This document discusses spherical crystallization, which is a particle engineering technique that transforms drug crystals into spherical shapes. It has several advantages over traditional manufacturing like reduced processing time and equipment needs. The document outlines the basic materials and methods used, including solvents, polymers, and factors that affect the process. Common evaluation tests and applications are also mentioned, along with references for further reading.

1. Presented by— Under the guidance of—
Pradeep Tiwari Mr. K. Mahalingan
Pharmaceutics Dept.
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2.  Introduction
 Advantages
 Materials and Methods
 Factors affecting the process of SC
 Evaluation
 Application
 References
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3. 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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4. 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.
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5. 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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6. 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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7. 1. Selection of the suitable solvents is tedious
process.
2. Maintenance of processing parameters
(temperature, agitation) is difficult.
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8. I. Drug
II. Polymers
III. 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.
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9. 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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10. 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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11. 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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12. 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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13. 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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14. 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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15. 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:-
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16. 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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17. 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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18. 3. Then the precipitated crystals were simultaneously
agglomerated with the incorporated polymer through
the wetting action of the bridging liquid.
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19. 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

20. 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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21.  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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22.  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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24.  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.
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