中国药学杂志

Manufacturer	Sample No.	Batch No.	Purchase information (in Chinese)
A	A1	20220823	Qianjin Pharmacy(千金大药房)
	A2	20220718	AliHealth Pharmacy(阿里健康大药房)
	A3	20220212	Bule Crose Pharmacy(蓝十字大药房)
B	B1	211102	Tongji Yaohang Pharmacy(同济药行大药房)
	B2	220101	Fushunhui Pharmacy(福顺惠大药房)
	B3	221002	Xilaiyi Pharmacy(喜来医大药房)
C	C1	020220461	Folks Pharmacy(人民百姓大药房)
	C2	20230110	Chunhexiang Pharmacy(春和祥大药房)
	C3	020221162	Yixinda Pharmacy(医心达大药房)

Manufacturer	Sample No.	Batch No.	Purchase information (in Chinese)
A	A1	20220823	Qianjin Pharmacy(千金大药房)
	A2	20220718	AliHealth Pharmacy(阿里健康大药房)
	A3	20220212	Bule Crose Pharmacy(蓝十字大药房)
B	B1	211102	Tongji Yaohang Pharmacy(同济药行大药房)
	B2	220101	Fushunhui Pharmacy(福顺惠大药房)
	B3	221002	Xilaiyi Pharmacy(喜来医大药房)
C	C1	020220461	Folks Pharmacy(人民百姓大药房)
	C2	20230110	Chunhexiang Pharmacy(春和祥大药房)
	C3	020221162	Yixinda Pharmacy(医心达大药房)

Component	Regression equation	r²	Linear range /mg·mL^-1
Manghaslin	Y=215.08X-0.003	1.000 0	0.002 3-0.226 4
Clitorin	Y=197.71X+0.061	1.000 0	0.002 0-0.198 4
Rutin	Y=270.77X+0.124 3	1.000 0	0.003 2-0.320 4
Nicotiflorin	Y=250.48X+0.125 5	1.000 0	0.003 0-0.302 4
Narcissoside	Y=270.34X+0.084 7	1.000 0	0.002 0-0.196 8

Component	Regression equation	r²	Linear range /mg·mL^-1
Manghaslin	Y=215.08X-0.003	1.000 0	0.002 3-0.226 4
Clitorin	Y=197.71X+0.061	1.000 0	0.002 0-0.198 4
Rutin	Y=270.77X+0.124 3	1.000 0	0.003 2-0.320 4
Nicotiflorin	Y=250.48X+0.125 5	1.000 0	0.003 0-0.302 4
Narcissoside	Y=270.34X+0.084 7	1.000 0	0.002 0-0.196 8

Component	m (Original) /mg	m (Added) /mg	m (Measured) /mg	Recovery /%	Average recovery /%	RSD /%
Manghaslin	0.035 6	0.029 8	0.066 5	103.83	101.97	1.60
	0.035 6	0.029 8	0.065 8	101.31
	0.035 6	0.029 8	0.065 6	100.78
	0.035 6	0.037 3	0.073 4	101.39	101.72	0.39
	0.035 6	0.037 3	0.073 4	101.62
	0.035 6	0.037 3	0.073 6	102.15
	0.035 6	0.044 7	0.081 0	101.52	99.82	1.81
	0.035 6	0.044 7	0.080 3	100.00
	0.035 6	0.044 7	0.079 4	97.93
Clitorin	0.038 5	0.031 7	0.069 9	98.89	99.93	1.71
	0.038 5	0.031 7	0.070 8	101.90
	0.038 5	0.031 7	0.069 9	99.00
	0.038 5	0.039 7	0.077 3	97.92	97.81	0.42
	0.038 5	0.039 7	0.077 1	97.35
	0.038 5	0.039 7	0.077 4	98.15
	0.038 5	0.047 6	0.087 3	102.59	101.19	1.66
	0.038 5	0.047 6	0.086 9	101.65
	0.038 5	0.047 6	0.085 8	99.33
Rutin	0.044 2	0.035 1	0.080 8	104.39	104.17	0.55
	0.044 2	0.035 1	0.080 9	104.60
	0.044 2	0.035 1	0.080 5	103.51
	0.044 2	0.043 9	0.089 0	102.09	103.02	0.84
	0.044 2	0.043 9	0.089 8	103.81
	0.044 2	0.043 9	0.089 5	103.17
	0.044 2	0.052 6	0.097 4	101.05	101.29	0.69
	0.044 2	0.052 6	0.097 9	102.08
	0.044 2	0.052 6	0.097 2	100.74
Nicotiflorin	0.024 5	0.019 5	0.043 3	96.37	97.78	1.33
	0.024 5	0.019 5	0.043 6	98.03
	0.024 5	0.019 5	0.043 8	98.93
	0.024 5	0.024 4	0.049 1	100.75	99.66	0.98
	0.024 5	0.024 4	0.048 6	98.85
	0.024 5	0.024 4	0.048 8	99.39
	0.024 5	0.029 3	0.054 8	103.52	103.50	0.67
	0.024 5	0.029 3	0.054 6	102.80
	0.024 5	0.029 3	0.055 0	104.18
Narcissoside	0.022 5	0.017 8	0.040 8	103.09	103.38	0.34
	0.022 5	0.017 8	0.040 9	103.28
	0.022 5	0.017 8	0.041 0	103.78
	0.022 5	0.022 3	0.043 7	95.20	97.42	1.99
	0.022 5	0.022 3	0.044 5	98.73
	0.022 5	0.022 3	0.044 4	98.33
	0.022 5	0.026 8	0.049 5	101.18	101.09	0.76
	0.022 5	0.026 8	0.049 3	100.27
	0.022 5	0.026 8	0.049 7	101.80

Component	m (Original) /mg	m (Added) /mg	m (Measured) /mg	Recovery /%	Average recovery /%	RSD /%
Manghaslin	0.035 6	0.029 8	0.066 5	103.83	101.97	1.60
	0.035 6	0.029 8	0.065 8	101.31
	0.035 6	0.029 8	0.065 6	100.78
	0.035 6	0.037 3	0.073 4	101.39	101.72	0.39
	0.035 6	0.037 3	0.073 4	101.62
	0.035 6	0.037 3	0.073 6	102.15
	0.035 6	0.044 7	0.081 0	101.52	99.82	1.81
	0.035 6	0.044 7	0.080 3	100.00
	0.035 6	0.044 7	0.079 4	97.93
Clitorin	0.038 5	0.031 7	0.069 9	98.89	99.93	1.71
	0.038 5	0.031 7	0.070 8	101.90
	0.038 5	0.031 7	0.069 9	99.00
	0.038 5	0.039 7	0.077 3	97.92	97.81	0.42
	0.038 5	0.039 7	0.077 1	97.35
	0.038 5	0.039 7	0.077 4	98.15
	0.038 5	0.047 6	0.087 3	102.59	101.19	1.66
	0.038 5	0.047 6	0.086 9	101.65
	0.038 5	0.047 6	0.085 8	99.33
Rutin	0.044 2	0.035 1	0.080 8	104.39	104.17	0.55
	0.044 2	0.035 1	0.080 9	104.60
	0.044 2	0.035 1	0.080 5	103.51
	0.044 2	0.043 9	0.089 0	102.09	103.02	0.84
	0.044 2	0.043 9	0.089 8	103.81
	0.044 2	0.043 9	0.089 5	103.17
	0.044 2	0.052 6	0.097 4	101.05	101.29	0.69
	0.044 2	0.052 6	0.097 9	102.08
	0.044 2	0.052 6	0.097 2	100.74
Nicotiflorin	0.024 5	0.019 5	0.043 3	96.37	97.78	1.33
	0.024 5	0.019 5	0.043 6	98.03
	0.024 5	0.019 5	0.043 8	98.93
	0.024 5	0.024 4	0.049 1	100.75	99.66	0.98
	0.024 5	0.024 4	0.048 6	98.85
	0.024 5	0.024 4	0.048 8	99.39
	0.024 5	0.029 3	0.054 8	103.52	103.50	0.67
	0.024 5	0.029 3	0.054 6	102.80
	0.024 5	0.029 3	0.055 0	104.18
Narcissoside	0.022 5	0.017 8	0.040 8	103.09	103.38	0.34
	0.022 5	0.017 8	0.040 9	103.28
	0.022 5	0.017 8	0.041 0	103.78
	0.022 5	0.022 3	0.043 7	95.20	97.42	1.99
	0.022 5	0.022 3	0.044 5	98.73
	0.022 5	0.022 3	0.044 4	98.33
	0.022 5	0.026 8	0.049 5	101.18	101.09	0.76
	0.022 5	0.026 8	0.049 3	100.27
	0.022 5	0.026 8	0.049 7	101.80

Manufacturer	Sample No.	m(per tablet)/mg
A	A1	1.38±0.01	1.54±0.01	3.00±0.02	1.62±0.03	1.16±0.00
	A2	1.28±0.01	1.41±0.01	2.38±0.02	1.35±0.01	0.94±0.01
	A3	0.98±0.00	1.13±0.00	2.28±0.01	1.27±0.00	1.00±0.00
B	B1	1.46±0.01	1.59±0.00	3.08±0.01	1.87±0.01	1.43±0.01
	B2	1.19±0.01	1.34±0.01	3.15±0.02	1.81±0.01	1.38±0.00
	B3	1.34±0.01	1.44±0.01	3.04±0.01	1.52±0.02	1.16±0.00
C	C1	1.17±0.03	1.47±0.03	3.05±0.03	1.64±0.04	1.44±0.04
	C2	1.07±0.01	1.07±0.02	2.87±0.02	1.38±0.02	1.11±0.03
	C3	0.97±0.02	1.05±0.02	2.61±0.01	1.20±0.01	1.06±0.02
RSD/%		14.65	15.11	11.45	15.63	15.65

Manufacturer	Sample No.	m(per tablet)/mg
A	A1	1.38±0.01	1.54±0.01	3.00±0.02	1.62±0.03	1.16±0.00
	A2	1.28±0.01	1.41±0.01	2.38±0.02	1.35±0.01	0.94±0.01
	A3	0.98±0.00	1.13±0.00	2.28±0.01	1.27±0.00	1.00±0.00
B	B1	1.46±0.01	1.59±0.00	3.08±0.01	1.87±0.01	1.43±0.01
	B2	1.19±0.01	1.34±0.01	3.15±0.02	1.81±0.01	1.38±0.00
	B3	1.34±0.01	1.44±0.01	3.04±0.01	1.52±0.02	1.16±0.00
C	C1	1.17±0.03	1.47±0.03	3.05±0.03	1.64±0.04	1.44±0.04
	C2	1.07±0.01	1.07±0.02	2.87±0.02	1.38±0.02	1.11±0.03
	C3	0.97±0.02	1.05±0.02	2.61±0.01	1.20±0.01	1.06±0.02
RSD/%		14.65	15.11	11.45	15.63	15.65

