CA1203800A - Process for obtaining laxative compounds from senna drug - Google Patents

Abstract

ABSTRACT

The present invention provides a process for obtaining laxative compounds from senna drug, wherein a) the senna drug is extracted with aqueous methanol by countercurrent percolation and the extract con-centrated at a temperature of ? 50°C. until the methanol has been completely removed from the extract;
b) the extract obtained is purified by continuous liquid-liquid extraction with an organic solvent;
c) the refined material (raffinate) obtained is trans-ferred to a crystallisation apparatus, acidified, while stirring, to a pH of 1.5 to 2.0, seeded with sennoside crystals, left to crystallise while stirring and the crystalline crude sennoside obtained separated off;
d) whereafter, the crude sennosides are, if desired, recrystallised and optionally e) 10 parts by weight of the mother liquor from c) mixed, while stirring, with 2 parts by weight of sodium chloride and the semi-solid mass coagulated on the surface is decanted off, washed and option-ally extracted with 95% methanol and the methanol fraction concentrated and the residue dried.

Description

~2~31~30~

The pre~ent invention i~ concerned with a proce~
for obtaining laxative c. ~u~d~ ~rom senna drug.
Senna drug con3i~ts of the dried leave~ and pods of the 6enna plant, for exæmple of Indian senna ~Ca~ia anqustifolla) and of E ~ tian senna (Cas~ia acutifolia). The laxative action o the ~enna drug i~
du~ to two c~ e~ of ~hemical e ~u,~, namely, 1) ~he senno~ides and 2) the non-senno~ide laxative-active ~ub~tance~ ~hereinafter referred to as ~S~5).
The laxative-active s~bstances in the ~enna drug are ~i ~ ular glyco~ide derivative~ of ths tw~
anthracene c~ r,~unds rhein and aloc ~ -'in. The mo~t important are ~ennosides A~ B, Al, C and D. Sennoside~
A, B and Al are bis-~luco~ylrhein anthrones and ~enno~ides c and D are glycosylrh~ln-glyco3yl~ n dianthrons d~
I~ addition to the ~onnosides~ the crude drug also contains aglucones (~ennidine~ ) and ~ther dec~ ion p~du~L~ and dsrivatives o~ the ~enn~ide~. Some of these can al~o have a laxatlve effect hut, at the sa~e time, can also be toxic and give rise to ~nde~irable side ef ects. :Side e~fect~ which are typical for ~enna preparations include n~ e~, vomiting, ~nnd, ~olic a~d diarrhoea.
Various pxoces~es~have ~een des~ibed for extract-ing the laxative-a~tive ~ubsta~e~ fr~m the ~enna drug~

~he mo~t important laxative a~tlYe glu~o~lde~, i.eO

.

1~3t3(~9 sennoside~ A and B, were isolated from the s~nna drug for the first time by Stoll et al. (see Helv. Chim.
Acta, XXXII, Fasciculus VI ~1949), 1892). Subsequently, many patent ~pecification~ have been published which describ~ processes for the preparation of ~enno~ide ~o~cen~rate~.
Hitherto, the preparation of the ^Qenna extract h~ gen~rally ~een carried out in tw~ stages. In the first stage, vegetable pigments, ~ata and other impur-itiea are remo~ed with an appropriate ~olvent, for e ~le chloro~on~, ether (see U.S. Pat~nt Speci~ication No.3,089,814) or with 90~ methanol (see Federal Republic of Ge_ y Patent Specification ~o.16 17 667)~ After this prel~ n~ry extraction~ the active gluco~idea are extracted from the drug in tw~ ~tagee wikh methanol, aq~eous methanol, ~ueous o~hanolior only with water.
In order to faci}itate the extra~tion, the methanol u3ed can be rendered ~lk~llne ~y t~e ~ddition of organi~ ba3es (see Federal ~pu~l~c of Ge. - y Pat~nt .5pecifi~tion ~o.23 397). The ~rganiG base~ fon~
methanol-~oluble ~alt3 with khe senno~ide~ which can ~ea~ily be~extracted. ~o~rs~er, a d~ad~antage o* this proce~ i6 th~t the extract contain~ a high content of impurities.
~t hag al80 keen ~ugge~ted to u~ extra~tio~
301vent~ acidified wi~h citric acid ~see ~l~nc~ Pa~ent v' Speci~ication ~o. M 6611 (lg6g)) or with oxali~ a~id I

12~3~30~3 ~ee Brit~h Patent Specifica~ion No.832,017)O In the latter case, 7~% ethanol wa~ used a~ solvent, If acidic methanol or acidic a~uaou~ methanol i~ u~sd for the extraction, the content of impurities in the extract is ~maller than when the extraction i~ carried out with basi~ 801vent~ or with water alone. ~owe~er, thi~
pro~e~s ha~ the disad~antage khat the sennosiden, which are acidic cc ~-u-3-q, are, a~ free acids, only sp~rin~ly soluble in the ~olvents used. ~onRequently, the amount of 301vent required for the ex~ra~tion i~ very large and can be as much a~ 15 to 20 time~ of the w0ight of the drug u6ed~
For the extra~tion of the drug, it i8 al~o known to use ~ixt~re~ of methanol-tetrah~L~furan, methanol-dioxan and tetrahydrofuran-dioxan acidi~ied wi~h pho~pho~ic acid ~ee ~ung. Telies, 6006 ~1973)) and aqueou~ pho phoric acid (see Federal ~epublic of Ge_ 9ny Patent Specification ~o. 1~ 17 667) a~ ~olvent~. IIo~. ver, these solvents a~tivate the glucosidase enzyme ~o tha~
some of the active gluco3ide i~ hydrolysed, especially when usi~g weaXly acidic ~olution~, the p~ value of which corre~pon~R to that of the original plant material.
~hi8 re~ult~ in a ~e~uc~ion of ~he ~ - -L of a~tive material in ~e extract ~ee also Fs~eral,~ep~hl;~ of Germany Patent ~pecification ~o.29 15 063).
Ac~ording ~o the prior ~rt, the ~enno~id~ ~on~en_ trate i~ obtain~ fro~ the extra~t~ in various way~.

