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Stability Studies of the Parental Solutions of Sympatol and Noradrenaline

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Stability Studies of the Parental Solutions of Sympatol and Noradrenaline Research Collection Doctoral Thesis Stability studies of the parental solutions of sympatol and noradrenaline Author(s): Agrawal, Devendra Kumar Publication Date: 1960 Permanent Link: https://doi.org/10.3929/ethz-a-000131813 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Prom Nr. 2887 STABILITY STUDIES OF THE PARENTAL SOLUTIONS of SYMPATOL AND NORADRENALINE THESIS PRESENTED TO THE SWISS FEDERAL INSTITUTE of TECHNOLOGY, ZURICH for THE DEGREE OF DOCTOR OF NATURAL SCIENCES by DEVENDRA KUMAR AGRAWAL Citizen of India Accepted on the recommendation of Prof. Dr. K. Steiger—Trippi and Prof. Dr. J. BUchi Job Printers, Allahabad 1960 Printed by Job Printers, 99, HewettRoad; Allahabad 1959—60 PREFACE Physiological action may be achieved by the administration of drugs in various forms. One of the most rapid means of obtaining such an action is by administering the drug in the form of an injection. The inclusion of various monographs in different Pharmacopoeias relating to in¬ jections points to the significant advantages of such a form of medica¬ ment. However one of the most intriguing problems before the pharmacist has been that of the stabilization of the galenicals in general and injec¬ tions in particular. In the words of Schou (1); "How is it that a question long known to be of great importance is still characterised by being insufficiently considered if not at all touched." The present work has been carried out to determine the con¬ ditions necessary for the stability of the parental solutions of two of the sympathomimetic amines : Sympatol and Noradrenaline. ACKNOWLEDGEMENTS The experimental work in connection with these investigations has been carried out at the School of Pharmacy of the Swiss Federal Institute of Technology, Zurich, under the supervision and guidance of Prof. Dr. K. Steiger. I have feelings of deep gratitude towards my teacher, Prof. Dr. K. Steiger for taking a keen inrerest in me, and giving his valu¬ able advice and guidance throughout the course of this work. My sincerest thanks are due to Messrs Volkart Foundation, Winter- thur, for their scholarship to assist me to complete my research, which was a material financial help to me throughout the course of my work. I am also thankful to Dr. Hippenmeier of the Kantons Apotheke, Zurich, for allowing me to work in his laboratories with the Zeiss Spectrophotometer, to Messrs Boehringer Sohn, Ingelheim am Rhein for supplying their original product of Sympatol and to Messrs Hoechst Farb- werke, Frankfurt for supplying Noradrenaline. DEDICATED TO MY DEAR PARENTS ERRATA Page Errata Correct 2 Aquoeus Aqueous 18 Stndarad Standard + + 33 NH3 NH2 1 1 39 apporximate approximate 55 ehl the 77 SB as 119 fig. 15 fig 16 120 fig. 16 fig. 15 fig. 16 (in Table) fig. 15 124 ZUSA M VIE MFASSUNG ZUSAMMEMFA& 124 siehe page siehe seite 125 abbau Abbau 127 Sprtzein Spritzen Hohlandeln Hohlnadeln CONTENTS Some considerations of Injections and Sympathomimetic amine s CHAPTER I Page Injections .. .. 1. Requirements .. 1 of .. 2. Manufacture injections .. 2 3. Stability of injections . 13 CHAPTER II Sympathomimetic amines 1. General considerations .. .. ..16 of 2. Therapeutic uses sympathomimetic amines .. 18 3. Relation between chemical structure and pharmacological activity of sympathomimetic amines 19 4. Classification of sympathomimetic amines .. 20 CHAPTER III Stability of Sympatol solutions 1. Problem 29 2. Working procedure 29 CHAPTER IV Sympatol 31 1. Synonyms 31 2. Synthesis 31 3. Tests 33 4. Methods of quantitative analysis described in the literature .. 34 5. Pharmacological actions .. 35 6. Clinical uses ..36 •• •• 7. Dosage .. CHAPTER V Testing of the materials and apparatus ..37 •• •• 1. Sympatol •• 39 2. Distilled water V1U Page 3. Ampules .. • • .. .. 39 4. Other materials .. .. 41 5. Apparatus .. .. .. .. 41 CHAPTER VI Methods of analysis for Sympatol 1. Quantitative methods .. .. .. 42 for of 2. Colour standards comparison the colour .. 57 3. pH determination .. .. 61 CHAPTER VII Determination of the stability of Sympatol solutions 1. Principles .. 62 of the solution 2. Preparation .. 62 3. of the Testing ampules .. 64 4. Discussion and conclusions of the results and of colour pH determination .. 70 5. Injection of Sympatol .. 71 CHAPTER VIII Stability studies of Noradrenaline (NA) solutions with respect to race mization 1. Introduction .. .. .. ..72 2. Problem .. .. .. ..72 CHAPTER IX Noradrenaline 1. names Synonyms and proprietary .. 73 2. Synthesis .. 73 3. Physical properties .. 74 4. tests Qualitative .. 74 5. Methods of quantitative analysis described .. 