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1	21.20	23.99	25.35	21.02	22.53
	A2	16.79	18.90	19.70	15.64	15.35
	A3	18.71	20.48	23.25	19.87	19.12
B	B2	32.73	35.60	37.91	30.48	33.94
	B3	48.81	51.87	50.34	45.89	43.55
C	C1	12.55	15.31	18.29	13.55	14.17
	C2	10.04	11.40	14.36	10.59	11.48
	C3	11.39	12.77	15.51	12.05	12.15

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1	21.20	23.99	25.35	21.02	22.53
	A2	16.79	18.90	19.70	15.64	15.35
	A3	18.71	20.48	23.25	19.87	19.12
B	B2	32.73	35.60	37.91	30.48	33.94
	B3	48.81	51.87	50.34	45.89	43.55
C	C1	12.55	15.31	18.29	13.55	14.17
	C2	10.04	11.40	14.36	10.59	11.48
	C3	11.39	12.77	15.51	12.05	12.15

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1/A2	46.88	44.84	43.75	42.06	34.21
	A1/A3	53.63	50.95	55.81	62.82	45.53
	A2/A3	69.56	73.28	59.12	50.43	52.51
B	B1/B2	32.73	35.60	37.91	30.48	33.94
	B1/B3	48.81	51.87	50.34	45.89	43.55
	B2/B3	42.75	42.64	48.17	39.63	44.83
C	C1/C2	56.61	49.19	51.42	52.85	56.26
	C1/C3	71.02	58.90	59.57	66.48	62.36
	C2/C3	70.00	70.22	75.19	68.05	83.60

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1/A2	46.88	44.84	43.75	42.06	34.21
	A1/A3	53.63	50.95	55.81	62.82	45.53
	A2/A3	69.56	73.28	59.12	50.43	52.51
B	B1/B2	32.73	35.60	37.91	30.48	33.94
	B1/B3	48.81	51.87	50.34	45.89	43.55
	B2/B3	42.75	42.64	48.17	39.63	44.83
C	C1/C2	56.61	49.19	51.42	52.85	56.26
	C1/C3	71.02	58.90	59.57	66.48	62.36
	C2/C3	70.00	70.22	75.19	68.05	83.60

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	16.904 1	0.980 3	16.999 5	0.979 8	13.482 4	0.992 4	10.499 5	0.996 4	9.534 2	0.997 2
	A2	16.355 0	0.963 3	5.870 7	0.997 3	-2.060 9	0.999 7	10.954 9	0.991 4	7.483 5	0.996 4
	A3	20.117 8	0.913 6	11.207 4	0.990 7	2.828 2	0.999 0	13.829 8	0.983 7	8.239 2	0.996 0
B	B1	34.379 6	-0.745 9	16.762 2	0.978 7	27.033 3	0.746 9	20.838 8	0.946 2	18.762 2	0.968 0
	B2	26.793 7	0.815 5	13.446 6	0.993 4	18.935 3	0.976 5	16.663 7	0.986 7	10.621 4	0.997 1
	B3	31.843 6	0.438 6	21.015 7	0.962 5	27.539 5	0.825 8	19.596 0	0.976 1	18.469 8	0.982 0
C	C1	15.914 2	0.891 6	13.085 4	0.946 6	-7.685 1	0.999 7	8.423 1	0.984 8	-1.938 9	0.998 9
	C2	13.171 6	0.834 0	12.086 6	0.873 4	5.282 6	0.979 0	3.617 0	0.986 1	4.110 2	0.984 3
	C3	16.935 5	0.737 9	15.517 3	0.816 1	3.476 3	0.991 8	10.789 7	0.948 7	4.996 6	0.987 9

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	16.904 1	0.980 3	16.999 5	0.979 8	13.482 4	0.992 4	10.499 5	0.996 4	9.534 2	0.997 2
	A2	16.355 0	0.963 3	5.870 7	0.997 3	-2.060 9	0.999 7	10.954 9	0.991 4	7.483 5	0.996 4
	A3	20.117 8	0.913 6	11.207 4	0.990 7	2.828 2	0.999 0	13.829 8	0.983 7	8.239 2	0.996 0
B	B1	34.379 6	-0.745 9	16.762 2	0.978 7	27.033 3	0.746 9	20.838 8	0.946 2	18.762 2	0.968 0
	B2	26.793 7	0.815 5	13.446 6	0.993 4	18.935 3	0.976 5	16.663 7	0.986 7	10.621 4	0.997 1
	B3	31.843 6	0.438 6	21.015 7	0.962 5	27.539 5	0.825 8	19.596 0	0.976 1	18.469 8	0.982 0
C	C1	15.914 2	0.891 6	13.085 4	0.946 6	-7.685 1	0.999 7	8.423 1	0.984 8	-1.938 9	0.998 9
	C2	13.171 6	0.834 0	12.086 6	0.873 4	5.282 6	0.979 0	3.617 0	0.986 1	4.110 2	0.984 3
	C3	16.935 5	0.737 9	15.517 3	0.816 1	3.476 3	0.991 8	10.789 7	0.948 7	4.996 6	0.987 9

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	19.016 2	0.967 5	18.332 8	0.972 6	15.853 6	0.986 6	15.595 3	0.987 4	15.539 6	0.987 6
	A2	16.868 7	0.952 9	7.166 8	0.995 8	0.917 5	0.999 2	10.044 1	0.992 2	4.824 1	0.997 9
	A3	18.338 8	0.943 8	6.730 1	0.996 9	1.650 2	0.999 2	11.224 6	0.991 4	4.867 7	0.998 2
B	B1	33.810 9	-0.755 2	21.116 0	0.926 6	26.346 0	0.753 0	24.985 1	0.824 2	21.400 0	0.928 3
	B2	26.608 9	0.807 7	12.167 3	0.994 8	18.851 9	0.974 8	18.172 8	0.978 8	13.141 7	0.994 0
	B3	31.548 0	0.458 7	20.658 8	0.964 4	27.262 3	0.831 3	21.567 9	0.959 4	20.116 6	0.971 7
C	C1	15.417 6	0.927 9	11.397 1	0.973 6	0.304 8	0.998 5	7.399 6	0.991 2	-3.166 2	0.999 4
	C2	9.651 0	0.931 4	8.069 1	0.953 8	0.367 7	0.993 9	1.066 8	0.992 7	-5.858 9	0.998 7
	C3	12.668 4	0.920 3	10.707 5	0.951 2	6.453 4	0.984 7	5.311 9	0.988 5	4.509 4	0.990 6

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	19.016 2	0.967 5	18.332 8	0.972 6	15.853 6	0.986 6	15.595 3	0.987 4	15.539 6	0.987 6
	A2	16.868 7	0.952 9	7.166 8	0.995 8	0.917 5	0.999 2	10.044 1	0.992 2	4.824 1	0.997 9
	A3	18.338 8	0.943 8	6.730 1	0.996 9	1.650 2	0.999 2	11.224 6	0.991 4	4.867 7	0.998 2
B	B1	33.810 9	-0.755 2	21.116 0	0.926 6	26.346 0	0.753 0	24.985 1	0.824 2	21.400 0	0.928 3
	B2	26.608 9	0.807 7	12.167 3	0.994 8	18.851 9	0.974 8	18.172 8	0.978 8	13.141 7	0.994 0
	B3	31.548 0	0.458 7	20.658 8	0.964 4	27.262 3	0.831 3	21.567 9	0.959 4	20.116 6	0.971 7
C	C1	15.417 6	0.927 9	11.397 1	0.973 6	0.304 8	0.998 5	7.399 6	0.991 2	-3.166 2	0.999 4
	C2	9.651 0	0.931 4	8.069 1	0.953 8	0.367 7	0.993 9	1.066 8	0.992 7	-5.858 9	0.998 7
	C3	12.668 4	0.920 3	10.707 5	0.951 2	6.453 4	0.984 7	5.311 9	0.988 5	4.509 4	0.990 6

