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Microprocessing photovitamin D3 using photo-high-T intensification.

Periodic Reporting for period 1 - Photovitamin Windows (Microprocessing photovitamin D3 using photo-high-T intensification.)

Reporting period: 2015-09-01 to 2017-08-31

Vitamin D (VD3), “sunshine vitamin” is produced in human skin by using sunlight as energy source. VD3 is very scarce in food and, sunscreen are usually used breaking its production. All these hurdles make difficult to reach the daily recommended ingestion/production of VD3, and this epidemic lack can only be balanced with artificial supplements.
Framed in this background, a holistic process improvement was carried out focusing in three pillars: (i) VD3 synthesis, (ii) unreacted 7-dehydrocholesterol (7DHC) recovery after the synthesis, and (iii) direct VD3 crystallization. The environmental impact of all improvements was evaluated through a Life Cycle Assessment (LCA). The novelty of the approach included, among others, the combination of thermal and UV-light intensification in the synthesis step. In this connection, UV-light was supplied using a mercury lamp and UV-laser pulses. The design was guided by productivity and efficiency rules, but also by sustainability, i.e. cost analysis and environmental impact through life-cycle assessment and green metrics (E-factor). This continuous micro-flow photo reactor was fully monitored using an ultrafast on-line sampler-analyser.

As a training objectives and dissemination, Prof. Hessel contributed in improving my skills in several aspects described in the technical report, wchich were considered as essential in my scientific career development plan.
Pillar 1. Synthesis: The study was carried out using two UV-light energy sources: UV mercury lamp and UV laser. LED was finally not used because with the current technology, the pulses are in the order of microseconds which means longer than the living time of the transition state and thus no effect was expected. Then, UV mercury lamp was used in order to check the performance of the conventional UV-lamps when using high pressure and high temperature at the same time (photo-high-p,T) (Paper 1). The use of pulsed UV laser was approached for the first time together with high-p,T (Paper 2). Thus, in addition to the pulsed photo-innovation, the continuous micro-flow photo process offered excellent control over residence time, irradiation, and energy transfer. This study was carried out in collaboration with the Dutch Institute For Fundamental Energy Research.

Pillar 2. Process Automation: An ultrafast on-line sampler-analyser (UHPLC) was coupled and tested with the photo-high-p,T setup. The sampler-analyser was also a prototype provided through an agreement with Agilent Technologies. The tests were performed sampling at different pressures and offered a process automation with easy sampling and short times analysis.
The outcome of pillars 1 and 2 can be summarized in:
+ Paper 1: Micro-flow high-p,T intensification of Vitamin D3 synthesis using an ultraviolet lamp.
+ Paper 2: Laser mediated continuous photo-high-p,T intensification of Vitamin D3 synthesis.

Pillar 3. Unreacted 7-dehydrocholesterol recovery: A procedure for recovering the unreacted 7DHC was designed. The new process gives 85% recovery of 7DHC with 99% crystal purity, without the need to evaporate the synthesis solvent and using friendly and cheap solvents, keeping the yield of VD3 in the same range. The output here will be:
+ Paper 3: Eco-friendly approach to continuously monitored photo-high-p,T production of Vitamin D3.

Pillar 4. Life Cycle Assessment (LCA): The Aspen process design is completed. The impact analysis will follow comparing the conventional process with the one resulted from this project. In this connection, DSM expressed its interest in this research and I visited their plant in Basel. Nevertheless, at the end DSM decided not to involve due to a low overall engagement in research collaboration and being already bound by some commitments. The LCA study highlights the improvements in terms of costs, but also in terms of safety and environment. It probes that high-p,T route follows the lines of Green Chemistry, contributing to energy with GWP and CED in 20-25 %/70-75 % fashion respectively. These results won the Poster Award of the Year 2016 of the International MicroNano Conference (see below). The output of this pillar is:
+ Paper 4: Life Cycle Assessment for continuous photo-high-p,T synthesis of Vitamin D3.
+ Paper 5: Green metrics and life cycle assessment for a new pathway for vitamin D3 synthesis.

Pillar 5. Vitamin D3 crystallization: A direct purification module for the crystallization of VD3 was designed. The main novelty is the possibility to use an in-line solvent swap step coupled to the process before the cooling. This approach comes from the need to change the solvent in order to enhance the supersaturation due to the lower solubility of VD3 in the new solvent. The crystallization was first tested in batch using acetonitrile (Paper 6), and the conditions were set in terms of quantity but also in terms of quality (Paper 7). This study was carried out in collaboration with the Prof. Khinast research group at the Graz University of Technology. In-flow, VD3 particles flow continuously to the filtration step. ~50% (w/w) crystals of VD3 are directly obtained in one run in just one minute of cooling time achieving also process intensification. The polymorphic form as well as the crystals shape and size properties were also described (Paper 8). This crystallization step was also considered in paper 4, in order to give a holistic view of the whole process.
This pillar already gave these 3 publications:
+ Paper 6: Chem Ing Tech 2016, 88, 1213.
+ Paper 7: Chem Eng Tech 2017, 40, 2016.
+ Paper 8: Continuous-flow in-line solvent-swap crystallization of Vitamin D3. Org. Proc. Res. Dev. 2017, accepted

Out of these 8 papers, this project was also recognised with 2 prizes: the “Poster of the Year 2016” at the MicroNano Conference (Amsterdam) and the “Green Pharmaceuticals Award” Mogan Mountain International Summit (China) ( The results were presented in 7 national and international conferences, mainly with oral presentations.
In the light of the outcome, this project gives a new perspective for the process of the synthesis of VD3. The more innovative paths are: (i) open the possibility to use flow chemistry in photo-high-p,T setups, (ii) the substitution of the mercury lamp by laser irradiation, (iii) the possibility to swap the solvent in-line and in-flow, (iv) a new pathway for a future production of VD3 with shorter times, with new kinds of control and monitoring, as well as (v) the possibility to use greener solvents according to the postulates of Green Chemistry. That strengthened the theoretical potential for shorter production time, meaning higher production capability, have higher selectivity, have higher energy efficiency, and also to get directly VD3 in crystalline shape. Even the crystallization of VD3 on its own had not been described before this project, even in batch, and thus is as such already beyond state of the art. All these issues could make this project very attractive for pharma companies and we expect to have the opportunity to follow-up the research progress in future.
Initially the project was planned as a study of the reaction synthesis and a study of crystallization. The process complexity was increased (e.g. considering evaporation), when getting deeper into the topic. Thus, finally a large research program was undertaken which fits the holistic idea given already in the proposal.
Vitamin D3 crystals obtained after the continuous crystalization process