Ⅳ	0.47	0.002	0.11	0.001
Impurity Ⅴ	0.91	0.005	0.22	0.001
Impurity Ⅵ	4.64	0.023	0.99	0.005
Impurity Ⅶ	2.51	0.013	0.58	0.003
Impurity Ⅷ	1.57	0.008	0.33	0.002
Impurity Ⅸ	1.08	0.005	0.20	0.001
Impurity Ⅹ	1.82	0.009	0.44	0.002
Impurity Ⅺ	3.77	0.019	0.99	0.005
Impurity Ⅻ	1.95	0.010	0.54	0.003
Impurity B	1.15	0.006	0.25	0.001
Impurity ⅩⅢ	1.07	0.005	0.24	0.001
Impurity ⅩⅣ	0.49	0.002	0.15	0.001
Impurity ⅩⅤ	1.08	0.005	0.33	0.002
Impurity ⅩⅥ	1.28	0.006	0.33	0.002
Impurity ⅩⅦ	2.65	0.013	0.60	0.003

Compound	LOQ	LOD
Gefitinib	0.61	0.003	0.12	0.001
Impurity A	0.88	0.004	0.20	0.001
ImpurityⅢ	0.93	0.005	0.24	0.001
Impurity Ⅳ	0.47	0.002	0.11	0.001
Impurity Ⅴ	0.91	0.005	0.22	0.001
Impurity Ⅵ	4.64	0.023	0.99	0.005
Impurity Ⅶ	2.51	0.013	0.58	0.003
Impurity Ⅷ	1.57	0.008	0.33	0.002
Impurity Ⅸ	1.08	0.005	0.20	0.001
Impurity Ⅹ	1.82	0.009	0.44	0.002
Impurity Ⅺ	3.77	0.019	0.99	0.005
Impurity Ⅻ	1.95	0.010	0.54	0.003
Impurity B	1.15	0.006	0.25	0.001
Impurity ⅩⅢ	1.07	0.005	0.24	0.001
Impurity ⅩⅣ	0.49	0.002	0.15	0.001
Impurity ⅩⅤ	1.08	0.005	0.33	0.002
Impurity ⅩⅥ	1.28	0.006	0.33	0.002
Impurity ⅩⅦ	2.65	0.013	0.60	0.003

Compound	Concentration range/μg·mL^-1	Regression equations	r	Correction factors
Gefitinib	0.115 0-4.598 8	y=36.100x+11.405	0.999 2	1.0
Impurity A	0.062 5-4.168 0	y=69.195x-3.265	0.999 7	0.52
Impurity Ⅲ	0.105 0-4.199 7	y=28.425x-2.375	0.999 4	1.27
Impurity Ⅳ	0.041 3-4.127 7	y=41.582x-1.512	0.999 7	0.87
Impurity Ⅴ	0.219 3 -4.386 0	y=35.096x-1.621	0.999 8	1.03
ImpurityⅥ	0.427 0-4.270 3	y=17.883x-2.013	0.999 5	2.02
Impurity Ⅶ	0.193 2-3.863 7	y=27.188x-1.560	0.999 3	1.33
Impurity Ⅷ	0.211 3-4.226 7	y=37.504x-1.718	0.999 2	0.96
Impurity Ⅸ	0.102 3-4.091 7	y=67.656x-3.166	0.999 6	0.53
Impurity Ⅹ	0.414 3-4.143 1	y=40.150x-2.747	0.999 8	0.90
Impurity Ⅺ	1.025 7-4.102 8	y=20.447x-1.773	0.999 4	1.77
Impurity Ⅻ	0.421 3-4.213 0	y=47.079x-6.089	0.999 1	0.77
Impurity B	0.102 7-4.106 2	y=31.084x-1.300	0.999 6	1.16
Impurity ⅩⅢ	0.104 4-4.175 6	y=34.750x-1.120	0.999 7	1.04
Impurity ⅩⅣ	0.107 0-4.281 5	y=43.632x-1.051	0.999 8	0.83
Impurity ⅩⅤ	0.222 1-4.442 6	y=27.209x-1.132	0.999 6	1.33
Impurity ⅩⅥ	0.210 4-4.208 6	y=29.395x-0.492	0.999 8	1.23
Impurity ⅩⅦ	0.439 1-4.390 8	y=17.389x-0.469	0.999 7	2.08

Compound	Concentration range/μg·mL^-1	Regression equations	r	Correction factors
Gefitinib	0.115 0-4.598 8	y=36.100x+11.405	0.999 2	1.0
Impurity A	0.062 5-4.168 0	y=69.195x-3.265	0.999 7	0.52
Impurity Ⅲ	0.105 0-4.199 7	y=28.425x-2.375	0.999 4	1.27
Impurity Ⅳ	0.041 3-4.127 7	y=41.582x-1.512	0.999 7	0.87
Impurity Ⅴ	0.219 3 -4.386 0	y=35.096x-1.621	0.999 8	1.03
ImpurityⅥ	0.427 0-4.270 3	y=17.883x-2.013	0.999 5	2.02
Impurity Ⅶ	0.193 2-3.863 7	y=27.188x-1.560	0.999 3	1.33
Impurity Ⅷ	0.211 3-4.226 7	y=37.504x-1.718	0.999 2	0.96
Impurity Ⅸ	0.102 3-4.091 7	y=67.656x-3.166	0.999 6	0.53
Impurity Ⅹ	0.414 3-4.143 1	y=40.150x-2.747	0.999 8	0.90
Impurity Ⅺ	1.025 7-4.102 8	y=20.447x-1.773	0.999 4	1.77
Impurity Ⅻ	0.421 3-4.213 0	y=47.079x-6.089	0.999 1	0.77
Impurity B	0.102 7-4.106 2	y=31.084x-1.300	0.999 6	1.16
Impurity ⅩⅢ	0.104 4-4.175 6	y=34.750x-1.120	0.999 7	1.04
Impurity ⅩⅣ	0.107 0-4.281 5	y=43.632x-1.051	0.999 8	0.83
Impurity ⅩⅤ	0.222 1-4.442 6	y=27.209x-1.132	0.999 6	1.33
Impurity ⅩⅥ	0.210 4-4.208 6	y=29.395x-0.492	0.999 8	1.23
Impurity ⅩⅦ	0.439 1-4.390 8	y=17.389x-0.469	0.999 7	2.08

Compound	LOQ RSD/%	1 μg·mL^-1 (0.05%) RSD/%	2 μg·mL^-1 (0.1%) RSD/%
Gefitinib	1.3	0.32	1.3
Impurity A	1.3	0.53	0.02
Impurity Ⅲ	0.99	0.87	0.47
Impurity Ⅳ	0.55	0.28	0.22
Impurity Ⅴ	1.7	0.50	0.09
Impurity Ⅵ	0.67	1.34	0.34
Impurity Ⅶ	1.8	0.53	0.54
Impurity Ⅷ	2.0	0.96	0.87
ImpurityⅨ	1.7	0.41	0.17
Impurity Ⅹ	2.2	0.19	0.22
Impurity Ⅺ	1.6	0.92	0.27
Impurity Ⅻ	1.1	1.7	0.64
Impurity B	1.7	0.55	0.39
Impurity ⅩⅢ	2.2	1.2	0.54
Impurity ⅩⅣ	1.7	0.37	0.11
Impurity ⅩⅤ	2.0	0.67	0.35
Impurity ⅩⅥ	2.0	0.31	0.15
Impurity ⅩⅦ	1.1	0.83	1.1

Compound	LOQ RSD/%	1 μg·mL^-1 (0.05%) RSD/%	2 μg·mL^-1 (0.1%) RSD/%
Gefitinib	1.3	0.32	1.3
Impurity A	1.3	0.53	0.02
Impurity Ⅲ	0.99	0.87	0.47
Impurity Ⅳ	0.55	0.28	0.22
Impurity Ⅴ	1.7	0.50	0.09
Impurity Ⅵ	0.67	1.34	0.34
Impurity Ⅶ	1.8	0.53	0.54
Impurity Ⅷ	2.0	0.96	0.87
ImpurityⅨ	1.7	0.41	0.17
Impurity Ⅹ	2.2	0.19	0.22
Impurity Ⅺ	1.6	0.92	0.27
Impurity Ⅻ	1.1	1.7	0.64
Impurity B	1.7	0.55	0.39
Impurity ⅩⅢ	2.2	1.2	0.54
Impurity ⅩⅣ	1.7	0.37	0.11
Impurity ⅩⅤ	2.0	0.67	0.35
Impurity ⅩⅥ	2.0	0.31	0.15
Impurity ⅩⅦ	1.1	0.83	1.1

