Ind. Eng. Chem. Prod, Res. Dev. 1902, 21, 432-437
432
HJorIkjaer, J.; Jensen, V. W. Ind. Eng. Chem. Prod. Res. Dev. 1976, 15, 46. Isshkl, T.; Kijima, Y.; Mlyauchi, Y. (to Mitsubishi Gas Chemical Co.) Japan Kokai 79-59211, July 26, 1979. Krzywkki. A.; Marczewsi, M. J . Mol. Catal. 1979, 6 , 431. Pauiik, F. E.; Roth, J. F. Chem. Commun. 1968, 1578. Pearson, R. G.; Mawby, R. J. “Halogen Chemistry”; Gutmann, V., Ed.; Vol. 3, Academic Press: New York, 1967; p 55. Rlzkalla, N.; Naglieri, A. N. (to Hakon) Ger. Offen. 2749955, May 11, 1978. Robinson, K. K.; Hershman, A.; Craddock, J. H.; Roth, J. F. J . Catal. 1972, 27, 380.
Roth, J. F.; Graddock, J. H.; Hershman, A.; Pauiik. F. E. CHEMECH 1971,
600. Schukz, R. G.; Montgomery, P. D. J . Catal. 1969, 13, 105. Scurreii, M. S.; Howe, R. F. J . Mol. Catal. 1960, 7 , 535. Shikada, T.; Miyauchi, M.; Fujimoto, K.; Tominaga, H. University of Tokyo, unpublished data, 1981. Yashima, T.; Orikasa, Y.; Takahashi, N.; Hara, N. J . Catal. 1979, 59, 53.
Received f o r review December 7, 1981 Accepted April 28, 1982
GENERAL ARTICLES Drug Interactions, Modeling, and Simulations Walter D. WosilaR’ and Rlchard H. Luecke Department of Pharmacology and Department of Chemical Engineering, University of Missouri, Columbia, Missouri 652 12
Drug interactionscan be dangerous, especially when multiple combinations of drugs are used. The anticoagulant warfarin is noted for its involvement in drug interactions in humans. Similar interactions are being studied in experimental animals, such as the rat, to obtain kinetic data as well as tissue concentrations which cannot be done safely in man. A model has been developed for the elimination of warfarin from the plasma and its excretion in the bile. The model includes organ masses and blood flow for plasma, liver, kidney, muscle, skin, gut, and bile; differential equations have been formulated for each organ. A computer program has been developed for the model to simulate drug interactions affecting the elimination of warfarin from the rat. The model has successfully simulated acute interactions such as the inhibitory effect of bromosulphophthalein and chronic interactions such as induction by phenobarbital, as well as damaged liver produced by CCI,.
Introduction Drugs are potentially dangerous, and multiple combinations of drugs used in therapy are potentially even more dangerous than the administration of a single drug (May et al., 1977; Hull et al., 1978). The anticoagulants and the antihypertensives are the classes of drugs reported to be most often involved in drug interactions. Drug interactions result when drugs used for different therapeutic purposes interfere with the action of one of the drugs, and the likelihood of such interactions increases dramatically as the number of drugs used in a patient increases. The anticoagulant warfarin which we have been studying will be used as an example to illustrate the principles involved. Warfarin has a wide variety of medical uses. The most common therapeutic goal is to prevent either the formation of a blood clot at a location in the body which may be harmful or to prevent the extension of an existing clot at such a location. Warfarin acts by inhibiting a key enzyme in the liver which is involved in the final stage of synthesis of clotting factors, and the desired degree of inhibition of the enzyme occurs over a rather narrow range of concentrations of warfarin. If the treatment is inadequate, the risk of coagulation still exists and the treatment is not beneficial. On the other hand, if the drug treatment is excessive, there is the risk of hemorrhage. The use of other drugs for a different therapeutic purpose such as antibiotics, analgesics, or sedatives can alter either the distribution or the rate of elimination of the anticoagulant, or both. Table I shows only a few selected examples of the different types of drug interactions which 0 196-4321 /82/ 1221-0432$01.25/0
Table I. Selected Interactions between Anticoagulants and Other Drugsa interacting drug clofibrate
a
adverse effect increased anticoagulation
barbiturates
decreased anticoagulation
thyroid hormone
increased anticoagulation
phenytoin
increased phenytoin toxicity
probable mechanism displacement from binding sites on serum albumin induction of microsomal enzymes in liver increased catabolism of clotting factors inhibition of microsomal enzymes
Medical Letter, March 6 , 1981.
