Fig. i. Change of light transmission (%) of sodium salicylate solutions on heating, i) Without stabilizers; 2) with sodium sulfite (0.1%); 3) solution ampuled in a m~dium of carbon dioxide; 4) with ascorbic acid (0.2%); 5) trilon B (0.002%); 6) rongalite (O.5%); 7) sodium thiosulfite (0.1%). The dotted line is the lowest permissible limit of the light transmission of solutions (standard No; 5a for determining the color of liquids by GLC). Time of heating (h) is shown on the abscissa.
80~ 60~ ~0 ~ 30" ZO' 10I
|,
I
J
12
DecompOsition products having Rf 0.00 and 0.i were detected in these solutions by paper chromatography. The solution prepared in a medium of carbon dioxide remained colorless and transparent after storage under the usual conditions for 3 years. Decomposition products were not detected in it by paper chromatography and the quantitative content of the preparatio~ Was within therequired limits [3]. LITERATURE CITED i. 2. 3. 4. 5. 6.
G . D . Arnaudov, Drug Therapy [in Russian], Sofia (1975), pp. 23-24. State Pharmacopoeia of the USSR, lOth ed. [in Russian], Moscow (1968), pp. 450-451. M . D . Mashkovskii, Drugs [in Russian], Vol. 2, Moscow (1977), pp. 263-265. E..I. Voropanov et al., Farmatsiya, No. 2, 25-31 (1973). L . N . Lukoshevichene and S, A. Minina, in: Contemporary Aspects of Investigations in Pharmacy [in Russian], Riga (1977), pp. 87-89. S . G . Tiraspol'skaya, Farmatsiya, No. 2, 75-79 (1973).
STUDY OF HEAT TRANSFER WHEN FREEZING SOLUTIONS OF THERMOLABILE PREPARATIONS L. S. Novikova and N. E. Chernov
UDC 615.451.014.413:66.047.25
Solutions of thermolabile preparations are dried by sublimation from the frozen state under vacuum [i, 2]. Solutions are frozen taking into consideration the eutectictemperature of preparations as this influences the quality of the finished product [3-5]. Freezing of solutions is carried out by various methods and regimes but this regimen must be determined for each preparation [6-8]. It is necessary to regulate the freezing process since the shape and dimensions of the crystals show an effect on the rate of solution of t~e dried preparation [2, 5, 8]. On freezing solutions of preparations the process of heat transfer from solutions to cooling medium is effected by various methods. The main physical process characterizing freezing is the water--ice phase change. Freezing out of water leads to a change in thermal physical characteristics, namely the heat capacity and heat transfer coefficient of an object. The aim of our investigations was to study heat transfer on freezing solutions of terrilytin, ristomycin sulfate, and streptomycin--calcium chloride complex under various conditions (in air and liquid cooling media). The obtained data made it possible to estimate the main thermal physical characteristics of the frozen solutions necessary for calculating the heat exchange processes. Kursk Medical Institute. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 13, No. i, pp. 86-90, January, 1978. Original article submitted July 3, 1978.