Impurities	Gefitinib	Gefitinib tablets
Impurity A	0.062 50	0	0.062 23	99.6	98.5	2.1	0	0.067 68	108.3	108.0	0.35
	0.062 50	0	0.060 14	96.2			0	0.067 50	108.0
	0.062 50	0	0.062 41	99.9			0	0.067 22	107.6
	1.042	0	1.109	106.4	106.5	0.73	0	1.110	106.5	106.8	0.28
	1.042	0	1.118	107.3			0	1.113	106.8
	1.042	0	1.102	105.7			0	1.116	107.1
	2.084	0	2.089	100.2	100.6	0.46	0	2.148	103.1	103.0	0.15
	2.084	0	2.095	100.5			0	2.144	102.9
	2.084	0	2.107	101.1			0	2.150	103.2
Impurity Ⅲ	0.105 0	0	0.102 5	97.6	94.5	5.3	0.043 46	0.103 2	56.9	57.2	1.29
	0.105 0	0	0.102 1	97.3			0.043 46	0.104 4	58.0
	0.105 0	0	0.093 2	88.7			0.043 46	0.102 9	56.7
	1.050	0	0.938 6	89.4	89.4	0.93	0.043 46	0.645 4	57.4	56.8	0.86
	1.050	0	0.947 4	90.2			0.043 46	0.636 5	56.5
	1.050	0	0.929 9	88.6			0.043 46	0.636 6	56.5
	2.100	0	1.896	90.3	90.6	0.57	0.043 46	1.264	58.2	56.0	4.8
	2.100	0	1.915	91.2			0.043 46	1.235	56.9
	2.100	0	1.896	90.3			0.043 46	1.154	53.0
Impurity Ⅳ	0.041 30	0	0.042 38	102.7	103.4	5.9	0	0.041 30	100.0	102.2	2.0
	0.041 30	0	0.045 41	110.0			0	0.042 36	102.6
	0.041 30	0	0.040 38	97.8			0	0.042 99	104.1
	1.032	0	1.096	106.2	105.1	0.94	0	1.108	107.4	107.4	0.14
	1.032	0	1.078	104.5			0	1.110	107.5
	1.032	0	1.079	104.5			0	1.106	107.2
	2.064	0	2.050	99.3	100.1	0.74	0	2.119	102.7	102.2	0.65
	2.064	0	2.067	100.2			0	2.117	102.6
	2.064	0	2.081	100.8			0	2.094	101.5
Impurity Ⅴ	0.219 3	0.419 4	0.654 4	107.2	108.6	1.9	0.082 08	0.307 7	102.9	103.3	0.70
	0.219 3	0.419 4	0.655 5	107.7			0.082 08	0.307 8	102.9
	0.219 3	0.419 4	0.662 8	111.0			0.082 08	0.310 5	104.2
	1.096	0.419 4	1.611	108.6	108.0	0.88	0.082 08	1.233	104.9	104.6	0.32
	1.096	0.419 4	1.593	106.9			0.082 08	1.226	104.3
	1.096	0.419 4	1.611	108.6			0.082 08	1.228	104.5
	2.193	0.419 4	2.635	102.1	102.0	0.63	0.082 08	2.281	100.5	100.5	0.02
	2.193	0.419 4	2.616	101.2			0.082 08	2.281	100.5
	2.193	0.419 4	2.643	102.5			0.082 08	2.282	100.5
Impurity Ⅵ	0.427 0	0	0.790 5	105.9	106.2	0.88	0	0.878 1	109.4	109.3	0.34
	0.427 0	0	0.796 5	107.3			0	0.875 6	108.8
	0.427 0	0	0.788 9	105.5			0	0.878 5	109.5
	1.068	0	1.537	113.6	107.4	5.2	0	1.513	104.9	104.9	0.43
	1.068	0	1.449	105.4			0	1.508	104.4
	1.068	0	1.424	103.0			0	1.518	105.3
	2.135	0	2.460	101.3	100.5	1.4	0	2.606	105.2	105.1	0.60
	2.135	0	2.409	98.9			0	2.619	105.8
	2.135	0	2.461	101.3			0	2.592	104.5
Impurity Ⅶ	0.193 2	0	0.198 5	102.7	104.0	1.7	0	0.208 9	108.1	107.3	0.95
	0.193 2	0	0.204 9	106.1			0	0.205 1	106.2
	0.193 2	0	0.199 5	103.3			0	0.208 0	107.6
	0.965 9	0	0.992 1	102.7	104.3	1.7	0	1.008 6	104.4	104.1	0.66
	0.965 9	0	1.003	103.8			0	0.998	103.3
	0.965 9	0	1.026	106.2			0	1.011	104.6
	1.932	0	1.945	100.7	100.7	0.46	0	1.964	101.7	101.4	0.38
	1.932	0	1.956	101.2			0	1.950	100.9
	1.932	0	1.938	100.3			0	1.961	101.5
Impurity Ⅷ	0.211 3	0.086 62	0.296 5	104.6	103.1	1.3	0.100 4	0.324 0	105.8	106.1	0.27
	0.211 3	0.086 62	0.292 2	102.5			0.100 4	0.325 2	106.4
	0.211 3	0.086 62	0.291 4	102.2			0.100 4	0.324 2	105.9
	1.057	0.086 62	1.185	105.0	105.2	0.46	0.100 4	1.213	105.2	104.9	0.32
	1.057	0.086 62	1.194	105.8			0.100 4	1.208	104.8
	1.057	0.086 62	1.184	104.9			0.100 4	1.206	104.6
	2.113	0.086 62	2.213	101.3	100.0	1.2	0.100 4	2.254	102.2	102.1	0.10
	2.113	0.086 62	2.164	99.0			0.100 4	2.250	102.0
	2.113	0.086 62	2.179	99.7			0.100 4	2.253	102.1
Impurity Ⅸ	0.102 3	0	0.094 77	92.6	96.6	3.59	0	0.101 7	99.4	100.9	1.6
	0.102 3	0	0.101 0	98.8			0	0.102 9	100.6
	0.102 3	0	0.100 8	98.5			0	0.105 0	102.7
	1.023	0	1.074	105.0	104.9	0.85	0	1.081	105.7	105.9	0.30
	1.023	0	1.082	105.7			0	1.082	105.8
	1.023	0	1.063	104.0			0	1.087	106.3
	2.046	0	2.055	100.4	100.1	0.27	0	2.061	100.8	100.9	0.13
	2.046	0	2.046	100.0			0	2.063	100.8
	2.046	0	2.045	99.9			0	2.066	101.0
Impurity Ⅹ	0.414 3	0.483 9	0.910 0	102.9	105.8	2.4	0	0.442 6	106.8	107.0	0.15
	0.414 3	0.483 9	0.929 1	107.5			0	0.443 9	107.1
	0.414 3	0.483 9	0.927 0	107.0			0	0.443 2	107.0
	1.036	0.483 9	1.549	103. 9	106.1	2.0	0	1.099	106.1	106.1	0.18
	1.036	0.483 9	1.574	106.3			0	1.096	105.8
	1.036	0.483 9	1.594	108.2			0	1.100	106.2
	2.072	0.483 9	2.475	97. 8	99.2	1.4	0	2.100	101.4	101.4	0.14
	2.072	0.483 9	2.502	99.1			0	2.097	101.2
	2.072	0.483 9	2.533	100.6			0	2.103	101.5
Impurity Ⅺ	1.026	0	1.023	99.7	103.0	3.3	0	1.070	104.4	104.7	1.1
	1.026	0	1.092	106.5			0	1.087	106.0
	1.026	0	1.056	102.9			0	1.065	103.9
	1.026	0	0.990 2	96.5	98.3	1.7	0	1.053	102.6	103.1	0.50
	1.026	0	1.009	98.4			0	1.063	103.7
	1.026	0	1.025	100.0			0	1.057	103.1
	2.051	0	2.001	97. 6	97.3	0.87	0	2.057	100.3	100.5	0.53
	2.051	0	2.008	97. 9			0	2.054	100.1
	2.051	0	1.975	96.3			0	2.075	101.1
Impurity Ⅻ	0.421 3	0	0.443 9	105.4	104.8	1.3	0	0.439 7	104.4	104.3	0.31
	0.421 3	0	0.445 7	105.8			0	0.440 6	104.6
	0.421 3	0	0.435 3	103.3			0	0.437 9	103.9
	1.053	0	1.074	102.0	106.0	3.5	0	1.094	103.9	104.1	0.57
	1.053	0	1.126	106.9			0	1.103	104.7
	1.053	0	1.151	109.3			0	1.091	103.6
	2.106	0	2.053	97.5	98.5	0.91	0	2.242	106.4	106.0	0.54
	2.106	0	2.082	98.8			0	2.219	105.3
	2.106	0	2.089	99. 2			0	2.236	106.1
Impurity B	0.102 7	0.495 2	0.594 9	97.0	96.9	2.1	0.706 2	0.811 3	102.3	107.2	4.0
	0.102 7	0.495 2	0.592 4	94.7			0.706 2	0.819 1	109.9
	0.102 7	0.495 2	0.596 7	98.8			0.706 2	0.818 6	109.4
	1.027	0.495 2	1.553	102.5	103.0	0.79	0.706 2	1.799	105.7	106.5	1.3
	1.027	0.495 2	1.568	104.0			0.706 2	1.799	105.7
	1.027	0.495 2	1.554	102.6			0.706 2	1.825	108.2
	2.053	0.495 2	2.489	98.2	98.9	0.63	0.706 2	2.782	102.6	102.6	0.14
	2.053	0.495 2	2.510	99. 2			0.706 2	2.778	102.4
	2.053	0.495 2	2.513	99.3			0.706 2	2.784	102.7
Impurity ⅩⅢ	0.104 4	0	0.117 3	112.3	104.2	7.0	0	0.111 5	106.8	107.1	1.1
	0.104 4	0	0.102 5	98.1			0	0.113 1	108.3
	0.104 4	0	0.106 5	102.0			0	0.110 7	106.0
	1.044	0	1.104	105.8	105.9	0.28	0	1.107	106.0	106.5	0.41
	1.044	0	1.109	106.2			0	1.112	106.5
	1.044	0	1.103	105. 7			0	1.116	106.9
	2.088	0	2.096	100.4	100.3	0.24	0	2.112	101.2	101.3	0.27
	2.088	0	2.089	100.0			0	2.109	101.0
	2.088	0	2.098	100.5			0	2.120	101.5
Impurity ⅩⅣ	0.107 0	0	0.102 8	96.0	96.3	0.48	0	0.100 2	93.7	93.2	0.53
	0.107 0	0	0.103 6	96.9			0	0.099 6	93.1
	0.107 0	0	0.102 8	96.1			0	0.099 2	92.7
	1.070	0	1.124	105.0	105.3	0.36	0	1.125	105.1	105.6	0.57
	1.070	0	1.125	105.1			0	1.138	106.3
	1.070	0	1.132	105.7			0	1.129	105.5
	2.141	0	2.138	99.9	100.0	0.28	0	2.172	101.5	101.2	0.23
	2.141	0	2.138	99.9			0	2.165	101.1
	2.141	0	2.148	100.3			0	2.163	101.0
Impurity ⅩⅤ	0.222 1	0	0.217 2	97.8	100.6	2.8	0	0.213 4	96.1	96.4	1.3
	0.222 1	0	0.223 1	100.5			0	0.217 3	97.9
	0.222 1	0	0.229 7	103.4			0	0.211 8	95.4
	1.111	0	1.187	106.9	105.7	0.97	0	1.183	106.5	106.7	0.32
	1.111	0	1.166	104.9			0	1.189	107.1
	1.111	0	1.169	105.3			0	1.182	106.4
	2.221	0	2.248	101.2	100.8	0.66	0	2.252	101.4	101.0	0.29
	2.221	0	2.221	100.0			0	2.241	100.9
	2.221	0	2.245	101.1			0	2.240	100.8
Impurity ⅩⅥ	0.210 4	0	0.211 1	100.4	101.6	1.6	0	0.194 5	92.4	93.2	0.83
	0.210 4	0	0.212 4	101.0			0	0.195 9	93.1
	0.210 4	0	0.217 6	103.4			0	0.197 8	94.0
	1.052	0	1.085	103.1	102.9	0.65	0	1.013	96.3	96.0	0.34
	1.052	0	1.089	103.5			0	1.007	95.7
	1.052	0	1.075	102.2			0	1.011	96.1
	2.104	0	2.137	101.5	100.9	0.58	0	1.985	94.3	94.3	0.05
	2.104	0	2.114	100.5			0	1.986	94.4
	2.104	0	2.118	100.6			0	1.984	94.3
Impurity ⅩⅦ	0.439 1	0.481 9	0.931 7	102.4	103.6	1.9	0	0.447 1	101.8	101.9	0.39
	0.439 1	0.481 9	0.946 4	105.8			0	0.445 8	101.5
	0.439 1	0.481 9	0.931 9	102.5			0	0.449 2	102.3
	1.098	0.481 9	1.635	103.9	104.1	0.81	0	1.138	103.7	104.3	0.64
	1.098	0.481 9	1.629	103.3			0	1.152	105.0
	1.098	0.481 9	1.647	105.0			0	1.143	104.1
	2.195	0.481 9	2.640	99.1	99.9	0.91	0	2.183	99.4	99.8	0.29
	2.195	0.481 9	2.654	99. 8			0	2.195	100.0
	2.195	0.481 9	2.679	100.9			0	2.193	99.9

