SPPflX
th1. 'h•• l. la a~out the appl1oatloa ot high-p.rtoraaao. 11quid ohroaatograplq (HPLO) '0 aoa. ape.ltlo real-11t••• paratl_ ani quant1t.tlon pro~l ••a regar41ng c.rtala 1acluatr1all7 ua.tul organ10 ,rodua'•• JI.mAl-paa•• adsorp'loa (.1110. ,el) and reTerad-pha •• partl tlOll (ltcm4" ph.1l11) ao4e. ot BPLO wer. ..plo," lD. tM • • tud,. Bo'h laooratle &D4 Iradl'" .lution .ode. were u." tor the ••paratlona an4 quantltatlOD.. th. suoc.sstul .imultan.ou. s.par.'lona laolud. seTeral altalo14s 1a sua oplua extrao'., aea1-a,.th.tl0 cod.ln. b ••• and lts llk.17 oarr,J over and .,nth.al. b7-produot t.purltl •• , 1-naphthllaa1n. fro. 2-naphth71aata. and other .truotural17 related lapur1tl••• an4 2-phen71gl101n. and 1 t. B-oarbaJllo,l- and h7d&lltoU preouraora. the ext.mal standard quantlta'1oa work laTolv•••• s&7 ot .ea1-a1Jl'h.ti0 codeill. bas. and anal ,sl. of the t1T. pr1llo1,al alltalolcla 1n gull op1ua, 'h. 2-1... er in bulk 1-aaphtb¥laa1n• ...pl.. (ault-p,. le.,..1) J th. \vo ao.t lU.l.T b7-produo' lal'uritl •• la .ea1-aJllth.tl0 oocl.lD.. base J aDd ~ (-)-2-pbeqlgl701ne . 'd. 'U1
It. -.carbaao71- aad hTdantola precursors 1n microbial traD.to~ a'loa reao'loa aix'urea.
the t he sl. 1. dlTlded tato tour ohapters and t he ~l r8 ' o~ter 1& subdlvlded into tvo S. c tlOA~. The highlights of t h. vork in eaoh ohapter 1. d •• erlb.e4 1D. this BUA1Dla17.
Til gltng-I
ISOORAfIO BIGB-1ElJOBKAlOJ LIQUID gBROJUfOGJUlHI 0' GUll OPIUII ~1Jl,OIDS O. J. BOBDED PHDn SfJ.'lI01U.RY PBASE
Seot1on .t.
Siaul tanecua Separation ot the Principal .Alkaloids 1a Gu. Opiua 'I aeTersed-lha.e B1&h-pertoraan.e Liquid Olu'oaatography U.1ng a pH 11 btll!er
Reversed-phaae BPLO on banded stat1on&r7 phase. ot TariO•• polarltles 1. a popular a04e tor aeparating princ1pal alkalold. ln sua aplua. Mo.t ot the ohroaatosrapber. haTe .a.. elther expenslTe aoetonltrile aloae or ln ooab1natlon with 10a-palr1D& reasent. d the aobl1e phase aodlt1en to aohieTe a slllultalleft.
Howeyer, .e aohleyed a almultaneou. 'a•• lln. aeparatlon ot all tbe pr1D.o1pal alkalolda (aorphine. oocleU.. the b ain. • Ilo.oapu. anel papayerla.) 1n Iacllan sua oplUli .nraot. on a reTer.eel-pha•• bonded ph..,l ooluan with a sl.ple aDd taexp.nalYe,but n.gleoted, a.thaaol--1%(w/T)aqu.oua aodlum aoetat. and 7aM trlethllamiae (pH 11) butter (58,42) w.a used aa the aobl1. pbaae. A 100d p.at ar-et17 tor all the p.aka waa obaen" with UV 4et.otl_ at 254 u. fh. high perc.ntage ot .ethaaol appears to bay. aoae prote.tlye tan... ce on the al110a backbone ot the paoklq at the hlgh apparent pH. HoweTer. tor extendiDg tbe llt. ot the aala oolusa a 81110a presaturator oolwm ls reooaa.ad.~
viil Olm"I
ISOOIAfIO HIGB-PBllfOIMJJOB LlQUD OBROJUtOQB.OBY 0' GUll OlIO IJ,lALOIDS OW A BODD PDI!L St.l!IOIABt lBASI
Seo'loa B
_ • .,. aDd .&aal,.18 .f • ..s..a,.'.. "10 004.1JM 1aII. ~ 18.. ra'10 a.TeraN-IJlaa. B1p.p.rtoaaao. Llqa14 ~~Iq
004.b.. 1. pbaraa••• U.oal.l, \he a.a' 1apon.a, .... Uae sua opl_ alkaloi4s with "1"14 p""",,loa Yo1_e fta.ldol 200 " .. alialold. ..lag . a1afW (oa.- t '0 . $ w/-) 0_'1'"u' of pa op1_. aoat. .f the, .... ta. pr04uCM4 ....1'.18117 1. dert... .01- .7Il~U.al17 ., £ ....~1.'1_ .f aorphi... On...... raw ••".rlel fer the ....faotv • • f .04.la., SeII1-retlae. aoJlph1ae
( •••q. 85~ -/w) 1. ".-..117 o"'aIIlaaM4 with ...0Al ••el •• ani" "".1' tJ'_ _ op1_ .\In.zaa 1ao1.'1on ,roc •••• Ia 'Ma ••n1_ w. ",on & 81aul t._.oa ••para'loa ot ••al .7JltAet.l. oodal.. , ... .troa \he 1IIU'...... aOJ'phine aIl4 ...ea1o f~~ _ 6 &014, .. well .. 'U4I t.YO GO_ .1Jl~.la '7-pr04uo:ta, ....1" i -