I

~z~!t31~0 A solid, sennoside-con~ n; n~ extract i~ obtained by gentle drying of the extract (~ee Federal Republic of Germany Patent Specification ~o. 16 17 667). ~he product then contains all the ~ub~tances pre~ent in the extract, th~ ~ennoside content of ~he product b~ing about 17 ~o 1~%.
~ owever, the senno~ide~ can be separated more selectively wh~n they are precipitated from a~ueous sol~tiQn~ by the additio~ of organic ~olvents. ~he product obtained contain~ le~s h~ t materials and ha3 a sennoside content of 60 to 7~%. The precipit~tion can be ~arried out by the addition of diethyl ether (~ee French Patent Specification ~o. M 611; ~a~yar G. et al., ~ung. Telje~, 6006 (1973?~ opropyl alcohol, after treatment wi~h a trongly acid ion ~c~n~e re~in (see Briti~ Patent Spe~ification ~o. 832,017) or ethanol (~ee Finni~h Patent Specification ~o. 4158~). The sennQ~ide~ ~n solution ca~ possi~ly be con~erted into the calcium -~a~t3 (see U.S. Patent Spec;~ication ~o~
3,08~,814 and Finnish Patent ~pec;f;cation ~o. 41588) and ~ubsQquently precipitated out by the addition o~
organi~ ~olv~nt~ so ~hat the a~tive glu~o~ide~ are obtained as calcium 3alta. ~he conte~t o~ s~n~ofii~e~
in the precip~tated ~ucL ~hen ~ to abo-~t 60 to 7~%~
For obt~n~n~ pure ~enno~ides~a~ ~ree acids, the ~enno3ides ar~ i~olated a~ calcium ~alts a~d the~e sal~.s I

~Z~38(~

then deco~L~sed wnth oxalic acid ~see Stoll et al., ~elv. Chim. Acta, XXXII, Fa3ciculus VI (1949), 1892).
Thu~, according to these known proce~e~, extract~
and var~ou~ kind~ of co~centrate~ cont~ n~ laxative-active ~ub~tance~ can be pro~nçe~ from the ~enna drug~
Th~ of laxative-active sub~tan~e~ in ~he con-centrates ~pen~ upon the eontent of the~e ~ub~tance~
in the or~inA~ drug and upon the production proce~s used. One dif~culty in the 3tandzrdisatio~ of the ~enna preparations i8 the determination of the ~en~a glyco~ides. ~he dr~g contains various c~ ~ro~n~ which are i~cluded in t~e deten~ination of ~he senna glyco~ides~
~o~.over~ the phy~iological action of the~e individual comro~n~s is not t~e ~am~ Since, with the help of ~on~entional methods of determi~ation, it i~ not pos~i~le to differentiate the senna glyco~ideo ~r~m ~he o~her c~, Lnds ~ich ha~e different phy~iologic~l aetions and po98ibly ~ide reacti~ns, it i~ di~ficult to ~o.l~ce preparations~ startinS~ from ~ .vt:~t.iorlal 3er~a extract~ ich alway3 p~o~lu~e the sam~ and reprod~ribl e action with ~he ~2me do3e,, It iB an obje~t of the3 pre~er~t in~rentlon to p~o-vide a proc:e~3~ for obt~ i n~ laxativ~ c~ fr~
the enna drug ~ h p~nnits t~e laxa~ive-active ~u~
stan~e~ to be o~tained in i, . ..~ed yield in the :rRost ~or~entrated form a po~3ible 5 whic:h are as f :r~e a~s po~iblç3 from c ~ with unde~ired side effe~t~.

3L2Q3~30~

ThUB, according to the pre~ent invention, ~here i~ provided a proce~s for obt~i ni n~ laxative ., . ~,~ul-d~
f rom senna drug, wherein a) the ~enna drug i~ extracted with aqueous methanol by countercurrent perc:olation and the extrac:t con-centrated at a t~mperature of 6 50~C. until the methanol ha~ b2en ~o~pletely ~. v~d fro~ ~he ~xtractS

,, bl the extract o~tained i~ puri~ied by ~on~ o~R
liquid-liquid extra~tion w~th an organic~ ~olvent, c) the refined material (raffinate) obtai~2ed i8 trans-ferr~d to a cry~talli~atisn apparatu3, acidified, while stirring, to a pH of about 1.5 to 2.0, ~ee~C~.
with senno ide ~:rystal~, left to cry~tall:ige while ~tirring an~ the cry~;t~ 1 i n~ ~rude ~a~n~o~i dea obtained ~parated off, d ) whereafter ~he crude senno~ide~ are, if desir~d, recrystalli3ed a~d ~ptionally e) 10 parts by ~eig~t o~ the mother liquor from ~tage c3 mixed, while stirring, with ~ parts by w2ight of ~odium chloride and ~he ~emi-~olid maB~ ~oagul-ated on ~he ~urface i8 d~canted off, ~ Rhed and optionally ~ Le~ ch 95% ~thanol and the met~anol ~rac~tlon c~..ce~-1 L~tea and th2 r~sidue dr~ed.
For ~arrying out the proces~ as:~cording to t~h~
E~re~ent i~v~ntion, mixtures of Iaethar~ol and water ara u~ed in whi~::h the ~nn~ ea are solubl~l, It i~

