apomorphine HCI stabi lization by Robert J. Engelhardt, Fred M. Schell and J. Leon Lichtin * Pomorphine, combined with iodides, according to some claims, is effective in the treatment of certain types of asthma. The following prescription taken from a textbook on allergy suggests a manner in which' it may be prescribed: 1
A
Apomorphine HCI Sat. sol. potass. iodide Co. syrup Sarsaparilla
gr. ii fl. dr. v q.s. ad. flo oz. iv
When this prescription was prescribed by a physIcian, the compounded product either varied greatly in appearance or soon underwent some degree of color change or precipitation. Considerable concern, therefore, was held for the stability and potency of the prescribed medication. The therapeutic merits of the combination, however, were deemed to be of sufficient value for a pharmaceutical investigation .to be undertaken. The aims of this investigation were to determine the Influence on the stability of the combination of a few possible variables operating within this prescription, to consider the possible stabilization of this formula and to explore other stable and palatable variations of it. Apomorphine is known to be unstable. Also alkaloids and iodides under some conqitions, will form ~ precipitate. 2 The usn describes a green color attributable to apomorphine decomposition and suggests the addition of acid, such as H CI, to stabilize it. A recent study of the stabilization of apomorphine .suggests that even though the color of its solution is quite dark, much aCtivity may yet remain. 3 o Grateful acknow.ledgment is made of the interest and support .of part of this project by I. Leonard Bernstein, MD, director of the alle!gy research laboratories, college . of medicme, University of Cincinnati. The apomorphine HCl, used in the study, was given through the . courtesy of Barclay E. Mackinnon of S.B. Penick and Company, New York.
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From previous studies, several substances have been suggested as stabilizers for apomorphine so'lutions. Among them are sodium bisulfite,4,5 hydrocyanic acid, 6 hypophosphorous acid 7 and ascorbic acid. 8 ,9 The ,last named of these, because of its pharmacological safety and ready availability to ~he pharmacist, appeared to be the most suitable to use in a formulation for internal administration and its use as a stabilizer received the greatest degree of experimental emphasis in this study. experiments and results
1. apomorphine HCl stock solution 65 :r:ng of apomorphine HCI were dissolved in 60 mlof distilled water (equivalent to about 0.11 percent or approximately 1: 1000).
2. citrate buffer One molar solution of citric acid (pH 1.6) and sodium citrate (pH 7.3) J.
Leon Licht;n, professor of pharmacy at the col/ege of pharmacy, University of Cincinn.ati, ;s a teacher in trye areas of pharmaceutical compounding and formulation, dermatologicals and cosmetics. His PhD in pharmaceutical chemistry is from Ohio State University. Robert J. Engelhardt is a registered pharmacist in Ohio and is presently working toward his MS in pharmacology at the University of Cincinnati. He is a member of Rho Chi and vice president of Beta Nu chapter and has been an undergraduate laboratory instructor and active member of the col/ege of pharmacy tribunal. Fred M. Schell is currently a graduate student at the University of Cincinnati college of pharmacy majoring in pharmaceutical chemistry. He is a member of Rho Chi and plans to continue grad~u ate work toward his PhD in organic chemistiy.
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
were mixed to obtain ariy desired pH within those limits. Measurement of pH was made on a Beckman po. tentiometer.
3. apomorphine HCl in citrate buffer 7.5 ml of the stock apomorphine solution were mixed with an equal volume of ·various citrate buffers ranging in pH from 1.6 to 7.3. ". Result: After 10 minutes, all the mixtures started to turn a characteristic green col9r, except that of ·the buHer of pH 4.6. This remained clear for one day. Th~ apomorp4ine HCI sohition itself, without buffer, turned green before any of the buffered solutions. After several days, a dark green precipitate was observed at the bottom of every bottle. .
4. apomorphine HCl, potassium iodide with and without buffer Equal volumes of the stock apomorphine and saturated KI solutions were mixed. In each case, a dark green color developed immediately. ,Buffering, with or without sodium thiosulfate, was determined to offer no solution to this instability and incompatibility. .
5. chelating agents and metallic salts The addition of solutions of salts of metals as iron, copper and molybdenum to , apomorphine produced varying and immediate colors. On the other hand, the addition to the stock solution of apomorphine HCI of an equal volume 6f EDTA or its sodium salts, in concentrations of 1: 10,000 or 1: 1,000, had little inhibitory action on the usual development of the green color and subsequent precipitate.
6. ascorbic acid in various concentrations with apomorphine HCl The addition to the stock solution of apomorphine HCI of equal volumes of 1:100, 1:1,000 and 1:10,000 ascorbic acid was done to determine the minimum concentration of ascorbic acid that might stabilize the alkaloid. . Result: The solutions 'c ontaining the 1: 1,000 and 1: 10,000 turned tan~ The solution containing 1: 100 ascorbic acid -( overall .c onceqtration equals 1: 200) remained clear for two months, after which it turned tan: Since the overall concentration bf apomorphine was about 1:2,000; it was concluded that in simple aqueous soluti9ns about 10 grams of ascorbic acid are required to stabilize a gram of apomorphine.
7.. stabilization of ascorbic acid solution by alcohol Two perc~nt ascorbic acid and alcohol were mixed in varying amoun~s so that the flnal alcohol concentration varied from six percent to 50 percent. The minimum ascorbic add strength used was one percent. Result: The mixture containing six percent alcohol turned yellow and unpleasantly odorous. As the alcohol
content increased, the amount of color and odor decreased. It was concluded that alcohol equivalent to eight to ten times the amount of ascorbic acid is required for stabilization. Illustrative of the value of the addition of alcohol is the following formula which remained clear and odorless for at least three weeks in both full and half-full bottlesApomorphine Hel Ascorbic acid Alcohol Water q.s.
