药学学报

No.	Time/min	Acetonitrile/%
1	0	5
2	0	5
3	2	5
4	3	20
5	12	22
6	14	46
7	26	100
8	28	100
9	29	5
10	30	5

No.	Time/min	Acetonitrile/%
1	0	5
2	0	5
3	2	5
4	3	20
5	12	22
6	14	46
7	26	100
8	28	100
9	29	5
10	30	5

Name	Flavor description	Flavor weight	Dose/g	Dose weight
Pogostemonis Herba	Slightly bitter	Bitter 0.5	85	0.083 5
Chrysanthemi Flos	Sweet, slightly bitter	Sweet 1, bitter 0.25	85	0.083 5
Forsythiae Fructus	Bitter	Bitter 1	85	0.083 5
Isatidis Folium	Slightly sour, bitter, astringent	Sour 0.5, bitter 0.5, astringent 0.25	141	0.138 5
Isatidis Radix	Slightly sweet, then bitter and astringent	Sweet 0.5, bitter 1	85	0.083 5
Rehmanniae Radix	Slightly sweet, slightly bitter	Sweet 0.5, bitter 0.25	85	0.083 5
Lycii Cortex	Slightly sweet and then bitter	Sweet 0.5, bitter 1	85	0.083 5
Cynanchi Atrati Radix et Rhizoma	Slightly bitter	Bitter 0.5	85	0.083 5
Menthae Haplocalycis Herba	Pungent, cool	Pungent 1	141	0.138 5
Gypsum Fibrosum	Light	Light 1	141	0.138 5

Name	Flavor description	Flavor weight	Dose/g	Dose weight
Pogostemonis Herba	Slightly bitter	Bitter 0.5	85	0.083 5
Chrysanthemi Flos	Sweet, slightly bitter	Sweet 1, bitter 0.25	85	0.083 5
Forsythiae Fructus	Bitter	Bitter 1	85	0.083 5
Isatidis Folium	Slightly sour, bitter, astringent	Sour 0.5, bitter 0.5, astringent 0.25	141	0.138 5
Isatidis Radix	Slightly sweet, then bitter and astringent	Sweet 0.5, bitter 1	85	0.083 5
Rehmanniae Radix	Slightly sweet, slightly bitter	Sweet 0.5, bitter 0.25	85	0.083 5
Lycii Cortex	Slightly sweet and then bitter	Sweet 0.5, bitter 1	85	0.083 5
Cynanchi Atrati Radix et Rhizoma	Slightly bitter	Bitter 0.5	85	0.083 5
Menthae Haplocalycis Herba	Pungent, cool	Pungent 1	141	0.138 5
Gypsum Fibrosum	Light	Light 1	141	0.138 5

No.	t_R/min	Name	Formula	Adduct	Found mass	Error/10^-6	MS²	MS³	Class
1	0.79	γ-Aminobutyric acid	C₄H₉NO₂	+H	104.070 51	-0.914	86.858 64, 59.721 45		Amino acid
2	0.80	Malic acid	C₄H₆O₅	-H	133.013 75	-3.733	114.872 16, 86.687 93, 70.717 41		Organic acid
3	0.80	Quinic acid	C₇H₁₂O₆	-H	191.055 21	-4.718	172.915 51, 126.803 86, 108.820 54, 84.758 36	108.772 55, 98.793 11, 84.831 68, 80.813 14	Organic acid
4	1.01	Citric acid	C₆H₈O₇	-H	191.018 81	-4.794	172.966 13, 128.796 78, 110.808 53		Organic acid
5	1.02	Valine	C₅H₁₁NO₂	+H	118.085 94	-2.669	101.893 60		Amino acid
6	1.02	Guanine	C₅H₅N₅O	+H	152.056 37	-2.081	134.782 88, 109.906 75, 108.758 09, 106.717 73		Purine
7	1.05	Epigoitrin	C₅H₇NOS	+H	130.031 74	-2.854	83.734 13, 69.827 96		Alkaloid
8	1.40	Guanosine	C₁₀H₁₃N₅O₅	-H	282.083 22	-4.154	149.936 28	150.069 05, 132.777 11, 125.857 57, 106.786 71, 81.847 73	Purine
9	1.40	Vanillic acid	C₈H₈O₄	-H	167.034 19	-4.742	151.825 61, 122.809 74, 107.803 42	122.916 06, 107.842 30	Organic acid
10	1.48	Leucine	C₆H₁₃NO₂	+H	132.101 62	-2.159	131.950 50, 85.799 97	85.981 98	Amino acid
11	1.65	Indole-3-carboxaldehyde	C₉H₇NO	+H	146.059 91	-0.893	117.870 03		Indole
12	2.07	Phenprobamate	C₉H₁₁NO₂	+H	166.086 15	-0.633	148.925 51, 119.902 73		Amino acid
13	2.21	Ferulic acid	C₁₀H₁₀O₄	-H	193.049 99	-2.283	177.936 98, 148.949 33, 133.907 14		Phenylpropanoid
14	3.09	Rosmarinic acid	C₁₈H₁₆O₈	-H	359.075 10	-5.962	196.960 30		Phenol
15	3.39	Loganic acid	C₁₆H₂₄O₁₀	-H	375.127 11	-6.825	168.979 71, 150.969 97, 124.906 36		Iridoid
16	3.70	Caffeic acid	C₉H₈O₄	-H	179.034 21	-4.312	134.942 79	134.908 52, 106.541 18, 90.754 52	Organic acid
17	4.28	Forsythoside E	C₂₀H₂₀O₁₂	+Na	485.161 87	4.927	339.140 35		Phenylpropanoid
18	4.44	Salicylic acid	C₇H₆O₃	-H	137.023 91	-3.703	92.875 89		Organic acid
19	4.44	Protocatechualdehyde	C₇H₆O₃	-H	137.023 91	-3.703	118.808 70, 108.883 68		Phenol
20	4.47	Decaffeoyl verbascoside	C₂₀H₃₀O₁₂	-H	461.164 40	-4.444	315.122 62, 297.108 40, 160.827 48, 134.989 01		Phenylpropanoid
21	4.56	Kukoamine A	C₂₈H₄₂N₄O₆	+H	531.316 83	-3.723	367.386 96, 164.883 09		Alkaloid
22	5.13	Verbascoside	C₂₉H₃₆O₁₅	-H	623.198 24	0.155	461.255 13, 315.252 75	315.172 42, 134.979 13	Phenylpropanoid
23	5.29	Geniposide	C₁₇H₂₄O₁₀	-H	387.129 73	0.155	225.108 40		Iridoid
24	5.71	Calceolarioside A	C₂₃H₂₆O₁₁	-H	477.137 97	-4.747	315.074 10, 297.060 55, 178.873 96, 160.921 08, 134.859 53		Phenylpropanoid
25	5.74	Forsythoside A*	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.246 40, 443.261 54, 179.055 18		Phenylpropanoid
26	5.80	Naringenin-7-O-β-D-glucopyranoside	C₂₁H₂₂O₁₀	-H	433.112 88	-2.632	271.139 80, 150.941 25		Flavonoid
27	6.04	Hesperidin	C₂₈H₃₄O₁₅	-H	609.180 11	-3.912	447.189 03, 429.292 91, 301.037 48, 179.064 33	286.095 52, 242.025 45, 150.921 17, 124.916 51	Flavonoid
28	6.10	3, 5-Di-O-caffeoylquinic acid*	C₂₅H₂₄O₁₂	-H	515.118 84	-1.280	353.085 94, 190.971 63, 178.883 30	190.899 60, 178.889 98, 172.938 14, 154.892 46, 134.891 28, 110.910 83	Phenylpropanoid
29	6.10	Isoquercitrin	C₂₁H₂₀O₁₂	-H	463.085 66	-5.483	299.956 91		Flavonoid
30	6.20	Saponin	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	431.173 83, 341.139 59, 311.172 55		Flavonoid
31	6.20	Luteolin-7-O-rutinoside	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	285.009 58		Flavonoid
32	6.28	Astragalin	C₂₁H₂₀O₁₁	-H	447.091 19	-4.685	284.979 00		Flavonoid
33	6.38	Cynaroside*	C₂₁H₂₀O₁₁	-H	447.091 00	-2.657	285.034 79		Flavonoid
34	6.44	Kaempferol	C₁₅H₁₀O₆	+H	287.054 35	-2.315	259.078 52, 230.931 98, 153.859 50		Flavonoid
35	6.58	Kaempferol-3-O-β-D-glucoside	C₂₁H₂₀O₁₁	+H	449.106 11	-3.847	162.894 29, 287.039 98		Flavonoid
36	6.65	Isoacteoside	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.244 20, 315.152 65		Phenylpropanoid
37	6.80	Eriodictyol	C₁₅H₁₂O₆	-H	287.054 78	-4.638	150.803 47, 134.835 27	108.807 39, 106.844 30, 82.934 88, 64.732 49	Flavonoid
38	6.92	Isoscoparin	C₂₂H₂₂O₁₁	-H	461.108 28	-1.420	371.088 81, 341.148 93		Flavonoid
39	7.02	Chlorogenic acid*	C₁₆H₁₈O₉	-H	353.086 18	-4.603	191.084 17, 178.882 42, 135.039 72	190.984 24, 172.951 84, 126.857 38, 110.913 15	Phenylpropanoid
40	7.11	Epipinoresinol-4′-O-β-D-glucoside	C₂₆H₃₂O₁₁	-H	519.185 49	-3.265	357.124 69, 338.999 88		Lignan
41	7.16	Isovitexin	C₂₁H₂₀O₁₀	-H	431.097 08	-2.992	341.109 07, 311.076 57		Flavonoid
42	7.34	Carvacrol	C₁₀H₁₄O	+H	149.096 10	-7.300	148.980 58		Phenol
43	7.40	Diosmin	C₂₈H₃₂O₁₅	-H	607.163 82	-4.485	299.001 90		Flavonoid
44	7.63	4-Hydroxyphenylacetic acid	C₈H₈O₃	-H	151.039 35	-4.750	108.920 41		Organic acid
45	8.16	Chrysoeriol	C₁₆H₁₂O₆	+H	301.070 04	-2.075	301.156 56		Flavonoid
46	8.22	Diosmetin	C₁₆H₁₂O₆	+H	301.069 89	-2.573	301.117 74		Flavonoid
47	11.38	Forsythin*	C₂₇H₃₄O₁₁	+Na	557.199 65	-3.748	395.307 01, 309.168 09, 184.855 62		Lignan
48	11.49	Martynoside	C₃₁H₄₀O₁₅	-H	651.226 32	-4.796	475.233 58		Iridoid
49	13.12	Luteolin	C₁₅H₁₀O₆	-H	285.039 55	-3.197	266.982 57, 257.131 77, 216.777 53, 198.997 44		Flavonoid
50	13.46	Acacetin	C₁₆H₁₂O₅	+H	285.075 16	-2.070	270.046 72, 285.130 77		Flavonoid
51	13.46	Linarin	C₂₈H₃₂O₁₄	+H	593.184 51	-3.324	285.018 74		Flavonoid
52	13.64	Wogonin	C₁₆H₁₂O₅	-H	283.059 84	-4.793	268.014 53, 239.158 97		Flavonoid
53	13.75	Acacetin	C₁₆H₁₂O₅	-H	283.059 84	-4.797	267.957 28		Flavonoid
54	14.85	Rhein	C₁₅H₈O₆	-H	283.024 57	-0.852	239.175 90, 182.536 04		Anthraquinones
55	15.05	Tilianin	C₂₂H₂₂O₁₀	+H	447.128 78	0.462	285.057 50		Flavonoid
56	17.84	Indirubin	C₁₆H₁₀N₂O₂	+H	263.081 18	-1.232			Alkaloid
57	19.61	Linolenic acid	C₁₈H₃₀O₂	+H	279.231 63	-4.740	261.166 63, 243.185 55, 94.845 15	243.132 89, 173.070 57, 134.859 38, 92.830 72	Organic acid

