Polarometric (Amperometric) titration in the analysis of narcotic substances

Abstract

In recent years so-called polarometric (amperometric) titration has achieved definite recognition among electrometric titration methods. By this method, changes in the intensity of current, when suitably connected to a constant voltage, are measured in terms of the amount of control agent added and the point of equivalence is determined graphically as the intersection of lines representing the value of the current intensity before and after the equivalence is established. The advantage of this titration method, currently to be found described in all modern textbooks on quantitative analysis, is its speed and, as it is at the same time reasonably accurate and requires only simple equipment, this makes it a popular choice in many different branches of chemical analysis.

Details

Author: Jaroslav Zyka
Pages: 35 to 40
Creation Date: 1958/01/01

Polarometric (Amperometric) titration in the analysis of narcotic substances

Jaroslav Zyka Institute of Analytical Chemistry of Charles University, Prague

In recent years so-called polarometric (amperometric) titration has achieved definite recognition among electrometric titration methods. By this method, changes in the intensity of current, when suitably connected to a constant voltage, are measured in terms of the amount of control agent added and the point of equivalence is determined graphically as the intersection of lines representing the value of the current intensity before and after the equivalence is established. The advantage of this titration method, currently to be found described in all modern textbooks on quantitative analysis, is its speed and, as it is at the same time reasonably accurate and requires only simple equipment, this makes it a popular choice in many different branches of chemical analysis.

Full reports covering the use of polarometric titration also in the analysis of medical preparations have been published recently (1), (2).

Many narcotic substances (among the organic bases particularly alkaloids), are often identified by their precipitation reaction with so-called alkaloid agents. These are precisely the cases where polarometric titration offers an eminently suitable method for speedily and simply studying such addition precipitation reactions, not only for the purposes of quantitative analysis, but also for studying the composition of the precipitates produced.

In our recent work we have examined these possibilities, and have successfully used polarometric titration for analysing a large number of organic bases, using certain heteropolyacids and heavy metal complexes as control solutions (6), (7). In every case we have relied on the fact that, even where a given organic base is not polarographically apparent, the control agent is polarographically reducible - and this is quite sufficient for the purpose of polarometric titration.

As we believe that this titration method also offers wide possibilities for the control of narcotic drugs, even where these take the form of medical preparations (injections, tablets), we shall review here the organic bases thus far determined by this method, with particular reference to compounds which can be classified as narcotic drugs.

Addition precipitation reactions of organic bases are usually divided into four groups. The first group comprises the so-called "alkaline" precipitating agents, such as sodium carbonate, hydroxides of the alkaline metals, sodium acetate, sodium phosphate, potassium cyanide, sodium benzoate, etc. These agents are not basically addition precipitating agents, for their function is merely, by the alkalinization which follows their addition, to cause the precipitation of the corresponding base from, for example, alkaloid salts, usually in amorphous form and as a rule not entirely quantitatively. This method cannot be used for polarometric titration, because none of these compounds is polarographically reducible in the conditions necessary for precipitation.

The second group of precipitating reagents consists, firstly, of simple oxyacids and, secondly, of heteropolyacids. Oxyacids and their salts, such as potassium dichromate, perchloric acid and chlorates, are used mostly for the microscopic determination of alkaloids, even where polarometric determination can also be used; for example, a description has been given of the titration of certain acridine derivatives using potassium dichromate as the control solution (8).

Far greater possibilities are offered by the heteropolyacids, such as silicotungstic acid, phosphotungstic acid and phosphomolybdic acid, which have the particular merit that their precipitation reactions with alkaloids or organic bases are very sensitive; the precipitates are slightly soluble and appear instantly and quantitatively, usually in well-defined crystallized form. Such agents are especially suitable for polarometric titration, as they are compounds which are readily reducible polarographically with the use of mercury dropping electrodes.

The third group consists of solutions of heavy metal complexes, such as K 2HgI 4, K 2CdI 4, K 2Hg(CNS) 4, K 2Cd(CNS) 4,KBiI 4, HAucl 4, H 2PtCl 6 and also such substances as the so-called Reinecke’s salts. These agents are also very suitable precipitants for polarometric titration and the observations made on the compounds mentioned above also apply essentially to these.