Godaa. ..'_1 et.Jaer u4 cx .....1a.t.ht... oalU. P~Y101l817 n- ,oned BPLO .ath04 •• we ..e4 • , ..... ph..,l ••1_ aa4 • alap1• .. la.zpa..l_ ..tbeDol.-. q...... 1 11M ,rs..tbl1__ 1\11l pboaplaa'. 'utter at p H 3.0 (20180) .... 1 ...ratl0 aobU. pha•• fer the _., aa4 ..a1781. .f .u1-a,.'Mt.l0 00481a. b_. !'* p.ak are. reapoa... .~ 254 a. .t•• ~loa ••Teleact.h ••re l1a.ed ., 1 ..., ap ,. 100 )IS oodeta. eD4 10 )lg eaob tor \he tvo b1-product impurities in 25-~ injection volume. The method vas tound to be suitable tor monitoring the progress of the methylation react10n and also to assess the qual1t1 ot code1ne produced.
QI APt ER-I I
(lUDI.t UTERSBD-PlUS:B BIGH-PERlOlUUBOE LIQUID OHROJlJ.!OGR.&lBlO SEfJ.lU!IOB O}' mGB! ALKALOIDS AID MEOONIO AOID AID QUAlTI!A!IOB 01 fiVE PRINCIPAL ALKALOIDS IIi GUK OPIUll
Re v~ rs ed-pha.e 1.coratlc BPLO on bonded statian&r,1 phaae. with di ffer ent polaritle. 1. a frequantl1 used method tor separation and quantitation ot gua opiua alkaloid,. Hovever, a coamon draw back ot 80me ot the earlier .ethods using th1s lI04e 1. that a h1ghl1 polar morphine elute. ahead ot other principal alkalold.
OR the tailing edge ot the earl1 eluting group ot peak. represent ing polJaerio and polar constituent.. In this situation a rellable lntegration ot the .orphine peat 1. difficult. fUrther, several chroaatographer. have reported low effectlveness ot reversed-phase colUllJls 1D. lsooratlc .ode tor basic compounds. In order to overoo.e these l1mitations, we used gradient elutlon 1n the present work. PreT1oual1, reversed-phase gradient elution lIode va8 applled to this separation problem with onl1 limited success. the separation of the tive princlpal alkaloids (llorphine, oodeine, thebaine, n08capiRe and papaverine), three minor alkaloid. (laudanosiRe, or,rptopine and naroeiRe), meconlc acid and so.e un identlfied constituents In gum oplum was achleved on a reversed pbase phenrl oolumn b7 gradlent BPLO using a slmple and inexpensive .obile phase s1stem. The llnear gradlent programae was started
x a' 5~ .... eaded a~ 7Q%(y/y) ••thallol 1D 1 IlH tr1.~h11 ...aa1_ pllo.phat. butfer (pH ') 1a 20 aiD. jll the t1Ye pr1Dolpal alkaloid. vere al.o 4.tera1ne4 w1 ~ 800d preolaloa. the .ethod req111n. -1111_. • ..ple preparat1i1l aD4 18 au ~abl. tor 1'OU,s.ae
91 t "U-III
SU.AJU.!IOlif 01 1-.J,PBfJlU,AIIlJlB 1R01l !HI nn; DOd IJIPUBItIBS AJlD SUB-JPK I,fiEt DEfEOflOI .&lID Qt1.D!Il'J.fIOK 0' 2-IUIllHILAMI.E BY BODAL !H.&S~ BIGB-PlaIOBJU.lO! LIQUID OIlROll..l!OGlUPBI
the tree baa. 1-Aaphtlqlaa1ne and c.r~a1n of it. aulphOD.1o acid 4eriYatlY••• 8n ... 41aso aU cOl1pl1Ag oOllp_eat. ill the preparatia of asO 41•• which lAol,," •• ao.e perm1 tt" s1llth.~10 food coloun. 'fecba1cal '....,h\lql.. 1a. 1a \18"81 17 produoe4 b1 reclllOtl_ .t 1-aS. traaaphthal.n. whioh 1 ~s.lt 111 1JlYariabll ooata II1aat.4 with the 2-111 tre- ls_er. fh. teohnioal 1-aaph\hTl.a1n• • 87 o_'alll s ..e 1.1'-41napbtb71aa1ae. 1.5-d1ea1noaaphthal... e. 1- m4 2-aapllthole aB4 lllYaria'17 a little of tb. 2-1aoaer (.u. 0.5% wi") .a 1apu.r1tie.. !h. 2-Dapht}qlaa1Jle bas 10Dg b... 1'8- as oogal.ed .. a Alman caro1Jlogen aadL a tonc ohemioal. It. a.lI- faoture .ad " •• 1. IlOV baDlle4 all OYer the vOl'ltt. It h8e been aotuall, touad to be pna_t 111 a._ l-naphtb71ftll1De ba'H~d aSO a11l'the'10 food ooloura, .oat probab17 aa a Oa:rq 9vttr upur1"7.