No.	t_R/min	Name	Formula	Adduct	Found mass	Error/10^-6	MS²	MS³	Class
1	0.79	γ-Aminobutyric acid	C₄H₉NO₂	+H	104.070 51	-0.914	86.858 64, 59.721 45		Amino acid
2	0.80	Malic acid	C₄H₆O₅	-H	133.013 75	-3.733	114.872 16, 86.687 93, 70.717 41		Organic acid
3	0.80	Quinic acid	C₇H₁₂O₆	-H	191.055 21	-4.718	172.915 51, 126.803 86, 108.820 54, 84.758 36	108.772 55, 98.793 11, 84.831 68, 80.813 14	Organic acid
4	1.01	Citric acid	C₆H₈O₇	-H	191.018 81	-4.794	172.966 13, 128.796 78, 110.808 53		Organic acid
5	1.02	Valine	C₅H₁₁NO₂	+H	118.085 94	-2.669	101.893 60		Amino acid
6	1.02	Guanine	C₅H₅N₅O	+H	152.056 37	-2.081	134.782 88, 109.906 75, 108.758 09, 106.717 73		Purine
7	1.05	Epigoitrin	C₅H₇NOS	+H	130.031 74	-2.854	83.734 13, 69.827 96		Alkaloid
8	1.40	Guanosine	C₁₀H₁₃N₅O₅	-H	282.083 22	-4.154	149.936 28	150.069 05, 132.777 11, 125.857 57, 106.786 71, 81.847 73	Purine
9	1.40	Vanillic acid	C₈H₈O₄	-H	167.034 19	-4.742	151.825 61, 122.809 74, 107.803 42	122.916 06, 107.842 30	Organic acid
10	1.48	Leucine	C₆H₁₃NO₂	+H	132.101 62	-2.159	131.950 50, 85.799 97	85.981 98	Amino acid
11	1.65	Indole-3-carboxaldehyde	C₉H₇NO	+H	146.059 91	-0.893	117.870 03		Indole
12	2.07	Phenprobamate	C₉H₁₁NO₂	+H	166.086 15	-0.633	148.925 51, 119.902 73		Amino acid
13	2.21	Ferulic acid	C₁₀H₁₀O₄	-H	193.049 99	-2.283	177.936 98, 148.949 33, 133.907 14		Phenylpropanoid
14	3.09	Rosmarinic acid	C₁₈H₁₆O₈	-H	359.075 10	-5.962	196.960 30		Phenol
15	3.39	Loganic acid	C₁₆H₂₄O₁₀	-H	375.127 11	-6.825	168.979 71, 150.969 97, 124.906 36		Iridoid
16	3.70	Caffeic acid	C₉H₈O₄	-H	179.034 21	-4.312	134.942 79	134.908 52, 106.541 18, 90.754 52	Organic acid
17	4.28	Forsythoside E	C₂₀H₂₀O₁₂	+Na	485.161 87	4.927	339.140 35		Phenylpropanoid
18	4.44	Salicylic acid	C₇H₆O₃	-H	137.023 91	-3.703	92.875 89		Organic acid
19	4.44	Protocatechualdehyde	C₇H₆O₃	-H	137.023 91	-3.703	118.808 70, 108.883 68		Phenol
20	4.47	Decaffeoyl verbascoside	C₂₀H₃₀O₁₂	-H	461.164 40	-4.444	315.122 62, 297.108 40, 160.827 48, 134.989 01		Phenylpropanoid
21	4.56	Kukoamine A	C₂₈H₄₂N₄O₆	+H	531.316 83	-3.723	367.386 96, 164.883 09		Alkaloid
22	5.13	Verbascoside	C₂₉H₃₆O₁₅	-H	623.198 24	0.155	461.255 13, 315.252 75	315.172 42, 134.979 13	Phenylpropanoid
23	5.29	Geniposide	C₁₇H₂₄O₁₀	-H	387.129 73	0.155	225.108 40		Iridoid
24	5.71	Calceolarioside A	C₂₃H₂₆O₁₁	-H	477.137 97	-4.747	315.074 10, 297.060 55, 178.873 96, 160.921 08, 134.859 53		Phenylpropanoid
25	5.74	Forsythoside A*	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.246 40, 443.261 54, 179.055 18		Phenylpropanoid
26	5.80	Naringenin-7-O-β-D-glucopyranoside	C₂₁H₂₂O₁₀	-H	433.112 88	-2.632	271.139 80, 150.941 25		Flavonoid
27	6.04	Hesperidin	C₂₈H₃₄O₁₅	-H	609.180 11	-3.912	447.189 03, 429.292 91, 301.037 48, 179.064 33	286.095 52, 242.025 45, 150.921 17, 124.916 51	Flavonoid
28	6.10	3, 5-Di-O-caffeoylquinic acid*	C₂₅H₂₄O₁₂	-H	515.118 84	-1.280	353.085 94, 190.971 63, 178.883 30	190.899 60, 178.889 98, 172.938 14, 154.892 46, 134.891 28, 110.910 83	Phenylpropanoid
29	6.10	Isoquercitrin	C₂₁H₂₀O₁₂	-H	463.085 66	-5.483	299.956 91		Flavonoid
30	6.20	Saponin	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	431.173 83, 341.139 59, 311.172 55		Flavonoid
31	6.20	Luteolin-7-O-rutinoside	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	285.009 58		Flavonoid
32	6.28	Astragalin	C₂₁H₂₀O₁₁	-H	447.091 19	-4.685	284.979 00		Flavonoid
33	6.38	Cynaroside*	C₂₁H₂₀O₁₁	-H	447.091 00	-2.657	285.034 79		Flavonoid
34	6.44	Kaempferol	C₁₅H₁₀O₆	+H	287.054 35	-2.315	259.078 52, 230.931 98, 153.859 50		Flavonoid
35	6.58	Kaempferol-3-O-β-D-glucoside	C₂₁H₂₀O₁₁	+H	449.106 11	-3.847	162.894 29, 287.039 98		Flavonoid
36	6.65	Isoacteoside	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.244 20, 315.152 65		Phenylpropanoid
37	6.80	Eriodictyol	C₁₅H₁₂O₆	-H	287.054 78	-4.638	150.803 47, 134.835 27	108.807 39, 106.844 30, 82.934 88, 64.732 49	Flavonoid
38	6.92	Isoscoparin	C₂₂H₂₂O₁₁	-H	461.108 28	-1.420	371.088 81, 341.148 93		Flavonoid
39	7.02	Chlorogenic acid*	C₁₆H₁₈O₉	-H	353.086 18	-4.603	191.084 17, 178.882 42, 135.039 72	190.984 24, 172.951 84, 126.857 38, 110.913 15	Phenylpropanoid
40	7.11	Epipinoresinol-4′-O-β-D-glucoside	C₂₆H₃₂O₁₁	-H	519.185 49	-3.265	357.124 69, 338.999 88		Lignan
41	7.16	Isovitexin	C₂₁H₂₀O₁₀	-H	431.097 08	-2.992	341.109 07, 311.076 57		Flavonoid
42	7.34	Carvacrol	C₁₀H₁₄O	+H	149.096 10	-7.300	148.980 58		Phenol
43	7.40	Diosmin	C₂₈H₃₂O₁₅	-H	607.163 82	-4.485	299.001 90		Flavonoid
44	7.63	4-Hydroxyphenylacetic acid	C₈H₈O₃	-H	151.039 35	-4.750	108.920 41		Organic acid
45	8.16	Chrysoeriol	C₁₆H₁₂O₆	+H	301.070 04	-2.075	301.156 56		Flavonoid
46	8.22	Diosmetin	C₁₆H₁₂O₆	+H	301.069 89	-2.573	301.117 74		Flavonoid
47	11.38	Forsythin*	C₂₇H₃₄O₁₁	+Na	557.199 65	-3.748	395.307 01, 309.168 09, 184.855 62		Lignan
48	11.49	Martynoside	C₃₁H₄₀O₁₅	-H	651.226 32	-4.796	475.233 58		Iridoid
49	13.12	Luteolin	C₁₅H₁₀O₆	-H	285.039 55	-3.197	266.982 57, 257.131 77, 216.777 53, 198.997 44		Flavonoid
50	13.46	Acacetin	C₁₆H₁₂O₅	+H	285.075 16	-2.070	270.046 72, 285.130 77		Flavonoid
51	13.46	Linarin	C₂₈H₃₂O₁₄	+H	593.184 51	-3.324	285.018 74		Flavonoid
52	13.64	Wogonin	C₁₆H₁₂O₅	-H	283.059 84	-4.793	268.014 53, 239.158 97		Flavonoid
53	13.75	Acacetin	C₁₆H₁₂O₅	-H	283.059 84	-4.797	267.957 28		Flavonoid
54	14.85	Rhein	C₁₅H₈O₆	-H	283.024 57	-0.852	239.175 90, 182.536 04		Anthraquinones
55	15.05	Tilianin	C₂₂H₂₂O₁₀	+H	447.128 78	0.462	285.057 50		Flavonoid
56	17.84	Indirubin	C₁₆H₁₀N₂O₂	+H	263.081 18	-1.232			Alkaloid
57	19.61	Linolenic acid	C₁₈H₃₀O₂	+H	279.231 63	-4.740	261.166 63, 243.185 55, 94.845 15	243.132 89, 173.070 57, 134.859 38, 92.830 72	Organic acid

