Process Developments

Process development is a multiparameter optimization problem. It is not surprising, therefore, that notv that the technology is available to parallelize and automate organic synthesis, it is applied in this field. 

Material/shape glass vessels glass vessels stainless steel (glass inserts) 

Comments flexible customizable platform various other modules for, e. g dosing of solids, evaporation, etc., are available 

Number/volume model Reactivate 10/4—15 mL or 1-3 mL wv (10 independent temperature zones) model Microvate 48/0.25-2 mL wv (12 independent temperature zones) 

Comments azeotropic water removal possible (optional) various OEM reaction blocks available 

There is at this writing no commercial-scale process for the production of succinic acid. There has been activity over the last several years, which is primarily found in the patent literature, to improve the fermentation as well as the downstream process. A great deal of effort was initially spent on Amerobiospirillum succiniciproducens, as this was the first organism observed which could produce succinic acid in levels high enough to envision a commercial process. 

Anaerobiospirillum succiniciproducens is a strict anaerobe and grows at an optimal temperature of 39 °C. A typical fermentation medium contains dextrose, peptone, yeast extract, and salts. The optimal pH range for this organism was determined to be between 5.8 and 6.4. This organism can produce approximately 30 g of succinate/1 fi-om a starting glucose concentration of 50 g/1. Calcium hydroxide is added to produce a calcium succinate product, which can be precipitated fi-om the broth (Datta 1992). 

The effect of medium components on the production of succinic acid by A. succiniciproducens was systematically studied. Sodium ion is essential for glucose transport, and an optimal level of 4 g of NaCl/1 was determined. In contrast, magnesium ion did not appear to affect growth or succinic acid production. A variety of complex nitrogen sources were also assessed, and a mixture of polypeptone, yeast extract, soytone, and peptone gave better results than any of these ingredients used alone (Lee et al. 1999). 

A large batch was run in an 80-1 fermenter. A high succinate yield of 87 wt.% of added substrate carbon was obtained in a fermentation time of 22.5 h (Datta et al. 1992). Biotin was shown to be an important microingredient. At 50 mg of added biotin/1, an increase in glucose consumption was seen, and both succinic and acetic acid were increased by 17 % and 30 %, respectively. Biotin can be found in corn steep liquor however. 

Some uncertainty exists in how the CO2 should be optimally supplied to the fermenter. Nghiem et al. (1997) found that supply of CO2 via 1.5 M Na2C03 was adequate and that sparging CO2 gas into the fermenter at 0.025 1/min lowered the rate and yield of succinate production, whereas acetate production was not affected. This is in contrast to the work of Datta (1992), who found that the fermentation did not start as rapidly without a CO2 sparge. In Datta s patent, increasing the partial pressure of CO2 produced better results, and at 100 % CO2, which is a partial pressure of 1 atm, the fermentation was finished in 21 h, in contrast to a fermentation time of 42 h at 30 % CO2 (Datta 1992). Possibly, CO2 solubility is a factor in the different results, as at pH 6.5, CO2 is three times more soluble than at pH 6.2 (Jones and Greenfield 1982). 

Three common concerns when developing an autoclave process for a specific component in the aerospace industry are (1) to meet the cure cycle specification, that is, to ensure that all regions of the component are experiencing 

6 Schematic of the tool removal process (a) prior to tool removal, part and tool in equilibrium, part conformed to tool shape (b) tooling removed, residual tool/part interface forces remain (c) add negative of interface loads to obtain stress free interface (d) predicted part shape after tool removal. 

As discussed previously, accurate prediction of the thermal history of the part is critical. Not only is the management of the thermal history important in its own right, for example to avoid exotherms,but it determines the degree of cure evolution. In turn, the coupled temperature and degree of cure history, which in a real part will vary with position throughout the structure, will determine flow behaviour and residual stress/deformation behaviour. Further to Section 13.2.1, determination of the system boundary conditions 

7 CFD simulation of airflow within a small research autoclave (1.5 m long, 1.15 m diameter). The circled numbers indicate the location of calorimeters used to measure the local HTC. (From reference 30.) 

