XV. THE CHEMIST IN THE PHARMACEUTICAL INDUSTRY RANDOLPH J. OWEN
Some of the problems which confront the control chemist in the fihafmaceutical industry are described by Mr. Randolph J. Owen. Mr. Owen has been connected with the E. L. Patch Company, manufacturing pharmacists, since 1925. For eight years he was employed as a chemist and since 1933 he has been plant superintendent. He is a graduate of Boston University and is the co-author of several papers. The accompanying picture shows the completely remodeled up-to-date control laboratory of the company.
+ + + + + + The pharmaceutical industry is one in which the chemist plays an important part. Many branches of chemical work may be found represented in this industry, some of which are analytical, organic, research, and biological. In this paper I will describe only the work of the analytical chemist who is directly tied up with the production of goods which are used to fill orders. Such a chemist is usually assigned to a department known as the Control Department. The Control Department in a pharmaceutical company is responsible for two principal duties. These are the control of quality of raw materials and control of finished goods. Other duties include research on methods of analysis, improvement of existing processes, and development of new products. The control chemist, in carrying out the work of the department, must make use of a great many branches of the science of chemistry. In addition, the control chemist is constantly making observations and comparisons upon many physical characteristics such as color, flavor, and odor. In controlling the quality of raw materials that are to be used in our products, the first step is to obtain
samples from several manufacturers. These samples are examined in various ways, depending upon the item and use to which i t is put. From the results of the examination, a source of supply is chosen. Future purchases should be made from this source. Should i t become desirable at any time to change the source of supply, new samples should be obtained and examined before buying any quantity. Having selected a satisfactory source of supply, raw materials are purchased. When shipments of raw materials are received, samples are examined by the Control Department. "The United States Pharmacopceia" is taken for a standard. "The United States Pharmacopceia" is a book which contains the names of drugs and chemicals most widely used by physicians, either alone or in mixtures with other drugs and chemicals in the treatment of disease and relieving the discomfort of the various ills to which mankind is subject. Following the name of each drug or chemical is a description and list of physical properties and a list of reliable qualitative tests for identity and for various impurities. In addition there is a method for a quantitative analysis and a statement of the degree of purity to which it should conform. The Food and Drug Law requires that all drugs and chemicals used for medicinal purposes be of United States Pharmacopceial quality. A typical chemical listed is ammonium chloride. A sample of a white crystalline salt is received marked ammonium chloride. First i t is identified by making qualitative tests in a test-tube for ammonia and for chloride. Ammonium chloride on ignition should volatilize without fusion. Then tests for impurities are made. Ammonium chloride should not show an immediate acid reaction, should not show the presence
of heavy metals, nor give a positive test for thiocyanate. If the tests for identity and purity are satisfactory, a quantitative analysis by the volumetric method is used. The salt should contain not less than 99.5 per cent. ammonium chloride. I recall testing a sample of ammonium chloride several years ago and finding a positive test for thiocyanate when there should have been a negative one. After one such experience as the above, a chemist realizes that all the tests for impurities are necessary. Extreme accuracy and care in testing every batch of material are the essential characteristics of a good control chemist. Thoroughness is a good watchword. The finished preparations may be described under some one of the following principal groups: solution, sirup, lotion, emulsion, powder, ointment, suppository,
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or tablet. There are a number of other types of preparations not included in this list. When a batch of any preparation has been made up by a manufacturing department, the Control Department is notified. A representative sample is taken for examination. Odor, taste, and appearance are three important physical characteristics which are examined. Comparison is made with standard samples. Accurate analysis is important from the viewpoint of the physician who is relying on the manufacturer for preparations containing definitely known doses of powdul drugs. The alkaloids are among the drugs for which the physician must have accuracy of dosage. Alkaloidal assays are interesting because of the many principles of chemistry illustrated. Some of these principles are volumetric analysis, weighing on the chemical balance, extraction with immiscible solvents, and the laws of solubility. Ten to twenty tablets from each batch are weighed to make sure that the per cent. variation between the highest weight and the lowest weight does not exceed a predetermined limit; also, to see if the average weight is identical with the calculated weight. Many chemical compounds in their pure state may be analyzed
quantitatively without any difticulty. When they have been combined into various mixtures the work of analysis is increased two and threefold. This is illustrated in the cases of many tablet mixtures. Organic compounds mixed together are often hard to separate completely and without decomposition. These timeconsuming determinations must be made carefully as the Bureau of Drug Control requires extreme accuracy in conforming to the Pure Food and Drug Laws. Not until the Control Department puts their O.K. on a batch of any preparation is it allowed to be bottled and put into stock. Now the question arises as to what happens when, upon examining a sample of a batch of a finished preparation, we find it does not measure up to standards. Occasionally such a situation is met. It is the duty of the Control Department to find out what is wrong and what the remedy should be. To do this, i t is often necessary to do some detective work to find causes. The process followed can best be understood by following through an actual case. A sample of sirup mixture was received. A comparison was made with a standard sample. A difference in color was noted. The standard was a clear, dark amber while the s a m ~ l ewas lieht-colored. nale
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were put into the mix. The foreman of the Manufacturing Department could find nothing out of the way. Then we went back to the laboratory and studied the formula. We considered only the ingredients that contributed to the color of the sirup. There were two such ingredients. From our experience in handling these two ingredients, we deduced the fact that one contributed more to the final color of the preparation than the other. This one was caramel. So we asked ourselves the question, Was the caramel put into the mix? A small amount of the sirup was obtained and caramel added in small portions until the color matched the standard. Calculations were then made to find the amount of caramel needed for coloring the entire batch of sirup. A coincidence was noted which was that the amount of caramel needed was identical with the amount called for by the formula. Circumstantial evidence was that the caramel was not put into the mix, although two men were sure that i t was weighed out and put in. It was ordered that the necessary amount of caramel be put in to make the color match the standard. Trouble with another preparation was not so easy to locate. The preparation was a clear, pale yellow liquid. We had made lot after lot of the preparation for several years with no trouble. One lot, after standing about thirty days, had precipitated a fine suspension, black-colored, which made the liquid appear
brownish black. This precipitate deiied filtration. It was so fine it would pass through filter paper. Filter aids were of no use. It was thoughtJhat the water supply might have caused the trouble. The purest distilled water available was tried without success. Every lot turned dark. The problem was tackled in the Control Department. The first step was to take each ingredient, mix i t with distilled water, and set i t aside for observation. The results were negative. The next step was to make every possible combination of two of the ingredients with water. After a few days a slight discoloration was noted in one mixture which was the slow formation of a black precipitate. This showed the way to solve the problem. It was necessary to change one ingredient. Although changing one ingredient gave a mixture which was satisfactory, it did not answer the question of why the discoloration. We had made the preparation for years without trouble and a t the time, samples three years old were bright and clear without a sign of
discoloration. There we stood unable to duplicate what we had once accomplished. A search of chemical literature was made. Reference was found to an incompatibility of these two chemicals. The authors claimed that there was a discoloration due to an impurity in one of these chemicals. We concluded that a trace of impurity in one of these chemicals used in this preparation had caused our trouble. There is also the work of improving methods of analysis. There are some old familiar chemicals for which practical methods of analysis have never been developed. Work is constantly progressing on new methods of analysis. Frequently, i t has been found difficult to separate some organic chemicals from one another. This has made the accurate control of tabletmixture a t times difficult. New chemicals are frequently being introduced and used. The routine portions of the work may, for some people, become monotonous. The variety of the usual problems that arise to be solved creates spice and interest in the work.