Equally favourable possibilities are offered by certain aromatic nitro-compounds and related substances such as picric, picrolonic, styphnic and flavianic acids (and, among other substances, also sodium alizarin sulfonate).

In all our titration experiments we had to determine what was the suitable voltage to be connected, taking into account the control agent used and the concentration and type of supporting electrolyte, and to find the pH most suitable for the quantitative reaction process. In the following paragraphs we have outlined the results which we obtained in the polarometric titration of organic bases (particularly alkaloids), including certain narcotic drugs, using solutions of the above-mentioned substances.

In titration with a control solution of silicotungstic acid, which was first used for the polarometric titration of nicotine (9) and nornicotine (10), we adopted, in accordance with the polarographic behaviour of this acid, a voltage of -0.65 V (versus a calomel-saturated electrode) and obtained good results in the titration of narcotine hydrochloride, cocaine, narceine, codeine phosphate and other bases and their salts (novocaine chloride, antipyrine, amidopyrine, atropine sulfate and cinchonine sulfate), which in every case precipitated in specific proportions, quantitatively and instantaneously best of all in an acid medium (4).

A control solution of phosphotungstic acid can also be used in a similar way, adopting a voltage of -0.4 V. We obtained good results in the titration of cocaine hydrochloride, narcotine, codeine phosphate and other compounds (antipyrine, amidopyrine, strychnine nitrate, quinine hydrochloride) (4), in approximately the same way as in the case of silicotungstic acid.

Phosphomolybdic acid is not suitable for this purpose, even where it produces a precipitate on a micro-scale with a number of organic bases and their salts; in polarometric titration the excess agent comes into contact with the mercury dropping from the electrode and produces a diminution in current intensity as a result of the reduction of molybdenum; thus the results are not readily reproducible.

Table 1 lists the identified compounds which are related to narcotic drugs and gives the most important conditions for titration with silicotungstic and phosphotungstic acid; it also states the ratio of the reaction between the base and the agent.

In all the experiments we used a volume of 10-20 ml and followed the procedure described in the following paragraphs.

With regard to control solutions of complex salts of heavy metals, we first experimented with the use of compounds of the type K 2HgI 4, K 2HgBr 4and K 2Hg(CNS) 4(6) for polarometric titration. We studied the relationship between the quantitative process of precipitation, the type of compound used in preparing the solution (HgO, HgCI 2, HgBr 2, Hg(CNS) 2), the quantity of anion complex-forming ingredients and the supporting electrolyte H 2SO 4, HNO 3, KI); we chose cinchonine and narcotine as standard substances for checking the reactions. We found that the titration process and the structure of the precipitate are powerfully influenced by all the above-mentioned factors, but that it is nevertheless possible to find conditions under which reproducible results can be obtained.

Table 1

Control solution and substance determined

Ratio in mole of titration agent to substance determined

Titration medium

Quantities determined(in mg)

0.01 M silicotungstic:
 
 
 
Cocaine hydrochloride
1 : 4
0.3 N HCL
30-100
Codeine phosphate
1 : 4
0.3 N HCL
40-100
Narceine
1 : 5
0.3 N HCL
20-50
Narcotine hydrochloride
1 : 5
0.3 N HCL
20-50
0.01 M phosphotungstic acid:
 
 
 
Cocaine hydrochloride
1 : 4
0.25 HCL
5-20
Codeibe phosphate
1 : 4
0.25 N HCL
20-40
Papaverine hydrochloride
1 : 4
0.25 N HCL
30-40
Nacrotine hydrochloride
1 : 4
0.25 N HCL
40-50

In our work we used a voltage of - 0.9 V, with a Volume of about 20 ml and with 20-200 mg doses of the sample; we found 0.1 M KNO 3 or 0.1 H 2SO 4satisfactory as the supporting electrolyte. Details are given in the original report (6). We found the best solution for titrating narcotine hydrochloride to be 0.05 M K 2HgI 4,prepared from mercuric chloride and potassium iodide in the ratio of HgC1 2: KI = 1 : 12, or a solution of 0.05M K 2HgBr 4prepared from mercuric chloride and potassium bromide (HgCl 2: KBr = 1/12) or from mercuric bromide and potassium bromide HgBr 2: KBr = 1/20 to 1/40); in each case two molecules of base reacted with one molecule of agent. We found the solution K 2Hg(CNS) 4, prepared differently, to be unsuitable for polarometric titration.