8 Evaluation of thermal histories for a 15 mm thick AS4/8552 part on a 15 mm thick Invar tool using a ID thermal simulation in COMPRO. (Re-created from reference 30.) 

The Bulk Drug Process as Part of the Drug Development 

Processing Responsibility in Bulk Drug Process Development73 

The purposes of this chapter are few and rather ambitious. First, to provide a sound perspective of bulk drug process work to the uninitiated and the relatively new practitioner, hopefully without prejudice to the benefit that the approach herein might afford to an experienced but still restless practitioner. All work in a forest that is dense and rich in its variety it should be regarded from a vantage now and then, and it is from such a deliberately selected vantage that the chapter unfolds. 

Then there is the promotion of the power that the purposeful convergence of chemistry, microbiology, and chemical/ 

As the last objective, the methods of bulk drug process development will be weaved discreetly, if not seamlessly, throughout the chapter (a) the principal issues that shape the methods, (b) the most trenchant choices confronting the process development team, and (c) some selected heuristics (i.e., empirical rules that, although lacking proof, are useful often enough) distilled from the author s experience. 

The balance between the four metrics is dependent upon the relative costs in a process. For example, a process with a high cost of biocatalyst will require a high biocatalyst yield, while those with a high cost of process plant will require a high space-time yield, and those with a high downstream processing cost will require a high product concentration to leave the reactor. 

For a multienz5une process, this evaluation is critically important to achieve a better theoretical xmderstanding of the process and to achieve useful modeling and process design. The reaction considerations describe the key characteristics necessary if one is to xmderstand how tire interaction between enz5unes and components can be interpreted for modeling. Furtiiermore, such information forms the basis for the 

Reagent data Physical and chemical properhes of the compounds involved in the reaction must be known (e.g., density, water solubility, viscosity, boiling point, Henry s constant, pK, pH stability). 

Cascade architecture A graphical representation of all reactions in the mulhen-zyme process is the basis for describing the final model structure. It includes the primary reachons, secondary reactions, and competing reactions. For a single enzyme, reachon mechanisms are well developed, and they are then included into the full model to describe the multienzyme process by combining the effect of the individual enzymes. In this way, the different possible reaction schemes are generated to give the cascade structure. 

Interaction matrix This matrix is used to identify the different interactions that can exist between compounds and enzymes in the process. Here, the structure defined in the previous step is required. In order to build the matrix, the compounds involved in the process (i.e., substrates, intermediates, by-products, products, etc.) are arranged in rows, and the enzymes are arranged in columns. In this way, the matrix is filled defining the relahonship between each compound and enzyme in turn, that is, substrate, product, inhibitor, or no interaction between a given compound and enzyme. This compiled information is extremely powerful to help make decisions about the relevant terms or kinetic parameters that must be added or removed from the reaction rate expressions and process model. The position of the new term/parameter in the final expression is defined by die enzyme kinetic mechanism, which shows how the compoxmd inhibits the enzyme, for example, competitive, uncompetitive, noncompetitive, or mixed inhibihon. Similarly the matrix helps define the process configuration ophons. 

Creative thinking is important not only in new process development, but also in continually reviewing and reevaluating existing processes for opportunities to make the process inherently safer. Many of the tools and techniques discussed in Section 4.2, on Research, are useful in the process development stage as well. It is appropriate to revisit the basic chemistry to study alternate options. 

In order to limit time and expenses for material, simulation programs able to calculate at least the typical process unit operations are increasingly applied. 

