OPTIMIZATION OF CHEMICAL AND BIOTECHNOLOGICAL PROCESSES
Main researcher
: BOŠNJAK, MARIJAN (4864) Assistants
MIHALJEVIĆ, KREŠO (177295)
VAMPOLA, MILAN (96161)
BOŠNJAK, NADA (4875)
GOMERČIĆ, KREŠIMIR (13853)
GOSAK, DARKO (115066)
ŠIROLA, IGOR (47120)
PAVLOVIĆ, NEDILJKO (126794)
CRNIĆ, ZDRAVKO (7092)
GAMULIN, STJEPAN (13074)
PRESTER, BERISLAV (96172)
Type of research: applied Duration from: 01/01/91. to 12/31/96. Papers on project (total): 57
Papers on project quoted in Current Contents: 2
Institution name: Pliva - Istraživački institut, Zagreb (60) Department/Institute: Biosynthesis and Biotechnology Address: Prilaz baruna Filipovića 25 City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (0)1 18-15-99
Fax: 385 (0)1 18-16-06
Fax: 385 (0)1 57-66-90
Summary: The project covers the optimization studies of typical
chemicaland biotechnological processes applicable in pharmaceutical
industry. In the period 1991-1993 the planned investigations were
succesfully performed and remarkable results achieved. Rectification
systems of different solvent mixtures (aceton-water, ethanol-water,
methanol-water, aceton-methanol, epiklorhydrin-xylen) were studied and
their behaviour mathematically defined, in connection with the studies
refering to other projects of PLIVA Research Insitute. Computer control
programmes were developped and computer controlled rectifications of
aceton-water and methanol-water mixtures were realized on the plant-scale.
Ca-gluconate solubility in different solvents was investigated and the
mathematical model defined showing Ca-gluconate solubility to be dependent
exponentially on the solvent concentration and reciprocal absolute
temperature. Computer simulation of the process of selective oxidation of
4(5)-nitroimidazol was performed applying the simple mathematical model
composed of 6 simultaneous differential equations. Simulated data fitted
well with those experimental, but the model should however be improved.
Computer controlled fed batch cultivation process of the yeast
Saccharomyces cerevisiae was developed and its application confirmed
experimentally on the laboratory scale. With some investment the procedure
could be applied on the industrial scale. Optimization of the process of
sorbitol conevrsion to sorbose was studied and an improved new procedure
of sorbose production based on fed batch cultivation of Gluconobacter
suboxydans bacterium was proposed and it is expected to be introduced on
the industrial scale. Actually, research efforts are oriented toward the
development of the control system for the proposed new procedure. The
formation of crystalline sorbose during the cultivation process was also
studied and the new method of crystalline sorbose production discovered.
The affect of water activity on bioprocess kinetics and effectiveness were
studied and relationships established. On the basis of the experiments the
"simple" (conversion of sorbitol to sorbose) and "complex"
(oxytetracycline biosynthesis) microbial processes were compared with
reference to integration and optimization of biotechnological processes,
and some common relationships were observed. In both cases it was
established that process efficiency could be increased when applying the
repeated use of microbial biomass. The procedure of 2-(3-benzoylphnyl)
propionic acid crystallization was optimized as well. Application of
semicontinuous crystallizer and aromatic hydrocarbons as solvented to
process improvement. Kinetics of biocatalytic oxidation of benzhydrol to
benzophenon, applying the biomass of G. suboxydans bacterium was also
studied. Oxidation was observed to be many times slower than that of
sorbitol to sorbose. The new method of fluoxetine synthesis being
discovered, is characterized with marked advantages when compared to those
already known.
Keywords: Process optimization, rectification computer control, aceton-water, methanol-water, Ca-gluconate solubility, mathematical modelling of 4(5)-nitroimidazol oxidation, yeast culltivaton computer control, conversion of sorbitol to sorbose, fed batch culture of G. suboxydans, crystalline sorbose production, water activity, oxytetracycline biosinthesis, process kinetics, biomass recycle, 2-(3-benzoylphenyl propionic acid crystallization, benzhydrol biocatalytic oxidation, fluoxetin synthesis
Research goals: The objective of scientific studies of different
chemical an dbiotechnological processes applicable in pharmaceutical
industry was to establish the process relationships and then to develop
the optimal particular processes and/or to develop the appropriate methods
(procedures) of their computer control. And another objective was to
propose the application (on the production scale) of new production
procedures develped on the basis of experimentally documented and
scientifically provenfindings. Expected: Defined mathematical model for
computer simulation of vapour-liquid equilibrium of different solvent
mixtures, i.e. of their rectification, then to have developed the
procedure of computer controlled rectification of aceton-water and
methanol-water mixtures. To have developed the procedure of computer
controlled bakeržs yeast fed batch culture, with its experimental
verification. Computer simulation of selective oxidation of 4(5)
nitroimidazol and defined mathematical model. New information on
Ca-gluconate solubility with defined mathematical model. The improved
procedure for 2(3-benzoylphenyl) propionic acid crystallization. New
information on the kinetics of oxytetracycline biosynthesis, established
process parametars and defined conditions for more efficient antibiotic
production on laboratory and plant scales, the finding that might have
economic benefits for the company. Possibility of increasing process
efficiency by microbial biomass recycle and discovering of new
relationships. Special emphasis given to the study of the process of
microbial oxidation of sorbitol to sorbose. Defined relations relevant for
the defining of the optimal production procedure which mainly refers to
the fed bach process of bacterium G. suboxydans cultivation. New
procedure to be applicable on the industrial scale. The developed
procedure of computer controlled process. Information on the formation of
crystalline sorbose during the cultivation process. Discovered new
application area for catalytic use of G. suboxydans biomass in converting
chemical compounds.
COOPERATION - PROJECTS
Name of project
: 1-08-045 Studije, konstrukcije i kloniranje
organizama za konverziju glukoze u ketokiseline Name of institution: PLIVA Istraživački institut City: 10000 - Zagreb, Croatia
OTHER ACHIEVEMENTS
Name
: Poboljšanje postupka proizvodnje oksitetraciklina Type of achievement: Technology Authors: Mihaljević Krešo, Gomerčić Krešimir, Bošnjak Marijan
Name
: Određivanje tetraciklinskih antibiotika metodom
visokotlačne tekućinske kromatografije (HPLC) Type of achievement: Technology Authors: Bošnjak Nada, Mihaljević Krešo
Name
: Novi postupak proizvodnje L-sorboze Type of achievement: Technology Authors: Bošnjak Marijan, Mihaljević Krešo, Pintar Pavao, Baranašić
Stjepan, Gomerčić Krešimir Other information about the project.