In the same way we studied the possibility of using the solutions K 2Cdi 4, K 2CdBr 4, K 2Cd(CNS) 4 and KBiBr 4, and found that the process of precipitation and the composition of the precipitate were influenced by the same factors as in the case of complex salts of mercury. We also found that the complex salts of cadmium and bismuth containing a sufficient quantity of bromide as an ingredient of the complex (in the case of cadmium and rhodanide), used as control agents in aqueous solutions, are more stable than analogous iodine compounds; however, as the iodine ingredient has a favourable effect in suppressing the solubility of the precipitate, we carried out titration with a control solution containing a bromide complex ingredient, but chose an iodide solution as the supporting electrolyte (volume about 20-30 ml) and so produced the solution K 2CdI 4or KBiI 4 "as required ".

We obtained good results in the titration of cinchonine, codeine and narcotine hydrochloride, ethylmorphine, atropine, papaverine, strychnine nitrate, pilocarpine hydrochloride, and arecoline hydrobromide (7).

Table 2 shows the technical conditions for the titration of certain compounds which may be met with in the analysis of narcotic drugs.

We did not find complex salts of antimony suitable for these purposes.

We also studied the possibility of precipitate titration of organic bases with a control solution of Reinecke’s salt (6) - [Cr(CNS) 4(NH 3) 2]NH 4which, as is known, forms highly insoluble products of addition with similar substances.

We applied a voltage of -1.1 to -1.2 V, which we established by tentative polarographic experimentation, and carried out titration in solutions of O.1 M H 2SO 4. We used a 0.04 M Reinecke’s solution, which must always be prepared as needed, since these solutions lose their precipitating capacity with age. Using a volume of about 20 ml and quantities of 20 to 50 mg of the sample, we obtained good results in titrating arecoline hydrobromide (1 : 2), atropine sulfate (1 : 1), cinchonine (1 : 3), strychnine nitrate (2: 1), ethylmorphine hydrochloride (1 : 2) and codeine (1 : 1); the molecular ratio in the precipitate between the agent and the base is given in parentheses.

The last group of substances, which gave good results when used as control agents, consists of certain aromatic nitro-compounds. Their advantages lies in the fact that, owing to the presence of nitro-groups, they are readily reducible at the mercury dropping electrode; this makes them particularly useful for polarometric titration. Their precipitating capacity varies with the different organic bases, and, as some of our experiments show, this permits of a certain selectivity in titration of this kind.

Table 2

Titration agent

Ratio of metal and complex forming compounds in titration agent

Substance determined

Ratio in mole of titration agent to substance determined

Titration medium

Applied voltage

Quantities Determined (in mg)

0.1 M K 2CdI 4
1: 4 to 1: 24
Narcotine hydrochloride
1 : 2
0.1 M KNO 3
- 1.1 V
80-150
 
 
Codeine hydrochloride
1 : 2
0.1 M KNO 3
- 1.1 V
80-200
0.1 M K 2CdB 4
1 : 10
Narcotine hydrochloride
1 : 2
2.5% KI
- 1.1 V
100-200
 
 
Codeine hydrochloride
1 : 2
2.5 % KI
- 1.1 V
50-200
0.1 M K 2Cd(CNS) 4
1 : 10
Narcotine hydrochloride
1 : 2
0.1M KNO 3
- 1.1 V
100-180
 
 
Papaverine hydrochloride
1 : 2
0.1 M KNO 3
- 1.1 V
80-180
 
 
Codeine hydrochloride
1 : 2
2.5 % KI
- 1.1 V
80-200
0.1 M KbiI 4
1 : 16
Ethylmorfinehydrochloride
1 : 1
0.1 M KNO 3
- 0.6 V
80-250
 
 
Codeine hydrochloride
1 : 1
0.1 M H 2SO 4
- 0.6 V
80-280
 
 
Papaverine hydrochloride
1 : 1
0.1 M KNO 3
- 0.6 V
100-300
0.1 M KbiBr 4
1 : 16
Papaverine hydrochloride
1 : 2
0.1 M H 2SO 4
- 0.7 V
100-200
 
