SEMINAR ON PHARMACEUTICAL FACTORS AFFECTING DOSAGE FORM (PREFORMULATION)

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SEMINARONPHARMACEUTICAL FACTORS AFFECTING
DOSAGE FORM(PREFORMULATION)
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INTRODUCTION

• DEFINITION
• Characterization of physical, chemical and
  mechanical properties of new drug molecule in
  order to develop safe, effective,and stable
  dosage form.
• GOAL OF PREFORMULATION
• To formulate an elegant, safe, efficacious dosage
  form with good bioavailability.
• To formulate new dosage form of already existing
  drug.
• Determination of all the properties of drug and
  the best suitable dosage form for the drug
  molecule.

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PHARMACEUTICAL FACTORSAFFECTING DOSAGE FORMS

• Pharmaceutical factor mainly include those
  parameters of drug which affect the final dosage
  form manufacturing process like..
• Flow property
• Density
• Compressibility
• Hygroscopicity
• Electrostatic charge
• Osmolarity
• Rheology
• Wettability
• Syringabilty

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1)FLOW PROPERTY

• (A) Introduction
• Flow property is an important factor that
  determines the fate of drug molecule.
• Sufficient flow is required for uniformity of
  dosage form. So it is necessary to judge the flow
  of material in preformulation stage of the dosage
  form.
• However extreme increase in flow may improve
  weight uniformity but may reduce content
  uniformity through increased segregation.
• (B) Method of determination
• By Angle of repose
• By hopper flow rate
• By bulk density
• By angle of spatula
• By vibrational capillary method

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LATEST TECHNOLOGY TO DETERMINE FLOW PROPERTY

• REPOSOGRAPH
• It is a stable instrument which at best can only
  indicate comparative flow properties.
• The formation of sharp cone would mean poor flow
  property while a good spread would indicate a
  superior flow property.

• FT (FREEMAN TECHNOLOGY) RHEOMETER
• An instrument for measuring flow property.
• It can discriminate between the samples that
  differ by 1 Moisture.
• Important for optimizing granulation because
  moisture variation have significant impact on
  final product quality.

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• NEW MEASUREMENT SYSTEM TO EVALUATE POWDER
  FLOWABILITY BASED ON VIBRATIONAL CAPILLARY
  METHOD
• Evaluates flowability of micrometer sizes
  particles under actual flow condition.
• The amplitude and frequency of vibration is
  controlled by computer and mass of powder
  discharged from vibrating capillary tube is
  measured by digital balance.
• The mass flow rate is measured by digital
  processing.
• Chemical Abstract ,Jan. 2007, 1469806

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Angle of Repose

• Indirect method of quantifying powder
  flowability,because of their relationship with
  interparticle cohesion.
• It is a maximum angle between the surface of a
  pile of powder horizontal plane.
• Angle of repose is measured by the equation
• tan?h /r
  
• here,
  hheight of conical heap
• 
  rradius of horizontal plane of powder

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DETERMINATION OF ANGLE OF REPOSE
Static angle of repose Fixed height cone, Fixed base cone, Tilting table
Dynamic angle of repose Rotating cylinder Rotating Drum
Drained angle of repose Ledge type, Crater type
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RELATION BETWEEN ANGLE OF REPOSE TYPE OF FLOW
TYPE OF POWDER
Angle of repose Type of flow Type of powder
lt25 Excellent Non cohesive
25-30 Good Non cohesive
30-40 Passable Cohesive
gt40 Very poor Very Cohesive
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HAUSNERS RATIO

• This is a simplex index that can be determined on
  small quantities of powder.
• Hausner-ratio Tapped densityß
  max)
• 
  poured density(Pß min)

Hausner ratio Type of Flow
lt1.25 1.25-1.5 gt1.5 Good flow Moderate Poor flow
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(C) FACTOR AFFECTING FLOW PROPERTY

• Particle size and Particle size distribution
• Particle shape and Surface roughness
• Density and Porosity
• Hygroscopicity
• Electrostatic charge

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(D) IMPROVEMENT OF FLOWABILITY

• By addition of glidant
• By addition of fine or by size reduction
• By wet granulation
• By removing static charge
• By densification with the help of slugging
• Using auger feed equipment
• By addition of flow activator. Eg. MgO
• By use silicon treated powder for Hygroscopic
  moist powder. e.g. silicon coated talc or
  Na-bicarbonate
• By altering process condition like vibration
  assisted hopper or forced feeder
• By use of spray drying Advantose 100 maltose
  powder has improved flow property than MCC by
  using this process.

