plasma-assisted crystallization
TRANSCRIPT
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Challenge the future
DelftUniversity ofTechnology
Plasma-assisted CrystallizationFor Submicron Crystals with Outstanding PropertiesNorbert 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
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Norbert Radacsi – Plasma-assisted Crystallization 1
Crystals are not perfect!
Inclusions Defects
Crystal line defect
Imperfections
RDX crystal with macrosteps generating
inclusions
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Norbert Radacsi – Plasma-assisted Crystallization
Solubility problems of drugs
2
Smaller crystal
Increased surface area
VS
MORE THAN 50% OF NEWLY DEVELOPED DRUGS ARE HAMPERING
SOLUBILITY PROBLEMS1
(1) Saharan, V. A.; Kukkar, V; Kataria, M.; Gera, M; Choudhury, P. M. Int. J. Health Res. 2009, 2, 107–124.
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Norbert Radacsi – Plasma-assisted Crystallization
Plasma-assisted Crystallization
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Norbert Radacsi – Plasma-assisted Crystallization
What is plasma?• Ionized gas
• 4th state of matter
• Most common phase in the universe
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Norbert Radacsi – Plasma-assisted Crystallization
Plasma-assisted Crystallization• Surface Dielectric Barrier Discharge (SDBD)
• Uses high voltage electrical power system
• Non-thermal atmospheric pressure plasma
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Norbert Radacsi – Plasma-assisted Crystallization
• Ar gas carries the solvent aerosol from nebulizer
• Plasma heats up the aerosol dropletsEVAPORATION
• Plasma charges the aerosol dropletsDISRUPTION
Coulombfission
Evaporation
- --
-- - -
--
-- --
-- -- -
-- - --- -
-----
-
--
--
Ar+
Ar+
Ar+
Ar+Ar
Ar
Ar
Ar
Ar
HEAT
HEAT
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Plasma Crystallization mechanism
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Norbert Radacsi – Plasma-assisted Crystallization
Plasma aided Crystallization Setup
20 - 35 W40-70 °C
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Norbert Radacsi – Plasma-assisted Crystallization
Application 1: Energetic materials
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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 quality7
RDX
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Norbert Radacsi – Plasma-assisted Crystallization 8
550 nm RDX crystals
Product morphologyRDX crystals from Plasma Crystallization
Agglomerated RDX crystalsLow concentration High concentration
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Norbert Radacsi – Plasma-assisted Crystallization
Product quality tests
Impact sensitivity
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Friction sensitivity
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Norbert Radacsi – Plasma-assisted Crystallization
Application 2: Active pharmaceutical compounds (API’s)
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Norbert Radacsi – Plasma-assisted Crystallization
Submicron-sized active pharmaceutical compounds
• Higher surface area
• Higher dissolution rate
• Higher bioavailability
• Reduced side-effects
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NIFLUMIC ACID
MORE THAN 50% OF NEWLY DEVELOPED DRUGS ARE
HAMPERING SOLUBILITY PROBLEMS
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Norbert Radacsi – Plasma-assisted Crystallization
400-900 nm Niflumic acid
Product morphologyNiflumic acid from Plasma Crystallization
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1 µm 5 µm
6 µm Niflumic acid aggregate
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Norbert Radacsi – Plasma-assisted Crystallization
Plasma-made excipient
• Poloxamer 188:
• a=80• b=27
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Poloxamer 188
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Norbert Radacsi – Plasma-assisted Crystallization 13
At pH 1.2 (simulated gastric juice) 14 mg/50 mlDissolution profile
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Norbert Radacsi – Plasma-assisted Crystallization 13
At pH 1.2 (simulated gastric juice) 14 mg/50 mlDissolution profile
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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
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Norbert Radacsi – Plasma-assisted Crystallization
Thank You for your attention!
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Norbert Radacsi – Plasma-assisted Crystallization 13
DC bias shift
Answer:
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Norbert Radacsi – Plasma-assisted Crystallization
Production rate:
Answer:
~ 200 mg/h