Impurities	Gefitinib	Gefitinib tablets
Impurity A	0.062 50	0	0.062 23	99.6	98.5	2.1	0	0.067 68	108.3	108.0	0.35
	0.062 50	0	0.060 14	96.2			0	0.067 50	108.0
	0.062 50	0	0.062 41	99.9			0	0.067 22	107.6
	1.042	0	1.109	106.4	106.5	0.73	0	1.110	106.5	106.8	0.28
	1.042	0	1.118	107.3			0	1.113	106.8
	1.042	0	1.102	105.7			0	1.116	107.1
	2.084	0	2.089	100.2	100.6	0.46	0	2.148	103.1	103.0	0.15
	2.084	0	2.095	100.5			0	2.144	102.9
	2.084	0	2.107	101.1			0	2.150	103.2
Impurity Ⅲ	0.105 0	0	0.102 5	97.6	94.5	5.3	0.043 46	0.103 2	56.9	57.2	1.29
	0.105 0	0	0.102 1	97.3			0.043 46	0.104 4	58.0
	0.105 0	0	0.093 2	88.7			0.043 46	0.102 9	56.7
	1.050	0	0.938 6	89.4	89.4	0.93	0.043 46	0.645 4	57.4	56.8	0.86
	1.050	0	0.947 4	90.2			0.043 46	0.636 5	56.5
	1.050	0	0.929 9	88.6			0.043 46	0.636 6	56.5
	2.100	0	1.896	90.3	90.6	0.57	0.043 46	1.264	58.2	56.0	4.8
	2.100	0	1.915	91.2			0.043 46	1.235	56.9
	2.100	0	1.896	90.3			0.043 46	1.154	53.0
Impurity Ⅳ	0.041 30	0	0.042 38	102.7	103.4	5.9	0	0.041 30	100.0	102.2	2.0
	0.041 30	0	0.045 41	110.0			0	0.042 36	102.6
	0.041 30	0	0.040 38	97.8			0	0.042 99	104.1
	1.032	0	1.096	106.2	105.1	0.94	0	1.108	107.4	107.4	0.14
	1.032	0	1.078	104.5			0	1.110	107.5
	1.032	0	1.079	104.5			0	1.106	107.2
	2.064	0	2.050	99.3	100.1	0.74	0	2.119	102.7	102.2	0.65
	2.064	0	2.067	100.2			0	2.117	102.6
	2.064	0	2.081	100.8			0	2.094	101.5
Impurity Ⅴ	0.219 3	0.419 4	0.654 4	107.2	108.6	1.9	0.082 08	0.307 7	102.9	103.3	0.70
	0.219 3	0.419 4	0.655 5	107.7			0.082 08	0.307 8	102.9
	0.219 3	0.419 4	0.662 8	111.0			0.082 08	0.310 5	104.2
	1.096	0.419 4	1.611	108.6	108.0	0.88	0.082 08	1.233	104.9	104.6	0.32
	1.096	0.419 4	1.593	106.9			0.082 08	1.226	104.3
	1.096	0.419 4	1.611	108.6			0.082 08	1.228	104.5
	2.193	0.419 4	2.635	102.1	102.0	0.63	0.082 08	2.281	100.5	100.5	0.02
	2.193	0.419 4	2.616	101.2			0.082 08	2.281	100.5
	2.193	0.419 4	2.643	102.5			0.082 08	2.282	100.5
Impurity Ⅵ	0.427 0	0	0.790 5	105.9	106.2	0.88	0	0.878 1	109.4	109.3	0.34
	0.427 0	0	0.796 5	107.3			0	0.875 6	108.8
	0.427 0	0	0.788 9	105.5			0	0.878 5	109.5
	1.068	0	1.537	113.6	107.4	5.2	0	1.513	104.9	104.9	0.43
	1.068	0	1.449	105.4			0	1.508	104.4
	1.068	0	1.424	103.0			0	1.518	105.3
	2.135	0	2.460	101.3	100.5	1.4	0	2.606	105.2	105.1	0.60
	2.135	0	2.409	98.9			0	2.619	105.8
	2.135	0	2.461	101.3			0	2.592	104.5
Impurity Ⅶ	0.193 2	0	0.198 5	102.7	104.0	1.7	0	0.208 9	108.1	107.3	0.95
	0.193 2	0	0.204 9	106.1			0	0.205 1	106.2
	0.193 2	0	0.199 5	103.3			0	0.208 0	107.6
	0.965 9	0	0.992 1	102.7	104.3	1.7	0	1.008 6	104.4	104.1	0.66
	0.965 9	0	1.003	103.8			0	0.998	103.3
	0.965 9	0	1.026	106.2			0	1.011	104.6
	1.932	0	1.945	100.7	100.7	0.46	0	1.964	101.7	101.4	0.38
	1.932	0	1.956	101.2			0	1.950	100.9
	1.932	0	1.938	100.3			0	1.961	101.5
Impurity Ⅷ	0.211 3	0.086 62	0.296 5	104.6	103.1	1.3	0.100 4	0.324 0	105.8	106.1	0.27
	0.211 3	0.086 62	0.292 2	102.5			0.100 4	0.325 2	106.4
	0.211 3	0.086 62	0.291 4	102.2			0.100 4	0.324 2	105.9
	1.057	0.086 62	1.185	105.0	105.2	0.46	0.100 4	1.213	105.2	104.9	0.32
	1.057	0.086 62	1.194	105.8			0.100 4	1.208	104.8
	1.057	0.086 62	1.184	104.9			0.100 4	1.206	104.6
	2.113	0.086 62	2.213	101.3	100.0	1.2	0.100 4	2.254	102.2	102.1	0.10
	2.113	0.086 62	2.164	99.0			0.100 4	2.250	102.0
	2.113	0.086 62	2.179	99.7			0.100 4	2.253	102.1
Impurity Ⅸ	0.102 3	0	0.094 77	92.6	96.6	3.59	0	0.101 7	99.4	100.9	1.6
	0.102 3	0	0.101 0	98.8			0	0.102 9	100.6
	0.102 3	0	0.100 8	98.5			0	0.105 0	102.7
	1.023	0	1.074	105.0	104.9	0.85	0	1.081	105.7	105.9	0.30
	1.023	0	1.082	105.7			0	1.082	105.8
	1.023	0	1.063	104.0			0	1.087	106.3
	2.046	0	2.055	100.4	100.1	0.27	0	2.061	100.8	100.9	0.13
	2.046	0	2.046	100.0			0	2.063	100.8
	2.046	0	2.045	99.9			0	2.066	101.0
Impurity Ⅹ	0.414 3	0.483 9	0.910 0	102.9	105.8	2.4	0	0.442 6	106.8	107.0	0.15
	0.414 3	0.483 9	0.929 1	107.5			0	0.443 9	107.1
	0.414 3	0.483 9	0.927 0	107.0			0	0.443 2	107.0
	1.036	0.483 9	1.549	103. 9	106.1	2.0	0	1.099	106.1	106.1	0.18
	1.036	0.483 9	1.574	106.3			0	1.096	105.8
	1.036	0.483 9	1.594	108.2			0	1.100	106.2
	2.072	0.483 9	2.475	97. 8	99.2	1.4	0	2.100	101.4	101.4	0.14
	2.072	0.483 9	2.502	99.1			0	2.097	101.2
	2.072	0.483 9	2.533	100.6			0	2.103	101.5
Impurity Ⅺ	1.026	0	1.023	99.7	103.0	3.3	0	1.070	104.4	104.7	1.1
	1.026	0	1.092	106.5			0	1.087	106.0
	1.026	0	1.056	102.9			0	1.065	103.9
	1.026	0	0.990 2	96.5	98.3	1.7	0	1.053	102.6	103.1	0.50
	1.026	0	1.009	98.4			0	1.063	103.7
	1.026	0	1.025	100.0			0	1.057	103.1
	2.051	0	2.001	97. 6	97.3	0.87	0	2.057	100.3	100.5	0.53
	2.051	0	2.008	97. 9			0	2.054	100.1
	2.051	0	1.975	96.3			0	2.075	101.1
Impurity Ⅻ	0.421 3	0	0.443 9	105.4	104.8	1.3	0	0.439 7	104.4	104.3	0.31
	0.421 3	0	0.445 7	105.8			0	0.440 6	104.6
	0.421 3	0	0.435 3	103.3			0	0.437 9	103.9
	1.053	0	1.074	102.0	106.0	3.5	0	1.094	103.9	104.1	0.57
	1.053	0	1.126	106.9			0	1.103	104.7
	1.053	0	1.151	109.3			0	1.091	103.6
	2.106	0	2.053	97.5	98.5	0.91	0	2.242	106.4	106.0	0.54
	2.106	0	2.082	98.8			0	2.219	105.3
	2.106	0	2.089	99. 2			0	2.236	106.1
Impurity B	0.102 7	0.495 2	0.594 9	97.0	96.9	2.1	0.706 2	0.811 3	102.3	107.2	4.0
	0.102 7	0.495 2	0.592 4	94.7			0.706 2	0.819 1	109.9
	0.102 7	0.495 2	0.596 7	98.8			0.706 2	0.818 6	109.4
	1.027	0.495 2	1.553	102.5	103.0	0.79	0.706 2	1.799	105.7	106.5	1.3
	1.027	0.495 2	1.568	104.0			0.706 2	1.799	105.7
	1.027	0.495 2	1.554	102.6			0.706 2	1.825	108.2
	2.053	0.495 2	2.489	98.2	98.9	0.63	0.706 2	2.782	102.6	102.6	0.14
	2.053	0.495 2	2.510	99. 2			0.706 2	2.778	102.4
	2.053	0.495 2	2.513	99.3			0.706 2	2.784	102.7
Impurity ⅩⅢ	0.104 4	0	0.117 3	112.3	104.2	7.0	0	0.111 5	106.8	107.1	1.1
	0.104 4	0	0.102 5	98.1			0	0.113 1	108.3
	0.104 4	0	0.106 5	102.0			0	0.110 7	106.0
	1.044	0	1.104	105.8	105.9	0.28	0	1.107	106.0	106.5	0.41
	1.044	0	1.109	106.2			0	1.112	106.5
	1.044	0	1.103	105. 7			0	1.116	106.9
	2.088	0	2.096	100.4	100.3	0.24	0	2.112	101.2	101.3	0.27
	2.088	0	2.089	100.0			0	2.109	101.0
	2.088	0	2.098	100.5			0	2.120	101.5
Impurity ⅩⅣ	0.107 0	0	0.102 8	96.0	96.3	0.48	0	0.100 2	93.7	93.2	0.53
	0.107 0	0	0.103 6	96.9			0	0.099 6	93.1
	0.107 0	0	0.102 8	96.1			0	0.099 2	92.7
	1.070	0	1.124	105.0	105.3	0.36	0	1.125	105.1	105.6	0.57
	1.070	0	1.125	105.1			0	1.138	106.3
	1.070	0	1.132	105.7			0	1.129	105.5
	2.141	0	2.138	99.9	100.0	0.28	0	2.172	101.5	101.2	0.23
	2.141	0	2.138	99.9			0	2.165	101.1
	2.141	0	2.148	100.3			0	2.163	101.0
Impurity ⅩⅤ	0.222 1	0	0.217 2	97.8	100.6	2.8	0	0.213 4	96.1	96.4	1.3
	0.222 1	0	0.223 1	100.5			0	0.217 3	97.9
	0.222 1	0	0.229 7	103.4			0	0.211 8	95.4
	1.111	0	1.187	106.9	105.7	0.97	0	1.183	106.5	106.7	0.32
	1.111	0	1.166	104.9			0	1.189	107.1
	1.111	0	1.169	105.3			0	1.182	106.4
	2.221	0	2.248	101.2	100.8	0.66	0	2.252	101.4	101.0	0.29
	2.221	0	2.221	100.0			0	2.241	100.9
	2.221	0	2.245	101.1			0	2.240	100.8
Impurity ⅩⅥ	0.210 4	0	0.211 1	100.4	101.6	1.6	0	0.194 5	92.4	93.2	0.83
	0.210 4	0	0.212 4	101.0			0	0.195 9	93.1
	0.210 4	0	0.217 6	103.4			0	0.197 8	94.0
	1.052	0	1.085	103.1	102.9	0.65	0	1.013	96.3	96.0	0.34
	1.052	0	1.089	103.5			0	1.007	95.7
	1.052	0	1.075	102.2			0	1.011	96.1
	2.104	0	2.137	101.5	100.9	0.58	0	1.985	94.3	94.3	0.05
	2.104	0	2.114	100.5			0	1.986	94.4
	2.104	0	2.118	100.6			0	1.984	94.3
Impurity ⅩⅦ	0.439 1	0.481 9	0.931 7	102.4	103.6	1.9	0	0.447 1	101.8	101.9	0.39
	0.439 1	0.481 9	0.946 4	105.8			0	0.445 8	101.5
	0.439 1	0.481 9	0.931 9	102.5			0	0.449 2	102.3
	1.098	0.481 9	1.635	103.9	104.1	0.81	0	1.138	103.7	104.3	0.64
	1.098	0.481 9	1.629	103.3			0	1.152	105.0
	1.098	0.481 9	1.647	105.0			0	1.143	104.1
	2.195	0.481 9	2.640	99.1	99.9	0.91	0	2.183	99.4	99.8	0.29
	2.195	0.481 9	2.654	99. 8			0	2.195	100.0
	2.195	0.481 9	2.679	100.9			0	2.193	99.9