For this purpose a number of commercial simulation programs are available, such as ASPEN PLUS, PROSIM or CHEMCAD. The calculation of the unit operations is based on the usual foundations for the design of thermal /2.11,2.12, 2.13/, chemical /2.14, 2.15, 2.16, 2.17/, biological /2.18, 2.19, 2.20/ and mechanical processes 12.22, 2.21/. Furthermore, the calculation of the unit operations usually requires comprehensive data on chemical media. Since sufficiently precise data on chemical media are often not available or simplified assumptions have to be made, one will usually not rely only on the results of the simulation calculation. Principally, the reversed way of proceeding is also possible The simulation calculation is preceded and then completed by experimental analyses. 

Even though the individual unit operations have been optimized experimentally and/or arithmetically, this does not naturally mean that the whole plant will run perfectly. The linking of the individual stages may lead to additional controlengineering problems. Here the so-called mini plant technology /2.23/ has become 

If a new process is finally found, the company will protect itself against the competition by means of corresponding licences. 

The planning of an absolutely new plant concept is not always required. Often plants already exishng in a similar form are to be realized. Thus the actual process work flow is already determined. 

When the prototype product satisfies all the requirements for the addition of a new product to the range, set by the business, it is ready for further development. 

The development of a process to make a new chemical entity is not a simple procedure and a project leader will need to be appointed, if one has not been there during the speculative research phase. Process development usually costs several times more than the expenditure on the initial product research and is not entered into lightly. The procedure adopted for process development needs thoughtful planning, if time and money are not to be wasted. The procedure, which is described here, is normally applied to novel chemical entities, but many of the aspects apply equally to the addition of a known material to a company s selling range. 

The answers to the above questions will enable the project leader, in collaboration with the relevant Managers, to assign the correct personnel to the project at the start of the development work and to plan for additions later on as required. 

The ability to extract much more understanding from high quality large experimental data sets focused even more attention on the need for better data quality. Jim Cawse [3] presented a Six Sigma study of a high throughput research process and was able to demonstrate that even more variability could be taken out of the process. This was possible because the repeatable steps could be studied to understand their contribuhon to the variability in the overall processes. The result was significantly better data quality, which enabled more powerful uses of the data sets. 

The rate at which new materials could be discovered soon began to cause another problem, which was that the bottleneck had begun to move down stream of the discovery process. As the road to commercialization requires the efforts of many different groups and corporate organizations the bottleneck on the journey began to appear in other areas. One immediate area that had problems was in process development. 

Ian Maxwell who left Shell to set up Avantium used to suggest in his presentations that one should scale down, to scale up . One reason to do this is that it becomes easier to deal with extreme conditions of corrosion, temperature, and pressure. In addition, since the mass is small, changing conditions can be rapid. Finally, much less material is needed both for the catalyst and for reactants. Another very powerful aspect of this concept is that as reactors get smaller it becomes possible to imderstand and model the reactor s performance so well that its impact on the chemistry being measured can be removed and the intrinsic chemistry can be determined. This is what enables VandenBussche to scale his data. He has 

This is a very important addition in that not only can the laboratory process characterization data be gathered more quickly by high throughput research concepts but, if done in the manner described by VandenBussche, the data can eliminate the need for extensive intermediate plant scale testing. VandenBussche is quick to point out that at this stage of comfort with the approach they still conhrm their results at intermediate scale but the time needed to do this is greatly reduced. 

As mentioned above, researchers in the area of catalyst discovery such as VandenBussche at UOP made the move from discovery to process development 

Screening for the best possible reaction conditions, the optimal media, and the most appropriate microorganisms is the first step in process development. This screening process is performed on a mL scale in shake flasks. These are 50 or 100 mL Erlenmeyer flasks that are gently agitated under controlled temperature. This is a simple, inexpensive way to get basic qualitative information about the reaction parameters. 