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	14.507 8	0.986 6	16.896 4	0.975 6	13.863 7	0.989 6	11.224 5	0.994 6	11.787 5	0.993 8
	A2	8.223 1	0.992 5	4.988 9	0.996 7	8.057 1	0.993 5	4.371 8	0.997 4	3.860 5	0.997 7
	A3	16.784 8	0.953 0	8.263 2	0.994 4	-5.554 1	0.999 8	12.203 1	0.986 4	8.362 2	0.994 8
B	B1	33.532 6	-1.822 5	27.485 0	0.377 7	26.126 2	0.596 9	26.820 8	0.520 4	24.031 2	0.761 2
	B2	25.658 5	0.819 3	11.970 2	0.994 1	17.325 2	0.979 5	18.496 9	0.972 6	13.755 0	0.991 6
	B3	30.660 7	0.399 6	21.570 2	0.938 1	26.064 3	0.826 9	25.734 6	0.840 6	23.138 5	0.916 7
C	C1	14.160 9	0.932 1	10.774 2	0.970 9	-8.817 3	0.999 8	8.568 7	0.984 7	1.948 4	0.997 1
	C2	8.219 7	0.930 8	6.920 3	0.950 0	-1.124 3	0.993 9	-1.141 1	0.993 9	-17.597 4	0.999 9
	C3	9.571 3	0.950 6	7.357 1	0.971 6	-3.923 7	0.998 5	4.368 2	0.987 8	-2.338 3	0.997 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	14.507 8	0.986 6	16.896 4	0.975 6	13.863 7	0.989 6	11.224 5	0.994 6	11.787 5	0.993 8
	A2	8.223 1	0.992 5	4.988 9	0.996 7	8.057 1	0.993 5	4.371 8	0.997 4	3.860 5	0.997 7
	A3	16.784 8	0.953 0	8.263 2	0.994 4	-5.554 1	0.999 8	12.203 1	0.986 4	8.362 2	0.994 8
B	B1	33.532 6	-1.822 5	27.485 0	0.377 7	26.126 2	0.596 9	26.820 8	0.520 4	24.031 2	0.761 2
	B2	25.658 5	0.819 3	11.970 2	0.994 1	17.325 2	0.979 5	18.496 9	0.972 6	13.755 0	0.991 6
	B3	30.660 7	0.399 6	21.570 2	0.938 1	26.064 3	0.826 9	25.734 6	0.840 6	23.138 5	0.916 7
C	C1	14.160 9	0.932 1	10.774 2	0.970 9	-8.817 3	0.999 8	8.568 7	0.984 7	1.948 4	0.997 1
	C2	8.219 7	0.930 8	6.920 3	0.950 0	-1.124 3	0.993 9	-1.141 1	0.993 9	-17.597 4	0.999 9
	C3	9.571 3	0.950 6	7.357 1	0.971 6	-3.923 7	0.998 5	4.368 2	0.987 8	-2.338 3	0.997 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	17.096 2	0.975 0	17.453 2	0.972 7	15.072 7	0.986 3	15.015 1	0.986 5	15.440 2	0.985 0
	A2	10.778 7	0.984 7	5.137 0	0.996 3	5.999 2	0.995 8	8.380 6	0.992 4	7.002 4	0.994 6
	A3	16.282 1	0.966 9	-0.349 6	0.999 5	3.949 3	0.998 6	8.117 8	0.996 1	1.536 3	0.999 2
B	B1	34.573 6	-1.838 3	24.970 8	0.742 7	27.085 2	0.602 8	27.098 8	0.601 5	24.076 4	0.812 8
	B2	24.398 8	0.910 8	19.832 7	0.971 5	19.378 1	0.976 9	17.015 7	0.987 2	15.360 0	0.991 5
	B3	31.730 3	0.415 5	21.681 6	0.952 6	27.845 6	0.798 6	23.561 9	0.931 0	22.377 6	0.948 7
C	C1	10.507 5	0.968 8	6.177 9	0.989 4	3.260 4	0.995 4	5.627 8	0.991 6	0.670 2	0.997 6
	C2	6.494 1	0.933 5	5.496 2	0.948 1	1.598 7	0.982 2	-6.549 5	0.997 7	-4.410 4	0.996 0
	C3	11.223 9	0.910 3	9.733 4	0.938 2	3.167 1	0.989 1	1.328 3	0.993 1	-0.524 4	0.995 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	17.096 2	0.975 0	17.453 2	0.972 7	15.072 7	0.986 3	15.015 1	0.986 5	15.440 2	0.985 0
	A2	10.778 7	0.984 7	5.137 0	0.996 3	5.999 2	0.995 8	8.380 6	0.992 4	7.002 4	0.994 6
	A3	16.282 1	0.966 9	-0.349 6	0.999 5	3.949 3	0.998 6	8.117 8	0.996 1	1.536 3	0.999 2
B	B1	34.573 6	-1.838 3	24.970 8	0.742 7	27.085 2	0.602 8	27.098 8	0.601 5	24.076 4	0.812 8
	B2	24.398 8	0.910 8	19.832 7	0.971 5	19.378 1	0.976 9	17.015 7	0.987 2	15.360 0	0.991 5
	B3	31.730 3	0.415 5	21.681 6	0.952 6	27.845 6	0.798 6	23.561 9	0.931 0	22.377 6	0.948 7
C	C1	10.507 5	0.968 8	6.177 9	0.989 4	3.260 4	0.995 4	5.627 8	0.991 6	0.670 2	0.997 6
	C2	6.494 1	0.933 5	5.496 2	0.948 1	1.598 7	0.982 2	-6.549 5	0.997 7	-4.410 4	0.996 0
	C3	11.223 9	0.910 3	9.733 4	0.938 2	3.167 1	0.989 1	1.328 3	0.993 1	-0.524 4	0.995 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	15.198 8	0.988 1	20.434 3	0.955 8	16.222 0	0.986 0	12.626 7	0.994 3	11.774 9	0.995 4
	A2	13.268 8	0.957 3	8.237 1	0.987 9	1.866 6	0.997 8	6.543 2	0.992 8	-1.527 8	0.999 0
	A3	17.041 0	0.947 8	8.343 6	0.994 1	-7.718 4	0.999 9	11.039 3	0.989 4	5.460 6	0.997 4
B	B1	34.274 3	-1.492 3	24.514 9	0.782 7	26.826 1	0.647 7	26.759 5	0.653 6	23.594 7	0.843 0
	B2	25.348 1	0.886 3	18.193 5	0.981 0	18.295 1	0.982 3	14.353 2	0.993 4	9.930 3	0.997 8
	B3	30.935 5	0.589 6	22.308 4	0.952 5	27.359 8	0.847 3	20.569 2	0.972 0	19.302 6	0.979 6
C	C1	12.400 1	0.949 8	8.971 0	0.978 7	2.728 5	0.995 9	5.122 7	0.992 6	-1.617 4	0.998 6
	C2	7.527 2	0.949 6	6.288 6	0.963 0	6.726 8	0.962 4	-5.527 5	0.998 2	2.353 8	0.987 4
	C3	9.936 9	0.933 7	8.241 9	0.956 6	2.649 7	0.990 2	-2.330 5	0.997 2	-6.600 2	0.999 0

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	15.198 8	0.988 1	20.434 3	0.955 8	16.222 0	0.986 0	12.626 7	0.994 3	11.774 9	0.995 4
	A2	13.268 8	0.957 3	8.237 1	0.987 9	1.866 6	0.997 8	6.543 2	0.992 8	-1.527 8	0.999 0
	A3	17.041 0	0.947 8	8.343 6	0.994 1	-7.718 4	0.999 9	11.039 3	0.989 4	5.460 6	0.997 4
B	B1	34.274 3	-1.492 3	24.514 9	0.782 7	26.826 1	0.647 7	26.759 5	0.653 6	23.594 7	0.843 0
	B2	25.348 1	0.886 3	18.193 5	0.981 0	18.295 1	0.982 3	14.353 2	0.993 4	9.930 3	0.997 8
	B3	30.935 5	0.589 6	22.308 4	0.952 5	27.359 8	0.847 3	20.569 2	0.972 0	19.302 6	0.979 6
C	C1	12.400 1	0.949 8	8.971 0	0.978 7	2.728 5	0.995 9	5.122 7	0.992 6	-1.617 4	0.998 6
	C2	7.527 2	0.949 6	6.288 6	0.963 0	6.726 8	0.962 4	-5.527 5	0.998 2	2.353 8	0.987 4
	C3	9.936 9	0.933 7	8.241 9	0.956 6	2.649 7	0.990 2	-2.330 5	0.997 2	-6.600 2	0.999 0

Manufacturer	Sample No.	t₅₀/h
A	A1	2.78±0.27	2.78±0.33	3.46±0.26	3.18±0.10	2.94±0.21
	A2	4.09±0.29	5.80±0.21	4.33±0.13	6.10±0.17	7.90±0.24
	A3	4.15±0.43	4.31±0.57	5.14±0.67	4.40±0.52	5.33±0.56
B	B1	0.70±0.23	0.77±0.28	0.98±0.44	0.70±0.34	0.74±0.31
	B2	1.56±0.23	1.65±0.24	1.91±0.30	1.81±0.27	1.64±0.33
	B3	1.02±0.26	1.06±0.28	1.29±0.33	1.08±0.32	1.12±0.28
C	C1	9.73±0.88	7.71±0.47	9.44±0.19	10.27±1.58	10.38±1.07
	C2	25.31±2.56	22.24±2.48	30.99±2.14	48.71±2.30	24.32±3.16
	C3	17.92±0.35	14.15±0.61	17.27±1.53	20.87±1.90	20.51±2.43

Manufacturer	Sample No.	t₅₀/h
A	A1	2.78±0.27	2.78±0.33	3.46±0.26	3.18±0.10	2.94±0.21
	A2	4.09±0.29	5.80±0.21	4.33±0.13	6.10±0.17	7.90±0.24
	A3	4.15±0.43	4.31±0.57	5.14±0.67	4.40±0.52	5.33±0.56
B	B1	0.70±0.23	0.77±0.28	0.98±0.44	0.70±0.34	0.74±0.31
	B2	1.56±0.23	1.65±0.24	1.91±0.30	1.81±0.27	1.64±0.33
	B3	1.02±0.26	1.06±0.28	1.29±0.33	1.08±0.32	1.12±0.28
C	C1	9.73±0.88	7.71±0.47	9.44±0.19	10.27±1.58	10.38±1.07
	C2	25.31±2.56	22.24±2.48	30.99±2.14	48.71±2.30	24.32±3.16
	C3	17.92±0.35	14.15±0.61	17.27±1.53	20.87±1.90	20.51±2.43

不同厂家银杏叶片中5种黄酮类成分的溶出度测定及其质量分析

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崔起平 ¹^,² , 易红 ² , 李春 ² , 吴哲 ² , 刘洪宇 ² , 郭凤倩 ² , 刘晓谦 ²^,^* , 王智民 ²^,^*

中国药学杂志 | 论著 2024,59(14): 1300-1311

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中国药学杂志 | 论著 2024, 59(14): 1300-1311

不同厂家银杏叶片中5种黄酮类成分的溶出度测定及其质量分析

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崔起平¹^,², 易红², 李春², 吴哲², 刘洪宇², 郭凤倩², 刘晓谦²^,^*, 王智民²^,^*

作者信息

¹ 广东药科大学,广州 510006

² 中国中医科学院中药研究所,中药质量控制技术国家工程实验室, 北京 100700

崔起平,女,硕士研究生研究方向:中药制剂质量评价研究

通讯作者:

* 刘晓谦,女,博士,研究员研究方向:中药制剂及质量评价研究 Tel:(010)64087242;

王智民,男,博士,研究员研究方向:中药化学与质量标准评价 Tel:(010)84014128

Quality Analysis of Five Flavonoids in Ginkgo biloba Leaves Tablets

Qiping CUI¹^,², Hong YI², Chun LI², Zhe WU², Hongyu LIU², Fengqian GUO², Xiaoqian LIU²^,^*, Zhimin WANG²^,^*

Affiliations

¹ Guangdong Pharmaceutical University, Guangzhou 510006, China

² Quality Control Technology for TCM of National Engineering Laboratory, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

出版时间: 2024-07-22 doi: 10.11669/cpj.2024.14.006

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摘要

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目的针对“原料相同所生产的中成药质量不同,如何开展质量一致性评价?”的问题,以原料组成基本清楚的银杏叶提取物为对象,构建流通池法测定银杏叶片溶出度的方法,并对其参数进行优化,以探讨中成药溶出度用于质量一致性评价的可行性。方法采用流通池闭环系统,将银杏叶片置于装满玻璃珠的流通池内,流速8 mL·min^-1,溶出介质为150 mL水,温度37 ℃,脉动频率0 Hz,于30,60,120,240,360,480 min取样3 mL(同时补充已预热的新鲜溶出介质3 mL),HPLC法测定各指标成分(manghaslin、蝶豆素、芦丁、烟花苷、水仙苷)含量,并计算累积溶出度,绘制溶出曲线。选择3个厂家9个批次的市售产品进行溶出度检查,并对其溶出曲线的相似因子和释放方程进行拟合。结果不同厂家同规格的银杏叶片的含量虽然一致性较好,但不同厂家不同批次的5种黄酮苷4 h的累计溶出度从10%到90%不等,差异极大,且多数低于70%的常规标准,说明尽管原料相同,不同的制剂水平和生产工艺细节,产品质量和临床疗效可能差异极大,因此要保证中成药制剂质量的有效性和一致性,开展溶出度检查至关重要。结论所建立的流通池溶出度测定方法能够较好地区分不同厂家样本的溶出行为,在一定程度上能够反映工艺及处方对产品质量的影响,对于规范药品生产具有应用价值。

