Methods for forecasting the usefulness of perfluorocarbons for blood substitutes

Journal of Fluorine Chemistry, 42 (1989) 403-412

403

Received: May 21, 1988; accepted: November 23, 1988

METHODS FOR FORECASTING THE USEFULNESS OF PERFLUOROCARBONS FOR EL000

SUBSTITUTES

STEPHAN RUOIGER Academy

of

Sciences

Chemistry,

of

Rudower

the

G.O.R.,

Chaussee

5,

Central

1199

Institute

Berlin

of

Inorganic

(G.D.R.)

SUMMARY It carbon

is

shown

(PFC)

application being tural of

of

the

additivity

bility

(high

These

findings

of

PFCs,

the

has

most

have

system,

the

support

of

efficient

the

mainly

latter,

from For

the

strucprediction

estimated

by means their

to

Ostwald-ripening

rela-

investigated.

well

corresponds

for the

structure-stability

with high as

on the

PFC-properties

As a basis

reported.

now been

PFCs,

perfluoro-

depends

important

been

correlate

volume

more

rate.

quantitative

volumes of

PFC-emulsion

the

already

PFCs

molar

of

substitution

estimation

stability,

several

molar

group

blood

and excretion

alone,

emulsion

development

for

improved

strategy

tionships

the

stability

formulas

the

that

of

emulsion

synthesis

that

emulsions

was found

of

Lawson’s

emulsion

emulsion

being

It

the

sta-

stability). main

process

deterioration.

INTRODUCTION Perfluorocarbon activity more

because

generally,

a medical under

such

storage

able to transport

emulsions

have

potential

use

transporting emulsions

from

the

much research substitutes

pharmaceutical as well

of

attracted

as blood

ought

conditions

high amounts

be excreted

0022-l 139/89/%3.50

their

as oxygen

viewpoint

different

and should

(PFC) of

oxygen

body

within

to

be nontoxic, as

or,

agents. stable

in the blood

and of

carbon

a reasonable

0 Elsevier Sequoia/Printed

From

stream,

dioxide, time.

in The Netherlands

404

It the

will

from

that

The toxicity

of size

particle size

is

now a major

results below

linked

of

limited

room

surface

activity

oxygen

transport

sure

the

only.

is

also

this

these

-

the

in

trated with

the

the

very

used

the

tural

parameters

rate

and emulsion

of

blood

looking

PFCs

As

obvious,

of

more

for

and their

pres-

use

more the problem

importance is

depend

have

to on the improve-

concen-

been

PFCs.

relationships

of

justified

regarding

useful

oxygen

between

increase

the

efforts

very

The

transport

properties

main

is

partial to

to

one

substitutes

syntheses

we were

task,

is

surface

[l].

either or

well-

substitutes

oxygen

stability. emulsion

for

-

the

up

the

relation

oxygen

has

been

stability

there

blood

and

prevent

a more

agents

unlikely

PFC

significant

or

one

to

emulsion use

direct

elevated

So that

Accordingly,

PFC-emulsions

of PFC

at

has of

substitutes

proposed

capacity

are

to

emulsifying

blood

emulsion.

on selection this

on

claimed).

frozen

enhance

To

because

on emulsion

of

perfluorocarbon. ments

mainly

components

which

be stored

blood

of

of

improve

rate all

with

its

disadvantage

chemistry

measures

whole

dependent

that

colloid

of

of

excretion say

such

from

stability

particles.

in

capacity

PFCs

depend

200 nm are

serious

must

and toxicity

level

content

PFC

it

However,

for

To

efficient

that

emulsion

emulsifier.

storage

The most

common practice

reaches

with

problem.

deterioration active

properties

(diameters

DA 20 is

is

these

an emulsion

known Fluosol it

all

emulsified.

the

Particle to

be shown

perfluorocarbon

Faced

between

solubility,

also

struc-

excretion

stability.

EXPERIMENTAL PFC

tions

data

were

were

done

DISCUSSION AN0 The

properties for Here

the

of

aim

even working

we report

taken

from

on a Robotron

the

literature

A 5120

cited.

The

computa-

microcomputer.

RESULTS

our

investigations

for

hypothetical

preparative the

state

was the compounds

prediction

of

as

guiding

principles

of

PFC-properties.

chemist. of

predictability

these

405

Oxygen

solubility:

system

for

volume ity. of

of

estimation

PFCs

Using useful

system

many

about

half-life

between

of

carbon

found,

by eqn.

On the

al.

