Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
lZ~73Z2
The invention realtes to the preparation of an inclu-
sion complex of N-(l-phenylethyl)-3,3-diphenylpropylamine and
hydrochloride thereof respectively, with cyclodextrin.
The inclusion complex can be prepared by reacting
N-(l-phenylethyl)~3,3-diphenylpropylamine base or hydrochloride
thereof with 1-3.0 mmoles cyclodextrine related to l mmole base
or hydrochloride thereof with stirring at 4-60 C in an aqueous
or ethanolic medium and where required treating the obtained
complex of the base with hydrochloric acid.
N-(l-phenylethyl)-3,3-diphenylpropylamine (referred
to hereinafter as phendiline), is a coronary dilatator calcium
antagonist (see Canadian Patent No. 709,858 issued on September
22, 1964). The substance is an oily liquid and its hydrochlo-
ride salt is used as an active lngredient of a pharmaceutical
composition known under the trade name Sensit. A solid pharma-
ceutical composition can be prepared only from hydrochloride.
Phendiline hydrochloride can not be well wet with water and it
is an extremely hydrophobic substance. Thus the rate and ex-
tent of the resorption of phendiline are not satisfactory.
The aim of the invention was to find a process by which
phendiline or its hydrochloride can be prepared in a form which
is more soluble and thus its resorption can be accelerated and
increased. We have now found that if phendiline or its hydro-
chloride is converted to a cyclodextrin inclusion complex the
obtained complex is much more soluble at a pH and ~emperature
corresponding to the gastric acid than the original molecule.
The ra-te and extent of the dissolution are increased.
-2-
~Z~)~3;~%
The cyclodextrin molecules are known to have a cylin~
dric structure, the inner surface thereof is apolar and thus
they
~r~ -2a-
~7~
~ 3-
are capable o~ binding hydrophobic mole~ules in the form of
a~ incluslon complex. Such hydrophobic molecules may be phen-
diline or it~ hydrochloride, the solubility of which in
water is very poor. Our ezperiment3 showed that when reacting
5 phendiline with cyclodextrins, two molecules of cyclodextrin
form an inclu~ion co~plex with phendiline, which 3urprisingly
loo~e~ one of it~ cyclodextrin ~olecule in an aqueou~
hydrochloric ~olution corresponding to the pH of the gastric
acid and it i9 readily converted to a molecul æ disper~e
10 ~tate. The solubility i~ thus increa~ed and a better
biological acti~ity can be observed. .Jhen 3tirring c~clo-
dextrin~ vigorou~ly ~ith phendiline in an aqueou3 and/or
ethanolic medium7 the phendil~ne molecule displaces the water
molecule~ being in the hollow of the cyclodextrin and due
15 to the formed apolar-apolar interaction an inclusion co~plex
is for~ed.
Thi~ inten~ive di~solution process of the ~olecular
encapsulating o~ cyclodextrin~ combined with salt for~ation
and partial loose of cyclodextrin i9 newc The essence of the
20 proce~s i~ that the ho~t molecule is ionized in the cyclo-
dextrin inclu3ion comple~ of the non-ionic ho~t molecule~
and due to the form~tion of the ionic bond the appearing
inten~iYe charge and the accompanying inte~3ive hydrated
state throw3 do~n the cyclodextrin ca~ing of the ho~t
25 moleculel I~ an inclusion complex o~ a non-ionic ho3t
molecule being not well soluble in water and having a
crystalline grid ~tructure i~ thu3 converted to ionic state,
then the cr~tal ~ranule disintegrate3 explo~ively and the
12~173Z2
-- 4 --
entire amount of ~ub3tance get~ to a molecular disper3e 3tate~
i.eO to a ~olution
The obtained molecule ~tructure i9 relatively well
soluble a~ its one end i3 hydrated due to the ionized state
5 and it~ other end - which i9 apolar to a great extent and
causes thus a poor ~olub.ility of the ~olecule ~ is covered
from out~ide by a hydrophil cyclodextrin ring.