基于UHPLC-LTQ-Orbitrap MSⁿ技术的小儿感冒口服液潜在苦味关键质量属性研究

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王晓萌 ¹^,² , 陆影 ¹^,² , 胡小艳 ¹^,² , 马金辰 ¹^,² , 郭新雨 ¹^,² , 韩燕雨 ¹^,² , 王静 ¹^,² , 张晓梦 ¹^,² , 李明爽 ¹^,² , 李楠 ¹^,² , 戴幸星 ¹^,² , 姚璐 ³ , 杜菁 ³^,^* , 吴志生 ¹^,²^,^*

药学学报 | 专题报道: 中药制造质量控制与智能制造 2023,58(10): 2882-2889

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药学学报 |专题报道: 中药制造质量控制与智能制造 2023 , 58 (10) : 2882 -2889

基于UHPLC-LTQ-Orbitrap MSⁿ技术的小儿感冒口服液潜在苦味关键质量属性研究

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王晓萌¹^,², 陆影¹^,², 胡小艳¹^,², 马金辰¹^,², 郭新雨¹^,², 韩燕雨¹^,², 王静¹^,², 张晓梦¹^,², 李明爽¹^,², 李楠¹^,², 戴幸星¹^,², 姚璐³, 杜菁³^,^*, 吴志生¹^,²^,^*

作者信息

1.北京中医药大学中药学院, 北京 102488

2.中药制药与新药开发教育部工程研究中心, 北京 102488

3.北京同仁堂科技发展股份有限公司, 北京 100079

通讯作者:

*杜菁, Tel: 86-10-87632888, E-mail: daturae@163.com;

吴志生, Tel: 86-10-53912101, E-mail: wzs@bucm.edu.cn

Characterization of potential bitterness critical quality attributes in Xiaoer Ganmao Oral Liquid based on UHPLC-LTQ-Orbitrap MSⁿ

Xiao-meng WANG¹^,², Ying LU¹^,², Xiao-yan HU¹^,², Jin-chen MA¹^,², Xin-yu GUO¹^,², Yan-yu HAN¹^,², Jing WANG¹^,², Xiao-meng ZHANG¹^,², Ming-shuang LI¹^,², Nan LI¹^,², Xing-xing DAI¹^,², Lu YAO³, Jing DU³^,^*, Zhi-sheng WU¹^,²^,^*

Affiliations

1. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China

2. Engineering Research Center of Chinese Medicine Production and New Drug Development, Beijing 102488, China

3. Beijing Tongrentang Technology Development Co., Ltd., Beijing 100079, China

出版时间: 2023-10-12 doi: 10.16438/j.0513-4870.2023-0121

文章导航

摘要

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采用超高效液相色谱-线性离子阱-串联静电场轨道阱质谱(UHPLC-LTQ-Orbitrap MSⁿ) 联合BitterX数据库对真实生产世界小儿感冒口服液无糖中间体的潜在苦味关键质量属性进行辨识。采用Acquity UPLC BEH C₁₈色谱柱(100 mm × 2.1 mm, 1.7 μm); 流动相为0.1%甲酸-水溶液(A)-乙腈(B), 梯度洗脱, 分别在正、负离子模式下对小儿感冒口服液无糖中间体进行数据采集。根据高分辨质谱提供的准分子离子峰和多级质谱碎片, 获取目标化合物的精确分子量和结构信息, 结合保留时间, 参照对照品、文献报道等相关数据对化合物进行分析, 共鉴定包括黄酮类、生物碱类、苯丙素类等共57个化学成分。进一步, 采用BitterX数据库预测化学成分与苦味受体结合的概率, 辨识潜在苦味关键质量属性, 最终预测得到其中包括地骨皮甲素、蒙花苷在内的33个潜在苦味化学成分。该研究较为全面地表征了小儿感冒口服液无糖中间体的化学物质基础, 为筛选苦味化合物提供了有效的方法, 为进一步改善小儿感冒口服液的苦味等不良口感提供了科学依据。