ID thl. a.otion a BPLO .ethod 1e reported for ~ 81aal'aaeou8
'a.elin••• para'laD ot 1-llaph'h71aatae and th. five assoclat•• iapur1,\le•• 1l8lle17. 2-JlapbthTlaa1De. 1.5-dl.... 1.Ollapl1thaleD. •• t.l'-41JlaphtbTlaa1De. 1- and. 2-naphthol. u8lng l i quid-solid ".orp~lQR mode aa a .1110. sel .,.tlaaarr phaa.. fhe ••bl1e
phaae ... 50~ .a~.r--.aturate4 filet-bTl .ther-li-hex.. e (25.15). fh. lIeth04 &._1e4 preol.. cl.'.l'II1aatloa ot trao. ,,0_"_ of
2-naphtbllaa1ne lmpurl '7 1.D ~.obld.oa1 1-aaph~1aa1Jl.... pl ••
ChI1ag t.o a hlgh d.egre. ot r.aol\l~loJl (b = 2.5) ao111 ...ed. ...~ .. _ these .truotural laOll.n.. fhe ••t1aatecl alal-_ ,.t•• table ..._, JI'\. ot a-aaphthl1d1DeLa_ 1500 pp. a-hexaa•• 01.tl_ ot 1-aapthfl-
aai•• 1. lI- 0.06 ppaCw/w)aD.C1 'b.a~ 1a bulk t-aapll'b71aalae 1.
S- O.OO4~ (./.~" the low r 11m! t 0911 lie i Dlp reyed tt.lnller y.~ ...11,.
CIM1Ill=U
lIO:lItOBI.lG 0 .. SfBUOtlRBOlnO HIOBOBIAL fUlSlOlUlltIOB 0' J}lt-5-J-iIDllJaDAftOL'I fO i(-)-2-PBBIl'LGLIOIllB .BY ISoOlUfIO UYERSD-:raUUI HI GB-P.IUOmt4I'OB LI QUID OBRO}UfOCJ!UPHI
j.(-)-2-phQTlg17c1ne 1 ... 1aporlallt etan1D& ..,.rial tor produolDs .ea1-.1Dthetl0 )l-l•• t_ aatlblotloa ...h .. pea10111laa
aDd o.phal•• portRa. .... tloaer1oal17 pure ~(-)-2-ph..,1&l701a.
OaB be prepared hI esplo7in& atereoapeolJ1o ea~.'l. traa.toraatlaa of PJt.-5-phu71bTdanto111 Tia the l-(-)-N-oarbam071-a-phe..,1sl70 1.. laterae41at. u1Dg baot.ria ••oh aa w0l!aot.X'1ua aacl , ••••••• ap.cl... A ...r y 1mponan't, ad.,an't,age of bldant.o1aa 1ii 'beir t ...l1. aD4 epontan.oua chem10al raoe.tz&t1aa even under all' o ~.810 oatall.is oonditions ( •• s., pH 8.5; temp. JO 0). Thu., ..
• re8ul" o~ onenoal raoell1zatlel1 of the a reaot1v•• (+)-5-pbelql
b1dan~ola and s1multan.ous ater.osele.ilv. m1oro~lal hl4rolJal.
