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tetrahydrozoline hydrochloride solutions
The compatibility of
tetrahydrozoline hydrochloride solutions by A. J. Spiegel, Ph.D., and C. F. Gerber*
HE PURPOSE of t his communicati on is to present fi ndings concerning the com patibility of the commercially ayailable tetrahydrozoline hy drochlor ide (T yzine) n asal and ophthalmic solutions (Visine eye drops) with other m edi camen ts tha t a re commonly used in the treatment of nasal and ophthalmic con ditions. It is felt that this study will aid the pharmacist and the physician in the compo unding and prescribing of ex temporaneous prescriptions utilizing tetrahydrozoline solutions. T etrahydrozoline hydrochloride is a sym path omimetic amine designated chemically as 2-(1,2,3,4-tetrahydro - l hy drochloride naphthyl)-imida zoline and having the em pirical formula C 13 H17N 2Cl. When applied topically t o the nasal mucosa, the drug causes vasoconstriction , which results in a reduction of local swelling and congestion . 1, 2,3 It is administered in 0.1% and 0.05% concentra ti ons and is also used as an
T
* R eceiv ed fr o m t h e P h a rm aceutica l Research a n d Dev elop m e n t Departm ent , Chas . Pfizer & Co ., Inc . I Ne w an d No noffi cia l Drugs, J. B . Lippincott Co ., P hil adel p hi a, 1958 , p . 2 13. 2 M e n ge r , H . C. , N .Y. S tate J . Med., 55, 81 2 (195 5). 3 P a r ish , F . A ., M ed . Tim es, 82 , 9 17 (1954) . C. F. GERBER has been a member of the Pharmaceutical Research and Development Department of Chas. Pfizer and Ca., Inc. for the past 6 years. He received his B.S. degree (1938) in biology from the City College of New York and his M.S. degree (1944) in biochemistry from New Yor k University. Mr. Gerb er has been engaged in phar ma ceutica l rese arch for a total of 20 years. DR . A. J. SPIEGEL is a member of the Pharmaceutical Research and Development Department of Chas. Pfizer and Co., Inc. He received his B.S. (1953) and M.S. (1955) degrees in Pharmacy from Columbia University and his Ph.D. (1957) from the University of Florida. Dr. Spiegel is a member of the APhA, the ACS, Sigma Xi, Rho Chi, and Rho Pi Phi.
404
ocular decongestant in concentrations of 0.05%. Tetrahy drozoline hydrochloride is a water-soluble salt consisting of a racemic mixture of two isomers. It is a white cry stalline solid having a melting point of 256- 257 ° C. The pH of a 1% aqueous solution is approximately 6.2.
tonic, borate buffered, sterile solution, containing thimerosal as the preservative. The solution is at pH 6.2- 6.3. Physical compatibility studies were made by combining a 0.1 % tetrahydrozoline hydrochloride nasal solution or a 0.05% tetrahydrozoline h ydrochloride ophthalmic solution with the additive under test in the concentration commonly employed. Observations in physical appearance were made initially and after storage for 1, 3, 7, and 30 days at 25°C. The results are shown in Tables I and II. The chemical stability of tetrahydrozoline hydrochloride nasal solution was also studied in combination with se-
Experimental
Tetrahydrozoline hydrochloride nasal solution is a 0.1% isotonic, citrate buffered, yellow colored solution containing thimerosal as the preservative. The solution is at pH 5.5. Tetrahy drozoline hydrochloride ophthalmic solution is a 0.05% clear, iso-
Table I-Physical Compatibility of Tetrahydrozoline Hydrochloride Nasal Solution after One Month Additive Antibiotics Sodium Penicillin G Dihydros treptomycin Sulfate Oxytetracycline HCI Chlortetracycline HCI Polymyxin B Sulfate Bacitracin Neomycin Sulfate Tyrothricin Antiseptics Cetyldimethylbenzyl Ammonium C hloride Cetylpyridinium Chloride Benzalkonium C hl o ride
H Ol'm ones Prednisolone Prednisone Hydrocortisone Lo cal Anesthetics Procaine HCI Benzyl Alcohol Butacaine Sulfate Cocaine HCI Tetracaine Hel Antihistamines Chlor p h eneramine Maleate Pyrilamine Maleate Others D-amphetamine S ulfate Hydroxyzine HCI Ephedrine Sulfate Chlorobut anol Silver Nitrate Mild Silver Protein Strong Sil ver Protein Boric Acid Ascorbic Acid Camphor Menthol
JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION
Concentration 10 ,000 50 , 5 5 500 500 1. a 0.2
u ./cc. mg./cc. mg./cc. mg ./cc. u ./cc, u ./cc. m g ./cc. mg. / cc.