are of medical importance in order to illustrate the diversity of the drug interactions which have been encountered in humans ( M e d i c a l L e t t e r , 1981). Pharmacological Properties of Warfarin There are a number of pharmacological properties of warfarin which must be considered in the formulation of a model for drug interactions. For example, most of the warfarin in plasma is reversibly bound (more than 99% of the drug) by serum albumin. Many other drugs are also bound reversibly at multiple binding sites on the protein as are various endogenous substances such as bilirubin and free fatty acids. Substances which may be bound at the 0 1982 American Chemical Society
Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 3, 1982 433
same sites on the protein as warfarin will compete with it. Such competition will increase the concentration of free or bound drug in the plasma. Such interactions are known as competitive displacement interactions. For example, warfarin and clofibrate, a hypolipidemic drug, share common binding sites on serum albumin. When used in combination, competition for available sites occurs with a displacement of warfarin resulting in an enhanced anticoagulant effect. Competitive displacement interactions between drugs occur relatively rapidly and are related to the relative affinities of the proteins for the competing drugs, the concentration of the protein and the concentrations of the competing drugs in the plasma. For tightly bound drugs in which only 1% of the total drug in the plasma is free, the displacement of only a small amount of bound drug would greatly increase the concentration of free drug. Interactions which occur relatively rapidly are also known as acute interactions. The coumarin anticoagulants are taken up by the liver which is (1)their site of action (inhibiting the carboxylation of glutamic acid residues in the blood clotting factors); (2) their site of metabolism which involves hydroxylation, reduction, and conjugation reactions; and (3) excretion of the metabolites in the bile. Acute Interactions Many of the enzymes involved in drug metabolism are broad in their specificity for substrates and are capable of metabolizing a wide variety of substances such as endogenous substances, drugs, or foreign materials entering the body from the environment. The rate of metabolism of a single drug (V) can often be described by a Michaelis-Menten equation which has an affinity term (K,)
as well as a term for the maximal velocity (Vma); [W] represents the concentration of warfarin. When two drugs or a drug and an endogenous substance share the same biochemical pathway, competition for limiting enzymes can occur similar to the compeition for protein binding described above. When this occurs, the normal rate of metabolism or excretion of the drugs under consideration is reduced with a resultant accumulation of that drug and possibly toxicity, depending upon the margin of safety of the drug. A given enzymatic pathway usually has different binding affinities (dissociation constants) and maximal velocities for the metabolism of the different substrates. Therefore, the degree of inhibition of metabolism of the drug under consideration will depend upon the concentration of the two drugs and the relative affinity of the enzyme for the drugs involved in their metabolism. If the drugs are present in adequate amounts, the onset of inhibition will be relatively rapid; such interactions are also classified as acute interactions. The consequence of such inhibition is to prolong the half-life of a drug and when subsequent doses of a drug are administered the concentration of the drug may be increased in the body into a toxic range. Thus, knowledge of the kinetics of repeated administration of a drug and drug accumulation is important for safe therapy. Chronic Interactions In contrast with acute interactions, some interactions may require repeated administration of a drug and require several hours for the onset of the interaction and days to reach the peak effect. Such interactions are known as chronic interactions. Typically chronic interactions are not a direct chemical concentration effect but result from a physiological change. For example, the daily adminis-
tration of phenobarbital (Table I) for 3 or 4 days can increase the concentration of enzyme(s) on the smooth endoplasmic reticulum in the liver which is responsible for the metabolism of phenobarbital as well as Warfarin and numerous other drugs. One consequence of accelerated metabolism of drugs is a shortening of their half-life in the body, reducing their concentration at sites of action, resulting in subeffective concentrations. A drug capable of such effects is known as an inducer of drug metabolism. The reason for the relatively slow onset of the inductive effect is the rate of synthesis of the enzymes involved in drug metabolism is relatively slow. Inductive effects often take several days to attain the maximal effects and these effects may persist for several days after the administration of the inducing drug has been discontinued and eliminated from the body. Both acute and chronic interactions can interfere with the desired therapeutic actions of warfarin. It has been said that drug-drug interactions are not necessarily dangerous, but not knowing they are occurring can be dangerous. If they are recognized, dosage or scheduling adjustments can be made for the drugs involved. Multiple D r u g Usage