Paclitaxel (Taxol) CAS 33069-62-4 Assay (HPLC) 97.0~102.0%

Paclitaxel
C47H51NO14 853.91
Benzenepropanoic acid, -(benzoylamino)--hydroxy-, 6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b -dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester, [2aR-[2a,4,4a,6,9(R*,S*),11,12,12a,12b]]-.
(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-1,2a,3,4,4a,6,9,10,11,12,12a,12b-Dodecahydro-4,6, 9,11,12,12b-hexahydroxy-4a,8,13,13-tetramethyl-7,11-methano-5H-cyclodeca[3,4]-benz[1,2-b]oxet-5-one 6, 12b-diacetate, 12-benzoate, 9-ester me (2R,3S) -N-benzoyl-3-phenylisoserine [33069-62-4].
Aia ʻo Paclitaxel ma lalo o 97.0 pākēneka a ʻaʻole ʻoi aku ma mua o 102.0 pākēneka o C47H51NO14, i helu ʻia ma ke kumu anhydrous, solvent-free.
[E akahele-He cytotoxic ka Paclitaxel.Pono e mālama nui i ka pale ʻana i nā ʻāpana o Paclitaxel a hōʻike i ka ʻili iā ia.]
Hoʻopaʻa a me ka mālama ʻana-E mālama i loko o nā pahu paʻa māmā, a mālama ʻia ma ka lumi wela.
Lepili-E hōʻike ana ka lepili i ke ʻano o ka hana i hoʻohana ʻia no ka hana ʻana i ka mea a me ka hoʻāʻo ʻana i nā pūhui pili e hoʻokō ai ka mea.
Nā kūlana hōʻike USP <11>-
USP Endotoxin RS
USP Paclitaxel RS Kaomi e nānā i ke kūkulu
USP Paclitaxel Huina Pili A RS
ʻO Cephalomannine.
USP Paclitaxel Puhui Pili B RS
10-Deacetyl-7-Epipaclitaxel.
USP Paclitaxel Huihuʻi Hoʻomaʻemaʻe RS
ʻO ka hui ʻana o Paclitaxel a me nā mea pili e pili ana: propyl analog, cephalomannine, sec-butyl analog, n-butyl analog, benzyl analog, baccatin VI, pentyl analog, a me 7-epipaclitaxel.
ʻike-
A: Infrared Absorption <197K>.
B: ʻO ka manawa paʻa o ka piko nui ma ka chromatogram o ka hoʻomākaukau Assay e pili ana i kēlā i loko o ka chromatogram o ka hoʻomākaukau maʻamau, e like me ka loaʻa ʻana ma ka Assay.
ʻO ka hoʻololi kikoʻī 781S: ma waena o 49.0 a me 55.0 ma 20, helu ʻia ma ke kumu anhydrous, solvent-free.
Hoʻoholo hoʻāʻo: 10 mg no ka mL, i ka methanol.
Nā ho'āʻo helu microbial <61> a me nā ho'āʻo no nā microorganism i kuhikuhi ʻia <62>-ʻAʻole ʻoi aku ka nui o ka helu microbial aerobic ma mua o 100 cfu no ka g.Hoʻokō ia i nā koi o nā hoʻokolohua no ka loaʻa ʻole o Staphylococcus aureus, Pseudomonas aeruginosa, ʻano Salmonella, a me Escherichia coli.
ʻO nā endotoxins bacterial 85-ʻAʻole i ʻoi aku ma mua o 0.4 USP Endotoxin Unit no ka mg o paclitaxel.
ʻO ka wai, ʻano Ic <921>: ʻaʻole ʻoi aku ma mua o 4.0%.
Ke koena ma ka ʻā ʻana <281>: ʻaʻole ʻoi aku ma mua o 0.2%.
Nā metala kaumaha, Keʻano II <231>: 0.002%.
Nā Puhui Pili-
hoʻāʻo 1 (no nā mea i kapa ʻia he kaʻawale mai nā kumu kūlohelohe)-Inā e hoʻokō ka mea i kēia hoʻāʻo, hōʻike ka lepili i ka hui ʻana i nā pūhui pili pili i ka USP Test 1.
