Supercritical Fluid Technology In Particle Design

Contents
2

Introduction Standard

Particle design & its Importance

micronization processes Vs supercritical fluid based techniques Supercritical fluid properties Particle formation processes with supercritical fluids Advantages Limitations Future perspective

Introduction
3

Small particles plays a vital role in the design of

conventional drug delivery systems and controlled drug delivery systems Traditionally distinct solid forms are prepared by precipitation, grinding, evaporation, milling, freeze drying, spray drying, etc.

Introduction
4

A newer approach to obtain micro/nano-particles is

represented by the supercritical fluid(SCF) technology Micronisation of API using SCF technology eliminates disadvantages of traditional processes

Particle Design & Its Importance

5

Formation of particles with desired properties

Size Shape Surface

Crystal
Density

Structure

Particle Design & Its Importance

6

Particle design of APIs

Making

solid dosage forms with suitable physicochemical properties Control biopharmaceutical properties Maximize the efficiency and minimize the required dosage Optimize the formulation

is important for

Y.T. et al., Adv. Drug Deliv. Rev. 60:328-338 (2008)

Standard Micronization Processes Vs Supercritical Fluid Based Techniques

7

Standard Micronization Processes

Multiple-step processes Difficult to control Mechanical

Supercritical Fluid Based Techniques

Single step process Easy to control No mechanical stress Little or no adhesion

leads to damage Increased surface energy leads to adhesion and agglomeration

stress

& agglomeration

Supercritical Fluid Properties

8

Temperature & pressure are above the critical P

and T values of component

The

physicochemical properties between the liquid and gas

the supercritical compressible. region

are
SCFs

intermediate
are highly

Near

R.B., Irene Pasquali, Int. J. Pharm. 364:176-187 (2008).

Supercritical Fluid Properties

9

Supercritical carbon dioxide (scCO2) is most widely

used Low and easily accessible critical temperature (31.2C) and pressure (7.4MPa) Inflammable Non-toxic Inexpensive

Supercritical Fluid Properties

10

SCF shows a density value appreciable for the

solvation power, while the viscosity and diffusivity facilitate the mass transfer Homogeneous and opalescent system without phase separation The solvent like properties are beneficial for drug solubilisation, polymer plasticization and extraction of organic solvents or impurities

Particle Formation Processes With Supercritical Fluid

11

Requirements of an ideal particle formation process

Operates

with relatively small quantities of organic solvent(s) Molecular control of process Single step, scalable process for solvent-free final product

P. York. Pharm. Sci. Technol. Today. 2:430-440 (1999).

Particle Formation Processes With Supercritical Fluid

12

Ability

to control desired particle properties

Suitable

for wide range of chemical types of

for preparing multi-component

therapeutic agents and formulation excipients

Capability

system
GMP

compliant process

Particle Formation Processes With Supercritical Fluid

13

Table 1 : Summary of available Supercritical fluid technology

Process Role of supercritical fluid
Solvent
Antisolvent Antisolvent Antisolvent/disp ersing agent Solute

Role of organic solvent

Co-solvent
Solvent Solvent Solvent/nonsolvent _

Mode of phase separation

Pressure/temper ature-induced Solvent-induced
Solvent-induced Solvent-induced Pressure/temper ature/solventinduced

1. RESS
2. GAS/ SAS 3. ASES 4. SEDS 5. PGSS

S.-D. Yeo, E. Kiran. A review. J. Supercrit. Fluid. 34:287-308 (2005).

1. The Rapid Expansion of Supercritical Solution (RESS) Process

14

Mechanism

Saturation of SCF with substrate(s)

Depressurizing the solution through heated nozzle

Rapid nucleation of the substrate(s)

Product

J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

15

RESS Equipment

Process Variables
Supersaturation

ratio
Temperature Pressure

J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

1. The Rapid Expansion of Supercritical Solution (RESS) Process

16

Factors influencing particle properties

Solute

solubility in SCF of orifice (expansion device) conditions in precipitator phenomena during expansion

Dimensions

Pressure/temperature Agglomeration Phase

process path followed during expansion

P. York. Pharm. Sci. Technol. Today. 2:430-440 (1999).

2. The Gas Anti-solvent (GAS) or Supercritical Antisolvent (SAS) Process

17

Mechanism
Step 1
Antisolvent Solution of Active Substance

Step 2
Mixing, expansion and supersaturation of solution mixture

Step 3
Solute precipitates in microparticles
I. Pasquali et al., Adv. Drug Deliv. Rev. 60:399-410 (2008).

