Perfluoro polycyclic compounds for use as synthetic blood and perfusion media

Novel emulsions of non-aromatizable perfluorinated compounds are useful as blood substitutes or as perfusion materials for the storage of organs such as kidneys prior to transplant. The compounds employed are polycyclic compounds and emulsions prepared from the perfluorinated derivatives thereof possess extremely high stability, zero or extremely low ultimate residue in the body, and a vapor pressure which is just about right for use in the body without adverse effects thereon.

BACKGROUND OF THE INVENTION 
The need for synthetic blood is well known. Blood is becoming increasingly 
expensive, it is perishable, it must be matched to the blood type of the 
recipient and the transfusion itself can cause hepatitis if rigid 
procedures are not followed. In addition, blood donations tend to be 
somewhat seasonal and they often do not coincide with the generally random 
demands therefor. 
A synthetic blood must have several characteristics. Initially, and quite 
obviously, it must have high oxygen and carbon dioxide solubility since 
its principal function is to transport oxygen and carbon dioxide. A 
synthetic blood also must be non-toxic and in this respect it is desirable 
that when the synthetic blood is replaced by natural blood there is no 
residue of the former left in vital body organs. 
Another characteristic of blood substitutes is that they must have certain 
vapor pressure requirements. The blood substitutes leave the body by being 
exhaled and by vaporization through the skin. Preferably the substitute 
leaves the body at about the same rate that new natural blood is being 
generated by the body. If the vapor pressure of the substitute is too low 
it stays in the body too long, wheres if it is too high it evaporates 
throughout the body's surface and may create problems akin to the "bends". 
Blood substitutes must also be capable of forming very stable emulsions 
with this capability being even more important with perfusion materials. 
Fluorocarbons are usually immiscible with blood and if used alone could 
cause embolisms. This problem is overcome by using it in an aqueous 
emulsion and obviously the emulsion should not separate in use or storage. 
In connection with perfusion materials this stability is even more strict 
because the oxygenators used to add oxygen to the perfusion material may 
catalyze emulsion breakdown. Another reason aqueous emulsions are employed 
is that salts are added to the water in order to maintain the body salt 
balance. 
The Green Cross Corporation, Osaka, Japan, has published a pamphlet dated 
Sept. 11, 1974 on perfluoro emulsions as oxygen and carbon dioxide 
carriers Also Clark et al. report on some of the compounds described in 
the present invention in Microvascular Research, Volume 8/3, 1974, also 
presented at the Oxygen Transport to Tissue Symposium, Atlantic City, 
N.J., Apr. 11, 1974. Certain of the subject matter of this latter article 
is also taught in U.S. Pat. No. 3,911,138 issued Oct. 7, 1975 to Clark 
which broadly describes cyclic perfluorohydrocarbons useful as blood 
substitutes and the like. 
The blood substitute and perfusion material of choice as described by these 
articles is perfluorodecalin. It has a number of desirable properties, but 
the compounds of the present invention are unexpectedly superior to 
perfluorodecalin in several respects, in particular emulsion stability, 
reduced liver retention time, and low toxicity, as described in detail 
below. 
SUMMARY OF THE INVENTION 
The novel blood substitutes and perfusion compounds of our invention are 
non-aromatizable perfluorinated polycyclic compounds having 9-18 carbon 
atoms and at least two bridgehead carbon atoms linked through a bridge 
containing at least one carbon atom. They have high oxygen solubility, 
very low body residue, form very stable emulsions, and have a very 
satisfactory vapor pressure for one or both uses.