Remarks clear clear clear, residue after 3 days clear, residue after 3 days clear clear clear precipitate formed cloudy , precipitate forms slowly
50,000 1 50,000 1 50 , 000 0.2 mg ./cc. 0.2 mg ./ cc. 0 . 2 m g ./cc.
1%
3% 1%
3% 2%
5 mg. / cc. 5 mg ./cc. 10 mg. / cc . 5 m g ./cc. 5 mg. / cc. 0 .5 % 0 .5 % 10-20 % 1 % 2 % 1 % 0 . 05 % 0 . 05%
cloudy , precipitate forms slowly cloudy, precipitate forms slowly
clear clear cl ear clear clear clear, residue atter few hrs. clea r clear, crystals tormed after weeks clear clea r clear clear clear clear precipitate formed readily dispersible, residue formed a fter one month not soluble clea r clea r , color change clear clear
TABLE
II-Physical Compatibility of Tetrahydrozoline Ophthalmic Solution After One Month Additive
Concentration
Hydrochloride Remarks
Antibiotics Sodium P e nicillin G Dihydrostrep tomycin Sulfate Oxytetracy cline H y drochloride Chlortetr a cycline Hydrochloride polymy xin B Sulfate Bacitra cin Neo mycin Sulfate
10 , 000 50 5 5 500 500 1
u ./ cc. m g. / cc. mg./cc . m g ./cc. u ./cc . u ./cc . m g. / cc .
clear clear clear, residue after 3 days clear, residue after 3 days · clear clear clear
Antiseptics , caustics Benzalkonium Chloride Cetylpyridinium Chlorid e Silver N itrate Mild S ilv er Protein Strong Sil v er Protein
1 50.000 1 50 , 000 0 .5 % 10 % 1 %
Mercuric Chloride Zinc Sulfate
50 , 000 1 %
clear clear
NOW-
precipitate formed readily dispersible . not readily dispersible , precipitate formed clear
An aHractive PERMANENT BINDER for the Journal of the American Pharmaceutical Association
clear
Hormones Prednisolone Prednisone Hydrocortisone
0 . 2 mg ./ cc. 0 . 2 mg./cc. 0 . 2 mg./cc.
clear clear clear
*
Local A nesthetics Procaine Hydrochloride Cocaine Hydrochloride Butyn Sulfate
clear clear clear, residue formed after 2 days
1%
2% 2%
Mydriat ics Atropine Sulfate Homatropine Hydrobromide
0 . 05 %-1 % 0 . 05 % -1 %
clear clear
0 . 05 %- 1 %
clear
0 .5% 0 .5%
clear clear
Miotics Piloca rpine
lected ingredients. A spectrophotometric assay method was employed. These samples were assayed initially and after 3 weeks' storage at 50°C. The results are tabulated in Table III.
Discussion of Results As can be seen from Tables I and II, tetrahydrozoline hydrochloride solutions are generally compatible, physically, with most of the substances tested. Tetrahy drozoline hydrochloride has, as would be expected, the incompatibilities of chlorides. This is shown by its reaction with silver compounds. Cationic surface active agents are contraindicated for use in tetrahydrozoline nasal solution since the yellow dye that is present is precipitated. Tyrothricin also precipitates this dye. Thjs is not true in the case of tetrahydrozoline ophthalmic solution since there is no dye present to react.
TABLE
Antibiotics such as the tetracyclines and the penicillins usually have a shelflife for a period of 2 to 3 days in aqueous solution under refrigerated conditions. After this period, in the case of the tetracyclines, a darkening and a residue appear. When combined with tetrahydrozoline solutions there is . no evidence of acceleration of this normal decomposition and, therefore, these solutions are compatible for the period of 2 to 3 days. The data presented in Table III indicates the extreme chemical stability of tetrahydrozoline hydrochloride, under accelerated conditions, with various additives such as corticoids, antihistamines and antibiotics. When adding other ingredients to tetrahydrozoline hydrochloride ophthal- _ mic solution aseptic techniques $hould be employed since the solution is sterile and the introduction of contaminants is to be avoided. •
III-Chemical Stability of Tetrahydrozoline Hydrochloride Nasal Solution After 3 Weeks at SOO
Additive Prednisolone Hydrocortisone Neomycin Penicillin G Potassium Sulfanilamide S ulfathiazole Procaine Hydrochloride Polymyxin B. Sulfate Pyrilamine Maleate Chlorpheneramine Maleate
Concentra tion 0 . 2 mg./cc. 0 . 2 mg./cc. 0 .6 mg./cc. 10 ,000 u ./cc. 20 mg ./cc. 5C mg ./cc. 10 mg./cc. 500 u ./cc. 5 mg./cc. 5 mg./cc.
