Achieving ultrapurity in pharmaceuticals by zone ... - ACS Publications

purity in organic chemicals has been described by. Handley (1) and Herington (2). This need arises from the more exacting demands placed upon the qual...
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Paul J. Jonnke

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and Roberl Friedenberg'

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State University of N e w York at Buffalo

Buffalo

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- .Pharmaceuticals by Zone Melting

The growing need for a high standard of purity in organic chemicals has been described by Haudley (1) and Herington (2). This need arises from the more exacting demands placed upon the quality of starting materials and intermediates so they can be relied upon to possess known properties. I n contrast, the more specific need and problems associated with ultrapurity in dmgs has been sparsely recognized ($,4). Several examples will be given to delineate the role taken by trace impurities in several important pharmaceuticals. One of the most dramatic demonstrations of the significance of ultrapurification and ultrapurity analysis of pharmaceuticals was a study published by Craig: et al. (6). I n an attempt to synthesize antimalarials of the atabrine or quinoline type (such as plasmochim) it was considered highly desirable to furnish the pharmocologist with materials in a high state of purity for testing purposes. They felt the question of purity of the sample should not be raised if unexpected toxicity or variation in the biological results appeared. It was t,heir belief that a small percentage of highly active impurity could modify greatly the response expected. Experience with similar compounds bad shown the presence of subst,antial percentages of isomers or of homologues frequently not expected; therefore, unequivocal proof and documentation of ultrapurity was demanded. Unfortunately, this study was conducted prior to the refinements now known in the field of ultrapurity analysis. Although the methodology and procedures are given in great detail by Craig, and scrupulous and painstaking care was taken in their experiments, the results are of limited usefulness. Countercurrent distribution methods were attempted for over a hundred compounds. Proof of purity was achieved with a few to 99.5'3,. Their method was applied to only those substances which gave a large shift of partition coefficient with a change in pH. Although this group of workers set out to obtaiu and to determine ultrapurity of their samples for pharmacological testing, it is highly questionable that they achieved their ends. That many toxic but

'Recipient of the Lundsford-Richardson Award-1963, and author to whom correspondence and reprint requests should he directed. This work was supported by research grant GM07967 U S . Public Health Service, Bethesda, Maryland. This paper is abstraoted from a dissertation submitted to the Graduate School, University of Connecticut, in partial fulfillment of the requirements for the Ph.D. degree.

highly effective synthetic antimalarials could yield useful drugs upon more rigorous ultrapurification is still a possibility. Schistosomiasis, hilharziasis or snail fever, next to malaria is the second most prevalent disease in the world (6). Approximately 200,000,000 cases of this disease are estimated throughout the world. Schistosomiasis is a term used for a number of conditions caused by trematode or fluke worms. Such infections are exceedingly common in many areas of the globe. I n some instances, the disease is almost symptomless, but in other cases it produces severe suffering and even death. Organic antimonials, particularly tartar emetic, have been the drugs of choice for this disease. All the antimonials now in use suffer from a low margin of safety due to impurities of organic bound lead. The Phannacopeia (7) limits lead impurities in tartar emetic to five parts per million, since lead is a cumulative poison in the body. As high as one percent of lead is commonly found in antimonials and ultrapure tartar emetic is not only rare but costly. As yet no antimonials have been prepared completely free from lead ions. Since the symptoms of lead poisoning from cumulative doses of drugs are well known, the need for a method of ultrapurification of organic antimonials is apparent. I n a similar vein, not only antimonials contain high percentages of organic bound lead but arsenicals and bismuth compounds as well. Arsenicals particularly are of importance due to the again growing need for these compounds when penicillin antibiotics produce sensitizing reactions in syphylitic patients. The purity of penicillin itself has confounded the medical world and presents a challenge to ultrapurification and ultrapurity analysis (8). I t is well known that there are at least five different penicillins which are produced by the conventional fermentation process. Thus, any given batch of fermentation penicillin may be an unknown mixture of types. The difficultiesinherent in removing proteinaceous materials from these penicillins in the micro range indicate that no one of these types has been isolated as an ultrapure product. It is these proteinaceous materials that cause the sensitizing reactions in humans. Countless researches have been conducted using these impure materials. They have dealt with chemical characterization, structure determination, qualitative and quantitative analytical methods, and most important of all, the specific therapeutic effects of the penicillin types of drugs. Frequently, the results of different investigators have disagreed. These examples show that the question of ultrapurity Volume 42, Number