DETAILED DESCRIPTION OF THE INVENTION 
The non-aromatizable polycyclic perfluoro compounds suitable for the 
present purpose are those having two bridgehead carbon atoms linked 
through a bridge containing at least one carbon atom. By the term 
bridgehead carbon atom is meant a carbon atom bonded to three other 
carbons in a cyclic compound having 2 or more rings. By the term 
"non-aromatizable" is meant a polycyclic perfluoro compound whose ring 
structure cannot be aromatized without destruction of its original 
carbon-to-carbon cyclic bonds. Thus, the perfluoro compounds of this 
invention are to be further distinguished from the perfluorodecalin above 
mentioned or other similar compounds which can be aromatized. This 
invention thus employs the perfluoro derivatives of such C.sub.9 -C.sub.18 
polycyclic compounds as bicyclononanes (e.g. bicyclo[3.3.1]nonane, 
2,6-dimethylbicyclo [3.3.1]nonane or 3-methylbicyclo[3.3.1]nonane), 
adamantane, methyl and dimethyladamantane, ethyladamantane, 
tetrahydrodicyclopentadiene, methyl and dimethylbicyclooctanes, 
ethylmethyladamantane, ethyldimethyladamantane, tetrahydrobinor-S, 
methyldiadamantane, triethyladamantane, trimethyldiadamantane, 
ethyldimethyldiadamantane, pinane, camphane, 1,4-6, 9-dimethanodecalin, 
bicyclo[4.3.2]undecane, bicyclo[5.3.0]decane and the like, or mixtures 
thereof. They can be made by known means. Preferably the polycyclic 
contains 9-12 carbon atoms and it generally will have not more than four 
rings, usually 2-3 rings. 
As synthetic blood, C.sub.8 materials (in perfluorinated form) have too 
high a vapor pressure to be useful. The C.sub.10 and C.sub.11 materials 
are just about right whereas the C.sub.9 s are a little on the high side 
re vapor pressure and the C.sub.12 s are a little on the low side. 
C.sub.10 and C.sub.11 materials have atmospheric boiling points between 
about 125.degree.-165.degree. C and this is a satisfactory criteria, with 
the preferred range between 125.degree. and 145.degree. C. This preferred 
range will be mostly C.sub.10 materials. 
It should be noted that even though C.sub.12 s are not suitable as blood 
substitutes they, and up to C.sub.18 s, can be used as perfusion compounds 
as in this application vapor pressure is not as important. Above C.sub.18 
the oxygen solubility of the material is generally too low. 
The polycyclic material is used in perfluorinated form. For the present 
purpose the term perfluorinated includes C.sub.9 -C.sub.18 polycyclics 
which are at least 95% by weight completely fluorinated (i.e., 
perfluorinated in the strict sense), preferably at least 98% and more 
preferably 100%. In all cases of less than 100% the balance will of course 
be highly fluorinated. 
The fluorination is carried out by known means. For example, the 
hydrocarbon or partially fluorinated hydrocarbon is passed slowly over a 
bed of CoF.sub.3 containing 2-3 times the stoichiometric amount of 
fluorine at 250.degree.-275.degree. C which effects partial fluorination. 
The procedure is then repeated at 300.degree.-350.degree. C to effect 
complete fluorination of all but a few percent impurities which are both 
saturated, partially fluorinated compounds and olefinic fluorocarbons. The 
former boil at least 10.degree. C higher than the desired perfluoro 
compound and are removed by distillation. The latter boil at essentially 
the same temperature so they are extracted with an amine such as 
diethylamine (DEA). Residual amine is removed with concentrated H.sub.2 
SO.sub.4. Residual acid is removed with 1% NaHCO.sub.3 solution which is 
then extracted with acetone. Finally, residual acetone is distilled off. 
It has been found that in some instances, vigorous perfluorination of the 
cyclic hydrocarbon results in partial ring-opening of the starting 
material, with the result that the perfluorinated product may actually be 
a mixture of some of the above-described polycyclic materials. Thus, for 
example, the perfluorination of methyladamantane by known means, 
principally involving, for example, CoF.sub.3 as the perfluorinating 
agent, provides a mixture of perfluorodimethylbicyclo [3.3.1]nonane and 
perfluoromethyladamantanes, while the corresponding product of 
dimethyladamantane is perfluorotrimethylbicyclo [5.3.0]nonane and 
perfluorodimethyladamantane. Similarly, perfluorination of 
tetrahydrodicyclopentadiene yields perfluorobicyclo [5.3.0]decane and 
perfluorotetrahydrodicyclopentadiene. These compounds of these mixtures 
may be separated by conventional means, as for example by distillation, 
chromatographic techniques and the like, and formulated individually. If 
desired, the mixtures themselves may be used instead in the blood 
formulations. 
Alternatively, as described in copending application Ser. No. 771,873, 
filed Feb. 25, 1977, in the name of Robert E. Moore and incorporated 
herein by reference, when the polycyclic hydrocarbon is first partially 
fluorinated under mild conditions with fluorinating agents other than 
CoF.sub.3 followed by vigorous perfluorination, with, e.g. CoF.sub.3 
little if any ring-opening results, and a substantially pure 
perfluorinated product corresponding essentially to the said hydrocarbon 
starting material is obtained for use in the described formulations. 
