SVIBOR - Project code: 2-15-320


Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69


SVIBOR - Collecting Data on Projects in Croatia

Project code: 2-15-320


Main researcher: BOŠNJAK, MARIJAN (4864)

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
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.


  1. 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


  1. Name: Poboljšanje postupka proizvodnje oksitetraciklina
    Type of achievement: Technology
    Authors: Mihaljević Krešo, Gomerčić Krešimir, Bošnjak Marijan

  2. Name: Određivanje tetraciklinskih antibiotika metodom visokotlačne tekućinske kromatografije (HPLC)
    Type of achievement: Technology
    Authors: Bošnjak Nada, Mihaljević Krešo

  3. Name: Novi postupak proizvodnje L-sorboze
    Type of achievement: Technology
    Authors: Bošnjak Marijan, Mihaljević Krešo, Pintar Pavao, Baranašić Stjepan, Gomerčić Krešimir

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Last update: 10/10/95