) of

[7]

as

1 (obviously,

the

molar

basis

weight

of

a very test

animals

of

and

expossible

relationship and the

fluorine

are

other

[5],

thorough

close

of

heteroatoms

not

rate, with

a number

number

not is

excretion

property

studied

within

PFC

parameter

the

[4],

range

strategy.

this

among others,

(NOC) as well

of

pressure

solubil-

solubilities

a narrow this

correlate

[6]. et

oxygen

a synthesis

importance

vapour

(rl,2

atoms

expressed

the

temperature

They

Therefore,

made to

oxygen

that

within

lie

additivity

and molar

estimate

[3]

of

a group

vaporization

also

show PFCs

Yamanouchi

developed of

could

could

of

been

as e.g.

work

correlations.

[2]

development

Because

solution

perimental

energy

they we

the

have

PFC-parameters, critical

al.

of

50 % as maximum. in

rate:

attempts

et

hypothetical)

important

Excretion

which

by

this (also

exceeding very

Lawson

the

less

number

atoms

(NOF)

important

in

this respect).

log’G1,2 = 0.254 (20.035) 1 we calculated

By Eqn. the

NOF- 0.151 (20.077)

half-life

values

the of

5,

(1)

NOC- 2.19 (21.06)

NOC and NOF, respectively, 10,

20 and 30 days

which

(Table

1).

TABLE 1 Relation ,S/2

PFC half-life

between

and structural

data

for

NOF

(retention

NOC and

given

in

a body)

NOF

NOC

and

wanted

t1,2

Idays/

NOC NUL

t:

8 10

x

l/2

= 5

V l/2

= 10

Z1,2

= 20

21,2

= 30

16.1”

17.3

18.5

19.2

17.3

18.5

19.7

20.4

12

18.5

19.7

20.9

21.6

14

19.7

20.9

22.1

22.8

16

20.9

22.1

23.2

23.9

decimal

numbers

are

given

for

orientation

only

fit

406

From Table carbon

1 one

atoms

short

time

with

cording

to

see

that

a perfluorochemical

and 18 fluorine

retention

compound

can

10 carbon

Table

atoms

atoms

1 should

is

between

(Z1,2

likely

to

5 and 10 days)

but

have

more

with

20 fluorine in

a Zl,2

10

exhibit

a

than

atoms,

the

e.g.

range

another

which from

ac-

20 to

30

days.

Emulsion

stability:

contribute These

to

are

latter

stepwise

two

result

particles

tively

low

Ostwald

as

can

We

estimated

sequently

the calculated

values

stability

in

water; of

volumes

Lawson’s

some

water.

of

un-

by comparaemphasize

[EI, 91.

Following

stability

their

of

any PFCs

From Hildebrand’s for

PFC

v = molar

parameter;

solubility

in

PFCs

subscript

and solubility

water

additivity solubilities

this in

volume; 1 = water;

vaporization

group

obtained for

dispersed

emulsion

The

2):

PFC

their

can

perfluorocarbon aggregates

expression

E = energy

molar

using

The PFC-solubilities sion

of

in

ripening.

researchers

in

following (eqn.

the

process

estimate

which

emulsions.

reversibly Soviet

solubility

2 = PFC;

PFCs by again

be

solubilities

be derived

of

results

decisive to

the

= molar fraction x2 d = Hiidebrand’s subscript

the

their theory

can

mechanisms

of

droplets

forces.

we tried

by calculating solubility water

larger

which

ripening

main

and Ostwald

coagulation

mechanical

argumentation

three

destabilization

in

whereas

are

coalescence

coagulation,

emulsified, changed

There

Fig.

way are 1.

parameters system according plotted

The necessary

of

some

and conto eqn.

against

2.

emul-

stability

are taken from Rozenberg and Makarov [ll] (quantitative

values) as well as from Riess and LeBlanc [I21 and Yokohama et al. [I31 (qualitative values).From Fig. 1 two conclusions are evident: firstly,the solubility values are too low to have physical significance and secondly, they reflect nevertheless- roughly the order of emulsion stability. The correlation between Rosenberg's sta-

407

I

I

1

091

10

PFC

EMULSION

100

STABILITY

IDAYS

1. Emulsion stability (exper.) and water solubility Fig. (talc.) of some PFCs (abbreviations see Table 2) 0 from [ll]; quantitative evaluation: Stability data: __- from 1121 (“poor, fair, good, very good, excellent”), from [13] (“fair, good, excellent”)

bility the

values

and PFC

differences

“good”, water

between

“excellent”)

even

95 % significance could

bility.

