“RESEARCH – CREATE – INNOVATE” INITIATIVE

Project Description

The object of the project is the development of an innovative industrial synthesis of two commercial targets from renewable raw materials (sugars), using the principles of flow chemistry and process intensification, in order to generate new technical knowledge in a field of high added value, providing additional competence and exporting momentum to the Greek generics sector, and assisting the development of increasingly valuable and compensable professional skills and proficiencies by the present and upcoming domestic scientific workforce.

The use of renewable raw materials for the industrial synthesis of Active Pharmaceutical Ingredients combines the availability of natural resources with highly controlled synthetic procedures. The enhancement of this approach with innovative synthetic transformations and with the inherent advantage of flow chemistry and continuous manufacturing is prone to provide a competitive edge, particularly in the case of commercial targets with high industrial production costs, currently produced from expensive raw materials with low efficiency and considerable environmental impact.

Pharmathen R&D API Operations, through collaboration with the University of Thessaloniki, in this project, and parent company Pharmathen, will strengthen the cooperation between the research sector and the pharmaceutical formulations industry (FDF), aiming at the vertical integration of research in the development of a Greek generic. The company systematically invests in applied industrial research in generic APIs and intermediates. Within the present project, the investment in the disruptive technology of flow chemistry and continuous manufacturing is strengthened internally, but also expanded to the Academic Research Community for the first time in Greece.

Pharmathen R&D API Operations boasts a portfolio of products with high added value, innovative and competitive processes, and has contributed to Drug Master File submissions to the European Authorities for several products and an expanding network of manufacturing and commercial partners in Asia and Europe. The highly trained team of applied industrial research and the state-of-the-art laboratory infrastructure are the driving force behind the numerous products currently and shortly at commercial production stage, and the relevant patent protection.

The research team in the University of Thessaloniki has been a consistent point of excellence in the field of organic synthesis and particularly in the chemistry of sugars, led by prominent Professor John K. Gallos.

Object and Objectives of the Project

The components of the drugs that are responsible for their biological action are known as Active Pharmaceutical Ingredients (APIs) and usually represent a significant percentage of the cost of the final formulation. The current challenge, in terms of their industrial scale composition, is to optimize the efficiency, safety and environmental impact of production processes, but also to meet the requirements for structural complexity, low commercial cost, marginally excellent quality and procedural / regulatory / legal compliance of the procedures followed.

Synthetic organic research has highlighted the possibility of using naturally available optically active substances (mainly sugars) as the source of the complexity of the chemical structures of many of today's Pharmaceutically Active Substances. This strategic approach has been combined with the development of innovative stereoselective methodologies, in order to maintain the available structural and chemical information already carried by the raw materials, but also to exploit this information for the further integration of synthetic dynamics and flexibility, and therefore in molecular constructions. At the same time, the wide availability and high rate of renewal of these natural resources is a significant advantage in terms of the burden on the natural environment and the overall environmental footprint in relation to pre-existing synthetic strategies. Therefore, the industrial application of the chemistry of sugars for the synthesis of Pharmaceutically Active Substances and their intermediates can contribute to the viability of the process in both environmental and economic terms.

This project aims to implement new synthetic methodologies using renewable raw materials (sugars and their derivatives) for the development of an industrially applicable process for the production of commercial target molecules, which will maximize the improvement of metric characteristics and data on efficiency and viability. compared to existing ones. In particular, the proposed project focuses on two such objectives, arising from Pharmathen's established internal procedures for evaluating and selecting objectives, a glycosyl donor and an advanced synthetic intermediate of the pharmaceutically active substance sacubitril.

This project specifically aims to:

1. Study the activity and selectivity of glycosyl donors and glycosylation methodologies.
2. Develop an innovative methodology from renewable raw materials for the synthesis of chiral intermediates that can be used for the preparation of sacubitril.
3. Study the innovative approaches to continuous flow chemistry, the application and evaluation of their competitiveness for the industrial production of commercial objectives.
4. Escalate the methodology and the development of a competitive and original industrial production process of two commercial objectives: a glycosyl donor and an advanced sacubitril intermediate.
5. Immediately disseminate and utilize the research results and secure the expected innovation and new intellectual property.

From the above objectives, it is clear that the subject of this project is in the priority area for Health and Medicines, and especially in the thematic area concerning the development of generic value-added products, with a particular priority the strengthening of innovation in the production process of the medicinal product. In addition, the utilization of the results of the proposed project will directly contribute to the development of new pharmaceutical products of high added value and exportability, which is also an overall goal of the program.

Project Implementation Methodology

Glycosylation: The structural and electronic characteristics of the groups that make up the glycosyl donor will be studied, as they significantly affect both the yield and the level of stereoselectivity of the reaction, usually leading to mixtures of α- and β-anomeric glucosides. The stereoselectivity of the reaction is of major importance, therefore the nature of the leaving group, the protecting groups and the activator as well as the experimental conditions of the reaction require a thorough experimental study to achieve optimization of the result. The proposed study of activity and selectivity of the glycosylation methodologies will focus on the optimization of the structural characteristics of the donor and the corresponding experimental conditions of its preparation, depending on the optimization of the yield parameters and stereoselectivity of the glycosylation specificity and glycosylation reaction with selected glycosyl receptors of all three species (N, O and C). With a given prestige and known value in this subject, the research team of the Aristotle University of Thessaloniki, led by Professor Mr. Gallos, is the most appropriate choice for conducting this study.