The perfluoropolycyclic is employed as a water emulsion containing more 
than 40% water by volume. Preferably the emulsion contains 10-30 volume 
percent of the perfluoropolycyclic. Normally the emulsion will contain 1-5 
volume percent of an emulsifier. The specific emulsifier employed is not 
critical but it should itself be nontoxic and should form a stable 
emulsion. The preferred emulsifier is a yolk-phospholipid as this is well 
known to be harmless in the body. Also suitable for perfusion purposes are 
the polyoxyethylenes and polyoxypropylenes available commercially as 
"Pluronics". "Pluronic F-68" has a molecular weight of 8350 and forms a 
very stable emulsion. However, it has been reported that "Pluronic" type 
materials precipitate plasma protein and hence they are preferably limited 
to perfusion, with the commercially available yolk-phospholipids used for 
blood substitutes. 
The emulsion can be formed with conventional high shear emulsifiers such as 
the Manton-Gaulin homogenizer. Typically, the particle size of the 
perfluoropolycyclic in the emulsion is 0.001-10 microns, frequently 
0.01-10 micron, usually 0.05-0.5 micron and preferably 50 weight percent 
of the particles have diameters of 0.05-0.3 micron. As is well known the 
particle size can be adjusted by the amount of shear employed. The smaller 
particle size is preferred since it has been found that the resulting 
emulsions are more stable as particle size is reduced. 
As indicated above, retention of the material in the body is important. The 
data below compare perfluorinated tributylamine (PFTBA), decalin (PFD), 
and methyldecalin (PFMD), with certain of the perfluorinated polycyclic 
hydrocarbons of this invention which have been obtained by perfluorinating 
the said polycyclic materials with just CoF.sub.3. Thus, in the table 
below "PFDMA" is the perfluorinated product derived from 
dimethyladamantane, i.e. a mixture of perfluorotrimethylbicyclo 
[3.3.1]nonane containing about 25 percent of other materials, principally 
perfluorinated dimethyladamantane. "PFMA" is the perfluorinated product of 
methyladamantane i.e., a mixture of perfluorodimethylbicyclo [3.3.1]nonane 
containing an unidentified amount of other compounds including 
perfluoromethyladamantane. Finally, "PFTHDCP" is the product of 
tetrahydrodicyclopentadiene, i.e. perfluorobicyclo [5.3.0] decane 
containing about 50 percent of other materials, principally 
perfluorotetrahydrodicyclopentadiene. 
Emulsions containing 10% of the material to be tested, surfactant and water 
are made up and tested in the manner specified in Science, Vol. 181, 
August 1973, page 681. Mice were injected with the various emulsions. The 
mice were killed at intervals thereafter, the liver analyzed, and the 
percentage of original amount of PF material injected and still in the 
liver was determined. The data below show these results. 
______________________________________ 
Percent of Dose in Liver 
After Stated Weeks 
Material 2 6 12 20 
______________________________________ 
PFD 4 2 2 -- 
PFMD 30 19 2 2 
PFTBA 38 30 30 30 
PFDMA 35 28 23 2 
PFMA 7 1 -- -- 
______________________________________ 
It is apparent that the PFMA (which had a small amount of higher boiling 
impurity which retards its release from the body) is as good or better 
than PFD. Even the PFDMA gets down to the 2% level of the PFD but it does 
take longer. 
The corresponding results of the liver and spleen analysis of mice infused 
at 150 cc/kg with PFTHDCP was as follows: 
______________________________________ 
TIME FROM % IN % IN 
INFUSION LIVER SPLEEN 
______________________________________ 
3 wks. 15.21 6.71 
3 wks-6 days 3.83 3.38 
______________________________________ 
The relative stability of a PFDMA emulsion and PFMA is excellent in that it 
is stable indefinitely, (e.g., over 6 months) at 4.degree.-7.degree. C 
whereas the PFD emulsion breaks down in several days at room temperature 
and in several weeks at 4.degree.-7.degree. C. PFTBA is also excellent. 
See for example the Journal of Microvascular Research, August 1974. In 
addition to emulsion stability, emulsion prepared from PFDMA and PFD (in 
the same manner) show optical densities of 0.1 and 0.4 respectively, which 
means that it forms a transparent emulsion in contrast to a 2.2 optical 
density obtained with PFTBA. The latter emulsion is very milky in 
appearance, indicating a larger particle size. 
