ENGINEERING
M A N UFAC T UR ING
& RESEARCH
I
LEGAL
SALES
LEONARD A. CULL0 and WILLIAM P. COLMAN Research Division, American Cyanamid Co., Stamford, Conn.
Development of a Process-A The process development pattern for tetrasodium EDTA, which proceeded along a definite series of steps from original idea to final plant design, applies to most development programs. The process development research team was given primary responsibility for coordinating interests of the legal, sales, manufacturing, engineering, and research departments, to bring the product into commercial production in the most economic and efficient manner possible.
P R O C E S S DEVELOPMENT is not conducted exclusively by the research department or laboratory, but requires the combined efforts of a number of groups within a company. The research department supplies the necessary technology, but must have assistance from the manufacturing, sales, legal, and engineering departments for efficient development of a new process or product. The following discussion illustrates the coordinating role of the research department in a specific case-development of a process for manufacturing tetrasodium EDTA [tetrasodium (ethylenedinitri1o)tetraacetic acid]. American Cyanamid’s interest in tetrasodium EDTA originated in the manufacturing department, where sequestering agents were used in making agricultural and pharmaceutical chemicals. The possibility of incorporating compounds of this type into dyes was of particular interest. Thus, a potentially large captive use and indications of an expanding external market provided an incentive
Case History
for studying syntheses of EDTA-type compounds. A careful search of application, product, and process patents and literature pertaining to EDTA and related compounds revealed a number of applicable processes. Those which involved a favorable patent status or an advantageous. raw material position were selected for experimental evaluation. Evaluation of Synthesis Routes
A standardized prpcedure can rarely be used for this type of evaluation, because each case must be judged on its own merits with regard to materials handling, specialized technology, and equipment requirements. This phase of the experimental program was primarily a screening operation. Order of magnitude effects of process variables was determined to pkovide a basis for estimating probable yields and approximate costs of manufacture. One of the first syntheses studied was the reaction between glycolonitrile and ethylenediamine (EDA). Although this route was promising from the yield standpoint, cost factors favored use of more basic materials, and interest was shifted to the reaction of hydrogen cyanide and formaldehyde with ethylenediamine. I n acid solution, this reaction produces the nitrile, which may be separated and hydrolyzed with caustic to tetrasodium EDTA. Under alkaline conditions, the tetrasodium salt is formed directly. Yields and product quality were satisfactory with either process, but as only one reaction step was involved, lower processing costs were indicated for the alkaline method. The final choice of synthesis route, the reaction of hydrogen cyanide, formaldehyde, and ethylene-diamine in alkaline medium involved consideration of patent position, product quality, and factors influencing manufacturing cost, such as raw materials, yields, and simplicity of operation.
Product Evaluation
Tetrasodium EDTA had a well established market and wide usage; therefore, much product evaluation work could be bypassed. The sales department investigated markets to estimate the long-range ultimate price and product quality desired. T o be realistic, these estimates must be based on considerable experience and numerous field contacts. In setting product specifications, careful judgment is required to ensure the highest quality product consistent with a cost which will permit competition with other grades on the market Process Chemistry
I n this phase of the work, the object was to identify variables and delineate their ranges. Primarily, elucidation of the prscess chemistry was emphasized rather than actual unit operations involved in commercial production. The dependent variables were yield and product quality, the latter including low residual cyanide and formaldehyde content, light color, and a high ratio of active to total solids. T o drive the reaction toward maximum yields, molar excesses of caustic, hydrogen cyanide, and formaldehyde relative to ethylenediamine were required. Competing with the main reaction were side reactions with ammonia involving both cyanide and formaldehyde. To retard these side reactions, the process was carried out at the boiling point in a strongly alkaline medium, thus minimizing ammonia concentration. Varying reaction times, investigated a t one level of molar ratios and two temperatures, had no significant effect on yields. Effectiveness of ammonia. stripping from the boiling solutions was studied in conjunction with rate experiments by sampling and titrating the condensate. Total ammoniaycollected was greater for longer runs than shorter, but the sequestering power of the-prodVOL. 50, NO. 10
OCTOBER 1958
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equation, represented as a three-dimensional contour surface, indicates best combinations of variables
t
CN-
ucts was essentially independent of reaction time. Yields were determined by titration in an alkaline medium with a standard calcium chloride solution, using an oxalate indicator. This method is not specific, because any compound which forms a calcium complex with a higher stability than calcium oxalate will titrate as tetrasodium EDTA; only total sequestering ability of the solution is measured. To avoid making an unknown mixture, an improved method of analysis was sought. As the literature revealed no quantitative analysis specific for tetrasodium EDTA, the aid of the Analytical Research Group was enlisted, and a method using an ion exchange chromatographic column and the nickel complex of EDTA was developed. While not available during laboratory investigations. this method provea invaluable in clarifying the relationships between process variables and real yield of tetrasodium EDTA in the later stages of process development. After the important variables had been identified and their ranges determined, a change in experimental approach was required. Data to this point had been collected by the classical method, where all independent variables but one ~ x r eheld constant. With the aid of the mathematical analysis group. a statistically designed experimental program to study three independent variables-HCN/EDA, CH20/EDA. set up. and temperature-was Responsibility for the project was shifted from the Product Research to the Process Development Department The chemists who had carried out the original studies were loaned to the Process Development Department, and the research team was expanded to include a chemical engineer. The engineer was brought in while the program was still in the laboratory stage to familiarize him with the experimental procedures. so that he could suggest the type of information needed to design a pilot plant. He could bring to the program his knowledge of equipment limitations and thus minimize investigations into areas impractical for plant operation.