Phendiline is not ~oluble in water, but e~en the
solubility o~ its hydrochloride is extremely poor. If the free
10 ba~e i5 treated with hydrochloric acid, then the hydrophobic
hydrochloride on the surface of the oil drop~ of the base not
only inhibits the di~æolution but the further salt for~ation
a~ well. If one ~olecule of phendlline form~ inclusio~ complex
with two molecule~ of cyclodextri~, a crystalline product is
15 obtained whlch is relatively not .~ell ~oluble in water~
I~, however this inclusion complex gets into acidic
~edium, such as ga~tric acid, then the nitrogen atom of the
phe~diline take~ up proton and beco~e~ thu~ ionic, knock~
down the cyclodextrin ring near to the nitrogen atom. As a
20 re~ult a structure is formed in which the ionic phenylethyl-
amino part of the phendiline is ~ree, predo~inantly hydratPd,
and the apolar diphenylpropyl group forms complex with one
molecule cgclodegtrin. A 2:1 compleæ is converted to a 1:1
complex in in acidic medium, ~hus ~hen the phendiline cyclo-
25 dextrin co~ple~ get~ into an acid, it readil~ getæ to a~olecular disper~e ~tate, i~e. it gets dis~olved.
~ oth the phendiline hydrochloride cyclodeætrin comple~
and the phendili~e cyclodextrin complex are well 301uble in
~LZ073;~
~, .
a-ter. 'l'hus both th" ~:l molar comple~Y of the basis
~orm (active ingredient content about ll 'ju), arld the l:l
molar complex o~ the hydrochlo:ride (active ingredien-t
content oa arl average 21 ',0) show an increased solubilit~
compared to phendiline hy~lrochloride and because o~ its
biological activi~y it is suitable ~or -the prepara-tion
o~ pharmaceutical composi-tiorls.
In order lo p~ove biological activity we
examined -the ef~ect of the inclusion o~' the ac-tive in-
gredient into an incl~sion comple~ with cyclodextrineupon the dissolu-tion and resorption of phendiline and
phendlline hydrochlori(~e under in vi-tro circurl~s-tances~
'llhe in vitro tests we~e jus-ti:Eied by the ~act that the
~neasurements are thus ~luch more reproducab~e -than by
carrying out the tests in vivo.
The (lissolu-tion and -the resorptiorl are subsequen-t
processe~ which depend ~rea-tl,y on each other. Under
physiolo~ical conditions resorption is partially
in~luenced b~ the pII relations at, the place o~ the
resorption and partially by the time spent by tlle
pharmacon a-t the place o~ the resorp-tion.
The average spent ti~le in each segment o~ the
gastro~intestinal system and the p~I values are a~ follows:
in -the stomach 0-30 rnin pH
25 at the be~inning of the
small intestine 30-60 wlin P~ - 5~6
in the ~ur-ther segment
o~ the small intestine 60~360 rmin pH = 6~7
07 3.~:2
- 6 -
The tes~ were carriecl out accordin~ly.
'l'he re~orption -testswere per~ormed on
Sartorius~ M 16750 Resorption rnodel, the used rnembranes
were suitable ~or rnodelling the resorp-tion frorl~ the
stomach ancl ~rorn the in-testine. On -the basi3 o~ the
te~t results the dif~usion (Kd) and the re~orption
rate constant (Ki) vJere calculatecl for the test substances.
The rt-~sult~ are sun1mclrized in the ~ollowi~g table.
~ubstance Kd tcm2 min 1~ K~ [mln l~
from the intestine
:E'ht~ntliline 6~9 x l~) 4 5~1 x lO 3
Phf~rldiline~ cyc~lo- ~ l-2
de~Ytrin-complex 1042 x lO 3 1.24 ~ 10
Phendilin(3.- llydrochloride6~7 x 10 ~ 9 ~9 x lO 3
Phf3ndilinc-h~ldroclllQriclt,- 3 -2
~-~-cyclotle~trin-cc~rrlplf3x1~,71 x 1()- L.52 x 10
Both ~d lnd Ki a~e more than 100 ~ hi~her in
ca~e o~` res~rption ~rorn t~Q itlteStine a9 a consequenct-
~20 of the complex ~orrnation~
'l'he deternin~tion o~ -t~le dis~c)lved (IIIG) ancl
the rcsnrbed (I!fi) active ingredient was per~orrned on
Saxtorius ~M 16751 type Ltise model C~I~ Stricker: Pharm.