To

bility are

data. from

be

The

Aprosin

PFC emulsion

with not

is

It

basis

for

stability

respect

looks the

this

we looked

most

to

accurate

as

data

if

the

more we

the

rate

of

= 0.64)

classes the

estimation for

(r

(“fair”,

particle

water of in

(t

- test;

solubility

its

accurate

found

and

corresponding

significant

and Kolpachkova[l4].They

stability

poor

statistically

level). the

prove

solubility

Yokoyama’s

are,

solubilities,

a PFC

water

emulsion emulsion

the

introduced

of stasta-

literature as measure

growth,extrapolated

for to

408 TABLE

2

Abbreviations

of

perfluorocarbons

F66E

Bis-F-hexylethene

FHE

F-dihexylether

FTEiA

F-tributylamine

FOBPA

F-dibutylpropylamine

used

in

F76M

F-N-(p-methylcyclohexyl)hexamethylenimine

FPE

F-dipentylether

FOEHA

F-diethylhexylamine

FPMP

F-Z-methoxy-Z-pentoxypropane

FTPA

F-tripropylamine

FBMA

F-dibutylmethylamine

FPP

F-N-pentylpiperidine

F44E

bis-F-butylethene

FOECMA

F-N,N-diethyl-(p-methylcyclohexyl)amine

FPH

F-3-propoxy-Z-methylpentane

FNBP

F-N-butylpipecolinc

F66M

F-N-(p-mcthylcyclohexyl)piperidine

FMBCH

F-l-methyl-4-tert.

FTN

F-trimethyl-bicyclol3.3.l)nonane

FEFA

F-N,N-diethyltetrahydrofurfurylamine

F66

F-N-cyclohexylpiperidine

FMA

F-N,N-dimethylcyclohexylmethylamine

FNPP

F-N-propylpipecoline

F56

F-N-cyclohexylpyrrolidine

Fig.

butylcyclohexane

FDMMCA

F-N,N-dimethyl-(p-methylcyclohexyl)amine

FM01

F-N-methyloctahydroisoindole

FE01

F-N-ethyloctahydroisoindole

FMPCH

F-l-methyl-4-isopropylcyclohexane

FHQ

F-N-methyldecahydroquinoline

FBC

F-bicycle-[5.3.0]decane

FOCI

F-1-oxadecalin

FOHQ

F-octahydroquinolizine

FDC

F-decalin

FHA

F-decahydroacenaphthene

FHI

F-perhydroindane

1

409

the

time

Table

the

emulsion

3 shows

together

for

with

was prepared

some

water

molar

The correlation

between

(r

exists

an even

i.e.

= 0.936)

molar

log

closer

= -0.020

w.

taken

calculated

stability with

24 hrs). from

Aprosin,

according

and water

Rozenberg’s

relationship This

by eqn.

nm per

to

eqn.

is

much

volumes.

than

volume.

by expressed

in

wo-values

solubilities,

and additionally better

PFCs the

(w.

to

relation

is

solubility

data;

however,

a much simpler

plotted

in Fig.

there

parameter, 2 and can

4:

v + 6.315

(r

= 0.941)

(4)

TABLE 3 Comparison growth

of

emulsion

stability

water solubility (according [141), volumes (calculated according to

Lawson

for

some

time

(rate

taken

4)

to

w.

zero,

Table

extrapolated

eqn.

particle Aprosin

2),

and molar

[2],

W

(FDC)

F-decahydroacenaphthene

F-2-methyldecalin F-tripropylamine F-tributylamine

234.6 242.3

150

-43.5

211.9

(FMBCH) 18.8

-58.9

283.2

5.3

-53

251.3

(FPI) (FBMA)

(FTBA)

F-dibutylether

265.0

-62.6

286.7

4.82

-62.6

286.7

0*

-77.3

356

-59.2

267.2

-69

313.4

0*

(FHE)

F-N-propylpipecoline

-55.2

1.3

(FPE)

F-dihexylether

5.9 6.3

11.1

(FEE)

F-dipentylether

(FNPP)

F-N-(p-methylcyclohexyl)piperidine

V

-46.7

(FTPA)

F-dibutylmethylamine

x-2

-46.9

(FMIJC)

F-5-isopropylperhydroindane

log

97.6 (FOMCH)

butylcyclohexane

0

64.3

(FHA)

F-1,3-dimethylcyclohexane F-1-methyl-4-tert.

see

PFCs

PFC

F-decalin

of from

(F66M)

-78.8

359.6

8.7

-54.1

256.8

3

-60.5

296.2

F-N,N-dimethylcyclohexylamine

(FDMCA)

35

-49.1

233.7

F-dimethylaminoperhydroindane

(FDMAI)

4.1

-53.1

264.5

2.1

-62.1

296.6

F-N,N-diethyl-(p-methylcyclohexy1)amine * estimated

value

for

In w

0

= -2

(FDECMA)

2,

410

c

, . 250

200

.

