Waving goodbye to traditional pharmaceutical synthesis

Efficient, scalable and with few by-products – could microwave assisted synthesis become a ‘green’ success story? Professor Anant Paradkar thinks so. Here he tells us why Development of novel pharmaceutical green technologies and process understanding has been the main area of interest for the Centre for Pharmaceutical Engineering Science (CPES) since its establishment in April 2010. These green technologies include microwave assisted synthesis, hot melt extrusion, ultrasound assisted crystallisation, injection moulding and milling. CPES has significant interest in physicochemical property improvement of poorly aqueous soluble drugs by these green techniques. CPES is also actively involved in process understanding using Process Analytical Technology (PAT). The Centre’s drive to explore more and more green technologies for pharmaceuticals has recently developed another green processing technique of microwave assisted synthesis. This technique has been successfully used to develop pharmaceutical cocrystals, and resulted in the first report suggesting use of microwaves for cocrystallisation. Microwaves are electromagnetic waves with a frequency in the range of 0.3 to 300 GHz. These are present between radio frequency and infra-red (IR) frequency in the electromagnetic spectrum. They are less energetic than IR-radiations and cause molecular rotations rather than vibrations, and interactions of microwaves with materials causes heating of the material. Microwaves used for household and industrial applications are of a selective and fixed frequency of 2.45 GHz. In order to be heated by microwaves, the microwave energy needs to be converted into heat – and for that to occur the material must absorb the microwaves, something that is dependent on the material’s dielectric properties. [caption id="attachment_37333" align="alignright" width="200"] Figure1: Schematic representation of microwave assisted cocrystallisation[/caption] Features of microwave assisted reactions:

• Microwave assisted reactions are green synthesis reactions
• Microwaves increase reaction rate
• Selective heating is involved in the process
• Uniform heating takes place during reactions
• Improves purity of the product
• Fewer by-products
• A wide range of temperatures can be used for reactions
• The technique can be scalable for industrial use.

Microwave heating is different from conventional heating for a chemical reaction. In conventional heating, heat is first transferred from an external heating source to the wall of the container containing reactants and solvents, and then to the reacting substances through the solvents. Thus, conventional heating is slow and energy is not utilised efficiently due to presence of thermal conductivity barriers. On the other hand, microwave heating is volumetric (or internal heating) as microwaves directly interact with reacting substances, causing a rapid increase in the temperature of the system. Two important mechanisms are involved in the microwave heating: dipolar polarisation and ionic conduction. In both these mechanisms, when samples are irradiated with microwaves, dipoles or ions of the sample start aligning with the applied field. Before microwave irradiation, dipoles or ions of the molecules present in the sample are in random motion. As soon as the applied field starts oscillating, dipoles or ions present in the sample align and realign with this alternating field. During this process heat is generated due to molecular friction between solvent and solute molecules. Dielectric properties such as dipole moment, polarity, dielectric constant and dielectric loss of the material play an important role in the microwave heating. Capability of particular substances (solid or liquid) to convert microwave energy into heat is governed by its loss factor, tan?. For a given substance, tan? is expressed as ratio of dielectric loss (?’’) to dielectric constant (?’) of that material. Dielectric loss of a substance represents the efficiency of that substance to convert the microwave energy into heat whereas the dielectric constant indicates the power of that substance to become polarised under microwave irradiation. Thus, for efficient microwave absorption and a faster heating reaction, the mixture should have high value of tan?. Materials are categorised as low, medium and high microwave absorbing based on the tan? value. Materials having tan?  < 0.1 are considered as low microwave absorbing while values between 0.1 to 0.5 represents medium absorbing, and  >0.5  high absorbing materials. Here, one should note that solvents with low tan? value can be used as a reaction medium provided that there is some other polar reagent involved in the reaction medium. Key applications of microwaves:

• In organic synthesis: oxidation, alkylation, deacetylation, knoevenagel condensation.
• In inorganic synthesis: nano-sized compounds, porous materials etc.
• Synthesis of graft polymers.
• Pharmaceutical drying processes.
• Extraction of natural constituents.
• Drying of organic materials.
• Waste management: carbonisation of organic waste.

At CPES we have successfully showed the application of microwave energy to synthesise pharmaceutical cocrystals for the first time. Cocrystals are crystalline compounds where two or more molecular species are held together by non-covalent bonds in the same crystal lattice. Cocrystal formation can modify the physicochemical properties and the bulk material properties whilst maintaining the intrinsic activity of the drug molecule. Pharmaceutical cocrystallisation is emerging as an attractive alternative to polymorphs, salts and solvates in the modification of an API during dosage form design. We have reported cocrystals of caffeine-maleic acid synthesis and the relation of different solvents’ physicochemical properties with the cocrystallisation process established¹. Caffeine:maleic acid cocrystals exist in two stoichiometries 1:1 and 2:1. Getting phase pure caffeine:maleic acid cocrystals is a difficult task. We have obtained caffeine:maleic acid 1:1 from water using microwaves. It represents a green approach as no organic solvent is used. Our group has also previously reported caffeine:maleic cocrystals using ultrasound assisted technology. We hypothesise that dielectric heating by microwaves will accelerate and maintain the saturated solution state of reacting components at the crystal interface leading to fast cocrystallisation, (Figure 1). The solubility of reacting components and the dielectric properties of the solvent will determine the form of cocrystal obtained. We have generated almost phase pure cocrystals of caffeine and maleic acid using different solvents. We observed that dielectric and physicochemical properties of solvents play an important role during microwave assisted cocrystallisation. Some solvents show better cocrystal yield while others fail. Two possible explanations for this include the differential solubility of the caffeine and maleic acid in the various solvents, and the varying abilities of the solutions to absorb microwave energy. It could be that some solvents allow heating at a rate which maintains a local saturation state at the reacting interface and enhances the probability of cocrystallisation. During heating by microwaves, two processes take place simultaneously. Firstly, a supersaturated solution with respect to the cocrystal phase forms and secondly some of the solvent will evaporate thereby further increasing the supersaturation. In principle, every molecule of caffeine and maleic acid has to pass through the solution phase before separating as a cocrystal. In other words the process of solution, supersaturation and crystallisation has to be completed in a short time span with a limited amount of solvent. Microwave processing accelerates these steps making it possible to obtain pure cocrystals in some solvents. Microwave assisted crystallisation is a green technology and CPES is working in close proximity with SMEs and pharmaceutical companies using such green technologies for polymorphs and cocrystal screening. We are in the process of publishing more examples of cocrystals and polymorphs through microwave assisted processing. References 1.    Microwave assisted synthesis of caffeine/maleic acid co-crystals: the role of the dielectric and physicochemical properties of the solvent CrystEngComm DOI: 10.1039/C3CE40292D Acknowledgement: UK India Education and Research Initiative (UKIERI) Author: Professor Anant Paradkar holds an Interdisciplinary Chair in Pharmaceutical Engineering Science and is Director of the Centre for Pharmaceutical Engineering Science (CPES), University of Bradford.