The cost of the fermentation medium becomes a critical factor upon scale-up. The best growth medium may not always be the most economical and the cheapest not always optimal for production. The constituents of the medium must reflect the composition of the biomass, which mainly comprises carbon, oxygen, hydrogen, sulphur, magnesium, potassium, and trace elements. The raw materials for the 

To prevent later problems, specific measurements and observations of fouling conditions should be made in development trials. The outcome should be a comprehensive set of guidelines, checklists, and workable procedtues, resulting in die development of a safe, stable, and nonfouling process. Some of the specific items to consider during development are  

If cleaning proves to be necessary, possible approaches should be considered during process development. Cleaning methods are broadly classified as mechanical or chemical. 

Mechanical cleaning usually requires opening of equipment. Techniques include manual stripping and wiping, rinsing, and blasting with abrasives or high-pressure liquid sprays. 

Even though there are a few drawbacks, as mentioned above, we felt that the Medicinal Chemistry route was straightforward and we should be able to use the original synthetic scheme for a first delivery with modifications as follows  

2) Protection of the nitrogen in 4 faced the classical N- versus O-alkylation selectivity issue, which was solved by selection of the solvent system. The original protecting group, pMB, was replaced with 9-anthrylmethyl (ANM), which provided the best enantioselectivity with the newly discovered asymmetric addition to the ketimine. 

3) Asymmetric acetylene addition should be pursued to avoid the tedious final enantiomer separation by silica gel column after derivatization with an excess of expensive camphanyl chloride. 

4) The final deprotection step must be modified to accommodate the new protective group (ANM) and an isolation method for a suitable crystalline form of 2 had to be developed. 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also 

TABLE 4.3 Component Classes and Formulation Example for Low-Dose FBG Formulations 

Phase Component Class Typical Ranges Example29 

Inner phase Drug Up to 1% Ethinyl estradiol 0.0375% Drospirenone 3.75% 

Therefore, the excipient selection will not only be performed based on the preformulation results, but also based on a careful consideration of physical parameters such as particle size and surface characteristics. 

Immediate release tablets, and thus the granules they are based on, typically consist of several different materials, including APIs and various excipients. Uniform 

One suggestion is to back extract with supercritical carbon dioxide, which is also a clean solvent. Another alternative is to do the reverse, i.e. extract the plant material first with carbon dioxide to obtain a concrete or oleoresin , which contains heavy materials, such as plant waxes. The concrete can then be treated with superheated water, as described below in the section on liquids. However, the use of supercritical carbon dioxide is probably not economically viable for most products. 

In some cases there is no problem. For example, the extraction of flowers, such as rose petals, leads to a white precipitate containing the fragrance compounds. This may be a product that can be accepted as an additive to soaps and other cos- 

Generally FCC units operate in a heat balanced mode whereby the heat generated by the burning of coke is equal to heat needed for the vaporization of the feed plus the heat of cracking. Also the pressure balance of an FCC unit is very important in order to ensure proper catalyst circulation and to prevent the contact between hydrocarbons (reactor) and air (regenerator). Overall this makes the optimal operation of a unit a very interesting challenge. 

The FCC process hardware and operation have continued to co-evolve with the catalyst and the changing economical and environmental requirements. 

Quick product disengaging and separation from catalyst. 

Catalyst coolers (internal and external heat-removal). 

Third-, Fourth- and Fifth- stage particulate capture systems. 

Since the mechanical properties fibers are excellent in NF-reinforced composites, increased use of BF as a reinforcement fiber should be expected. However, it is 

For the above reason, Doshisha University and Kobe Steel started joint development of the continuous granulation method by NF, which is not used in the manufacture of cotton yam, but used with short fibers such as BF. First, NF of the short fiber is wrapped in the TP resin nonwoven fabric similar to the ingredients in rolled sushi. Simultaneously, a denaturing agent is also mixed in order to improve the interface adhesiveness of the NF and TP resin. In addition, a cohesive force is directly supplied by the screw of the TSE. The nonwoven fabric made of TP resin is melted by the shear stress of the TSE. As a result, the short fibers of the NF are compounded with the TP resin. PP, PET, and PLA are used as the nonwoven fabric [20, 21]. 