 
Narcotine hydrochloride
1 : 2
0.1s M KNO 3
- 0.7 V
80-250
0.05 M K 2HgI 4
1 : 12
Narcotine hydrochloride
1 : 2
0.1 M KNO 3
- 0.7 V
20-200
0.05 M K 2HgBr 4
1 : 12
Narcotine hydrochloride
1 : 2
0.1 M KNO 3
- 0.7 V
20-200

We experimented with the use of picric, picrolonic, styphnic and flavianic acids (3), (11) and, in addition to these nitrocompounds, sodium alizarin sulfonate (which is, of course a different kind of substance) as control agents for the polarometric titration of organic bases.

Of the compounds which we tried, the most, satisfactory in the titration of papaverine hydrochloride, strychnine nitrate and cinchonine was picric acid. We used a voltage of -0.4 V. (Under these conditions, salts of cocaine, codeine and atropine, for example, did not precipitate.) Picrolonic, styphnic or flavianic acids did not give very good results, because they require buffered solutions; they are, however, in principle for the polarometric titration of organic bases, and we shall test them in some of our future experiments (for titration with picrolonic acid the voltage should be -0.8V or -1.36V; with styphnic acid, -0.32V; in titrating with flavianic acid, which gives good results with cinchonine and quinine hydrochloride, we found a voltage of -1.2 V to be suitable).

In our experiments we found a solution of sodium alizarin sulphonate to be suitable for the titration of papaverine hydrochloride, narcotine, quinine, cinchonine and strychnine nitrate in buffered solutions at pH 4-6, containing 0.3 N KC1 as a supporting electrolyte and with a voltage of - 0.65 V.

Table 3

Control solution and substance determined

Ratio in mole of titration agent to substance determined

Titration medium

Quantitiesdetermined(in mg)

0.01 M Picric acid :
 
 
 
Papaverine hydrochloride
1: 1
pH 4.6-7
5-50
0.01 M Sodium alizarin sulphonate:
 
 
 
Papaverine hydrochloride
1: 1
0.6 N KCI
10-20
Narcotine hydrochloride
1: 1
0.3 N KCI
20-40

We determined the proper voltage by checking the polarographic behaviour of the compounds in question, which usually show several polarographic wave-lengths (according to the pH of the solution), only some of which are suitable for polarometric titration. Table 3 lists compounds of the narcotics series which can be titrated in this manner.

In all our polarometric titration experiments we used apparatus provided with a dropping mercury electrode for the cathode and a saturated calomel electrode for the anode, connected with the titration liquid by a salt bridge filled with a 15% solution of potassium nitrate. The necessary voltage was provided by means of a Kohlbrausch coil with a 2-volt battery. We used a galvanometer with a polarograph for measuring the intensity of the current, and an electromagnetic stirrer for mixing the liquid.

We generally carried out the titrations in the following manner (described here in summary form only; some details are given in the works cited in the bibliography appended to this report). A quantity of the sample corresponding to approximately 10-20 ml 0.01 M of a solution of an organic base or its salt is placed in a small titration vessel (suitable weights are given in the tables) and the titration medium is prepared by adding acid, buffer or supporting electrolyte as indicated for the various specific compounds. In order to support the formation of precipitate we recommend working with a small volume - about 20 ml. If necessary, a few drops of gelatine or other surface-active substance are added as a maximum suppressor - a common practice in polarometric titration. Titration then proceeds as usual in polarometric titration; i.e., after each addition of control agent (usually 0.01 M) the titrated liquid is thoroughly mixed, the precipitate formed is allowed to settle and the figure showing the intensity of the current is noted. It is usually possible to read off this figure after mixing only briefly, since the precipitation of the base with the control agent occurs practically instantaneously (especially if a substance such as silicotungstic acid is used); but, if a substance such as picric acid is used, it is better to mix the titrated liquid several times and wait until the intensity of current remains steady. Since, in the titrations described, what appears polarographically is only the titration agent and not the precipitated organic base or its salts, the practical values of the intensity of the current do not change until the point of equivalence is reached; only after that point is there a rise in the linearly diffuse current of the excess control agent and therefore also in the value of the current; thus, the graphic representation of the titration process consists of two lines in the form of a reversed letter L, corresponding to the values of the current intensity before and after equivalence, which intersect at equivalence.