~1 ~tqdaDto11la". R,k-5-Ph'B71Q4aat.1a 1. Q.uanti ~atl "'11 trau toJ'S" lat. the £(-)-I-oar)am011- 1nterJledla\'. J\lrtherllore. -OIl. xli 'aoMrS.. a.oa .. Mn'ao,.119 ape baT. an &441 ~101lal 'IlQIDe
oall.4 J.-oarltaaol1-l-aa1no ao14 aa14olq4rolaa. oapabl. .f a w.~.!!l1
4.oarltaaol1atlon of ~h. 1nt.ra"la~' to produo. 1(-)-2-phaa71- all01n•• Ia ••traat to a pnno.'ll re,onecl r ....I'IIe4-plla •• p-a41•• 't ••'hod •••1.,1. lso.ratl0 IILO a.thol vaa d.T.lop •• forL.1aultaa.oQ.•
~a•• l1a ••• paratloa ~. d.t.rata.tloa of l(-)-2-pbaDll&l7ola•• 1(-)-J-oarbaao71 lat.ra.. lat. aa4 5-,heBl1bJd.. '.1a 1a aiorebial r'ao'laa a1xt~. u'las a oh.ap.r )0Dd" ph..,l ~l1.,•• 01 .... !h. a.bl1. ,ba.. ... • a1xt~ of a.~ol aa4 7 aM ,rt.tbll _0Il1_ pho.phat. 'lItt.r (pH ,.0) and the Uf d.t.otloa v •• at
215 DIl. !h••• tb04 ... toua4 to It. preol•• and sUitable tor aOD1'.r1a& 'h. ,roar... of -.'h th. t1)" of alorobial 'raa.toraa'laa••
x111 l4£'ggc91;P (ChQ\e" 1 aD4 1 I ) pattA of ge19 11 rela»_ " la41a
Oplua vaa OIl. ot t oe earll•• ' dna pre,aratlO1l cll.oo.... n4 aDd ~r.peu'1 ••1 lJ used ~1 aaak1D4 ,. all.Yla'. pala. l' baa been nowa tor at l •••t 3,500 ,.&1"8, 'lle earU•• ' _thea'lo,'" a ..pl ••• a towad ln ",e toIIb of ..,,'1.. Olla (15t,h ..nwl'J' B.a. l. It Ie sell.ralll no.pi.ed ..oq ld.at.onaD4I tha" t,he .arll••• •nd..... ot dl"UC 1&" .t opiW1 4.'.. aa t ar baot .a the 8tJ1 ...mzo, B. c. tb. POPP7 plea" (IM'"[ '-p'felM WIa.) pro1»8_17 011.&1 ••'" aOIl ••b.n 1n 'be .OWl'ri.. borel.dna tbe e.at.n xed1 \errane.. (l'all. GrMC. aDd t,he Aalan part 01 turkel J tra wh.n l' Pl'o pqa te4 .a ~ t,.ard t,broqh ladl. awl Oh1Aa. file aatloaa .f the Bas\ proDab17 1 ••1'11" of opl_ fro. the Ua"a. In In41a oplua oult,1 ....t1oa 1s kDOVD to h... been well eat.bIiah el bl ~ esr11 1 ~h .ent '..l Z7 aa4 baa 1».. a oons1d.rable ow:oe of "YOU. to auoee ••l .. gOftBJMllU. Op1um 11&. kA_ 1a Oblaa eYea earli.r. Bo•• yer. ,roba_l, du. to laok of l ars- 8Cal_ cult,l"'at,loa lnl'la117. Oh1a ••• laported mo.' ot their op1. requlrement, i ro. Illdla. In 1751. at'er Plas ••" t,_ llldl .. opl_
.onopol, ha4 pa ••~ 4 tro. 'be MO 'll8 .0 the Brlt,l.la Ba., lAdle OapaBl. UD4er \h. c..,dJ'. direotl_ t.be tloo4 of oplua
.zpo~. \0 Cbiaa kept, rialng 11.141ac muob of .0De, tor the a07al
••Y,J. Ooa ••qu ea\lJ, Oblaa yea 4ralDe4 ot al~yel' ~1 tbe .., ot P~U. aD.4 'he ••p.ror 4eore" oouaWI'II... flft... Tbl. tluall, oula1aat.ed ln ~. fate~l Opiua ~ ar bet.w.. n t,he Brlt,lah ea4 Obta•••• tbe out,oaae vaa a bumll1atlag dete.' tor t.he OhiD ••_ (Trea'1 of JaJllt1na. 1842)aD4 t ortwlo. tG tbe natora ., t.he V&1 Of Oplua-te4
xly Ohina trade. !he lastlng bltternels In Ohlna vaa a poteat faotor in the loclal and polltlcal 1mbrogll0 that ultimately lead to one of the momentou8 upheaYa!s of the 20th C&DtUr,J. In both t he World 'are, Indla has proyed to be a valuable souroe of oplum for the manufacture of morphine and relate. 4rugs. On the other hand In41a and Ohina were the lirat countries to f aoe addlctlon problema with widespread nOA-medical use of Op1WR among general population. In 1949, GOTernaellt of Indla deCided to s top opium consumption for noa-medioal and qua81- medloal uses l n t he country oompletely from 1958-59. The legal oultlYat loa of oplum pOPP1,vh1ch is conl1ned to the state. ot Madhya prade.h, uttar Pr ad esh and Ra3 asthaa.and the production ot opia. haa been atriot17 controlled b1 the GoYernment. leklll-Hlde Nature of lopPI Among varlaU8 spec1es of POPPI. onll "PGlTer 80me1ferua Linnaeus and iapaver setiserua (wild variety) species of the genul Papaver (Greek word tor poppy) are capable of produc1ng op1ua.