Compound	RSD/%
Gefitinib	1.92	-	-
Impurity A	1.08	-	-
Impurity Ⅲ	1.99	-	-
Impurity Ⅳ	0.95	-	-
Impurity Ⅴ	0.99	3.96	0.76
ImpurityⅥ	0.95	-	-
Impurity Ⅶ	1.24	-	-
Impurity Ⅷ	1.21	2.84	-
Impurity Ⅸ	0.83	2.67	-
Impurity Ⅹ	1.02	-	1.64
Impurity Ⅺ	2.77	-	-
Impurity Ⅻ	2.11	-	-
Impurity B	2.18	3.15	1.28
Impurity ⅩⅢ	0.68	1.71	-
Impurity ⅩⅣ	1.45	1.86	-
Impurity ⅩⅤ	0.90	-	-
Impurity ⅩⅥ	1.52	-	-
Impurity ⅩⅦ	1.20	2.27	1.55

Compound	RSD/%
Gefitinib	1.92	-	-
Impurity A	1.08	-	-
Impurity Ⅲ	1.99	-	-
Impurity Ⅳ	0.95	-	-
Impurity Ⅴ	0.99	3.96	0.76
ImpurityⅥ	0.95	-	-
Impurity Ⅶ	1.24	-	-
Impurity Ⅷ	1.21	2.84	-
Impurity Ⅸ	0.83	2.67	-
Impurity Ⅹ	1.02	-	1.64
Impurity Ⅺ	2.77	-	-
Impurity Ⅻ	2.11	-	-
Impurity B	2.18	3.15	1.28
Impurity ⅩⅢ	0.68	1.71	-
Impurity ⅩⅣ	1.45	1.86	-
Impurity ⅩⅤ	0.90	-	-
Impurity ⅩⅥ	1.52	-	-
Impurity ⅩⅦ	1.20	2.27	1.55

Variable	Parameters
Initial parameters	Instrument:Agilent 1260 Infinity Ⅱ Column:Kromasil(0.46 mm×250 mm,5 μm) Mobile phase A:1% ammonium acetate solution, pH 6.2; Mobile phase B:acetonitrile; Column temperature:30 ℃; Flow rate:1.0 ml·min^-1;
Column	Welch Ultimate(0.46 mm×250 mm,5 μm) Waters Xbridge(0.46 mm×250 mm,5 μm) Dikma Diamonsil Plus(0.46 mm×250 mm,5 μm) Shimadzu ShimNex CS(0.46 mm×250 mm,5 μm) Dikma Diamonsil C₁₈(2)(0.46 mm×250 mm,5 μm) CAPCELL PAK MGⅡ(0.46 mm×250 mm,5 μm) Waters SunFire(0.46 mm×250 mm,5 μm) TechMate ST(0.46 mm×250 mm,5μm) Waters XSelect HSS(0.46 mm×250 mm,5 μm) Phenomenex Gemini(0.46 mm×250 mm,5 μm)
Instrument	Agilent 1260 Infinity
Column temperature	28 ℃
	32 ℃
pH	6.1
	6.3

Variable	Parameters
Initial parameters	Instrument:Agilent 1260 Infinity Ⅱ Column:Kromasil(0.46 mm×250 mm,5 μm) Mobile phase A:1% ammonium acetate solution, pH 6.2; Mobile phase B:acetonitrile; Column temperature:30 ℃; Flow rate:1.0 ml·min^-1;
Column	Welch Ultimate(0.46 mm×250 mm,5 μm) Waters Xbridge(0.46 mm×250 mm,5 μm) Dikma Diamonsil Plus(0.46 mm×250 mm,5 μm) Shimadzu ShimNex CS(0.46 mm×250 mm,5 μm) Dikma Diamonsil C₁₈(2)(0.46 mm×250 mm,5 μm) CAPCELL PAK MGⅡ(0.46 mm×250 mm,5 μm) Waters SunFire(0.46 mm×250 mm,5 μm) TechMate ST(0.46 mm×250 mm,5μm) Waters XSelect HSS(0.46 mm×250 mm,5 μm) Phenomenex Gemini(0.46 mm×250 mm,5 μm)
Instrument	Agilent 1260 Infinity
Column temperature	28 ℃
	32 ℃
pH	6.1
	6.3

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity B/%	Impurity ⅩⅢ/%	Impurity ⅩⅣ/%	Impurity ⅩⅤ/%	Impurity ⅩⅦ/%	Maximum unknown impurity/%	Total /%
DA203M-4-181201	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181202	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181203	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
0038L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.002	0.03	0.04
0039L61N	ND	ND	ND	ND	0.01	ND	ND	ND	0.004	0.02	0.04
0040L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.006	0.02	0.05
E02200701	0.01	ND	ND	ND	0.01	ND	ND	ND	0.02	ND	0.04
E02200702	ND	ND	ND	ND	0.02	ND	ND	ND	0.02	0.01	0.05
E02200801	ND	ND	ND	ND	0.01	ND	ND	ND	0.01	0.01	0.03
GEA2009001	ND	ND	ND	ND	ND	ND	ND	0.002	ND	ND	0.002
GEA2009002	ND	ND	ND	ND	ND	ND	ND	0.005	ND	0.03	0.04
20190301	ND	0.02	ND	ND	0.01	ND	ND	ND	0.01	0.02	0.08
20201201	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
20201202	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
8220024	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.01	0.01
8220025	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.02	0.04
8220026	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.03	0.05
689200801	ND	ND	ND	0.01	0.03	ND	ND	ND	ND	0.02	0.07
689200802	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
689200803	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
20181001	0.01	0.01	0.01	ND	0.01	0.02	0.03	ND	ND	0.01	0.09
20200603	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.07
20200701	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.08
606110231	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.04
606110232	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.05
606110233	ND	ND	ND	ND	0.02	ND	ND	ND	ND	0.01	0.02

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity B/%	Impurity ⅩⅢ/%	Impurity ⅩⅣ/%	Impurity ⅩⅤ/%	Impurity ⅩⅦ/%	Maximum unknown impurity/%	Total /%
DA203M-4-181201	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181202	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181203	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
0038L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.002	0.03	0.04
0039L61N	ND	ND	ND	ND	0.01	ND	ND	ND	0.004	0.02	0.04
0040L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.006	0.02	0.05
E02200701	0.01	ND	ND	ND	0.01	ND	ND	ND	0.02	ND	0.04
E02200702	ND	ND	ND	ND	0.02	ND	ND	ND	0.02	0.01	0.05
E02200801	ND	ND	ND	ND	0.01	ND	ND	ND	0.01	0.01	0.03
GEA2009001	ND	ND	ND	ND	ND	ND	ND	0.002	ND	ND	0.002
GEA2009002	ND	ND	ND	ND	ND	ND	ND	0.005	ND	0.03	0.04
20190301	ND	0.02	ND	ND	0.01	ND	ND	ND	0.01	0.02	0.08
20201201	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
20201202	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
8220024	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.01	0.01
8220025	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.02	0.04
8220026	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.03	0.05
689200801	ND	ND	ND	0.01	0.03	ND	ND	ND	ND	0.02	0.07
689200802	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
689200803	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
20181001	0.01	0.01	0.01	ND	0.01	0.02	0.03	ND	ND	0.01	0.09
20200603	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.07
20200701	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.08
606110231	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.04
606110232	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.05
606110233	ND	ND	ND	ND	0.02	ND	ND	ND	ND	0.01	0.02