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Statistical Experiment
First, a factorial experiment was set u p in which all combinations of the three factors at two levels could be examined. The principal conclusions drawn from the data so obtained were that total excess cyanide and formaldehyde strongly influence yields. and reaction temperature has a small but definite effect. The factorial experiment allowed only a two-level estimate for each factor; therefore. it was augmented to permit more detailed exploration of the factor space. From the completed experiment a predictive equation was developed which can be represented as a three-dimensional contour surface (Figure 1). This approach provides a means for predicting combinations of variables which should give optimum process results. TVhen the experiment was completed, sufficient information was available to make a reliable estimate of yields realizable in commercial operation. Patent protection was reviewed carefully by the legal staff, and further experimental work was recommended to strengthen patent claims. With the considerable information regarding reaction rates, product yields, and unit operations involved, the engineer could estimate manufacturing costs. In this procedure. areas of uncertainty became evident and formed the basis for pilot plant design. Before pilot plant studies were started, the process \vas submitted as a proposal addressed to the general manager of the operating division which supported the work. This proposal described the product and process, properties and end uses, patent position. market potential, and estimated development time schedule. Following approval to transfer the process to the pilot plant, engineers from the Engineering and Construction Division were brought in as consultants. Scale-up Tests
Scale-up is often the most difficult step in process development, and can-
INDUSTRIAL AND ENGINEERING CHEMISTRY
not be standardized. Usually the difficulty is proportional to the number and type of phases present. In the tetrasodium EDTA process, a homogeneous liquid phase reaction was involved and only limited scale-up investigation was required. The work was carried out in a 100-gallon kettle. With all other variables constant, varying agitator speed from 144 to 290 r.p.m. had no effect on yield or product quality. Equipment limitations prevented extending the range of agitation studies. Howe er: on further scale-up to the plant reactor, the importance of agitation became evident when inadequate agitation caused difficulties during start-up. This problem was solved by increasing agitator speed and improving the sparging of hydrogen cyanide and formaldehyde into the reactor. The pilot plant equipment was also used to gather information on raw material specifications, materials handling, operating procedures, and process control requirements. The effects of ammonia removal and reaction time were studied further in the pilot plant, using ion exchange analysis to determine real yields of tetrasodium EDTA. Whereas the total sequestering power of the solution was little affected by reaction time, quantity of ammonia removed and yield of tetrasodium EDTA increased with increasing reaction time. This suggested that at short reaction times, ammonia, formaldehyde, and cyanide react to form other sequestrants such as nitrilotriacetic acid. Plant Design
During scale-up studies, design engineers were in constant contact with members of the research team. When the work had progressed sufficiently, they wrote a process evaluation status report Lvhich covered plant design factors such as unusual requirements for services. materials of construction, and plant sites, and an estimate of manufacturing cost and capital investment. The section devoted to process evaluation tabulated information required to complete the plant design and recommended areas for further investigation. As a result of this close contact during scale-up studies. the timetable for designing and constructing the commercial unit was substantially shortened and the transition from pilot plant to commercial production was accomplished with minimum start-up difficulties. RECEIVED for review September 21, 1957 ACCEPTED June 26, 1958
Division of Industrial and Engineering Chemistry, Chemical Processes Symposium, 132nd Meeting, ACS, New York, N. Y . , September 1957.