0.130 2.400 20.000 120.000
gm gm ml ml
8. apomorphine HCl with increasing amounts of sucrose in aqueous solution Dissolving apomorphine HCI in USP syrup ranging from the offi·c ial strength down to 50 percent of that strength did not appear to retard the decomposition at all. An of the solutions decomposed at the same rate. 9. apomorphine HCl, potassium iodide and ascorbic acid one percent The following formula remained clear, colorless and odorless for two weeks. After this, it became tan and odorous of ascorbic acid breakdown, again demonstrating the stabilizing value of the alcohol. Apomorphine Hel Ascorbic acid Saturated sol. potass. iodide Distilled water q.s.
0.13 gm 1.20 gm
Apomorphine Hel Saturated sol. potass. iodide Zentron (R) q.s. ad
18.50 ml 120.00 ml
10. apomorphine HCl, one percent ascorbic acid and alcohol in various vehicles Apomorphine Hel Ascorbic acid Saturated sol. potass. iodide Alcohol Vehicle':' (or dist. water) q.S.
hicle showed no visible evidence of decomposition for four weeks. After four weeks (in the case of water) and two months (in the case of simple syrup), both a yellow color and an odor of the breakdown of ascorbic acid developed. It was difficult to judge color change They apin the colored syrups. peared, however, to be stable for at least one month. After two months, the characteristic odor of ascorbic add breakdown occurred. In none of these cases, however, was there any evidence of decomposition of the apomorphine. The above preparations had a pH range of 3 to 3.5. 11. apomorphine HCl in Zentron O Zentron (Eli Lilly and Company), a liquid iron and vitamin preparation though somewhat lower in ascorbic acid and in alcohol than the above preparation, was tried as a vehicle for the apomorphine. A solution of 0.130 gm apomorphine in 120 ml of Zentron was reasonably palatable and remained unchanged in appearance for four months. 12. apomorphine HCl and potassium iodide in Zentron The following formula, except for the vehicle, corresponds to the ultimate formula sought-
0.130 gm 1.200 gm 18.500 ml 20.000 ml 120.000 ml
• Vehicles used were cherry syrup, compound sarsaparilla syrup, glycyrrhiza syrup and simple syrup.
Directions: Dissolve the ascorbic acid in a minimum amount of water. Add the apomorphine HCI and dissolve. To this, add 70 ml of distilled water or vehicle. Add 20 ml alcohol and the saturated potassium iodide solution. Finally, add distilled water or vehicle to make the total volume 120 ml. None of the vehicles Result: masked the poor taste caused by the ascorbic acid and therefore all were judged unsatisfactory from the viewpoint of palatability. When cherry syrup in the above formula was added to make 240 ml instead of 120 mil (increasing the dose taken by the patient to 10 ml), the palatability was greatly improved. Stability: The preparation made with water or simple syrup as the ve-
Zentron consists ofFerrous sulfate Thiamine hydrochloride Riboflavin Pyridoxine hydrochloride Vitamin B12 crystalline Pantothenic acid Nicotinamide Ascorbic acid Alcohol 2% q.s.
references 1. Feinberg, S.M., Allergy in Practice, Yearbook Publishers, Chicago, Ill., 509 ( 1944 ) 2. Honkomp, L., and Lichtin, J.L., "Alkaloidal Iodides," Am. I. Pharmacy, 130, 395-403 (1958) 3. Burkman, A.M., l .P.S ., 54, 325(1965) 4. Ionescu-Matiu, Al., et al., Ann. Pharm. Franc., 6, 137-43(1948) through Chem. Abstr., 43, 1150a 5. Nogueira Prista, L., et al., Anais. Fac. Farm. Porto, 18, 139-49( 1958) through Chem. Abstr., 53, 14415b 6. Amsterdamsche Chininefsbriek, N.V., Dutch, 52, 365 ( 1942) through Chem. Asbtr., 41, 3928d 7. Corbelli, U., Boll. chem. farm., 50, 871-3, Chern. Z entr., 1912, I, 1242- 3, J. Soc. Chem. Ind., 31, 406 through Chem. Abstr., 7, 1952c 8. Parrak, V., et al., Pharmazie, 14, 685-89 (1959) through Chem. Abstr., 54, 11378d 9. Steiger, K., and Bergmann, M., Schweiz. Apoth. Ztg., 84, 812-13(1946) through Chem. Abstr., 41, 1809b
0.130 gm 18.500 ml 120.000 ml
Directions: Dissolve the apomorphine ·H CI in a minimum amount of water. Immediately add about 90 ml Zentron. Add to this the saturated potassium iodide solution. Add sufficient Zentron to make a total volume of 120 mI. Mix thoroughly. Shelf Stability: The formula given above in the previous section was placed in clear and amber bottles which were both full and half-full. One each of the above containers was placed in a dark place, a well-lighted place (reached by the sun's rays several hours each day), a refrigerator and a warm place of about 35-40 degrees C. Results: With visual examination all remained unchanged at least four months with the exception of the ones stored in a warm place. These were, however, visibly unchanged for one month. The change in the samples in a warm place, apparently, was free iodine-as the addition of sodium thiosulfate immediately bleached the color. o
summary and remarks To the pharmacist are submitted several formulas that enable him to offer to the physician a means of stabilizing apomorphine with or without potassium iodide, for about four weeks. A warning label stating that the prescription is not to be taken after three or four weeks is a wise course to consider. A clinical study to determine if a synergistic effect exists between the potassium iodide and the apomorphine is being planned. •
100 mg 1 mg 1 mg 0 .5 mg 5 mcg 1 mg 5 mg 35 mg 5ml
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Vol. NS8, No.4, April 1968
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