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity Ⅻ/%	Impurity B/%	Impurity XIII/%	Impurity ⅩⅫ/%	Maximum unknown impurity /%	Total /%
2031190301	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190302	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190303	0.04	ND	ND	0.02	0.02	0.02	ND	0.03	0.01	0.17
DC1B0149	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0150	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0151	0.01	ND	ND	ND	ND	0.03	ND	ND	0.02	0.07
1R200701	0.01	ND	ND	0.02	ND	0.01	ND	0.01	0.03	0.06
20080711	0.01	ND	ND	0.01	ND	0.01	ND	0.02	ND	0.05
20190108	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.02	0.08
20190109	0.01	0.03	ND	ND	ND	0.01	ND	0.01	0.02	0.10
20200708	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.01	0.06
200510132	0.02	ND	ND	ND	ND	0.01	ND	ND	0.01	0.05
200606132	0.02	ND	ND	ND	ND	0.003	ND	ND	0.01	0.04
200606232	0.02	ND	ND	ND	ND	ND	ND	ND	0.01	0.05
20181201	0.02	0.01	0.01	ND	ND	0.01	0.003	ND	0.01	0.08
20190102	0.01	0.01	0.02	ND	ND	0.01	0.01	ND	0.01	0.11
20200701	0.01	ND	0.02	ND	ND	0.03	0.004	ND	0.01	0.10
2004014	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.04
2004015	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.05
2005013	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.06

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity Ⅻ/%	Impurity B/%	Impurity XIII/%	Impurity ⅩⅫ/%	Maximum unknown impurity /%	Total /%
2031190301	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190302	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190303	0.04	ND	ND	0.02	0.02	0.02	ND	0.03	0.01	0.17
DC1B0149	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0150	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0151	0.01	ND	ND	ND	ND	0.03	ND	ND	0.02	0.07
1R200701	0.01	ND	ND	0.02	ND	0.01	ND	0.01	0.03	0.06
20080711	0.01	ND	ND	0.01	ND	0.01	ND	0.02	ND	0.05
20190108	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.02	0.08
20190109	0.01	0.03	ND	ND	ND	0.01	ND	0.01	0.02	0.10
20200708	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.01	0.06
200510132	0.02	ND	ND	ND	ND	0.01	ND	ND	0.01	0.05
200606132	0.02	ND	ND	ND	ND	0.003	ND	ND	0.01	0.04
200606232	0.02	ND	ND	ND	ND	ND	ND	ND	0.01	0.05
20181201	0.02	0.01	0.01	ND	ND	0.01	0.003	ND	0.01	0.08
20190102	0.01	0.01	0.02	ND	ND	0.01	0.01	ND	0.01	0.11
20200701	0.01	ND	0.02	ND	ND	0.03	0.004	ND	0.01	0.10
2004014	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.04
2004015	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.05
2005013	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.06

吉非替尼原料与片剂中有关物质测定方法研究

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钱敏 , 宋冬梅 , 乐健 ^*

中国药学杂志 | 论著 2024,59(1): 67-77

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中国药学杂志 | 论著 2024, 59(1): 67-77

吉非替尼原料与片剂中有关物质测定方法研究

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钱敏, 宋冬梅, 乐健^*

作者信息

上海市食品药品检验研究院, 国家药品监督管理局化学药品制剂质量分析重点实验室, 上海 201203

钱敏,女,副主任药师研究方向:化学药品与药用辅料的质量标准研究

通讯作者:

*乐健,男,主任药师研究方向:药品质量控制与研究 Tel:(021)50798193

Determination of Related Substances in Gefitinib Raw Materials and Tablets

QIAN Min, SONG Dongmei, LE Jian^*

Affiliations

NMPA Key Laboratory for Quality Analysis of Chemical Drug Preparations, Shanghai Institute for Food and Drug Control, Shanghai 201203, China

出版时间: 2024-01-08 doi: 10.11669/cpj.2024.01.009

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摘要

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目的建立吉非替尼与吉非替尼片中有关物质的测定方法,用于评价各企业产品的质量,为本品种收录于新版《中国药典》提供方法储备。方法采用CAPCELL PAK C₁₈ MGⅡ色谱柱(4.6 mm×250 mm,5 μm),以10 g·L^-1乙酸铵溶液(用冰乙酸调节pH值至6.20±0.05)(A)-乙腈(B)为流动相,梯度洗脱,流速为1.0 mL·min^-1,柱温30 ℃;检测波长为247 nm,进样体积10 μL。结果吉非替尼与17个杂质的浓度在各自定量限至相当于主成分的0.2%的范围内,与峰面积呈良好线性关系(r均大于0.999 0),回收率介于89.4%~108.6%之间,定量限介于0.5~4.6 ng之间(相当于主成分的0.002%~0.02%),检测限介于0.1~1.0 ng之间(相当于主成分的0.001%~0.005%),吉非替尼原料中检出主要杂质为杂质B,吉非替尼片中检出主要杂质为杂质B与杂质Ⅴ。结论该方法高效、灵敏、准确,耐用性良好,可用于吉非替尼和吉非替尼片中杂质的质量控制,为国家药典标准增订提供了可靠的方法。

关键词

吉非替尼 / 有关物质 / 测定 / 质量控制

Abstract

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OBJECTIVE To establish a method for the determination of related substances in gefitinib and gefitinib tablets, evaluate the quality evaluation of products from different manufacturing enterprise and reserve methods for the new version of the Chinese Pharmacopoeia. METHODS HPLC experiment was performed on a column of CAPCELL PAK C₁₈ MGⅡ (4.6 mm×250 mm,5 μm) with the mobile phase of 1% ammonium acetate solution (adjust pH to 6.20±0.05 with glacial acetic acid) (A)-acetonitrile (B) with gradient elution. The flow rate was 1.0 mL·min^-1, the column temperature was maintained at 30 ℃, and the detection wavelength was set at 247 nm. The injection volume was 20 μL. RESULTS Gefitinib and 17 impurities showed good linear relationships with the peak area in the range between the LOQs and 0.2% of the principal component (r>0.999 0). The recoveries are between 89.4% and 108.6%. The LOQs are between 0.5 ng and 4.6 ng (equivalent to 0.002% to 0.02% of the principal component), and the LODs are between 0.1 ng and 1.0 ng (equivalent to 0.001% to 0.005% of the principal component). The results showed that the main impurity detected in gefitinib raw material was impurity B, while the main impurities detected in gefitinib tablets were impurity B and impurity Ⅴ. CONCLUSION This method is efficient, sensitive, accurate, and has good durability. It can be used for the quality control of impurities in gefitinib and gefitinib tablets. And it provides a reliable method for updating national pharmacopoeia standards.

Key words

gefitinib / related substance / content determination / quality control

引用本文

钱敏, 宋冬梅, 乐健. 吉非替尼原料与片剂中有关物质测定方法研究. 中国药学杂志, 2024 , 59 (1) : 67 -77 . DOI: 10.11669/cpj.2024.01.009

QIAN Min, SONG Dongmei, LE Jian. Determination of Related Substances in Gefitinib Raw Materials and Tablets[J]. Chinese Pharmaceutical Journal, 2024 , 59 (1) : 67 -77 . DOI: 10.11669/cpj.2024.01.009

正文

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吉非替尼是一种特异性较高的酪氨酸激酶抑制剂^[1],是第一个用于治疗非小细胞肺癌的分子靶向药物。吉非替尼片(商品名:易瑞莎)由阿斯利康(AstraZeneca)研发,于2002年率先在日本获批上市,2005年经原国家食品药品监督管理局批准在我国上市。该产品的专利保护期于2016年结束^[2],近年来,国内多家企业申报仿制药,截至2021年本课题研究时,国内已获批原料药与片剂生产企业各8家。欧洲药典^[3]收载有吉非替尼与吉非替尼片,其他各国药典均未收载。本研究为国家药典委标准提高课题,旨在拟订国家药品标准。

吉非替尼有多种合成路线^[4-9],阿斯利康专利公开的合成路径是以3-羟基-4-甲氧基苯甲醛为起始原料,首先制得3-羟基-4-甲氧基苯腈,再经醚化、硝化、水解、环合、氯化、3-氯-4-氟苯胺胺化制得。国内多家生产企业以6-羟基-7-甲氧基喹唑啉酮为起始原料,经乙酰化、氯化、3-氯-4-氟苯胺胺化、醚化等工艺制得。也有采用3-羟基-4-甲氧基-6-硝基-苯甲酸乙酯为起始原料,经醚化、还原、环合、氯化、3-氯-4-氟苯胺胺化制得。这些合成路径均较复杂,可能产生的杂质种类较多。目前国内获批的各生产企业注册标准中都控制了多个杂质,杂质种类各不相同。这些杂质按照限度可分为痕量的潜在基因毒性杂质(甲磺酸酯类、取代苯胺类等)和微量的中间体、工艺杂质与降解产物。其中,基因毒性杂质不在本文范围,将另文报道。本文主要研究各注册标准中有关物质项涉及的已知杂质共17个,见图1。杂质B、杂质Ⅷ、杂质Ⅹ、杂质ⅩⅤ是由合成原料3-氯-4-氟苯胺中存在的3-氟-4-氯苯胺、2-氟-3氯苯胺、3,4-二氟苯胺、3,4-二氯苯胺参与反应而产生的工艺杂质。其中最主要的杂质3-氟-4-氯苯胺产生了杂质B。由于3-氯-4-氟苯胺是所有企业的工艺中都使用的合成原料,因此吉非替尼产品中几乎全部检出杂质B。杂质Ⅺ与杂质ⅩⅦ来源于以6-羟基-7-甲氧基喹唑啉酮为起始物料的合成路线,是由起始物料中含有羟基取代位置不同的杂质参与反应而得。测定结果表明采用该合成路线的吉非替尼中均检出了杂质ⅩⅦ。杂质Ⅴ是由吉非替尼结构中吗啉基的氮原子的孤对电子与氧原子形成配位键,反应生成的吉非替尼氮氧化物,是最主要的降解杂质。

作为国家标准,应能适用于每个生产企业产品的质量控制,有关物质项的色谱系统需能够分离吉非替尼与上述全部已知杂质。由于欧洲药典、各企业注册标准以及文献报道 ^[10-15]的色谱系统均不能达到上述要求,本课题研究在EP10.0的基础上通过改变色谱柱、调整流动相pH值、建立梯度洗脱程序,开发建立了一个新的色谱条件,能够同时分离测定吉非替尼与吉非替尼片中的17个已知杂质,方法学验证结果表明,该方法专属性强、灵敏度高、耐用性良好,可用于进行吉非替尼与吉非替尼片的有关物质研究,为该品种国家药典标准增订提供了可靠的方法。本研究征集的吉非替尼原料与吉非替尼片样品,涵盖了目前国内市场所有生产企业的产品,其测定结果也一定程度上反映了各企业产品的质量差异。本文还对样品中主要杂质的产生及研究中发现的问题进行了分析。

1 仪器与试药

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Agilent 1260 Infinity高效液相色谱仪、Agilent 1260 Infinity Ⅱ高效液相色谱仪(美国Agilent公司);CP225D型电子天平(德国Sartorius公司);SevenCompact型酸度计(德国Mettler Toledo公司);Milli-Q型超纯水系统(Millpore公司);超声仪(上海科导超声仪器有限公司)。

吉非替尼原料药(国内8家生产企业及原研企业提供);吉非替尼片(国内7家生产企业及原研企业提供)。吉非替尼及各杂质对照品信息见表1。乙腈为色谱纯;水为超纯水;其他试剂均为分析纯。

2 方法与结果

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2.1 溶液制备

溶剂:体积分数0.2%三氟乙酸溶液-乙腈(体积比8∶2)。

2.1.1 系统适用性溶液

取各杂质对照品,精密称定,加溶剂溶解并稀释制成每1 mL中分别含各杂质0.1 mg的溶液,作为杂质对照品储备溶液;取吉非替尼对照品100 mg,置50 mL量瓶中,精密加入各杂质对照品储备溶液1 mL,用溶剂溶解并稀释到刻度,摇匀,作为系统适用性溶液。

2.1.2 对照品溶液

取吉非替尼对照品10 mg,精密称定,置100 mL量瓶中,加溶剂溶解并稀释至刻度,摇匀,作为吉非替尼对照品储备溶液;精密量取1 mL与“2.1.1”项下杂质对照品储备溶液1 mL,置同一50 mL量瓶中,用溶剂稀释至刻度,摇匀,作为对照品溶液。

2.1.3 吉非替尼供试品溶液

取本品100 mg,精密称定,置50 mL量瓶中,加溶剂溶解并稀释至刻度,摇匀,作为吉非替尼供试品溶液。

2.1.4 吉非替尼片供试品溶液

取本品细粉适量(约相当于吉非替尼100 mg),精密称定,置50 mL量瓶中,加溶剂适量,超声10 min,放冷,用溶剂稀释至刻度,摇匀,滤过,取续滤液作为吉非替尼片供试品溶液。

2.2 色谱条件

用CAPCELL PAK C₁₈ MGⅡ色谱柱(4.6 mm×250 mm,5 μm);流动相A:1% 醋酸铵溶液(用冰乙酸调节pH值至6.20±0.05),流动相B:乙腈,梯度洗脱:0~1 min,19%B;1~5 min,19%~33% B;5~25 min, 33% B;25~35 min,33%~50% B;35~50 min,50% B;流速为1.0 mL·min^-1;柱温:30 ℃;检测波长:247 nm。进样体积10 μL。按外标法计算各杂质的含量,未知杂质以吉非替尼为对照品计算。

2.3 专属性试验

取空白辅料(8个片剂生产企业所用各种辅料的混合物),按“2.1.4”项方法配制阴性溶液。分别量取系统适用性溶液、吉非替尼供试品溶液、吉非替尼片供试品溶液、阴性溶液,按“2.2”项的色谱条件进样,记录色谱图,见图2。系统适用性溶液色谱图显示各杂质峰及吉非替尼峰之间均能良好分离;阴性溶液色谱图显示空白辅料对测定无干扰;吉非替尼供试品溶液与吉非替尼片供试品溶液色谱图显示,各色谱峰之间的分离度良好,未知杂质及空白辅料对测定无干扰。