It has also been found that our perfluorinated materials are very nontoxic. 
The LD.sub.50 after infusion (ml/kg) of our materials compared with others 
are follows: 
______________________________________ 
LD.sub.50 
Emulsion 1 Hr. 3 Days 7 Days 
______________________________________ 
10.9% PFD 190 160 159 
10 % PFDMA 200 175 175 
5 % PFMA 200 200 200 
10 % PFTBA 200 120 120 
______________________________________ 
As noted above the perfluorinated materials of the invention have high 
oxygen and carbon dioxide solubility. For example the perfluorinated 
materials can normally contain about 40-60 cc oxygen per 100 cc 
fluorocarbon and the carbon dioxide solubility is about twice this. 
Normally blood will absorb about 20 cc oxygen per 100 cc of blood with 
carbon dioxide solubility being twice that of oxygen. The compositions of 
our invention will normally contain 30-60 cc of oxygen per 100 cc of the 
perfluorinated material but ratios as low as 10 cc per 100 cc can be used, 
and higher amounts such as 100 cc per 100 cc can be used where available. 
All the foregoing solubilities are at 25.degree. C and 760 milliliters 
mercury. The compounds in the higher end (C.sub.12 -C.sub.18) of the 
C.sub.9 -C.sub.18 carbon atom range perform in the manner described above 
except that their oxygen solubility decreases. Above C.sub.18 the 
solubility is not high enough to make these compounds practical 
candidates. 
EXAMPLE 1 
Tetrahydrodicyclopentadiene (24.15 g) was pumped at 0.494 cc/min through a 
stirred horizontal CoF.sub.3 bed which was thermally graded from 
200.degree. to 250.degree. C between the inlet and outlet respectively. 
The crude product weighed 63.6g. This product was dried over mole sieves 
and 55.8g was passed through the reactor for a second time. The reactor 
was thermally graded from 300.degree. to 375.degree. C. during this second 
pass. The crude product from the second pass weighed 60.8g for an 87% 
yield. 
Gas chromatographic analysis showed a mixture containing about 35% 
perfluorotetrahydrodicyclopentadiene and 50% perfluorobicyclo [5.3.0] 
decane. 
The mixture was then water-washed to remove residual HF. If was then 
refluxed with aqueous KOH(10%) for 1 hour, and dried over mole sieves. 
This product was then distilled to remove light and heavy ends, followed 
by processing by preparative gas chromatography (1/2 inch .times. 42 feet 
20% SE 30 in 30/60 Chromosorb P). Each of the identified components of the 
mixture was isolated in &gt; 98% purity. The components were then each 
exhaustively extracted with diethylamine until no further discoloration 
was observed. 
EXAMPLE 2 
In accordance with the procedures of Example 1, methyladamantane (10 g), 
dissolved in 10cc n-hexane, was pumped through the CoF.sub.3 reactor, 
thermally graded from 225.degree. C to 275.degree. C, at 0.247 cc/min. The 
crude product, which weighed 26.7g, was dried over mole sieves dissolved 
in perfluoro n-heptane (5cc), and passed through the rector a second time 
at 0.494 cc/min. The reactor was graded from 250.degree. C to 350.degree. 
C for the second pass. 
Gas chromatographic analysis showed a mixture containing .about. 5% 
perfluoromethyladamantane and &gt; 90% perfluorodimethylbicyclo [3.3.1] 
nonane. 
The mixture ws then separated in accordance with the procedures of Example 
1 to yield each of the identified products in high purity. 
EXAMPLE 3 
In accordance with the procedures of Example 1, 1,3-dimethyladamantane 
(18g) was pumped through the CoF.sub.3 reactor, held at 250.degree. C in 
all 4 zones, at 0.247 cc/min. The crude product, which weighted 53.5g, was 
dried over mole sieves and passed through the reactor again at 0.382 
cc/min. During the second pass the reactor zones were thermally graded 
from 225.degree. to 325.degree. C. The crude product, which weighted 50.2g 
(85% yield) was analyzed by gas chromatography and showed to be a mixture 
containing .about. 5% perfluorodimethyladamantane and &gt; 90% 
perfluorotrimethylbicyclo [3.3.1]nonane. 
The mixture was then separated in accordance with the procedures of Example 
1 to yield each of the identified products in high purity. 
