11 Tips on How to Control Crystal Growth in Pharmaceutical Suspensions

Crystal growth, also known as Ostwald ripening is simply the change in the particle size distribution in pharmaceutical suspensions. It a process whereby small particles in suspension seem to disappear and large particles grow after repeated temperature changes in both directions during storage.

Since suspensions are saturated solutions of particulate substance, small changes in temperature that occur during shelf storage may change particle size distribution and polymorphic form of a drug, particularly if the solubility of the drug is temperature-dependent. Therefore, as the temperature is increased, the small particles of the drug will dissolve, which is followed by crystal growth as the temperature is decreased.

The basis for Ostwald ripening is found in an equation and it applies to the equilibrium solubility of small particles:

ln S/S^o = 2Vγ/ rRT

Where S^o is the solubility of infinitely large particles, S the solubility of a small particle of radius r, γ the surface tension, and V the molar volume of the solid.

Crystal growth in pharmaceutical suspensions may cause a drastic change in the particle size distribution that might affect physical stability and bioavailability of suspensions.

How to Control Crystal Growth in Pharmaceutical Suspensions

Crystal growth and changes in particle size distribution can be largely controlled by using one or more of the following procedures and techniques:

1. Selecting a narrow range of particle sizes (1–10 microns).

2. Selecting the highest melting point crystalline form of the drug.

3. Using controlled precipitation techniques rather than high-energy milling to reduce particle size.

4. Using water-dispersible surfactant wetting agents to overcome free surface energy effects.

5. Using a protective colloid (gelatin, gum, cellulose derivative) to form a barrier around the particle.

6. Increasing the intrinsic viscosity of the suspending vehicle.

7. Avoiding temperature extremes during processing and storage.

8. Avoiding conditions of supersaturation of insoluble drug particles.

9. Slowing crystallization techniques instead of using shock cooling or flash evaporation.

10. Avoiding impurities, foreign substances, and exotic recrystallizing solvents.

11. Establishing reproducible, crystallizing conditions in order to reduce consistent material.

References

• Jain, G., Khar, R. and Ahmad, F. (2012). Theory and Practice of Physical Pharmacy. India: Elservier.
• Mahato, R and Narang, A. (2018). Pharmaceutical Dosage Forms and Drug Delivery (3^rd ed.).New York: Taylor & Francis Group, LLC.

How to Control Crystal Growth in Pharmaceutical Suspensions