The nonwoven fabric made from PP was used in the sample trial production experiment A 5wt% of PP was denatured with maleic acid and simultaneously mixed in the nonwoven fabric. The NF materials in the nonwoven fabric are called roller materials. These roller materials were manually injected into the screw of TSE and the pellet with 50-60 wt% BE was manufactured. The extruding machine used for the trial production is Kobe Steel KTX-30 and has the following technical specifications. 

This system consists of the four following parts. 

1) the delivery part of a continuous nonwoven fabric sheet  

Experience led to the introduction of catalysts based on nickel nitrate and oxalate, followed by lactate or formate as well as the original carbonates, all supported on infusorial earth, pmnice, or even charcoal to increase activity. Reduction procedures were foimd to be important in obtaining the highest catalyst activity. Reoxidation of nickel before use had to be avoided. Mixed nickel oxide and copper oxide reduced more easily than nickel oxide alone.  

As Raney fotmd in the 1920s, catalyst reproducibility was a real problem dttring a period when just about every small operator made his own catalyst. The ready availibility of Raney nickel supplied in an easily activated form and then the more reliable and active prereduced nickel catalysts provided by Harshaw were a relief for producers and led to further developments in the process. 

During the early period of development operating corrditions evolved for the treatment of different fats and oils depending on the extent and type of rm-saturation. More practical ways of mixing the oil and hydrogen were introduced and selective hydrogenation became more important. 

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Delayed Coking", is a semi-continuous process, developed at the end of the 1930 s. The reaction is conducted at 450-500°C under relatively low pressure, four atmospheres, maximum. 

Much of the vanadium metal being produced is now made by calcium reduction of V2O5 in a pressure vessel, an adaption of a process developed by McKechnie and Seybair. 

The design of bioseparation unit operations is influenced by these governmental regulations. The constraints on process development grow as a recovery and purification scheme undergo licensing for commercial manufacture. 

S. E. Builder, R. van Reis, N. Paoni, and J. Ogez, "Process Development and Regulatory Approval of Tissue-Type Plasminogen Activator," in... 

Until World War 1 acetone was manufactured commercially by the dry distillation of calcium acetate from lime and pyroligneous acid (wood distillate) (9). During the war processes for acetic acid from acetylene and by fermentation supplanted the pyroligneous acid (10). In turn these methods were displaced by the process developed for the bacterial fermentation of carbohydrates (cornstarch and molasses) to acetone and alcohols (11). At one time Pubhcker Industries, Commercial Solvents, and National Distillers had combined biofermentation capacity of 22,700 metric tons of acetone per year. Biofermentation became noncompetitive around 1960 because of the economics of scale of the isopropyl alcohol dehydrogenation and cumene hydroperoxide processes. 

Acrylonitrile is produced in commercial quantities almost exclusively by the vapor-phase catalytic propylene ammoxidation process developed by Sohio... 

The propylene-based process developed by Sohio was able to displace all other commercial production technologies because of its substantial advantage in overall production costs, primarily due to lower raw material costs. Raw material costs less by-product credits account for about 60% of the total acrylonitrile production cost for a world-scale plant. The process has remained economically advantaged over other process technologies since the first commercial plant in 1960 because of the higher acrylonitrile yields resulting from the introduction of improved commercial catalysts. Reported per-pass conversions of propylene to acrylonitrile have increased from about 65% to over 80% (28,68—70). 

Such a concept was originally used in a process developed and Hcensed by UOP under the name UOP Sorbex (59,60). Other versions of the SMB system are also used commercially (61). Toray Industries built the Aromax process for the production of -xylene (20,62,63). Illinois Water Treatment and Mitsubishi have commercialized SMB processes for the separation of fmctose from dextrose (64—66). The foUowing discussion is based on the UOP Sorbex process. 

Single-Cell Protein. Systems involving single-cell proteins are often very large throughput, continuous processing operations such as the Pmteen process developed by ICI. These are ideal for air-lift bioreactors of which the pressure cycle fermenter is a special case (50). 