The following examples, disclosed in co-pending application Ser. No. 
771,873 (supra), illustrate an alternate method for preparing the 
perfluoro polycyclic materials used in the emulsions of this invention, 
wherein there are employed partially fluorinated polycyclic hydrocarbons 
as intermediates in the preparation of substantially pure perfluorinated 
materials. 
In particular, the following four examples demonstrate the preparation of 
partially fluorinated adamantanes which may then be perfluorinated in 
accordance with Example 8. 
EXAMPLE 4 
Adamantane dicarboxylic acid (22.4g-0.1 mole) and SF.sub.4 (27.0g-25% 
excess) were heated in a hoke bomb for 24 hours at 110.degree. C. The 
contents of the pressure vessel were cooled, extracted with CCl.sub.4, 
filtered and the CCl.sub.4 evaporated off. The residue consisted of 21.8g 
of bistrifluoromethyl adamantane (80% yield). 
EXAMPLE 5 
2-adamantanone (15.0g-9.1 mole) and SF.sub.4 (13.g-25% excess) were heated 
as in Example 1. The product was worked up as described in Example 1 to 
give 12.9g of 2,2-difluoro adamantane (75% yield). 
EXAMPLE 6 
5,7-dimethyl-1,3-adamantane dicarboxylic acid (25.2g-0.1 mole) and SF.sub.4 
(27.0g-25% excess) were heated and worked up as in Example 1 to give 18g 
of 3,5-dimethyl-5,7-bis(trifluoromethyl) adamantane (60%). 
EXAMPLE 7 
1,3-dimethyl adamantane (42g) is added slowly to a slurry of MnF.sub.3 (1 
lb) in perfluoro 1-methyl decalin. After all the hydrocarbon has been 
added the mixture is heated with rapid stirring to 200.degree. C for 24 
hours, and the product extracted with Freon 113 and distilled to remove 
both the Freon 113 and perfluoro 1-methyl decalin. The distillation 
residue consists of partially fluorinated 1,3-dimethyl adamantane in which 
the average molecule contains approximately 8 fluorine atoms; e.g. 
C.sub.12 H.sub.12 F.sub.8. 
EXAMPLE 8 
Bistrifluoromethyl adamantane (24cc; 33.67g; 0.123 moles) from Example 4 
was charged into a preheater at 0.247cc/min. The preheater temperature was 
250.degree. C, and in the CoF.sub.3 reactor divided into four heating 
zones, the temperature was graduated from 250.degree. C in Zone 1 to 
300.degree. C in Zone 4. The product line was kept at 225.degree. C. After 
all the hydrocarbon had been charged to the reactor, the reactor was 
purged with nitrogen for 3.25 hours. The crude product weighed 46.0g. This 
material was water washed until the pH of the water was 5. 
This material from the second stage was dried over mole sieves overnight 
and then 45.84g was recharged at a rate of 0.764 cc/min. to the reactor 
which was graduated from 275.degree. C in Zone 1 to 380.degree. C in Zone 
4 for the final stage. The reactor was purged with nitrogen for 4 hours 
before removing the product receiver containing 47.8g. fluorocarbon; 75% 
material balance g.c. analysis showed the product contained 90% perfluoro 
1,3-dimethyl adamantane, confirmed by mass spectrography and .sup.19 FNMR. 
A similar run was made with 1,3-bis(trifluoromethyl)-5,7-dimethyl 
adamantane to give a 55% yield of perfluoro tetramethyl adamantane. 
In a similar fashion 2,2-difluoro adamantane and 
3,5-dimethyl-5,7-bis(trifluoromethyl) adamantane of Examples 5 and 6 were 
reacted with CoF.sub.3 in accordance with the procedures of Example 8 to 
give the corresponding perfluoroadamantanes in high purity and yield. 
EXAMPLE 9 
Exo-tetrahydrodicyclopentadiene (35 g) is added slowly to a slurry of 
MnF.sub.3 (1 lb) in perfluoro(1-methyl) decalin solvent. After all the 
hydrocarbon has been added, the mixture is heated to 200.degree. C and 
stirred rapidly for 24 hours. The product is extracted with Freon 113 and 
distilled to remove both the Freon 113 and perfluoro (1-methyl) decalin. 
The distillation residue consists of partially fluorinated 
tetrahydrodicyclopentadiene in which the average molecule contains 
approximately 7 fluorine atoms: C.sub.10 H.sub.9 F.sub.7. 
