PREVENTION OF CRYSTAL GROWTH

PREVENTION OF CRYSTAL GROWTH : 

PREVENTION OF CRYSTAL GROWTH By i.venkateswarlu, A.S.N.Pharmacy college, Tenali.

CONTENTS : 

CONTENTS INTRODUCTION FACTORS INFLUENCING & PREVENTION IN SUSPENSIONS OSTWALD RIPENING IN EMULSIONS CRYSTAL GROWTH INHIBITORS AND THEIR MECHANISM OF ACTION CONCLUSION REFERENCES

INTRODUCTION : 

INTRODUCTION In pharmaceutical formulations, crystal growth is a destabilizing process during the storage. Crystal growth in Results in Aerosols Valve clogging and inaccuracy of drug. Ophthalmic preparations Occular irritation. Parenterals Difficulty in syringeability and injectability. 1 Topical pastes Gritty texture during application. 2 Invivo Drug induced crystal nephropathy (eg: Acyclovir, Ciprofloxacin). 3

Crystal growth in Suspensions : 

Crystal growth in Suspensions Source of worry to formulators Cause drastic change in PSD → effect physical stability and bioavailability of suspensions. If a size reduced and unstable polymorph is used to prepare a suspension→ conversion to a stabler form will occur and this result in crystal growth. Sedimentation → local increase in particle concentration→ increased particle growth due to shortened interparticle diffusion distances. 4

FACTORS INFLUENCING & PREVENTION IN SUSPENSIONS : 

FACTORS INFLUENCING & PREVENTION IN SUSPENSIONS The factors affecting the potential for crystal growth in a suspension are: 1) Particle size distribution. 2) Dissolution and recrystallization. 3) Changes in pH and temperature. 4) Polymorphism and solvate formulation. 1

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Ostwald ripening is the growth of large particles at the expense of smaller ones, as a result of a difference in the solubility of the particles of varying sizes. Small particles become smaller, where as large particles become larger upon storage. 3 The ostwald-freundlich equation ln c1/c2 = [2M ﻻ / ρ RT 1/R1-1/R2] where c = solubility of particles of radii R1 & R2 M = molecular weight ﻻ = surface energy of solid ρ = density of solid R = gas constant T = absolute temperature 1) Particle size disrtibution

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The Ostwald-Freundlich equation shows that the solubility (c1) is higher for smaller particles (R1) than the solubility (c2) is for larger particles (R2). 1 Prevention Ostwald ripening can be minimized by minimizing the particle size distribution in the suspension. Selection of particles with a narrower range of particle sizes. Selection of a more stable crystalline form of the drug. Avoidance of the use of high energy milling during particle size reduction. Use of a wetting agent (water dispersible surfactant) in formulation to dissipate free surface energy of particles. 1

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2 ) Dissolution and Recrystallization Recrystallization of dissolved smaller molecules on larger particles occurs during Ostwald ripening. 1 The rate of dissolution is slower for larger particles compared to smaller particles. 2 Too much surfactant causes drug to be solubilised & precipitated. 1

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Prevention checking surfactant conc. & HLB, changing content of suspension vehicle. protective colloids, such as gelatin, gums or cellulosic derivatives form a film barrier around the particles thus inhibiting dissolution and subsequent crystal growth. Increase the viscosity of the vehicle to retard particle dissolution & subsequent crystal growth. 1 Avoiding temperature fluctuations avoids recrystallization . 3 The exipients that tend to increase the particle solubility should be kept to a minimum. 4

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3) Changes in ph and temperature: changes in p H & temperature causes variable particle sizes and thus leads to crystal growth due to ostwald ripening. 1 p H : P H of a solution effects dissolution rate of crystals along with crystal growth. Maximum crystal growth was found in the neutral solutions & lower crystal growth rates in both acidic & alkaline solutions. E.g., change in p H resulting from mixing trimethoprim solution with phosphate buffer can lead to crystallization. 3

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Temperature: Small fluctuations in temperature can accelerate ostwald ripening. crystal growth due to temperature fluctuations during storage is of importance in suspensions subjected to temperature cycling of 20 0 C or more. 3 Temperature changes results in cooling of an already saturated solution. 1