关键词

关键质量属性 / UHPLC-LTQ-Orbitrap MSⁿ / 苦味物质 / 质谱分析

Abstract

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To identify the bitter compounds of real-world Xiaoer Ganmao Oral Liquid sugar-free intermediates, an integrated strategy has been developed by using ultra-high performance liquid chromatography with linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MSⁿ) method and BitterX database prediction. The chromatographic operating conditions were as follows, chromatographic column: Acquity UPLC BEH C₁₈ (100 mm × 2.1 mm, 1.7 μm), mobile phase: 0.1% formic acid-water solution (A)-acetonitrile (B) with gradient elution. The data were collected in positive and negative ion modes, respectively. The accurate molecular mass and structural information of the target compounds were obtained based on quasi-molecular ions and fragmentation ions provided by high-resolution mass spectrometry. The compounds were identified by combining retention time, reference substances, reports, and other relevant data, and a total of 57 constituents including flavonoids, alkaloids, and phenylpropanoids were finally identified. Further, the BitterX database was used to predict binding probability of compounds to bitter receptors and identify potential bitter critical quality attributes, finally 33 potential bitter compounds, including kukoamine A and linarin, were predicted. This study comprehensively characterized the material basis of Xiaoer Ganmao Oral Liquid sugar-free intermediates, it provides an effective method for bitter compound screening and a reference for further improving the undesirable taste of Xiaoer Ganmao Oral Liquid.

Key words

critical quality attribute / UHPLC-LTQ-Orbitrap MSⁿ / bitterness / mass spectrometry

引用本文

王晓萌, 陆影, 胡小艳, 马金辰, 郭新雨, 韩燕雨, 王静, 张晓梦, 李明爽, 李楠, 戴幸星, 姚璐, 杜菁, 吴志生. 基于UHPLC-LTQ-Orbitrap MSⁿ技术的小儿感冒口服液潜在苦味关键质量属性研究. 药学学报, 2023 , 58 (10) : 2882 -2889 . DOI: 10.16438/j.0513-4870.2023-0121

Xiao-meng WANG, Ying LU, Xiao-yan HU, Jin-chen MA, Xin-yu GUO, Yan-yu HAN, Jing WANG, Xiao-meng ZHANG, Ming-shuang LI, Nan LI, Xing-xing DAI, Lu YAO, Jing DU, Zhi-sheng WU. Characterization of potential bitterness critical quality attributes in Xiaoer Ganmao Oral Liquid based on UHPLC-LTQ-Orbitrap MSⁿ[J]. Acta Pharmaceutica Sinica, 2023 , 58 (10) : 2882 -2889 . DOI: 10.16438/j.0513-4870.2023-0121

正文

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苦味质量属性是影响中药口服液体制剂开发及生产过程控制的质量属性之一^{[1, 2]}。在2015年版《中华人民共和国药典》一部所收载的618种中药材中, 以苦味为主味的药材有200种, 占32.4%。同时, 苦味是众多不良口感中存在最广泛、最令人难以接受的滋味之一, 且人感知苦味的阈值较其他味觉低, 以苦味为主不良口感的存在, 使中药开发的适口性面临着巨大的挑战。小儿感冒口服液的用药人群为儿童, 其组方中有8味药的描述中均涉及苦。苦味物质基础影响其口感, 进而影响儿童患者用药顺应性, 因此明确其苦味关键质量属性, 对口感进行优化是生产制造过程中亟待解决的现实问题^[3]。

目前, 针对中药大品种小儿感冒口服液的物质基础研究鲜有报道, 本实验采用超高效液相色谱-线性离子阱-串联静电场轨道阱质谱(UHPLC-LTQ-Orbitrap MSⁿ) 技术对其化学成分进行研究, 结合对照品及相关文献, 根据质谱信息快速分析鉴定化合物, 研究小儿感冒口服液潜在苦味关键质量属性。BitterX数据库是一种在线开放平台, 能够将化学物质的分子结构与苦味受体hTAS2Rs家族的蛋白结构进行整合以预测结合率, 是苦味物质基础研究和新苦味物质发现的有力工具, 将液质联用技术解析得到的化学成分通过BitterX预测最终得到潜在苦味关键质量属性。研究结果对明确小儿感冒口服液的药效物质基础、质量控制、口感提升等具有重要意义。

材料与方法

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试剂小儿感冒口服液无糖中间体(批号18261372, 北京同仁堂股份有限公司); 超纯水(规格500 mL/瓶, 广州屈臣氏食品饮料有限公司); 甲酸(批号151871, CAS号64-18-6, 质量分数≥ 95.0%)、乙腈(批号WXBB5870V, CAS号75-05-8, 质量分数≥ 99.9%) (美国赛默飞世尔科技有限公司); 对照品绿原酸(批号5077, CAS号327-97-9, 质量分数≥ 98.0%)、3, 5-O-二咖啡酰奎宁酸(批号8334, CAS号89919-62-0, 质量分数≥ 98.0%)、木犀草苷(批号10527, CAS号5373-11-5, 质量分数≥ 98.0%)、连翘苷(批号3212, CAS号487-41-2, 质量分数≥ 98.0%)、连翘酯苷A (批号3639, CAS号79916-77-1, 质量分数≥ 98.0%)、靛玉红(批号10164, CAS号479-41-4, 质量分数≥ 98.0%) (上海诗丹德标准技术服务有限公司)。

仪器 Ultimate 3000超高效液相色谱仪, LTQ-Orbitrap XL质谱仪, 配有电喷雾离子源(ESI)、Xcalibur 2.1化学工作站(美国赛默飞世尔科技有限公司); TG16MW台式高速离心机(湖南赫西仪器有限公司); SQP电子分析天平(德国Satorius公司)。

理论滋味量化描述 统计组方中药物在《中药药典》中性状项下的记载, 根据味的排序分别赋值1、0.5、0.25; 并根据味的描述程度, 直接描述赋值1 (如“苦”)、弱化描述赋值0.5 (如“微苦”)、强化描述赋值1.5 (如“极苦”“苦甚”); 排序分值乘以描述程度分值为药物味的最终得分; 计算药物在复方中的剂量权重。药物味的最终得分乘以剂量权重为该味在复方中的贡献值, 将全方某一味分值相加, 即得全方该味的分值。

样品制备 对照品溶液制备: 取上述对照品适量, 精密称定, 置于量瓶中, 加入甲醇溶液并定容制成混合对照品溶液。供试品溶液制备: 取小儿感冒口服液无糖中间体, 以10 000 r·min^-1离心10 min后取上清液备用。

色谱条件 Waters Acquity UPLC BEH C₁₈色谱柱(100 mm × 2.1 mm, 1.7 μm); 流动相0.1%甲酸-水溶液(A)-乙腈(B); 梯度洗脱程序见表 1; 柱温35 ℃; 进样2 μL; 流速0.3 mL·min^-1。

质谱条件 使用LTQ-Orbitrap XL质谱仪进行正、负两种模式扫描测定, 采用电喷雾离子源, 鞘气和辅助气均为氮气; 鞘气流速40 arb, 辅助气流速20 arb (1 arb = 0.33 L·min^-1); 碰撞气为氦气; 电离源电压3.0 kV; 离子源温度350 ℃; 管透镜电压110 V; 干燥气流速15 L·min^-1; 碰撞电压6~10 V; 一级质谱图谱采用傅里叶变换高分辨全扫描(FT), 扫描范围m/z 100~1 200; 检测分辨率30 000; 二级质谱数据采用数据依赖型扫描(DDS)。

质谱数据分析 基于数据库、文献记载的小儿感冒口服液10味药的化学成分及多级碎片信息, 建立小儿感冒口服液化学成分数据库。采用高分辨数据处理软件Xcalibur Qual Browser, 根据各成分的原子组成计算精确相对分子质量, 在小儿感冒口服液化学成分数据库中搜索化合物。参照对照品的保留时间, 筛选分子质量数误差δ < 5 ppm的化学成分, 结合二、三级质谱裂解规律及相关文献报道, 推测其可能的化学成分信息。

BitterX数据库预测 将小儿感冒口服液无糖中间体液质解析所得化合物的CAS号、MOL文件或结构式上传至BitterX数据库中, 预测化合物与各苦味受体结合的概率^[4], 定义结合概率大于70%的化合物为小儿感冒口服液的潜在苦味化学成分。

