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

Norbert Radacsi – Plasma-assisted Crystallization 1

Crystals are not perfect!

Inclusions Defects

Crystal line defect

Imperfections

RDX crystal with macrosteps generating

inclusions

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.

Norbert Radacsi – Plasma-assisted Crystallization

Plasma-assisted Crystallization

Norbert Radacsi – Plasma-assisted Crystallization

What is plasma?• Ionized gas

• 4th state of matter

• Most common phase in the universe

3

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

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

5

Plasma Crystallization mechanism

Norbert Radacsi – Plasma-assisted Crystallization

Plasma aided Crystallization Setup

20 - 35 W40-70 °C

6

Norbert Radacsi – Plasma-assisted Crystallization

Application 1: Energetic materials

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

Norbert Radacsi – Plasma-assisted Crystallization 8

550 nm RDX crystals

Product morphologyRDX crystals from Plasma Crystallization

Agglomerated RDX crystalsLow concentration High concentration

Norbert Radacsi – Plasma-assisted Crystallization

Product quality tests

Impact sensitivity

9

Friction sensitivity

Norbert Radacsi – Plasma-assisted Crystallization

Application 2: Active pharmaceutical compounds (API’s)

Norbert Radacsi – Plasma-assisted Crystallization

Submicron-sized active pharmaceutical compounds

• Higher surface area

• Higher dissolution rate

• Higher bioavailability

• Reduced side-effects

10

NIFLUMIC ACID

MORE THAN 50% OF NEWLY DEVELOPED DRUGS ARE

HAMPERING SOLUBILITY PROBLEMS

Norbert Radacsi – Plasma-assisted Crystallization

400-900 nm Niflumic acid

Product morphologyNiflumic acid from Plasma Crystallization

11

1 µm 5 µm

6 µm Niflumic acid aggregate

Norbert Radacsi – Plasma-assisted Crystallization

Plasma-made excipient

• Poloxamer 188:

• a=80• b=27

12

Poloxamer 188

Norbert Radacsi – Plasma-assisted Crystallization 13

At pH 1.2 (simulated gastric juice) 14 mg/50 mlDissolution profile

Norbert Radacsi – Plasma-assisted Crystallization 13

At pH 1.2 (simulated gastric juice) 14 mg/50 mlDissolution profile

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

Norbert Radacsi – Plasma-assisted Crystallization

Thank You for your attention!

Norbert Radacsi – Plasma-assisted Crystallization 13

DC bias shift

Answer:

Norbert Radacsi – Plasma-assisted Crystallization

Production rate:

Answer:

~ 200 mg/h