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2. DENSITY

• (A) INTRODUCTION
• The ratio of mass to volume is known as density.
• Density Mass (gms.)/ Volume (ml.)
• TYPES OF DENSITY
• (a) Bulk density
• (b)Tapped density
• (c)True density
• (d)Granule density - may affect
  compressibility, tablet porosity, disintegration,
  dissolution

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(B) Method of Determination
Parameter Method
1. Bulk density Measuring cylinder
2. Tapped Density Mechanical Device Mercury Displacement
3. True Density Helium densitometer (Helium Pycnometer) Mercury Instrution Porosimetry
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• Bulk density measurement
• It is determined by pouring presieved (40-mesh)
  bulk drug into a graduate cylinder via-a large
  funnel and measuring the volume and weight.
• Tapped density measurement
• It is determined by placing a graduated cylinder
  containing an known mass of drug or formulation
  on a mechanical tapper apparatus, which is
  operated for a fixed numbers of
  taps(about-1000)untill the powder bed volume has
  reached a minimum.

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• Measurement of True Density
• True density can be determined using three
  methods
• displacement of a liquid,
• displacement of a gas (pycnometry), or
• floatation in a liquid.
• The liquid displacement is tedious and tends to
  underestimate the true density.
• Displacement of a gas is more accurate, but needs
  relatively expensive instrumentation. Gas
  pycnometers rely on the measurement of pressure
  changes, as a reference volume of gas, typically
  helium, added to, or deleted from, the test cell.
• As an alternative, the floatation method is
  simple to use and inexpensive.

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• An improved method for fast online measuring of
  density of solid substances
• A densitometer for measuring of bulk density of
  solid liquid consists of one vibrator means, to
  support pre-weighed samples to be tested in
  container with predefined shapes on this vibrator
  atleast one ultrasonic sensor operatively
  connected to control unit such that sensor is
  adapted to transmit and receive reflected
  ultrasonic pulses to ascertain density of samples
  utilizing the said values of the fill levels of
  samples in containers.
• (chemical abstract ,October
  2007)

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(C) CORRELATION WITH FLOWABILITY Carrs
index Tapped density- Bulk density/ Tapped
density

• Hausner ratio Tapped density / Bulk density

• (D) IMPORTANCE
• In case of combination therapy or physical
  mixture ,if both drug or drug excipients have
  different density then creates problem of
  segregation (demixing).
• Important in decide size type of processing
  equipment. E.g. decide size of capsule
  formulation, Suppositories.
• Devereux et.al. compared GI transit time of
  multiple unit formulation of densities 2.8g/cm3
  1.5g/cm3 found significantly delayed gastric
  emptying of heavier pdt.
• (Review article, IJPS,
  sept-oct,2008)

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3. COMPRESSIBILITY

• INTRODUCTION
• Compressibility is the ability of powder to
  decrease in volume under pressure.
• Neumann and Carr developed a simple test to
  evaluate flowability of a powder by comparing the
  poured (fluff) density (Pßmin)and tapped density
  (Pßmax) of a powder and the rate at which it
  packed down.
• Useful empirical guide is given by the Carr's
  compressibility index. here compressibility is
  misnomer since compression is not involved.

• compressibility Tapped density bulk
  density 100 Tapped
  density

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Relationship between powder flowability and
compressibility
SR. NO COMPRESSIBILTY RANGE FLOW DESCRIPTIONS
1 5-15 Excellent (free flowing granules)
2 12-16 Good ( free flowing powder granules)
3 18-21 Fair to passable ( powder granules
4 23-28 Poor ( very fluid powder)
5 28-35 Poor ( fluid cohesive powder)
6 35-38 Very poor ( fluid cohesive powder)
7 gt40 Extremely poor ( cohesive powder)
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(B) The characteristics Of material may be -

• 1. PLASTICITY
• Plastic material are capable of permanent
  deformation, also exhibit a degree of brittleness
  (fragmentability)
• But plastic material will get bonding after
  Viscoelastic deformation.
• 2. FRAGMENTABILITY
• If material is fragmentable, neither lubricant
  mixing time nor dwell time affecting the tablet
  strength.

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• 3. ELASTICITY
• E.g. paracetamol, acetyl salicylic acid
  
• If material is elastic, it rebound when
  compression force is released.
• Elastic material may lead to capping lamination
• They require wet massing to induce plasticity or
  plastic tableting material.
• 4. PUNCH FILMING STICKING
• This may lead to chipping of tablet.