It is apparent from the foregoing that polarometric titration, the merits of which, as one of the electrometric titration methods, are well known so far as rapidity of procedure and simplicity of apparatus are concerned, may be useful also for analysing those narcotics which have the character of organic bases or their salts, particularly if use is made, as titration agents, of the compounds known as "alkaloid reagents", which, in an addition reaction with those substances, form precipitates that are highly insoluble and, under suitable conditions, have a well-defined structure.

This type of titration may be important in two ways. Firstly, it provides a very quick and reliable means of examining the structure of the precipitates that are formed a possibility which may be useful in theoretical studies of addition reactions between organic bases and precipitating agents. Secondly, it is of practical importance in that it provides a simple means for the determination of certain narcotics. We were not particularly concerned with narcotics in our studies of the precipitation reactions of organic bases; we merely draw attention here to the possible use of the method, as we believe it can be extensively used in this field. It is highly probable that, just as suitable conditions were found for titrating the compounds mentioned in this report, it would be very easy, by analogy (possibly by slightly changing, say, the medium and the weights) to undertake the titration of other similar substances. Our experiments so far indicate that silicotungstic acid and picric acid offer in this respect the best possibilities as titration agents. Both these compounds are readily available in laboratories, and their factor can easily be determined visually by titration with a hydroxide control solution. Particular attention should be drawn to the universal utilization of silicotungstic acid, which, of all the known alkaloid reagents, forms the least soluble precipitates with organic bases. Consequently, it can be used on a micro scale; also it requires very simple titration media, as the quantitative reaction, with well-defined reaction products, is usually obtained by titration in a weak acid medium of hydrochloric acid (0.05 to 0.5 N HCl).

It may be that this universal quality of silicotungstic acid (and possibly of other precipitating agents) is in a way a disadvantage, because it does not allow sufficient selectivity in titration. If we bear in mind, however, the cases in which polarometric titration of this kind can be applied, it is obvious that this disadvantage will not arise, since in the control of narcotic drugs, whether as a basic substance or as a medicament (injections, drops, tablets), single compounds rather than mixtures will be encountered as a rule. In Czechoslovakia, for example, this titration method is used in the State Institute for Control of Medicaments with very good results for analysing commercial products and various medicaments with the character of organic bases; polarometric titration is particularly useful in checking the active substances in tablets, as there is no need to isolate the compound first by breaking the tablet down into its ingredients: all that is necessary is to dissolve the tablet in water or a weak acid medium and then titrate.

The purpose of this report was merely to draw attention in general terms to the possibility of using polarometric titration in the analysis of narcotic substances having the character of organic bases; we believe that in future this simple electrometric titration method will find widespread application in this field also.

Bibliography

  1. KALVODA R. & ZYKA J.: Pharmazie 7, 535 (1952), Acta Pharmac. Intern. 2, 365 (1954), Ceskoslov. farm. 1, 379 (1952).

  2. KONOPIC N.: Osterr. Chem. Ztg. 54, 289 (1953), 55, 127 (1954).

  3. ZYKA J.: Pharmazie 10, 170 (1955).

  4. SOUCKOVÁ M. & ZYKA J.: Ceskoslov. farm. 4, 181, 227, 301 (1955).

  5. KRACMAR J.: Ceskoslov. farm. 5, 578 (1956).

  6. CIHZOVA M. & ZYKA J.: Ceskoslov. farm. 5, 572 (1956).

  7. SCHILLEROVA V. & ZYKA J.: Ceskoslov. farm. 6, 93 (1957).

  8. BLAZEK A., KALVODA R. & ZYKA J.: Cas. ces, Lekarn, ved. prl. 63, 138 (1950).

  9. DE ANGELIS J.: Ric. Sci. 21, 62 (1951).

  10. WILLITS C. O. & RICCIONE C.: Anal. Chem. 23, 1713 (1951).

  11. ZYKA J.: Ceskoslov. farm. 4, 301 (1955).

Professor P. O. Wolff

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On 16 November 1957, Professor P. O. Wolff died in Geneva.

