Crystallization and particle engineering in the pharmacuetical industry
Download
1 / 27

CRYSTALLIZATION AND PARTICLE ENGINEERING IN THE PHARMACUETICAL INDUSTRY - PowerPoint PPT Presentation


  • 178 Views
  • Uploaded on

CRYSTALLIZATION AND PARTICLE ENGINEERING IN THE PHARMACUETICAL INDUSTRY. CHE 702 SPRING 2007. Laila Jai Jallo. Outline. Basic Concepts of crystallization Particle Engineering. BASIC CONCEPTS OF CRYSTALLIZATION . Supersaturation limit. Metastable zone. C. E. A. B. F. Concentration.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'CRYSTALLIZATION AND PARTICLE ENGINEERING IN THE PHARMACUETICAL INDUSTRY' - kyoko


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Crystallization and particle engineering in the pharmacuetical industry

CRYSTALLIZATION AND PARTICLE ENGINEERING IN THE PHARMACUETICAL INDUSTRY

CHE 702

SPRING 2007

Laila Jai Jallo


Outline
Outline PHARMACUETICAL INDUSTRY

  • Basic Concepts of crystallization

  • Particle Engineering


Basic concepts of crystallization
BASIC CONCEPTS OF CRYSTALLIZATION PHARMACUETICAL INDUSTRY


Supersaturation

Supersaturation limit PHARMACUETICAL INDUSTRY

Metastable zone

C

E

A

B

F

Concentration

Solubility curve

D

Supersaturation

  • For crystallization to occur, solution must be supersaturated

  • Supersaturation means that at a given temperature, the actual solute concentration exceeds the saturation concentration

  • A supersaturated solution is metastable. All crystallizers operate in the metastable zone

  • Metastable solutions contain clusters of molecules. Clusters grow large with time. Eventually will grow large enough for nucleation to occur.

100%

antisolvent

100%

solvent

Solvent composition


Crystallization kinetics
Crystallization kinetics PHARMACUETICAL INDUSTRY

  • Two distinct rates

    • Nucleation rate

    • Growth rate

  • General factors that affect kinetics

    • Supersaturation

    • Solvent

    • Temperature

    • Impurities

    • Solution viscosity, surface tension


Crystallization kinetics1
Crystallization Kinetics PHARMACUETICAL INDUSTRY

  • Why does it matter?

    • Determines crystal size

    • Determines crystal shape

    • Determines processing time

    • Kinetics information is essential for crystallizer design, continuous crystallization, ...

    • May be important for polymorph control


Crystallization kinetics how does it affect crystal size

Relative nucleation rate vs. growth rate PHARMACUETICAL INDUSTRY

Particle size is reduced by increased nucleation rate and minimized growth rate ---and vice versa

Nucleation rate increases much faster with increasing supersaturation compared to the growth rate

If you want small particles, increase supersaturation and vice versa

Graph

Rate

Supersaturation

Crystallization kineticsHow does it affect crystal size?

Nucleation

  • Growth


Crystallization kinetics how does it determine crystal shape

Aspirin example PHARMACUETICAL INDUSTRY

1 crystal Form

Different crystal shapes depending on solvent

Different dissolution behavior

Crystallization kineticsHow does it determine crystal shape?


Growth of crystals
Growth of Crystals PHARMACUETICAL INDUSTRY

  • Nucleation – “Birth” of a new crystal

  • Crystal Growth – growth of existing crystal

  • Ratio of rate of nucleation to growth controls the size distribution of product obtained


Particle engineering
Particle Engineering PHARMACUETICAL INDUSTRY


Main objectives of articles reviewed
Main Objectives of articles reviewed PHARMACUETICAL INDUSTRY

  • To produce particles for pulmonary delivery

    (1 - 5microns)

  • To design processes with fewer unit operations and that which minimize the adverse effect of the methods on the properties of the drug particles

  • To produce particles with narrow size distribution


In situ micronization of disodium cromoglycate for pulmonary delivery
In-situ-micronization of disodium cromoglycate for pulmonary delivery

  • Materials

    • Disodium cromoglycate(DSCG)

    • Hydroxypropylmethylcellulose (stabilizer)

    • Isoproply alcohol (anti-solvent)

  • Method

    • Crystallization by solvent exchange

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Crystallization procedure
Crystallization procedure delivery

  • 4g/100ml drug dissolved in 1% (w/v) solution of HPMC in water.

