Spherical crystallization

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SPHERICAL CRYSTALLIZATION

• Presented by
• Pradeep Tiwari
• Pharmaceutics 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.

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• 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

1. Drug
2. Polymers
3. Good Solvents - which solubilize drug/s. It
   should be volatile, immiscible with non solvent.
4. Non Solvents - which causes precipitation or
   crystallization of drug/s.
5. Bridging liquids - which causes preferential
   wetting of crystals/solids and forms
   liquid bridges during process.

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Methods

• Various methods are available for
  preparation of spherical crystals of Drugs which
  are as follows-
• Solvent Change Method (SC)
• Quasi Emulsion Solvent Diffusion (QESD)
• Ammonia Diffusion Method (AD)
• Neutralization Method

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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-

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

• 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.

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• 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
• Hausners ratio
• Carrs 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
  11-4.
• Mahanty S, Sruti J, NiranjanPatra Ch, Bhanoji Rao
  ME. Particle Design of drugs by Spherical
  Crystallization Techniques. IJPS and
  Nanotechnology 2010 3912-14.
• Patil PB, etal . Spherical Agglomeration- Direct
  Tabletting technique. IRJP 20112(11), 30-35.
• Tiwari S and Verma P. Spherical crystallization-
  A novel drug delivery system. IJPLS 20112(9),
  1065-1068.
• Prathipati S etal . Spherical crystallization
  A method to improve physicochemical properties.
  IJPSRR 201114, 60-63.

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