Plasma-assisted Crystallization
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Plasma can be used for many applications. One novel application is to produce nanoparticles. Learn more by reading my paper: Cold plasma synthesis of high quality organic nanoparticles at atmospheric pressure - N Radacsi, A Van der Heijden, AI Stankiewicz, JH Ter Horst Journal of nanoparticle research 15 (2), 1-13
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Plasma-assisted Crystallization
- 1. Challenge the future Delft University of Technology Plasma-assisted Crystallization For Submicron Crystals with Outstanding Properties Norbert Radacsi, Intensified Reaction & Separation Systems Co-authors: A. I. Stankiewicz, R. Ambrus, Y. L. M. Creyghton, A. E. D. M. van der Heijden and J. H. ter Horst Submicron
- 2. Norbert Radacsi – Plasma-assisted Crystallization 1 Crystals are not perfect! Inclusions Defects Crystal line defect Imperfections RDX crystal with macrosteps generating inclusions
- 3. Norbert Radacsi – Plasma-assisted Crystallization Solubility problems of drugs 2 Smaller crystal Increased surface area VS (1) Saharan, V. A.; Kukkar, V; Kataria, M.; Gera, M; Choudhury, P. M. Int. J. Health Res. 2009, 2, 107–124.
- 4. Norbert Radacsi – Plasma-assisted Crystallization Plasma-assisted Crystallization
- 5. Norbert Radacsi – Plasma-assisted Crystallization What is plasma? • Ionized gas • 4th state of matter • Most common phase in the universe 3
- 6. Norbert Radacsi – Plasma-assisted Crystallization Plasma-assisted Crystallization • Surface Dielectric Barrier Discharge (SDBD) • Uses high voltage electrical power system • Non-thermal atmospheric pressure plasma 4 Electrode Counter electrode Dielectric ~ AC Discharge electrodes Plasma Counter electrode Dielectric ~ AC
- 7. Norbert Radacsi – Plasma-assisted Crystallization • Ar gas carries the solvent aerosol from nebulizer • Plasma heats up the aerosol droplets EVAPORATION • Plasma charges the aerosol droplets DISRUPTION Coulomb fission Evaporation - - - - - - - - - - - -- - - -- - - - - -- - - - - - -- - - - - - Ar+ Ar+ Ar+ Ar+Ar Ar Ar Ar Ar HEAT HEAT 5 Plasma Crystallization mechanism
- 8. Norbert Radacsi – Plasma-assisted Crystallization Plasma aided Crystallization Setup Temp 74 C Flow rate 10 l/min Oscilloscope Ar gas tank Flow meter Collison nebulizer Surface DBD plasma Current meter High voltage probe Capacitor Capacitor AC+DC power supply Pulse generator Thermometer Analyzing PC IGBT TNO ± 5 MΩ DC 6
- 9. Norbert Radacsi – Plasma-assisted Crystallization Application 1: Energetic materials
- 10. Norbert Radacsi – Plasma-assisted Crystallization Reduced sensitivity explosives • Initiation occurs at defects in the crystal structure (hot spots) • High quality explosives have less defects therefore are less sensitive • Nano-sized explosives are considered to contain less defects • Nano-sized crystals have higher quality 7 RDX
- 11. Norbert Radacsi – Plasma-assisted Crystallization 8 550 nm RDX crystals 1 µm Product morphology RDX crystals from Plasma Crystallization 1 µm Agglomerated RDX crystals Low concentration High concentration
- 12. Norbert Radacsi – Plasma-assisted Crystallization Product quality tests Impact sensitivity 9 0 50 100 150 200 250 300 350 400 Frictionloadneeded forignition(N) Conventional RDX 550 nm RDX 0 1 2 3 4 5 Impactenergyneeded forignition(N) Friction sensitivity
- 13. Norbert Radacsi – Plasma-assisted Crystallization Application 2: Active pharmaceutical compounds (API’s)
- 14. Norbert Radacsi – Plasma-assisted Crystallization Submicron-sized active pharmaceutical compounds • Higher surface area • Higher dissolution rate • Higher bioavailability • Reduced side-effects 10 NIFLUMIC ACID
- 15. Norbert Radacsi – Plasma-assisted Crystallization 400-900 nm Niflumic acid Product morphology Niflumic acid from Plasma Crystallization 11 1 µm 5 µm 6 µm Niflumic acid aggregate 1 µm 1 µm
- 16. Norbert Radacsi – Plasma-assisted Crystallization Plasma-made excipient • Poloxamer 188: • a=80 • b=27 12 Poloxamer 188 3 µm
- 17. Norbert Radacsi – Plasma-assisted Crystallization 13 At pH 1.2 (simulated gastric juice) 14 mg/50 ml Dissolution profile 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 120 DissolvedNIF[%] Time [min] Submicron-sized NIF Conventional NIF Conventional NIF +Conventional Mannitol and Poloxamer
- 18. Norbert Radacsi – Plasma-assisted Crystallization 13 At pH 1.2 (simulated gastric juice) 14 mg/50 ml Dissolution profile 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 120 DissolvedNIF[%] Time [min] Submicron-sized NIF Submicron-sized NIF +Conventional Mannitol and plasma-made Poloxamer Conventional NIF +Conventional M +plasma-made Poloxamer Conventional NIF Conventional NIF +Conventional Mannitol and Poloxamer
- 19. Norbert Radacsi – Plasma-assisted Crystallization Conclusions • Nano-sized explosive crystals less sensitive? • Nano-sized drug crystals outstanding dissolution rates! 1714 Cold plasma can be used for production of submicron-sized crystals
- 20. Norbert Radacsi – Plasma-assisted Crystallization Thank You for your attention!