Diluent-Hoʻomākaukau e like me ka kuhikuhi ʻana i ka Assay.
Hoʻonā A-E hoʻomākaukau i ka acetonitrile kānana a hoʻopau ʻia.
Pane B-E hoʻomākaukau i ka wai kānana a hoʻopau ʻia.
ʻĀpana paʻalima-E hoʻohana i nā hui like ʻole o ka Solution A a me ka Solution B e like me ke kuhikuhi ʻana no ka ʻōnaehana Chromatographic.Hana i nā hoʻololi inā pono (e nānā i ka System Suitability ma lalo o Chromatography 621).
ʻO ka hoʻonā kūpono o ka ʻōnaehana-Hoʻoheheʻe i ka nui o ka USP Paclitaxel Related Compound A RS a me USP Paclitaxel Related Compound B RS i loko o ka methanol e loaʻa ai kahi hopena i ʻike ʻia ma kahi o 10 µg o kēlā me kēia mL.E hoʻololi i 5.0 mL o kēia hāʻina i loko o kahi pahu volumetric 50-mL, e hoʻoheheʻe me ka Diluent i ka nui, a hui pū.
ʻO ka hoʻonā maʻamau-Dissolve, me ke kōkua o ka sonication, kahi helu pono i kaupaona ʻia o USP Paclitaxel RS ma Diluent, a dilute quantitatively, a me stepwise inā pono, me ka Diluent e loaʻa i kahi hopena i ʻike ʻia ma kahi o 5 µg no mL.
Hoʻoholo hoʻāʻo-E hoʻohana i ka hoʻomākaukau Assay.
Pūnaehana Chromatographic (e nānā i ka Chromatography <621>)-Ua lako ka chromatograph wai me kahi mea ʻike 227-nm a me kahi kolamu 4.6-mm × 25-cm i loaʻa iā 5-µm packing L43.ʻO ka nui o ke kahe ʻana he 2.6 mL i kēlā me kēia minuke.Mālama ʻia ka mahana o ke kolamu ma 30. Hoʻonohonoho ʻia ka chromatograph penei.
Manawa (minuke) Hoʻonā A (%) Haʻina B (%) Elution
0–35 35 65 hoʻokalakupua
35–60 35®80 65®20 kaha kaha laina
60–70 80®35 20®65 kaha kaha laina
70–80 35 65 isocraticChromatograph ka hoʻonā kūpono Pūnaehana, a hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina Hana: ʻo ka manawa paʻa pili ma kahi o 0.78 no ka paclitaxel pili pūhui A a me 0.86 no ka paclitaxel pili pūhui B (pili i ka manawa paʻa no ka paclitaxel i loaʻa mai. ka ho'āʻo hoʻonā);a ʻo ka ʻōlelo hoʻoholo, R, ma waena o ka pūhui pili paclitaxel A me ka pūhui pili paclitaxel B ʻaʻole i emi iho ma mua o 1.0.Chromatograph the Standard solution, a hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina Hana: ʻaʻole ʻoi aku ma mua o 2.0%.
Ke Kaʻina Hana - Hoʻokomo i ka leo (ma kahi o 15 µL) o ka hoʻonā hoʻāʻo i loko o ka chromatograph, hoʻopaʻa i ka chromatogram, a ana i nā wahi no nā piko nui.E helu i ka pākēneka o kēlā me kēia haumia ma ka ʻāpana o Paclitaxel i lawe ʻia e ke kumu:
100(Palima / ru)
ʻo F ka mea pane pili no kēlā me kēia peak haumia (e nānā i ka Papa 1 no nā waiwai);ʻO ri ka wahi kiʻekiʻe no kēlā me kēia haumia;a ʻo rU ka wahi kiʻekiʻe no ka paclitaxel.