2.4 强破坏试验

取吉非替尼(批号:DA203M-4-181201与606110231)100 mg与吉非替尼片(批号:2031190301与2004014)细粉适量(约相当于吉非替尼100 mg)各6份,分别进行强酸(加1 mol·L^-1盐酸溶液5 mL,室温放置4 h,加1 mol·L^-1氢氧化钠溶液5 mL,加乙腈2.5 mL)、强碱(加1 mol·L^-1氢氧化钠溶液5 mL,室温放置4 h,加1 mol·L^-1盐酸溶液5 mL,加乙腈2.5 mL)、氧化(加溶剂5 mL使溶解,加3%过氧化氢溶液1 mL,室温放置4 h)、紫外光照(254 nm波长紫外光下放置4 h)、高温(105 ℃加热48 h)、超声(加溶剂适量使溶解,以频率53 kHz超声30 min)破坏处理后,用溶剂稀释制成含吉非替尼2 mg·mL^-1的溶液。量取上述溶液按“2.2”项的色谱条件进样,记录色谱图,见图3。强破坏试验结果显示:吉非替尼在强酸、强碱、紫外光照、超声处理的试验条件下较稳定,各杂质未见增加;在氧化破坏试验条件下,杂质Ⅴ显著增加;在高温破坏试验条件下,杂质Ⅴ被较大程度降解,吉非替尼片中杂质Ⅻ显著增加。破坏试验记录的色谱图中各色谱峰之间均能良好分离,本方法专属性良好。

分别计算各破坏条件下吉非替尼测定值与所有杂质检出量的总和,与未破坏的样品中吉非替尼与各杂质含量的总和比较,计算百分比。结果均介于97.4%~101.7%之间,可以认为化学质量守恒。

2.5 定量限与检测限

取“2.1.1”项杂质对照品储备溶液与“2.1.2”项吉非替尼对照品溶液,逐级定量稀释,按“2.2”项的色谱条件进样并记录色谱图,以峰高的信噪比(S/N)分别为3和10所对应的进样量作为检测限与定量限。测定结果见表2。

2.6 线性与校正因子

取吉非替尼对照品与各杂质对照品储备溶液,逐级定量稀释制成浓度范围包含从定量限附近至约相当于主成分的0.2%(4 μg·mL^-1)的系列溶液,按“2.2”项的色谱条件进样并记录色谱图,记录色谱图,分别以峰面积对相应浓度进行线性回归。试验结果见表3。

2.7 精密度

取线性试验项下定量限浓度、相当于主成分的0.05%和0.1%浓度的各对照品溶液,按“2.2”项的色谱条件分别进样3针,计算各浓度溶液峰面积的RSD,即为进样精密度,结果见表4。

以“2.8”回收率试验项下各杂质9份加标回收率的RSD作为重复性试验,吉非替尼原料中17个杂质的RSD在0.24%~7.0%之间,吉非替尼片中17个杂质的RSD在0.05%~4.8%之间。

2.8 回收率试验

取吉非替尼(批号:DA203M-4-181201)100 mg与吉非替尼片(批号:2004014)细粉适量(约相当于吉非替尼100 mg),精密称定,置50 mL量瓶中,分别精密加入各杂质对照品贮备液适量,用溶剂稀释至刻度,摇匀,分别作为定量限浓度、相当于主成分的0.05%与相当于主成分的0.1%加样回收率试验溶液,每个浓度平行操作3份。按“2.2”项的色谱条件进样测定,并计算回收率,结果见表5。

2.9 稳定性

取浓度为2 μg·mL^-1混合对照品溶液、吉非替尼供试品溶液(批号:20181001,检出杂质最多者)与吉非替尼片供试品溶液(批号:2031190301,检出杂质最多者)室温放置,分别于0、2、6、11、18、23、32、45、55、67与79 h时,按“2.2”项的色谱条件进样测定,计算各化合物峰面积的相对标准偏差(RSD),结果见表6。结果表明上述溶液在室温下79 h内较稳定。

2.10 耐用性

适当改变流动相pH值、流速、柱温以及更换不同品牌色谱柱等色谱条件(表7),考察方法的耐用性。在改变上述色谱条件时,除调节流动相pH值至6.3时,杂质Ⅹ峰与杂质Ⅺ峰(分离度最小者)之间的分离度小于1.5,其余条件下系统适用性溶液色谱图中各色谱峰之间均能完全分离。说明杂质Ⅹ峰与杂质Ⅺ峰的分离对pH较敏感,因此拟订标准中对流动相pH值的描述为“用冰乙酸调节pH值至6.20±0.05”。本研究工作结果显示多个品牌色谱柱均能满足测定要求,因此,本方法满足国家标准通用性的要求。

2.11 样品测定

本研究征集了目前已获批的国内企业及原研企业的吉非替尼与吉非替尼片样品,测定结果见表8~9。结果显示,各企业产品中检出的杂质种类不尽相同,所有企业生产的吉非替尼原料中都检出杂质B,其中5个生产企业以6-羟基-7-甲氧基喹唑啉酮为起始原料,其产品中均检出杂质ⅩⅦ;吉非替尼片中主要杂质为杂质B与杂质Ⅴ。

3 讨论

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本研究在欧洲药典的基础上进行优化。比较了水相分别为醋酸铵溶液与磷酸盐缓冲液的流动相系统,结果表明,用醋酸铵溶液-乙腈作流动相时,可以获得更尖锐、更对称的色谱峰。需要分离的目标化合物中,主峰及其后洗脱的杂质,通过调整梯度洗脱程序中乙腈的比例,能够比较容易实现,且不同色谱柱中重现性较好。方法优化的难点在于实现杂质Ⅲ~杂质Ⅻ各峰之间的分离。预实验发现,流动相pH值改变时,杂质Ⅴ峰与杂质Ⅻ峰的保留时间变化不大,其余各杂质峰保留时间缩短;柱温调整时,杂质Ⅲ峰、杂质Ⅵ峰保留时间的变化趋势与其他峰相反。研究中利用上述杂质在色谱系统中的保留特性,优化确定了流动相的pH值以及梯度洗脱程序。使得采用不同品牌色谱柱分析时,各杂质峰之间分离度良好,出峰顺序一致,说明该色谱方法的通用性良好。

吉非替尼在水中不溶,在乙腈中溶解。试验中发现,吉非替尼或吉非替尼片细粉加入乙腈-水后,超声处理3~5 min,产生约1%的杂质Ⅴ,且杂质Ⅴ的量与超声仪的频率呈正相关。在乙腈-水中加入酸,可有效的阻止该氧化反应。分析其原因,可能是酸的氢离子优先与吗啉基氮原子的孤对电子形成共价键,阻止其与氧原子反应,起到了保护作用。因此,用0.2%三氟乙酸溶液代替溶剂中的水。同时,为了避免杂质A峰(保留时间最短)因溶剂效应而出现裂峰的现象,调整乙腈比例至接近洗脱梯度的起始比例。研究确定了溶剂为0.2%三氟乙酸溶液-乙腈(80∶20),验证结果表明,吉非替尼或吉非替尼片细粉中加入该溶剂,超声(53 kHz)处理30 min,杂质Ⅴ的含量均未见增加。

杂质Ⅻ是一种合成中间体。强破坏试验结果表明,吉非替尼片经高温破坏后,杂质Ⅻ的含量显著增加,而吉非替尼原料在各强破坏实验条件下均未产生杂质Ⅻ。说明杂质Ⅻ是一种与辅料相关的降解产物,片剂中的辅料促进吉非替尼脱去丙基吗啉,从而生成杂质Ⅻ。“2.11”项测定结果显示,吉非替尼中均未检出杂质Ⅻ,吉非替尼片中仅一批样品检出杂质Ⅻ。将所有原料与片剂的样品常温放置两年后测定,结果显示,吉非替尼原料中仍未检出杂质Ⅻ,吉非替尼片中均检出杂质Ⅻ,其含量在0.05%~0.1%之间。这一结果证明了吉非替尼片中的辅料对降解有一定的影响,提醒相关生产企业应关注辅料相容性的问题。

针对吉非替尼片经高温破坏,杂质Ⅻ的含量显著增加,同时杂质Ⅴ显著降低的情况,我们进行了杂质Ⅴ与杂质Ⅻ的相关性研究。实验结果表明,杂质Ⅴ与空白辅料混合后,经高温破坏,产生杂质Ⅻ与吉非替尼。我们推测,在辅料的作用下,部分杂质Ⅴ脱去氮氧化丙基吗啉,生成杂质Ⅻ;也有部分杂质Ⅴ被还原成吉非替尼,吉非替尼再被降解,生成杂质Ⅻ。因此,“2.4”项吉非替尼片高温破坏后,检测到的杂质Ⅻ来源于吉非替尼与杂质Ⅴ(主要来源于吉非替尼)。

“2.8”项回收率试验结果显示,杂质Ⅲ在吉非替尼原料中加样回收率平均值为91.5%,而在吉非替尼片中的加样回收率平均值为56.7%,另取空白辅料按“2.8”项进行回收率试验,3个浓度水平加样回收率的平均值为54.6%,说明辅料与杂质Ⅲ发生了作用。杂质Ⅲ是根据原料药合成路线推测可能存在的合成杂质,强破坏试验未产生该杂质,说明它不是降解产物。因此杂质Ⅲ作为工艺杂质在原料中进行控制,在制剂中可不再作为已知杂质控制,杂质Ⅲ加样回收率偏低的结果,不影响该方法用于片剂的质量控制。

本研究涉及17个已知杂质,在方法开发与验证阶段全部采用杂质对照品试验,按外标法计算,以获得全面的验证数据,使得研究内容充分、完整。而在拟订国家标准时,综合考虑杂质对照品的易得性以及质量标准的便捷性、经济性,不需要全部杂质都采用对照品按外标法计算,可选择主要工艺杂质或降解产物(杂质B与杂质Ⅴ)作为已知杂质控制,其余杂质作为其他未知杂质,杂质定量采用加校正因子的主成分自身对照法计算。对于在合成中产生的工艺杂质,已经在原料药中控制的,在制剂的生产与贮存中不会增加,则在制剂中可以不作为已知杂质控制。

基金

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国家药典委员会药品标准提高制修订研究课题资助(2020H057)
国家药典委员会药品标准提高制修订研究课题资助(2020H058)

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2024年第59卷第1期

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doi: 10.11669/cpj.2024.01.009

接收时间：2023-07-05
首发时间：2025-11-12
出版时间：2024-01-08

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收稿日期：2023-07-05

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国家药典委员会药品标准提高制修订研究课题资助(2020H057)

国家药典委员会药品标准提高制修订研究课题资助(2020H058)

作者信息

上海市食品药品检验研究院, 国家药品监督管理局化学药品制剂质量分析重点实验室, 上海 201203

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*乐健,男,主任药师研究方向:药品质量控制与研究 Tel:(021)50798193

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Compound	Lot.	Purity/%
Gefitinib	420019-201902	99.8
Impurity A	420045-201701	100
Impurity Ⅲ	20191428	96.5
Impurity Ⅳ	GTFN-223-180901	99.8
Impurity V	9011461N1DYS	99.5
Impurity Ⅵ	XS120711-01	96.7
Impurity Ⅶ	LS50U72	99.58
Impurity Ⅷ	2-0-GFNB-191	97.30
Impurity Ⅸ	GTFN-227-180901	99.7
Impurity Ⅹ	XS150206-01	97.9
Impurity Ⅺ	20190614	96.4
Impurity Ⅻ	562-3201	98.25
Impurity B	20190523-1	96.3
Impurity ⅩⅢ	20190617	96.3
Impurity ⅩⅣ	XS120625-01	98.2
Impurity ⅩⅤ	200203-5D-C09	99.70
Impurity ⅩⅥ	RRW757	96
Impurity ⅩⅦ	200301-8D-133	98.36

Compound

Lot.

Purity/%

Gefitinib

420019-201902

99.8

Impurity A

420045-201701

100

Impurity Ⅲ

20191428

96.5

Impurity Ⅳ

GTFN-223-180901

99.8

Impurity V

9011461N1DYS

99.5

Impurity Ⅵ

XS120711-01

96.7

Impurity Ⅶ

LS50U72

99.58

Impurity Ⅷ

2-0-GFNB-191

97.30

Impurity Ⅸ

GTFN-227-180901

99.7

Impurity Ⅹ

XS150206-01

97.9

Impurity Ⅺ

20190614

96.4

Impurity Ⅻ

562-3201

98.25

Impurity B

20190523-1

96.3

Impurity ⅩⅢ

20190617

96.3

Impurity ⅩⅣ

XS120625-01

98.2

Impurity ⅩⅤ

200203-5D-C09

99.70

Impurity ⅩⅥ

RRW757

Impurity ⅩⅦ

200301-8D-133

98.36

Compound	LOQ	LOD
Gefitinib	0.61	0.003	0.12	0.001
Impurity A	0.88	0.004	0.20	0.001
ImpurityⅢ	0.93	0.005	0.24	0.001
Impurity Ⅳ	0.47	0.002	0.11	0.001
Impurity Ⅴ	0.91	0.005	0.22	0.001
Impurity Ⅵ	4.64	0.023	0.99	0.005
Impurity Ⅶ	2.51	0.013	0.58	0.003
Impurity Ⅷ	1.57	0.008	0.33	0.002
Impurity Ⅸ	1.08	0.005	0.20	0.001
Impurity Ⅹ	1.82	0.009	0.44	0.002
Impurity Ⅺ	3.77	0.019	0.99	0.005
Impurity Ⅻ	1.95	0.010	0.54	0.003
Impurity B	1.15	0.006	0.25	0.001
Impurity ⅩⅢ	1.07	0.005	0.24	0.001
Impurity ⅩⅣ	0.49	0.002	0.15	0.001
Impurity ⅩⅤ	1.08	0.005	0.33	0.002
Impurity ⅩⅥ	1.28	0.006	0.33	0.002
Impurity ⅩⅦ	2.65	0.013	0.60	0.003

