Ultrasonic Technologies for Pharmaceutical Industry
Ultrasonic Activation of Crystallisation, Extraction and Emulsification Processes of Medicinal Preparations Production, Investigation of Phycico-Chemical Mechanisms, Development and Demonstration of Technologies
Tech Area / Field
- CHE-IND/Industrial Chemistry and Chemical Process Engineering/Chemistry
3 Approved without Funding
National Academy of Sciences of the Republic of Belarus / Institute of Technical Acoustics, Belarus, Vitebsk
- Vitebsk State Medical University, Belarus, Vitebsk\nNational Academy of Sciences of the Republic of Belarus / Institute of General and Inorganic Chemistry, Belarus, Minsk
- Coventry University, UK, Coventry\nUniversity of Trieste, Italy, Universiti of Trieste\nUniversity of Bath / Department of Chemistry, UK, Bath
Project summaryProject objective: development of new scientific and technical principles of ultrasonic activation of crystallisation, extraction and emulsification processes, creating of highly efficient technologies for high-quality medicinal preparations production based on these principles.
Statement of the Problem.
The methods of ultrasonic activation of crystallisation, extraction and emulsification processes widely used in pharmaceutical industry to increase the rate and completeness of medicines fabrication have an essential disadvantage consisting in the fact that the action of cavitation causes chemical destruction and oxidation of obtained products and therefore leads to the decrease or full loss of their medicinal properties (Proc. 7th Meeting Europ. Soc. Sonochem., Biarritz-Guethary, France, 2000: Hoffmann M.R., p. 71; Petrier C., p. 73; Chemat F., p. 221; Paniwnyk L., p. 241). Up to now, the problem of increasing the efficiency of these methods, namely, of providing the high intensifying action of ultrasound with simultaneous prevention or limitation of the chemical substance destruction induced by cavitation is not solved both on a scientific and technical level. This problem is of a great (not only technical and economical, but also social) significance because pharmaceutics is a part of the human health protection system.
In this project, we propose to develop new principles of ultrasonic activation of crystallisation, extraction and emulsification processes used in the production of medicinal preparations. For the first time the specific regimes for generation of ultrasonic oscillations will be used. Under these regimes, the major intensifying factor will be not a high-energy collapse of cavitation bubbles, but highly intensive microflows and acoustic streams causing the vortical turbulization. For the first time we propose to use the protectors of cavitation chemical destruction in order to minimize the influence of free-radical products formed during high-energetic collapse of cavitation bubbles and, as a consequence, to prevent chemical damage to the molecules of crystallized, extracted or emulsified substances. The implementation of these novel approaches to the production of medicinal preparations will favour the world progress in pharmaceutical industry because of the essential intensification of pharmaceutical production and improvment of drug quality.
Project Participants Competence.
Three institutions: ITA NASB, IGIC NASB and VSMU - take part in the project. The team from ITA NASB has a the great experience in the investigations on the crystallisation and ultrasonic processes, the participants from IGNC NASB – in the investigations on the ultrasonic activation of chemical reactions, extraction and emulsification processes. The participants from VSMU are specialised in the field of studying the physical-chemical and pharmacological properties of medicinal preparations. The “weapon” scientists (from ITA NASB and IGIC NASB) taking part in the project are specialists in radio-electronic equipment and different testing devices for missiles, in techniques for guidance and control of missiles including launching and impact systems as well as in materials and technologies needed for the production of chemical weapon agents. During last years they have conducted the investigations closely related to the topic of this project. High qualification of the project participants and the available results of their investigations allow us to consider that the project will be carried out successfully.
The following results are expected to be obtained during the realization of the project:
– novel methods of ultrasonic activation of crystallization, extraction and emulsification processes providing a high degree of acoustic turbulization and low-energy cavitation level;
– the elucidated regularities and mechanisms of crystallisation, extraction and emulsification processes; the developed protectors of chemical destruction which will be adapted to the functioning in ultrasonic fields and will minimize the cavitation – induced free - radical transformations in liquid media;
– the results of investigations on the physicochemical and pharmacological properties of medicinal preparations produced in the conditions of ultrasonic activation;
– pilot installation for realization of ultrasound-activated crystallisation, extraction and emulsification pro-cesses used in the production of medicinal preparations; the established optimized conditions for the ultrasound treatment combined with the use of cavitation protectors and developed on this basis ultrasonic technologies for the production of medicinal preparations.