Patients are often treated with multiple combinations of drugs for several needed therapeutic purposes. For example, elderly persons may take four to seven types of medications daily, and that figure may be doubled for patients in nursing homes. The average number of drugs used in hospitalized patients has been reported to be about eight during the course of a hospital stay and many patients may be exposed to as many as 20-30 drugs. Thus, the total number of combinations of drugs used may be great. As pointed out before, the risk of drug interactions increased greatly as the number of drugs used increased (May et al., 1977; Hull et al., 1978). Also, the multiplicity of sites at which drug interactions may occur presents a complex and intricate situation for modeling. One important goal of modeling drug interactions is to develop models which will permit us to organize and quantify the multiplicity of interactive effects which can occur, with the view that this information will permit us to design rational courses of drug treatment when it is necessary to use multiple combinations of drugs. Polyexponential Model Modeling of drug elimination, for the past few decades, usually has been based on measurements of the concentration of drug in the plasma (C,,),or on the total amount of drug remaining in the body. The data are usually obtained from studies in normal subjects, occasionally in patients with disease. The log of the concentration of drug in the plasma is often biphasic and occasionally triphasic. Such values have lead to the classical model used to describe the kinetics of drug elimination which is described by a polyexponential formula
CP
= Aie-krt
(2)
The individual terms correspond to compartments (Figure 1)which are abstract and do not represent specific identifiable anatomical organs or regions. For a two-compartment model, the two mathematical terms are easily associated with the so-called central and peripheral compartments; for a three-term model the compartments have been referred to as the central, the shallow, and the deep compartments. The concentrations of drugs at the specific site of action or toxicity is not included in this type of model. The concentration of the drug in the different tissues must then be assumed as some function of the concentration of drug in the plasma.
---
434
Ind. Eng. Chem. Prod. Res. Dev., VoI. 21, No. 3, 1982
--1
e,"
Figure 1. Scheme for three compartment model. The constants KLbK,,, KIL and K3, are first-order transfer constants between the shallow (compartment2) and central compartmentsand deep (compartment 3) and central compartments, respectively. K,, is the elimination rate constant from the central compartment.
Drugs are usually distributed nonuniformly between the plasma and the different organs of the body. For example, the concentration of Warfarin is extremely low in the brain and relatively high in the plasma, liver, and the skin. It is usually assumed that there is some sort of equilibrium distribution (or partition) between the plasma and tissue. In many cases a linear or nearly linear relationship exists between the concentration of a drug in the plasma and in the tissue, a t least for the range of concentrations involved in therapy. Despite these qualifications the polyexponential model has provided much useful information, such as rate constants and half-lives for many drugs, in a concise form. It is not, however, very useful for the analysis of interaction data. Physiological Flow Model Bischoff (1975) and others have developed an altemate model form known as the physiological flow model (PFM) which is based upon organ weights or volumes, rates of blood flow to the organs, and the ratio (R)of the concentrations of drugs in the different tissues to the concen-
tration in plasma (Figure 2). Values for each of these parameters are required for the organs involved in the distribution, action, and elimination of the drug. Each organ is modeled as an unsteady state continuously stirred tank reactor. Physical equilibrium between plasma and body tissues is assumed to be instantaneous. Differential equations (Figure 2) can be set up from the mass balances to describe the concentration of drug in each tissue compartment (rate of change of drug in organ) = (rate of input of drug into organ) (rate of output of drug from organ) (3) Organs involved in the metabolism or excretion of a drug such as the liver and/or kidney require an additional negative term for metabolism or excretion (Figure 2). Anticoagulants and antineoplastic drugs are excreted mainly in the bile while sulfas are excreted in the urine and some drugs such as melphalan are excreted in both bile and urine. The PFM is comprehensive and flexible enough to encompass this range of possibilities of drug elimination. This mathematical model has the great advantage that the drug concentrations at the sites of action, elimination, or toxicity are estimated as a function of time. Six compartments provide good mass balances for warfarin; other drugs many require more and different compartments. For example, the anaesthetic thiopental is noted for its lipid solubility in which case the adipose tissue is an important compartment to include in the model. We have developed a computer program (Luecke and Wosilait, 1978; Luecke et al., 1980) for this type of model and tested it experimentally with the anticoagulant warfarin. However, the model can be used for other drugs by Pia" -
vP dcp.