Ind. 33, 157 (1971), ~1. Sticlcer: ~ru~s in Germany 14,
93 (1971)~-
l~icr~ure 1 ~ilOWS -the dissolui;ion o~ phendiline
~derna ~k
~2~17'3;2 2
7 --
and phendiline cyclodextrine complex in some seg~ents
o~ lheg~astro-intestinal system in -time where ~ stands
for the dis~ol~l-tion o~ phencliline and ~CD stands ~or
the dissolution o~' the phendiline-ayclodextrine cornplex.
In the 100. minute 75 mg. phendiline base were
dissolved wherea~ the amount o~ the dissolved phendiline-
~D-complex amounted to 150 m~
q'he amoUn-t 0~ the resorbed phendiline, phendiline-
CD-complex as well as phendiline hydrochloride and
10 phendiline-,ydrochloride CD-complex ~rom the gastro
in-tes-tinal tract is shown in ~îgure 2 where I~ stands
~or -the resorbed amol1nt o~ phendiline, ~-CD stands for
-the reso:rbed amount of phendiline-cyclodextrine~-Gomplex,
l~HCl s-tands ~or the resorbed arnoun-t of phendiline~-hydro-
15 chloride and I~lEICl~CD stands ~or the resorbed amount of
phendiline-hydrochloride-cyclodex-trine-complex.
~irnilarly to the di~olu-tion Yal~es both in case
of'-the base and the sal-t the amount o~ the resorbed
ac-tive in~redient from the intestinal tract increased
20 ~o a double value as a result of the complex ~ormation.
~`hus the same ac-tivity can be achieved by a hal~ dosage~
In the toxicological test~ we examined the acute
-toxici-ty of phe~diline, phendiline-cyclodextrine-complex7
and phendiline-hydrochloride and phendiline-hydrochloride-
25 cyclodex-trine-cornplex in mice intraperitoneally. The -test
C subs-tances were admi~istered -to 10 male and 10 ~male
animals in each ~rroup by -the r~eans o~ 5 ,0 Tween 80.
-~
~r~d~ rk
~;~6) ,~3;~2
- 8 --
The dose~s were calculated in case of the complexe~
on phendiline active in~redient. The -test results are
summarized in the f'ollowin~ table.
Intraperitoneal administra ion
Obse~vatio~ time LDs~ (mg.Jk~.)
phendiline 24 47.54
phendiline-c~clo~-
dextrine-complex 24 157.47
phendiline-hydrochloride 1 81.14
phendiline-hydrochloride~
CD-complex 1 160.55
J ministration
phendiline 72 512.41
phendiline-CD-complex 72 624.65
phendiline~h~drochloride 24 522.24
phendiline-hydrochloride~
C~-comple~ 24 954.88
The phendiline cyclodextrin Gomplexes according
to the invention are whi-te powdery microcrys-talline
substances, which can be u-tilized in the form of
pharmaceutical composi-tions. ~he pharmaceutical composi-
tions contain an effective amount of the cyclodextrin-
732;~
9 _
phendiline inclusion eomplex optionally admixed
with pharmaeeutically accep-table organie or in-
organic carriers~ The mos-t suitable forms may be
tablets, dragées9 capsules, s~rups. These eomposi
-tions contain the active ingredien-t admixed with
diluents, such a~ lac-to~e, dextrose, sucrose,
glycine and/or lubricants, such a3 siliceous~ earth,
talcum, s-tearic acid and sal-ts thereof, polyethylene
rrlycol, binding agents, ~illing agents, dyes,
flavouring agen^ts. The co~positions may contain
further biologicall~ active componen-ts. ~he eompo
sitions may be prepared by me-thods known per se,
sueh as mixing, granula-tin~ preparing dragées by
coating. Thè active ingredient content o~ the eompo-
sition~ may vary ~rom 10 to 40 ;~v. rl'he dosage dependson various factors, sueh as the ro~te o~ administra-
tion, the state and age o~ the patient ete.