When the thus obtained partially fluorinated tetrahydrodicyclopentadiene is 
then perfluorinated with CoF.sub.3 in accordance with the procedures of 
Example 8, there is obtained substantially pure exo-and 
endo-perfluorotetrahydrodicyclopentadiene in high yield, and essentially 
free of by-products. 
EXAMPLE 10 
In accordance with the procedures of Example 9, but substituting partially 
fluorinated camphane, hydrogenated pinane, 1,4-methanodecalin or 
1,4,5,8-dimethanodecalin for partially fluorinated 
tetrahydrocicyclopentadiene, there is obtained the corresponding 
perfluorinated cyclocarbon in high yield, and substantially free of any 
degradation ring-opened by products. 
EXAMPLE 11 
Fluoroolefins and acetylenes, readily undergo Diels-Alder type reactions to 
function as dienophiles in 1,4-cyclo-addition reactions; their reactivity 
towards dienes is generally higher than that of their hydrocarbon 
analogues. The following examples demonstrate the preparation of partially 
fluorinated cyclocarbons which may then be exhaustively fluorinated in 
accordance with the procedures of Example 8 to provide 
perfluorocyclocarbons in high yield and essentially free of ring-opened 
by-products: 
A. Reaction of cyclopentadiene with hexafluoro-but-2-yne at 100.degree. C 
for 24 hours gives 2,3-bis (trifluoromethyl) bicyclo [2.2.1] heptadiene 
which, upon hydrogenation over platinum, gives 2,3-bis(trifluoromethyl) 
bicyclo [2.2.1] heptane. 
B. Also, in a like manner, octafluoro-but-2-ene and cyclopentadiene react 
to give 2,3-difluoro-2,3-bis(trifluoromethyl) bicyclo[2.2.1] heptane 
which, after hydrogenation over ruthenium gives 
2,3-bis(trifluoromethyl)bicyclo [2.2.1] heptane. 
EXAMPLE 12 
Norbornadiene (1 mole) and a 25% molar excess of hexafluorocyclopentadiene 
are heated for 24 hours at 100.degree. C to give 
##STR1## 
which, after treatment with CoF.sub.3 in accordance with the procedures of 
Example 5 yields highly pure perfluoro 1,4,5,8-dimethanodecalin. 
The following examples are included to further illustrate one method for 
preparing the synthetic blood and perfusion emulsions of this invention 
from the above-described perfluoro polycyclic compounds. 
EXAMPLE 13 
To 10 cc perfluorotricyclo [3.3.1] nonane is added 5 gm Pluronic F68 
emulsifier. Distilled water is then added to the mixture to form a total 
volume of 50 cc. The solution is filtered through a 10-micrometer 
millipore filter, and the solution, which is cooled by an ice bath to 
about 0.degree.-5.degree. C, is sonicated with an ultrasonic vibrator. 
During the sonication the optical density of 5 cc samples is measured at 
regular intervals until a constant optical density value is obtained, 
signifying that the smallest particle size emulsion possible has been 
obtained. The sonication is then stopped, and a stable aqueous emulsion of 
20% by volume of perfluorotricyclo [3.3.1] nonane is recovered. 
EXAMPLE 14 
In accordance with the procedures of Example 13, but substituting 
perfluoromethyladamantane for the nonane compound, and using 
yoke-phospholipid emulsifier, there is obtained a stable, aqueous emulsion 
of 20% by volume of perfluoromethyladamantane. 
EXAMPLE 15 
To 5 cc perfluorotetrahydrodicyclopentadiene is added 25 gm Pluronic F68 
emulsifier. Distilled water is then added to the mixture to form a total 
volume of 500 cc. The solution is filtered through a 10-micrometer 
millipore filter and the solution homogenized in a Manton-Gaulin 
homogenizer filtered with a cooler. During homogenization, the optical 
density of 5 cc samples of emulsion is measured at regular intervals until 
a constant optical density value is obtained, signifying that the smallest 
particle size emulsion possible has been obtained. The homogenization is 
then stopped, and a stable aqueous emulsion of 10% by volume of 
perfluorotetrahydrodicyclopentadiene is recovered. 
