SPHERICAL CRYSTALLIZATION

Presented by—Pradeep TiwariPharmaceutics Dept.

Under the guidance of—

Mr. K. Mahalingan

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Contents…

Introduction Advantages Materials and Methods Factors affecting the process of SC Evaluation Application References

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Introduction

Kawashima et al(1986) used the spherical crystallization technique for size enlargement of the drug in the field of pharmacy.

Spherical Agglomeration is the novel

particle engineering technique that can transform directly the fine crystals produced in the crystallization process into a spherical shape of drug/s with or without exciepients from good solvent and bridging liquid by addition of a non solvent.

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The traditional drug manufacturing procedures (granulation) involves following steps:-

Crystallization → filtration → drying → formulated powders blending → granulation → drying → tabletting.

This is a slow and time consuming process.

Where as in spherical crystallization the process could be reduced to:-

Crystallization → filtration → drying → dry blending → tabletting. 4

It means less equipment and space, lower labour costs, less processing time, and lower energy consumption in the direct tabletting process.

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Advantages-

1. Micromeritic properties of the drug crystals shall be drastically improved by inducing spherical shape to the crystals.

2. Utilization of this process improves wettability and dissolution rate of drugs.

3. This technique could be used for masking of the bitter taste of drugs.

4. No dose dumping.5. Stirring of drug and exciepients in liquid

medium ensures homogeneity of drug.

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Disadvantages-

1. Selection of the suitable solvents is tedious process.

2. Maintenance of processing parameters (temperature, agitation) is difficult.

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Materials

I. DrugII. PolymersIII. Good Solvents - which solubilize

drug/s. It should be volatile, immiscible with non solvent.

IV. Non Solvents - which causes precipitation or crystallization of drug/s.

V. Bridging liquids - which causes preferential wetting of crystals/solids and forms liquid bridges during process. 8

Methods

Various methods are available for preparation of spherical crystals of Drugs which are as follows-

1. Solvent Change Method (SC)2. Quasi Emulsion Solvent Diffusion (QESD)3. Ammonia Diffusion Method (AD)4. Neutralization Method

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1. Solvent Change Method

Solvent change method involves simultaneous crystallization and agglomeration of two or more drugs from a good solvent and bridging liquid by addition of a non-solvent.

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Steps Involved:- Good solvent + Drug In poor solvent Formation of crystals with

addition of bridging liquid(drop wise) Continuous

agitation Precipitated crystals and aggregation

with bridging liquid

Spherical agglomerates

Enlarged spherical agglomerates

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The Drawback of this system is that it provide low yield because the drug shows significant solubility in the crystallization solvent due to co-solvency effect. This method is not applicable for water insoluble drugs.

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2. QESD Method

In this method affinity between the drug and a good solvent is stronger than that of the drug and poor solvent.

The emulsion is stabilized by the

selection of suitable polymer which is required for proper crystallization.

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Steps Involved:-

Drug + Good solvent Into poor solvent Formation of Emulsion Continuous

agitation Good solvent which act as a bridging

liquid diffuses out into poor solvent

phase

Formation of Spherical agglomerates

Polymeric solution

Stabilized spherical agglomerates

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3. Ammonia Diffusion Method

In this technique ammonia-water system is used as the good solvent and bad solvent is selected depending upon the drug solubilittty in that solvent which is usually acetone.

This technique usually meant for Amphoteric drugs which cannot be agglomerated by conventional procedures .

The whole process is completed in three

stages:- 15

First, the drug dissolved in ammonia water is precipitated while the droplets collect the crystals (Figure I).

Simultaneously, ammonia in the agglomerate diffuses to the outer organic solvent (Figure II).

Its ability to act as a bridging liquid weakens and subsequently spherical agglomerates are formed (Figure III).

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4. Neutralization Method

This technique involves the formation of fine crystals by neutralization and consequently their agglomeration by a bridging liquid.

1. The drug was dissolved in alkaline solution and then poured into an acidic solution containing polymers and bridging liquid under constant agitation.

2. The drug crystals are precipitated out by neutralization of the base with acid.

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3. Then the precipitated crystals were simultaneously agglomerated with the incorporated polymer through the wetting action of the bridging liquid.

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Factor Affecting the process of Spherical crystallization:-

1. Temperature- Temperature has significant influence on the shape, size and texture of the agglomerates .The solubility of drug is affected by the temperature change.

2. Mode and intensity of agitation-The stirring speed must be optimized. High speed agitation is necessary to disperse the bridging liquid through the system. But in some cases increasing stirring rate, may cause reduction in agglomerate formation due to increased disruptive forces. Higher stirring rates produces agglomerates that are less porous and more resistant to mechanical stress. 19

3. Amount of bridging liquid- The spherical agglomeration method has been applied to plenty of drugs, and it has been observed that the properties of spherical agglomerates were very much sensitive to the amount of bridging liquid.

4. Residence time- The time for which the agglomerates remain suspended in reaction mixture effect the agglomerates strength.

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Evalution of Agglomerates:-

Shape and size of agglomerates. Solubility Angle of repose Hausner’s ratio Carr’s index. Porosity Mechanical properties like crushing

strength and friability.

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Application of SC:-

To improve the flowability and compressibility.

For masking bitter taste of drug.

For increasing solubility and dissolution rate of

poorly soluble drug.

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List Of Various Drugs On Which Spherical Agglomeration Technique Has Been Tried For

Improving Tabletability:-

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References:- Gupta MM, Srivastava B, Sharma M, Arya V. Spherical

Crystallization: A tool of Particle Engineering for making drug powder suitable for direct compression. . IJPR and Development 2010; 1:1-4.

Mahanty S, Sruti J, NiranjanPatra Ch, Bhanoji Rao ME. Particle Design of drugs by Spherical Crystallization Techniques. IJPS and Nanotechnology 2010; 3:912-14.

Patil PB, etal . Spherical Agglomeration- Direct Tabletting technique. IRJP 2011;2(11), 30-35.

Tiwari S and Verma P. Spherical crystallization- A novel drug delivery system. IJPLS 2011;2(9), 1065-1068.

Prathipati S etal . Spherical crystallization : A method to improve physicochemical properties. IJPSRR 2011;14, 60-63. 24

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