The most important technical results will be covered by patents. Scientific significance of project results. For the first time the regularities and mechanisms of crystallisation, extraction and emulsification processes in the conditions of ultrasonic activation in the presence of protectors of cavitation-induced free-radical reactions will be clarified. The compositions of protectors inhibiting the cavitation damage to the chemical substances will be also developed for the first time.
Practical Significance of Project Results.
The complex ultrasonic technologies uncluding crystallisation, extraction and emulsification processes adapted to the use for producing the medicinal preparations will be developed. These technologies will provide the essential (4-7 times) increase of the rates of crystallisation, extraction and emulsification process as well as the completeness of product crystallisation and extraction (by 15-25%), the high quality of products (an increase of dispersion degree of crystal substances and emulsions, an improvement of homogeneity and repeatability of properties, a decrease of impurity concentrations and chemical damages). Practical recommendations on increasing the effectiveness of ultrasonic activation of crystallisation, extraction and emulsification processes applied in different branches of industry (food, chemical, microbiological, perfume, cosmetic, etc.) will be proposed.
Commercial Significance of Project Results.
The technological processes for the extraction of biologically valuable substances from the natural raw materials as well as for their crystallization and emulsification to be developed in the course of this project will be characterized by a number of advantages over the currently used ones and will be of a commercial importance for their further practical application after completing the project. A number of patent applications (concerning the compositions of cavitation protector and the ways for their production; the arrangements and the ways for the activation in the absence of cavitation, etc.) and licence agreements will be submitted. This will create the basis for the financial profit due to the intellectual property of the project participants.
Applications of Project Results.
The developed technologies will be approved at the join-stock company «Belmedpreparaty» (Minsk., Belarus) for the production of such medicines as paracetamol, extracts from vegetable substances, vitamin – hydroxyapatite complex, etc. It is planned also to approve the equipment for ultrasonic disagglomeration of crystal sediment obtained during crystallisation by the method of supercritical fluids (SCF) at the enterprise BDP (Bradford, UK). After completing the project, we plan to conduct a search for the interested organizations in order to create the production sections (1) for production of drug substances using the extraction under the action of ultrasound (ITA NANB and VSMU) and (2) for producing the ultrasonic equipment for the activation of technological processes in liquid media (IGIC NASB). The substances produced will be sold to join-stock company «Belmedpreparaty» (Minsk, Belarus) and commercial & production union “Pharmacy” (Minsk, Belarus) for fabrication of medicines ready for the use. The equipment produced will be sold to various plants in Belarus. The potential end-users of the project results in the world are: Asta Medica AG, Knoll AG (Germany), Nycomed Austria GMBH (Austria), Novo Nordisk A/S (Denmark), Glaxo Wellcome (UK), Schering-Plough (Belgium), Hoffmann-La Roche Ltd (Switzeland), Sanofi Pharma Bristol-Myers Cquibb SNC (France), Sagmel Inc (USA).
Compliance with ISTC Aims and Tasks.
The project corresponds entirely to ISTC aims and tasks because it:
– is direct to the re-orientation of weapon scientists and engineers to peaceful activities in the field of technologies for the pharmaceutical production;
– promotes the integration of scientists taking part in the project into the international scientific community by means of joint investigations on the physical-chemical action of cavitation in the presence of protectors (together with the collaborators from Italy and Great Britain);
– is aimed to the support of fundamental and applied researches having peaceful purposes, notably in the field of pharmaceutics, and, as a consequence, contributes to the solution of very important national and international problem of health protection;
– will reinforce the transition of the project participants to the way of the self-financing by involving them into a market-based economy and small business related with the production of medicines and ultrasonic equipment.
Scope of Activities.
The duration of the project is 30 months. Total amount of project efforts is 300.5 man/months, including 181.5 man/months of weapon specialists efforts (60.4%). Three institutions take part in the project: ITA NASB (168.5 man*months), IGIC NASB (120.5 man/months) and VSMU (11.5 man/months). The investigations on the tasks 1, 2, 4 will be conducted by the teams from ITA NASB and IGIC NASB, task 3 – by the specialists of VSMU.