  • Anti-solvent isopropyl alcohol (miscible with water) poured rapidly from a beaker into drug solution.

  • Resulting mixture continuously stirred using a magnetic stirrer.

  • Ratio of drug solution to solvent is 1:8, and temperature was room temperature

  • HPMC in solution is adsorbed onto the newly created particle surfaces. This is the particle formation step.

  • Dispersion is spray dried under standardized conditions. Note that spray drying in this process is to dry pre-formed particles and not for particles formation as in the case of solutions spray drying.

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Particle characterization
Particle Characterization delivery

  • SEM

  • Particle size distribution

  • X-Ray diffractometry

  • Aerodynamic particle size analysis

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Sem images
SEM Images delivery

  • (a) jet-milled

  • (b,c) in-situ-micronized

    DSCG

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Particle size distribution
Particle Size distribution delivery

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


X ray diffractometry
X-Ray Diffractometry delivery

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Aerodynamic particle size analysis
Aerodynamic Particle size analysis delivery

Source: H. Steckel et al./European Journal of Pharma. and Biopharma. 55 (2003) 173-180


Production of salbutamol sulfate for inhalation by high-gravity controlled antisolvent precipitation

  • Materials

    • Salbutamol Sulfate

    • Isoproply alcohol

  • Method

    • Crystallization by high-gravity controlled precipitation (HGCP) Through anti-solvent crystallization

Source: H. Chiou et al. /International Journal of Pharmaceutics 331 (2007) 93-98


Crystallization procedure1
Crystallization Procedure high-gravity controlled antisolvent precipitation

  • RPB: a reactor in which two liquid stream feed through distributors are mixed in the center of the packed bed, by high gravity due to centrifugal force.

  • 1. Port for loading initial reagents or to clean the reactor.

  • 2. Outlet to first liquid

  • 3. inlet to first liquid

  • 4. Inlet to second liquid

  • 5. Outlet of RPB

  • Four runs at 50Hz and four different times: 30, 60, 90, 120 minutes were used

  • Resulting suspension was spray dried

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


Particle characterization1
Particle Characterization high-gravity controlled antisolvent precipitation

  • SEM

  • Particle size distribution

  • X-Ray diffractometry

  • Product stability

  • Aerosol performance

Source: H. Chiou et al./International Journal of Pharmaceutics 331(2007) 93-98


Sem images1
SEM Images high-gravity controlled antisolvent precipitation

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


Particle size distribution1
Particle size distribution high-gravity controlled antisolvent precipitation

  • After spray drying, there was a shift of the particle size distribution towards the smaller size.

  • This is due to the high shear at the nozzle which breaks the elongated particles shown by the SEM images above.

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


X ray diffraction
X-Ray diffraction high-gravity controlled antisolvent precipitation

  • After spray drying SS suspension, it’s crystal structure still shows the same x-ray pattern as the raw material.

  • The solution of SS however, after spray drying could give particles of about 4.4µm, but is amorphous.

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


Product stability
Product stability high-gravity controlled antisolvent precipitation

  • a. Amorphous SS powder absorbed 10.1% moisture and then recrystallizes. Recrystallization makes powder poorly dispersible.

  • b. HGCP powder is less hygroscopic (0.6% water uptake at RH of 90%)

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


Aerosol performance
Aerosol performance high-gravity controlled antisolvent precipitation

Source: H. Chiou et al./International Journal of Pharmaceutics 331 (2007) 93-98


Conclusion
Conclusion high-gravity controlled antisolvent precipitation

  • Basic concepts of crystallization like supersaturation, metastable zone, crystallization kinetics-nucleation and growth were discussed.

  • Using solvent exchange method particles of pulmonary delivery sizes were produced

  • Characterizations of the powders produced indicate that they are suitable for pulmonary delivery.

  • Nano particles can be produced from these processes at higher supersaturation.


ad