- 21. Norbert Radacsi – Plasma-assisted Crystallization 13 DC bias shift Answer: !4000$ !3000$ !2000$ !1000$ 0$ 1000$ 2000$ 3000$ 4000$ 5000$ 6000$ 0$ 1000$ 2000$ 3000$ 4000$ 5000$ 6000$ 7000$ 8000$ 9000$ 10000$ Poten&al)difference)[V]) Time)[µs])
- 22. Norbert Radacsi – Plasma-assisted Crystallization Production rate: Answer: ~ 200 mg/h
Hinweis der Redaktion
- Good morningLadies and Gentleman! I would like to draw your attention to this beautiful diamond crystal with its perfect crystal structure . This is a symbol of perfection, but the truth is that in reality it doesn’t exists.
- They contain imperfections, like inclusions or defects. On the picture we can see an RDX crystal with macrosteps generating inclusions. We all know that inclusions are generally quite big, they are in the micron-sized range. So can we make the crystals better if they are smaller? So…
- Does crystal size matter? Is there any difference between a macro-sized or a nano-sized crystal quality? Or I could say: ‘Do nano-sized...” We think yes. ‘Nano-sized explosive crystals should be less sensitive, making them safer to handle. And nano-sized drugs should have higher bioavailability, making them more effective. But it is not easy to make nano-sized crystals!
- The first application is creating submicron-sized energetic materials, or I could say…
- ...explosives. Reduced sensitivity explosives are the future explosives, because it’s safer to handle them and unwanted initiations can be avoided. We have used 2 military explosives: RDX and HMX. Imperfections are very important if we investigate energetic crystals, because...
- Around 500 nm sized RDX crystals. But if the concentration is relatively high or the potential difference is relatively low, we get hollow sphere crystals. They are probably created because the crystallization starts before the coulomb-fission could happen. The solution droplet is evaporating and crystallization starts where the supersaturation the highest is: at the surface from the droplet. That’s how we get these unusual hollow spheres. If we go back to the previous slide one can see
- To check the product quality sensitivity tests were used. The BAM fallhammer was used to check the impact sensitivity. The explosive is in a small cylinder closed with a pellet. A dropweight hits the pellet and from the drop height and mass we can easily calculate the energy, which was needed for ignition. This movie shows an explosion. And the result were that… donut shaped HMX needs maybe more energy for impact ignition because this shape can absorb energy.
- There are many pharmaceutical compounds which are poorly water soluble. But if we make them nano-sized, they have higher... Our model compound was niflumic acid, a nonsteroidal anti-inflammatory and analgetic drug.
- And the result was also 500 nm crystals with low concentration and high pot. Difference. But when relatively higher solution concentrations or lower potential voltage was applied, unusual rod and ribbon-shaped crystals were observed with the electron microscope. We were thinking about 2 explanation for that. One is that the extreme crystallization conditions, like electric field, charged crystals/droplets or the extremely fast crystallization, which is around 2 ms resulted in a new polymorph of the compound. Other idea is that the orientation of crystal growth was controlled by the electric field between the nozzle and grounded plate. Since niflumic acid has an elongated molecular structure with 3 Fluor atoms at the tail, it might be that the molecules were aligned during the crystallization.
- There are many pharmaceutical compounds which are poorly water soluble. But if we make them nano-sized, they have higher... Our model compound was niflumic acid, a nonsteroidal anti-inflammatory and analgetic drug.
- In the reality certain excipients are added to the niflumic acid in the tablet. These excipients are used to increase the wettability of the drug and prevent aggregation. One can see from the graph that the niflumic acid with the excipients had significantly higher dissolution rate. The reason for that is that the solubility of nano-sized crystals does not increase a lot if they aggregate. When the excipients are present, aggregation is prevented and the nano-sized drug crystals can dissolve very fast.
- In the reality certain excipients are added to the niflumic acid in the tablet. These excipients are used to increase the wettability of the drug and prevent aggregation. One can see from the graph that the niflumic acid with the excipients had significantly higher dissolution rate. The reason for that is that the solubility of nano-sized crystals does not increase a lot if they aggregate. When the excipients are present, aggregation is prevented and the nano-sized drug crystals can dissolve very fast.
- So we arrived to the conclusion where I came back to our research question:
- In the reality certain excipients are added to the niflumic acid in the tablet. These excipients are used to increase the wettability of the drug and prevent aggregation. One can see from the graph that the niflumic acid with the excipients had significantly higher dissolution rate. The reason for that is that the solubility of nano-sized crystals does not increase a lot if they aggregate. When the excipients are present, aggregation is prevented and the nano-sized drug crystals can dissolve very fast.
- In the reality certain excipients are added to the niflumic acid in the tablet. These excipients are used to increase the wettability of the drug and prevent aggregation. One can see from the graph that the niflumic acid with the excipients had significantly higher dissolution rate. The reason for that is that the solubility of nano-sized crystals does not increase a lot if they aggregate. When the excipients are present, aggregation is prevented and the nano-sized drug crystals can dissolve very fast.