75 in the literature 6. actions Pharmacological .. 78 7. Clinical uses .. 80 8. Dosage .. 80 CHAPTER X Testing of the material 1. Noradrenaline hydrochloride .. 81 IX Page CHAPTER XI Determination of fresh and deteriorated Noradrenaline in solution 1. Introduction .. 83 .. .. ... 2. UV. method 84 Spectrophotometric .. .. 3. methods .. .. 87 Colorimetric .. ' 4. Summary .. .. .. 94 CHAPTER XII Racemizations studies of the dilute solution of Noradrenaline 1. Method for concentrating the solution and for deter¬ mining the optical rotation 96 2. Preparation of the solution 97 3. Results 98 4. Summary of the results of racemization studies 102 5. Discussion and conclusions 105 CHAPTER XIII Prediction of the stability of the solutions of Noradrenaline with respect to racemization 1. Introduction 106 2. 106 Order of reaction ... 3. Temperature coefficient 108 4. Experimental 109 5. Racemization studies at 50°, 60° and 70° 117 121 6. Summary .. CHAPTER XIV Summary 122 References 127 The following abbreviations have been used in the text ° scale = Temperature has been given in centigrade g = Gramme ml = Millilitre AR = Analytical reagent NA = Noradrenaline Some Considerations of Injections and Sympathomimetic amines CHEATER I INJECTIONS . Injections are sterile aqueous or nonaqueous solutions or suspen¬ sions intended for administration under, or through one or more layers of skin or mucous membrane. This form of medicament has several advantages (2) :— (a) Instantaneous physiological action is achieved especially if the drug is given intravenously. (b) Drugs which may be useless or may lose their potency if given orally can be easily administered. (c) Drugs can be administered even when the patient is unable to take anything orally. (d) The physician controls the amount of medicament given, and so there is no possibility of over dosage. 1. Reqnirenjents General requirements for the injections may be summarised as follows :-— (a) They should be clear, free from dust particles and homogeneous if the substance is insoluble. (b) They should be sterile. (c) They should be isotonic with blood serum. (d) They should have the same pH value as that of the blood serum, if the conditions permit. when (e) They should not give rise to any undesirable effects injected. (f) They should be stable. In order to comply with the above requirements it is important the manufacture of that every care is being taken during injections. 2 2. Manufacture of Injections Butikofer (3) has discussed the different aspects of the manu¬ facture of injections. The following scheme summarises the steps invol¬ ved for their manufacture : Solvent Active ingredient Additive Container I I ' I test test test test (physical & (physical & .(physical & (alkali) chemical) chemical) chemical) ( I Chromic-acid-bath Pyrogen test Pyrogen test I cleaning I Solution sterilization Filtration I Filling Closing Sterilization I Tests Sterility Pyrogen pH checking Visual (dust particles, colouration) Labelling I Packing Expedition we shall discuss In the following pages the important points con¬ cerning the requirements of injections. 2.1. Solvent 2. 1. 1. Aquoeus :ol\ents Water for injection is used for the preparation of parental solutions for which most of the pharmacopoeias give a separate monograph. It is prepared by distilling potable or distilled water from a neutral glass still, fitted with an efficient device to prevent the entrainment of droplets. It is important that water for injection is free:from dissolved gases like carbon dioxide as it could precipitate dissolved 'substances like phenobarbitone sodium, sulphadiazine sodium, theophylline with ethylenediamine, pentobarbitone sodium, sodium dihydrocholic etc., while the presence of oxygen could oxidize such substances as adrenaline, noradrenaline, ascorbic acid, para-amino-salicylic-acid, apomorphine, mersalyl etc. Further it should be free from metallic ions especially iron and copper as they considerably accelerate the processes of oxidation. Schou Gredsted and (4) have investigated the oxygen content of differ¬ ent types of water which is reproduced in table I. Table I Oxygen content of water at 20°. 1. Collected directly from the apparatus 1-2 to 2-34 ml/litre 2. Distilled water stored in ordinary containers 6-35 ml/litre 3. Boiled and rapidly cooled 4-0 ml/litre 4. Sterilized by autoclaving in Erlenmeyer flasks, 2-46 to plugged with nonabsorbent cotton wool. (120*20 min). 3-58 ml/litre 5. Water freed of oxygen through liberation of COa 0-45 ml/litre by added bicarbonate. From the above table' it is clear that the oxygen content of water varies considerably under different conditions of storage. In the case of those substances which are easily oxidized it is essential that the water which is used for their solution should contain the
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