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is becoming more important to biochemistry, pharmacology, and clinical medicine. Another excellent example of this is adrenalin (9), which is often indicated for bronchial spasms. Nor-adrenalin which is said to have one hundredth of the activity of natural adrenalin when comparing bronchial dilation, is often found as an impurity and must be limited. Many other ultrapurification problems could be described (4). Often, they may involve decomposition products. For example, tetracychine derivatives decompose when contaminated with trace quantities of metals and must therefore he rendered completely free of these impurities. Many such problems of autooxidation have been minimized by the addition of antoxidants and chelating agents. With the availability of ultrapure pharmaceuticals many of these preservatives would be unnecessary. Ultrapurity Redefined

The concept of purity has been defined in a multitude of ways depending on the point of view of the investigator and the approach used. It is not possible to review here all the interpretations of what scientists regard as a "pure" substance. Adequate summaries are available (9, 10). From the above discussion of the ultrapurity of pharmaceuticals it is evident that a definition of "purity" based on intended use is relevant. Weissberger (12) states that a material is sufficiently pure if it does not contain impurities of such nature and in such quantity as to interfere with the use for which it was intended. Since trace impurities in drugs, in parts per million, are known to have significant pharmacological effects, "ultrapurity" is only an extension into the micro region of what a pure substance is. A unified concept of ultrapurity has been developed by considering the method and rationale of determining the unchanging physical properties of a substance after repeated fractionations (18). The concepts of "identity" and "singleness of entity" a t the micro level are intrinsically involved in these properties as well as the method of assay (13). Clarsiflcation of Ultrapurification Methods and Zone Melting

Both in the laboratory and commercially, the key final step in producing a medicinal compound for use is its purification. One of the older classifications of purification processes was based on chemical and physical means. But more recently the trend has been to classify such processes according to the number of phases formed (14). For example, some methods use barriers or concentration gradients within a single phase, such as in molecular sieving, electrodialysis, electrophoresis, thermal diffusion, and foam fractionation. Other methods work by adding chemicals or applying heat to form a second rich phase of the desired component; those include solvent extraction, ion exchange, chromatography, and zone melting. I n order to understand the advantages and disadvantages of a given process, it is pertinent to establish an ideal criterion of characteristics of ultrapurification. The following suggest the necessary qualifications: generality, sensitivity, contamination, efficiency, cost, and sound theoretical basis. 158 / Journal of Chemical Education

The most important quality is one of generality. The procedure should ultrapurify independent of the nature of the contaminants. Whether a process for example can ultrapurify heat sensitive materials, such as proteins, or trace quantities of organic hound metallic ions, gives a large margin of utility to the method. The sensitivity of the method should allow for analysis in the parts per million range and this sensitivity should not change with the nature of the contaminants. Contamination: The method should be free from the addition of foreign substances in the process itself or should effect complete removal of any such substances if by the nature of the method they are required. The fractionation procedure under optimum conditions theoretically should allow 100% removal of impurities in a reasonable amount of time. The cost of equipment and/or reagents should not he prohibitive. The process itself should be based on sound principles of ultrapurification so that by knowing the parameters of a given system, calculations can he performed to predict final concentration of contaminants. It is, of course, not possible for one method to meet all of these qualifications in their entirety. It is hoped that these standards can be approached a t least in their order of importance. A comparison of different methods of purification to this ideal criterion is given elsewhere (IS) and only an evaluation of zone refining techniques will he given here. Zone refining (15) alone, as a group of ultrapurification techniques, suffers least from the two major disadvantages of most other methods, i.e., generality and contamination from a solvent. One of the methods in this group, called "zone precipitation" (16),can heused with all types of organic materials regardless of their nature; and in another type of zone refining, denoted as "zone melting" (or "zone freezing" when applied to liquids) there is no contact with another solvent. All other ultrapurification methods, other than distillation, that form two phases must have contact with other suhstances. This is then the outstanding advantage of the zone melting procedure. As an ultrapurification process, the potentialities of this group are limited only by the efficiency, cost, and sensitivity of the methods applied. Zone Melting Process Contrasted for Inorganic and Organic Materials