结果

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1 理论滋味特征量化描述

小儿感冒口服液药物组成、滋味描述及其赋值、剂量及其权重见表 2。

小儿感冒口服液苦味的最终得分为0.5 × 0.083 5 + 0.25 × 0.083 5 + 1 × 0.083 5 + 0.5 × 0.138 5 + 1 × 0.083 5 + 0.25 × 0.083 5 + 1 × 0.083 5 + 0.5 × 0.083 5 = 0.45、酸味0.07分、淡味0.14分、甘味0.21分、辛味0.14分、咸味0分。计算得出苦味在所有滋味中占比最高, 达44.55%, 因此, 苦味是小儿感冒口服液中需要重点关注的滋味。

2 小儿感冒口服液化学成分的结构鉴定

采用上述色谱、质谱条件, 分别获取正、负离子模式下的小儿感冒口服液无糖中间体数据, 正、负离子下的总离子流图(total ion chromatogram, TIC) 见图 1, 峰号与表 3中编号一致。最终共鉴定化学成分57个, 其中黄酮类22个、生物碱类3个、苯丙素类9个、有机酸类8个、环烯醚萜类3个、嘌呤类2个、氨基酸类4个、酚类3个、木脂素类2个、吲哚类1个、蒽醌类1个, 相关质谱信息见表 3。

2.1 黄酮类化合物的结构鉴定

本研究共检测到小儿感冒口服液无糖中间体中22个黄酮类成分, 主要来自复方中的菊花、地黄、板蓝根和连翘。黄酮类化合物是以2-苯基色原酮为基本骨架而衍生的化合物, 现在泛指3个碳原子连接2个苯环形成的一类化合物。其中的黄酮苷类成分在二级质谱碎片信息中常可见脱去不同类型糖基的苷元碎片离子, 黄酮苷元成分的二级碎片质谱图中, 常见裂解H₂O、CH₃、CO、CO₂等分子后产生的不同的碎片离子信息。

小儿感冒口服液无糖中间体中主要推测得到以木犀草素为代表的黄酮类成分及木犀草苷为代表的黄酮苷类成分。其中化合物33在负离子模式下一级质谱中得到准分子离子峰m/z 447.091 00 [M-H]^-, 预测分子式可能为C₂₁H₂₀O₁₁, 误差为-2.657, 与木犀草苷一致。进一步, 在其二级质谱中发现碎片离子为m/z 285.034 79, 可推断为失去一分子葡萄糖的木犀草素苷元[M-H-C₆H₁₀O₅]^-。对比木犀草苷对照品的二级质谱碎片信息, 发现两者的保留时间及裂解规律一致, 推测化合物33为木犀草苷, 其裂解过程见图 2A。化合物26、27、29~32、35、43、51、55在二级质谱中均存在失去糖基的碎片离子^[5-9]。

化合物49在负离子模式下一级质谱中得到准分子离子峰m/z 285.039 55 [M-H]^-, 预测分子式可能为C₁₅H₁₀O₆, 误差为-3.197, 与木犀草素一致。进一步, 在其二级质谱中发现碎片离子m/z 266.982 57、257.131 77、216.777 53、198.997 44, 推测碎片离子m/z 266.982 57是由准分子离子峰失去一分子水形成的[M-H-H₂O]^-, 碎片离子m/z 257.131 77是由准分子离子峰失去一分子CO而形成[M-H-CO]^-, 碎片离子m/z 216.777 53是由A环破裂丢失C₃O₂碎片而形成[M-H-C₃O₂]^-, 在此基础上失去一分子水得到碎片离子m/z 198.997 44 [M-H-C₃O₂-H₂O]^-。结合文献报道的质谱行为^[10], 推测化合物49为木犀草素。化合物34、50、52、53同样存在脱去H₂O、CH₃、CO等分子的情况^[11-13]。

2.2 苯丙素类化合物的结构鉴定

本研究共检测到小儿感冒口服液无糖中间体中9个苯丙素类成分^[14], 主要来自复方中的地黄、菊花和连翘。苯丙素是天然存在的一类苯环与三个直链碳连接(C₆-C₃基团) 构成的化合物。一般具有苯酚结构, 是酚性物质。包括苯丙烯、苯丙醇、苯丙酸、香豆素及木脂素类等。

小儿感冒口服液无糖中间体中主要推测得到以绿原酸、阿魏酸为代表的苯丙酸类成分, 以及以连翘脂苷A为代表的苯乙醇苷类。其中, 化合物39在负离子模式下一级质谱中得到准分子离子峰m/z 353.086 18 [M-H]^-, 预测分子式可能为C₁₆H₁₈O₉, 误差为-4.603, 与绿原酸一致。进一步, 在其二级质谱中发现碎片离子m/z 191.084 17、178.882 42、135.039 72, 推测碎片离子m/z 191.084 17为准分子离子峰脱去C₉H₆O₃形成[M-H-C₉H₆O₃]^-, 碎片离子m/z 178.882 42为准分子离子峰脱去C₇H₁₀O₅而形成[M-H-C₇H₁₀O₅]^-, 在此基础上脱去一分子CO₂形成135.039 72 [M-H-C₇H₁₀O₅-CO₂]^-。在其三级质谱中发现碎片离子m/z 172.951 84、110.913 15, 推测分别为[M-H-C₉H₆O₃-H₂O]^-和[M-H-C₉H₆O₃-2H₂O-CO₂]^-。对比绿原酸对照品的二、三级质谱碎片信息, 发现两者的保留时间及裂解规律一致, 推测化合物39为绿原酸, 其裂解过程见图 2B, 质谱信息见图 3。通过与标准品及文献报道的质谱行为对比, 化合物28同样出现了脱去C₉H₆O₃基团的行为^[15], 推测为3, 5-二-O-咖啡酰奎宁酸, 即异绿原酸A。

化合物25在负离子模式下一级质谱中得到准分子离子峰m/z 623.197 20 [M-H]^-, 预测分子式可能为C₂₉H₃₆O₁₅, 误差为-1.514, 与连翘脂苷A一致。进一步, 在其二级质谱中发现碎片离子m/z 461.246 40、443.261 54、179.055 18, 推测碎片离子m/z 461.246 40为准分子离子峰先脱去1分子鼠李糖, 形成碎片离子[M-H-C₆H₁₀O₅]^-, 在此基础上脱去一分子水形成碎片离子m/z 443.261 54 [M-H-C₆H₁₀O₅-H₂O]^-, 进一步脱去C₁₃H₁₂O₆形成碎片离子m/z 179.055 18 [M-H-C₆H₁₀O₅-H₂O-C₁₃H₁₂O₆]^-。对比连翘脂苷A对照品的二级质谱碎片信息, 发现两者的保留时间及裂解规律一致, 推测化合物25为连翘脂苷A。

2.3 有机酸类化合物的结构鉴定

本研究共检测到小儿感冒口服液无糖中间体中8个有机酸类成分, 负离子模式下的响应效果优于正离子模式。有机酸类化合物多存在羰基、酚羟基等酸性基团, 常见小分子有机酸类多通过脱去CO₂、H₂O、HCOOH等形成对应的二级碎片离子。

化合物4在负离子模式下一级质谱中得到准分子离子峰m/z 191.018 81 [M-H]^-, 预测分子式可能为C₆H₈O₇, 误差为-4.794, 与柠檬酸一致。进一步, 在其二级质谱中发现碎片离子m/z 172.966 13、128.796 78、110.808 53, 推测准分子离子峰先脱去一分子水形成m/z 172.966 13 [M-H-H₂O]^-, 在此基础上脱去一分子CO₂形成m/z 128.796 78 [M-H-H₂O-CO₂]^-, 接着又脱去一分子水形成m/z 110.808 53 [M-H-H₂O-CO₂-H₂O]^-, 结合文献报道的质谱行为^[9], 推测化合物4为柠檬酸, 其裂解过程见图 2C。同时, 化合物2、9、16、18、57也存在脱去CO₂、H₂O等形成对应的二级碎片离子。