.

-

, * 300

’

.

*

I . 350

molar volume v Icm’(

Fig. 2; in term

Correlation between emulsion stability (expressed of velocity of initial particle growth) and molar volume of some PFCs(abbreviations see Table 3). Stability data from 1141; molar volumes estimated according to [2] (see Table 3).

According rate

of

to

eqn.

particle for

explanation

this

Ostwald-ripening. coarsening emulsified driving sures

4 high growth,

liquid)

: smaller

stability

linked

phenomenon

with

can

Ostwald-ripening

by transferring force

emulsion is

of

from this

droplets

be is

of high

given

smaller

process have

droplets is

the

higher

on the

a process

perfluorocarbon

(or to

difference vapor

a PFC,that

molar of more

larger in

pressures

is

volume.

low

An

basis

of

emulsion generally, droplets.

vapour than

The pres-

larger

411

TABLE

4

Partial

contributions

molar

PFC

volume

structural

the

23.1

-

CF -

-38.3

-N-

-16.3

-o-

19.0

5-ring

37.7

6-ring

39.9

diffusion of

it

can

water

for

PFCs

portant,

of

Table

1)

has

290

cm’/Mol,

are

preferably

well as

if water

more

prediction

of

the

as

a possible

rate search

to as

shown cyclic

and emulsion for

number a high in

most

carbon

molar Fig.

with

PFCs

of

2).

and contain

volume

stable

(equal

Obviously, oxygen

atoms

ex-

properties for

stability (as

the

emulsions.

basis

synthesis

are

a small

to Thus,

should

important

atoms

able

determine

molecules

PFC

and give

are droplets.

PFC

should

Larger

rates

molecules

PFC

substitutes to

atoms as

[Z])

emulsified

through

PFC

diffusion

As excretion one

proceed between

deterioration.

blood

fluorine

only

layer

rate

emulsion

smaller

al.

-15.0

-c-

the

et

to

V

CF2 -

strategy. of

Lawson

-

Our aim was the of

from

element

However,

hibit

(taken

elements

54.8

penetrate rate

structural

CF3

-

ones.

of

ratio

most of

number

exemplified to

such (see

or

in

larger

than

compounds Table

im-

4).

412

REFERENCES U. GroB, H.

Reichelt and E. Dijhring, Tenside/Detergens

(1988) in press. 0.0. Lawson, J. Moacanin, K.V. Scherer, T.F. Terranova and J.D. Ingham, J. Fluorine Chem., -12 (1978) 221. H. Meinert, U. GroB, M. Kupfer, St. Riidiger and L. Kolditz, Periodicum biologorum, 87 (1985) 141. R. Naito, Plasma Forum,Tl980)

153.

J.G. Riess and R. Follana, Revue Franc. de Transf. et d'Immuno-hematologie, -27 (1984) 191. L.C. Clark, Jr., and R.E. Moore, U.S. Pat. 4 289 499 (1981) (to Childrens Hospit. Med. Center). K. Yamanouchi, M. Tanaka, Y. Tsuda, K. Yokoyama, S. Awazu and Y. Kobayashi, Chem. Pharm. Bull., -33 (1985) 1221.

e A.S. Kabalnov, Yu.0. Aprosin, 0.6. Pavlova-VerSvkina, A.V. Pertzov and E.D. Shchukin, Kolloid. Zh., -48 (1986) 27. (Russian) 9

A.S. Kabalnov, A.V. Pertzov and E.D. Shchukin, J. Coll. Interface Sci., 118 (1987) 590.

10

J.H. Hildebrand and R.L. Scott, 'The Solubility of Nonelec-

11

G.Ya. Rozenberg and K.N. Makarov, Zh. vses. khim. ob. im.

trolytes ‘,

Reinhold Publishing, New York, 3rd Edition, 1955.

Mendelejeva, 30 (1985) 387. (Russian) 12 13

J.G. Riess and M. LeBlanc, Pure Appl. Chem.,,-54 (1982) 2383. K. Yokoyama, K. Yamanouchi and T. Suyama, Life Chemistry Reports, 2 (1983) 35.

14

Yu.0. Aprosin and N.A. N.I. Afonin (ed.),

Kolpachkova,

in A.G. Fedorenko

and

'Biol. Akt. Emul'sii Eksp. Klin., Tsentr.

Nauchno Issled. Gematol. Perelivaniya Krovi', Moscow, 1983, 32-50. (Russian)