As a purification process, the zone melting technique has facilitated the production of ultrapure metals in the field of inorganic chemistry and it has provided the potential for achieving ultrapurity of organic compounds. Both the theoretical and the practical considerations in the zone melting of metals have been treated a t great length (16). For organic compounds, however, these considerations have evolved slowly from experiences in the inorganic field, many of which have been carried over to the organic counterpart in toto (17). Although a number of comparisons have been drawn (3,18) between the zone melting of metals and of organic compounds, little effort has been made to carefully analyze the fundamental differences in principle between the two fields from a physical chemical

point of view, resulting in a wide divergence in approach, confusion in nomenclature, and lack of clarity as to the problems involved. The assumption that the zone melting of metals is similar enough in kind to zone melting of organic compounds that it may be applied to the latter with but few alterations is highly questionable. Attention must be focused on the underlying differences between the two techniques with emphasis on the causal factors governing the process. The establishment of a basic theory attending ultrapurification by zone melting will enable those interested in the practical application to direct their attention to the most efficient procedure. The methods now available are cited in the literature (17) and no attempt will be made to review them. Rather, the remainder of this article is concerned with the underlying principles and theory which govern the choice of experimental conditions when zone melting for ultrapurification of organic compounds is performed under ideal conditions.

situation which actually exists (19) shows that the interface has width. I n other words, with zone movement involving a distance differential and with the necessity of a temperature differential at the interface, the width of the interface will, in the limit, approach a sharp boundary, but can be defined for practical reasons, as a region with actual dimensions where this equilibrium process is occurring. Thus, the interface is limited to exact dimensions which approach a sharp boundary as the conditions approach ideality. I n order to further analyze the conditions necessary for zone melting, it is essential to understand the treatment of simple systems by phase diagrams. For purposes of clarity, only two types of phase diagrams will he treated here in detail; other phase diagrams may be regarded as special adaptations of these two (20). Since it is theoretically possible to treat binary mixtures of "ideal" substances at infinite dilution, only the extreme ends of Figures 1 and 2 are to be considered.

The Concept of Ideal Equilibrium Conditions

Zone melting, defined as a process (15), denotes a method whereby a molten zone travels slowly through a solid crystalline charge, and while traveling, redistributes the soluble impurities or solutes in the charge. The dynamics of this process are based upon what happens a t the two liquid-solid interfaces (the melting interface and freezing interface) of the molten zone as it traverses the charge. At the melting interface, the crystalline solid melts and is merely mixed into the molten zone. The manner of redistribution of impurities depends mainly upon what happens a t the freezing interface. It is to he shown in this section that under "ideal equilibrium conditions" with substances behaving ideally and with no solid solution format'ion, only one zone pass is necessary to produce an ultrapure material. I n referring to ideal conditions, as distinguished from ideal substances, the term is used in the thermodynamic sense, implying a reversible process. The conditions satisfying a thermodynamic, reversible, equilibrium process, involve the path taken from state I to state 11. When the conditions are ideal for a reversible process the system is a t maximum efficiency and a reversible path connects intermediate states, all of which are equilibrium states. This means that any variables which are changing in the system, are changing so slowly (and in the limit infinitely slowly) that a t every instant they are exactly the same and just equal to the identical opposing variables outside the system. Since the definitions of reversible equilibrium processes are well delineated by many authors in clear mathematical terms, (20, Sf), the validity of their application to the zone melting process can be best understood by referring to those mathematical treatments. Although these treatments will not be presented here, they are the basis for much of the theory that follows. The application of the idea of thermodynamic equilibrium at the freezing interface in the zone melting process involves equilibrium of two variables between the system and its surroundings. First, a temperature equilibrium, and second, the infinitesimal movement of the zone. These two variables create an interface which, by definition, must he sharp. Yet, the physical

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WEIGHT FRACTION I M P U R I T Y Figure 1.

