Crystal Growth Mechanism And Prevention Of Crystal Growth

Presented by V.Madhu Dep't of pharmaceutics. Skc college of pharmacy

CONTENTS Introduction Crystal growth mechanism Crystal growth in disperse systems Factors affecting crystal growth Crystal growth inhibitors Prevention of crystal growth Conclusion References

Introduction :

In pharmaceutical formulations crystal growth is a destabilizing process , during the storage. Crystal growth in pharmaceutical Suspensions may cause a drastic change in the particle size distribution that might effect physical stability and bioavailability of suspensions. Crystal growth in Aerosols may results in valve clogging and inaccuracy of drug. In sterile products like Ophthalmic preparations produces ocular irritation. In Parenterals, may results in difficult syringeability and injectability of drug, also affect intended performance of product.

Definition of CRYSTAL:

A crystal can be defined as a solid particle, which is formed by solidification (crystallization) process (under suitable environment) in which structural units are arranged by a fixed geometric pattern or lattice.

CRYSTAL GROWTH MECHANISM

Crystal growth is a layer by layer process, which involves creation of nuclei, followed by growth of nuclei into macroscopic crystals. The formation of crystals from solutions involves three steps A. Supersaturation B. Nucleus formation C. Crystal growth

Supersaturation:
When the solubility of a compound in a solvent exceed the saturation solubility, the solution becomes supersaturated and the compound may crystallize.

Theory explains super saturation postulates a definite relationship between concentration and temperature at which crystals will spontaneously form in an unseeded solution.

Stable zone: Metastable zone: Unstable zone:

Miers theory states that in a solution completely free from any foreign particles spontaneous nucleation occurs at supersaturation and not near the saturation concentration.

Nucleation :
once supersaturation is achieved, nucleation is a next essential step for crystallization to occur. in supersaturated solution to form a clusters and to give lattice arrangement finally to form a nuclei this process called as nucleation.

Types: primary nucleation Secondary nucleation

Crystal growth :

Crystal growth As stable nuclei form, they grow into macroscopic crystals. This portion of the crystallization process is known as crystal growth. This process consists of several stages through which the growth units pass.

These include the following: 1. Adsorption of the growth unit at the impingement site.

2. Diffusion of the growth units from the site of impingement to a growth site. 3. Incorporation into the lattice.

The total phenomenon of crystal growth has been explained on the basis of various theories as follows. surface energy theory diffusion theory adsorption theory dislocation theory

Crystal Growth in Disperse Systems: Crystal growth in disperse systems may be attributed to one or more of the following mechanisms. 1.Ostwald Ripening : The growth of large particles at the expense of smaller ones, because of a difference in solubility rates of different size particles.

This effect can be expressed by the following relationship S k log---------=-----------So 2.303.r

Where S is the initial solubility of small particles S0 is the solubility rate of large particles at equilibrium r is the particle radius in cm k is a constant that includes surface tension, temperature, molar volume and thermodynamic terms ( k=1.2110-6)

Temperature fluctuation:
Crystal growth due to temperature fluctuations during storage is of importance especially when the suspensions are subjected to temp cycling of 20C or more. These effects depend on the magnitude of temperature change, the time interval and the effect of temperature on the drugs solubility and subsequent Recrystallization process.

Polymorphic transformation:
Drugs may undergo a change from one metastable polymorphic form to a more stable polymorphic form. This leads to the formation of distinct new crystalline entities during storage is possible. For Ex: An originally anhydrous drug in a suspension may rapidly or slowly form a hydrate. These various forms may exhibit different solubilities, melting points.

Factors Affecting Crystal Growth :

Particle size distribution, Dissolution and Recrystallization, Changes in pH and Temperature, Polymorphism and Solvate formation

Crystal Growth Inhibitors :

Crystal Growth Inhibitors Surfactants : Anionic - Sodium lauryl sulfate, sodium dodecyl sulphate, sodium dodecyl benzene sulphonates . Cationic Quaternary ammonium compounds like Benzylkonium chloride, Benzathonium chloride. Nonionics : Tweens, Spans, Carbowaxes (High molecular weight PEGs) Pluronics. Polymers : PVP, PEGs, Poly alcohol, poly ethylene oxide Protective colloids

PREVENTION OF CRYSTAL GROWTH :

1.Selection of particles with a narrow range of particle sizes, such as micro crystals between 1 and 10 mm. 2. Selection of a stable crystalline drug form that usually exhibits lower solubility in water. The crystalline form that is physically most stable usually has the highest melting point. 3. High-energy milling should not be used during particle size reduction. Micro crystals are best formed by controlled precipitation techniques or shock cooling. 4. A water-dispersible surfactant wetting agent dissipates the free surface energy of particles by reducing the interfacial tension between the solid and the suspending vehicle. 5. A protective colloid, such as gelatin , gum, or a cellulosic derivative, is used to form a film barrier around the particles, inhibiting dissolution and subsequent crystal growth. 6. The viscosity of the suspending vehicle is increased to retard particle dissolution and subsequent crystal growth.

7. Temperature extremes during product storage (freezethaw conditioning) must not occur. 8. Supersaturation favours the formation of needle like crystals and should be avoided. 9. Rapid or shock cooling and high agitation favour the formation of thin, small crystals and should be avoided. Slow crystallization by evaporation yields compact crystals. 10. Experimentation with different crystallizing solvents is recommended to change crystal size and shape.

11. Impurities and foreign substances during crystallization affect the reproducibility and aggregation potential of many drug particle systems. 12. Constant crystallizing conditions are essential. Batch-to-batch variation in crystal size and shape is often associated with poor control of processing and crystallization procedures.

CONCLUSION CONCLUSION By this the knowledge and concept of crystal growth naturally forms the basis for understanding how the crystals form and various factors which influence the crystal growth, such an understanding of crystal growth studies widely used to describe how to improve physical stability of pharmaceutical formulations.

REFERENCES :

1. Mullin, J.W. Crystallization; Butterworth-Heinemann Ltd.: Oxford, 2001. 2. Myerson, A.S. Handbook of Industrial Crystallization; Butterworth-Heinemann: Oxford, 2002. 3. Crystallization Technology Handbook; Mersmann; A., Ed.; Marcel Dekker: New York, 1995. 4. Zettlemoyer, A.C. Nucleation; Marcel Dekker: New York, 1969. 5. Perepezko, J.H. Nucleation reactions in undercooled liquids. Mater. Sci. Eng. A. 1994, 178 (12), 105111. 6. Perepezko, J.H. Kinetic processes in undercooled melts. Mater. Sci. Eng. A. 1997, 226, 374382. 7. Fletcher, N.H. Nucleation by crystalline particles. J. Chem. Phys. 1963, 38, 237. 8. Carter, P.W.; Ward, M.D. Topographically directed nucleation of organic-crystals on molecular single-crystal substrates. J. Am. Chem. Soc. 1993, 115 (24), 11,52111,535. 9. Rodrguez-Hornedo, N.; Murphy, D. Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J. Pharm. Sci. 1999, 88 (7), 651660. 10. Ostwald, W. Studien Uber Die Biltong und Umwandlung Fester Korper Z. Phys. Chem. 1897, 22, 289