Thr ough t he ages opium haa repre ~ ent.d a great potentlal for good and evil. The otten quoted r emar k of S7denham t hat. 'w1thout the help of opi um . raw would be suf ficiently hard-heart ed to pract1se medicine' cont1nues to hold true eYen after three hundred fears.
Op ium 18 still 1n use tod87. both as the extrao~ (e. g •• • epenthe) sad as a reoonstltuted mixture of pur e alkalo1ds (PaP e rv ~ retum) . In India'. ancient AlUl'Vedic S1st •• of medlo1ne, it i. used tor sprue. ast hma, scorpion b1te etc. Morphine 1s the mo st abundant and i mportant alkal o1d of gua op1um. It is a powerful analge.l0 and !la.roo'le , and h .-; g 8'tlmulaD.t. aot lOA as "ell. III the trea\. ••n ' of ehrOll1o pala III burna. oancer, k14o.e1 atOll.. aO\1 te paaoreatltla and othel' t er zlaal lllness •• morphlAe 18 . '111 111- 41apel1 l1i a bl.. It l s carriea "7 SIIDv.l.aJ'lO •• and •••1'7 UIaJ lat8nt17 platoOD aedlo&1 aan; a bad11 lnJured O8e =a7 ge~ 1t laJ.ot.4 la•• a . "aol. righ' through the olot.h1ag. KorphlJle 18 alao ll 16 M lor cODa. 'lYe b. ~ r alluro ".caua. l' 4115' •• blood v ••••l •• pre v.nting flu1d troa baot1as up l a to t he lunSa. Tun i s ,., another M art-.ami no etteet of ap1a.. III
Baal&44 and 1at.11 1n .,0.1' o o~t.r1e8 \bel'. 1& a • • dlos1 laaovatloa kaown a t he modern hosplce aov• • eat. A hosplce l s a pl ao. tor t he teral anll y l11.h.re palo. control 1& es •• ntlBl par\ ot t he work. Here agaln aorph1ne, whioh 18 u81181ll ad.1a1 st.n4 bl moath, has DO p ••r 8. Ia En tain, efta h.rolll laJeotlOJl l s l .gal tor caretul17 cont.rol1" a.410al u •• aa 111 the Oa •• ot a u all proportl_ ot patlent s who oannot bwallov Il.ar the .n4. He rolD b.las sore 01ub1., l' can b. lD Jected In a 8mal1er yolua. of va'.r sa eo.par" t.o aorph1lle. fheretore, tor tbe oocaaioaa! pa'leat wbo ae.da a big do •• 1a a Baa11er Yoluae, hero1n 1. a or. efreot.ly•• Man '. ta oillation with a1n4-warpinS aDd b047-vreoklna su'D i.l t auo.. preclatea vr1 t ten b1atoq. Dna \18e &lUI ab'i.. 1. all 1n dlVisible par t ot oly111zatloa through buDdr ed. ot leal'S. 1\ has been a oure•• t ma410llle aD4 oomlort, as well a8 protlt. gre.d and de spair. Opl ua C.orphlae) hae .... n 011. ot tbe ao t dangerous and w14espre&4 drugs of abase. hove.er, late11 lt haa b.en 0.erahadow.4 to a l arge extent b7 that ot \,. aor. potent 1 ' f6-~l ao.\11 d.rivative oall.4 h.rolD. Tb18!beoau .. herolD i 8 relBtlve17 8laple to make, .asler to ooaoeal and much aore
xvi protlta~le to trade. Its addlct10n ~rlD g. m1sery to lnauaera~le tam1l1e. worldwide. A 19th oentur.J EDgllah ess&1iet Thoaas De
Quinoel d ••oribed oplum as Bubtle and mlght,. In 'The Oonte •• lon~ of p~ Engl l sh Op l um-Bater', he v1v1d11 tell. how he flrst ex perienced muslc 11ke perfume, 11T1ng a hundred Tears ln ODe night, ecst asle. of dlvine enJoyment. But eyentua1ll, addictlon and horror-.thouaands of lear. ln atone coff lna, canceroua k1 ss.. trom orooodl1es.
The addi ot1on to narootlc drugs 8uoh as heroln constltutes • serious ev11 tor the 1Adlrtdual and a Boclal and economl0 danger to mankind. It tends to be a long-term two-fold de Ta ~ tat1ag effect. Phls10al efi ct. are man1fested ln drug non-aTailabl11t,
8ymptoa. such 5 lllness, Aausea and bodr ache, PS1cholog1cal etfects a an. craving tor the drug than anything else, that mq become one's l1fe-co pan1on. MaDl heroln or morphine addlct. v111 not atop at anything to ge t 1t--lle, crawl t hrough a aever and beg, steal. eTeD. prostltute tbemselves. There i &~rOwlng evidence of close llnk. between drug traffloking and arms amugg-
11ng • subverslon and lnternatlonal terrorla••
Wb!IJ.t 1 s 'WI op11l1l1 About elghty days trom planting. the petals of oplum p OPPT flower drop and the green oTar1 oapsule oontainlng t he grOwing
.eed. svells . Suoh a o aps~le 1s then shal l ow17 1nolsed with a speolal tool to release a milky, alkalold-rioh aap wh1ch rapidly drle~, dar kens i n t he air aud t~l'Jl8 gumm7--tha' l a gUll op1141l. Fresh gua opium colleoted trom tour to fiye suece.slve 'lanclng.' ls s tored 1n l ar ge open t anka where it 1 ~ drled down slowl l to about 10 ~ .o1st u ~content. This blaok or dar. Drown 8e~1-
xvll 80114 1. t he gua oplua ot coameroe.