~2C)3~90a~

preferable to use 70~ methanol ~lnce the -~solubility of the ~enno~ide~ lie~ at a methanol con-centration of 60 to 70%. ~he extra~tion i~ carried out in portion~ and preferably at a ~lightly elevated temp-erature but at mo~t at a ~olvent temperature of ~35 & .
Since there iæ a danger that the Aennosidea would ~e~ ~-se, ele~ated temperature-~ have previously been avoided. ~o~ ve , w~ have,~urpri~ingly, ~ound that the ~ennoside.~ do not 'e~ e at a slightly elevated temp2rature when methanol is u~ed as solvent.
q~he drug extraction i~ carried out in a ccunf,er-current percolation plant. In general, 2 to 4 percol-ator~ are u~ed. If the extraction ~olvent i ~ to be rr^~, it is allowed to circulate through an external heat e~h~n~er in which it i5 thereby ~. ~' to the d~sired te~perature kut at mo~t to 35 & 9 Th~ more per~olators are used, the le~s m~t the solvent be warmed. The extract obtA~ne~ then contains le~s ~ar~-ful impurities and the sennosides ~rystalli~e out com-pletely ~r~m the mother l~quor.
Before the extraction, it ~3 p~eferable to 9well the dry drug in a 301vent, for whi~h pUrpO8~ it i8 pref~rable to u~e the post-percolate from a previo~ly ex~ ~L~d drug~ ~or thi~ pu~poae, the dry dru~ i~
pla~ed in a percolator, co~ered wQth a perforated plate w~th a weight of about 0.7 ~g./dm2 and th~ ~olve~t or po~t-percolate ~ ed in. The weight of the . ; ~ of ~L2~3~3~)0 g ~olvent required is about three times the weight of the dry drug. It ia pre~erably left to stand ovexnight and ~he extraction i8 ~ e' the next day.
~ he extraction take~ place over the cour~e o~
16 to 20 hour~, during which time the nece~a ~ u~,~
of 7~% ~ethanol iq allowed to flow through the dry mas~.
Since it i8 preferable to use eeveral percolator~, when ~arrying out the extraction the ~olven~ ir~t passed into the percolator of the serie~ of percolator~ which contain~ the weake~t drug, i.e. the one which ha~ already been mo~t extracted and which i8 to ke the next one to be emptied. The ~olvent i~ p~ed fr~m thi8 percolator to the next percolator and ~o forth. ~he mai~ extract iR taken fr~m the percolator which wa8 the la~t on~ to be filled~ After removal of an appropriate -~ ~ of extract, there i~ additionally obt~ne~ a poat-per~olat~
wh~ch can be u~ed ~or ~welling a new batch of dry drug.
For thi-~ purpo~e, the percolator cont~inln~ the w~ake~t drug i3 smptied, ~illed with a quantity of drug, the poqt-percolate pa~se~ in and the extraction carried out on the next day~
A~cording to the pro~ess of the pre~en i~Yention, it is po~sible to extract 1 part o ~he dry drug wn~h only 4 part~ of extractio~ ~olvent. If 7~% m~thanol i~
u~ed at ambient temp~rature, then the r~sidual : ul~t of substance in the drug i~ ~out 41~ per per~oIator in the ~eries of percola~or~. With tw~ percolators, the ~LZ03~30(~

extracti~n yield i9 (1 - 0.412) x 100 = 83% and with three percolator~ connected in ~erieA it i~ 0.413) x 100 - 93%.
After khe extraction, the methanol is ~ :ved practically quantitatively from the percolate, the volume of the bottom product obt~inla~ being a~out one fifth of the volume o~ the percolate. The m~thanol .is ~ d with the u~e of a ~. distillation apparatu~
equipped wsth a fractionation column. Re~tl~e of the danger of hydroly~is o~ the senno3ide~, the temperature must not ~-~ce~ ~so&.
The conc~trate obtA; n~ contain~, in addition to the senno~id~, all pLO~UC~8 which can be ~ cLed w~th methanol fro~ the original plant material. The CQ~entrate i8 preferably mixed with about 5% butan-2-ol in ord~r to keep t~e fats in ~he co~ntrate in emulsion and al~o to a~t as a pre~erva~-ive 90 that the grow~h of mlcro-organi~m3 and pu~r~factio~ of the ~olution ~u~e~
thereby are inhi h; ted .
A~ter di~tilling off the methanol, t~e co~centrate is purified by liquid-lisIuid extr~ction with an orgarlic sslvent. ~e ~ol~nt used can be an alcohol or ketsne wllich is partly soluble in water, for P. ~e, h~tanol, me~hyl ethyl ~etone or met~yl i3c~propyl ketone~ the pref~arred solvent being butarl-2-olO l!he li~uid~ uid extraction i8 ~arried out as a continuon~ proce~ a partitio~ing apparatu~ with a ~paration effect of a~o~t 12~13801~

