Improvements in the Manufacture of a Pharmaceutical Substance.
Year: 1896

page_text: Date of Application. 5th May. 1896
Complete Specification Left, 3rd Feb., 1897-Accepted, 27th Mar.. 1897
ISIONAL SPECIFICATION.
[Communicated from abroad by THE FARBENFABRIKEN, vormals FRIEDRICH
BAYER & Co., of Elberfeld, Germany.]
Improvements in the Manufacture of a Pharmaceutical Substance.
I HENRY EDWARD NEWTON, of The Office for Patents, 6 Bream's Buildings,
Chancery Lane in the County of London, Patent Agent, do hereby declare the
nature of this invention to be as follows:-
In the Specification of Letters Patent No. 12295%, my foreign correspondents
described a process for the production of the so-called active substance of the
thyroid gland, which process consists in boiling thyroid glands of sheep, or of
other animals, with dilute acids or alkalies, in order to change the insoluble
albuminous bodies contained in the glands into soluble compounds, an undissolved
portion being thus obtained, consisting of the said active substance in concentrated
form, free from noxious or unnecessary matters.
My foreign correspondents have now found that, as the said active substance
itself is decomposed, if the boiling be continued with the said agents for a longer
time than is necessary, it is advantageous to boil only to the point where the
undissolved portion contains the maximum of the active substance which my
foreign correspondents briefly term in this specification "thyroiodine." Until
now this point of the process could not be distinguished because it was impossible
to determine the quantity of thyroiodine contained in the said portion, as the
chemical composition of this body was hitherto quite unknown.
My foreign correspondents have now ascertained that thyroiodine contains iodine
chemically bound, and that the activity of a thyroiodine preparation corresponds
with the quantity of iodine contained therein, and they have based upon this fact
a method of analytically determining the thyroiodine.
In carrying out the process for the production of thyroiodine from thyroid
glands, which process is described in the Specification of Letters Patent No. 12295",
my foreign correspondents only boil thyroid glands with dilute acids or alkalies
until the insoluble portion contains the maximum of iodine, which point
may be distinguished by analytical researches made from time to time during
the process.
My foreign correspondents have further found that the isolation of thyroiodine
from thyroid glands may also be effected by an artificial digestion of the glands,
that is to say, by treating the same with very dilute hydrochloric acid and
pepsine, at about from 40 to 45 degrees Centigrade. Thus, the greater part of
the glands is dissolved, a residue being obtained which contains almost the whole
thyroiodine of the glands used in the process.
My foreign correspondents give the following example. The parts are by
weight:-

page_text: 2 per thousand HCI and from pepsine) is allowed to stand during 24 hours at a
temperature of about from 40 to 45 degrees Centigrade, a solution and a small
quantity of an undissolved residue being thus obtained. The liquid is filtered off,
and the undissolved part is washed with water, repeatedly extracted with hot
90 per cent. alcohol, and the solutions thus obtained are evaporated. The resulting
mass, which is slightly coloured, principally consists of thyroiodine, which, by a
treatment with ligroine or the like, is freed from fat and fatty acids contained in
the raw substance.
With the aid of the above described new method of determining thyroiodine,
my foreign correspondents have found further valuable improvements in the
production of this body. They have previously discovered that, on boiling thyroid
glands with dilute acids, the thyroiodine contained therein remains undissolved;
now they have ascertained that, on continuously extracting the glands with boiling
water, one part of the thyroiodine contained therein is dissolved. On subsequently
boiling the watery solution thus produced with dilute acids, the thyroiodine
precipitates in a very pure state. My foreign correspondents therefore proceed in
the manufacture of thyroiodine as follows:-
EXAMPLE II.
Thyroid glands, cut in small pieces, are subjected to the action of boiling water
so long as iodine is contained in the resulting solutious, which may be determined
by analytical researches. The watery solutions are mixed with a small quantity of
sulphuric acid (say, about one per cent.), and are then boiled for about 5 hours.
Thus, the thyroiodine contained therein separates. It may be purified with the aid of
the processes described in the Specification of the Patent No. 12295" above referred
to. A small quantity of thyroiodine contained in the filtered-off liquid is isolated
in the manner likewise defined in the said specification.
In order to precipitate the thyroiodine from the watery solution, other mineral
acids or alkalies may be employed, instead of sulphuric acids used in the preceding
example.
As above mentioned, on boiling thyroid glands with water, only one part of the
thyroiodine contained therein is dissolved, the other part being insoluble in hot
water. On studying the causes of this fact, my foreign correspondents have
discovered that the thyroiodine is contained in the glands in combination with two
different albuminous bodies, whereof one shows the properties of a globuline
body the other those of a serum albumen. The compound consisting of thyroiodine
and the said globuline is insoluble in water, while that consisting of thyroiodine
and the serum albumen dissolves. Therefore, on extracting thyroid glands with
boiling water in the hereinbefore defined manner, only the last named compound
dissolves, the globuline compound remaining undissolved. My foreign corre-
pondents now have discovered a process how to extract the latter substance from
the glands. Namely, they have found that on boiling thyroid glands with
so-called physiological (that is to say, 0.75 per cent.) solution of common salt, the
compound consisting of thyroiodine and the above mentioned globuline body, as
well as that consisting of thyroiodine and the said serum albumen, dissolves with
readiness, and that on mixing the liquid thus obtained with about fifteen or twenty
times the quantity of water, the globuline compound, as it is almost insoluble in a
very dilute salt solution, precipitates in the form of colourless flakes, which
precipitation may be hastened by introducing carbonic acid into the liquid. On
filtering off, mixing the filtrate with some drops of dilute acetic acid, and heating
the liquid up to boiling, the serum albumen compound contained therein separates.
The two albuminous compounds of thyroiodine thus isolated, which contain almost
the whole thyroiodine of the glands used in the process, may be employed, as such,
for medical purposes, or they may serve as materials for the production of pure
thyroiodine, which is effected by means of the heretofore defined processes, viz., by
boiling the albuminous substances with dilute mineral acids, or with dilute alkalics,

