Nanopowder Production and Characteristics Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy BELGAUM Cell No: /4/20121FDP on Nanotechnology, VTU, Belgaum.

Nanotechnology 13/4/2012FDP on Nanotechnology, VTU, Belgaum.2

Nanotechnology may be defined as the ability to work at the molecular level, atom by atom, to create large structure with fundamentally new molecular organization. Many pharmaceutical companies are performing research to decline the particle size. If drugs were able to have smaller particle size they would be better absorbed by digestive tract lining therefore the amount necessary would be reduced making medicines more affordable. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.3 Nanotechnology

Manufacturing Methods Several mechanically or chemically based methods are currently in use to manufacture nanomaterials. Major mechanical methods include ball milling, laser ablation, etching, sputtering, sonification and electroexplosion. Major chemical methods include chemical vapor deposition (CVD), sol-gel processing and molecular pyrolysis. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.4

What is a Nanopowder Nanopowder is a material fabricated on the nanoscale with grain and feature sizes typically under 100 nanometres. The basis of nanotechnology is the ability to form nano-sized particles, for example nanopowders, which are solid particles that measure on the nanoscale. Nanopowders have been of extreme interest in the pharmaceutical field. Drug delivery has been impacted in several ways due to the advances in nanopowder technology. 13/4/20125FDP on Nanotechnology, VTU, Belgaum.

Production of Nanopowder Conventional Methods - Milling, grinding, jet milling, crushing, and air micronization Super Critical Fluids (SCF) 1.Rapid Expansion of Supercritical Solutions (RESS) 2.Supercritical Anti-Solvent (SAS) 3. Aerosol Solvent Extraction System (ASES) 4.Solution Enhanced Dispersion by Supercritical fluids (SEDS) 5.Particles from Gas Saturated Solutions (PGSS) 6.Depressurization of Expanded Liquid Organic Solution (DELOS) 13/4/2012FDP on Nanotechnology, VTU, Belgaum.6

Conventional Methods Conventional methods of particle size reduction include milling, grinding, jet milling, crushing, and air micronization. CM might not accomplish the desired amount of particle size reduction. CM drawback is associated with the physical and chemical properties of the materials undergoing size reduction. Certain compounds are chemically sensitive or thermo-liable, such as explosives, chemical intermediates, or pharmaceuticals which can not be processed using conventional methods due to the physical effects of these methods. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.7

Super Critical Fluid A SCF is defined as a substance above its critical temperature (T) and critical pressure (P). The critical point represents the highest temperature and pressure at which the substance can exist as a vapor and liquid in equilibrium. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.8

Rapid Expansion of Supercritical Solutions (RESS) is a crystallization technique that uses the properties of a supercritical fluid, typically CO 2, as a solvent to facilitate nanopowder production. The RESS process is described in two steps: solubilization and particle formation. The driving force for this process is caused by the rapid depressurization of the supercritical fluid dissolved with the solute of interest through a nozzle to cause fast nucleation and fine particle gene ration 13/4/2012FDP on Nanotechnology, VTU, Belgaum.9 Rapid Expansion of Supercritical Solutions (RESS)

Schematic of RESS Process 13/4/201210FDP on Nanotechnology, VTU, Belgaum.

Supercritical Anti-Solvent The Supercritical Anti-Solvent process (SAS) uses solvent/anti-solvent binary systems to induce the formation of nano and micro-size particles. The supercritical fluid (i.e. CO 2 ) acts as an anti- solvent that causes the crystallization of the solute. The main driving force for this process is the droplet formation, which is caused by the solvent/anti-solvent interaction. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.11

Schematic of SAS Process 13/4/201212FDP on Nanotechnology, VTU, Belgaum.

ASES method involves spraying the solution as fine droplets into the supercritical fluid. The dissolution of the supercritical fluid is followed by a large volume expansion, which is called the anti-solvent effect. This cause a reduction in the liquid solvating power and a sharp increase in the supersaturated within the liquid mixture, which leads to small and uniform particles 13/4/2012FDP on Nanotechnology, VTU, Belgaum.13 Aerosol Solvent Extraction System ( ASES)

Schematic of ASES Process 13/4/201214FDP on Nanotechnology, VTU, Belgaum.