Sugar derivatives as synthetic intermediates: Sacubitril is an inhibitor of the enzyme neprilysin. The proposed retrosynthetic analysis is designed based on disconnections leading to chiral and appropriately activated intermediates. The synthetic approach of the present project is designed to combine stereoselective mechanisms, leading to highly complex structures in just a few steps, with the effective management and exploitation of the chemical dynamics pre-existing in sugar derivatives. These synthetic pathways are based on the scientific experience of Pharmathen's research team, and especially of the corresponding Aristotle University of Thessaloniki, on sugar chemistry, are based on innovative structural transformations and reaction sequences, and incorporate the logic of economy of chemical stages (shortcut synthesis), in order to enable their direct application in the industrial composition of sacubitril.

Development of industrial production processes: Development of a production process suitable for application on an industrial scale, which meets a number of sustainability requirements: in terms of the total cost of raw materials and industrial processes of reaction and isolation of intermediates and the product, in terms of the required excellent and controlled quality of the final product, in terms of detailed proof of this quality and certification of its control methods as well as in terms of personnel safety when using active reagents and carrying out large-scale processes and the overall environmental footprint of this industrial activity. The extensive experience gained by its research team of Pharmathen R&D API Operations during the last 10 years of successful activity in this field, ensures the achievement of project objectives related to the development of sustainable industrial production processes.

Continuous flow chemistry: A study of the application of continuous flow chemistry in order to improve the results of the planned transformations, but also the search for new and advantageous synthetic approaches to the target molecules of the project. The supervision of this particularly demanding activity is intended to be undertaken by Assistant Professor Mr. Zografos, with significant experience in the control of complex chemical transformations. The results of this laboratory research in flow chemistry will be applied directly by the laboratory of Pharmathen R&D API Operations, as it already has the appropriate equipment of continuous flow of pilot scale and basic experience of 2 years in the relevant procedures.

Description of work units and deliverables

Summary Presentation of Work Units (WU) and Deliverables
 

WU1 - Study of activity and selectivity of glycosylation methodologies

Deliverables:

1. Glycosylation methodologies from renewable raw materials (Reference - AUTh)
2. Implementation and evaluation of the competitiveness of glycosylation methodologies in commercial objectives and planning of their exploitation strategy (Report - Pharmathen)

WU2 - Innovative synthetic approaches to sugar derivatives

Deliverables:

1. Innovative synthetic methodologies for the preparation of sugar derivatives as advanced synthetic intermediates of pharmaceutically active substances (Reference - AUTh)
2. Implementation and evaluation of the competitiveness of sugar derivatives synthesis methodologies for commercial purposes and planning of their exploitation strategy (Report - Pharmathen)

WU3 - Study, application and evaluation of continuous flow chemistry in key stages of synthetic methodologies

Deliverables:

1. Design, implementation and evaluation of the competitiveness of continuous flow chemistry for the industrial production of commercial targets (Reference - Pharmathen)

WU4 Development of a process for industrial production of a commercial target - glycosyl donor

Deliverables:

1. Commercial Target Industrial Production Process - Glycosyl Donor (Reference -Pharmathen)

WU5 - Development of industrial production process for commercial purpose - advanced synthetic intermediate

Deliverables:

1. Commercial Target Industrial Production Process - advanced sacubitril synthetic intermediate (Reference - Pharmathen)

Expected results

The expected results of this project refer to the production and consolidation of new scientific knowledge, during WU 1, 2 and 3, and to its transformation into a commercially viable innovation, as deliverable in WU 4 and 5.

In particular, WU1 research information will be obtained from the study of the parameters governing glycosylation reactions and their effect on yield and selectivity, and will be aimed at optimizing the yield and selectivity of the preparation reactions of the appropriate glycosylate donor for selected species. , which lead to target molecules of commercial value. The conclusions of the WU2 synthetic study are expected to describe the optimal laboratory synthetic approach to the selected advanced structural intermediate of sacubitril. In the context of focused WU3, the application of continuous flow chemistry to appropriately selected synthetic stages of WU1 and 2 aims to investigate and evaluate specific interventions in terms of their impact on the metric characteristics of an industrial composition of project target molecules.

The use of new stereoselective synthetic approaches for the conversion of sugars into chiral and activated intermediates, is a significant extension of existing knowledge and methodology and its extension to the composition of complex substrates. At the same time, the application of stereoselective methodology in the development of a competitive production process for the synthesis of drugs from renewable raw materials and the application of the principles of continuous flow processes in organic synthesis, is an important development of current industrial practice, and therefore innovation that can be exploited. intellectual property with high return and added value.

Based on the above potential advantages of the methodology, the purpose of WU 4 and 5 is to transform the produced knowledge into sustainable production processes with a comparative advantage over the existing ones, so that it is possible to transfer the produced technology directly on a pilot and commercial scale, its utilization for the direct commercial exploitation of the produced innovation and the maximization of the return on total investment (return on investment) in the present business venture.