EXAMPLE 16 
In accordance with the procedures of Example 15, but substituting 
perfluoromethylbicyclooctane for the cyclopentadiene compound, and using 
yolk-phospholipid, there is obtained a stable, aqueous emulsion of 10% by 
volume of perfluoromethylbicyclooctane. 
EXAMPLE 17 
To 100 cc perfluoroethylbicyclooctane is added 50 gm Pluronic F68 
emulsifier. Distilled water is then added to the mixture to form a total 
volume of 500 cc. The solution is filtered through a 10-micrometer 
millipore filter and the solution homogenized in a Manton-Gaulin 
homogenizer filtered with a cooler. During homogenization, the optical 
density of 5 cc samples of emulsion is measured at regular intervals until 
a constant optical density value is obtained. The homogenization is then 
stopped, and a stable, aqueous emulsion by 20% by volume of 
perfluoroethylbicyclooctane recovered. 
EXAMPLE 18 
In accordance with the procedures of Example 17, but substituting 
perfluoroethylmethyladmantane for the bicyclooctane compound, there is 
obtained a stable, aqueous emulsion of 20% by volume of 
perfluoroethylmethyladamantane. 
EXAMPLE 19 
In accordance with the procedure of Example 13, but starting with 
perfluoroethyldimethyladamantane, there is obtained a stable, aqueous 
emulsion of 10% by volume of said perfluoroethyldimethyladamantane. 
EXAMPLE 20 
In accordance with the procedures of Example 13, but substituting 
perfluorotetrahydrobinor-S for the nonane compound, there is recovered a 
stable, aqueous emulsion of 20% by volume of said 
perfluorotetrahydrobinor-S. 
EXAMPLE 21 
In accordance with the procedures of Example 15, but starting with 
perfluoromethyldiamantane, and using yolk-phospholipid emulsifier, there 
is obtained a stable, aqueous emulsion of 10% by volume of said 
perfluoromethyldiamantane. 
EXAMPLE 22 
In accordance with the procedures of Example 17, but starting with 
perfluorotriethyladamantane, there is recovered a stable, aqueous emulsion 
of 20% by volume of said perfluorotriethyladamantane. 
EXAMPLE 23 
In accordance with the procedures of Example 13, but using 
perfluorotrimethyldiamantane and yolk-phospholipid as the emulsifier, 
there is obtained a stable, aqueous emulsion of a 10% by volume of said 
perfluorotrimethyldiamantane. 
EXAMPLE 24 
In accordance with the procedures of Example 15, but using 
perfluoroethyldimethyldiamantane, there is obtained a stable, aqueous 
emulsion of a 10% by volume of perfluoroethyldimethyldiamantane. 
EXAMPLE 25 
In accordance with the procedure of Example 13, but substituting 
perfluorodimethanodecalin for the nonane compound, and yolk-pholpholipid 
for Pluronic F68, there is obtained a stable, aqueous emulsion of 10% by 
volume of said perfluorodimethanodecalin. 
EXAMPLE 26 
In accordance with the procedure of Example 15, but substituting 
perfluoromethyldimethanodecalin for the nonane compound, there is obtained 
a stable, aqueous emulsion of 10% by volume of said 
perfluoromethyldimethanodecalin. 
EXAMPLE 27 
In accordance with the procedure of Example 13, but substituting 
perfluorotetrahydromethyldicyclopentadiene for the nonane compound, there 
is obtained a stable, aqueous emulsion of 10% by volume of said 
perfluorotetrahydromethyldicyclopentadiene. 
EXAMPLE 28 
In accordance with the procedure of Example 13, but substituting 
perfluoroethyladamantane for the nonane compound, and yolk-phospholipid 
for Pluronic F68, there is obtained a stable, aqueous emulsion of 10% by 
volume of said perfluoroethyladamantane. 
EXAMPLE 29 
To 5 cc perfluoroadamantane is added 2.5 gm Pluronic F68 emulsifier. 
Distilled water is then added to the mixture to form a total volume of 50 
cc. The solution is filtered through a 10-micrometer millipore filter; and 
the solution, which is cooled by an ice bath to about 0.degree.-5.degree. 
C, is sonicated with an ultrasonic vibrator. During sonication, the 
optical density of 5 cc samples of emulsion is measured at regular 
intervals until a constant optical density value is obtained, signifying 
that the smallest particle size emulsion possible has been obtained. The 
sonication is then stopped, and a stable, aqueous emulsion of 10% by 
volume of perfluoroadamantane is recovered.