Papa 1
Manawa Paʻa Paʻa Pili Mea pane (F) palena inoa (%)
0.24 1.29 Baccatin III 0.2
0.53 1.00 10-Deacetylpaclitaxel 0.5
0.57 1.00 7-Xylosylpaclitaxel 0.2
0.78 1.26 Cephalomannine (Paclitaxel pili pūhui A) a11
0.78 1.26 2'',3''-Dihydrocephalomannine a21
0.86 1.00 10-Deacetyl-7-epaclitaxel (huihui pili Paclitaxel B) 0.5
1.10 1.00 Benzyl analog3 b12
1.10 1.00 3'',4''-Dehydropaclitaxel C b22
1.40 1.00 7-Epicephalomannine 0.3
1.85 1.00 7-Epipaclitaxel 0.5
1 ʻAʻole paʻa paha ka ʻōlelo hoʻoholo no kēia mau piko, ma muli o nā huina pili i loaʻa;ka huina o a1 a me a2 aole i oi aku mamua o 0.5%.
2 ʻAʻole paʻa paha ka ʻōlelo hoʻoholo no kēia mau piko, ma muli o ka nui o nā mea i loaʻa;ʻaʻole ʻoi aku ka nui o ka b1 a me ka b2 ma mua o 0.5%.
3 Ua hāʻawi ʻia kēia inoa kemika i ka pūhui pili, benzyl analog:Baccatin III 13-ester me (2R,3S)-2-hydroxy-3-phenyl-3-(2-phenylacetylamino)propanoic acid.
Ma waho aʻe o ka ʻoi ʻole o nā palena no nā haumia pili i ka paclitaxel ma ka Papa 1, ʻaʻole i ʻoi aku ma mua o 0.1% o nā mea haumia hoʻokahi;a ʻaʻole i ʻoi aku ma mua o 2.0% o ka nui o nā haumia i loaʻa.
hoʻāʻo 2 (no nā mea i hoʻopaʻa ʻia e like me ka mea i hana ʻia e kahi kaʻina semisynthetic)— Inā hoʻokō ka mea i kēia hoʻāʻo, hōʻike ka lepili i ka hui pū ʻana me USP Related Compound Test 2.
Hoʻohana-hoʻohana i ka acetonitrile.
Pane A-E hoʻohana i ka hui ʻana o ka wai a me ka acetonitrile (3:2).
Pane B-E hoʻohana i ka acetonitrile i kānana ʻia.
ʻĀpana paʻalima-E hoʻohana i nā hui like ʻole o ka Solution A a me ka Solution B e like me ke kuhikuhi ʻana no ka ʻōnaehana Chromatographic.Hana i nā hoʻololi inā pono (e nānā i ka System Suitability ma lalo o Chromatography 621).
ʻO ka hoʻonā kūpono o ka ʻōnaehana-Hoʻoheheʻe i ka nui o ka USP Paclitaxel RS a me USP Paclitaxel Related Compound B RS ma ka Diluent, haʻalulu a sonication inā pono, e loaʻa i kahi hopena i ʻike ʻia ma kahi o 0.96 mg a me 0.008 mg no ka mL, kēlā me kēia.
Ho'āʻo hoʻonā-E hoʻololi e pili ana i 10 mg o Paclitaxel, i kaupaona pono, i ka 10-mL volumetric ipu, hoʻoheheʻe i loko a dilute me ka Diluent i ka leo, lulu a sonicating ina pono, a hui.
Pūnaehana Chromatographic (e nānā i ka Chromatography 621)— Ua lako ka chromatograph wai me kahi mea ʻike 227-nm a me kahi kolamu 4.6-mm × 15-cm i loaʻa iā 3-µm packing L1.ʻO ka nui o ke kahe ʻana ma kahi o 1.2 mL i kēlā me kēia minuke.Mālama ʻia ka mahana o ke kolamu ma 35. Hoʻonohonoho ʻia ka chromatograph penei.
Manawa (minuke) Hoʻonā A (%) Haʻina B (%) Elution
0-20 100 0 hoʻokalakupua
20-60 100®10 0®90 kaha kaha laina
60-62 10®100 90®0 gradient laina
62-70 100 0 isocraticChromatograph ka hoʻonā kūpono Pūnaehana, a e hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina Hana: ʻo ka manawa paʻa pili ma kahi o 0.94 no ka hui paclitaxel pili B a me 1.0 no ka paclitaxel;ʻaʻole emi ka ʻōlelo hoʻonā, R, ma waena o ka hui paclitaxel pili B a me ka paclitaxel ma lalo o 1.2;a ʻo ka ʻokoʻa maʻamau pili no ka hoʻopiʻi hou ʻana ʻaʻole ia ma mua o 2.0%.