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Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 3, 1982 435
Table 11. Parameters Which Are Used in the Model and Can Be Varied To More Closely Simulate Medical Conditions simulate tissue parameter plasma cp 1. For some drugs a linear relationship between total concentration of drug and free drug concentration does not exist in which case programs can be used to compute free drug. 2. Hypoalbuminemia is produced in some diseases which affects the binding of drugs and the concentration of free drug. 3. Other drugs may be present which displace bound drug thereby elevating the concentration of free drug. muscle V, 1. The total amount of muscle may be decreased as cachexia or in amputees. kidney QK 1. Some drugs affect the rate of blood flow to the kidney. 2. Ageing and disease decrease the total amount of kidney. VK 3. Ageing and disease decrease the function of the kidney. KK 1. Surgery may decrease the amount of liver and some drugs (inducers) increase the liver VL amount of liver. 2. Blood flow can be altered by drugs or obstruction. QL 3. The amount of ligandin (a protein in the liver which binds drugs) can be altered which RL can affect the uptake of drugs by the liver. 4. Other drugs used may inhibit drug metabolism by competition at enzymatic sites or increase drug metabolism by induction. a combi5. Liver disease or chemicals producing liver damage may alter more than one of nation these parameters. ~~
~
PREINJECTION (12)
I
,NJECT l
NOVOBIOCIN (4)
1
0
20
40
60
80 MINUTES
100
120
20
40
60
80
100
120
Minutes
Figure 3. Concentration of warfarin in tissues as a function of time. Plasma and bile concentrations of warfarin and its metabolites are measured experimentally after the intravenous injection of the drug. The tissue concentrations are computed values based upon the physiological flow model and the differential equations in Figure 2.
Figure 4. Effect of tolbutamide and novobiocin on the excretion of warfarin. Tolbutamide and novobiocin were injected separately at 60 min. These experiments illustrate opposite types of acute elimination interactions.
including the organs which are involved in the distribution or elimination of any given drug and by changing the apparent partition coefficients which are characteristic for that drug. The tissue concentrations of drugs cannot be safely sampled in human subjects but they can be measured in experimental animals. There are species differences in metabolism and excretion of drugs between experimental animals and man which can pose some problems in the development of a model. In extrapolating the results from experimental animals to man, parameter adjustments may be necessary in the PFM and in other cases more fundamental model changes such as in elimination chemistry are needed. Nevertheless, there have been a number of successful scale-ups from experimental animals to humans (Chen and Gross, 1979). The PFM also permits one to estimate the concentration of a drug in organs which contain the sites of action or in organs in which toxicity may occur (Figure 3). The PFM also provides a vivid illustration of the changes in drug concentration occurring in different tissue during the early distribution phase, especially after intravenous administration of a drug. This is of special importance for drugs such as many antineoplastic drugs which are given intravenously and have a narrow margin of safety. The model also shows the slow accumulation of a drug such as warfarin in the ski4 which constitutes a sizeable fraction
of the body mass and has a relatively slow blood flow. Also, the PFM model permits one to predict and simulate drug interactions (Luecke and Wosilait, 1979). The flexibility of the model permits one to study the effects of perturbations of unsteady states in order to get a better understanding of which parameters are most sensitive to the presence of disease or other drugs (Table 11). Experimental Testing of the Model The rat was selected as an experimental animal because it has been used extensively for the study of drug metabolism and the pharmacology of the anticoagulants. Thus there is a great deal of useful data in the literature in the pharmacology of warfarin in the rat. More than 90% of the warfarin injected in an anaesthatized rat is excreted in the