10 theoretical step~. The pH of the fed-in çon~entrate 801ution i~ thereby about 5.4 to 5.6 since, at thi~ pH, the ~alts of the aglucone ~c ~ pre3ent in the senna drug are hydroly~ed to ~uch an extent that the aglucones are removed pra~tically quantitati~ely from the raffinate.
B2fore use, the b~ta~ 2-ol e~ployed ~or the ~xtraction i8 preferably ~aturated ~ h ~ater. The *ed-in conce~late which is to b~ c~ed i~ a very con-centrated solution with a content of dry material of about 20 to 3~%. It ~ntain~ salt~, ~ugar~, amino acid~ a~d other water~oluble ~ which ori~inate fro~ the plant mas~. The extr~tion i8 pr2ferab1y carried out in such a ~nner that the run-off ratio of butan-2-ol : raffina~e i~ ab~ut 0.7 to 0.8 : 1, By means of the li.quid-liquid extraction, ~ata, harmful plant pigment~ hlorophylls and carotin~id3, f r~e f atty acids, steroid~, agluconi~ anthL~rle derivatives, neutral glucoBides ~ ~eget~bla wa~e~ and wax al~ohol ,~flavone~ and other ph~ , etc. are removed fr~m ~h2 solutionO In thi~ way, ~h~ raffinate obtain~d iB fr~ed from hA 'ul i~puriti~ to such an e~t~ hat the ~ain ~ of the ~ennoelde~ can ka cry~talli~ed out dire~tly ~ron th~ raffinat~ pha~e by acidification with a ~ineral a~id to a p~ of about 1.2 tv 2.0, the ~ineral a~id u~d pre~erab~y being hydro-chloric or ~ulphvric acid4 ~2~3~30~9 In order to crystalli~e the senno~ides ~rom th~
raffinate pha~e, thi~ i~ placed in a contai~er and an - -~r.~ of acid i8 p~e~ in, while stirring, until t~e p~ value of the olution i~ a~out 1.5 to 2Ø The ~olUtioR i 7 then ~eeded with ~ennoside c ~tal~ and left to crystallise for 1 week, while ~tirr$ng~
on the other hand, the cry~talli~ation can al90 be ~arried out in a continuou~ly operating cry8talïi3--ation apparatuæ. ~h~ raffi~ate phase ~here~ ~
for about 1 week in this cry~tallisation apparatu3 and iR there'Dy divided betwee~ 2 or more contai~ers cGn~ccLed in ~erie3 which discharge into a de~ er. The crystall-isation container~ are con~;m~o~Aly gently stirred and, fox acidification, a ~olutio~ of the mineral a~id i8 introduced, with ~tirring, into the first containar.
The vertical l~m;nAr ~low in the container~ i8 ~bou 0.3 to 0~4 ~m./minute. Thi9 rat~ of flow en~ure~ a ~ati~facto~y ~e~ tion. The crystallised p~v~u~L
i~ filtered off, ~ ~h~d with water and methanol or acetone and then dried. I~ de~ir~d, ~he ~rude product i~ e~lysLalli~d, a~ Yr7~ne~ hereinaft~r.
A fractio~ o~ ~h~ ~e~na drug which is importa~t with regard to tha biologi~al action~ i8 ~he fra~tion ~oa~in;~ the non ~nno~ide l~xati~e-~cti~e sub$tan~e~
(NSL~S)~ Thi~ fr~tion oc~ur~ in varying ~ -~u~t~ i~
crude drug~, extract~ a~d $enna p~eparation~
addition, the~e ~ubsta~ce~ are for~ed ~71ri n~ the drug ~2~3~(3~

extracti~n. ~he laxative activi~y of th~ crude ~SLAS
fraction amounts to about 6~% of the laxative activity of the muxture of pure ~ennosides. However, the intra~renous toxicity of the :rude ~SLAS f raction l~ Ul~
to about 20 time~ the toxicity of the mixt~re o~ the pure s~nno~ides,. ~he che}nical propertie~ of the 2iSI~S
fraction, its so~ubility in variou~ ~olvents, the partition propertie~ and *he behavivur in the case of ~alt for~nation L~. 'n~ one of the corre~pon~;ng prope~tie~
of the sennoside~.
The ~SLAQ fraction contain~ tbe re ddue~ of the ~enno~ide~ whi~h ~1 -;n in the mother liquor in the caae of the c~yQtallisation o~ th~ raffinate phase a~ter th~ purification extrastion with the organic solventD ~he ~enno~ide content of the crude NSLAS
fraction æmounts to 5 to 10%. Thi~ fraction thereby contain3 5 to 1~% o~ rhein-8-~lucoside a~d 80 to 9~%
of c~ , the chemi-al ~trueture and phy~iological actions of which are hither~o unknown. The crude ~SLAS
fraction can b~ divided into approximat~ly two egually large fractions by le~h;n~ ~ut wi~h 95% methanolO The portion whi~h iB ;n~otuhle in 95% methanol i~ a brown powder. ~hiæ hi~herto unknown c _- ' chromatograph~
in the ~a~e ~f gel chro~ato~L~ y li~ a ~om~ R
0~ UI~ and ha3 a r~tentio~ volu~ w~ orr~pond~
to a mol~ular weight of ro~ 1000 t9 10,000~ ~he portion o~ ~he ~SLAS fra~tion w~i~h i~ ~oluble in 95%

3~0~;9 m~thanol consist~ of ~ ~,G~nd~ with low molecular weight3. This fraction contain~ about 20~ of ~enno-~ides. ~he main portion o~ this fraction con~i~ts of ~ompound~ which hav~ not previou~ly been identified in the senna drug or are ~ ~etely unk~own.
The c~ude ~SLAS fraction can b2 readily ~eparated when the mother liquor of the senno~ides i~ ~ixed wqth a ~alt, for ~ e ~odiu~ chloride. Fsr thi~ pu~po e, after filtering off the ~enno~ides, 2 part~ by weight of ~olid ~odium chloride are gr~u~y added, with con-tinuous ~tirring, to 10 part~ o the mother liquor and stirring is continued for 1 to 2 hour~. Sub~equently, tha semi-solid mass which ha~ coagulated on the ~urface of the ~olid i 9 decant2d o~f fr~m the ~olutio~ A~
by 8u5p~n~i n~ in water, the ~ pPn~ on i~ R~irred over-night and the pr~cipitate allow~d to ~ettls out ~he next day, ~he~eafter th~ bulk of th~ wR~h solution i~
decanted of~. ~he pr~ipita~e i~ ~iltered off with a ~u~tion filter or with a ~iltration cen~rifuge, -~ ~h~
with water and anhydrou3 ~ethanol and dried in a ~urrent of air at a~bient t~mperature. When aen~a pod~
are u~ed a~ raw ~aterial, the yi~ld of ~rude ~SLA~
fraction i9 about 1.5 to 1.6~ o the weight of raw ~aterial u~edv The precipitat$on by ~al~ing ou ca~
al~o be ~arried out from a dilute ~olution.
~ he crude ~en~o~i~e~ ob ained after th~ erystall-isati~n ~an, if de~ired, be recrystalli~d. For thia ~2al3801C~