Ke Kaʻina Hana-E hoʻokaʻawale i nā puke like (ma kahi o 15 µL) o ka Diluent a me ka solution Test i loko o ka chromatograph, e hoʻopaʻa i nā chromatograms, a e ana i nā wahi no nā piko āpau.E mālama ʻole i nā piko ma muli o ka Diluent.E helu i ka pākēneka o kēlā me kēia haumia ma ka ʻāpana o Paclitaxel i lawe ʻia e ke kumu:
100(Palima / mau)
i loko o F ka mea pane pili no kēlā me kēia haumia (e nānā i ka Papa 2 no nā waiwai);ʻO ri ka wahi kiʻekiʻe no kēlā me kēia haumia i loaʻa mai ka hopena hoʻāʻo;a ʻo rs ka huina o nā ʻāpana o nā piko a pau i loaʻa mai ka hāʻina hoʻāʻo.
Papa 2
Manawa Paʻa Paʻa Pili Mea pane (F) palena inoa (%)
0.11 1.24 10-Deacetylbaccatin III 0.1
0.20 1.29 Baccatin III 0.2
0.42 1.39 Paʻi kiʻi2 0.1
0.47 1.00 10-Deacetylpaclitaxel 0.5
0.80 1.00 2-Debenzoylpaclitaxel-2-penenoate 0.7
0.921 1.00 Ua wehe ʻia ke apo oxetane, neʻe ka acetyl a me benzoyl2 x1
0.921 1.00 10-Acetoacetylpaclitaxel x2
0.941 1.00 10-Deacetyl-7-epaclitaxel (hui pili Paclitaxel B) x3
1.37 1.00 7-Epipaclitaxel 0.4
1.45 1.00 10,13-Bissidechainpaclitaxel2 0.5
1.54 1.00 7-Acetylpaclitaxel 0.6
1.80 1.75 13-Tes-baccatin III 0.1
2.14 1.00 7-Tes-paclitaxel 0.3
1 ʻAʻole paʻa paha ka ʻōlelo hoʻoholo no kēia mau piko, ma muli o nā huina pili i loaʻa;ka huina o x1, x2, a me x3 aole i oi aku mamua o 0.4%.
2 Ua hāʻawi ʻia kēia mau inoa kemika i nā pūhui pili Photodegradant;Ua wehe ke apo Oxetane, ua neʻe ka acetyl a me benzoyl;a me 10,13-Bissidechainpaclitaxel:
Paʻi kiʻi
(1R,2R,4S,5S,7R,10S,11R,12S,13S,15S,16S)-2,10-diacetyloxy-5,13-dihydroxy-4,16,17,17-tetramethyl-8-oxa- 3-oxo-12-phenylcarbonyloxypentacyclo[11.3.1.01,11.04,11.07,10]heptadec-15-yl
(2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
Ua wehe ʻia ke apo o Oxetane, ua neʻe ka acetyl a me benzoyl
(1S,2S,3R,4S,5S,7S,8S,10R,13S)-5,10-diacetyloxy-1,2,4,7-tetrahydroxy-8,12,15,15-tetramethyl-9-oxo- 4-(phenylcarbonyloxymethyl)tricyclo[9.3.1.03,8]pentadec-11-en-13-yl
(2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
10,13-Bissidechainpaclitaxel
Baccatin III 13-ester me (2R,3S) -2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoic acid, 10-ester me (2S,3S) -2-hydroxy-3-phenyl-3-(phenylcarbonylamino )ʻakika propanoic
Ma waho aʻe o ka ʻoi ʻole o nā palena no nā haumia pili i ka paclitaxel ma ka Papa 2, ʻaʻole i ʻoi aku ma mua o 0.1% o nā mea haumia hoʻokahi;a ʻaʻole i ʻoi aku ma mua o 2.0% o ka nui o nā haumia i loaʻa.
ho'āʻo 3 (no nā mea i hoʻopaʻa inoa ʻia e ke kaʻina hana fermentation cell plant)— Inā hoʻokō ka mea i kēia hoʻāʻo, hōʻike ka lepili i ka hui pū ʻana me USP Related Compound Test 3.
