Process early developments

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

The lost foam casting process originated in 1958 but due to strong patents that covered the process early development was restricted. Only... 

The lost foam casting process originated in 1958 but due to strong patents that covered the process early development was restricted. Only when the patent expired around 1980 was free development possible and during the 1990s much work was done and the lost foam casting process is now a technical and commercial success. 

Formaldehyde, HCHO, is a primary and necessary constituent of the first five synthetic adhesives in the listing. It is a simple organic chemical first identified during the latter half of the 1800s. Its irritating and toxic odor and preservative properties were known from the time of its early development. It is a ubiquitous chemical, formed naturally in small quantities by every process of incomplete combustion as well as in normal biologic processes. The human body has a natural formaldehyde level of about 3 lg/g, ie, 3 parts per million (ppm) in the blood at all times. 

The Aromax process was developed in the early 1970s by Toray Industries, Inc. in Japan (95—98). The adsorption column consists of a horizontal series of independent chambers containing fixed beds of adsorbent. Instead of a rotary valve, a sequence of specially designed on—off valves under computer control is used to move inlet and withdrawal ports around the bed. Adsorption is carried out in the Hquid phase at 140°C, 785—980 kPA, and 5—13 L/h. PX yields per pass is reported to exceed 90% with a typical purity of 99.5%. The first Aromax unit was installed at Toray s Kawasaki plant in March 1973. In 1994, IFP introduced the Eluxyl adsorption process (59,99). The proprietary adsorbent used is designated SPX 3000. Individual on-off valves controlled by a microprocessor are used. Raman spectroscopy to used to measure concentration profiles in the column. A 10,000 t/yr demonstration plant was started and successfully operated at Chevron s Pascagoula plant from 1995—96. IFP has Hcensed two hybrid units. 

Manufacture of Fatty Acids and Derivatives. Splitting of fats to produce fatty acids and glycerol (a valuable coproduct) has been practiced since before the 1890s. In early processes, concentrated alkaU reacted with fats to produce soaps followed by acidulation to produce the fatty acids. Acid-catalyzed hydrolysis, mostly with sulfuric and sulfonic acids, was also practiced. Pressurized equipment was introduced to accelerate the rate of the process, and finally continuous processes were developed to maximize completeness of the reaction (105). Lipolytic enzymes maybe utilized to spHt... 

Two Other chemical processes that rely on hydrothermal processing chemistry are wet oxidation and supercritical water oxidation (SCWO). The former process was developed in the late 1940s and early 1950s (3). The primary, initial appHcation was spent pulp (qv) mill Hquor. Shordy after its inception, the process was utilized for the treatment of industrial and municipal sludge. Wet oxidation is a term that is used to describe all hydrothermal oxidation processes carried out at temperatures below the critical temperature of water (374°C), whereas SCWO reactions take place above this temperature. 

The early developments of solvent processing were concerned with the lubricating oil end of the cmde. Solvent extraction processes are appHed to many usefiil separations in the purification of gasoline, kerosene, diesel fuel, and other oils. In addition, solvent extraction can replace fractionation in many separation processes in the refinery. For example, propane deasphalting (Fig. 7) has replaced, to some extent, vacuum distillation as a means of removing asphalt from reduced cmde oils. 

The polymer is exposed to an extensive heat history in this process. Early work on transesterification technology was troubled by thermal—oxidative limitations of the polymer, especially in the presence of the catalyst. More recent work on catalyst systems, more reactive carbonates, and modified processes have improved the process to the point where color and decomposition can be suppressed. One of the key requirements for the transesterification process is the use of clean starting materials. Methods for purification of both BPA and diphenyl carbonate have been developed. 

In the early 1990s, processes were developed for the production of 1,4-butanediol and y-butyrolactone by gas-phase catalytic hydrogenation of maleic anhydride (131—134). Succinic anhydride is obtained as a partial hydrogenation by-product in these processes. It can be recycled to complete the hydrogenation to the desired products, or be separated and purified. This process could in the future become a significant commercial route for succinic anhydride. 

The 1990s reduction process was based on work started in the early 1930s. A magnesium vacuum reduction process was developed for reduction of titanium tetrachloride to metal. Based on this process, the U.S. Bureau of Mines (BOM) initiated a program in 1940 to develop commercial production. Some years later, the BOM pubHcized its work on titanium and made samples available to the industrial community. By 1948, the BOM produced batch sizes of 104 kg. In the same year, Du Pont aimounced commercial availabiHty of titanium, thus beginning the modem titanium metals industry (1). 

The first successful appHcation of heterogeneous azeotropic distillation was in 1902 (87) and involved using benzene to produce absolute alcohol from a binary mixture of ethanol and water. This batch process was patented in 1903 (88) and later converted to a continuous process (89). Good reviews of the early development and widespread appHcation of continuous azeotropic distillation in the prewar chemical industry are available (90). 

The first major objective for the inherent safety review is the development of a good understanding of the hazards involved in the process. Early understanding of these hazards provides time for the development team to implement recommendations of the inherent safety effort. Hazards associated with flammability, pressure, and temperature are relatively easy to identify. Reactive chemistry hazards are not. They are frequently difficult to identify and understand in the lab and pilot plant. Special calorimetry equipment and expertise are often necessary to fully characterize the hazards of runaway reactions and decompositions. Similarly, industrial hygiene and toxicology expertise is desirable to help define and understand health hazards associated with the chemicals employed. 

A prototype system implemented with the Formulogic shell has recently been reported by Pfizer [21]. The system has been designed to use preformulation data on new drugs and recommend early development formulations, predict product properties, and select processing conditions suitable for scale-up. 

It should be checked whether the process fulfils the state and local regulations concerning environmental protection, safety, and occupational health hazards. These criteria are not directly applicable in the early development. stages. 

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