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Tetrahydrozoline Hydrochloride Potency After 3 Weeks a 0 . 99 mg ./cc. 1. 0 m g./cc. 1 . 0 mg./cc. 1 . 1 m g./cc. 1.1 mg./cc. 1 . 0 mg./cc. 1 . 0 mg ./cc. 1.0 mg./cc. 1 . 0 mg./cc. 1. 0 mg./cc.
title, year and volume
Combination sets lor Practical Pharmacy and Scientific Editions: (Before 1957) $5.50 a pair (1957 and after) $6.00 a pd ir Sinsle Editions: ScientiRc $3.25 each Practical (Old size) $3.25 each Practical (Ne ~ size) $3.75 each
Add 30¢ per binder for postage handling in U.S.-Foreign postage extra.
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SUCKERT LOOSE LEAF COVER CO. 11911 Grand River Ave., Detroit 4, Michigan Send •••• binders for the Journal of American Pharmaceutical Association •••• Practical Pharmacy Edition for years ••••••• Vols..•••.••.••.• •••. Scientific Edition for years ...••.. Vols ............• Combination for years ...•..• Vols ........•..• '. Will remit $ ..... in 10 days or return binders. Name •....•••...............•...•.••• Address •....•••.....•..•..........••• City ••••.••••...••.. Zone ••.. State ..••• .
a Initial Assay 1.0 mg./cc.
VOl. 20, NO.7, JULY, 1959/ PRACTICAL PHARMACY EDITION
405
tetrahydrozoline hydrochloride solutions by A. J. Spiegel, Ph.D., and C. F. Gerber*
HE PURPOSE of t his communicati on is to present fi ndings concerning the com patibility of the commercially ayailable tetrahydrozoline hy drochlor ide (T yzine) n asal and ophthalmic solutions (Visine eye drops) with other m edi camen ts tha t a re commonly used in the treatment of nasal and ophthalmic con ditions. It is felt that this study will aid the pharmacist and the physician in the compo unding and prescribing of ex temporaneous prescriptions utilizing tetrahydrozoline solutions. T etrahydrozoline hydrochloride is a sym path omimetic amine designated chemically as 2-(1,2,3,4-tetrahydro - l hy drochloride naphthyl)-imida zoline and having the em pirical formula C 13 H17N 2Cl. When applied topically t o the nasal mucosa, the drug causes vasoconstriction , which results in a reduction of local swelling and congestion . 1, 2,3 It is administered in 0.1% and 0.05% concentra ti ons and is also used as an
T
* R eceiv ed fr o m t h e P h a rm aceutica l Research a n d Dev elop m e n t Departm ent , Chas . Pfizer & Co ., Inc . I Ne w an d No noffi cia l Drugs, J. B . Lippincott Co ., P hil adel p hi a, 1958 , p . 2 13. 2 M e n ge r , H . C. , N .Y. S tate J . Med., 55, 81 2 (195 5). 3 P a r ish , F . A ., M ed . Tim es, 82 , 9 17 (1954) . C. F. GERBER has been a member of the Pharmaceutical Research and Development Department of Chas. Pfizer and Ca., Inc. for the past 6 years. He received his B.S. degree (1938) in biology from the City College of New York and his M.S. degree (1944) in biochemistry from New Yor k University. Mr. Gerb er has been engaged in phar ma ceutica l rese arch for a total of 20 years. DR . A. J. SPIEGEL is a member of the Pharmaceutical Research and Development Department of Chas. Pfizer and Co., Inc. He received his B.S. (1953) and M.S. (1955) degrees in Pharmacy from Columbia University and his Ph.D. (1957) from the University of Florida. Dr. Spiegel is a member of the APhA, the ACS, Sigma Xi, Rho Chi, and Rho Pi Phi.