The details of the invention are furthar
demonstrated in the ~ollowing Examples whieh merely
serve ~or illustration
73Z~
~0
and not for limita~ion.
3xample 1
lQ g. (7.5 mmoles) o~ ~-cyclodextrin contaLning 15 ~,~' of
5 water are suspendèd in 40 ml. of ~Ja~er at room temperature
whereafter 0.96 g. ~3 mmoles) of phendiline in 2 ml. of 96 ~0
by volume are addea dropwise under vigorous stirringA ~he
suspension is then stirred ~or further 5 hours, filtered and
dried. 9 2 g~ of air-dried phendiline~ ~cyclodextrin complex
10 are obtained. Phendiline content: g.7 % by weight. ~.e
product is a white powder without characteristic melting
point. Determination of the phendiline content o~ the
complex: 0.05 g, o~ the product is dissolved in 25 ml, o~
50 ~o ~ volume of ethanol and it i9 sub~ected to photometry
15 at wave length 258 nm against 50 ~ by volume ethanol. The
phendiline content is determined by means of a calibration
curve.
3~ample 2
26.~ g (20 ~moles) o~ ~cyclodextrin containing 15 ~jd
of water are di~sol~ed in a mixture of 350 ml. of water and
- 50 ml. of ethanol of 96 ~ by volume at 60C~ and a mixture
of 3.15 g. (lO mmoles) of phendiline and 40 ~l. of 96 ,0 b~
volume ol ethanol is added within 30 minutes under vigorous
25 stirring. ~he mixture i~ cooled to room temperature within
6 hours and allowed to s-tand overnight at ~4C. ~he
~recipitated crystals are filtered, ancl air dried~ ~hus
28.~ g of phendiline ~-cyclodextrin complex are obtained,
12~73Z2
phendiline conten-t: lG,7 ~JO by weight.
~{ample 3
13.3 g o~ ~ cyclodextrine (10 mmcles) containing 15 ,~
5 humidity are suspended in 10 ml, of distilled ~ater in a
mortar. A solution of 1.55 g, (5 mmole~) o~ phendiline in 5 ~1.
96 ~ by volume of ethanol is added. ~ diluted suspension is
obtained which is homogeni~ed under steady trituration, After
about thirty minutes the suspension becomes oint~ent like and
10 the obtained substance is placed to an exsiccator a~d dried
above phosphorous pento~ide for 24 hour~. The solid complex
which iR ~ree o~ ~olvent and water trace~ is pulverized.
12.5 g. oP phendiline ~cyclodextrin comple~ are obtained,
phendiline content: 11.8 ~J~
2,1 g. (1.~ ~molej of ~ -cyclodextrin containing 15 ~
o~ water are dis~olved in 15 ml. of water at 40~ A ~ixture
of 0,158 g. (0.5 m~ole) of phendiline and 1 ml. of 96 ~,~0 by
20 volume ethanol is added dropwise under stirring. ~he crystal~
start to precipitate during the addition, ~he suspension is
cooled to room te~perature within 2 hours and stored at +4C
overnight. A~ter ~iltration and air drying 0.66 g. o~
phendiline- ~ -cyclodextrin complex is ob-tained, phendiline
25 content: 11.3 ,~ by ~Jeight.
3xam~1e 5
___._
1.0 g, (1.0 ~ole) of ~ e~clodextrin is dissol~ed at
. ~
3;~:Z
,t Z
40 ~ in 7 ~1 of distilled water. A mixture o~ 0.158 g.
(0,5 mmole) phendiline in 1 ml. of 96 ~ by volume ethanol is
added dropwise under stirring. The crystals start to
precipitate during the addition. The ~uspension i~ cooled to
5 room temperature within 2 hour~, ~tored overnight at *4oC,
filtered and dried. 0.5 g. of phendiline ~ cyclodextrin
comple~ is obtained, containing 12~2 ~ by weight of phendiline.