Soolo-eooBoml0 role of op1ua pOPPI c~ltlT atloA ln 1441a
Indla l H the largest pOPPI grower, the ~lgg8at, and the onll legal (1101t) p rod~o.r ot gum oplum in tbe world and ful tills ea. 45% ot the world'. total annual aorph1ne requ1re.ellt (oa. 2OOt). Abou t 800-10oot In4181l oplW1 l s banes tH anualll troll ll.L 24, 000- 32, 000 ha. POPPI grovlag, oplWD colle.tloD. an4 prooes.1ng i s extremell l abour lntenalTe; each capsula mal _. handled aa -any a8 ten t1me. and 1t takes uearlr 3,000 popples to produoe 1. 6 Kg oplua. Thi. be t cash crop businesa proTide. a large number of Jobs, ne ~ly two .1ll1on persoAs ln about 6.900 Tillages are d1rectl, 1llTolve4.
The opium growl ng 110enoe 1. oons1der 4 aa a status .rm~ol bl the 80clotl ln opium growing . re~8 a. 1t l s aoneidered aa an 1ndloatlon that 8 lDe.U 1s hardworking and hone8t. This 18 b.c a~& e If one i & not produoing enoU&h, or 1s suspected ot Dot selling all the opium to the gOTero ••nt. a8 requlred , on. will be de-llcensed. fUrther, popp1es cond1t10n the so11 esp~c l alll well for maize. Therefor . bl rotating mai ze and opium,' faraers
Od have both food and 1ncoae. Op1um and oplat esexport earu apnreclable tore1gn exohange a. well. Ind1a supplies two-th1rd. of the total op1ates anualll required b7 pharmaceut1oal. companies in t he U . ~3 . A . and alao export to U. S. S. R., Prance, the Unlted ~ ingdo. and Japan.
Che.loal ooaposltlon of au. 0i1um Gum op1um (pH 4t05) 1s a highly oomplex mixt ure. A t7Ploal ehem1cal oompos1tlon of Ind1aA gu. oplum with peroentage valsh'
xviii TABL.S I
CREMI (JAIl CO"rpOSI TION OF I NDI AN GUM u.t .i.li d
Oonstituent. A,p:proxllllnte MinWlt 111 a t,rpical r ange .amPl~% Total Al kaloid (% v/w) ( ~ v~) o04teut
. .. 1. Morph1n 9-14 10. 5 (45) 2. Codeine 1.25-4.0 3. 4 (15) ,. Thebaine 1.5-3.0 2. 2 ( 10)
4. No.scap1ne -~ . (')-10.0 6. 3 (27) 5. .fap3Terine 0. :>- 2. 75 0. 6 (2. 5) 6. ti ther alkaloid. <1 . 0 0. 5 «S) (&1 i nor)
7. f.1econic 801,\ • • • 11.0 ••• 8. Latex, gUES, • •• 21.0 ••• lf8X and t at s 9. Sugars, protein., ••• 15. 0 • •• and ammonia
10. Sulphuric aud • •• 8 . 0 ••• l actic aoid
1'.Total Wlknown ••• J . O ••• 12. Water •• • 13.5 •••
Total 100 (100) oontrlbution ot eaoh principal alkaloid to total alkaloid oontent is S1TeD in Table I. Ind1an gwa op1um contains over 35 known alkaloids whioh are ma1al1 present as aeconates. The tiTe prino1pal al~alo1da together con&t1t~te 1 8-25~ D7 velgh'. Op1um alkalo1ds tall into two d1st1not classea, aamel1, the phenanthrene (e.g., morphine. codeine, thebaine eto.) and the benzll1soqu1nol1ne group (e.g., papavenne, .uaroe1ne, noso.a.p1ne tc. ). Tho elkalolds of the tormer grQup only are highlJ c. (ldlc't1ve a.o.d, theretore, under full legal control both nationally and 1utern~t1on alll'T ~b ls II).
Extracti on ot al~alold. in opla.