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2 S O L I D PHASES

WEIGHT FRACTION IMPURITY Figure

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In the zone melting of metals, solid solutions are common and the phase diagram of Figure 1 may be used to analyze the process. Directly connected with this phase diagram is the segregation coefficient k given by the slopes of the liquidns and solidus curves which measure the relative solubility of the impurity in the solid and in the liquid zone. Unfortunately, the interpretation for solid solutions of metals a t temperatures over 1000°C has been incorrectly applied to the interpretation of eutectic organic mixtures. Although Figures 1 and 2 are classified as "equilibrium phase diagrams" at a given concentration, it is only in Figure 1 that a segregation coefficient can be interpreted. Several authors, independent of the zone melting subject, have discussed the correct interpretation of a eutectic phase mixture. Findlay (20) described the process as follows: "If a liquid solution having a composition to the left of the eutectic point is cooled down, following an isopleth, the solid component A will commence to crystallize out pure." White (21) states that as crystallization of the pure component proceeds, the removal of this component leaves a greater coucentration of impurity in the melt. Therefore, in the zone melting of eutectics under equilibrium conditions that are ideal, theoretically, 100% pure component should separate out with one zone pass and no segregation coefficient is possible. Only if "nonideal equilibrium conditions" attend the zone melting of a eutectic will a segregation coefficient appear. Perhaps the most noteworthy example of the purification of a eutectic type phase system is the purification of sea water. The same principles are applicable to zone freezing techniques as to zone melting. It has Volume 42, Number 3, March 1965

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been shown ($2) that it is possible to approach ideal equilibrium conditions with the zone freezing of sea water, obtaining by a single zone pass ice which approaches 100yo purity. With organic substances, so much emphasis has been given the use of the segregation coefficient with multiple zone passes, that little effort has been made to control conditions such that one zone pass is all that is required. The principal concept then, supported by much evidence presented elsewhere ( I S ) in the theory of the zone melting of organic compounds, is that organic materials in contrast to metals of temperatures over 100O0C form eutectic mixtures with impurities and require only one zone pass under ideal equilibrium conditions to attain ultrapnrity. Literature Cited

HANDLEY, R.,Mjg. Chemist, 27, 451-3, 381, 167 (1956). HERINGTON, E., Analyst, 84. 680 (1959). WILEY,F. H., Drug Std.,24, 67 (1956). FRIEDENBERG, R., WILCOX,W., AND BACK,N., Chem. Rev., 64, 187 (1964). H., TITUS,E., AND GOLUMBIC, C., (5) CRAIG,C. L., MIGHTON, Anal. Chem. 20, 134 (1948). (6) BURGER,A,, "Medicind Chemistry," 2nd ed., Interscience Publishers (John Wiley), New York, 1960.

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(7) The U. S. Pharmacopeis, XVI 62 (1960). (8) STRONG, F. C., Anal. Chem., 19, 968 (1947). (9) DRIVER,J. E., "Textbook of Pharmaceutical Chemistry," 7th ed., Oxford University Press, London, 1960. (10) EYEING,HENRY,Anal. Chem., 20, 98 (1948). R. B., Anal. Chem., 20, 96 (1948). (11) BARNES, (12) WEISSBERGER, A,, PROSHAUER, E. A,, et al., "Organic Solvents," in Technique of Organic Chemistry VII, A. editor, 2nd ed., Interscience Publishers WEISBBERGER, (John Wiley), New York, 1955. R., Thesis, University of Connecticut, 1963. (13) FRIEDENBERG, (14) BERKNER, L. V., Intern. Science and Technology (Feb. 1963), p. 46. (15) PARR,N., "Zone Refining m d Allied Techniques," George Newnes Ltd., London, 1960. (16) ELDIB,I. A., Ind. Eng. Chem., Process Design Develop. 1, 2 114R7.>

(17) HERINGTON, E. F. G., "Zone Melting of Organic Compounds," John Wiley and Sons, Inc., New York, 1963. (18) GOODMAN, C., Research 7, 168 (1954). J. W., "IMicroscopi~Study of (19) THOMAS,L. J., WESTWATER, Solid-Liquid Interfaces During Melting and Freezing," AICHI-ASME, Fifth National Heat Transfer Conference (August, 1962). (20) FINDLAY, A., "Phase Rule," 9th ed., Dover Publications, Inc., New York, 1951. . 24, 393 (1920). (21) WHITE,W. J., P h y ~Chem., (22) HIMES,R. C., MILLER,S. E., AND GOERING,H. L., Ind. Eng. Chern., 51, 1345-8 (1959).