1.8 g. of a cyclodextrin mixture containing 11 -~0
water (dry s~lbstance content according to high pressure
liquid chromato~raphy: 70 ,~ ~ cyclodextrin, 20 ~ cyclo-
dextrin, 104 ~ ~ -cyolodextrin, average molecul~r w~ight:
11517 mmoles: 1.4) are dis~ol~ed in a mi~ture oP 20 ml~ of
15 di~tilled water and 3 ml. of 96 ~ by volume of ethanol at
60C. A mixture of 0.22 g, (0.7 ~ole) of phendiline and
2 ml. o~ 96 ~ by volume of ethanol are added dropwise under
vigorous s~irring. ~he mi~tuxe i3 cooled to room temperature
withi~ 3 hours a~d allowed to ~tand at +4qC over~ight. The
~0 precipitated cr~stalline product is filtered and air-dried
1.3 g. o~ product are obtained, phendiline co~tent. 11 ~ by
~eight
~9~
4 g. of ~-cyclodextrin (3 mmol~s) containing 15 ~0 o~
water are dissolved i~ 35 mlO of ~ater at 60C. A solution
of 1.05 g. t3 mmole3) of phendili~e hydrochloride in R ml.
of 96 ~0 by volume ethanol i~ added dropwise~ ~he mixture i~
~0~73'~
~3
cooled to room temperature ~ithin 5 hour3, and allowed to
stand overnight at +4C. The precipitated white cry~talline
product is filtered and dried. The air-dried phendiline-
-cyclodextrin complex a~sunt~ to 3.8 g., containing 22.2
5 by weight of phendiline hgdrochloride.
~ample 8
13,4 g, (10 mmoleR) of ~-cyclodextrin contai~ing 15
of water are ai~qolved in a mixture of 160 ml, of water and
10 10 ml. of I~ h~drochloric acid at 50~ A 901uticn of 3.15 g.
(10 mmoles) o~ phendiline in ~0 ml. of 96 ~ by volume ethanol
iq added. The mixture is cooled to room temperature withln
4 hours and allowed to stand over~ight at ~ 4C. ~he pre~
cipitated crystc~lline substance i~ filtered and drled. 11.2 g.
15 of phendiline-nydrochloride ~ cyclodextrin oomplex axe
obtained. Phendiline-hydrochloride content: 20.5 ~o by weight.
5.0 g. o~ phendiline- ~ cyclodextrin complex prepared
20 according to 3xample 2 (phendiline content: 10.7 % by ~eight)
are di~sol~ed in a ~ixture of 35 ml. of water and 2 ml. of IN
hydrochloric acid at 37C. ~he ~olution i~ allowed to stand
for 24 hours at room temperature and the precipitated
crystalline ~ubstance i8 ~iltered. 2.0 g. of air-dried
25 phendiline hydrochloride ~-cyclode~trLn are obtained,
phendiline co~tent: 21.2 ~, by weight.
~20732~
3xam~le lC
Roent~en di~fraction as~a~ to prove that accordin~ to
The roentgen diffraction powder diagram~ o~ ~cyclo~
5 dextrin and phendiline ~ cyclodextrin co~plex 3ho~ that the
characteristic reflexion peak~ appear at significantly
di~ferent 2 ~ angle values proving the diPferent crystal
structures. ~s the molecule enclosed to comple~ is liquid
the dif~erent crystal ~tructure~ proves the complex formation.
Th~ o
~ he thermoanalgtical a~ay sho~Js characteristic
difference~ between the phendiline~-pcyclodextrin complex
15 and the physical mi~ture of ~hendiline and ~ c~clodextrin
complex~ Phendilin~ start~ to evaporate respecti~ely to
decompo~e at 150~C and 98 ~,~ mass change can be observed up
to 250C.
Cyclode~trin decomposes at 270C and at 300C ~-
20 -c~clodextrin melts ~ith dec~mposition.