purpo~e, the crude s~nno~ide~ are ~ pen~ed in a mixture of acetone and water (50:50) to give an approx-imately 10% su~pension, dissolved by the addition of ~odium hydroxide to a p~ o~ about 7.5 to 9, with ~odi~m ~alt formation, and the ~en~osides again precipitated out ~y a~ju~ting the solution with hydrochloric acid to a p~ of about 1.5 to 2, ~eparated off, wn~he~ with ~queous a~etone and dried.
A~cording to the pre~ent invention, the laxative-active c~...~oul~d~ ~ont~i ne~ in the ~enna drug can be divided into two fraction~, ~a~ely, into a 3~nnoside fraction and into an ~SLAS fraction. The latter fraction can be divided into two further fractio~s, ~amely, into a Ure~in~ and into a low mole~ular wei~ht ~ra~tion.
The laxative activity o~ all fractions acco~nt3 for about 9~% of ~he total laxative activity of the s~nna drug. ~he valu~ for the laxative a~tivity ~nd the intravenous toxicity of the fractions, which were detenmi~ed by experiment~ on mice, are given in the following Table:
~BL~

property ~enno~ide crude ~SLAS fraction fraction 9~% ~ethanol- ar~in~
~oluble ~ra~tion fraction laxative action 100 100 ~10 LD5~ . ~g~/~g.~100 4100 130 ~2~3~0~1 ~ hu~, ~th the process according to the preBent invention, it is po~ible to obtain the ~nno~ide~ in t lOOX purity from the crude drug. Furthermore, it i8 al~o po~sible to i901~te the ~SLAS crude ~xaction in a conc~n~rated form frorn the mother liquor~ of the ~eN~osides. In addition, in the case of the p~o~:e~
a~:cordin~ to the present invention ~or obt~ ~i ng laxative-active ~ub~tance~ from ~enna dr~g, a prel i ~n_ ary extraction of the drug i~ no 1~n~er raquired, a~ i8 nece~ary in ~he ca~e c~f ~he previously known proc2sses, Sirlce the ~ennosida~ obta~ned b~ the proca~
according to ~he pre~3erit inventiQ~ are ch~ically ~nd p~ ogically c _ letely chara~cterised, t~ey can be used for the for~u~ation of - 'içi n;~ i tio~ls with definite galenical propertie~. In contradi~tinc:t1 on thereto, acc~ordi~g to the previou~ly k~own pr~e~es, only more or les~ inde~Einite galenie~l extract~ ca~ be obtained.
q~he pre~ent inverltion a:l~o provides laxati~re co~po3ition8 contA; ni n~ at least one laxati~re c _ obt~inP~ by the proc2s~ of th~ preserAt inv~ntiorl, in a~xture with a ~olid or liquid ph~ 7.celltical ~i ~ U~T~t or carrier.
q~he following :E3xa~ are given ~or the purpo~e of illu~trating the pre~ent i~ tion:-r le 1.
40 ks. ,~nl,~ of ~e~a d~g are plac:e!d into tw~

3~

.~7-serie~-conne~ted percolator~ ~ th a volume of 250 litres which are covered with perforated ~teel plates. The sol~ent u~ed for the extraction i9 70% meth~nol which is ~upplied to the drug in ~le fir~t percolator. A
bottom plate covered with a ~ilter ~loth i3 pre~ent on the ~ottom of the percola~or. By ~eans of an emptying coek provided below this plate, the ~olution i8 pa~sed to the dxug pr~sent in the ~econd per~ola~or, the ~ol~ent thereby being allowed to f1QW freely through the fir~t percolator. The rate of flow of the ~olvent i~ adjusted by means of the emptying coc~ on the firs-t percolator~
~he run-off o~ the .~eon~ percolator i~ adju~ted in ~uch a manner ~.hat the level of the ~ol~ent in the second percolator i~ high ~nough to cover th~ p~rforated ~t~el plate, w~ich ha~ a weight of 0.7 kg~/~m2.
~ or the extra~tion of 40 kg. of senna drug, a total of 160 litre3 of solvent are u~ed. After this L of 7~% meth.anol has passed throug~ ~oth p~rcol-ator~ and an appropriat~ ~ - ui~ of percolate ha~ been collected, the emptyin~ pipe o the percolator i8 conn~ted to a po~t-p~rcolate ~ontainex and an additio~al 60 litre~ of 70~ m~tha~ol ar~ p~ed thr4~gh ~h~ percol-ator~. Yherea~ter, residual free eol~ent i~ pa~Qd fro~
the ~ir~t percolator into the upp~r part of th~ ee~ond per~olatbr and the po~t p~rcolate i~ ~olle~tsd until a total o~ L20 litr~ hav~ been obtai~ed. Th~ fir~t per~olator is then emptied, again ~illed with 40 Xg.