Compound

LOQ

LOD

m/ng

Percentage/%

m/ng

Percentage/%

Gefitinib

0.61

0.003

0.12

0.001

Impurity A

0.88

0.004

0.20

0.001

ImpurityⅢ

0.93

0.005

0.24

0.001

Impurity Ⅳ

0.47

0.002

0.11

0.001

Impurity Ⅴ

0.91

0.005

0.22

0.001

Impurity Ⅵ

4.64

0.023

0.99

0.005

Impurity Ⅶ

2.51

0.013

0.58

0.003

Impurity Ⅷ

1.57

0.008

0.33

0.002

Impurity Ⅸ

1.08

0.005

0.20

0.001

Impurity Ⅹ

1.82

0.009

0.44

0.002

Impurity Ⅺ

3.77

0.019

0.99

0.005

Impurity Ⅻ

1.95

0.010

0.54

0.003

Impurity B

1.15

0.006

0.25

0.001

Impurity ⅩⅢ

1.07

0.005

0.24

0.001

Impurity ⅩⅣ

0.49

0.002

0.15

0.001

Impurity ⅩⅤ

1.08

0.005

0.33

0.002

Impurity ⅩⅥ

1.28

0.006

0.33

0.002

Impurity ⅩⅦ

2.65

0.013

0.60

0.003

Compound	Concentration range/μg·mL^-1	Regression equations	r	Correction factors
Gefitinib	0.115 0-4.598 8	y=36.100x+11.405	0.999 2	1.0
Impurity A	0.062 5-4.168 0	y=69.195x-3.265	0.999 7	0.52
Impurity Ⅲ	0.105 0-4.199 7	y=28.425x-2.375	0.999 4	1.27
Impurity Ⅳ	0.041 3-4.127 7	y=41.582x-1.512	0.999 7	0.87
Impurity Ⅴ	0.219 3 -4.386 0	y=35.096x-1.621	0.999 8	1.03
ImpurityⅥ	0.427 0-4.270 3	y=17.883x-2.013	0.999 5	2.02
Impurity Ⅶ	0.193 2-3.863 7	y=27.188x-1.560	0.999 3	1.33
Impurity Ⅷ	0.211 3-4.226 7	y=37.504x-1.718	0.999 2	0.96
Impurity Ⅸ	0.102 3-4.091 7	y=67.656x-3.166	0.999 6	0.53
Impurity Ⅹ	0.414 3-4.143 1	y=40.150x-2.747	0.999 8	0.90
Impurity Ⅺ	1.025 7-4.102 8	y=20.447x-1.773	0.999 4	1.77
Impurity Ⅻ	0.421 3-4.213 0	y=47.079x-6.089	0.999 1	0.77
Impurity B	0.102 7-4.106 2	y=31.084x-1.300	0.999 6	1.16
Impurity ⅩⅢ	0.104 4-4.175 6	y=34.750x-1.120	0.999 7	1.04
Impurity ⅩⅣ	0.107 0-4.281 5	y=43.632x-1.051	0.999 8	0.83
Impurity ⅩⅤ	0.222 1-4.442 6	y=27.209x-1.132	0.999 6	1.33
Impurity ⅩⅥ	0.210 4-4.208 6	y=29.395x-0.492	0.999 8	1.23
Impurity ⅩⅦ	0.439 1-4.390 8	y=17.389x-0.469	0.999 7	2.08

Compound

Concentration
range/μg·mL^-1

Regression
equations

Correction
factors

Gefitinib

0.115 0-4.598 8

y=36.100x+11.405

0.999 2

1.0

Impurity A

0.062 5-4.168 0

y=69.195x-3.265

0.999 7

0.52

Impurity Ⅲ

0.105 0-4.199 7

y=28.425x-2.375

0.999 4

1.27

Impurity Ⅳ

0.041 3-4.127 7

y=41.582x-1.512

0.999 7

0.87

Impurity Ⅴ

0.219 3 -4.386 0

y=35.096x-1.621

0.999 8

1.03

ImpurityⅥ

0.427 0-4.270 3

y=17.883x-2.013

0.999 5

2.02

Impurity Ⅶ

0.193 2-3.863 7

y=27.188x-1.560

0.999 3

1.33

Impurity Ⅷ

0.211 3-4.226 7

y=37.504x-1.718

0.999 2

0.96

Impurity Ⅸ

0.102 3-4.091 7

y=67.656x-3.166

0.999 6

0.53

Impurity Ⅹ

0.414 3-4.143 1

y=40.150x-2.747

0.999 8

0.90

Impurity Ⅺ

1.025 7-4.102 8

y=20.447x-1.773

0.999 4

1.77

Impurity Ⅻ

0.421 3-4.213 0

y=47.079x-6.089

0.999 1

0.77

Impurity B

0.102 7-4.106 2

y=31.084x-1.300

0.999 6

1.16

Impurity ⅩⅢ

0.104 4-4.175 6

y=34.750x-1.120

0.999 7

1.04

Impurity ⅩⅣ

0.107 0-4.281 5

y=43.632x-1.051

0.999 8

0.83

Impurity ⅩⅤ

0.222 1-4.442 6

y=27.209x-1.132

0.999 6

1.33

Impurity ⅩⅥ

0.210 4-4.208 6

y=29.395x-0.492

0.999 8

1.23

Impurity ⅩⅦ

0.439 1-4.390 8

y=17.389x-0.469

0.999 7

2.08

Compound	LOQ RSD/%	1 μg·mL^-1 (0.05%) RSD/%	2 μg·mL^-1 (0.1%) RSD/%
Gefitinib	1.3	0.32	1.3
Impurity A	1.3	0.53	0.02
Impurity Ⅲ	0.99	0.87	0.47
Impurity Ⅳ	0.55	0.28	0.22
Impurity Ⅴ	1.7	0.50	0.09
Impurity Ⅵ	0.67	1.34	0.34
Impurity Ⅶ	1.8	0.53	0.54
Impurity Ⅷ	2.0	0.96	0.87
ImpurityⅨ	1.7	0.41	0.17
Impurity Ⅹ	2.2	0.19	0.22
Impurity Ⅺ	1.6	0.92	0.27
Impurity Ⅻ	1.1	1.7	0.64
Impurity B	1.7	0.55	0.39
Impurity ⅩⅢ	2.2	1.2	0.54
Impurity ⅩⅣ	1.7	0.37	0.11
Impurity ⅩⅤ	2.0	0.67	0.35
Impurity ⅩⅥ	2.0	0.31	0.15
Impurity ⅩⅦ	1.1	0.83	1.1

Compound

LOQ
RSD/%

1 μg·mL^-1
(0.05%) RSD/%

2 μg·mL^-1
(0.1%) RSD/%

Gefitinib

1.3

0.32

1.3

Impurity A

1.3

0.53

0.02

Impurity Ⅲ

0.99

0.87

0.47

Impurity Ⅳ

0.55

0.28

0.22

Impurity Ⅴ

1.7

0.50

0.09

Impurity Ⅵ

0.67

1.34

0.34

Impurity Ⅶ

1.8

0.53

0.54

Impurity Ⅷ

2.0

0.96

0.87

ImpurityⅨ

1.7

0.41

0.17

Impurity Ⅹ

2.2

0.19

0.22

Impurity Ⅺ

1.6

0.92

0.27

Impurity Ⅻ

1.1

1.7

0.64

Impurity B

1.7

0.55

0.39

Impurity ⅩⅢ

2.2

1.2

0.54

Impurity ⅩⅣ

1.7

0.37

0.11

Impurity ⅩⅤ

2.0

0.67

0.35

Impurity ⅩⅥ

2.0

0.31

0.15

Impurity ⅩⅦ

1.1

0.83

1.1

Impurities	Gefitinib	Gefitinib tablets
Impurity A	0.062 50	0	0.062 23	99.6	98.5	2.1	0	0.067 68	108.3	108.0	0.35
	0.062 50	0	0.060 14	96.2			0	0.067 50	108.0
	0.062 50	0	0.062 41	99.9			0	0.067 22	107.6
	1.042	0	1.109	106.4	106.5	0.73	0	1.110	106.5	106.8	0.28
	1.042	0	1.118	107.3			0	1.113	106.8
	1.042	0	1.102	105.7			0	1.116	107.1
	2.084	0	2.089	100.2	100.6	0.46	0	2.148	103.1	103.0	0.15
	2.084	0	2.095	100.5			0	2.144	102.9
	2.084	0	2.107	101.1			0	2.150	103.2
Impurity Ⅲ	0.105 0	0	0.102 5	97.6	94.5	5.3	0.043 46	0.103 2	56.9	57.2	1.29
	0.105 0	0	0.102 1	97.3			0.043 46	0.104 4	58.0
	0.105 0	0	0.093 2	88.7			0.043 46	0.102 9	56.7
	1.050	0	0.938 6	89.4	89.4	0.93	0.043 46	0.645 4	57.4	56.8	0.86
	1.050	0	0.947 4	90.2			0.043 46	0.636 5	56.5
	1.050	0	0.929 9	88.6			0.043 46	0.636 6	56.5
	2.100	0	1.896	90.3	90.6	0.57	0.043 46	1.264	58.2	56.0	4.8
	2.100	0	1.915	91.2			0.043 46	1.235	56.9
	2.100	0	1.896	90.3			0.043 46	1.154	53.0
Impurity Ⅳ	0.041 30	0	0.042 38	102.7	103.4	5.9	0	0.041 30	100.0	102.2	2.0
	0.041 30	0	0.045 41	110.0			0	0.042 36	102.6
	0.041 30	0	0.040 38	97.8			0	0.042 99	104.1
	1.032	0	1.096	106.2	105.1	0.94	0	1.108	107.4	107.4	0.14
	1.032	0	1.078	104.5			0	1.110	107.5
	1.032	0	1.079	104.5			0	1.106	107.2
	2.064	0	2.050	99.3	100.1	0.74	0	2.119	102.7	102.2	0.65
	2.064	0	2.067	100.2			0	2.117	102.6
	2.064	0	2.081	100.8			0	2.094	101.5
Impurity Ⅴ	0.219 3	0.419 4	0.654 4	107.2	108.6	1.9	0.082 08	0.307 7	102.9	103.3	0.70
	0.219 3	0.419 4	0.655 5	107.7			0.082 08	0.307 8	102.9
	0.219 3	0.419 4	0.662 8	111.0			0.082 08	0.310 5	104.2
	1.096	0.419 4	1.611	108.6	108.0	0.88	0.082 08	1.233	104.9	104.6	0.32
	1.096	0.419 4	1.593	106.9			0.082 08	1.226	104.3
	1.096	0.419 4	1.611	108.6			0.082 08	1.228	104.5
	2.193	0.419 4	2.635	102.1	102.0	0.63	0.082 08	2.281	100.5	100.5	0.02
	2.193	0.419 4	2.616	101.2			0.082 08	2.281	100.5
	2.193	0.419 4	2.643	102.5			0.082 08	2.282	100.5
Impurity Ⅵ	0.427 0	0	0.790 5	105.9	106.2	0.88	0	0.878 1	109.4	109.3	0.34
	0.427 0	0	0.796 5	107.3			0	0.875 6	108.8
	0.427 0	0	0.788 9	105.5			0	0.878 5	109.5
	1.068	0	1.537	113.6	107.4	5.2	0	1.513	104.9	104.9	0.43
	1.068	0	1.449	105.4			0	1.508	104.4
	1.068	0	1.424	103.0			0	1.518	105.3
	2.135	0	2.460	101.3	100.5	1.4	0	2.606	105.2	105.1	0.60
	2.135	0	2.409	98.9			0	2.619	105.8
	2.135	0	2.461	101.3			0	2.592	104.5
Impurity Ⅶ	0.193 2	0	0.198 5	102.7	104.0	1.7	0	0.208 9	108.1	107.3	0.95
	0.193 2	0	0.204 9	106.1			0	0.205 1	106.2
	0.193 2	0	0.199 5	103.3			0	0.208 0	107.6
	0.965 9	0	0.992 1	102.7	104.3	1.7	0	1.008 6	104.4	104.1	0.66
	0.965 9	0	1.003	103.8			0	0.998	103.3
	0.965 9	0	1.026	106.2			0	1.011	104.6
	1.932	0	1.945	100.7	100.7	0.46	0	1.964	101.7	101.4	0.38
	1.932	0	1.956	101.2			0	1.950	100.9
	1.932	0	1.938	100.3			0	1.961	101.5
Impurity Ⅷ	0.211 3	0.086 62	0.296 5	104.6	103.1	1.3	0.100 4	0.324 0	105.8	106.1	0.27
	0.211 3	0.086 62	0.292 2	102.5			0.100 4	0.325 2	106.4
	0.211 3	0.086 62	0.291 4	102.2			0.100 4	0.324 2	105.9
	1.057	0.086 62	1.185	105.0	105.2	0.46	0.100 4	1.213	105.2	104.9	0.32
	1.057	0.086 62	1.194	105.8			0.100 4	1.208	104.8
	1.057	0.086 62	1.184	104.9			0.100 4	1.206	104.6
	2.113	0.086 62	2.213	101.3	100.0	1.2	0.100 4	2.254	102.2	102.1	0.10
	2.113	0.086 62	2.164	99.0			0.100 4	2.250	102.0
	2.113	0.086 62	2.179	99.7			0.100 4	2.253	102.1
Impurity Ⅸ	0.102 3	0	0.094 77	92.6	96.6	3.59	0	0.101 7	99.4	100.9	1.6
	0.102 3	0	0.101 0	98.8			0	0.102 9	100.6
	0.102 3	0	0.100 8	98.5			0	0.105 0	102.7
	1.023	0	1.074	105.0	104.9	0.85	0	1.081	105.7	105.9	0.30
	1.023	0	1.082	105.7			0	1.082	105.8
	1.023	0	1.063	104.0			0	1.087	106.3
	2.046	0	2.055	100.4	100.1	0.27	0	2.061	100.8	100.9	0.13
	2.046	0	2.046	100.0			0	2.063	100.8
	2.046	0	2.045	99.9			0	2.066	101.0
Impurity Ⅹ	0.414 3	0.483 9	0.910 0	102.9	105.8	2.4	0	0.442 6	106.8	107.0	0.15
	0.414 3	0.483 9	0.929 1	107.5			0	0.443 9	107.1
	0.414 3	0.483 9	0.927 0	107.0			0	0.443 2	107.0
	1.036	0.483 9	1.549	103. 9	106.1	2.0	0	1.099	106.1	106.1	0.18
	1.036	0.483 9	1.574	106.3			0	1.096	105.8
	1.036	0.483 9	1.594	108.2			0	1.100	106.2
	2.072	0.483 9	2.475	97. 8	99.2	1.4	0	2.100	101.4	101.4	0.14
	2.072	0.483 9	2.502	99.1			0	2.097	101.2
	2.072	0.483 9	2.533	100.6			0	2.103	101.5
Impurity Ⅺ	1.026	0	1.023	99.7	103.0	3.3	0	1.070	104.4	104.7	1.1
	1.026	0	1.092	106.5			0	1.087	106.0
	1.026	0	1.056	102.9			0	1.065	103.9
	1.026	0	0.990 2	96.5	98.3	1.7	0	1.053	102.6	103.1	0.50
	1.026	0	1.009	98.4			0	1.063	103.7
	1.026	0	1.025	100.0			0	1.057	103.1
	2.051	0	2.001	97. 6	97.3	0.87	0	2.057	100.3	100.5	0.53
	2.051	0	2.008	97. 9			0	2.054	100.1
	2.051	0	1.975	96.3			0	2.075	101.1
Impurity Ⅻ	0.421 3	0	0.443 9	105.4	104.8	1.3	0	0.439 7	104.4	104.3	0.31
	0.421 3	0	0.445 7	105.8			0	0.440 6	104.6
	0.421 3	0	0.435 3	103.3			0	0.437 9	103.9
	1.053	0	1.074	102.0	106.0	3.5	0	1.094	103.9	104.1	0.57
	1.053	0	1.126	106.9			0	1.103	104.7
	1.053	0	1.151	109.3			0	1.091	103.6
	2.106	0	2.053	97.5	98.5	0.91	0	2.242	106.4	106.0	0.54
	2.106	0	2.082	98.8			0	2.219	105.3
	2.106	0	2.089	99. 2			0	2.236	106.1
Impurity B	0.102 7	0.495 2	0.594 9	97.0	96.9	2.1	0.706 2	0.811 3	102.3	107.2	4.0
	0.102 7	0.495 2	0.592 4	94.7			0.706 2	0.819 1	109.9
	0.102 7	0.495 2	0.596 7	98.8			0.706 2	0.818 6	109.4
	1.027	0.495 2	1.553	102.5	103.0	0.79	0.706 2	1.799	105.7	106.5	1.3
	1.027	0.495 2	1.568	104.0			0.706 2	1.799	105.7
	1.027	0.495 2	1.554	102.6			0.706 2	1.825	108.2
	2.053	0.495 2	2.489	98.2	98.9	0.63	0.706 2	2.782	102.6	102.6	0.14
	2.053	0.495 2	2.510	99. 2			0.706 2	2.778	102.4
	2.053	0.495 2	2.513	99.3			0.706 2	2.784	102.7
Impurity ⅩⅢ	0.104 4	0	0.117 3	112.3	104.2	7.0	0	0.111 5	106.8	107.1	1.1
	0.104 4	0	0.102 5	98.1			0	0.113 1	108.3
	0.104 4	0	0.106 5	102.0			0	0.110 7	106.0
	1.044	0	1.104	105.8	105.9	0.28	0	1.107	106.0	106.5	0.41
	1.044	0	1.109	106.2			0	1.112	106.5
	1.044	0	1.103	105. 7			0	1.116	106.9
	2.088	0	2.096	100.4	100.3	0.24	0	2.112	101.2	101.3	0.27
	2.088	0	2.089	100.0			0	2.109	101.0
	2.088	0	2.098	100.5			0	2.120	101.5
Impurity ⅩⅣ	0.107 0	0	0.102 8	96.0	96.3	0.48	0	0.100 2	93.7	93.2	0.53
	0.107 0	0	0.103 6	96.9			0	0.099 6	93.1
	0.107 0	0	0.102 8	96.1			0	0.099 2	92.7
	1.070	0	1.124	105.0	105.3	0.36	0	1.125	105.1	105.6	0.57
	1.070	0	1.125	105.1			0	1.138	106.3
	1.070	0	1.132	105.7			0	1.129	105.5
	2.141	0	2.138	99.9	100.0	0.28	0	2.172	101.5	101.2	0.23
	2.141	0	2.138	99.9			0	2.165	101.1
	2.141	0	2.148	100.3			0	2.163	101.0
Impurity ⅩⅤ	0.222 1	0	0.217 2	97.8	100.6	2.8	0	0.213 4	96.1	96.4	1.3
	0.222 1	0	0.223 1	100.5			0	0.217 3	97.9
	0.222 1	0	0.229 7	103.4			0	0.211 8	95.4
	1.111	0	1.187	106.9	105.7	0.97	0	1.183	106.5	106.7	0.32
	1.111	0	1.166	104.9			0	1.189	107.1
	1.111	0	1.169	105.3			0	1.182	106.4
	2.221	0	2.248	101.2	100.8	0.66	0	2.252	101.4	101.0	0.29
	2.221	0	2.221	100.0			0	2.241	100.9
	2.221	0	2.245	101.1			0	2.240	100.8
Impurity ⅩⅥ	0.210 4	0	0.211 1	100.4	101.6	1.6	0	0.194 5	92.4	93.2	0.83
	0.210 4	0	0.212 4	101.0			0	0.195 9	93.1
	0.210 4	0	0.217 6	103.4			0	0.197 8	94.0
	1.052	0	1.085	103.1	102.9	0.65	0	1.013	96.3	96.0	0.34
	1.052	0	1.089	103.5			0	1.007	95.7
	1.052	0	1.075	102.2			0	1.011	96.1
	2.104	0	2.137	101.5	100.9	0.58	0	1.985	94.3	94.3	0.05
	2.104	0	2.114	100.5			0	1.986	94.4
	2.104	0	2.118	100.6			0	1.984	94.3
Impurity ⅩⅦ	0.439 1	0.481 9	0.931 7	102.4	103.6	1.9	0	0.447 1	101.8	101.9	0.39
	0.439 1	0.481 9	0.946 4	105.8			0	0.445 8	101.5
	0.439 1	0.481 9	0.931 9	102.5			0	0.449 2	102.3
	1.098	0.481 9	1.635	103.9	104.1	0.81	0	1.138	103.7	104.3	0.64
	1.098	0.481 9	1.629	103.3			0	1.152	105.0
	1.098	0.481 9	1.647	105.0			0	1.143	104.1
	2.195	0.481 9	2.640	99.1	99.9	0.91	0	2.183	99.4	99.8	0.29
	2.195	0.481 9	2.654	99. 8			0	2.195	100.0
	2.195	0.481 9	2.679	100.9			0	2.193	99.9