关键词

银杏叶片 / 黄酮苷 / 流通池法 / 溶出度 / 溶出曲线

Abstract

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OBJECTIVE To evaluate the quality consistency for the different qualities of Chinese medicine preparation (PCM) with the same raw material? and develop a method for measuring dissolution rate of Ginkgo biloba leaves tablets(GLT) as a model by flow-through cell(FTC) method. METHODS A closed-loop flow tank system was adopted, the GLT were placed in the circulating tank which was preloaded with glass beads, taking 150 mL water as the dissolution medium, with the flow rate of 8 mL·min^-1, the temperature was (37±0.5) ℃, the pulse frequency was 0 Hz, and sampling 3 mL each at 30, 60, 120, 180 and 240 min, respectively, at the same time, 3 mL of preheated fresh dissolution medium were replenished. HPLC analysis was conducted to determine the contents and cumulative dissolution rates of five ingredients (manghaslin, clitorin, rutin, nicotiflorin and narcissoside), and corresponding dissolution curves were plotted. Nine batches of markerted GLT from three manufactures were determined, and their similarity factors and dissolution models were fitted. RESULTS The contents of five flavonoids glycosides in GLT from the same specification of different manufacturers were consistent, but their cumulative dissolution rates in 4 hours were from 10% to 90% within different batches from different manufacturers, and most of them were lower than the conventional standard of 70%. It indicates that although the raw materials are same, different production processes details may lead to great differences in marketed product qualities and clinical efficacy. Therefore, to ensure the effectiveness and consistency of the quality of PCM, it is very important to carry out dissolution rate inspection in PCM quality standard. CONCLUSION The established FTC dissolution test method can distinguish the dissolution behavior of samples from different manufacturers, which could reflect the influences of technology and prescription on product quality, which has important practical value for regulating medicinal production.

Key words

Ginkgo biloba leaves tablet / flavonoid / flow-through cell method / dissolution rate / dissolution curve

引用本文

崔起平, 易红, 李春, 吴哲, 刘洪宇, 郭凤倩, 刘晓谦, 王智民. 不同厂家银杏叶片中5种黄酮类成分的溶出度测定及其质量分析. 中国药学杂志, 2024 , 59 (14) : 1300 -1311 . DOI: 10.11669/cpj.2024.14.006

Qiping CUI, Hong YI, Chun LI, Zhe WU, Hongyu LIU, Fengqian GUO, Xiaoqian LIU, Zhimin WANG. Quality Analysis of Five Flavonoids in Ginkgo biloba Leaves Tablets[J]. Chinese Pharmaceutical Journal, 2024 , 59 (14) : 1300 -1311 . DOI: 10.11669/cpj.2024.14.006

正文

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银杏叶片是以银杏叶提取物为原料制成的片剂,临床用于治疗高血压,动脉硬化,冠心病,心绞痛,脑中风以及阿尔茨海默病症等多种疾病^[1-2],其主要药效成分为银杏黄酮^[3]和银杏内酯^[4-5]。目前,银杏叶片在防治心脑血管疾病中成药中占有较大的市场份额^[6],生产厂家众多;由于均为标准提取物投料,仅采用含测项进行成品质量控制(产品检查合格),不能反映制剂在体内是否能溶出进而发挥药效(难溶出就难被吸收)。随着中成药高质量发展的要求,溶出度检查已成为评价其品质的推荐项^[7],鉴于银杏叶片是以标准提取物投料的典型代表品种,建立合适的溶出度评价方法,具有较强的可行性,且有利于找出共性的质量问题,对于保障中成药有效性、质量一致性和批间疗效一致性具有示范意义。

流通池法(flow-through cell method,FTC)作为一种被2020年版《中国药典》新收载的溶出度检查方法,具有①可克服因缺乏下沉条件而导致的饱和或吸附作用的平衡;②可更好地模拟药物在人体内的溶出行为^[8];③具有良好的体内外相关性等优点^[9],被2020年版《中国药典》收录^[10],特别是可根据药物溶出行为特性灵活调节溶媒体积的特点,能有效地克服中成药药效成分含量低带来的难检测缺陷,在中成药质量评价中具有广阔的应用前景。

不同厂家银杏叶片的溶出度研究报道较少,且多为转篮法,所用溶出介质体积大,对于含量低的成分不易检出。银杏叶片多选用黄酮苷元作为检测指标,但该法供试品处理过程极为复杂,对于样本量少、检测点多的溶出度检测,不仅检测误差大,且操作难度高。本研究采用FTC法测定银杏叶片中5种成分(manghaslin、蝶豆素、芦丁、烟花苷、水仙苷)溶出度评价方法的基础上,对主流厂家的样本进行筛查,采用相关分析方法找出不同厂家产品间的溶出行为差异;构建的新方法可在较小的溶出介质体积下直接测定,解决了中药制剂中低含量成分的溶出度检测难题;并探讨构建其溶出度检查标准及其用于中成药质量控制的可行性,以保障中成药的有效性。

1 材料

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1.1 仪器

RT 7流通池法溶出系统(深圳市锐拓仪器设备有限公司)、戴安-U3000高效液相色谱仪(美国戴安公司)、BSA224S-CW型1/1万电子天平(德国 Sartorius 公司)、XSE105型1/10万电子天平(瑞士梅特勒·托利多公司)。

1.2 试剂与试药

Manghaslin对照品(批号:031301)、蝶豆素对照品(批号:006301)、烟花苷对照品(批号:S-007501),均购自于成都德思特生物技术有限公司,纯度均大于98%;芦丁对照品(批号:L-00102202015)、水仙苷对照品(批号:S-00102202015),购自于成都瑞芬思生物科技有限公司,纯度均大于98%。

甲醇(色谱级)、甲醇、磷酸(分析级)、水(自制,去离子水)。

银杏叶片(厂家A:批号:20220823、20220718、20220212,厂家B:批号:211102、220101、221002,厂家C:批号:020220461、20230110、020221162),均为薄膜衣片,规格:2020年版《中国药典》规格(2),具体信息见表1。

2 方法与结果

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2.1 溶液制备

2.1.1 对照品溶液配制

分别精密称取manghaslin、蝶豆素、芦丁、烟花苷、水仙苷对照品适量,置于棕色量瓶中,加入甲醇溶解并稀释至刻度,分别制成质量浓度为0.226 4、0.198 4、0.320 4、0.302 4、0.196 8 mg·mL^-1的混合对照品储备液,备用。

2.1.2 含量测定用供试品溶液配制

取银杏叶片10片,研细混匀,称取约2片重量的银杏叶片粉末,精密称定,置具塞锥形瓶中,精密加入甲醇25 mL,密塞,称定质量,超声25 min(250 W,45 kHz),取出,冷却至室温,加甲醇补足减失的质量,摇匀,用0.22 μm滤膜过滤,取续滤液,即得。

2.1.3 阴性对照溶液配制

取去离子水溶液,用0.22 μm滤膜过滤,取续滤液,即得。

2.2 HPLC法色谱条件

色谱柱:Welch C₁₈色谱柱(4.6 mm×250 mm,5 μm),流动相甲醇(A)-0.2%磷酸水溶液(B),梯度洗脱(0~10 min,30%~40% A;10~30 min,40%~45% A;30~32 min,45%~60% A;);检测波长为360 nm;柱温30 ℃;流速1 mL·min^-1;进样量10 μL。色谱图见图1。结果表明,银杏叶片中5种黄酮苷成分有较好的分离度。

2.3 溶出条件

采用流通池闭合系统,将银杏叶片置于锥形部装满1 mm玻璃珠的流通池内,流速8 mL·min^-1,溶出介质为150 mL水,温度37 ℃,脉冲频率0 Hz,搅拌速率300 r·min^-1,取样前等待4 min,于30,60,120,180,240 min取样3 mL(同时补充同温度的新鲜介质3 mL)。收集各时间点的样品测定各成分含量,并计算累计溶出度。累计溶出度计算见公式1。

公式(1)X_n=

[ρ n × 150 + (ρ 1 + ρ 2 + … + ρ n - 1) × 3] m × M

×100%

其中,n为取样点的个数,X_n为第n个时间点的累积溶出度,%;ρ_n为第n个时间点的质量浓度,mg·mL^-1;150 为溶出介质体积,mL;3 为取样体积,mL;m为片质量,g;M为指标成分含量,mg·g^-1。

3 结果与分析

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3.1 方法学考察

3.1.1 线性关系

精密吸取“2.1.1”项下混合对照品溶液适量,分别加甲醇稀释5、10、25、50、100倍,即得系列混合对照品溶液,按“2.2”项下方法测定,以质量浓度(X,mg·mL^-1)为横坐标,峰面积(Y)为纵坐标绘制标准曲线,计算各成分的回归方程及相关系数(r²),见表2。结果表明,各成分在特定浓度范围与峰面积呈现良好线性关系。

3.1.2 精密度

取“2.1.1”项下同一混合对照品溶液,按“2.2”项下方法连续进样6次,记录峰面积并计算相对标准偏差(RSD)。结果manghaslin、蝶豆素、芦丁、烟花苷、水仙苷峰面积的RSD分别为0.54%、0.55%、0.54%、0.56%、0.56%,RSD<2%,表明仪器的精密度良好。

3.1.3 重复性

取B3批次银杏叶片,按“2.3”项下方法进行溶出度测定,于4 h时,取溶出液6份,分别按“2.2”项下方法测定,记录各指标成分的峰面积,并计算RSD。结果manghaslin、蝶豆素、芦丁、烟花苷、水仙苷溶出度的RSD分别为0.29%、0.71%、0.83%、0.77%、0.96%,均<2%,表明方法的重复性良好。

3.1.4 溶液稳定性

取B3批次银杏叶片4 h的溶出度测定样品溶液,分别于室温放置第0、1、2、4、8、12、24 h检测,记录峰面积并计算RSD。结果manghaslin、蝶豆素、芦丁、烟花苷、水仙苷RSD分别为0.56%、0.60%、0.40%、0.88%、1.89%,RSD<2%,表明溶出样本溶液在24 h内稳定性良好。

3.1.5 加样回收率

对照品储备液制备:按“2.1.1”项下方法,配制manghaslin、蝶豆素、芦丁、烟花苷、水仙苷质量浓度分别为0.186 4、0.198 3、0.213 9、0.121 9、0.111 5 mg·mL^-1的混合对照品溶液备用。

样品的制备:取10 mL量瓶,分别加入上述对照品储备液0.16、0.20、0.24 mL(分别平行3份),再分别加入按“2.3”项下方法制备的银杏叶片4 h时溶出液(B3批次,manghaslin、蝶豆素、芦丁、烟花苷、水仙苷质量浓度分别为0.007 1、0.007 7、0.008 8、0.004 9、0.004 5 mg·mL^-1)5 mL,并以新鲜溶出介质定容至刻度,混匀,滤过,取续滤液,即得。