Pane A-E hoʻomākaukau i ka hui ʻana o ka wai a me ka acetonitrile (3:2).
Pane B-E hoʻomākaukau i ka acetonitrile i kānana a hoʻopau ʻia.
ʻĀpana paʻalima-E hoʻohana i nā hui like ʻole o ka Solution A a me ka Solution B e like me ke kuhikuhi ʻana no ka ʻōnaehana Chromatographic.Hana i nā hoʻololi inā pono (e nānā i ka System Suitability ma lalo o Chromatography 621).
Pūnaehana kūpono hoʻonā-Dissolve USP Paclitaxel Impurity Mixture RS i ka acetonitrile, sonicating ina pono, e loaa i ka hoʻonā 'ike 'ike o ma kahi o 1 mg no mL.
Hoʻonā maʻamau-E hoʻopau i ka nui o ka USP Paclitaxel RS i kaupaona pono ʻia i ka acetonitrile, e hoʻoheheʻe ʻia inā pono, e kiʻi i kahi hopena i ʻike ʻia ma kahi o 1 mg no ka mL.
Hoʻoholo hoʻāʻo-E hoʻololi i kahi 10 mg o Paclitaxel, i kaupaona pololei ʻia, i kahi pahu volumetric 10-mL.E hoʻoheheʻe i loko a hoʻoheheʻe ʻia me ka acetonitrile i ka nui, sonicating inā pono, a hui pū.
Pūnaehana Chromatographic (e nānā i ka Chromatography 621)— Ua lako ka chromatograph wai me kahi mea ʻike 227-nm a me kahi kolamu 4.6-mm × 15-cm i loaʻa iā 3-µm packing L1.ʻO ka nui o ke kahe ʻana ma kahi o 1.2 mL i kēlā me kēia minuke.Hoʻolālā ʻia ka chromatograph penei.
Manawa (minuke) Hoʻonā A (%) Haʻina B (%) Elution
0-28 100 0 hoʻokalakupua
28-33 100®98 0®2 kaha kaha laina
33–58 98®10 2®90 kaha kaha laina
58-60 10 90 hoʻokalakupua
60-63 10®100 90®0 gradient laina
63-70 100 0 isocraticChromatograph ka hoʻonā kūpono System, a hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina hana: ʻo ka hoʻonā, R, ma waena o paclitaxel a me benzyl analog ʻaʻole i emi iho ma mua o 1.8.Chromatograph the Standard solution, a hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina Hana: ʻaʻole ʻoi aku ma mua o 2.0%.[nota—No ke kumu o ka ʻike kiʻekiʻe, ua hāʻawi ʻia nā manawa paʻa pili ma ka Papa 3. Ua ana ʻia nā manawa paʻa pili me Paclitaxel.]
Papa 3
Ka palena manawa hoʻopaʻa inoa pili (%)
Propyl analog1 0.54 0.2
Cephalomannine (Paclitaxel pili pūhui A) 0.76 0.5
sec-Butyl analog2 0.81 0.2
n-Butyl analog3 0.89 0.1
Benzyl analog 1.10 0.4
Baccatin VI 1.23 0.2
Pentil analog4 1.31 0.2
7-Epipaclitaxel 1.51 0.4
1 Ua hāʻawi ʻia kēia inoa kemika i ka hui like Propyl analog:Baccatin III 13-ester me (2R,3S)-3-bunoylamino-2-hydroxy-3-phenylpropanoic acid.
2 Ua hāʻawi ʻia kēia inoa kemika i ka pūhui pili sec-Butyl analog:Baccatin III 13-ester me (2R,3S) -2-hydroxy-3-(2-methylbunoylamino) -3-phenylpropanoic acid.