SEDS method was developed to achieve smaller droplet size and intense mixing of supercritical fluid and solution for increased mass transfer rates. The supercritical fluid is used for its chemical properties and as a ‘spray enhancer’ by mechanical effects. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.15 Solution Enhanced Dispersion System (SEDS)

Schematic of SEDS Process 13/4/201216FDP on Nanotechnology, VTU, Belgaum.

Particle From gas Saturated Solution (PGSS) The Particle from Gas Saturated Solution (PGSS) process uses a SCF, usually CO 2, as a solute to crystallize a solution. The PGSS process can be used to create micro and nano sized particles with the ability to control particle size distribution. The driving force of the PGSS is a sudden temperature drop of the solution below the melting point of the solvent. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.17

Particle From gas Saturated Solution (PGSS) This occurs as the solution is expanded from a working pressure to atmospheric conditions due to the Joule-Thompson effect. The rapid cooling produces amorphous powder which is mainly used in pharmaceutical industries. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.18

Schematic of PGSS Process 13/4/201219FDP on Nanotechnology, VTU, Belgaum.

Depressurization of an Expanded Liquid Organic Solution (DELOS) Depressurization of an expanded liquid organic solution (DELOS) is a process that uses a supercritical fluid, as a co- solvent for the formation of micro and nano- sized particles. DELOS process is best for organic solutes in organic solvents and it is particularly useful for pharmaceuticals, dyes, and polymers, where conventional methods of particle size reduction tend to be ineffective due to physical and chemical limitations 13/4/2012FDP on Nanotechnology, VTU, Belgaum.20

Schematic of DELOS Process 13/4/201221FDP on Nanotechnology, VTU, Belgaum.

Applications of Nanopowders Nanopowder has many applications in different fields Ceramics used in nano sized powders are more ductile at elevated temperatures compared to coarse grained ceramics and can be sintered at low temperatures Nano sized powders of iron and copper have hardness about 4-6 times higher than the bulk materials because bulk materials have dislocations. Nano sized copper and silver are used in conducting ink and polymers 13/4/2012FDP on Nanotechnology, VTU, Belgaum.22

Nano powder has various applications in the pharmaceutical and medical field. Drug delivery has impacted by the advancement in nano powders smaller particles are able to be delivered in new ways to patients, through solutions, oral or injected, and aerosol, inhaler or respirator. New production processes allow for encapsulation of pharmaceuticals which allow for drug delivery where needed with in the body. 13/4/2012FDP on Nanotechnology, VTU, Belgaum.23 Applications of Nanopowders

Nanopowder Characteristics 1. Morphology 2. Surface 3. Chemical 4. Other 13/4/2012FDP on Nanotechnology, VTU, Belgaum.24

1. MORPHOLOGY i. Size (Primary particle) ii. Size (Primary/aggregate/agglomerate) iii. Size distribution iv. Molecular weight v. Structure/Shape vi. Structure/Shape(3D structure) 13/4/2012FDP on Nanotechnology, VTU, Belgaum.25

i. Size (Primary particle) a. TEM – Transmission electron microscopy b. SEM – Scanning electron microscopy c. AFM – Atomic absorption spectroscopy d. XRD – X-ray diffraction 13/4/2012FDP on Nanotechnology, VTU, Belgaum.26

ii. Size (primary/aggregate/agglomerate) a. TEM – Transmission electron microscopy b. SEM – Scanning electron microscopy c. AFM – Atomic force microscopy d. DLS – Dynamic light scattering e. FFF – Field flow fractionation f. AUC – Analytical ultracentrifugation g. CHDF – Capillary hydrodynamic fractionation h. XDC – X-ray disk centrifuge i. HPLC – High performance liquid chromatography j. DMA(1) – Differential mobility analyzer 13/4/2012FDP on Nanotechnology, VTU, Belgaum.27