Por 8~y reliable determtaat10n ot theae ~l k 9101d8, &val1- abl11 t7 of a proper extractlon t6chnlq,ue is vi tal tor 3uob a coaplex matrix 8,8 gum op1ua. The 1laport ~m t f~c tor;l t o be borne in mind tor a eff ect1 ve extraot1on procedllre il101ude I (1) aaoag a ajor aLkal01ds only morphine 1s both ~ mode r ately strong base
(pKa 1.S'n and a weak acid (pKa 9. 85), (11) mo r phine b C! sC! ls only aparingly soluble in manJ' of tihe Dol vents; (111) G.ll the alkaloid sal t li.> Fre modtn-e. t ely eolublG ln \later; (iv) codelAe bEt s e (pKa 7.95) 18 f a1r11 sol\4ble in solvents; {v) noscapi.ne
(pKa 6.18) and papayer1ne (pKa 5. 93) are weak ba ~ es; and (Ti) theba1ne 1s not so sta.ble at pH val~e& les t. thtLIL 3-lj.
Op1ua dart vea Grusa
Gum opium 1s ~ maJor tee4stook of the pharmaceutical 1ndustrl for tbe ~roduc tlon o! ~ c~h1~e c~d &ub sequent11 codeine and other derivatlTes. Morph1ne , the %ost abandant al kalo1d l~ Ind131l gua op1um, 1tself f1nda l1m1ted ther ap eatl~ al applioat1ons. Phenuthren. Benzzll.oqu1nolln!.. _ Qtber
A.P 00 ode1D.. Codaa1ne OOI7dalls A.P om0 rp hine O~ top1ne vodeine Gnosoopln. (DL-noscaplne) D•• oxlcodelnep Hyd rocctarulne li1droxl°odelnon•• Luthopine M.t hyl mol"!'}1 1. !!'e t'hi!'!~:: la~daA l d lne (tritoplne) ~ orph1n. .DL-Laudanine Morphcncla Laud an,osin. ~orp il o ·th.ba1ne Meconldlne Beopine liaroelnA ol'mvrph1ne Baroo'tollne Orlpevinc oxynarcotlne Phentld1hydrothebalne Pap vere..;n1ne i891.ldo.norph1.n.e Pr otoplne Pseudot.t.ebaine Rhoead1ne 'Ieroonlne l anthal1ne ',.P apaveraldlne)
xxi However. the newer slow release formulatlons haye inore a~ e d it. cl1nical use in the 19808. Mo . t morphiae i8 converted lnto semi-sy.nthettc oodelne (approximat e ~ orld productlon volume : 200 t, a8 alkal oi d) because the ava1labllltl of the latter a& a natural al ~alold i8 too small .
jIBLIOG1U1BI 1. '»eaand and aupp11 of opiate. for medloal aD4 .01entifl0 ne.ds' I8port of the laternatiaaal Barootl0. Oontrol Board for 1980, Unlted Batlon., Be.lork, (1981).
2. StaU.t10s OIl naroo'10 drug- for 198', Un1 te4 1,'1_, Mev lort, (1984). S. Hua1ll Zaheer (Oha1l'1larl, :alltorial Board) , the Wealth of In41a (j, dlo'1onarJ of Ind1aa Jaw material. and Indu8trial produc"_),Rav Katerials, Vol. VII , p.24O, Oouno1l of Soient1f1c and Industrial Re.earch (OSI~), Be. Delhl, 1966. 4. P.T. Wh1te, the Bat10anl Geogryhio Wanne, .1§I (1985) 143-188, reb. 1985. 5. R.J. Br,rant, The manufacture of .ed1cinal alkaloids from the op1ua pOPP7-- • _renew ot a traditional b10technolo87, 9h!!. lit. (Loadon). (1988) 146-15', 7th Karoh. 1988.
xxi 1 1
IRlngE (Ph'pte£! I snd II)
Ohraaa'.grapb7 Of Gum Oplua Alkaloidsl A General Overvie.