78
0091-150X/79/1301- 0078507.50
9 1979 Plenum Publishing Corporation
EXPERIMENTAL
The equipment for s t u d y i n g t h e process of freezing the solutions of the investigated preparations consisted of 5 small beakers with thermocouples connected to a PCR-I potentiometer through a multipoint switch. The beakers were made of stainless steel and had different diameters (No. 1 0.05 m, No. 2 0.06 m, No. 3 0.07 m, No. 4 0.08 m, No. 5 0.09 m). The thermocouples (chromel--copel) made it possible to check the temperature of the investigated solutions and of the freezing media in the chamber. Freezing in an air medium was effected with a cold chamber where the temperature was maintained automatically at 233~ For freezing in a liquid-cooled medium (95% ethyl alcohol) the freezing compartment of a KS-6 unit for drying blood plasma was used. This is a metallic vessel with an evaporator placed under the base. The alcohol in the vessel was cooled to 233~ The time to freeze solutions of preparations was determined in the following manner. Solutions of one of the preparations being investigated of known concentration and 0.0254 kg in amount were placed in beakers and thermostated for 7.2 9 10 s sec at 293 • 0.1~ At the end of this time the beakers with thermocouples were placed in the cooling medium which was air or liquid. In addition to the medium the thickness of the layer of frozen solution was changed (0.0028-0.0079 m) since the surface for heat exchange was changed. The change of temperature of the solutions was monitored during 3 9 102 sec. The time of freezing was curtailed on reducing the thickness of the layer of solution and increasing its Surface. This was characteristic of all the solutions of the investigated preparations. Results are expressed graphically (Figs. 1-3). On freezing of all solutions in the liquid cooling medium the graphs were smooth curves due to the high rate of freezing; critical points werenot recorded by the instrument. For a 2% terrilytin solution in a liquid cooling medium the freezing times for layers of various thickness were 2.7 9 103 to 9 9 102 sec (see Fig. la), for a 3% ristomycin solution 1.8 9 103 to 6 102 sec (see Fig. 2a), and for a 7% solution of streptomycin-calcium chloride complex 2.1 9 103 to 9 9 102 sec (see Fig. 3a). On freezing solutions of the preparations in an air medium there were critical points on the graphs which divided the curves into two portions. At these points some uneven increase or constancy of temperature for a short time was observed. This phenomenon is explained by crystallization of the frozen solution accompanied by release of the heat of crystallization. The critical point indicated the end of the period of cooling the solution [9]. In Figs. ib, 2b, and 3b, the curves represent a reflection of the whole process of freezing identical test samples (0.0254 g) of solutions of terrilytin, ristomycin sulfate, and streptomycin--calcium sulfate complex in an air-cooling medium. The time of freezing a 2% terrilytin solution was 5.4 103 to 3.6 103 sec (see Fib. ib), of ristomycin sulfate solution 4.2 - 103 to 2.7 103 sec (see Fig. 2b) and of streptomycin--calcium sulfate solution 4.8 103 to 3.6 9 l0 s sec (see Fig. 3b). It is evident on the curves perature zone did not depend on freezing process mainly depended cludes the crystallization zone cooling the solution, was almost
for all the solutions that the cut-off of the critical temthe thickness of the freezing layer. The duration of the on the rate of passing through the second stage which insince the first stage, the zone of ice crystal formation on identical in time for all experiments.
The freezing process for the solutions of preparations consisted of three periods. First was the formation of ice crystals on freezing the solutions. Then the second period began when the cooling process was slowed down and a characteristic discontinuity occurred in the direction of a temperature increase. In the third period the temperature fell. The obtained experimental data made it possible to draw the conclusion that the freezing process for the investigated solutions of preparations occurred in accordance with temperature data given in the literature [i0]. The presence of critical points on the freezing curves for the investigated solutions made it possible to study these processes and determine the heat transfer coefficient in the sections of curves before the critical points and after them. Heat transfer takes place at variable temperatures of the heat transfer agent. The temperature of the heat transfer agent 79
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Figs. 1-3. Freezing curves for 2% terrilytin solution (la, b), 3% ristomycin sulfate solution (2a, b), and 7% solution of BtreptOmycin-calcium chloride complex (3a, b). Sample size was 0.0254 kg. Temperature ~ is given on the ordinate and time in sec on the abscissa. Numbers on the curves are beaker numberS, a) Liquid medium; b) air medium.