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Prevention Each dispersion should be examined for p H stability over an adequate storage period. Any changes in the p H values could be indicative of a potential instability problem. 5 Avoidance of temperature extremes during product storage such as exposure to freeze thaw conditioning. 3 Factors controlling the sensitivity of crystalline suspensions to fluctuating temperatures were investigated by using a temperature cycling apparatus. 4 Create protective coating around particles with protective colloids(barriers to free energy). 1

4) Polymorphism and Solvate formulation: : 

4) Polymorphism and Solvate formulation: Drugs may undergo a change from one metastable polymorphic form to a more stable polymorphic form. The formation of distinct new crystalline entities during storage is possible. For e.g., an originally anhydrous drug in a suspension may rapidly or slowly form a hydrate. Crystal growth may also arise when the more energetic amorphous form of a drug exhibits significantly greater solubility in water than the corresponding crystalline forms. 3

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One of the main reasons why crystal polymorphism causes difficulties is that the appearance of new polymorphs is often unexpected. E.g., 2 years after introduction of the anti viral NORVIR drug batches into the market began to fail some final product tests. --The problem was found to be that a new poorly soluble crystal polymorph of the active pharmaceutical ingredient RITONAVIR had formed in these batches. 2 Prevention: Lower interfacial tension to reduce free surface energy of particles. Modify drug precipitation procedure. 1

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OSTWALD RIPENING IN EMULSIONS Increase in droplet size via molecular diffusion can occur even when particles have excellent barriers to coalescence. Stabilization may be achieved by the addition of high boiling point or high molecular weight compositions to the internal phases to reduce the escaping tendency of the diffusible components. It can also be achieved by processing the emulsion so that a relatively monodisperse system results. 1

CRYSTAL GROWTH INHIBITORS AND THEIR MECHANISM OF ACTION : 

CRYSTAL GROWTH INHIBITORS AND THEIR MECHANISM OF ACTION The impurity that slows down crystal growth is called ‘crystal growth inhibitor’. Any substance other than the crystallizing compound is considered as an impurity. E.g., of crystal growth inhibitors: Polymers: poly vinyl pyrrolidine , poly ethylene glycol, poly alcohol, poly ethylene oxide, bovine serum albumin (protein type polymer).

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Protective colloids: Synthetic: SCMC, HPC, HPMC, MC Natural: gelatin, serum albumin, casein, dextrin. Surfactants 8 Anionic Cationic Non ionics sodium lauryl sulphate, sodium dodecyl sulphate benzylkonium chloride, benzathonium chloride tweens, spans, carbowaxes (high mol. Wt. PEGs)

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Mechanism of action: surfactants and polymers act as crystal growth inhibitors if they adsorb strongly on the crystal faces. Thus preventing solute deposition. 6 Protective colloids such as gelatin, gums, or cellulosic derivatives form a film barrier around the particle thus inhibiting dissolution and subsequent crystal growth. 1 The addition of cellulose derivatives, carboxy methyl cellulose, to the suspension has been shown to prevent Ostwald ripening in some circumstances. 2

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CONCLUSION Control over crystal growth is very important in pharmaceutical manufacturing as crystal size significantly effects the handling and formulation of the pharmaceutical product. 2

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REFERENCES 1) Pharmaceutical dosage forms: dispersed systems vol.2 edited by Herbet A.Libermann, Martin A.Rieger & Gilbert S.Banker, pages:7,73,74,189,220,354,360. 2) The physiochemical basis of pharmaceuticals by humphery moynihan, Abina crean, pages:119,120,138,195,196. 3) Modern pharmaceutical vol-I, basic principles &systems-edited by alexander T.florence, Juergen siepmann, Pages:275,384,385. 4) Pharmaceutical emulsions &suspensions-edited by francoise nielloud, Gilbert marti-mestres, pages:119,120,138,195,196. 5) Modern pharmaceutics edited by Gilbert S.banker , christopher T.Rhodes ,pages:251,252.

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6) Colloids in agrochemicals edited by Tharwart F. Tadros, colloids & interface series, p:190. 7) Prevention of Crystal Growth in Acetaminophen Suspensions by the use of Polyvinyl Pyrrolidone and Bovine Serum Albumin by Madjid saeedi, Naser dallalpoor-mohammadi, Djavad farid s DARU Volume 11, No 3, 2003 (http://journals.tums.ac.ir/upload_files/pdf/89.pdf) 8)http://sundoc.bibliothek.uni-halle.de/diss-online/02/03H046/t3.pdf

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