iii. Size distribution a. TEM – Transmission electron microscopy b. SEM – Scanning electron microscopy c. AFM – Atomic force microscopy d. DLS – Dynamic light scattering e. AUC – Analytical ultracentrifugation f. FFF – Field flow fractionation g. HPLC – High performance liquid chromatography h. SMA – Scanning mobility particle sizer 13/4/2012FDP on Nanotechnology, VTU, Belgaum.28

iv. Molecular weight a. SLS – Static light scattering b. AUC – Analytical ultracentrifugation c. GPC – Gel permeation chromatography 13/4/2012FDP on Nanotechnology, VTU, Belgaum.29

v. Structure Shape a. TEM – Transmission electron microscopy b. SEM – Scanning electron microscopy c. AFM – Atomic force microscopy d. NMR – Nuclear magnetic resonance 13/4/2012FDP on Nanotechnology, VTU, Belgaum.30

vi. Stability (3D structure) a. DLS – Dynamic light scattering b. AUC – Analytical ultracentrifugation c. FFF – Field flow fractionation d. SEM – Scanning electron microscopy e. TEM – Transmission electron microscopy 13/4/2012FDP on Nanotechnology, VTU, Belgaum.31

2. SURFACE i.Surface area ii.Surface charge iii.Zeta potential iv.Surface coating composition v.Surface coating coverage vi.Surface reactivity vii.Surface-core interaction viii.Topology 13/4/2012FDP on Nanotechnology, VTU, Belgaum.32

i. Surface area a. BET – Brunauer, Emmett, and Teller method 13/4/2012FDP on Nanotechnology, VTU, Belgaum.33

ii. Surface charge a. SPM – Surface probe microscopy (AFM, STM, NSOM/SNOM, etc) b. GE – Gel electrophoresis c. Titration methods - 13/4/2012FDP on Nanotechnology, VTU, Belgaum.34

iii. Zeta potential a. LDE – Laser doppler electrophoresis b. ESA – Electroacoustic spectroscopy c. PALS – Phase analysis light scattering 13/4/2012FDP on Nanotechnology, VTU, Belgaum.35

iv. Surface coating composition a. SPM – Surface probe microscopy (AFM, STM, NSOM/SNOM, etc.) b. XPS – X-ray disk centrifuge c. MS – Mass spectrometry (GCMS, TOFMS, SIMS, etc.) d. RS – Raman spectroscopy e. FTIR – Fourier transform infrared spectroscopy f. NMR – Nuclear magnetic resonance 13/4/2012FDP on Nanotechnology, VTU, Belgaum.36

v. Surface coating coverage a. AFM – Atomic force microscopy b. AUC – Analytical ultracentrifugation c. TGA – Thermal gravimetric analysis 13/4/2012FDP on Nanotechnology, VTU, Belgaum.37

vi. Surface reactivity a. Varies with nanomaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.38

vii. Surface-core interaction a. SPM – Surface probe microscopy (AFM, STM, NSOM, etc. ) b. RS – Raman spectroscopy c. ITC – Isothermal titration calorimetry d. AUC – Analytical ultracentrifugation e. GE – Gel electrophoresis 13/4/2012FDP on Nanotechnology, VTU, Belgaum.39

viii. Topology a. SEM – Scanning electron microscopy b. SPM – Surface probe microscopy (AFM, STM, NSOM/SNOM, etc.) c. MS – Mass spectrometry (GCMS, TOFMS, SIMS, etc.) 13/4/2012FDP on Nanotechnology, VTU, Belgaum.40