Impurities

Gefitinib

Gefitinib tablets

ρ(Added)
/μg·mL^-1

ρ(Original)
/μg·mL^-1

ρ(Measured)
/μg·mL^-1

Recovery
/%

Average
/%

RSD
/%

ρ(Original)
/μg·mL^-1

ρ(Measured)
/μg·mL^-1

Recovery
/%

Average
/%

RSD
/%

Impurity A

0.062 50

0.062 23

99.6

98.5

2.1

0.067 68

108.3

108.0

0.35

0.062 50

0.060 14

96.2

0.067 50

108.0

0.062 50

0.062 41

99.9

0.067 22

107.6

1.042

1.109

106.4

106.5

0.73

1.110

106.5

106.8

0.28

1.042

1.118

107.3

1.113

106.8

1.042

1.102

105.7

1.116

107.1

2.084

2.089

100.2

100.6

0.46

2.148

103.1

103.0

0.15

2.084

2.095

100.5

2.144

102.9

2.084

2.107

101.1

2.150

103.2

Impurity Ⅲ

0.105 0

0.102 5

97.6

94.5

5.3

0.043 46

0.103 2

56.9

57.2

1.29

0.105 0

0.102 1

97.3

0.043 46

0.104 4

58.0

0.105 0

0.093 2

88.7

0.043 46

0.102 9

56.7

1.050

0.938 6

89.4

0.93

0.043 46

0.645 4

57.4

56.8

0.86

1.050

0.947 4

90.2

0.043 46

0.636 5

56.5

1.050

0.929 9

88.6

0.043 46

0.636 6

56.5

2.100

1.896

90.3

90.6

0.57

0.043 46

1.264

58.2

56.0

4.8

2.100

1.915

91.2

0.043 46

1.235

56.9

2.100

1.896

90.3

0.043 46

1.154

53.0

Impurity Ⅳ

0.041 30

0.042 38

102.7

103.4

5.9

0.041 30

100.0

102.2

2.0

0.041 30

0.045 41

110.0

0.042 36

102.6

0.041 30

0.040 38

97.8

0.042 99

104.1

1.032

1.096

106.2

105.1

0.94

1.108

107.4

0.14

1.032

1.078

104.5

1.110

107.5

1.032

1.079

104.5

1.106

107.2

2.064

2.050

99.3

100.1

0.74

2.119

102.7

102.2

0.65

2.064

2.067

100.2

2.117

102.6

2.064

2.081

100.8

2.094

101.5

Impurity Ⅴ

0.219 3

0.419 4

0.654 4

107.2

108.6

1.9

0.082 08

0.307 7

102.9

103.3

0.70

0.219 3

0.419 4

0.655 5

107.7

0.082 08

0.307 8

102.9

0.219 3

0.419 4

0.662 8

111.0

0.082 08

0.310 5

104.2

1.096

0.419 4

1.611

108.6

108.0

0.88

0.082 08

1.233

104.9

104.6

0.32

1.096

0.419 4

1.593

106.9

0.082 08

1.226

104.3

1.096

0.419 4

1.611

108.6

0.082 08

1.228

104.5

2.193

0.419 4

2.635

102.1

102.0

0.63

0.082 08

2.281

100.5

0.02

2.193

0.419 4

2.616

101.2

0.082 08

2.281

100.5

2.193

0.419 4

2.643

102.5

0.082 08

2.282

100.5

Impurity Ⅵ

0.427 0

0.790 5

105.9

106.2

0.88

0.878 1

109.4

109.3

0.34

0.427 0

0.796 5

107.3

0.875 6

108.8

0.427 0

0.788 9

105.5

0.878 5

109.5

1.068

1.537

113.6

107.4

5.2

1.513

104.9

0.43

1.068

1.449

105.4

1.508

104.4

1.068

1.424

103.0

1.518

105.3

2.135

2.460

101.3

100.5

1.4

2.606

105.2

105.1

0.60

2.135

2.409

98.9

2.619

105.8

2.135

2.461

101.3

2.592

104.5

Impurity Ⅶ

0.193 2

0.198 5

102.7

104.0

1.7

0.208 9

108.1

107.3

0.95

0.193 2

0.204 9

106.1

0.205 1

106.2

0.193 2

0.199 5

103.3

0.208 0

107.6

0.965 9

0.992 1

102.7

104.3

1.7

1.008 6

104.4

104.1

0.66

0.965 9

1.003

103.8

0.998

103.3

0.965 9

1.026

106.2

1.011

104.6

1.932

1.945

100.7

0.46

1.964

101.7

101.4

0.38

1.932

1.956

101.2

1.950

100.9

1.932

1.938

100.3

1.961

101.5

Impurity Ⅷ

0.211 3

0.086 62

0.296 5

104.6

103.1

1.3

0.100 4

0.324 0

105.8

106.1

0.27

0.211 3

0.086 62

0.292 2

102.5

0.100 4

0.325 2

106.4

0.211 3

0.086 62

0.291 4

102.2

0.100 4

0.324 2

105.9

1.057

0.086 62

1.185

105.0

105.2

0.46

0.100 4

1.213

105.2

104.9

0.32

1.057

0.086 62

1.194

105.8

0.100 4

1.208

104.8

1.057

0.086 62

1.184

104.9

0.100 4

1.206

104.6

2.113

0.086 62

2.213

101.3

100.0

1.2

0.100 4

2.254

102.2

102.1

0.10

2.113

0.086 62

2.164

99.0

0.100 4

2.250

102.0

2.113

0.086 62

2.179

99.7

0.100 4

2.253

102.1

Impurity Ⅸ

0.102 3

0.094 77

92.6

96.6

3.59

0.101 7

99.4

100.9

1.6

0.102 3

0.101 0

98.8

0.102 9

100.6

0.102 3

0.100 8

98.5

0.105 0

102.7

1.023

1.074

105.0

104.9

0.85

1.081

105.7

105.9

0.30

1.023

1.082

105.7

1.082

105.8

1.023

1.063

104.0

1.087

106.3

2.046

2.055

100.4

100.1

0.27

2.061

100.8

100.9

0.13

2.046

100.0

2.063

100.8

2.046

2.045

99.9

2.066

101.0

Impurity Ⅹ

0.414 3

0.483 9

0.910 0

102.9

105.8

2.4

0.442 6

106.8

107.0

0.15

0.414 3

0.483 9

0.929 1

107.5

0.443 9

107.1

0.414 3

0.483 9

0.927 0

107.0

0.443 2

107.0

1.036

0.483 9

1.549

103. 9

106.1

2.0

1.099

106.1

0.18

1.036

0.483 9

1.574

106.3

1.096

105.8

1.036

0.483 9

1.594

108.2

1.100

106.2

2.072

0.483 9

2.475

97. 8

99.2

1.4

2.100

101.4

0.14

2.072

0.483 9

2.502

99.1

2.097

101.2

2.072

0.483 9

2.533

100.6

2.103

101.5

Impurity Ⅺ

1.026

1.023

99.7

103.0

3.3

1.070

104.4

104.7

1.1

1.026

1.092

106.5

1.087

106.0

1.026

1.056

102.9

1.065

103.9

1.026

0.990 2

96.5

98.3

1.7

1.053

102.6

103.1

0.50

1.026

1.009

98.4

1.063

103.7

1.026

1.025

100.0

1.057

103.1

2.051

2.001

97. 6

97.3

0.87

2.057

100.3

100.5

0.53

2.051

2.008

97. 9

2.054

100.1

2.051

1.975

96.3

2.075

101.1

Impurity Ⅻ

0.421 3

0.443 9

105.4

104.8

1.3

0.439 7

104.4

104.3

0.31

0.421 3

0.445 7

105.8

0.440 6

104.6

0.421 3

0.435 3

103.3

0.437 9

103.9

1.053

1.074

102.0

106.0

3.5

1.094

103.9

104.1

0.57

1.053

1.126

106.9

1.103

104.7

1.053

1.151

109.3

1.091

103.6

2.106

2.053

97.5

98.5

0.91

2.242

106.4

106.0

0.54

2.106

2.082

98.8

2.219

105.3

2.106

2.089

99. 2

2.236

106.1

Impurity B

0.102 7

0.495 2

0.594 9

97.0

96.9

2.1

0.706 2

0.811 3

102.3

107.2

4.0

0.102 7

0.495 2

0.592 4

94.7

0.706 2

0.819 1

109.9

0.102 7

0.495 2

0.596 7

98.8

0.706 2

0.818 6

109.4

1.027

0.495 2

1.553

102.5

103.0

0.79

0.706 2

1.799

105.7

106.5

1.3

1.027

0.495 2

1.568

104.0

0.706 2

1.799

105.7

1.027

0.495 2

1.554

102.6

0.706 2

1.825

108.2

2.053

0.495 2

2.489

98.2

98.9

0.63

0.706 2

2.782

102.6

0.14

2.053

0.495 2

2.510

99. 2

0.706 2

2.778

102.4

2.053

0.495 2

2.513

99.3

0.706 2

2.784

102.7

Impurity ⅩⅢ

0.104 4

0.117 3

112.3

104.2

7.0

0.111 5

106.8

107.1

1.1

0.104 4

0.102 5

98.1

0.113 1

108.3

0.104 4

0.106 5

102.0

0.110 7

106.0

1.044

1.104

105.8

105.9

0.28

1.107

106.0

106.5

0.41

1.044

1.109

106.2

1.112

106.5

1.044

1.103

105. 7

1.116

106.9

2.088

2.096

100.4

100.3

0.24

2.112

101.2

101.3

0.27

2.088

2.089

100.0

2.109

101.0

2.088

2.098

100.5

2.120

101.5

Impurity ⅩⅣ

0.107 0

0.102 8

96.0

96.3

0.48

0.100 2

93.7

93.2

0.53

0.107 0

0.103 6

96.9

0.099 6

93.1

0.107 0

0.102 8

96.1

0.099 2

92.7

1.070

1.124

105.0

105.3

0.36

1.125

105.1

105.6

0.57

1.070

1.125

105.1

1.138

106.3

1.070

1.132

105.7

1.129

105.5

2.141

2.138

99.9

100.0

0.28

2.172

101.5

101.2

0.23

2.141

2.138

99.9

2.165

101.1

2.141

2.148

100.3

2.163

101.0

Impurity ⅩⅤ

0.222 1

0.217 2

97.8

100.6

2.8

0.213 4

96.1

96.4

1.3

0.222 1

0.223 1

100.5

0.217 3

97.9

0.222 1

0.229 7

103.4

0.211 8

95.4

1.111

1.187

106.9

105.7

0.97

1.183

106.5

106.7

0.32

1.111

1.166

104.9

1.189

107.1

1.111

1.169

105.3

1.182

106.4

2.221

2.248

101.2

100.8

0.66

2.252

101.4

101.0

0.29

2.221

100.0

2.241

100.9

2.221

2.245

101.1

2.240

100.8

Impurity ⅩⅥ

0.210 4

0.211 1

100.4

101.6

1.6

0.194 5

92.4

93.2

0.83

0.210 4

0.212 4

101.0

0.195 9

93.1

0.210 4

0.217 6

103.4

0.197 8

94.0

1.052

1.085

103.1

102.9

0.65

1.013

96.3

96.0

0.34

1.052

1.089

103.5

1.007

95.7

1.052

1.075

102.2

1.011

96.1

2.104

2.137

101.5

100.9

0.58

1.985

94.3

0.05

2.104

2.114

100.5

1.986

94.4

2.104

2.118

100.6

1.984

94.3

Impurity ⅩⅦ

0.439 1

0.481 9

0.931 7

102.4

103.6

1.9

0.447 1

101.8

101.9

0.39

0.439 1

0.481 9

0.946 4

105.8

0.445 8

101.5

0.439 1

0.481 9

0.931 9

102.5

0.449 2

102.3

1.098

0.481 9

1.635

103.9

104.1

0.81

1.138

103.7

104.3

0.64

1.098

0.481 9

1.629

103.3

1.152

105.0

1.098

0.481 9

1.647

105.0

1.143

104.1

2.195

0.481 9

2.640

99.1

99.9

0.91

2.183

99.4

99.8

0.29

2.195

0.481 9

2.654

99. 8

2.195

100.0

2.195

0.481 9

2.679

100.9

2.193

99.9

Compound	RSD/%
Gefitinib	1.92	-	-
Impurity A	1.08	-	-
Impurity Ⅲ	1.99	-	-
Impurity Ⅳ	0.95	-	-
Impurity Ⅴ	0.99	3.96	0.76
ImpurityⅥ	0.95	-	-
Impurity Ⅶ	1.24	-	-
Impurity Ⅷ	1.21	2.84	-
Impurity Ⅸ	0.83	2.67	-
Impurity Ⅹ	1.02	-	1.64
Impurity Ⅺ	2.77	-	-
Impurity Ⅻ	2.11	-	-
Impurity B	2.18	3.15	1.28
Impurity ⅩⅢ	0.68	1.71	-
Impurity ⅩⅣ	1.45	1.86	-
Impurity ⅩⅤ	0.90	-	-
Impurity ⅩⅥ	1.52	-	-
Impurity ⅩⅦ	1.20	2.27	1.55

Compound

RSD/%

Standard
solution

Gefitinib
Sample solution

Gefitinib tablet
Sample solution

Gefitinib

1.92

Impurity A

1.08

Impurity Ⅲ

1.99

Impurity Ⅳ

0.95

Impurity Ⅴ

0.99

3.96

0.76

ImpurityⅥ

0.95

Impurity Ⅶ

1.24

Impurity Ⅷ

1.21

2.84

Impurity Ⅸ

0.83

2.67

Impurity Ⅹ

1.02

1.64

Impurity Ⅺ

2.77

Impurity Ⅻ

2.11

Impurity B

2.18

3.15

1.28

Impurity ⅩⅢ

0.68

1.71

Impurity ⅩⅣ

1.45

1.86

Impurity ⅩⅤ

0.90

Impurity ⅩⅥ

1.52

Impurity ⅩⅦ

1.20

2.27

1.55

Variable	Parameters
Initial parameters	Instrument:Agilent 1260 Infinity Ⅱ Column:Kromasil(0.46 mm×250 mm,5 μm) Mobile phase A:1% ammonium acetate solution, pH 6.2; Mobile phase B:acetonitrile; Column temperature:30 ℃; Flow rate:1.0 ml·min^-1;
Column	Welch Ultimate(0.46 mm×250 mm,5 μm) Waters Xbridge(0.46 mm×250 mm,5 μm) Dikma Diamonsil Plus(0.46 mm×250 mm,5 μm) Shimadzu ShimNex CS(0.46 mm×250 mm,5 μm) Dikma Diamonsil C₁₈(2)(0.46 mm×250 mm,5 μm) CAPCELL PAK MGⅡ(0.46 mm×250 mm,5 μm) Waters SunFire(0.46 mm×250 mm,5 μm) TechMate ST(0.46 mm×250 mm,5μm) Waters XSelect HSS(0.46 mm×250 mm,5 μm) Phenomenex Gemini(0.46 mm×250 mm,5 μm)
Instrument	Agilent 1260 Infinity
Column temperature	28 ℃
	32 ℃
pH	6.1
	6.3

Variable

Parameters

Initial parameters

Instrument:Agilent 1260 Infinity Ⅱ
Column:Kromasil(0.46 mm×250 mm,5 μm)
Mobile phase A:1% ammonium acetate solution, pH 6.2;
Mobile phase B:acetonitrile;
Column temperature:30 ℃;
Flow rate:1.0 ml·min^-1;

Column

Welch Ultimate(0.46 mm×250 mm,5 μm)
Waters Xbridge(0.46 mm×250 mm,5 μm)
Dikma Diamonsil Plus(0.46 mm×250 mm,5 μm)
Shimadzu ShimNex CS(0.46 mm×250 mm,5 μm)
Dikma Diamonsil C₁₈(2)(0.46 mm×250 mm,5 μm)
CAPCELL PAK MGⅡ(0.46 mm×250 mm,5 μm)
Waters SunFire(0.46 mm×250 mm,5 μm)
TechMate ST(0.46 mm×250 mm,5μm)
Waters XSelect HSS(0.46 mm×250 mm,5 μm)
Phenomenex Gemini(0.46 mm×250 mm,5 μm)

Instrument

Agilent 1260 Infinity

Column temperature

28 ℃

32 ℃

6.1

6.3

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity B/%	Impurity ⅩⅢ/%	Impurity ⅩⅣ/%	Impurity ⅩⅤ/%	Impurity ⅩⅦ/%	Maximum unknown impurity/%	Total /%
DA203M-4-181201	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181202	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
DA203M-4-181203	0.02	ND	ND	0.02	0.02	ND	ND	ND	0.01	0.01	0.09
0038L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.002	0.03	0.04
0039L61N	ND	ND	ND	ND	0.01	ND	ND	ND	0.004	0.02	0.04
0040L61N	ND	ND	ND	ND	0.01	ND	0.002	ND	0.006	0.02	0.05
E02200701	0.01	ND	ND	ND	0.01	ND	ND	ND	0.02	ND	0.04
E02200702	ND	ND	ND	ND	0.02	ND	ND	ND	0.02	0.01	0.05
E02200801	ND	ND	ND	ND	0.01	ND	ND	ND	0.01	0.01	0.03
GEA2009001	ND	ND	ND	ND	ND	ND	ND	0.002	ND	ND	0.002
GEA2009002	ND	ND	ND	ND	ND	ND	ND	0.005	ND	0.03	0.04
20190301	ND	0.02	ND	ND	0.01	ND	ND	ND	0.01	0.02	0.08
20201201	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
20201202	ND	0.01	ND	ND	0.01	ND	ND	ND	ND	0.02	0.08
8220024	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.01	0.01
8220025	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.02	0.04
8220026	ND	ND	ND	ND	ND	ND	ND	ND	ND	0.03	0.05
689200801	ND	ND	ND	0.01	0.03	ND	ND	ND	ND	0.02	0.07
689200802	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
689200803	ND	ND	ND	ND	0.01	ND	ND	ND	ND	ND	0.01
20181001	0.01	0.01	0.01	ND	0.01	0.02	0.03	ND	ND	0.01	0.09
20200603	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.07
20200701	0.01	ND	0.02	ND	0.03	0.03	ND	ND	ND	0.01	0.08
606110231	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.04
606110232	ND	ND	ND	ND	0.03	ND	ND	ND	ND	0.01	0.05
606110233	ND	ND	ND	ND	0.02	ND	ND	ND	ND	0.01	0.02

Lot.

Impurity
Ⅴ/%

Impurity
Ⅷ/%

Impurity
Ⅸ/%

Impurity
Ⅹ/%

Impurity
B/%

Impurity
ⅩⅢ/%

Impurity
ⅩⅣ/%

Impurity
ⅩⅤ/%

Impurity
ⅩⅦ/%

Maximum unknown
impurity/%

Total
/%

DA203M-4-181201

0.02

0.01

0.09

DA203M-4-181202

0.02

0.01

0.09

DA203M-4-181203

0.02

0.01

0.09

0038L61N

0.01

0.002

0.03

0.04

0039L61N

0.01

0.004

0.02

0.04

0040L61N

0.01

0.002

0.006

0.02

0.05

E02200701

0.01

0.02

0.04

E02200702

0.02

0.01

0.05

E02200801

0.01

0.03

GEA2009001

0.002

GEA2009002

0.005

0.03

0.04

20190301

0.02

0.01

0.02

0.08

20201201

0.01

0.02

0.08

20201202

0.01

0.02

0.08

8220024

0.01

8220025

0.02

0.04

8220026

0.03

0.05

689200801

0.01

0.03

0.02

0.07

689200802

0.01

689200803

0.01

20181001

0.01

0.02

0.03

0.01

0.09

20200603

0.01

0.02

0.03

0.01

0.07

20200701

0.01

0.02

0.03

0.01

0.08

606110231

0.03

0.01

0.04

606110232

0.03

0.01

0.05

606110233

0.02

0.01

0.02

Lot.	Impurity Ⅴ/%	Impurity Ⅷ/%	Impurity Ⅸ/%	Impurity Ⅹ/%	Impurity Ⅻ/%	Impurity B/%	Impurity XIII/%	Impurity ⅩⅫ/%	Maximum unknown impurity /%	Total /%
2031190301	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190302	0.03	ND	ND	0.02	ND	0.02	ND	0.01	0.01	0.10
2031190303	0.04	ND	ND	0.02	0.02	0.02	ND	0.03	0.01	0.17
DC1B0149	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0150	0.01	ND	ND	ND	ND	0.02	ND	ND	0.01	0.05
DC1B0151	0.01	ND	ND	ND	ND	0.03	ND	ND	0.02	0.07
1R200701	0.01	ND	ND	0.02	ND	0.01	ND	0.01	0.03	0.06
20080711	0.01	ND	ND	0.01	ND	0.01	ND	0.02	ND	0.05
20190108	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.02	0.08
20190109	0.01	0.03	ND	ND	ND	0.01	ND	0.01	0.02	0.10
20200708	0.01	0.02	ND	ND	ND	0.01	ND	0.01	0.01	0.06
200510132	0.02	ND	ND	ND	ND	0.01	ND	ND	0.01	0.05
200606132	0.02	ND	ND	ND	ND	0.003	ND	ND	0.01	0.04
200606232	0.02	ND	ND	ND	ND	ND	ND	ND	0.01	0.05
20181201	0.02	0.01	0.01	ND	ND	0.01	0.003	ND	0.01	0.08
20190102	0.01	0.01	0.02	ND	ND	0.01	0.01	ND	0.01	0.11
20200701	0.01	ND	0.02	ND	ND	0.03	0.004	ND	0.01	0.10
2004014	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.04
2004015	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.05
2005013	0.01	ND	ND	ND	ND	0.03	ND	ND	ND	0.06

Lot.

Impurity
Ⅴ/%

Impurity
Ⅷ/%

Impurity
Ⅸ/%

Impurity
Ⅹ/%

Impurity
Ⅻ/%

Impurity
B/%

Impurity
XIII/%

Impurity
ⅩⅫ/%

Maximum unknown
impurity /%

Total
/%

2031190301

0.03

0.02

0.01

0.10

2031190302

0.03

0.02

0.01

0.10

2031190303

0.04

0.02

0.03

0.01

0.17

DC1B0149

0.01

0.02

0.01

0.05

DC1B0150

0.01

0.02

0.01

0.05

DC1B0151

0.01

0.03

0.02

0.07

1R200701

0.01

0.02

0.01

0.03

0.06

20080711

0.01

0.02

0.05

20190108

0.01

0.02

0.01

0.02

0.08

20190109

0.01

0.03

0.01

0.02

0.10

20200708

0.01

0.02

0.01

0.06

200510132

0.02

0.01

0.05

200606132

0.02

0.003

0.01

0.04

200606232

0.02

0.01

0.05

20181201

0.02

0.01

0.003

0.01

0.08

20190102

0.01

0.02

0.01

0.11

20200701

0.01

0.02

0.03

0.004

0.01

0.10

2004014

0.01

0.03

0.04

2004015

0.01

0.03

0.05

2005013

0.01

0.03

0.06