3 小儿感冒口服液潜在苦味关键质量属性辨识

化学成分与苦味受体的结合概率如图 4所示, 化合物编号与表 3中编号一致。预测得到33种化合物与至少一种苦味受体结合概率大于70%, 其中, 地骨皮甲素能与5种苦味受体结合, 蒙花苷能与4种苦味受体结合, 毛蕊花糖苷、木通苯乙醇苷A、连翘脂苷A、紫云英苷、异毛蕊花糖、表松酯素-4′-O-β-D-葡萄糖苷、香叶木苷、汉黄芩素、大黄酸能与3种苦味受体结合; 33种化合物中共有黄酮类17种, 生物碱类2种, 苯丙素类6种(包括苯乙醇苷类5种), 有机酸类2种, 氨基酸类(苦味肽的组成部分) 1种, 木脂素类1种(木脂素糖苷), 蒽醌类1种, 吲哚类1种, 酚类2种。在所得13种苦味受体中, T2R14与23种化合物、T2R39与24种化合物的结合率大于70%。

讨论

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本研究首先基于中国药典对于药物滋味的记载, 将滋味描述语言按照一定规则转换成滋味量化值, 结合剂量权重计算药物各滋味分值, 表征了苦味的严重程度, 对其苦度进行初步定量评价, 对苦度定量评价及口感改善方式的选择等相关研究具有一定指导意义。

进一步, 建立了一种UHPLC-LTQ-Orbitrap MSⁿ结合BitterX数据库的潜在苦味关键质量属性辨识方法, 对小儿感冒口服液无糖中间体中化学成分进行了解析, 并最终获取了33种潜在苦味化学成分, 与文献^[16]报道苦味化合物多呈生物碱、黄酮类、苷类及苦味肽等一致, 预测得到的化合物中有26种在此范围内, 表明此方法可有效筛选苦味化合物, 并且筛选得到的地骨皮甲素(生物碱类)、蒙花苷(黄酮类) 极有可能为小儿感冒口服液关键的苦味物质基础。此外, 与苦味受体T2R14、T2R39结合概率大于70%的化合物数量最多。本研究以简便、快速的方法对苦味关键质量属性进行高通量筛选, 为其口感改善的必要性提供了依据, 在此基础上可进一步将潜在苦味关键质量属性抽提以进行验证。该结果同时为明确小儿感冒口服液药效物质基础、提升质量控制水平、阐明口感提升的机制研究等提供参考。

作者贡献: 王晓萌、陆影负责实验研究、分析数据和文章撰写; 胡小艳、郭新雨、韩燕雨、王静、张晓梦负责实验研究; 马金辰、李明爽、戴幸星、姚璐负责思路指导; 吴志生研究员、杜菁副研究员、李楠副研究员负责思路指导和对文章的知识性内容进行审阅并提供研究经费。

利益冲突: 所有作者均声明没有利益冲突。

基金

收起

国家重点研发计划项目(2022YFC3501902)
国家优秀青年科学基金项目(82022073)
国家自然科学基金项目(82274110)
中央高校基本科研业务费北京中医药大学揭榜挂帅项目(2022-JYB-JBZR-018)
中央高校基本科研业务费北京中医药大学揭榜挂帅项目(2022-JYB-JBZR-019)

参考文献

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文献

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参考文献引证文献

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2023年第58卷第10期

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doi: 10.16438/j.0513-4870.2023-0121

接收时间：2023-02-07
首发时间：2025-11-21
出版时间：2023-10-12

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出版历史

收稿日期：2023-02-07
修回日期：2023-06-06

基金

国家重点研发计划项目(2022YFC3501902)

国家优秀青年科学基金项目(82022073)

国家自然科学基金项目(82274110)

中央高校基本科研业务费北京中医药大学揭榜挂帅项目(2022-JYB-JBZR-018)

中央高校基本科研业务费北京中医药大学揭榜挂帅项目(2022-JYB-JBZR-019)

作者信息

1.北京中医药大学中药学院, 北京 102488

2.中药制药与新药开发教育部工程研究中心, 北京 102488

3.北京同仁堂科技发展股份有限公司, 北京 100079

通讯作者:

*杜菁, Tel: 86-10-87632888, E-mail: daturae@163.com;

吴志生, Tel: 86-10-53912101, E-mail: wzs@bucm.edu.cn

参考文献

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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

No.	Time/min	Acetonitrile/%
1	0	5
2	0	5
3	2	5
4	3	20
5	12	22
6	14	46
7	26	100
8	28	100
9	29	5
10	30	5

No.

Time/min

Acetonitrile/%

100

Name	Flavor description	Flavor weight	Dose/g	Dose weight
Pogostemonis Herba	Slightly bitter	Bitter 0.5	85	0.083 5
Chrysanthemi Flos	Sweet, slightly bitter	Sweet 1, bitter 0.25	85	0.083 5
Forsythiae Fructus	Bitter	Bitter 1	85	0.083 5
Isatidis Folium	Slightly sour, bitter, astringent	Sour 0.5, bitter 0.5, astringent 0.25	141	0.138 5
Isatidis Radix	Slightly sweet, then bitter and astringent	Sweet 0.5, bitter 1	85	0.083 5
Rehmanniae Radix	Slightly sweet, slightly bitter	Sweet 0.5, bitter 0.25	85	0.083 5
Lycii Cortex	Slightly sweet and then bitter	Sweet 0.5, bitter 1	85	0.083 5
Cynanchi Atrati Radix et Rhizoma	Slightly bitter	Bitter 0.5	85	0.083 5
Menthae Haplocalycis Herba	Pungent, cool	Pungent 1	141	0.138 5
Gypsum Fibrosum	Light	Light 1	141	0.138 5