按“2.2”项下方法测定各成分含量并计算各成分的加样回收率及RSD,结果见表3。结果manghaslin、蝶豆素、芦丁、烟花苷、水仙苷的回收率在97%~105%之间,回收率RSD<2%,表明本方法准确度良好,可用于溶出度样品的测定。

3.2 HPLC法含量结果

9个批次manghaslin、蝶豆素、芦丁、烟花苷和水仙苷的含量分别在0.97~1.46 mg每片、1.05~1.59 mg每片、2.28~3.08 mg每片、1.20~1.87 mg每片、0.94~1.44 mg每片之间,表明不同厂家间含量的批间一致性较好,这也显示了采用标准提取物投料的优势,各厂家样本含量一致性较好。结果见表4。

3.3 流通池溶出条件的考察

分别考察了溶出介质、流速、玻璃珠用量、脉冲频率等条件对溶出行为的影响,并最终确定了适宜的溶出条件。

3.3.1 溶出介质选择

由于药物溶出行为主要发生在胃、肠等部位,因此溶出介质分别模拟了胃、小肠部位的pH条件,分别配制pH1.0 盐酸溶液,pH 6.8 磷酸盐缓冲溶液以及纯水,测定银杏叶片5种黄酮苷成分的累积溶出度,溶液配制方法参考《普通口服固体制剂溶出度试验技术指导原则》^[11]。

取B1批次银杏叶片样品,于“2.3”项下溶出条件分别绘制其在不同溶出介质中的溶出曲线,结果见图2。由结果可知,银杏叶片中5种黄酮类成分在纯水及pH 6.8 磷酸盐缓冲溶液中溶出行为较为一致,且溶出速度较为适宜,但其在pH 1.0 盐酸溶液中溶出速度较慢,鉴于本研究目的在于构建能够控制不同厂家药品质量的溶出度测定方法,且溶出时间不宜太长,故选择纯水作为溶出介质。

3.3.2 流速选择

选择同一批次银杏叶片(B1批次),参照“2.3”项下溶出条件,比较流速分别为8、16、20 mL·min^-1对溶出速率的影响。结果见图3。结果显示,不同流速对测定银杏叶片5种黄酮苷成分溶出度的影响不大,故选择8 mL·min^-1作为溶出实验的条件。

3.3.3 玻璃珠用量的选择

流通池法是通过选择在流通池底部放置或去除玻璃珠模拟层流和湍流2种不同流体力学模式。2种流动方式中,层流可以使溶媒在流通池内均匀流动,可模拟胃肠道被食物填充后的情况;湍流模式下溶出介质以比较急促的方式流动,模拟空腹情况。

选择同一批次银杏叶片(B1批次),参照“2.3”项下溶出条件,分别考察不加玻璃珠,加入一半锥体高度的玻璃珠(约2.4 g),锥体全部填充玻璃珠(约6.6 g),保持其他溶出条件不变,对比玻璃珠的加入量对溶出曲线的影响,结果见图4。

结果显示,随着玻璃珠用量的增加,药物前期的溶出速率变慢,特别是溶出的前1 h尤为明显,但2 h以后,玻璃珠加入与否对累积溶出度无影响。为使条件具有适当的区分力,因此选用较常见的在流通池的锥体部装满玻璃珠的条件。

3.3.4 脉冲频率考察

选择同一批次银杏叶片(B1批次),参照“2.3”项下溶出条件,对比脉冲频率分别为0及120 Hz时对银杏叶片溶出行为的影响。由图5可知,脉动频率对银杏叶片的5种黄酮苷成分的溶出度测定影响不大,故选择脉冲频率设置为0 Hz。

最终确定溶出条件为:流通池闭环系统,溶出介质为150 mL水,流速为8 mL·min^-1,流通池锥体部位装满1 mm玻璃珠,脉冲频率为0 Hz。

3.4 溶出度测定结果

3.4.1 不同厂家溶出度对比与分析

A、B、C 3个厂家银杏叶片,manghaslin、蝶豆素、芦丁、烟花苷和水仙苷溶出曲线结果见图6。

为了更好地表征不同批次之间银杏叶片溶出行为的差异性,根据《普通口服固体制剂溶出曲线测定与比较指导原则》^[12],溶出曲线相似性多采用非模型依赖法的相似因子法。本研究以溶出行为较好的B1批次为参照,采用DDSolver软件计算其余8个批次不同成分的相似因子(f₂),结果见表5。一般情况下,当2条溶出曲线f₂数值不小于50时,可认为2条溶出曲线相似。

虽然3个厂家间各指标成分含量无明显差异,除B3批次蝶豆素和芦丁与B1批次相似度较高外,其余批次各成分溶出曲线与B1批次均有较大差异,提示不同厂家之间银杏叶片之间的溶出行为差异较大(表5、图6)。从溶出速率看厂家B>厂家A>厂家C,且4 h的累积溶出度仅B厂家样本可以达到80%(多数化学药品均规定在限定时间内累积溶出度应达到70%以上),其余厂家样品指标成分的累积溶出度均明显偏低,特别是C厂家样本,各成分4 h的累计溶出度不及40%,体外溶出度低提示其体内吸收可能存在吸收利用率较低的风险。而造成不同厂家样品溶出度行为差异明显的原因可能与其处方构成及制剂工艺细节有关。

为了考察生产企业内部的溶出度批间差异,分别计算了相同厂家不同批次银杏叶片中5种黄酮苷溶出曲线的f₂,结果见表6。

A、B厂家的样本均存在不同程度的批间差异,而两个厂家样本间的溶出曲线批间差异表现为不同类型(表6):A厂家整体溶出趋势较为一致,但2 h后的溶出速率批间差异明显,而B厂家的样本批间差异则主要体现在溶出的前2 h差异较大。溶出曲线的批间差异提示可能存在工艺不稳定等问题。厂家C不同批次之间的5种黄酮苷成分溶出曲线虽相似度较高,但该结果可能与其整体溶出速率较慢有关,从而使累积溶出度偏差较小,过缓的溶出速率可能给药物的体内吸收和生物利用率带来风险。

3.4.2 溶出曲线模型拟合

为了探究银杏叶片5种黄酮苷成分的溶出机制,采用DDSolver软件分别进行零级释放方程、一级释放方程、Higuchi with F₀方程、Hixson-Crowell with Tlag方程和Weibull方程的拟合,模型拟合程度用赤池信息量准则(AIC)与拟合系数(r²)为指标。AIC越小,表明偏差越小,越精准;r²的取值范围为0~1,它越接近于1,表明曲线拟合效果越好,结果见表7~11。

由表5可以看出,不同厂家不同批次的拟合数据略有不同,但拟合趋势基本一致,各指标成分的溶出动力学行为基本符合Weibull方程,提示各厂家样本溶出曲线虽有差异,但其溶出机制较为一致,其释放速率常数与扩散系数成正比,且随时间变化而变化。

选定Weibull模型对流通池法测定的溶出曲线数据进行拟合,得到特征溶出参数t₅₀(药物溶出50%所需时间),结果见表12。可以看出不同厂家之间的t₅₀差异极其明显,即使是同一厂家不同批次的溶出参数也存在一定差异,A厂家的A2、A3批次的t₅₀值比A1批次稍大;B厂家样本2 h内样本各成分溶出度均可达50%以上;C厂家整体溶出慢,且批间差异极大。

4 讨论

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随着中药现代化的发展,溶出度评价逐渐应用于包含中药成分的复杂固体制剂的质量研究,合理的溶出度评价可反映出原料药、辅料和制剂工艺的差异性,用于评价该类固体口服制剂的内在质量^[13-14]。

本研究构建的流通池溶出度测定方法,能够对样本间的溶出行为差异进行区分,体现了该方法在中成药质量控制中具有良好的灵敏度和辨识度。同时对于中成药而言,较小的溶出介质用量也保证了各指标成分的有效检出,证明该方法可以用于银杏叶片的溶出度评价。

4.1 FTC法参数的选择

溶出度可反映工艺稳定性,并可预测其在体内的起效程度,只有当溶出条件具有区分力,能够反映不同药品差异时,溶出度评价才能得到科学结论^[15]。

本研究分别考察了流速、脉冲频率以及玻璃珠用量对于银杏叶片中5种黄酮苷溶出行为的影响,流速及脉冲频率对溶出曲线均无明显影响,而溶媒流动方式的改变,即加入玻璃珠与不加入玻璃珠形成的层流和湍流对于溶出度的测定影响较大,湍流会加快药物的释放,适合难溶性药物的溶出,层流则更具有缓和的剪切力,药物的溶出速率则相对较慢。

4.2 含量测定方法的选择

考虑到银杏叶片以银杏叶标准提取物为原料,其中主要成分为银杏黄酮和内酯,其中银杏黄酮的含量约为24%,银杏内酯含量为6%^[16],故选择了相对含量较高的5种黄酮类成分——蝶豆素、manghaslin、芦丁、烟花苷、水仙苷开展溶出度检查。《中国药典》对于银杏叶片中黄酮苷含量测定采用酸水解后检测黄酮苷元,并计算总黄酮苷含量(水解苷元转化法),处理过程较为复杂,但溶出实验样本多,样本量小,不易采用此方法进行含量测定。因此本研究采用HPLC法直接测定各黄酮原型成分,并经系统的方法学验证,证实了本含量测定方法可以实现各成分的准确定量。

4.3 关于银杏叶片溶出度检查限度的建议与思考

银杏叶片生产厂家众多,相同规格片重均不同,辅料用量及种类亦存在差异,但其主药投料量一致,且为采用标准提取物投料,因而具备了采用溶出度检查来比较不同厂家生产的银杏叶片差异。本研究选择了3个主流厂家的9批银杏叶片进行溶出度方法的示范性研究。结果发现,不同厂家同规格的银杏叶片的含量一致性较好,但不同厂家不同批次的5种黄酮苷成分4 h的累计溶出度范围为10%~90%,差异极其明显,推测与辅料、生产工艺和过程有直接关系,提示只有从原料和制备工艺入手开展系统研究,才能保证中成药制剂质量的一致性,开展溶出度检查对于控制中成药质量至关重要。

参照溶出度检查限度规定:多数化学药品均规定在限定时间内累积溶出度应达到70%以上^[17],普通制剂的检查时间点为30 min~2 h,而中成药中目前仅益心酮分散片和穿心莲内酯滴丸有溶出度检查的限度要求,限度分别为30 min溶出度≥70%和45 min溶出度≥75%。本研究所检测的市售银杏叶片4 h的溶出度仅部分厂家能够达到70%的限度,且各厂家样本差异极大,提示制定其溶出度检查标准仍面临较大困难,但从规范中药制剂生产,提升药品质量,保证临床用药安全有效角度考虑,构建适宜的溶出度检查限度,探寻溶出度低的原因对于提升制剂质量仍较为迫切。

