Crystallization and particle engineering in the pharmacuetical industry
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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.

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CRYSTALLIZATION AND PARTICLE ENGINEERING IN THE PHARMACUETICAL INDUSTRY

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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

  • Basic Concepts of crystallization

  • Particle Engineering


Basic concepts of crystallization

BASIC CONCEPTS OF CRYSTALLIZATION


Supersaturation

Supersaturation limit

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

  • Two distinct rates

    • Nucleation rate

    • Growth rate

  • General factors that affect kinetics

    • Supersaturation

    • Solvent

    • Temperature

    • Impurities

    • Solution viscosity, surface tension


Crystallization kinetics1

Crystallization Kinetics

  • 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

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

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

  • 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


Main objectives of articles reviewed

Main Objectives of articles reviewed

  • 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

  • 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

  • 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

  • (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

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


X ray diffractometry

X-Ray Diffractometry

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


Aerodynamic particle size analysis

Aerodynamic Particle size analysis

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


Crystallization and particle engineering in the pharmacuetical industry

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

  • 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

  • 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

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


Particle size distribution1

Particle size distribution

  • 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

  • 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

  • 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

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


Conclusion

Conclusion

  • 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.


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