3 Ua hāʻawi ʻia kēia inoa kemika i ka pūhui pili n-Butyl analog:Baccatin III 13-ester me (2S,3S)-2-hydroxy-3-(pentanoylamino)-3-phenylpropanoic acid.
4 Ua hāʻawi ʻia kēia inoa kemika i ka hui like Pentyl analog:Baccatin III 13-ester me (2R,3S) -3-(hexanoylamino) -2-hydroxy-3-phenylpropanoic acid.
Ke Kaʻina Hana-E hoʻokomo i ka leo (ma kahi o 12 µL) o ka hoʻonā hoʻāʻo i loko o ka chromatograph, e hoʻopaʻa i ka chromatogram, a e ana i nā wahi no nā piko a pau.E helu i ka pākēneka o kēlā me kēia haumia ma ka ʻāpana o Paclitaxel i lawe ʻia e ke kumu:
100(ri / rU)
i loko o ka ri ka pane o kēlā me kēia haumia;a ʻo rU ka huina o nā ʻāpana o nā piko a pau i loaʻa mai ka haʻina hoʻāʻo.Ma waho aʻe o ka ʻoi ʻole o nā palena no nā haumia pili i ka paclitaxel ma ka Papa 3, ʻaʻole i ʻoi aku ma mua o 0.1% o nā mea haumia ʻē aʻe;a ʻaʻole i ʻoi aku ma mua o 2.0% o ka nui o nā haumia i loaʻa.
hoʻāʻo-
Diluent-Hoʻomākaukau i ka hui ʻana o ka methanol a me ka acetic acid (200: 1).
ʻĀpana Mobile-E hoʻomākaukau i ka hui ʻana o ka wai a me ka acetonitrile (11:9).Hana i nā hoʻololi inā pono (e nānā i ka System Suitability ma lalo o Chromatography 621).
Hoʻomākaukau maʻamau-Dissolve, ka hoʻohana 'ana i ka sonication ina pono, he pololei i kaupaona nui o USP Paclitaxel RS i ka Diluent, a dilute quantitatively, a stepwise ina pono, me ka Diluent e loaʻa i ka hoʻonā 'ike ka hoʻopaʻa 'ana ma kahi o 1 mg no mL.
Hoʻomākaukau hoʻāʻo-E hoʻoneʻe ma kahi o 10 mg o Paclitaxel, i kaupaona pololei ʻia, i kahi pahu volumetric 10-mL.E hoʻoheheʻe i ka Diluent, me ka hoʻohana ʻana i ka sonication inā pono, e hoʻoheheʻe me ka Diluent i ka leo, a hui.
Pūnaehana Chromatographic (e nānā i ka Chromatography <621>)-Ua lako ka chromatograph wai me kahi mea ʻike 227-nm a me kahi kolamu 4.6-mm × 25-cm i loaʻa iā 5-µm packing L43.ʻO ka nui o ke kahe ʻana he 1.5 mL i kēlā me kēia minuke.Chromatograph i ka hoʻomākaukau maʻamau, a e hoʻopaʻa i nā pane kiʻekiʻe e like me ke kuhikuhi ʻana no ke Kaʻina Hana: ʻo ke kumu huelo ma waena o 0.7 a me 1.3;a ʻo ka ʻokoʻa maʻamau pili no ka hoʻopili hou ʻana ʻaʻole i ʻoi aku ma mua o 1.5%.
Kaʻina hana-Hoʻokaʻawale i nā puke like (ma kahi o 10 µL) o ka hoʻomākaukau maʻamau a me ka hoʻomākaukau ʻana i ka Assay i loko o ka chromatograph, e hoʻopaʻa i nā chromatograms, a ana i nā wahi no nā piko nui.E helu i ka nui, ma mg, o C47H51NO14 ma ka mahele o Paclitaxel i laweia e ke kumu:
10C(rU / rS)
i loko o ka C ka manaʻo, i ka mg per mL, o USP Paclitaxel RS i ka hoʻomākaukau maʻamau;a ʻo rU a me rS nā pane kiʻekiʻe no ka paclitaxel i loaʻa mai ka hoʻomākaukau Assay a me ka hoʻomākaukau maʻamau.