~03~0~

~3enna drug and the po~t-percolate i~ on to the dnlg, 120 litres of po~t-percolate being sufficient to ~over the drug in the percolate. Sub~e~erltly, a piped connec~ivn i~ made from the run-off to a pun~
and a heat G~srr~nger and from there to the cover o:E
th~ percolator and the ~olution i~ all~wed o circulate until th~ te~perature of the ~olution iB ~t30 C. It i~
then left to ~tand overnightO
~ he followinçT day, thi~ per~olator i~3 ~onn~t~d to the one previou~ly extracte~ and the extraction carri~d out in the a~ve-described ----r.
For each 40 ~g. of drug there are collected 160 litres of percolate from whic~h the methanol i~ remo~red in a vactlum rotary evaporator eqn;~pe~l with a pAt~ke~9 column. ~out 30 litre~ of bottom produc~t are c>btained whic~ i8 extracted in the Nmixer-~settler~ apparatu~
( 10 stage ) using 40 litre~ of wat~r-~aturateZ butan-2-ol .
About 38 to 40 litre3 of aqueous raffinate are obtained and about 3S:) to 32 litres of butim-2-ol extrac~. The aqueous raffinate i~ acidified wi~h 93~ sulphuric: a~:id~
while stirring, duEins~ the ~our~e of 20 hours, 1~.69G by volume ( re~erred to the ~olume of liquid ~o l~e acid:ii~3d ) thereby being u~ed. ~e acidified ~;olution then haE~ a pH of 1.5 tc: 2.0~ ~t~r ~tirring for ~ further 6 daya, the precipi~ate i~ allo~red to depo6it overnight, :l~ilt~red, 5he~ with water unl:il the wa~h wat~r i8 ~olourlea~, hed wi~h m~than~l and dried in a current o ~ir a~

a ~
~v ambient temp~rature. ~he yield per 40 kg. of raw material is 760 to 790 g. (dry substance) with a sennoside content of 90 to 9~%. ~hu~, the yield i~
about 70% of the amount of 3enno~ide pres~nt in the raw material.
O. 5 kg" of crude produck iB sus3>ended in 5 litre~
of an acetone~ r mixture (1:1 v~v), 48% aqueo~ls ~odium hydroxide are added thereto, while stirring, until the p~l of the ~olution i~ 80 5 to 9 . Insoluble residue iæ filtered off and 35% hydrochloric acid i8 added to the filtrate u~til ~he p~ of the 301ution i~
1.5 ~o 2. Stirring i. conti~ued until cry~talli~ation ~c ~ 8 and then the s~lution iq left to cry~talll~e for at least 3 hour~. The precipitate is filtered of~
~rom the ~olution, wa~hed on the filter with 0.5 litre of water and 0.5 litre of acetone and dried at ambient tempera~ure wikh a current of air. one fi~th of he mother liquor can be mixed with wash water ~nd wa3h acetone and thi~ ~olution u~ed a3 cry~talli~a~ion ~olve~t for the next ~qually large portion of crude product. The yield per 0.5 kg. of cxude product i~ 0,460 kg. ldry ~bstanc~ h a elmosid2 c~lsnl~e~l~ of 9B to 99X.
le 2.
q~he pros:eduxe d2ss:!ribed in ~ le ~ ~aploy~
b~ usi~g thr~e ~erie3-cvr~eeLed perc~olator~ and without nq the 70% mçt~anolO Otherwi~e the pr~:edure i~ a~
describi~d in ~ 1, u~ing 160 litre~ of ~ol~er~t per 3~0~

40 kg. of drug. Prom 40 kg. of drug there i3 obtained 0.890 kg. o~ Qennoside crude product with a ~e~no~ide content of 9~% (dry ~ub~tance)~ The crude product ca~
be recry~talli~ed a~ in r , r - le 3O
Extra~tion, r~moval of methanol fro~ th~ ~xtra~t and liquid-liquid extraction are car~ied out a~ de~-cribed in r-- le 1. A ter t~e treatm~nt wi~h but~n~2-ol, th~ sennoside mixture i~ ~rystalli~ed from the raffinate in a continuously-operating cry~talli~ation apparatus. For ~he ~rystalli~ativn, u~e i3 made of two containers, co~n~t~d one after the other, and a third container a~ decanter, which i8 ~o~-n~c Led i~
0erie~ to the others. Se~i iation of the ~n~o~ide mixture i 8 caxried ~ut in 'ch~ latter container, the ~ain æmount o~ the pre~ipitate there'~y being ~eparat~d from the ~o~her liquor. For ~his purpo~e, the raffinate pha~e obtained after the purifi~atio~ with hutan-2-ol i8 ~QSe~ at a rate ~E about 2 litreR/hour ints:~ the fir~t co~tainer~ 93% Sulphuric a~id i~ ~imul~n~ou~ly , in an - ~u~ of 1.6% by volu~ of the raffi~ateD
into thi~ contain~r~ I~ order to pr~v~n~ ~e~ at at ~hi~ point, ~he liquid in th~ first container i~
~tirr~d continuou~ly. '~he ~ pen~ion fr~m ~he fir~t eontainer i~ ~hen pA~e~ via an ~nres~ te~ overflow into ~he ~e~on~ ~ont~iner, whi~h i~ al~o equipped with a 8ti rrer~ and from there, via an unre~tri~ted o~erflow 38~)~

into th2 third container, where the precipitate i~
allowed to .Qettle, the mother liquor being allowed to run off vla an unre~tricted overflow to a wa3te ~olvent container. The precipitate i~ d fr~m the third decanter, throug~l a cock provided o~ the bottom thereof, in the fonm of a thick ~usp~nsion which i~ filtered wnth a ~uction filter, w~hs~ with water and ~thanol and dried in a curr~nt of air at ambient temperature.
The yield p~r 40 kg. of ~ude material ~ed i~ 790 g., the ~en~oside cont~nt of ~hi~h i~ 91%.