4.4 关于中成药构建溶出度检查可行性的思考

目前溶出度检查在中成药中应用较少,仅益心酮分散片和穿心莲内酯滴丸^[16]规定了需做该项检查,但作为推荐性的检查项,中成药中开展溶出度检查是未来发展的趋势。中成药生产工序长、原料质量波动大、成分多、含量偏低是客观事实,且受到生产工艺等因素的影响,加剧了批间质量波动的风险,给溶出度检查带来巨大挑战,影响了溶出度检查在中成药中的推广应用。随着均一化投料技术的广泛应用及过程控制技术的推广,可提升中成药质量的批间一致性,给溶出度检查创造条件。前述提到的益心酮分散片和穿心莲内酯滴丸也是在克服了有效成分低、提取物批间差异大的前提下,形成了切实可行的溶出度控制方法。本研究所选的银杏叶片虽同样采用标准提取物投料,但由于研发早,对溶出度认识不足,加之不同厂家间辅料、工艺等存在差异,故其溶出曲线存在较大差异,但该现象也证实了在中成药中开展溶出度检查具有迫切的现实意义,对于规范药品生产、保证药品质量具有重要意义。

基金

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国家重点研发计划项目(2023YFC3504000)
中国中医科学院科技创新工程项目(CI 2021A04308)
中国中医科学院科技创新工程项目(CI 2021A04407)

参考文献

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2024年第59卷第14期

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文章信息

doi: 10.11669/cpj.2024.14.006

接收时间：2024-03-19
首发时间：2026-01-14
出版时间：2024-07-22

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作者

出版历史

收稿日期：2024-03-19

基金

国家重点研发计划项目(2023YFC3504000)

中国中医科学院科技创新工程项目(CI 2021A04308)

中国中医科学院科技创新工程项目(CI 2021A04407)

作者信息

¹ 广东药科大学,广州 510006

² 中国中医科学院中药研究所,中药质量控制技术国家工程实验室, 北京 100700

通讯作者:

* 刘晓谦,女,博士,研究员研究方向:中药制剂及质量评价研究 Tel:(010)64087242;

王智民,男,博士,研究员研究方向:中药化学与质量标准评价 Tel:(010)84014128

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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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Manufacturer	Sample No.	Batch No.	Purchase information (in Chinese)
A	A1	20220823	Qianjin Pharmacy(千金大药房)
	A2	20220718	AliHealth Pharmacy(阿里健康大药房)
	A3	20220212	Bule Crose Pharmacy(蓝十字大药房)
B	B1	211102	Tongji Yaohang Pharmacy(同济药行大药房)
	B2	220101	Fushunhui Pharmacy(福顺惠大药房)
	B3	221002	Xilaiyi Pharmacy(喜来医大药房)
C	C1	020220461	Folks Pharmacy(人民百姓大药房)
	C2	20230110	Chunhexiang Pharmacy(春和祥大药房)
	C3	020221162	Yixinda Pharmacy(医心达大药房)

Manufacturer

Sample
No.

Batch
No.

Purchase information
(in Chinese)

20220823

Qianjin Pharmacy(千金大药房)

20220718

AliHealth Pharmacy(阿里健康大药房)

20220212

Bule Crose Pharmacy(蓝十字大药房)

211102

Tongji Yaohang Pharmacy(同济药行大药房)

220101

Fushunhui Pharmacy(福顺惠大药房)

221002

Xilaiyi Pharmacy(喜来医大药房)

020220461

Folks Pharmacy(人民百姓大药房)

20230110

Chunhexiang Pharmacy(春和祥大药房)

020221162

Yixinda Pharmacy(医心达大药房)

Component	Regression equation	r²	Linear range /mg·mL^-1
Manghaslin	Y=215.08X-0.003	1.000 0	0.002 3-0.226 4
Clitorin	Y=197.71X+0.061	1.000 0	0.002 0-0.198 4
Rutin	Y=270.77X+0.124 3	1.000 0	0.003 2-0.320 4
Nicotiflorin	Y=250.48X+0.125 5	1.000 0	0.003 0-0.302 4
Narcissoside	Y=270.34X+0.084 7	1.000 0	0.002 0-0.196 8

Component

Regression
equation

r²

Linear range
/mg·mL^-1

Manghaslin

Y=215.08X-0.003

1.000 0

0.002 3-0.226 4

Clitorin

Y=197.71X+0.061

1.000 0

0.002 0-0.198 4

Rutin

Y=270.77X+0.124 3

1.000 0

0.003 2-0.320 4

Nicotiflorin

Y=250.48X+0.125 5

1.000 0

0.003 0-0.302 4

Narcissoside

Y=270.34X+0.084 7

1.000 0

0.002 0-0.196 8

Component	m (Original) /mg	m (Added) /mg	m (Measured) /mg	Recovery /%	Average recovery /%	RSD /%
Manghaslin	0.035 6	0.029 8	0.066 5	103.83	101.97	1.60
	0.035 6	0.029 8	0.065 8	101.31
	0.035 6	0.029 8	0.065 6	100.78
	0.035 6	0.037 3	0.073 4	101.39	101.72	0.39
	0.035 6	0.037 3	0.073 4	101.62
	0.035 6	0.037 3	0.073 6	102.15
	0.035 6	0.044 7	0.081 0	101.52	99.82	1.81
	0.035 6	0.044 7	0.080 3	100.00
	0.035 6	0.044 7	0.079 4	97.93
Clitorin	0.038 5	0.031 7	0.069 9	98.89	99.93	1.71
	0.038 5	0.031 7	0.070 8	101.90
	0.038 5	0.031 7	0.069 9	99.00
	0.038 5	0.039 7	0.077 3	97.92	97.81	0.42
	0.038 5	0.039 7	0.077 1	97.35
	0.038 5	0.039 7	0.077 4	98.15
	0.038 5	0.047 6	0.087 3	102.59	101.19	1.66
	0.038 5	0.047 6	0.086 9	101.65
	0.038 5	0.047 6	0.085 8	99.33
Rutin	0.044 2	0.035 1	0.080 8	104.39	104.17	0.55
	0.044 2	0.035 1	0.080 9	104.60
	0.044 2	0.035 1	0.080 5	103.51
	0.044 2	0.043 9	0.089 0	102.09	103.02	0.84
	0.044 2	0.043 9	0.089 8	103.81
	0.044 2	0.043 9	0.089 5	103.17
	0.044 2	0.052 6	0.097 4	101.05	101.29	0.69
	0.044 2	0.052 6	0.097 9	102.08
	0.044 2	0.052 6	0.097 2	100.74
Nicotiflorin	0.024 5	0.019 5	0.043 3	96.37	97.78	1.33
	0.024 5	0.019 5	0.043 6	98.03
	0.024 5	0.019 5	0.043 8	98.93
	0.024 5	0.024 4	0.049 1	100.75	99.66	0.98
	0.024 5	0.024 4	0.048 6	98.85
	0.024 5	0.024 4	0.048 8	99.39
	0.024 5	0.029 3	0.054 8	103.52	103.50	0.67
	0.024 5	0.029 3	0.054 6	102.80
	0.024 5	0.029 3	0.055 0	104.18
Narcissoside	0.022 5	0.017 8	0.040 8	103.09	103.38	0.34
	0.022 5	0.017 8	0.040 9	103.28
	0.022 5	0.017 8	0.041 0	103.78
	0.022 5	0.022 3	0.043 7	95.20	97.42	1.99
	0.022 5	0.022 3	0.044 5	98.73
	0.022 5	0.022 3	0.044 4	98.33
	0.022 5	0.026 8	0.049 5	101.18	101.09	0.76
	0.022 5	0.026 8	0.049 3	100.27
	0.022 5	0.026 8	0.049 7	101.80

Component

m
(Original)
/mg

m
(Added)
/mg

m
(Measured)
/mg

Recovery
/%

Average
recovery
/%

RSD
/%

Manghaslin

0.035 6

0.029 8

0.066 5

103.83

101.97

1.60

0.035 6

0.029 8

0.065 8

101.31

0.035 6

0.029 8

0.065 6

100.78

0.035 6

0.037 3

0.073 4

101.39

101.72

0.39

0.035 6

0.037 3

0.073 4

101.62

0.035 6

0.037 3

0.073 6

102.15

0.035 6

0.044 7

0.081 0

101.52

99.82

1.81

0.035 6

0.044 7

0.080 3

100.00

0.035 6

0.044 7

0.079 4

97.93

Clitorin

0.038 5

0.031 7

0.069 9

98.89

99.93

1.71

0.038 5

0.031 7

0.070 8

101.90

0.038 5

0.031 7

0.069 9

99.00

0.038 5

0.039 7

0.077 3

97.92

97.81

0.42

0.038 5

0.039 7

0.077 1

97.35

0.038 5

0.039 7

0.077 4

98.15

0.038 5

0.047 6

0.087 3

102.59

101.19

1.66

0.038 5

0.047 6

0.086 9

101.65

0.038 5

0.047 6

0.085 8

99.33

Rutin

0.044 2

0.035 1

0.080 8

104.39

104.17

0.55

0.044 2

0.035 1

0.080 9

104.60

0.044 2

0.035 1

0.080 5

103.51

0.044 2

0.043 9

0.089 0

102.09

103.02

0.84

0.044 2

0.043 9

0.089 8

103.81

0.044 2

0.043 9

0.089 5

103.17

0.044 2

0.052 6

0.097 4

101.05

101.29

0.69

0.044 2

0.052 6

0.097 9

102.08

0.044 2

0.052 6

0.097 2

100.74

Nicotiflorin

0.024 5

0.019 5

0.043 3

96.37

97.78

1.33

0.024 5

0.019 5

0.043 6

98.03

0.024 5

0.019 5

0.043 8

98.93

0.024 5

0.024 4

0.049 1

100.75

99.66

0.98

0.024 5

0.024 4

0.048 6

98.85

0.024 5

0.024 4

0.048 8

99.39

0.024 5

0.029 3

0.054 8

103.52

103.50

0.67

0.024 5

0.029 3

0.054 6

102.80

0.024 5

0.029 3

0.055 0

104.18

Narcissoside

0.022 5

0.017 8

0.040 8

103.09

103.38

0.34

0.022 5

0.017 8

0.040 9

103.28

0.022 5

0.017 8

0.041 0

103.78

0.022 5

0.022 3

0.043 7

95.20

97.42

1.99

0.022 5

0.022 3

0.044 5

98.73

0.022 5

0.022 3

0.044 4

98.33

0.022 5

0.026 8

0.049 5

101.18

101.09

0.76

0.022 5

0.026 8

0.049 3

100.27

0.022 5

0.026 8

0.049 7

101.80

Manufacturer	Sample No.	m(per tablet)/mg
A	A1	1.38±0.01	1.54±0.01	3.00±0.02	1.62±0.03	1.16±0.00
	A2	1.28±0.01	1.41±0.01	2.38±0.02	1.35±0.01	0.94±0.01
	A3	0.98±0.00	1.13±0.00	2.28±0.01	1.27±0.00	1.00±0.00
B	B1	1.46±0.01	1.59±0.00	3.08±0.01	1.87±0.01	1.43±0.01
	B2	1.19±0.01	1.34±0.01	3.15±0.02	1.81±0.01	1.38±0.00
	B3	1.34±0.01	1.44±0.01	3.04±0.01	1.52±0.02	1.16±0.00
C	C1	1.17±0.03	1.47±0.03	3.05±0.03	1.64±0.04	1.44±0.04
	C2	1.07±0.01	1.07±0.02	2.87±0.02	1.38±0.02	1.11±0.03
	C3	0.97±0.02	1.05±0.02	2.61±0.01	1.20±0.01	1.06±0.02
RSD/%		14.65	15.11	11.45	15.63	15.65