Name

Flavor description

Flavor weight

Dose/g

Dose weight

Pogostemonis Herba

Slightly bitter

Bitter 0.5

0.083 5

Chrysanthemi Flos

Sweet, slightly bitter

Sweet 1, bitter 0.25

0.083 5

Forsythiae Fructus

Bitter

Bitter 1

0.083 5

Isatidis Folium

Slightly sour, bitter, astringent

Sour 0.5, bitter 0.5, astringent 0.25

141

0.138 5

Isatidis Radix

Slightly sweet, then bitter and astringent

Sweet 0.5, bitter 1

0.083 5

Rehmanniae Radix

Slightly sweet, slightly bitter

Sweet 0.5, bitter 0.25

0.083 5

Lycii Cortex

Slightly sweet and then bitter

Sweet 0.5, bitter 1

0.083 5

Cynanchi Atrati Radix et Rhizoma

Slightly bitter

Bitter 0.5

0.083 5

Menthae Haplocalycis Herba

Pungent, cool

Pungent 1

141

0.138 5

Gypsum Fibrosum

Light

Light 1

141

0.138 5

No.	t_R/min	Name	Formula	Adduct	Found mass	Error/10^-6	MS²	MS³	Class
1	0.79	γ-Aminobutyric acid	C₄H₉NO₂	+H	104.070 51	-0.914	86.858 64, 59.721 45		Amino acid
2	0.80	Malic acid	C₄H₆O₅	-H	133.013 75	-3.733	114.872 16, 86.687 93, 70.717 41		Organic acid
3	0.80	Quinic acid	C₇H₁₂O₆	-H	191.055 21	-4.718	172.915 51, 126.803 86, 108.820 54, 84.758 36	108.772 55, 98.793 11, 84.831 68, 80.813 14	Organic acid
4	1.01	Citric acid	C₆H₈O₇	-H	191.018 81	-4.794	172.966 13, 128.796 78, 110.808 53		Organic acid
5	1.02	Valine	C₅H₁₁NO₂	+H	118.085 94	-2.669	101.893 60		Amino acid
6	1.02	Guanine	C₅H₅N₅O	+H	152.056 37	-2.081	134.782 88, 109.906 75, 108.758 09, 106.717 73		Purine
7	1.05	Epigoitrin	C₅H₇NOS	+H	130.031 74	-2.854	83.734 13, 69.827 96		Alkaloid
8	1.40	Guanosine	C₁₀H₁₃N₅O₅	-H	282.083 22	-4.154	149.936 28	150.069 05, 132.777 11, 125.857 57, 106.786 71, 81.847 73	Purine
9	1.40	Vanillic acid	C₈H₈O₄	-H	167.034 19	-4.742	151.825 61, 122.809 74, 107.803 42	122.916 06, 107.842 30	Organic acid
10	1.48	Leucine	C₆H₁₃NO₂	+H	132.101 62	-2.159	131.950 50, 85.799 97	85.981 98	Amino acid
11	1.65	Indole-3-carboxaldehyde	C₉H₇NO	+H	146.059 91	-0.893	117.870 03		Indole
12	2.07	Phenprobamate	C₉H₁₁NO₂	+H	166.086 15	-0.633	148.925 51, 119.902 73		Amino acid
13	2.21	Ferulic acid	C₁₀H₁₀O₄	-H	193.049 99	-2.283	177.936 98, 148.949 33, 133.907 14		Phenylpropanoid
14	3.09	Rosmarinic acid	C₁₈H₁₆O₈	-H	359.075 10	-5.962	196.960 30		Phenol
15	3.39	Loganic acid	C₁₆H₂₄O₁₀	-H	375.127 11	-6.825	168.979 71, 150.969 97, 124.906 36		Iridoid
16	3.70	Caffeic acid	C₉H₈O₄	-H	179.034 21	-4.312	134.942 79	134.908 52, 106.541 18, 90.754 52	Organic acid
17	4.28	Forsythoside E	C₂₀H₂₀O₁₂	+Na	485.161 87	4.927	339.140 35		Phenylpropanoid
18	4.44	Salicylic acid	C₇H₆O₃	-H	137.023 91	-3.703	92.875 89		Organic acid
19	4.44	Protocatechualdehyde	C₇H₆O₃	-H	137.023 91	-3.703	118.808 70, 108.883 68		Phenol
20	4.47	Decaffeoyl verbascoside	C₂₀H₃₀O₁₂	-H	461.164 40	-4.444	315.122 62, 297.108 40, 160.827 48, 134.989 01		Phenylpropanoid
21	4.56	Kukoamine A	C₂₈H₄₂N₄O₆	+H	531.316 83	-3.723	367.386 96, 164.883 09		Alkaloid
22	5.13	Verbascoside	C₂₉H₃₆O₁₅	-H	623.198 24	0.155	461.255 13, 315.252 75	315.172 42, 134.979 13	Phenylpropanoid
23	5.29	Geniposide	C₁₇H₂₄O₁₀	-H	387.129 73	0.155	225.108 40		Iridoid
24	5.71	Calceolarioside A	C₂₃H₂₆O₁₁	-H	477.137 97	-4.747	315.074 10, 297.060 55, 178.873 96, 160.921 08, 134.859 53		Phenylpropanoid
25	5.74	Forsythoside A*	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.246 40, 443.261 54, 179.055 18		Phenylpropanoid
26	5.80	Naringenin-7-O-β-D-glucopyranoside	C₂₁H₂₂O₁₀	-H	433.112 88	-2.632	271.139 80, 150.941 25		Flavonoid
27	6.04	Hesperidin	C₂₈H₃₄O₁₅	-H	609.180 11	-3.912	447.189 03, 429.292 91, 301.037 48, 179.064 33	286.095 52, 242.025 45, 150.921 17, 124.916 51	Flavonoid
28	6.10	3, 5-Di-O-caffeoylquinic acid*	C₂₅H₂₄O₁₂	-H	515.118 84	-1.280	353.085 94, 190.971 63, 178.883 30	190.899 60, 178.889 98, 172.938 14, 154.892 46, 134.891 28, 110.910 83	Phenylpropanoid
29	6.10	Isoquercitrin	C₂₁H₂₀O₁₂	-H	463.085 66	-5.483	299.956 91		Flavonoid
30	6.20	Saponin	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	431.173 83, 341.139 59, 311.172 55		Flavonoid
31	6.20	Luteolin-7-O-rutinoside	C₂₇H₃₀O₁₅	-H	593.149 54	-2.787	285.009 58		Flavonoid
32	6.28	Astragalin	C₂₁H₂₀O₁₁	-H	447.091 19	-4.685	284.979 00		Flavonoid
33	6.38	Cynaroside*	C₂₁H₂₀O₁₁	-H	447.091 00	-2.657	285.034 79		Flavonoid
34	6.44	Kaempferol	C₁₅H₁₀O₆	+H	287.054 35	-2.315	259.078 52, 230.931 98, 153.859 50		Flavonoid
35	6.58	Kaempferol-3-O-β-D-glucoside	C₂₁H₂₀O₁₁	+H	449.106 11	-3.847	162.894 29, 287.039 98		Flavonoid
36	6.65	Isoacteoside	C₂₉H₃₆O₁₅	-H	623.197 20	-1.514	461.244 20, 315.152 65		Phenylpropanoid
37	6.80	Eriodictyol	C₁₅H₁₂O₆	-H	287.054 78	-4.638	150.803 47, 134.835 27	108.807 39, 106.844 30, 82.934 88, 64.732 49	Flavonoid
38	6.92	Isoscoparin	C₂₂H₂₂O₁₁	-H	461.108 28	-1.420	371.088 81, 341.148 93		Flavonoid
39	7.02	Chlorogenic acid*	C₁₆H₁₈O₉	-H	353.086 18	-4.603	191.084 17, 178.882 42, 135.039 72	190.984 24, 172.951 84, 126.857 38, 110.913 15	Phenylpropanoid
40	7.11	Epipinoresinol-4′-O-β-D-glucoside	C₂₆H₃₂O₁₁	-H	519.185 49	-3.265	357.124 69, 338.999 88		Lignan
41	7.16	Isovitexin	C₂₁H₂₀O₁₀	-H	431.097 08	-2.992	341.109 07, 311.076 57		Flavonoid
42	7.34	Carvacrol	C₁₀H₁₄O	+H	149.096 10	-7.300	148.980 58		Phenol
43	7.40	Diosmin	C₂₈H₃₂O₁₅	-H	607.163 82	-4.485	299.001 90		Flavonoid
44	7.63	4-Hydroxyphenylacetic acid	C₈H₈O₃	-H	151.039 35	-4.750	108.920 41		Organic acid
45	8.16	Chrysoeriol	C₁₆H₁₂O₆	+H	301.070 04	-2.075	301.156 56		Flavonoid
46	8.22	Diosmetin	C₁₆H₁₂O₆	+H	301.069 89	-2.573	301.117 74		Flavonoid
47	11.38	Forsythin*	C₂₇H₃₄O₁₁	+Na	557.199 65	-3.748	395.307 01, 309.168 09, 184.855 62		Lignan
48	11.49	Martynoside	C₃₁H₄₀O₁₅	-H	651.226 32	-4.796	475.233 58		Iridoid
49	13.12	Luteolin	C₁₅H₁₀O₆	-H	285.039 55	-3.197	266.982 57, 257.131 77, 216.777 53, 198.997 44		Flavonoid
50	13.46	Acacetin	C₁₆H₁₂O₅	+H	285.075 16	-2.070	270.046 72, 285.130 77		Flavonoid
51	13.46	Linarin	C₂₈H₃₂O₁₄	+H	593.184 51	-3.324	285.018 74		Flavonoid
52	13.64	Wogonin	C₁₆H₁₂O₅	-H	283.059 84	-4.793	268.014 53, 239.158 97		Flavonoid
53	13.75	Acacetin	C₁₆H₁₂O₅	-H	283.059 84	-4.797	267.957 28		Flavonoid
54	14.85	Rhein	C₁₅H₈O₆	-H	283.024 57	-0.852	239.175 90, 182.536 04		Anthraquinones
55	15.05	Tilianin	C₂₂H₂₂O₁₀	+H	447.128 78	0.462	285.057 50		Flavonoid
56	17.84	Indirubin	C₁₆H₁₀N₂O₂	+H	263.081 18	-1.232			Alkaloid
57	19.61	Linolenic acid	C₁₈H₃₀O₂	+H	279.231 63	-4.740	261.166 63, 243.185 55, 94.845 15	243.132 89, 173.070 57, 134.859 38, 92.830 72	Organic acid

No.

