ANALYTICAL EDITION
March, 1945
Benedetti-Pichler. A. A., and Rachele. J. R.. raid.. 12, 233
sodium salt of dicblorofluorescein, 2.5 ml. of a 2% solution of dextrin, and 0.2 ml. of 1% aqueous solution of Triton N.E. (Rohm &. Haas Go., Philadelphia, Pa.). This was titrated with approximately 0.1 molar silver nitrate. The end point was recognized by observin5 !be color of the particles of silver chloride by means of dark6el illumination furnished by Epi-condenser W of Zeiss. The results of a series of determinations of the ratio volume silver nitrate over volume sodium chloride are listed in Table 111. Both solutions were added from the same buret, and the volumes are given in divisions of the tnicrometer scale. The ratio determined on the macro scale with the customary stopcock burets could he closely reproduced on the microgram
(1940).
Benedetti-Piohler, A. A., and Sigpia, S., Ibid.. 14, 828 (1942). Clippinger, D. R., Ibid., 11, 216 (1939). Emich, F., and W'errnuth, S., in Gtiihler, A,, Tiede, E., and Richter. F.. "Handbueh der Arbeitsmethoden in der anorganischen Chemie", Vol. 2, pp. 671-6. Berlin. Walter de Gruyter. 1925. Hybbinette, AnnaGreta, and Benedetti-Piohler, A. A,. Mikmchemie. 30, 15 (19421.
Kirk. P. L., Jbid., 14, 1 (1933). Linderstrom-Lang. K.. and Holter, H., Compt. rend. t r e ~ lab. . Cadsbwg., 19, No. 14 (1933). Peffer, E. L., and Mulligan, G. C., Natl. Bur. Standards, Cilc.
SCSk.
LITERATURE CITED (1) Benedetti-Piehler, A. A,, IND.ENQ. C ~ E M .ANAL. . ED.,9, 483 (1937). (2) Benedetti-Pichler, A. A,, "Introduction to the Microtechnique of Inorganic Analysis", New York, John Wiley & Sons, 1942.
(3) Benedetti-Piohler. A. A,, and Ceiola. M.. IND. EN& CHEM., ANAL.Eo.. 14, 813 (1942).
C434 (1941).
PRESENTED before the Division of Analytical and Micro Chemistry at the 108th Meeting of the AYERIOAN C H E M I OSOCIETY, A~ New York. N. Y. Abstraoted from the thesis svbmitted by Anne G. Loscalao to the faculty of the Graduate School of Arts and Sciences. New York University. in partial fulfillment of t h e requirements for the degree of doctor of philosophy.
Ampoule Testing with Manometric Apparatus AL STEYERMARK,
Hoffmann-La
Roche, Inc., Nutley, N. J.
Deterioration of pharmaceutical preparations in sealed ampoules, when accompanied by evolution of carbon dioxide, can be determined by use of the Van Slyke manometric blood gas apparatus. A specially constructed flask is used and the method i s similar to that of Van,Slyke and Folch for determination of carbon.
P tests
HARMACEUTICALS, packsged in the form of ampoules for parenteral injection, must be subjected to rigid laboratory for the purpose of control, both when freshly prepared and after a period of time. When deterioration of a product OCOULS, on aging, i t is often accompanied by the formation of a precipitate or a change in color, either of which is detected by inspection. However, in some cases there is no differencein appearance, since the decompmition is accompanied by no change in color and its products are either in solution or in the gaseous phase. Consequently, inspection shows nothing and the ampoules must be opened and tested. On opening, any gas is lost and in ampoules containing such smdl quantities as 1 mg. of active ingredient, increased pressure due to deeomposition would not be noticed. This paper presents a method for determining the amount of carbon dioxide formed in the above manner. Use is made of the Van Slyke manometric blood gss apparatus, the method being Bimilar to that described by Van Slyke and Folch (6) for the determination of carbon. Tbe reader should be thoroughly acquainted with the above-mentioned paper before attempting the work described here. Although determinations of other gases in sealed ampoules have not been attempted, i t is believed that these could be accomplisbed by modifying be methods of Van Slvke (1-6, 7, 8)to include use of the flask escnbed below.
k .