bile. The bile can be collected drop by drop, (about 8 pL/drop and about 5 drops/min) from a polyethylen'e cannula inserted in the bile duct. This procedure provides a very sensitive means of obtaining data to analyze the basic kinetics of the elimination of warfarin as well as the relatively rapid changes in kinetics. which occur when a second drug is administered producing an acute interaction. For example, after the intravenous injection of 14C warfarin, radioactivity appears in the bile after a lag period of 5 to 7 min. breaches a peak in 15-20 min and thereafter gradually declines in concentration in both the plasma and in the$bile(see control curve in Figure 4). The major distribution of warfarin to the different body tissues
436
Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 3, 1982
takes place in about 30 min. Measurements of warfarin in both the plasma and its metabolites in the bile provide baseline kinetic data for drug elimination interactions. The basic elimination can be altered by disease or by other drugs. Figure 3 shows the computed tissue concentrations of warfarin as a function of time using the physiological flow model. Figure 4 shows the experimental observations produced by the injection of a second drug. Note that phenylbutazone, an antiinflammatory drug, increases the concentration of warfarin in the bile. In other studies it was found that phenylbutazone and tolbutamide (an oral antidiabetic drug) produced an additive effect (Pepper and Wosilait, 1977). Note that the antibiotic novobiocin produced a marked depression in the excretion of warfarin. Rifamycin and BSP also produce a marked depression. The Computer Program A computer program was developed to carry out the computations for the physiological flow model (Figure 2). The normal weights (or volumes) of the individual organs are computed using equations related empirically to the total body weight. For example, liver volume or mass is calculated by the following (Bischoff, 1975) (W = body weight) (4) liver volume = 34W.07 Other organ volumes are computed using similar relationships with different coefficients and exponents. Normal blood flow to the different organs is approximated in like fashion using parameters which have been determined by physiologists. In case of unusual blood flow to an organ, the blood flow in the model may be altered to correspond to the changes occurring in vivo. Parameter changes and some structural alterations in the program may be needed for different drugs. The tissue to plasma binding ratio (or the apparent partition coefficient; R value) must be determined experimentally for each drug. In simple cases, the binding ratio for a given organ is assumed to be a constant value for different drug concentrations over therapeutic ranges. In more complex situations, variations of the binding ratio may occur with changes in concentration of a drug and appropriate equations are included, if the data are available. When combinations of drugs are employed, the independent R values for each drug alone are used, at least at this stage of our development. The oral and the intramuscular routes of administration are commonly used in therapy and the program bas been developed to accomodate such routes of administration. The total amount of drug eliminated is computed by integration using a Runge-Kutta fourth-order routine. Many drugs are also given repetitively, i.e., fixed doses at fixed intervals, for example, every 8 h. Again, the program has been structured to accomodate repeated administration of a drug. Acute Interactions For experimentally testing acute drug interactions with warfarin a second drug is injected 60 min after warfarin to perturb the +ate which exists at that time (Figure 4). Competitive displacers of warfarin from binding sites on s e w albumin, such as tolbutamide, or oxyphenbutazone, rapidly increase $he concentration of free warfarin which is then taken up by the liver. This produces an increase in the concentration of warfarin and its metabolites in the bile (Pepper and Wosilait, 1977). Much of our experimental testing of drug elimination interactions has been with the diagnostic agent BSP which is excreted in the bile, as is warfarin. BSP can be readily measured colorimetrically in both plasma and bile which provides extremely valuable data for testing purposes. BSP inhibits the excretion of warfarin within a few min-