Manufacturer

Sample
No.

m(per tablet)/mg

Manghaslin

Clitorin

Rutin

Nicotiflorin

Narcissoside

1.38±0.01

1.54±0.01

3.00±0.02

1.62±0.03

1.16±0.00

1.28±0.01

1.41±0.01

2.38±0.02

1.35±0.01

0.94±0.01

0.98±0.00

1.13±0.00

2.28±0.01

1.27±0.00

1.00±0.00

1.46±0.01

1.59±0.00

3.08±0.01

1.87±0.01

1.43±0.01

1.19±0.01

1.34±0.01

3.15±0.02

1.81±0.01

1.38±0.00

1.34±0.01

1.44±0.01

3.04±0.01

1.52±0.02

1.16±0.00

1.17±0.03

1.47±0.03

3.05±0.03

1.64±0.04

1.44±0.04

1.07±0.01

1.07±0.02

2.87±0.02

1.38±0.02

1.11±0.03

0.97±0.02

1.05±0.02

2.61±0.01

1.20±0.01

1.06±0.02

RSD/%

14.65

15.11

11.45

15.63

15.65

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1	21.20	23.99	25.35	21.02	22.53
	A2	16.79	18.90	19.70	15.64	15.35
	A3	18.71	20.48	23.25	19.87	19.12
B	B2	32.73	35.60	37.91	30.48	33.94
	B3	48.81	51.87	50.34	45.89	43.55
C	C1	12.55	15.31	18.29	13.55	14.17
	C2	10.04	11.40	14.36	10.59	11.48
	C3	11.39	12.77	15.51	12.05	12.15

Manufacturer

Sample No.

Manghaslin

Clitorin

Rutin

Nicotiflorin

Narcissoside

21.20

23.99

25.35

21.02

22.53

16.79

18.90

19.70

15.64

15.35

18.71

20.48

23.25

19.87

19.12

32.73

35.60

37.91

30.48

33.94

48.81

51.87

50.34

45.89

43.55

12.55

15.31

18.29

13.55

14.17

10.04

11.40

14.36

10.59

11.48

11.39

12.77

15.51

12.05

12.15

Manufacturer	Sample No.	Manghaslin	Clitorin	Rutin	Nicotiflorin	Narcissoside
A	A1/A2	46.88	44.84	43.75	42.06	34.21
	A1/A3	53.63	50.95	55.81	62.82	45.53
	A2/A3	69.56	73.28	59.12	50.43	52.51
B	B1/B2	32.73	35.60	37.91	30.48	33.94
	B1/B3	48.81	51.87	50.34	45.89	43.55
	B2/B3	42.75	42.64	48.17	39.63	44.83
C	C1/C2	56.61	49.19	51.42	52.85	56.26
	C1/C3	71.02	58.90	59.57	66.48	62.36
	C2/C3	70.00	70.22	75.19	68.05	83.60

Manufacturer

Sample No.

Manghaslin

Clitorin

Rutin

Nicotiflorin

Narcissoside

A1/A2

46.88

44.84

43.75

42.06

34.21

A1/A3

53.63

50.95

55.81

62.82

45.53

A2/A3

69.56

73.28

59.12

50.43

52.51

B1/B2

32.73

35.60

37.91

30.48

33.94

B1/B3

48.81

51.87

50.34

45.89

43.55

B2/B3

42.75

42.64

48.17

39.63

44.83

C1/C2

56.61

49.19

51.42

52.85

56.26

C1/C3

71.02

58.90

59.57

66.48

62.36

C2/C3

70.00

70.22

75.19

68.05

83.60

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	16.904 1	0.980 3	16.999 5	0.979 8	13.482 4	0.992 4	10.499 5	0.996 4	9.534 2	0.997 2
	A2	16.355 0	0.963 3	5.870 7	0.997 3	-2.060 9	0.999 7	10.954 9	0.991 4	7.483 5	0.996 4
	A3	20.117 8	0.913 6	11.207 4	0.990 7	2.828 2	0.999 0	13.829 8	0.983 7	8.239 2	0.996 0
B	B1	34.379 6	-0.745 9	16.762 2	0.978 7	27.033 3	0.746 9	20.838 8	0.946 2	18.762 2	0.968 0
	B2	26.793 7	0.815 5	13.446 6	0.993 4	18.935 3	0.976 5	16.663 7	0.986 7	10.621 4	0.997 1
	B3	31.843 6	0.438 6	21.015 7	0.962 5	27.539 5	0.825 8	19.596 0	0.976 1	18.469 8	0.982 0
C	C1	15.914 2	0.891 6	13.085 4	0.946 6	-7.685 1	0.999 7	8.423 1	0.984 8	-1.938 9	0.998 9
	C2	13.171 6	0.834 0	12.086 6	0.873 4	5.282 6	0.979 0	3.617 0	0.986 1	4.110 2	0.984 3
	C3	16.935 5	0.737 9	15.517 3	0.816 1	3.476 3	0.991 8	10.789 7	0.948 7	4.996 6	0.987 9

Manufacturer

Sample
No.

Zero-orderr kinetic equation

First-order kinetic equation

Higuchi with F₀

Hixson-Crowell with Tlag

Weibull

AIC

r²

AIC

r²

AIC

r²

AIC

r²

AIC

r²

16.904 1

0.980 3

16.999 5

0.979 8

13.482 4

0.992 4

10.499 5

0.996 4

9.534 2

0.997 2

16.355 0

0.963 3

5.870 7

0.997 3

-2.060 9

0.999 7

10.954 9

0.991 4

7.483 5

0.996 4

20.117 8

0.913 6

11.207 4

0.990 7

2.828 2

0.999 0

13.829 8

0.983 7

8.239 2

0.996 0

34.379 6

-0.745 9

16.762 2

0.978 7

27.033 3

0.746 9

20.838 8

0.946 2

18.762 2

0.968 0

26.793 7

0.815 5

13.446 6

0.993 4

18.935 3

0.976 5

16.663 7

0.986 7

10.621 4

0.997 1

31.843 6

0.438 6

21.015 7

0.962 5

27.539 5

0.825 8

19.596 0

0.976 1

18.469 8

0.982 0

15.914 2

0.891 6

13.085 4

0.946 6

-7.685 1

0.999 7

8.423 1

0.984 8

-1.938 9

0.998 9

13.171 6

0.834 0

12.086 6

0.873 4

5.282 6

0.979 0

3.617 0

0.986 1

4.110 2

0.984 3

16.935 5

0.737 9

15.517 3

0.816 1

3.476 3

0.991 8

10.789 7

0.948 7

4.996 6

0.987 9

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	19.016 2	0.967 5	18.332 8	0.972 6	15.853 6	0.986 6	15.595 3	0.987 4	15.539 6	0.987 6
	A2	16.868 7	0.952 9	7.166 8	0.995 8	0.917 5	0.999 2	10.044 1	0.992 2	4.824 1	0.997 9
	A3	18.338 8	0.943 8	6.730 1	0.996 9	1.650 2	0.999 2	11.224 6	0.991 4	4.867 7	0.998 2
B	B1	33.810 9	-0.755 2	21.116 0	0.926 6	26.346 0	0.753 0	24.985 1	0.824 2	21.400 0	0.928 3
	B2	26.608 9	0.807 7	12.167 3	0.994 8	18.851 9	0.974 8	18.172 8	0.978 8	13.141 7	0.994 0
	B3	31.548 0	0.458 7	20.658 8	0.964 4	27.262 3	0.831 3	21.567 9	0.959 4	20.116 6	0.971 7
C	C1	15.417 6	0.927 9	11.397 1	0.973 6	0.304 8	0.998 5	7.399 6	0.991 2	-3.166 2	0.999 4
	C2	9.651 0	0.931 4	8.069 1	0.953 8	0.367 7	0.993 9	1.066 8	0.992 7	-5.858 9	0.998 7
	C3	12.668 4	0.920 3	10.707 5	0.951 2	6.453 4	0.984 7	5.311 9	0.988 5	4.509 4	0.990 6

Manufacturer

Sample
No.

Zero-orderr kinetic equation

First-order kinetic equation

Higuchi with F₀

Hixson-Crowell with Tlag

Weibull

AIC

r²

AIC

r²

AIC

r²

AIC

r²

AIC

r²

19.016 2

0.967 5

18.332 8

0.972 6

15.853 6

0.986 6

15.595 3

0.987 4

15.539 6

0.987 6

16.868 7

0.952 9

7.166 8

0.995 8

0.917 5

0.999 2

10.044 1

0.992 2

4.824 1

0.997 9

18.338 8

0.943 8

6.730 1

0.996 9

1.650 2

0.999 2

11.224 6

0.991 4

4.867 7

0.998 2

33.810 9

-0.755 2

21.116 0

0.926 6

26.346 0

0.753 0

24.985 1

0.824 2

21.400 0

0.928 3

26.608 9

0.807 7

12.167 3

0.994 8

18.851 9

0.974 8

18.172 8

0.978 8

13.141 7

0.994 0

31.548 0

0.458 7

20.658 8

0.964 4

27.262 3

0.831 3

21.567 9

0.959 4

20.116 6

0.971 7

15.417 6

0.927 9

11.397 1

0.973 6

0.304 8

0.998 5

7.399 6

0.991 2

-3.166 2

0.999 4

9.651 0

0.931 4

8.069 1

0.953 8

0.367 7

0.993 9

1.066 8

0.992 7

-5.858 9

0.998 7

12.668 4

0.920 3

10.707 5

0.951 2

6.453 4

0.984 7

5.311 9

0.988 5

4.509 4

0.990 6

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	14.507 8	0.986 6	16.896 4	0.975 6	13.863 7	0.989 6	11.224 5	0.994 6	11.787 5	0.993 8
	A2	8.223 1	0.992 5	4.988 9	0.996 7	8.057 1	0.993 5	4.371 8	0.997 4	3.860 5	0.997 7
	A3	16.784 8	0.953 0	8.263 2	0.994 4	-5.554 1	0.999 8	12.203 1	0.986 4	8.362 2	0.994 8
B	B1	33.532 6	-1.822 5	27.485 0	0.377 7	26.126 2	0.596 9	26.820 8	0.520 4	24.031 2	0.761 2
	B2	25.658 5	0.819 3	11.970 2	0.994 1	17.325 2	0.979 5	18.496 9	0.972 6	13.755 0	0.991 6
	B3	30.660 7	0.399 6	21.570 2	0.938 1	26.064 3	0.826 9	25.734 6	0.840 6	23.138 5	0.916 7
C	C1	14.160 9	0.932 1	10.774 2	0.970 9	-8.817 3	0.999 8	8.568 7	0.984 7	1.948 4	0.997 1
	C2	8.219 7	0.930 8	6.920 3	0.950 0	-1.124 3	0.993 9	-1.141 1	0.993 9	-17.597 4	0.999 9
	C3	9.571 3	0.950 6	7.357 1	0.971 6	-3.923 7	0.998 5	4.368 2	0.987 8	-2.338 3	0.997 7

Manufacturer

Sample
No.