APPARATUS
A specially constructed flask replaces the combustion tube
used by Van Slyke and Folch, since the carbon dioxide is already present and does not need generation. Figure 1shows the flask and its relation t o the rest of the system. It consists of a 1OC-ml. round-bottomed flssk (a, Figure 2) having a ground joint to which in attached a distilling tube, b, that is bent so that it may be con-
191
Figure
1. Gas Formation Determination in A m p u l e s
10 I
zol
3I9
l
SO l
LO l
70 l
80 l
90 l
100 110 l l -._._
Figure 2.
Table
Temp.
c.
26.5 26.5 27 26.5 27 28 27.5 28 28 27 a
Vol. 17, No. 3
INDUSTRIAL AND ENGINEERING CHEMISTRY
192
Amounts of Carbon Dioxide Presented with 5-MI. Ampoules of a Pharmaceutical Product Satisfactory Unsatisfactory Blank Values, Ampoules Ampoules c, at PCOI at PCOIat 2.000 M1. 2.000 Ml. COa 2.000 M1. COz Factors" Mm. Mm. Me. Mm. Mg. 0 0.00 0,001363 0:007 5 0.001363 0 0:oo 0.001360 0:36 7i:5 0.001363 0.32 .. 65 0.001360 0.31 .. 63 0.001354 0.32 .. .. 64.5 0.0013S7 0.25 .. 51 0.001354 0.22 .. 45 0.3013S4 0:oo 0 .. .. 0.001360
..
.. .. I
l
IS% $40 (50 mm l
l
J
Y
Diagram of Apparatus
1.
..
!LO
.
Obtained from Table I, page 529, 6.
the extraction chamber as shown in Figure 1. The entire system is evacuated and the air removed from it in the usual manner. The alkaline hydrazine solution (prepared according to the directions of the above authors) is added to the extraction chamber, and the ampoule is broken by deptession of the plunger. With the system under reduced pressure, the contents are sucked from the ampoule into the bottom of the flask and mixed with the hydrochloric acid, if used. The carbon dioxide is then absorbed by 25 excursions, after which its pressure is measured in the way described by Van Slyke and Folch. The blank values are obtained by repeating the procedure without having an ampoule present. Table I gives the data obtained with satisfactory and unsatisfactory ampoules of the same pharmaceutical product, the latter showing evidence of deterioration of the type resulting in evolution of carbon dioxide. ACKNOWLEDGMENT
nected onto the Van S1 ke Folch extraction chamber, c. Attached to the side of the &skis a compartment, d, for holding the ampoule, which varies with the size of the article to be tested, different flasks being required for each size of ampoule. This compartment is similar in shape to an inverted ampoule having a very thick-walled neck, e. To the upper half of the compartment is attached a heavy glass rod plunger, f, which passes through the ground joint, g, and rubber tubing, h, which permits motion. PROCEDURE
To ensure the proper pH for complete extraction of c-,rbon dioxide, several milliliters of dilute hydrochloric acid are added to the flaak, except where addition of acid causes decomposition of the substance in the ampoule with evolution of carbon dioxide. The exact quantity of acid added will depend y o n the pH of the material under test. The tip of the ampoule isscratched with a file, care being taken not to produce a track through which gas minht escaDe. The amDoule is then Dlaced in the compartment. neck down; the plunger-is attached, and the flask is connected to
The work for this paper was carried out with the experimental assistance of Janet K. Farnow. LITERATURE CITED
. (1) Harington, C.R.,and Van Slyke, D. D., J. B i d . Chem., 61,575 (1924). (2) Peters, J. P.,and Van Slyke, D. D., "Quantitative Clinical Chemistry, Vol. 11, Methods", Baltimore, Williams & Wilkina Co., 1932. (3) Sendroy, J., Jr., and Liu, S.H., J. Biol. Chem.,89,133 (1930). (4) Van Slyke, D.D., Ibid., 83,425 (1929). (5)Ibid., 130,545 (1939). (6) Van Slyke, D. D., and Folch, J., Zbid., 136,509 (1940). (7) Van Slyke, D.D., and Hiller, Alma, Ibid., 78,807 (1928). (8) Van Slyke, D.D., and Neill, J. M . , Ibid., 61,523 (1924). PBESENTZD before the Division of Analytical and Micro Chemistry, Symuoaiurn on Practical Applications of Microchemistry, at the 108th Meeting br the AMERICANCAEMICALSOCIETY, New York, N. Y.