18

GAS/SAS Equipment

Process variables
Rate of

Temperature

addition of antisolvent

and pressure in precipitator

J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

2. The Gas Anti-solvent (GAS) or Supercritical Antisolvent (SAS) Process

19

Factors influencing particle properties

Solute Solute Degree Organic

solubility in organic solvent insolubility in SF of expansion of organic solvent in SF solvent/SF antisolvent ratio

P. York. Pharm. Sci. Technol. Today. 2:430-440 (1999).

2. The Gas Anti-solvent (GAS) or Supercritical Antisolvent (SAS) Process

20

Rate

of addition of SF antisolvent conditions in precipitator followed during particle process path

Pressure/temperature Phase

nucleation

3. Aerosol Solvent Extraction System (ASES) Process

21

Mechanism
Step 1
Spraying of active substance & solvent mixture

Compressed SCF (CO2)

Step 2

Dissolution into the liquid droplets due to large volume expansion

Sharp rise in the supersaturation within the liquid mixture

Step 3

Formation of small & uniform particles

J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001)

22

ASES Equipment

Process Variables
Temperature

Liquid solution

pressure
Operating

vessel pressure
J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

3. Aerosol Solvent Extraction System (ASES) Process

23

Factors influencing particle properties

Solute Liquid

solubility in organic solvent solution pressure

Degree

of expansion of organic solvent in SF

of orifice (expansion device)

Dimensions Temperature

of operating vessel

4. Solution Enhanced Dispersion by Supercritical Fluids (SEDS) process

24

Mechanism

Active substance solution

Simultaneous spraying of SCF
Spontaneous contact of liquid solution & SCF

Particle precipitation

S.-D. Yeo, E. Kiran. J. Supercrit. Fluid. 34:287-308 (2005).

25

SEDS Equipment

Process Variables
Type of nozzle

Combination of

processing media
Temperature
J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

4. Solution Enhanced Dispersion by Supercritical Fluids (SEDS) process

26

Advantages
It

can be used for the water soluble compounds

Proteins Peptides

Binary

system can be utilized for scaling-up according to GMP requirement

Suitable

Highly

controlled & reproducible technique

Manufacturing

I. Pasquali et al., Eur. J. Pharm. Sci. 27:299-310 (2006).

5. Particles from Gas-Saturated Solutions/Suspensions (PGSS) Process

27

Mechanism

SCF (CO2) is dissolved in solution or melt of solid

Expansion of gas saturated solution

Generation of solid particles or liquid droplets

J. Fages et al., Powder Technol. 141:219-226 (2004).

28

PGSS Equipment

Process Variable
Pressure

Temperature

J. Jung, M. Perrut. J. Supercrit. Fluids. 20:179-219 (2001).

5. Particles from Gas-Saturated Solutions/Suspensions (PGSS) Process

29

This process is designed for making particles of

materials that absorb supercritical fluid at high concentrations

The technique can be used for formation of

microspheres with an embedded substance

Highly suitable for polymer powder production,

particularly for coating applications

J. Fages et al., Powder Technol. 141:219-226 (2004).

Advantages
30

Supercritical fluid based techniques

mild

operating temperatures step process and recycle of fluid technology free products

single

recovery green solvent

I. Pasquali et al., Eur. J. Pharm. Sci. 27:299-310 (2006).

Advantages
31

SEM images

of nabumetone
(b) After RESS process

(a) Before RESS process

C.-S. Su et al., J. Supercrit. Fluids. 50:69-76 (2009).

Advantages
32

Comparison of particle size and dissolution rate

Mean particle size= 32.6 m (original) Mean particle size= 3.3 m (processed)

KW= 0.0217 min-1 (original) KW= 0.0749 min-1 (Processed)

C.-S. Su et al., J. Supercrit. Fluids. 50:69-76 (2009).

Limitations
33

Poor solubility of pharmaceutical ingredients in supercritical fluids Difficult to scale-up

Particle Nozzle

aggregation
blockage

When co-solvents are used advantage of green technology is

lost
N2O and light hydrocarbons are hazardous and less environment

friendly
P. York. Pharm. Sci. Technol. Today. 2:430-440 (1999).

Conclusion
34

Control over the morphology of the particles is shown to

be better
Feasibility to produce particle under cGMP conditions Up to certain extend limitations of conventional processes

can be overcome by supercritical fluid technology

Solubility issues limits the development of these techniques

and need to be solved

Future Perspective
35

The

potential of this innovative technology still remains

largely unexplored.
The universality of SAS will ensure future developments Multidisciplinary

approach

should

be

focused

on

thermodynamic and kinetic factors to control physical form of particles

The

concepts

of

clean

or

green

chemistry

and

sustainable technology

Thank You

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