The ~other liquor of r - ~le 1 (o~t~ine~ after the cry~tallisation from the aqueous raffinate) i~
treated with ~odium chloride. For thi~ pu~po~e, 40 litres of mother liquor (Correspon~; n~ ko 40 kg. of or;gin~lly u~ed raw ~aterial) are gr~t~Ally mixed, while Rtirring, with 8 kg. of ~odium chloride. A
brownish, ~emi-solid pre~ipi~ate i~ th~reby obtainedO
S~irring i~ con~lnl~d for ~ hour~ a~d the precipitate i8 macerat~d in ~he 501ution until the ~ext day. The mother liq~tor ~ ~hen deca~ d ~ff from the pr~ipita~e, the pre~ipit~te i5 ~u~n~e~ in 40 litre~ of water, ~he 3~t.~p~n.~ion i~ ~ irred for 20 hour~ ~nd the precipit~te allowed to settle out. The precipitate i~ ~hen ~iltered off wi~h a suction filter, ~ h~ Wit~ a copiou~ L-~of ~ater, dried at ambi~nt temperature in a ~urrent of air and the dried aubstan~e p~e~ khr~ugh a 0.5 ~.

me~h ~ieve. X~ yield i~ 0~60 ~gO

~Q31~0~

The high pre3~ure liquid chromatography (RPLC~
analysi~ shows that the precipitate contain~ about 5%
of senno~ides and al~o 5~ of rhein-8-gluco~ide. The laxative activity o~ this material îs about 58% of the laxative activity o~ the ~enno~ides. The toxicity, determined ~y intra~enous ~ ni~tratio~ i~ LD50 =
430 mg./kg. (mouse)~ Thus, this fra~tion contain3 ~nkno~l c~ whi~h, on the one hand, ha~e a laxati~e acti~ity but, on ~e other hand, po~es~ ~
~reater toxicity than the s~nnnside~. The laxati~e activity ~f thl~ non-~enno~ide fraction acc~ur,~s for about 40% of the total laxat.ive activity of the original drug and of the crude extrack.
48 g~ of the crude ~SLAS fra~tion a~e le~-he~ out 12 time~ wnth 500 mlO - ,unt~ of 95~ methanolO For this purpo3e, the gr~und powder i~ stirred w~th each portion of 95% ~ethanol for at lea~t 2 hour~. The methanol wash fraction~ are c~ ~ n~ and evaporated to dryn~ he weight of the residue obtained i~ 22 g.
Its laxative activity is ~he 3~me a~ in ~he ca~ of th~ pure ~nnoside~ and it~ to~icity i~ L~50 i.v~ ~
4100 ~g~/kg~ (mou~e). m e xe~i~o~ portion, whi~h i8 in~ol~ble in 9~ methanol, i~ dri~d, ~he yield bei~g 20.8 g. The laxativ~ activity i~ than 10% of the la~ative activity of t~e ~enno~lde and ~he toxicity i~
LD50 i.v. - 130 mg.~kgO ~hu~, the ~LA~ fraction l~olated 3~

from ~he mother liquor of the ~nn~ides by ~alting out contain~ laxativ~-active, non-toxic co~pounds of unknown chemical ~tructure which are ~oluble in 95% methanol ~nd ~ very toxic re~inous portion which has only a low laxative activity and the chemical stru~ture of which i 8 al 30 U~CI10~1.
r - le 5.
me ~xtractiLon, li~uid-liquid extraction and re-~ry tallisation described in the following are illu~-trated ~c~ -tically in Figure~ 1, 2 and 3 of the i~lf - ~ -nyi~g drawing~.
The drug ii~ extra~ted at ambient temperature in a 4-~tage cou~ter~urrent percolation plant. For thi~
pu~po~e, 40 kg. of ~enna pod~ are intLoil~ced daily into one of four coni~al containers and weighed down wnth a perforated plate.
7~% Methanol i~ pa~ed in countercurrent through the battery of 4 percolators in an i . t aueh ~hat the rre~hly intro~u~ pod~ are ~omp~etely ~overed with liquid. Ater a maceration period of at least 1~ hour3, per~olation i cont; n~le~ until a total o~ a~out 160 litr~s of 7~% m~hanol have pa~ed ~hrough. ~r~m the ~ontain~r co~ered with fr~h olv~nt, the extraction liquid i~ th~n p~39e~ co~pletely into th~ next con~ainer ~o~ne~ted in ~eri2~ and ~he extraction re~idue dri~d in order to L~ er ~he ~olvent. ~he co~tainer i~ n~w ready to recei~e the next 40 ~g. batch o~ drug ana thi~

~38~

i~ 3witched o~er to the end of the battery. me degree of efficiency of the extraction per percolation ~tage i8 about 6~%. ~rom each 40 kg. of senna pod~, there are obtained about 120 litre~ of primary extract which are con~entrated to about 30 litres under YaCuum in a rotary evaporator equipped with a fractionating column. The temperature in the product container mUBt thereby n~t exceed 50C.
I~ order to keep the followqng liquid-liquid extraction free rom dist~lrb~nce~ the methanol must be c~mpletely removed. After a~er~ ni n~ ga~ chromato-graphi~ally that the ~o~e~trate is free from methanol, it is ~ubsequently mixed with akout 2% of ~utan-2-ol.
The pH value of thi~ extract i8 about 5.8.
For th~ subsequent liquid~ uid extr~tioh, the ooncentrate i2 p~se~ in a 10-~tage mixer ~eparator battery ~each ~tage about 5 litres), without pre~iou~
filtration, ~ounter to butan-2-ol. In the ca#e of a run-in rate of butan-2-ol : extract ~n~ntrate of 1.5 : 1, the xatio o~ butan-2-ol extract : extra~t ra~finat~ i~ 0.7 to 0~8 ~ ha a~era~e r2sidence ti~e ~or ~a~h ~tag~ i8 about 20 minute~
~ he extract raffinate i~ than adju~ted with 94%
phUri~ a~id to a p~ of 2 and pa~ed to a 3-~tage ~rystalli~ation appar~t~
~ o initiate the cry~talli~ation, it i~ ~eed~d an~ ~hen left to ~ry talli~e at ~mbient temperature o~