page_text: or by acting on the said bodies with artificial gastric juice, in the manner
hereinbefore defined.
My foreign correspondents give the following example in order to illustrate
their process of isolating the above defined albuminous compounds of thyroiodine,
and the production of thyroiodine itself from these compounds. The parts are by
weight.
EXAMPLE III.
One part of thyroid glands of sheep, cut into small pieces, is boiled with
2 parts of a 0-75 per cent. common salt solution during about 24 hours. The
solution thus obtained is filtered off from the undissolved residue; it is then
mixed with a small quantity of dilute acetic acid, and boiled for some minutes.
Colourless flakes then separate, consisting of a mixture of the globuline compound
and the serum albumen compound of thyroiodine hereinbefore defined.
In order to isolate the two different albuminous compounds, the above mentioned
solution, obtained by extracting thyroid glands with the salt solution, is mixed
first with about 40 parts of water, the globuline compound being thus precipitated.
The serum albumen compound is produced by subsequently mixing the filtered off
liquid with some drops of dilute acetic acid.
In order to convert the albumen compounds of thyroiodine thus produced into
the pure thyroiodine itself, they are treated (either separately or in mixture) with
dilute mineral acids or alkalies, or with artificial gastric juice, in the manner
heretofore described. For example, my foreign correspondents boil one part of
the albuminous compounds, isolated in the above defined manner, with 10 parts of
a 10 per cent. sulphuric acid during about 12 hours, and isolate the thyroiodine,
thus freed from albumen, in the manner described in the specification of the above
mentioned patent.
Dated this 5th day of May 1896.
NEWTON & SON,
Agents for the Applicant.
Improvements in the Manufacture of a Pharmaceutical Substance.
I HENRY EDWARD NEWTON of The Office for Patents, 6, Bream's Buildings,
Chancery Lane, in the County of London, Patent Agent, do hereby declare the
nature of this invention and in what manner the same is to be performed, to
be particularly described and ascertained in and by the following statement :-
In the Specifications of Letters Patent 1229595 and 208275, my foreign
correspondents have described a process for the production of the so-called active
substance of the thyroid gland, which process consists in boiling thyroid glands
from sheep or other animals with dilute acids or alkalies.
My foreign correspondents have now found that, as the said active substance is
itself decomposed if the boiling with the said agents be continued for a longer time
than is necessary, it is advantageous, when acids are used, to boil only until the
undissolved portion is found to contain a maximum amount of the active
substance, which my foreign correspondents briefly term hereinafter "iodothyrine.".
Hitherto this point of the process could not be distinguished, as it was impossible
to determine the quantity of iodothyrine contained in the said insoluble portion,
the chemical composition of this substance being unknown.
My foreign correspondents have now ascertained that iodothyrine contains
iodine in combination, and that the activity of iodothyriue preparation depends on

page_text: A mixture of one part of finely minced fresh thyroid glands from sheep, carefully
freed from fatty particles and the like, and 150 parts of artificial gastric juice (that
is to say, a solution containing 1 or 2 per thousand of hydrogen chloride and
1 per cent. of pepsine), is allowed to stand during 24 hours at a temperature of
about 45 degrees Centigrade. A solution is thus obtained, in which a small quantity
of undissolved matter is present.
This undissolved substance is filtered off, washed with water, and then repeatedly
extracted with hot 90 per cent. alcohol. On evaporation, the alcoholic solutions
thus obtained yield a slightly coloured mass, chiefly consisting of iodothyrine.
This raw product is freed from fat and fatty acids by a subsequent treatment with
ligroin or the like.
Of course, my foreign correspondents do not limit themselves to the directions
given in the above example, as the quantity of artificial gastric juice, the degree of
concentration thereof, the duration of digestion, and the temperature, can be varied
within wide limits, without thereby altering the nature of this invention.
My foreign correspondents have also discovered that iodothyrine exists in the
gland in combination with two different albuminous substances, one of which has
the properties of a globulin, the other exhibiting those of a serum albumen,
Moreover, they have devised a process for isolating these albuminous double
compounds, and of preparing therefrom pure iodothyrine. They find that, on
digesting the thyroid glaud with a dilute solution of common salt, the double
compound of iodothyrine and the above mentioned globulin, as well as that
consisting of iodothyrine and the said serum albumeu, are both readily dissolved,
aud that, on mixing the solution thus obtained with about fifteen or twenty times its
bulk of water, the globulin compound, being almost insoluble in very dilute salt
solution, is obtained in the form of a colourless floculent precipitate, which
precipitation, if necessary, may be hastened by passing carbonic acid through the
liquid. On mixing the filtrate containing the soluble serum albumen compound
with a small quantity of dilute acetic acid, and heating the liquid to the boiling
point, the serum albumen compound contained therein also separates. Of course,
the two albuminous double compounds can be precipitated together simply by
coagulation. The two albuminous compounds of iodothyriue thus isolated, either
jointly or separately containing almost the whole of the iodothyrine of the gland
used in the process, may be employed, as such, for medical purposes, or they may
serve as materials for the production of pure iodothyrine, by means of the heretofore