Althouah oplua haa been 1n use BS a druS tor over tven\, flve oen\ur1es , then l ~ no OODsensua le' on a uni form • • ' hod eyen for the alau1taneou. determlaat10a of mo rph1ne and other aajor oplum alkaloid ••
.::' oae elaa.leal . etbods are AAOW'Il to 11eld low a8881 n.ulte 1 tor .orp h 1 ~ . in gua oplum. Pharmaoopoeial .ethod. lavolve a r ather tedlou pre • • ps r atlOJ1 of morphiA trom t he matrlx rollov" b, t he quantita'lve 48tel'llloat101l. the llm1t--1; 1.ons and d.1rtloultle. of cln8810al methods ot quantit.t1oR of vp1um a!ka!o14a 2 were brl etll reYlewed b1 4legl er et 81 • In ~eneral, t hese • • thode are Dot versatil ., speolfl0 and rapid eRough. Obreaato grapblo .et bods hay hel ped to overcaae t h se limitations . A aurye, of reoent literature reveals t bat \he que.t ror better ohroaatograph1o me t hod s tor t he 81aultaneous aeparatloD and determ1aation ot the pr1aolpal opium alkalolds, namel" .orphlne , codeine, t hebaine, noscap lne and papaTerlDe, atl11 cont1nues. The ma30r tactors lnYolyed in the anal¥sis of gua opium ~l k lol ds area (1) coaplexi tl of ~be ma trix 1tself; (11) lllc lilet. reooyel7 of alkaloids i rom t be matrix 4ur1l:La extract10D owing to s olubility llaitatlon.J(liU wea ~ ly ba8io nature or noscapine and pAp ayerlne;(ly) lnet nbll1t, of thebaine
t p t~ ~3; and (Y) stroDa adsorption of n1ghll polar (aapboterlo) alkalolds 11k. aorpbine on st at10ner l pha~ e s . 2
Ohromatographic aethods haye been extenalYell used tor the separatlon and determlnatlon ot the flve principal alkalolds in gum opium. Thill-laJer chroJllatograptq (fLO) 1. nov preterred over pape r ehromatograpby for the l dent1f loat10D ot al¥alolds aDd sore~ ot gua op1um sample. prior to further examinat10n bl other ohroaatographio .ethod••
Gas chromutography (Ge ) s eparat10n ot morphine and other alkalolds harlng h.Ydroxyl groups ofien produoe t all1ng peak•• This is most probabll' due to their amphoteric nature which fayours strong adsorpt1on at actiye sites ot the coluan paokings resultlng in deceptively low ~alT8is results. Therefore, for
.1multaneous GO Beparat1o~ ot various opium alkalo1d. on cOAyentlonal col uruns pre-der1Yatlzation i& nece88ar,J. GO ot theba1ae at a low t emperature ~iYes & very broad peak, ,et, at o 3 higher temperatures (~285 C) thermal degradatiC!1 oooura aaklng the GO assSJ diff 1oult. The other maJor alkaloid. in op1um lacking hydroxyl gro\lpa, lu.me11, lloBoaplne and papaYerine, are
Dot easl1T derivat1zed. T~UB, a 8imultaneous separatlon ot oplua alkal o1ds by GO 1s rather ~1ft1cult. However, reoant application of fu s ~ d s1l1ca oapillary colwma resulted in nOD- 4,5 t alling GO peaks even tor UDder1y ~tlzed morph1ne • In new ot above l1m1tat10Ds, high.,erformance liquid chroaatographl (HPLO ) is often preferred over GO and TLO for the s1aultaDeOU8 aua1,sis of gum opium alkalotds. 6-10 6,7,9-11, 6,7,9,11-13 J.ppl1ca t1on of TLC , GO and liPLO for the separat ion and determination of alkaloids 1n opiua ha. been extensively reviewed. Obviou 1y, there 1s no single '1deal' ohrOmatographic a.thod tor solving every re8~-l1te problem 1n this area; one mar Jud101ously seleot e1ther a suitable literature 3 method or ta1lor a new one depend1ng on the goals a1me d at vis-a-vis t1me and resources ava1lable. 1. E. Broohmann- Hanssen, J . Pharm. scl., §! (1972) 111 8; £LA., II ( 1912) 662}8 •• 2. H. W. Ziegler, T. H. Bea8le1.Sr. and D. 1. Smith, J, ASSOC. Of f . AQal . Ohe • • , ~ (1975 ) 888.
3. I.-F. WU and R. li. DObbers tein, .1, Ohromatosr•• J.12. (1977) 65.
4. Analytloal ~uppl1es Oatalog and Chromatographl Gul de. Hewlett Packard, U. S. A., 1988. p. 88. 5. C. D. Cook, Lab. t r act., Ji (1985) 69. 6. T. A. Gough and P. B. Baker• .1 , ChroaatoBr. Sol., ~ (1982) 289.
7. T. A. Gough and P. .E . Baker, J , Chromatogr. 80\., 51 (1 983 ) 145. 8, A. Baarhe1m Svendsen and R. Verpoort e, Ohroma tograihz of Al kaloids (Journal of Ohroaatogr aphl LIbrary, Vo • 23 A) , Elsev16r, Amsterdam , 1983, Oh.1 2, p. 221 .
9. V. Navar atnam and Hoe Kak ~ l, Bull. Jarc., ~ (1984) 15; £asl. Abatr•• iL (1985 ) 2E10. 10. Y. Hashimot o, K. Kawanishi and M. Morlyasu in A. Brossl (Ed ltor), the Alkal§ftd s , Vol.32. AC ademic Press, San Dlego, U. S. A., 1 8, Ch,1,pp,1-77. 1f . R. Verpoorte and A. Baerhe1m Svendsen, ¥hr om a to § ra~b¥ of t:kalOi d& (Journal of CvroaatographJ Llbrar.r, Vo • ~3 B , ElseVI er, Amsterdam, \~ 4 , Ch.7, p.291,
12. J . I~ . Janioot, M. Caude and R. Rosset, .Analp.~. li (1 986) 441; Anal . Abs'r•• ~ (1981 ) 3E10 .. 13. T. D. W1lson, J . Lig. Chromato~r., i (1 986) 2309,