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(C) METHOD OF IMPROVEMENT

• If plastic material add fragmentable excipient
  e.g.. Lactose .
• If Elastic material By plastic tableting
  material Wet granulation ,
  Pre compression.
• If sticky material By change in salt
  form, By using high excipient ratio,
  By wet massing, By
  addition of Mg-stearate.

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• NPTAB Technology
• Innovative technology combining pellet coating
  with direct compression.
• Active drug is sprayed on carrier containing
  sugar sphere these layered spheres are directly
  compressed.
• Multifunctional co-processesed excepients with
  improved compression properties are used for
  improved tabletting performance.
• (CHEMICAL ABSTRACT, July 20,2009,151,
  No.3 63288g)

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4. HYGROSCOPICITY

• (A) INTRODUCTION
• Hygroscopicity - It is the tendency of material
  to absorb moisture from atmosphere be dynamic
  equilibrium with water in the atmosphere.
• Deliquescent - It is the hygroscopic substance
  which absorb moisture from air and they can be
  liquefied by partially or wholly forming
  solution.
• Efflorescent - a substance which loses water to
  form a lower hydrate or become anhydrous is term
  as efflorescent.

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• List of examples
• Hygroscopic Deliquescent
  Efflorescent
• Ephedrine
  atropine
• Hyoscymine
  cocaine
• Phenobarbital
  codeine
• Pilocarpine
  scopolamine
• Physostigmine caffeine
• Glycerinated gelatin PEG base of suppository
  are hygroscopic in nature.

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• (B) METHOD OF DETERMINATION
• To carry out study, sample of compound are
  accurately weighed into container and placed at
  various humid condition for period of upto 2
  weeks.
• If Weight gain Deliquescent or Hygroscopic
• If Weight loss Efflorescent
• Also determined by TGA, GC, KF titration
• Versaperm has deviced a WVTR meter that can
  measure the permeability of package to moisture
  in as little as
• 30 min.so that humidity can be accurately
  controlled.

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• (C) IMPORTANCE
• It affects the flow property.
• It affects compression characteristic ,
  granulation hardness of final tablet.
• It also affects compaction.
• Important in aerosol.
• Affects chemical stability of hydrolysable drug.

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• (E) METHODS OF IMPROVEMENT
• For granulation of hygroscopic material use
  non-aqueous solvent.
• For efflorescent material , use anhydrous salt.
• Add finely powdered adsorbents like MgO or Mg
  carbonate.
• Perform the entire tableting operation under
  controlled humidity condition.
• Store in desiccant, foil, blister, glass bottle.
• Use of Ion-exchange resins.
• Eg. Complexation of Ranitidine with
  Indion234.
• ( Journal of Pharmaceutical Research,
  vol.8.No.2, Apr
  2009112-115)

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• Examples
• Starch is hygroscopic ,but on pregelatinization
  it exhibits lower propensity for moisture, thus
  providing excellent stabilization for moisture
  sensitive active drugs.
• A new multifunctional excipient, Galen IQ.
• Problem associated with Hygroscopic material
• Stick- slip mechanism of powder flow
• It is pulsatile flow of granular material. It
  causes problem in die filling for tableting.
• The length of stick slip event increases with
  moisture content, increasing load, etc .
• (Chemical
  Abstract vol.1469803)

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• 5. ELECTROSTATIC CHARGE
• INTRODUCTION
• Electrostatic charges are the consequence
  of classic attraction repulsion effect between
  the charges.
• Electrostatic charge is produced
• By separation of positive negative charge
• By mechanical impact
• By friction between two surface
• By rupturing of particle
• By separation of solid liquid surface
• Pharmaceutical processing procedure such
  as mixing,micronizing, milling, sieving, rubbing,
  compressing, spray drying congealing, pan
  coating packaging can induce static charge.

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• (B) METHOD OF DETERMINATION
• INOSTAT, measures negative charge on the surface
  in volts/cm, when material is flowing from
  hopper.
• ELPI(13-stage Electrical Low Pressure Impactor),
  gives detailed charge profile of MDI aerosol
  particles. This has practical application on lung
  deposition of MDI aerosol.
• Electrostatic testers which consists of
  electrostatic voltage sensing probes.