3. CHEMICAL i.Chemical composition (core, surface) ii.Purity iii.Stability (chemical) iv.Solubility (chemical) v.Structure (chemical) vi.Crystallinity vii.Catalytical activity 13/4/2012FDP on Nanotechnology, VTU, Belgaum.41

i. Chemical composition (core, surface) a. XPS – X-ray photoelectron spectroscopy b. MS – Mass spectrometry (GCMS, TOFMS, SIMS, etc.) c. AAS – Atomic absorption spectroscopy d. ICP-MS – Inductively coupled plasma mass spectrometry e. RS – Raman spectroscopy f. FTIR – Fourier transform infrared spectroscopy g. NMR – Nuclear magnetic resonance 13/4/2012FDP on Nanotechnology, VTU, Belgaum.42

ii. Purity a.ICP-MS - Inductively coupled plasma mass spectrometry b.AAS – Atomic absorption spectroscopy c.AUC – Analytical ultracentrifugation d.HPLC – High performance liquid chromatography e.DSC – Differential scanning calorimetry 13/4/2012FDP on Nanotechnology, VTU, Belgaum.43

iii. Stability (chemical) a.MS – Mass spectrometry (GCMS, TOFMS, SIMS, etc.) b.HPLC – High performance liquid chromatography c.RS – Raman spectroscopy d.FTIR – Fourier transform infrared spectoscopy 13/4/2012FDP on Nanotechnology, VTU, Belgaum.44

iv. Solubility (chemical) a. Varies with nanomaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.45

v. Structure (chemical) a.NMR – Nuclear magnetic resonance b.XRD – X-ray diffraction 13/4/2012FDP on Nanotechnology, VTU, Belgaum.46

vi. Crystallinity a.XRD - X-ray diffraction b.DSC – Differential scanning calorimetry 13/4/2012FDP on Nanotechnology, VTU, Belgaum.47

viii. Catalytic activity Varies with nanomaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.48

4. OTHER i.Drug loading ii.Drug potency/functionality iii.In vitro release (detection) iv.Deformability 13/4/2012FDP on Nanotechnology, VTU, Belgaum.49

i. Drug loading a.MS – mass spectrometry (GCMS, TOFMS, SIMS, etc.) b.HPLC – High performance liquid chromatography c.UV-Vis – Ultraviolet-visible spectrometry d.Varies with nanomaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.50

ii. Drug potency/functionality a. Varies with nanomaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.51

iii. In vitro release (detection) a.UV-Vis - Ultraviolet-visible spectrometry b.MS – Mass spectrometry (GCMS, TOFMS, SIMS, etc.) c.HPLC – High performance liquid chromatography d.Varies with nonmaterial 13/4/2012FDP on Nanotechnology, VTU, Belgaum.52

iv. Deformability a.AFM – Atomic force microscopy b.DMA(2) – Dynamic mechanical analyzer 13/4/2012FDP on Nanotechnology, VTU, Belgaum.53

13/4/2012FDP on Nanotechnology, VTU, Belgaum.54 AASAFMAUC BET CHDFDLS Instruments for Nanocharacterstics

13/4/2012FDP on Nanotechnology, VTU, Belgaum.55 DMA(1)DMA(2)DSC ESAFFF Instruments for Nanocharacterstics

13/4/2012FDP on Nanotechnology, VTU, Belgaum.56 FTIR GEGPC HPLCICP-MS ITC Instruments for Nanocharacterstics

13/4/2012FDP on Nanotechnology, VTU, Belgaum.57 LDEMS NMR PALS SEM RS Instruments for Nanocharacterstics

13/4/2012FDP on Nanotechnology, VTU, Belgaum.58 SLSSMASPMTEM TGA UV-VisXDCXPSXRD

RESSPGSSDELOS ApplicationSmall MolHigh purityLarge Mol Role of SCFSolventSoluteCo Solvent Driving forcePressureTemperature Working pressure DependenceSCFMorphologySCF Working temperature dependenceSCFHighestSCF Length of procedure2 Steps 3 Steps Particle sizeMicro & Nano Micro & Nano Micro & Nano EncapsulationYes 13/4/2012FDP on Nanotechnology, VTU, Belgaum.59 Conclusion

THANK YOU Cell No: /4/2012FDP on Nanotechnology, VTU, Belgaum.60