Zero-orderr kinetic equation

First-order kinetic equation

Higuchi with F₀

Hixson-Crowell with Tlag

Weibull

AIC

r²

AIC

r²

AIC

r²

AIC

r²

AIC

r²

14.507 8

0.986 6

16.896 4

0.975 6

13.863 7

0.989 6

11.224 5

0.994 6

11.787 5

0.993 8

8.223 1

0.992 5

4.988 9

0.996 7

8.057 1

0.993 5

4.371 8

0.997 4

3.860 5

0.997 7

16.784 8

0.953 0

8.263 2

0.994 4

-5.554 1

0.999 8

12.203 1

0.986 4

8.362 2

0.994 8

33.532 6

-1.822 5

27.485 0

0.377 7

26.126 2

0.596 9

26.820 8

0.520 4

24.031 2

0.761 2

25.658 5

0.819 3

11.970 2

0.994 1

17.325 2

0.979 5

18.496 9

0.972 6

13.755 0

0.991 6

30.660 7

0.399 6

21.570 2

0.938 1

26.064 3

0.826 9

25.734 6

0.840 6

23.138 5

0.916 7

14.160 9

0.932 1

10.774 2

0.970 9

-8.817 3

0.999 8

8.568 7

0.984 7

1.948 4

0.997 1

8.219 7

0.930 8

6.920 3

0.950 0

-1.124 3

0.993 9

-1.141 1

0.993 9

-17.597 4

0.999 9

9.571 3

0.950 6

7.357 1

0.971 6

-3.923 7

0.998 5

4.368 2

0.987 8

-2.338 3

0.997 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	17.096 2	0.975 0	17.453 2	0.972 7	15.072 7	0.986 3	15.015 1	0.986 5	15.440 2	0.985 0
	A2	10.778 7	0.984 7	5.137 0	0.996 3	5.999 2	0.995 8	8.380 6	0.992 4	7.002 4	0.994 6
	A3	16.282 1	0.966 9	-0.349 6	0.999 5	3.949 3	0.998 6	8.117 8	0.996 1	1.536 3	0.999 2
B	B1	34.573 6	-1.838 3	24.970 8	0.742 7	27.085 2	0.602 8	27.098 8	0.601 5	24.076 4	0.812 8
	B2	24.398 8	0.910 8	19.832 7	0.971 5	19.378 1	0.976 9	17.015 7	0.987 2	15.360 0	0.991 5
	B3	31.730 3	0.415 5	21.681 6	0.952 6	27.845 6	0.798 6	23.561 9	0.931 0	22.377 6	0.948 7
C	C1	10.507 5	0.968 8	6.177 9	0.989 4	3.260 4	0.995 4	5.627 8	0.991 6	0.670 2	0.997 6
	C2	6.494 1	0.933 5	5.496 2	0.948 1	1.598 7	0.982 2	-6.549 5	0.997 7	-4.410 4	0.996 0
	C3	11.223 9	0.910 3	9.733 4	0.938 2	3.167 1	0.989 1	1.328 3	0.993 1	-0.524 4	0.995 7

Manufacturer

Sample
No.

Zero-orderr kinetic equation

First-order kinetic equation

Higuchi with F₀

Hixson-Crowell with Tlag

Weibull

AIC

r²

AIC

r²

AIC

r²

AIC

r²

AIC

r²

17.096 2

0.975 0

17.453 2

0.972 7

15.072 7

0.986 3

15.015 1

0.986 5

15.440 2

0.985 0

10.778 7

0.984 7

5.137 0

0.996 3

5.999 2

0.995 8

8.380 6

0.992 4

7.002 4

0.994 6

16.282 1

0.966 9

-0.349 6

0.999 5

3.949 3

0.998 6

8.117 8

0.996 1

1.536 3

0.999 2

34.573 6

-1.838 3

24.970 8

0.742 7

27.085 2

0.602 8

27.098 8

0.601 5

24.076 4

0.812 8

24.398 8

0.910 8

19.832 7

0.971 5

19.378 1

0.976 9

17.015 7

0.987 2

15.360 0

0.991 5

31.730 3

0.415 5

21.681 6

0.952 6

27.845 6

0.798 6

23.561 9

0.931 0

22.377 6

0.948 7

10.507 5

0.968 8

6.177 9

0.989 4

3.260 4

0.995 4

5.627 8

0.991 6

0.670 2

0.997 6

6.494 1

0.933 5

5.496 2

0.948 1

1.598 7

0.982 2

-6.549 5

0.997 7

-4.410 4

0.996 0

11.223 9

0.910 3

9.733 4

0.938 2

3.167 1

0.989 1

1.328 3

0.993 1

-0.524 4

0.995 7

Manufacturer	Sample No.	Zero-orderr kinetic equation	First-order kinetic equation	Higuchi with F₀	Hixson-Crowell with Tlag	Weibull
A	A1	15.198 8	0.988 1	20.434 3	0.955 8	16.222 0	0.986 0	12.626 7	0.994 3	11.774 9	0.995 4
	A2	13.268 8	0.957 3	8.237 1	0.987 9	1.866 6	0.997 8	6.543 2	0.992 8	-1.527 8	0.999 0
	A3	17.041 0	0.947 8	8.343 6	0.994 1	-7.718 4	0.999 9	11.039 3	0.989 4	5.460 6	0.997 4
B	B1	34.274 3	-1.492 3	24.514 9	0.782 7	26.826 1	0.647 7	26.759 5	0.653 6	23.594 7	0.843 0
	B2	25.348 1	0.886 3	18.193 5	0.981 0	18.295 1	0.982 3	14.353 2	0.993 4	9.930 3	0.997 8
	B3	30.935 5	0.589 6	22.308 4	0.952 5	27.359 8	0.847 3	20.569 2	0.972 0	19.302 6	0.979 6
C	C1	12.400 1	0.949 8	8.971 0	0.978 7	2.728 5	0.995 9	5.122 7	0.992 6	-1.617 4	0.998 6
	C2	7.527 2	0.949 6	6.288 6	0.963 0	6.726 8	0.962 4	-5.527 5	0.998 2	2.353 8	0.987 4
	C3	9.936 9	0.933 7	8.241 9	0.956 6	2.649 7	0.990 2	-2.330 5	0.997 2	-6.600 2	0.999 0

Manufacturer

Sample
No.

Zero-orderr kinetic equation

First-order kinetic equation

Higuchi with F₀

Hixson-Crowell with Tlag

Weibull

AIC

r²

AIC

r²

AIC

r²

AIC

r²

AIC

r²

15.198 8

0.988 1

20.434 3

0.955 8

16.222 0

0.986 0

12.626 7

0.994 3

11.774 9

0.995 4

13.268 8

0.957 3

8.237 1

0.987 9

1.866 6

0.997 8

6.543 2

0.992 8

-1.527 8

0.999 0

17.041 0

0.947 8

8.343 6

0.994 1

-7.718 4

0.999 9

11.039 3

0.989 4

5.460 6

0.997 4

34.274 3

-1.492 3

24.514 9

0.782 7

26.826 1

0.647 7

26.759 5

0.653 6

23.594 7

0.843 0

25.348 1

0.886 3

18.193 5

0.981 0

18.295 1

0.982 3

14.353 2

0.993 4

9.930 3

0.997 8

30.935 5

0.589 6

22.308 4

0.952 5

27.359 8

0.847 3

20.569 2

0.972 0

19.302 6

0.979 6

12.400 1

0.949 8

8.971 0

0.978 7

2.728 5

0.995 9

5.122 7

0.992 6

-1.617 4

0.998 6

7.527 2

0.949 6

6.288 6

0.963 0

6.726 8

0.962 4

-5.527 5

0.998 2

2.353 8

0.987 4

9.936 9

0.933 7

8.241 9

0.956 6

2.649 7

0.990 2

-2.330 5

0.997 2

-6.600 2

0.999 0

Manufacturer	Sample No.	t₅₀/h
A	A1	2.78±0.27	2.78±0.33	3.46±0.26	3.18±0.10	2.94±0.21
	A2	4.09±0.29	5.80±0.21	4.33±0.13	6.10±0.17	7.90±0.24
	A3	4.15±0.43	4.31±0.57	5.14±0.67	4.40±0.52	5.33±0.56
B	B1	0.70±0.23	0.77±0.28	0.98±0.44	0.70±0.34	0.74±0.31
	B2	1.56±0.23	1.65±0.24	1.91±0.30	1.81±0.27	1.64±0.33
	B3	1.02±0.26	1.06±0.28	1.29±0.33	1.08±0.32	1.12±0.28
C	C1	9.73±0.88	7.71±0.47	9.44±0.19	10.27±1.58	10.38±1.07
	C2	25.31±2.56	22.24±2.48	30.99±2.14	48.71±2.30	24.32±3.16
	C3	17.92±0.35	14.15±0.61	17.27±1.53	20.87±1.90	20.51±2.43

Manufacturer

Sample
No.

t₅₀/h

Manghaslin

Clitorin

Rutin

Nicotiflorin

Narcissoside

2.78±0.27

2.78±0.33

3.46±0.26

3.18±0.10

2.94±0.21

4.09±0.29

5.80±0.21

4.33±0.13

6.10±0.17

7.90±0.24

4.15±0.43

4.31±0.57

5.14±0.67

4.40±0.52

5.33±0.56

0.70±0.23

0.77±0.28

0.98±0.44

0.70±0.34

0.74±0.31

1.56±0.23

1.65±0.24

1.91±0.30

1.81±0.27

1.64±0.33

1.02±0.26

1.06±0.28

1.29±0.33

1.08±0.32

1.12±0.28

9.73±0.88

7.71±0.47

9.44±0.19

10.27±1.58

10.38±1.07

25.31±2.56

22.24±2.48

30.99±2.14

48.71±2.30

24.32±3.16

17.92±0.35

14.15±0.61

17.27±1.53

20.87±1.90

20.51±2.43