utes after injection similarly t~ novobiocin in Figure 4. The peak inhibitory effect occurs relatively soon and its duration of inhibition by BSP is shorter than with novobiocin. Thus, the kinetics of a nearly complete elimination interaction experiment can be measured over a period of about 60 min providing test data for (1)the onset of effect, (2) the time and magnitude of peak interaction, and (3) the duration of interaction (Luecke and Wosilait, 1978, 1979). Chronic Interactions Chronic drug interactions can be experimentally produced by phenobarbital. If phenobarbital is injected intraperitoneally into a rat once a day for 2 to 3 days, there is an increase in liver mass, blood flow to the liver, and in the concentration of drug metabolizing enzymes in the liver. Such animals show an increased capacity for excretion of warfarin in the bile compared with control animals. Dr. Brian Sadler has adjusted the model to fit the changes which occurred as a result of treatment with phenobarbital, and resultant simulations have produced a good fit with the experimental observations (Sadler et al., 1980). Liver Damage Some patients have liver damage from disease or exposure to toxic materials which can reduce the rate of drug metabolism and elimination. Such situations can be simulated by producing liver damage experimentauy in rats by the intraperitoneal injection of agents such as carbon tetrachloride (1mL/kg). The injection of CCl, 24 h prior to study produced liver damage w@ch significantly reduced the rate of excretion of warfqin and other drugs. Sadler has changed the parameters and program in accord with the pathological changes and obtained very good simulation of the reduced rate of excretion of warfarin which was measured in the animals treated with CCll (Sadler et al., 1980). Concluding Comments In summary, we have a number of experimental situations involving acute and chronic drug interactions and liver damage which have been successfully simulated indicating some of the potential of the drug interaction model. These are for only a few of the many possible combinations of drugs which are used or pathological states which can be encountered. Other altered states such as pregnancy, old age, and s w a t i o n which are known to alter the elimination kinetics of drugs could be readily tested. Other investigators studying antineoplastic drugs have successfully scaled up the results of animal studies in laboratory animals to'the human level for the basic elimination, but not for drug interactions affecting the elimination of the antineoplastic drugs. Currently, we are studying the effect of phenobarbital and CCl, on the excretion of the antineoplastic drug adriamycin, and the general experimental results (unpublished) obtained are similar to the results with warfarin. These studies are of special interest because antineoplastic drugs are noted for their toxicity and narrow margin of safety. Finally, the elimination interaction model can be used to clarify some of the puzzling problems in research in multiple interactions and in teaching the complexities of multiple drug interactions which might be encountered during multiple drug treatment thereby making therapy both more effective and safer. Literature Cited Bischoff, K. 8. Cancer Chem. Rep. 1875, 59, 777. Bischoff, K. 8.; Dedrick, R. L.: Zaharko, D. S ; Longstreth, J. A. J . Pharm. Sci. 1871, 80, 1128. Chen, H. S.;Gross, J. F.; Cancer Chemother. Pharmacol. 1979, 2 , 85.
Ind. Eng. Chem. Prod. Res. Dev. 1982, 21, 437-441 Hull, J.; Murray, W. J.; Brown, H. S.;Wllllams, B. 0.;Chi, S.L.; Koch, G. G.: Clln. phermecol. Ther. 1978. 24, 644. Luecke, R. H.; Woellalt, W. D. Comp. Prog. Bbmed. 1978, 8 , 35. Luecke, R. H.; Wosilalt, W. D. J . Phemcdrln. Bbpharm. 1979, 7 . 629. Luecke, R. H.; Thomason, L. E.;Wosilatt, W. D. Comp. Prog. Biomed. 1980, 1 7 , 88. Mav. F. E.: Stewart. R. B.: Cluff. L. E. Clin. pharmacal. Ther. 1975. 22. 322. Mebicar Letter 1981,23, i f . Pepper, E.; wosilatt, w. D. Res. Com. them. path. phermacol. 1977, 78, 275.
437
Sadler, B. M.; Luecke, R. H.; Wosilait, W. D. The Pharmacolcgist, 1980, 22, 3.
Received for reuiew October 23, 1981 Accepted March 18, 1982
Supported, in part, by Grant HL 15698 from the Department of Health and Human Services.