The ammonium chloride process, developed by Asahi Glass, is a variation of the basic Solvay process (9—11). It requires the use of soHd sodium chloride but obtains higher sodium conversions (+90%) than does the Solvay process. This is especially important ia Japan, where salt is imported as a soHd. The major difference from the Solvay process is that here the ammonium chloride produced is crystallized by cooling and through the addition of soHd sodium chloride. The resulting mother Hquor is then recycled to dissolve additional sodium chloride. The ammonium chloride is removed for use as rice paddy fertilizer. Ammonia makeup is generally suppHed by an associated synthesis plant. 

Nickel and Cobalt. Often present with copper in sulfuric acid leach Hquors are nickel [7440-02-0] and cobalt [7440-48-4]. Extraction using an organophosphoric acid such as D2EHPA at a moderate (3 to 4) pH can readily take out the nickel and cobalt together, leaving the copper in the aqueous phase, but the cobalt—nickel separation is more difficult (274). In the case of chloride leach Hquors, separation of cobalt from nickel is inherently simpler because cobalt, unlike nickel, has a strong tendency to form anionic chloro-complexes. Thus cobalt can be separated by amine extractants, provided the chloride content of the aqueous phase is carefully controUed. A successhil example of this approach is the Falcon-bridge process developed in Norway (274). 

A process developed in Israel (263) uses solvent extraction using a higher alcohol or other solvating solvent. This removes phosphoric acid and some hydrochloric acid from the system driving the equiHbrium of equation 42 to the right. The same principle can be appHed in other salt—acid reactions of the form... 

The alkalized zinc oxide—chromia process developed by SEHT was tested on a commercial scale between 1982 and 1987 in a renovated high pressure methanol synthesis plant in Italy. This plant produced 15,000 t/yr of methanol containing approximately 30% higher alcohols. A demonstration plant for the lEP copper—cobalt oxide process was built in China with a capacity of 670 t/yr, but other higher alcohol synthesis processes have been tested only at bench or pilot-plant scale (23). 

Acetic Acid and Anhydride. Synthesis of acetic acid by carbonylation of methanol is another important homogeneous catalytic reaction. The Monsanto acetic acid process developed in the late 1960s is the best known variant of the process. 

The U.S. domestic commercial potassium nitrate of the 1990s contains 13.9% N, 44.1% I+O, 0—1.8% Cl, 0.1% acid insoluble, and 0.08% moisture. The material is manufactured by Vicksburg Chemical Co. using a process developed by Southwest Potash Division of AMAX Corp. This process uses highly concentrated nitric acid to catalyze the oxidation of by-product nitrosyl chloride and hydrogen chloride to the mote valuable chlorine (68). The much simplified overall reaction is... 

Aloisture Absorbent Synthetic Paper. Processes for making a water absorbent synthetic paper with dimensional stabihty have been developed by several companies. In a process developed by Mitsubishi Rayon, acrylic fiber is insolubilized by hydra2ine and then hydroly2ed with sodium hydroxide. The paper, formed from 100 parts fiber and 200 parts pulp, has a water absorption 28 times its own weight (96). Processes for making hygroscopic fibers have also been reported in the patent Hterature. These fibers are used in moisture absorbing nonwovens for sanitary napkins, filters, and diapers. 

Electrically Conducting Fibers. FlectricaHy conducting fibers are useful in blends with fibers of other types to achieve antistatic properties in apparel fabrics and carpets. The process developed by Nippon Sanmo Dyeing Co., for example, is reportedly used by Asahi in Casbmilon 2.2 dtex (2 den) staple fibers. Courtaulds claims a flame-resistant electrically conductive fiber produced by reaction with guanadine and treatment with copper sulfide (97). 