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TABLE i. Data on Heat Transfer on Freezing Solutions
F, m 2
Solution
K, W / m z 9deg "liqu!d m e / d i u " m ~ ' ~ - m e d i u m from begin- | from begin- from critining to end | ning to Ihe cal point to ] ] critical end I | point I
Terrilytin
0,0028 0,0039 0,0050 0,0064 0,0079 0,0028 0,0039 0,0050 0,0064
Ristomycin sulfate
Streptomycin-calcium chloride complex The same
0,0079 0,0028 0,0039 0,0050 0~ 0,0079
68,9 64,3 57,0 68,1 74,8 85,8
75,2 73,9 78,2 100,4 69,2 58,8 54,7 54,0 59,7
32,3 24,8 17.6
30,0 27,2 22.8
13,6 13,0 32,9
17,8 14,9 4O,O
23,6 18,4
33,8 32,4
15,3
20,3
14,4 I 1,3 27,4 19,6 12,0 9,8
28,4 26,3 37,8 24,0
17,4 15,4
usually changed along the surface of the wall separating them. The difference of temperature between the heat transfer agents was also changed comrespondingly. The coefficients of heat output (Q) on freezing the investigated solutions of preparations allowing for the change in temperature difference (AT m) was determined from the heat transfer equation Q = K'F" ATm, whereK is the coefficient of heat transfer and F is the freezing surface. Heat transfer coefficients found on the basis of the experimental data with allowance for the freezing surface are given in Table i. The heat transfer coefficient for a terrilytin solution on freezing in a liquid medium was 57.0-74.8 W/m2.deg, in an air medium up to the critical point 13.0-32.3 W/m2.deg, and after the critical point to the end of the freezing process 14.9-30.0 W/m2.deg. The heat transfer coefficient for ristomycin sulfate solution on freezing in a liquid medium was 73.9-100.4 W/m2-deg, on freezing in air medium up to the critical point was 11.332.9 W/m2.deg, and from the critical point to the end of the process was 26.3-40.0 W/m2"deg. The heat transfer coefficient for a solution of streptomycirr-calcium chloride complex in liquid medium was 54.0-69.2 W/m2"deg, in an air medium up to the critical point 9.8-27.4 W/m 2" deg, and from the critical point to the end of the freezing process was 15.4-37.8 W/m2-deg. Further the duration of freezing for the terrilytin solution in liquid medium at 233~ was within the limits 9 9 102 to 2.9 9 103 sec, in air 3.9 9 102 to 5.4 9 103see; for ristomycin sulfate solution in liquid medium 6 9 102 to 1.8 9 103 sec, in air 3 - 103 to 4.8 9 103 sec; for a solution of streptomycin--calcium chloride complex in liquid medium 9 9 102 to 2.1 103 sec, and in air 2.9 9 103 to 5.1 ~ 103 sec. The optimum layer thickness for a solution being frozen at 233~ 0.004-0.006 m.
may be regarded as
The calculated heat transfer coefficients make it possible to calculate the heat exchange surface which it is necessary to take into account on drying thermolabile preparations by a sublimation method. LITERATURE CITED i. 2. 3. 4. 5. 6.
N . E . Chernov, S. T. Shebanova, and I. P. Gorodetskii, Khim.-Farm. Zh., No. 4, 101-105 (1977). R. Grivs, in: Application of Freeze Drying to Biology [in Russian], Moscow (1956), pp. 124-181. L . S . Novikova, Yu. E.Shevchenko, and N. E. Chernov, Khim.-Farm. Zh., No. ii, 100-102 (1977). N . E . Chernov and I. P. Gorodetskii, in: Second All-Union Conference on Pharmaceuticals. Materials, Riga (1974), pp. 106-107. E . E . Nikitin and I. V. Zvyagin, Freezing and Drying Biological Preparations [in Russian], Moscow (1971), pp. 17-21. Yu. I. Novikov, in: Ninth Belorussian Republic Conference on Blood Transfusion. ~ t e r i a l s . Minsk (1964), pp. 31-32. 81
7. 8.
9. i0.
82
I.A. Radaeva, S. I. Kqcherga, S. P. Shul'kina, et al., in: Eighteenth International Congress of the Dairy Industry. Proceedings, Moscow (1972), pp. 269-270. Yu. I. Novikov, in: Belorussian Scientific-Research Institute for Hematology and Blood Transfusion. Summaries of Reports of the Plenum of the Scientific Council, Vitebsk (1967), pp. 131-139 ~citation 3). A. V. Lyukov and A. A. Gryazhov, Molecular Drying [in Russian], Moscow (1956). A. V. Lykov, Theories of Drying [in Russian], Moscow (1968), pp. 334-362.