New Approach to High Solids Coatings Mohinder S. Chaltha* and Henk van Oene Polymer Science Deparfment, Engineering and Research Staff, Ford Motor Company, Dearborn, Michigan 48 12 1
Alkyl acid phosphates have been found to react with cycloaliphatic diepoxy, bis(4,5-epoxy-2-methylcyclohexylmethyl) adlpate (Araldite CY 178,Ciba-Geigy), to produce hydroxy oligomeric phosphate resins. These hydroxy oligomers have been cross-linked with hexamethoxymethyl melamine to obtain high solids coatings. Infrared spectra of the reaction mixture of the diepoxy and the acid phosphates show that a rather rapid reaction occurs in the early stages of the reaction and then it slows down to leave some unreacted acid if the acid-epoxy are employed in stoichiometric amounts. When the epoxy is treated with acid phosphate in the presence of hexamethoxymethyl melamine (Cymel 301), infrared spectra of the reaction mixture show that the hydroxy-melamine reaction takes place in the later stages of baking and is catalyzed with the residual acid. Due to an initial high reactivity of the reslns, the paint Is formulated as a two-package system. The coatings, cured at 130 OC for 20 min on primed panels, exhibtt excellent gloss, impact strength, adhesion, and weathering properties and they are promising for automotive topcoats.
Introduction Coatings with high solids content (65 vol % solids) are attractive for meeting emission control regulations and because of their lower energy consumption. To obtain high soIids coating with adequate spray viscosity, one must start with low molecular weight resins which, on curing, produce desireable networks only if the cross-linking reaction employed is fast and proceeds without undesirable side reactions. After examining a number of inherently fast chemical reactions, we have selected the reaction of epoxy resins with partial esters of phosphoric acid for a detailed investigation. The reactions of phosphoric acid esters with epoxy resins have previously been employed to obtain fast curing adhesives (St. Cyr, 1961), corrosion inhibiting coatings (Cupery, 1954), fire resistant materials (Apice, 1969), and high solids coatings (Chattha, 1980). Partial esters of phosphoric acid are also known to be very effective catalysts for the melamine cure of hydroxy resins. We have employed both the properties (high reactivity and efficient catalysis) (Chattha et al., 1980) of phosphoric acid esters in the development of high solids coatings from epoxy, methoxymethyl melamine and/or hydroxy resins. Experimental Section Infrared spectra were' recorded on a Perkin-Elmer 453 spectrophotometer and the thermal analyses were performed on a DuPont 950 thermogravimetric analyzer. Molecular weights of the polymers were determined by gel permeation chromatography using polypropylene glycol P2000 (Waters Associates, Inc.) as standard. The weathering of coatings was examined on @-Panel Company's QUV cyclic weatbering tester employing cycles of 8 h of light at 60 O C , followed by 4 h of darkness and humidity at 50 PC.
Materials. Acrylate and methacrylate monomers were used without inhibitor removal; technical grade toluene, acetone, butyl acetate, and methyl amyl ketone were used as solvents. Industrial grade low viscosity aliphatic epoxy resin (Araldite CY178), bis(4,5-epoxy-2-methylcyclohexylmethyl) adipate, was bought from Ciba-Geigy Corporation and was used without further purification. Hexamethoxymethyl melamine (Cymel 301) was obtained from American Cyanamid and was used as received. Butyl phosphate was obtained from Hooker Chemical Co., and monoethyl phosphate was prepared by controlled hydrolysis of ethylphosphorodichloridatein butyl acetate. The starting ethylphosphorodichloridatewas prepared by controlled reaction of ethanol with phosphorus oxychloride and was purified by double fractionation over a Vigreux column. Preparation of Monoethylphosphate. Ethylphosphorodichloridate (125 g, 0.77 mol) was dissolved in 150 mL of butyl acetate, placed in a round-bottom flask, and cooled with an ice-water mixture. Cold water (28 g, 1.56 mol) was added dropwise with stirring and simultaneous vacuum application with a water aspirator. The reaction mixture was stirred under vacuum for 3 days and then it was titrated with sodium hydroxide to obtain monoethylphosphate solution with acid equivalent weight of 120. Polymerization. The following mixture of monomers was used for the polymer synthesis. One hundred grams 2-hydroxyethyl acrylate methyl methacrylate styrene butyl methacrylate
wt,g
400 400 200 1000
wt,%
20 20 10 50
of tert-butyl perbenzoate was added to the above monomer mixture and the resulting solution was added dropwise 0 1982 American
Chemical Society