404
ocular decongestant in concentrations of 0.05%. Tetrahy drozoline hydrochloride is a water-soluble salt consisting of a racemic mixture of two isomers. It is a white cry stalline solid having a melting point of 256- 257 ° C. The pH of a 1% aqueous solution is approximately 6.2.
tonic, borate buffered, sterile solution, containing thimerosal as the preservative. The solution is at pH 6.2- 6.3. Physical compatibility studies were made by combining a 0.1 % tetrahydrozoline hydrochloride nasal solution or a 0.05% tetrahydrozoline h ydrochloride ophthalmic solution with the additive under test in the concentration commonly employed. Observations in physical appearance were made initially and after storage for 1, 3, 7, and 30 days at 25°C. The results are shown in Tables I and II. The chemical stability of tetrahydrozoline hydrochloride nasal solution was also studied in combination with se-
Experimental
Tetrahydrozoline hydrochloride nasal solution is a 0.1% isotonic, citrate buffered, yellow colored solution containing thimerosal as the preservative. The solution is at pH 5.5. Tetrahy drozoline hydrochloride ophthalmic solution is a 0.05% clear, iso-
Table I-Physical Compatibility of Tetrahydrozoline Hydrochloride Nasal Solution after One Month Additive Antibiotics Sodium Penicillin G Dihydros treptomycin Sulfate Oxytetracycline HCI Chlortetracycline HCI Polymyxin B Sulfate Bacitracin Neomycin Sulfate Tyrothricin Antiseptics Cetyldimethylbenzyl Ammonium C hloride Cetylpyridinium Chloride Benzalkonium C hl o ride
H Ol'm ones Prednisolone Prednisone Hydrocortisone Lo cal Anesthetics Procaine HCI Benzyl Alcohol Butacaine Sulfate Cocaine HCI Tetracaine Hel Antihistamines Chlor p h eneramine Maleate Pyrilamine Maleate Others D-amphetamine S ulfate Hydroxyzine HCI Ephedrine Sulfate Chlorobut anol Silver Nitrate Mild Silver Protein Strong Sil ver Protein Boric Acid Ascorbic Acid Camphor Menthol
JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION
Concentration 10 ,000 50 , 5 5 500 500 1. a 0.2
u ./cc. mg./cc. mg./cc. mg ./cc. u ./cc, u ./cc. m g ./cc. mg. / cc.
Remarks clear clear clear, residue after 3 days clear, residue after 3 days clear clear clear precipitate formed cloudy , precipitate forms slowly
50,000 1 50,000 1 50 , 000 0.2 mg ./cc. 0.2 mg ./ cc. 0 . 2 m g ./cc.
1%
3% 1%
3% 2%
5 mg. / cc. 5 mg ./cc. 10 mg. / cc . 5 m g ./cc. 5 mg. / cc. 0 .5 % 0 .5 % 10-20 % 1 % 2 % 1 % 0 . 05 % 0 . 05%
cloudy , precipitate forms slowly cloudy, precipitate forms slowly
clear clear cl ear clear clear clear, residue atter few hrs. clea r clear, crystals tormed after weeks clear clea r clear clear clear clear precipitate formed readily dispersible, residue formed a fter one month not soluble clea r clea r , color change clear clear
TABLE
II-Physical Compatibility of Tetrahydrozoline Ophthalmic Solution After One Month Additive
Concentration
Hydrochloride Remarks
Antibiotics Sodium P e nicillin G Dihydrostrep tomycin Sulfate Oxytetracy cline H y drochloride Chlortetr a cycline Hydrochloride polymy xin B Sulfate Bacitra cin Neo mycin Sulfate
10 , 000 50 5 5 500 500 1
u ./ cc. m g. / cc. mg./cc . m g ./cc. u ./cc . u ./cc . m g. / cc .
clear clear clear, residue after 3 days clear, residue after 3 days · clear clear clear
Antiseptics , caustics Benzalkonium Chloride Cetylpyridinium Chlorid e Silver N itrate Mild S ilv er Protein Strong Sil v er Protein
1 50.000 1 50 , 000 0 .5 % 10 % 1 %
Mercuric Chloride Zinc Sulfate
50 , 000 1 %
clear clear
NOW-
precipitate formed readily dispersible . not readily dispersible , precipitate formed clear
An aHractive PERMANENT BINDER for the Journal of the American Pharmaceutical Association
clear
Hormones Prednisolone Prednisone Hydrocortisone
0 . 2 mg ./ cc. 0 . 2 mg./cc. 0 . 2 mg./cc.
clear clear clear
*
Local A nesthetics Procaine Hydrochloride Cocaine Hydrochloride Butyn Sulfate
clear clear clear, residue formed after 2 days
1%
2% 2%
Mydriat ics Atropine Sulfate Homatropine Hydrobromide
0 . 05 %-1 % 0 . 05 % -1 %
clear clear
0 . 05 %- 1 %
clear
0 .5% 0 .5%
clear clear
Miotics Piloca rpine
lected ingredients. A spectrophotometric assay method was employed. These samples were assayed initially and after 3 weeks' storage at 50°C. The results are tabulated in Table III.