~e physical mi:~ture looses its cyclodextrin water
content at 100 ~ and at 150C to 250C it~ phendiline content.
~he active ingredient releases ~rom the comple~ only when
the cyclodeætrin decompo3e~ i,e~ at 270 to 300C.
~he thermoanalytical assay also ~hows that phendiline
and ~-cyclodeætrin form a co~p]ex at a molar ratio of 1~2.
In case of phendiline eæces3 the exce3s phendiline behave~
l~ke i~ a physical mixture, i.e. the decomposition start~
" lZ07322
already at 150 to 250C.
~2~ .
As~a~ o~ ~olubilit~ of phend-line h~drochloride ~
-cyclodextrin comple~ ~re~ared according to_3x~mple 7.
hendiline hydrochloride 13-cyclodextrin complex
corre~ponding to 200 mg. phendiline active ingredient are
dissol~ed at 37~ and stirred by a magnetic stirrer at
150 rot./~in. ~he active ingredient content of the samples
0 i9 determined by spectrophotometry.
~ he following tabl~ summarizes the result3 OL the
dis~olution rate a~a~: ~
Time ~hendiline h~drochloride ~ c~clode,Y-trin
complex
~inutes phendlline conc. ~./ml.
l 13.3
12.7
12.9
203G 12
13.
120 1~.6
0~22 g, (0.6 mmole~ of phendiline hydrochloride i~
25 stirred at 37C for 3 hours in 3 ~l. of water and in ~ cyclo-
dextrin solutions of ~arious concentration by a ~agnetic
stlrrer at 150 rot./min rate. The concentration of the
dis~olred phendiline hydrochloride i9 determined by spec~ro-
~ 73~2t6
photometry and expres~ed in phendiline equi~alents, The test
result~ are ~ummarized a3 follo~"3:
~-cyclodextrin concentration phendiline ~-cyclode~trin
concentration ~mole
5 mg~ mole/l. mg./ml. mm~e~0 phend.iline mmole
13.2 4.39 13.9 0.95
17,6 5.95 18~6 0.95
22.0 6.94 ~2,0 1.00
26,4 7~51 2~.8 1,10
~he molar ratio value3 o~ ~ cyclodextri~ mole/phendiline
~ole i~ the last column of the table show~ that phendiline
hydrochloride ~orm~ ~ubstantially an 1:1 comple~ with ~ cyclo-
de~trin,
P ~ aining Phendiline 3-c~clo-
phendiline-3-cyclodeætrin complex 398 g.
magnesium stearate 5 g.
colloidal silicic acid 7 g~
B microcry~talline cellulo~s (~vicel .?~ 102) 90 gO
~he aboYe ~ub~tance~ are mixed together, ho~ogenized and
tablet~ o~ an average weight of 500 ~g. and diameter of 13 ~m,
25 are compre~ed from the powder mixture. The tablets contain
on an arerage about 45 mg. o~ phendiline cor~e~ponding to
50 mg. of phendiline hydrochlorideO Thi~ tablet contaLns an
equi~alent amount of acti~e ingredient to a tablet contalning
;
~dQrn~
73ZZ
50 mg. of phendiline hydrochloride.
3~ample 13
-c~clodextr.in accord n~ to Example ~.
phendiline-3 cyclode~trin complex5 g.
methyl-p-o~y-benzoate 0,1 g r
aroma o.5 g.
carboxymeth~l cellulose sodium0,9 g.
microcrystallin~ cellulo~e (Avicel RC) 1,1 g~
sorbitol 35 g.
distilled water ad 100 ml.
Carboxymethyl oellulo3e ~qodiulD is dis~olved in about a
hal~ volume of water9 the microcry~talline cellulose is
15 di~solved in the solution and afte:r swelling of the cellulose
the phendiline ~cyolodextrin complex is admixed to the
solution~ Methyl~p-oxybenzoate, the aroma and sorbit~l are
dissclved in the remaining water and the obtained solution i5
added to the suspension prep æ ed above. The volwme o~ the
20 suspension is filled up to 100 ml. and ho~ogenized,