t_R/min

Name

Formula

Adduct

Found mass

Error/10^-6

MS²

MS³

Class

0.79

γ-Aminobutyric acid

C₄H₉NO₂

104.070 51

-0.914

86.858 64, 59.721 45

Amino acid

0.80

Malic acid

C₄H₆O₅

-H

133.013 75

-3.733

114.872 16, 86.687 93, 70.717 41

Organic acid

0.80

Quinic acid

C₇H₁₂O₆

-H

191.055 21

-4.718

172.915 51, 126.803 86, 108.820 54, 84.758 36

108.772 55, 98.793 11, 84.831 68, 80.813 14

Organic acid

1.01

Citric acid

C₆H₈O₇

-H

191.018 81

-4.794

172.966 13, 128.796 78, 110.808 53

Organic acid

1.02

Valine

C₅H₁₁NO₂

118.085 94

-2.669

101.893 60

Amino acid

1.02

Guanine

C₅H₅N₅O

152.056 37

-2.081

134.782 88, 109.906 75, 108.758 09, 106.717 73

Purine

1.05

Epigoitrin

C₅H₇NOS

130.031 74

-2.854

83.734 13, 69.827 96

Alkaloid

1.40

Guanosine

C₁₀H₁₃N₅O₅

-H

282.083 22

-4.154

149.936 28

150.069 05, 132.777 11, 125.857 57, 106.786 71, 81.847 73

Purine

1.40

Vanillic acid

C₈H₈O₄

-H

167.034 19

-4.742

151.825 61, 122.809 74, 107.803 42

122.916 06, 107.842 30

Organic acid

1.48

Leucine

C₆H₁₃NO₂

132.101 62

-2.159

131.950 50, 85.799 97

85.981 98

Amino acid

1.65

Indole-3-carboxaldehyde

C₉H₇NO

146.059 91

-0.893

117.870 03

Indole

2.07

Phenprobamate

C₉H₁₁NO₂

166.086 15

-0.633

148.925 51, 119.902 73

Amino acid

2.21

Ferulic acid

C₁₀H₁₀O₄

-H

193.049 99

-2.283

177.936 98, 148.949 33, 133.907 14

Phenylpropanoid

3.09

Rosmarinic acid

C₁₈H₁₆O₈

-H

359.075 10

-5.962

196.960 30

Phenol

3.39

Loganic acid

C₁₆H₂₄O₁₀

-H

375.127 11

-6.825

168.979 71, 150.969 97, 124.906 36

Iridoid

3.70

Caffeic acid

C₉H₈O₄

-H

179.034 21

-4.312

134.942 79

134.908 52, 106.541 18, 90.754 52

Organic acid

4.28

Forsythoside E

C₂₀H₂₀O₁₂

+Na

485.161 87

4.927

339.140 35

Phenylpropanoid

4.44

Salicylic acid

C₇H₆O₃

-H

137.023 91

-3.703

92.875 89

Organic acid

4.44

Protocatechualdehyde

C₇H₆O₃

-H

137.023 91

-3.703

118.808 70, 108.883 68

Phenol

4.47

Decaffeoyl verbascoside

C₂₀H₃₀O₁₂

-H

461.164 40

-4.444

315.122 62, 297.108 40, 160.827 48, 134.989 01

Phenylpropanoid

4.56

Kukoamine A

C₂₈H₄₂N₄O₆

531.316 83

-3.723

367.386 96, 164.883 09

Alkaloid

5.13

Verbascoside

C₂₉H₃₆O₁₅

-H

623.198 24

0.155

461.255 13, 315.252 75

315.172 42, 134.979 13

Phenylpropanoid

5.29

Geniposide

C₁₇H₂₄O₁₀

-H

387.129 73

0.155

225.108 40

Iridoid

5.71

Calceolarioside A

C₂₃H₂₆O₁₁

-H

477.137 97

-4.747

315.074 10, 297.060 55, 178.873 96, 160.921 08, 134.859 53

Phenylpropanoid

5.74

Forsythoside A*

C₂₉H₃₆O₁₅

-H

623.197 20

-1.514

461.246 40, 443.261 54, 179.055 18

Phenylpropanoid

5.80

Naringenin-7-O-β-D-glucopyranoside

C₂₁H₂₂O₁₀

-H

433.112 88

-2.632

271.139 80, 150.941 25

Flavonoid

6.04

Hesperidin

C₂₈H₃₄O₁₅

-H

609.180 11

-3.912

447.189 03, 429.292 91, 301.037 48, 179.064 33

286.095 52, 242.025 45, 150.921 17, 124.916 51

Flavonoid

6.10

3, 5-Di-O-caffeoylquinic acid*

C₂₅H₂₄O₁₂

-H

515.118 84

-1.280

353.085 94, 190.971 63, 178.883 30

190.899 60, 178.889 98, 172.938 14, 154.892 46, 134.891 28, 110.910 83

Phenylpropanoid

6.10

Isoquercitrin

C₂₁H₂₀O₁₂

-H

463.085 66

-5.483

299.956 91

Flavonoid

6.20

Saponin

C₂₇H₃₀O₁₅

-H

593.149 54

-2.787

431.173 83, 341.139 59, 311.172 55

Flavonoid

6.20

Luteolin-7-O-rutinoside

C₂₇H₃₀O₁₅

-H

593.149 54

-2.787

285.009 58

Flavonoid

6.28

Astragalin

C₂₁H₂₀O₁₁

-H

447.091 19

-4.685

284.979 00

Flavonoid

6.38

Cynaroside*

C₂₁H₂₀O₁₁

-H

447.091 00

-2.657

285.034 79

Flavonoid

6.44

Kaempferol

C₁₅H₁₀O₆

287.054 35

-2.315

259.078 52, 230.931 98, 153.859 50

Flavonoid

6.58

Kaempferol-3-O-β-D-glucoside

C₂₁H₂₀O₁₁

449.106 11

-3.847

162.894 29, 287.039 98

Flavonoid

6.65

Isoacteoside

C₂₉H₃₆O₁₅

-H

623.197 20

-1.514

461.244 20, 315.152 65

Phenylpropanoid

6.80

Eriodictyol

C₁₅H₁₂O₆

-H

287.054 78

-4.638

150.803 47, 134.835 27

108.807 39, 106.844 30, 82.934 88, 64.732 49

Flavonoid

6.92

Isoscoparin

C₂₂H₂₂O₁₁

-H

461.108 28

-1.420

371.088 81, 341.148 93

Flavonoid

7.02

Chlorogenic acid*

C₁₆H₁₈O₉

-H

353.086 18

-4.603

191.084 17, 178.882 42, 135.039 72

190.984 24, 172.951 84, 126.857 38, 110.913 15

Phenylpropanoid

7.11

Epipinoresinol-4′-O-β-D-glucoside

C₂₆H₃₂O₁₁

-H

519.185 49

-3.265

357.124 69, 338.999 88

Lignan

7.16

Isovitexin

C₂₁H₂₀O₁₀

-H

431.097 08

-2.992

341.109 07, 311.076 57

Flavonoid

7.34

Carvacrol

C₁₀H₁₄O

149.096 10

-7.300

148.980 58

Phenol

7.40

Diosmin

C₂₈H₃₂O₁₅

-H

607.163 82

-4.485

299.001 90

Flavonoid

7.63

4-Hydroxyphenylacetic acid

C₈H₈O₃

-H

151.039 35

-4.750

108.920 41

Organic acid

8.16

Chrysoeriol

C₁₆H₁₂O₆

301.070 04

-2.075

301.156 56

Flavonoid

8.22

Diosmetin

C₁₆H₁₂O₆

301.069 89

-2.573

301.117 74

Flavonoid

11.38

Forsythin*

C₂₇H₃₄O₁₁

+Na

557.199 65

-3.748

395.307 01, 309.168 09, 184.855 62

Lignan

11.49

Martynoside

C₃₁H₄₀O₁₅

-H

651.226 32

-4.796

475.233 58

Iridoid

13.12

Luteolin

C₁₅H₁₀O₆

-H

285.039 55

-3.197

266.982 57, 257.131 77, 216.777 53, 198.997 44

Flavonoid

13.46

Acacetin

C₁₆H₁₂O₅

285.075 16

-2.070

270.046 72, 285.130 77

Flavonoid

13.46

Linarin

C₂₈H₃₂O₁₄

593.184 51

-3.324

285.018 74

Flavonoid

13.64

Wogonin

C₁₆H₁₂O₅

-H

283.059 84

-4.793

268.014 53, 239.158 97

Flavonoid

13.75

Acacetin

C₁₆H₁₂O₅

-H

283.059 84

-4.797

267.957 28

Flavonoid

14.85

Rhein

C₁₅H₈O₆

-H

283.024 57

-0.852

239.175 90, 182.536 04

Anthraquinones

15.05

Tilianin

C₂₂H₂₂O₁₀

447.128 78

0.462

285.057 50

Flavonoid

17.84

Indirubin

C₁₆H₁₀N₂O₂

263.081 18

-1.232

Alkaloid

19.61

Linolenic acid

C₁₈H₃₀O₂

279.231 63

-4.740

261.166 63, 243.185 55, 94.845 15

243.132 89, 173.070 57, 134.859 38, 92.830 72

Organic acid