Foreign Collaborators Role.
The scope of cooperation with a foreign institutions:
– information exchange in the course of project implementation; submission of comments to the technical reports on a given project;
– cross-checking of results obtained in the course of testing the quality of medicines produced in conditions of ultrasonic activation;
– assistance for project participants to join international meetings; conduction of joint seminars and workshops;
– joint patenting;
– preparation of scientific publications;
– discussions on the commercial perspectives of project results;
– collaborators from the University of Trieste will participate in the investigations of sonochemical processes;
– collaborators from the University of Bradford and BPD will take part in the joint investigations of the processes of medicine fabrication;
– University of Bradford and BPD will use the equipment for ultrasonic disagglomeration, created in the course of the project.
Technical Approaches and Methodology.
During carrying out the project, the experience of the project participants and the results of their previous investigations in corresponding fields will be used. In particular, space-time distribution of disperse phase elements (cavitation bubbles, crystal particles and drops) in a liquid medium will be controlled with a technique developed in ITA NASB and based on the use of a digital video camera connected with an optical microscope and computer (on the registration of particles using the effect of dispersed/reflected light). The same method (in combination with the technique of tracer particles) will be used for the investigation on the liquid media hydrodynamics (velocity and trajectory of microflows and acoustic streams). For detailed studies of the acoustochemical processes the unique methods developed in IGIC NASB will be used which are based on the application of the spectroscopic sonoluminescence device functioning in a regime of quanta counting and the precision potentiostatic device for measuring the electrode potentials and charge flows under the action of cavitation. The equipment for the generation of ultrasonic oscillations of different types in investigated media will be constructed on the modular principle that will provide a transfer to the creation of pilot installation without any essential expenses. Different effects of processing will be provided due to varying the regimes of generation of ultrasonic oscillations (torsion-, transversal- and piston-type, with different degree of anharmonicity, pulse type and others) as well as dimensions and configurations of ultrasound emitters. Frequency and amplitude of oscillations will be controlled with frequencymetry, impedometry and optical microscopy techniques, cavitation activity - with the use of sensitive cavitometer. Structural and physicochemical properties of medicinal preparations will be studied using the arsenal of standard methods (optical and electronic microscopy, X-ray diffractometry, chromatography, IR- and UV-spectrometry, ionometry, mass-spectrometry, sieve analysis). Especial attention will be paid to revealing the impurities and the products of chemical destruction. The stability during storage will be also studied. Standard facilities will be used for the investigation of pharmacological properties of medicines in vitro and in vivo (including the processes of freeing and absorption in the model media). The assistance of foreign collaborators in such testing will be of essential importance. The mathematical model of acoustic-induced crystallisation will be based on the cluster theory of nucleation in supersaturated solutions (taking into account some propositions of the theory developed in ITA NASB). The essential attention will be given to the studying of joint action of low- and high-frequency ultrasound (in accordance with the approach developed in IGIC NASB). In particular, it is proposed to create a high volume concentration of nuclei of cavitation bubbles by high-frequency ultrasound and then to inject energy into them by the low-frequency ultrasound. As a result, the average energy of the bubble collective collapse will essentially rise and, at the same time, the top energy of each inpidual bubble collapse will decrease. It is important that in all these experiments the chemical activity of cavitation will be controlled by two independent methods: by the output of free-radical products (chemical methods) and by in situ analysis of the harmonics of cavitation acoustic spectrum - immediately in the course of sonoinduced crystallisation, extraction and emulsification. The objects of experimental investigations will be both real medicines as well as their models In the experiment on crystallisation, a special attention will be paid to high-molecular organic substances (paracetamol, L-prolin, lomephloxacin, riphampicin), which are extremely difficult to crystallize from solutions under usual conditions (without ultrasound). The experiments on ultrasonic disagglomeration will be aimed to improve the processes of medicines fabrication (paracetamol, ephedrine, etc) by SCF method. Lilac flower, willow rind and other materials will be used in the experiments on extraction. Various types of oil-water systems will be used in the experiments on emulsification.
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