page_text: My foreign correspondents give the following Example B, in order to illustrate
the process of isolating the above defined albuminous compounds of iodothyrine,
and of producing iodothyrine itself from these compounds. The parts are by
weight.
EXAMPLE B.
One part of the minced thyroid gland from sheep, is digested with 2 parts of an
aqueous solution containing 0.75 per cent. common salt, during about 24 hours.
The liquid mixture thus obtained is filtered, and a small quantity of dilute acetic
acid having been added to the filtrate, it is boiled for several minutes. A colourless
flocculent precipitate is thus separated, which consists of a mixture of the compounds
of iodothyrine with globulin and serum albumen.
In order to isolate these two different albuminous compounds, the above mentioned
solution, obtained by extracting the thyroid gland with salt solution, is first mixed
with about 40 parts of water, and the globulin compound which is thus precipitated
is filtered off. The serum albumen compound is subsequently separated from the
filtrate by adding a little dilute acetic acid, and heating the mixture.
Naturally, my foreign correspondents do not limit themselves to the particulars
given in the last example, as these can be varied within certain limits.
In order to convert the said albuminous compounds of iodothyrine into pure
iodothyrine, they are treated (either separately or admixed) with dilute mineral
acids or alkalies in a manner analogous to that described in the Specifications of
Letters Patent No. 122955 and 2082795, or with artificial gastric juice in the
manner heretofore described. If, for example, one part of the albuminous compounds
isolated in the above defined manner, is boiled with 10 parts of 10 per cent. sulphuric
acid during about 12 hours, the iodothyrine is obtained free from albumen, and can
be isolated in the manner described in the last named specifications.
Having now particularly described and ascertained the nature of the said
invention, and in what manner the same is to be performed (as communicate l
to me from abroad), I declare that what I claim is :-
1. In the process described in the Specification of Letters Patent No. 12295", for
producing the active principle of the thyroid glands, the improvement which
consists in boiling the glands from sheep or the like with dilute acids just until the
insoluble residue is found to contain the maximum amount of iodine, which stage
may be ascertained by determining from time to time, during the process, the
quantity of iodine contained in the residue insoluble in acid.
2. In the process described in the Specification of Letters Patent No. 2082795,
for preparing the effective substance of thyroid gland, the improvement which.
consists in heating the glauds with alkalies only until the insoluble residue is found
to contain the least possible quantity of iodine.
3. The isolation of so-called iodothyrine from thyroid glands, which process is
effected by digesting the glands, at ordinary temperature, (say, from 40° to
45° Centigrade), with artificial gastric juice, filtering off the insoluble product,
extracting the same with alcohol, evaporating the alcoholic solution, and
subsequently purifying the residue in a suitable manner.
4. For the separation from thyroid glands, of double compounds containing the
iodothyrine in combination with albuminous matters (viz., globulin or serum
albumen),-
a) The process which consists in digesting glands with a dilute solution of
common salt, filtering, adding a small quantity of acetic acid to the filtrate,.
boiling, and subsequently isolating the globulin and serum
compounds thus precipitated together, owing to coagulation; or
albumen

page_text: b) The process which consists in digesting glands with a dilute solution of
common salt, filtering, adding to the filtrate thus obtained an excess of
water, (allowing carbonic acid to pass through the liquid or not, as may be
desirable), filtering off the globulin compound thus separated, adding a small
quantity of acetic acid to the filtrate, subsequently boiling and finally
filtering off the serum albumen compound thus coagulated.
5. The process for isolating iodothyrine from the albuminous double compounds
defined in the foregoing Claim 4, by treating these compounds with dilute acids,
dilute alkalies, or artificial gastric juice, in the manner described in the Specifi-
cations of Letters Patent No. 12295 and 20827%, or in the manner defined by the
preceding Claim 3.
6. As new products of manufacture, the globulin and serum albumen double
compounds of iodothyrine produced in the manner herein before defined, or in any
other process yielding the same result.
NEWTON & SON,
Agents for the Applicant.