Professor Wolff was a well-known figure in the field of international control of narcotic drugs through his studies of drug addiction and his work as chief of the Addiction-producing Drugs Section of the World Health Organization.

Born in Berlin in 1894, he studied at the university there and obtained degrees as Doctor of Medicine and Doctor of Philosophy. He specialized in pharmacology, and one of his main interests was the study of drug addiction and drug addicts. He became a privat-docent at the University of Berlin. In 1931 he participated as an expert in the Geneva Conference for the limitation of the manufacture of narcotic drugs.

At the time when the national socialist regime came to power in Germany, Professor Wolff decided to go into exile. He came to Geneva and was for many years a regular contributor to the Journal suisse de Médecine. At the same time he carried out missions and wrote several studies for the League of Nations, and for several governments - in particular the Government of the United States of America.

In 1939 Professor Wolff went to Argentina on a mission for the League of Nations. He remained in that country until 1948 and worked there in constant liaison with the Argentine health authorities and a number of scientific bodies.

In 1949 he returned to Geneva and entered the World Health Organization, where, until he retired in 1954, he was the chief of the Addiction-producing Drugs Section.

After he retired, Professor Wolff continued his scientific activities, giving numerous lectures and writing scientific articles, as well as participating actively in the work of several international congresses. Towards the end of his life he became honorary professor in the faculty of pharmacology of Berlin’s Free University.

Professor Wolff was in the full sense of the word a scholar. He wrote, in four languages, a great number of articles on many subjects, in particular cannabis, the coca leaf, opium and drug addiction in general, and it can be said that he made a significant contribution to the development of international control of narcotic drugs. At the end of his life he started a comprehensive study of synthetic narcotic drugs and wrote on that subject several authoritative papers.

It was characteristic that his scientific pursuits, though they led to great achievement, were not his only fulfilment. Throughout his life he never stopped being interested in many other aspects of human endeavour and culture. During his numerous travels he collected works of art which were amongst the treasured companions of his last years.

Professor Wolff had fought in the first world war as an officer in the German army and he had been gassed. For years he was a sick man and knew his fate, but he suffered without flinching. Up to his very last day he was working on scientific material he had written, and those who saw him at the last can say that he was a man who never gave up.

The editors of the Bulletinwish to extend their heartfelt condolences to his family.

Professor Axel Jermstad

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On 4 November 1957, Professor Jermstad died in Oslo.

Professor Jermstad was a well-known figure in the field of pharmacology and in particular of the analysis of the alkaloids of opium.

Born on 19 May 1880, he began a course of studies at the University of Oslo but went abroad very early in life and acquired the broad outlook and wide knowledge of men and cultures which was to be one of the characteristic traits of his personality. In Switzerland, he received his degree of Doctor in Philosophy in 1920 for his thesis entitled : "Monographie und Kritik der Methoden zur Bestimmung des Morphins im Opium ", a work which later proved to be a milestone in opium research. He then travelled and studied in Germany. He had the true scientist's spirit and was never content with what he had achieved : he went to France to round out his already wide knowledge of pharmacognosy and organic chemistry and, in 1927, he received a degree of Doctor in Pharmacy at Strasbourg. He then went back to his native Norway and was entrusted with a chair at the University of Oslo. In 1932 he was nominated Dean of the Institute of Pharmacy, a post he held until 1948.

He published numerous valuable publications in the field of opium and in 1954 he was chosen to participate in the expert committee appointed by the Secretary-General of the United Nations, in pursuance of a resolution of the Economic and Social Council, to evaluate the work already done in developing and testing methods to establish the geographical origin of opium by chemical and physical means. Professor Jermstad was already collaborating in the programme established by the United Nations to develop such methods. As chairman of this committee, Professor Jermstad made a significant contribution to the work of the United Nations in the field of the international control of narcotic drugs.

Member or honorary member of a number of scientific associations around the world, Professor Jarmstad was a man of high professional status and of broad culture as well. All the people who have known him remember him not only as a scholar, but also as an upright and outspoken man, the best of colleagues and the truest of friends.