for 5 day~ he cry~tal ~lurry obtained i~ rsmoved from ~he bottoqn of the third cry~tallisation cont~iner.
q~e withdrawn cry~tal ~lurry 1~ ~uction filtered ar~d the mother liquor returned to the crystalli sation apparatus~, The cry~tal~ are sub~equ~ntly wa~hed with water and then with methanol a~d dried in a vc.~u, at 40C. Crude enno~ide E3 are obtA; n~ with a d~sre~ of purity o~ about 90%. For ecovi:ring the butan-2-ol, the ~utan 2-ol extract i ~ completely evaporated, a dark bro~ to blac~ re idue being obtained. g~h~
di~tillate is again used for the li~uid-liquid extraction .
The crude senno~ide~ Qbtained are then sus~n~rlec~
in an acetone~ ter mixture (50/50) to give a 10%
suspen~ion and c . ~etely dissolved b~ the addition of an a~ue~ls aolution of sodium hyd~4xid~ lmtil the pH is a~ou~ 7 ~ 5, ~odiu~ ~alt formation thereby taking plac~. The sennoside~ ar~ therl prec:ipitat{3d out again by adjusting the pH of th~s ~olution to 2 wit~ hy~ochlvr:ic acidO q~he pre~ipitated pL~ ci, i~ separated off, brie~ly ~ ~he~ with a~Eueous ac~eto~e and driedl In ~hi~ ~day, the~e are obtain6~dl about ~ referr~d to th~ ~er~na pc~d u~ed) of pure ~nno~iLdes (A and B~.,

Claims (23)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for obtaining laxative compounds from senna drug, wherein a) the senna drug is extracted with aqueous methanol by countercurrent percolation and the extract concentrated at a temperature of ? 50°C. until the methanol has been completely removed from the extract;
b) the extract obtained is purified by continuous liquid-liquid extraction with an organic solvent;
c) the refined material (raffinate) obtained is transferred to a crystallisation apparatus, acidified, while stirring, to a pH of 1.0 to 2.0, seeded with senno-side crystals, left to crystallise while stirring and the crystalline crude senno-sides obtained separated off;
d) whereafter the crude sennosides are, if desired, recrystallised.

2. A process according to claim 1, including mixing 10 parts by weight of the mother liquor from c), while stirring, with 2 parts by weight of sodium chloride, decanting off the semi-solid mass coagulated on the surface, and washing and drying the residue.

3. A process according to claim 2, wherein the washed coagulated mass is extracted with 95% methanol and the methanol fraction is concentrated.

4. A process according to claim 1, wherein 70%
methanol is used as extraction solvent in stage a).

5. A process according to claim 1, wherein the extraction in stage a) is carried out at an elevated temperature of at most 35°C.

6. A process according to claim 1, wherein the countercurrent percolation is carried out in a battery of 2 to 4 percolators connected in series.

7. A process according to claim 3, 4 or 5, wherein the countercurrent percolation is carried out in a battery of 2 to 4 percolators connected in series.

8. A process according to claim 1, 5 or 6, wherein the senna drug is swollen in a post-percolate before the percolation.

9. A process according to claim 1, 5 or 6, wherein the concentrate obtained in stage a) is mixed with about 5% butan-2-ol.

10. A process according to claim 1, wherein the organic solvent used in stage b) is butanol, methyl ethyl ketone or methyl isopropyl ketone.

11. A process according to claim 10, wherein the organic solvent used is butan-2-ol saturated with water.

12. A process according to claim 11, wherein the run-off ratio of butan-2-ol:raffinate is 0.7 to 0.8:1.

13. A process according to claim 1, 5 or 6, wherein acidification in stage c) is carried out with hydrochloric acid or sulphuric acid.

14. A process according to claim 1, 5 or 6, wherein the crude sennosides obtained in stage c) are, for recrystallisation, suspended in an acetone-water mixture (50/50) to give an approximately 10% sus-pension, which is completely dissolved by adding sodium hydroxide until the pH is 7.5 to 9, with the formation of sodium salts, whereafter the sennosides are again precipitated out by adjusting the solution with hydrochloric acid to a pH of about 1.5 to 2, separated off, washed with aqueous acetone and dried.

15. A process for obtaining laxative compounds from senna drug comprising:
a) extracting the senna drug with aqueous methanol by countercurrent percolation to obtain an extract;

b) concentrating the extract at a temperature not greater than 50°C until the methanol has been completely removed from the extract to form a concentrate;
c) purifying the concentrate obtained by continuous liquid liquid extraction with an organic solvent to obtain a purified material;
d) transferring the purified material to a crystallization apparatus;
e) acidifying the purified material, while stirring, to a pH of 1.5 to 2.0 to form an acidified solution;
f) seeding the acidified solution with sennoside crystals; and g) separating off the crystalline crude sennoside.

16. A process according to claim 15, wherein senna pods are swollen in a post-percolate before the percolation step of a).

17. A process according to claim 15 or 16, wherein the concentrate obtained in stage b) is mixed with about 5% butan-2-ol.

18. A process according to claim 1, including a step of recovering crystalline sennosides of high purity.

19. A process according to claim 18, com-prising recovering crystalline sennosides in a purity of more than 90%.

20. A process according to claim 19, further including recrystallizing the recovered crystalline sennosides to produce crystalline sennosides in a purity of 98 to 99%.

21. Crystalline sennosides of high purity, whenever produced by the process of claim 18, or by an obvious chemical equivalent.

22. Crystalline sennosides having a purity of more than 90%, whenever produced by the process of claim 19, or by an obvious chemical equivalent.

23. Crystalline sennosides having a purity of 98 to 99%, whenever produced by the process of claim 20, or by an obvious chemical equivalent.