Discussion of Results As can be seen from Tables I and II, tetrahydrozoline hydrochloride solutions are generally compatible, physically, with most of the substances tested. Tetrahy drozoline hydrochloride has, as would be expected, the incompatibilities of chlorides. This is shown by its reaction with silver compounds. Cationic surface active agents are contraindicated for use in tetrahydrozoline nasal solution since the yellow dye that is present is precipitated. Tyrothricin also precipitates this dye. Thjs is not true in the case of tetrahydrozoline ophthalmic solution since there is no dye present to react.
TABLE
Antibiotics such as the tetracyclines and the penicillins usually have a shelflife for a period of 2 to 3 days in aqueous solution under refrigerated conditions. After this period, in the case of the tetracyclines, a darkening and a residue appear. When combined with tetrahydrozoline solutions there is . no evidence of acceleration of this normal decomposition and, therefore, these solutions are compatible for the period of 2 to 3 days. The data presented in Table III indicates the extreme chemical stability of tetrahydrozoline hydrochloride, under accelerated conditions, with various additives such as corticoids, antihistamines and antibiotics. When adding other ingredients to tetrahydrozoline hydrochloride ophthal- _ mic solution aseptic techniques $hould be employed since the solution is sterile and the introduction of contaminants is to be avoided. •
III-Chemical Stability of Tetrahydrozoline Hydrochloride Nasal Solution After 3 Weeks at SOO
Additive Prednisolone Hydrocortisone Neomycin Penicillin G Potassium Sulfanilamide S ulfathiazole Procaine Hydrochloride Polymyxin B. Sulfate Pyrilamine Maleate Chlorpheneramine Maleate
Concentra tion 0 . 2 mg./cc. 0 . 2 mg./cc. 0 .6 mg./cc. 10 ,000 u ./cc. 20 mg ./cc. 5C mg ./cc. 10 mg./cc. 500 u ./cc. 5 mg./cc. 5 mg./cc.
Opens flat asa bound book
* Made of durable, imitation leather Will preserve your Journals permanently Each cover holds 12 issues Easy to follow instructions
* Stamped with number
Others Chlorobutanol Methocel 4000 cps.
* * * *
Do your own binding in only a matter of minutes
Tetrahydrozoline Hydrochloride Potency After 3 Weeks a 0 . 99 mg ./cc. 1. 0 m g./cc. 1 . 0 mg./cc. 1 . 1 m g./cc. 1.1 mg./cc. 1 . 0 mg./cc. 1 . 0 mg ./cc. 1.0 mg./cc. 1 . 0 mg./cc. 1. 0 mg./cc.
title, year and volume
Combination sets lor Practical Pharmacy and Scientific Editions: (Before 1957) $5.50 a pair (1957 and after) $6.00 a pd ir Sinsle Editions: ScientiRc $3.25 each Practical (Old size) $3.25 each Practical (Ne ~ size) $3.75 each
Add 30¢ per binder for postage handling in U.S.-Foreign postage extra.
MAIL THIS COUPON NOW ---MONEY BACK IF NOT SATISFIEC---
SUCKERT LOOSE LEAF COVER CO. 11911 Grand River Ave., Detroit 4, Michigan Send •••• binders for the Journal of American Pharmaceutical Association •••• Practical Pharmacy Edition for years ••••••• Vols..•••.••.••.• •••. Scientific Edition for years ...••.. Vols ............• Combination for years ...•..• Vols ........•..• '. Will remit $ ..... in 10 days or return binders. Name •....•••...............•...•.••• Address •....•••.....•..•..........••• City ••••.••••...••.. Zone ••.. State ..••• .
a Initial Assay 1.0 mg./cc.
VOl. 20, NO.7, JULY, 1959/ PRACTICAL PHARMACY EDITION
405