A worldwide Hst of spandex fiber and related elastomer producers is shown in Table 2. Most process developments have occurred in the United States, Germany, Japan, and Korea. A large proportion of worldwide capacity is controlled by Du Pont, either directly or through subsidiaries and joint ventures. These include three plants in North America, two in South America, two in Europe, and two in Asia. 

Pulp-like olefin fibers are produced by a high pressure spurting process developed by Hercules Inc. and Solvay, Inc. Polypropylene or polyethylene is dissolved in volatile solvents at high temperature and pressure. After the solution is released, the solvent is volatilised, and the polymer expands into a highly fluffed, pulp-like product. Additives are included to modify the surface characteristics of the pulp. Uses include felted fabrics, substitution in whole or in part for wood pulp in papermaking, and replacement of asbestos in reinforcing appHcations (56). 

T. Nagata, "New Process Developments foi Polynosic Fibres," Proceedings of the 28 th Dombim International Man Made Fibres Conference, Austria, Sept. 1989. 

An improved version of the THPC—amide process, developed in 1972, is based on a finish containing THPC, cyanamide, and disodium phosphate [13708-85-5] Na2HP04. It has the advantage of removing the mutagenicaHy suspect TMM from the finish while retaining many of its attributes (81). 

Flame-Retardant Treatments For Wool. Although wool is regarded as a naturally flame-resistant fiber, for certain appHcations, such as use in aircraft, it is necessary to meet more stringent requirements. The Zirpro process, developed for this purpose (122,123), is based on the exhaustion of negatively charged zirconium and titanium complexes on wool fiber under acidic conditions. Specific agents used for this purpose are potassium hexafluoro zirconate [16923-95-8] [16923-95-8] K ZrF, and potassium hexafluoro titanate [16919-27-0], K TiF. Various modifications of this process have been... 

The earhest frothing process developed was the Dunlop process, which made use of chemical gelling agents, eg, sodium fluorosiUcate, to coagulate the mbber particles and deactivate the soaps. The Talalay process, developed later, employs freeze-coagulation of the mbber followed by deactivation of the soaps with carbon dioxide. The basic processes and a multitude of improvements are discussed extensively in Reference 3. A discussion more oriented to current use of these processes is given in Reference 115. 

In the cuspation—dilation thermoforming process developed in AustraHa, sheet formation is promoted by expanding blades extending into aU areas and distributing the material uniformly throughout the mold. This process is claimed to deHver uniform distribution of high barrier components of sheet coextmsions and laminations. The process also permits almost vertical side waUs to cups (2). 

The Provesteen process, developed by Phillips Petroleum Company, employs a proprietary 25,000-L continuous fermentor for producing Hansenu/a jejunii the sporulating form of C. utilis from glucose or sucrose at high cell concentrations up to 150 g/L. The fermentor is designed to provide optimum oxygen and heat transfer (69,70). 

LPC Processes. Process development for LPC production dates from the United Kingdom and Hungary from 1920—1940 (89,90). Table 9 presents some of the processing methods that are used or under development in the 1990s. 

The Vepex process developed in Hungary (Table 9) involves disintegration of plant materials followed by double screw pressing to maximize juice production. Green chloroplastic protein is removed by direct steam-injection heat treatment at 82°C with the addition of flocculents and centrifugation. The white protein fraction is separated from the chlorophyU-free process juice by direct steam injection at 80°C, followed by centrifugation and drying (94). 

Process development unit (PDU) results with unspecified hardwood. 

Shale Oil. In the United States, shale oil, or oil derivable from oil shale, represents the largest potential source of Hquid hydrocarbons that can be readily processed to fuel Hquids similar to those derived from natural petroleum. Some countries produce Hquid fuels from oil shale. There is no such industry in the United States although more than 50 companies were producing oil from coal and shale in the United States in 1860 (152,153), and after the oil embargo of 1973 several companies reactivated shale-oil process development programs (154,155). Petroleum supply and price stabiHty has since severely curtailed shale oil development. In addition, complex environmental issues (156) further prohibit demonstration of commercial designs. 

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