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• C) FACTORS AFFECTING STATIC CHARGE
• Effect of particle shape. e.g.- PCM
• Fine crystalline form gtCrystalline form gt
  Granules with EC gt Granules with starch.
• Effect of tablet excipient. e.g.- Acetaminophen
  with
• mannitol() gt SDL() gt Mg stearate()
• Effect of Particle size.
• Effect of moisture.

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• (D) IMPORTANCE
• In preformulation of suspension .
• Affects flow property of powder.
• Affects mixing process.
• For thermal stability of emulsions.
• It may damage tablet machine.
• It may affect compression coating.

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E) METHOD OF REMOVAL OF STATIC CHARGE

• Addition of diluents or lubricant.
• Surface coating of particle with amphiphilic
  substance of o/w type. Eg Aerosol.
• Use crystallization method using more polar
  solvent.
• By granulation.
• Store under influence of air with sufficient
  humidity.
• Super critical fluid technology.
• Example Poloxamer reduce electrostatic charge on
  the surface of polystyrene.

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6. OSMOLARITY

• A) INTRODUCTION
• It is a colligative property
• DEFINITIONS
• Osmoles No. of osmotically active particles in
  solution.
• Osmolarity osmoles or milliosmoles per liter of
  solution.
• Osmolality osmoles or milliosmoles per kg of
  solvent.
• Isoosmotic when two different solutions are
  separated by semipermiable membrane have same
  osmotic pressure so called as isoosmotic.
• Isotonic when two different solutions are
  separated by biological membrane have same
  osmotic pressure so called as isotonic.

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(B) Method of Determination

• Osmolality should be measured carefully with a
  vapour pressure or freezing point osmometer or
  cryoscopic osmometer.
• Vapour pressure osmometer Measures concentration
  of osmotically active particles that reduce V.P
  of solution.
• Membrane osmometer This invention is directed to
  a membrane osmometer for direct measurement of
  osmotic pressures.
• ( United States Patent
  4455864 )
• Clifton nanolitre osmometer

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• (C) IMPORTANCE
• Normal serum osmolality to be 285
  mosmol/kg.
• Maintain osmolarity by 1variation.
• It should be proper maintained in
• Oral nutrition fluid
• Peripheral infusion
• Parenteral product
• Ophthalmic preparation
• Administration of Paratonic solution can lead to
  crenulation or lysis of RBC.

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7. RHEOLOGY

• (A) DEFINITION
• It describes flow of liquid and/or
  deformation of solid under stress.
• (B) TYPE OF FLOW
• Newtonian flow
• Non Newtonian flow

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• NEWTONIAN FLOW
• It is a flow in which a direct proportionality
  exists between shear stress and shear rate. E.g.
  water, simple organic liquid dilute suspension
  , Glycerin.

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• NON NEWTONIAN FLOW
• Where there no direct relation between shear
  stress and shear rate.
• There are three type
• (1) PLASTIC FLOW
• It is the Newtonian system at shear stress
  above yield value. Eg. Flocculated suspension.
• (2) PSEUDOPLASTIC FLOW
• Here yield value not associated .As
  applies shear stress increasing, viscosity
  decreases and disarranged molecules begin to
  align their long axes inline of molecules.
• Eg. Aq. Dispersion of tragacanth, Na-CMC,
  PVP.
• (3) DILATANT FLOW
• Opposite to pseudoplastic flow
• Increase in the shear rate, increasing in
  resistance to flow as viscosity increases.
• E.g. deflocculated suspension of Mg magma

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RHEOGRAM
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• (C) DETERMINATION OF VISCOSITY
• Capillary viscometer
• Falling sphere viscometer
• Cup and bob viscometer
• Cone and plate viscometer
• Brook field viscometer
• Ultrasonic Shear Rheometer - For analysing
  protein solution rheology.
• Instron Capillary Rheometer - Measures viscosity
  as a function of rate of shear temp at a high
  rate of shear.

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• D)IMPORTANCE
• 1 FLUID
• For mixing
• For particle size reduction of disperse system
• Passing though orifice, pouring, packaging in
  bottle, passing though hypodermic needle.
• Flow though pipe
• Physical stability of disperse system
• 2 QUASISOLIDS
• Spreading and adherence to skin
• Removal from jar
• Capacity of solids to mix with liquid
• Release of drug from base

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• 3 SOLID
• Flow of powder from hopper and into a die cavity
  in tableting or in encapsulation
• Packagability of powder or granules solids.
• 4 PROCESSING
• Production capacity of the equipment
• Processing efficiency
• THIXOTROPHY
• In thixotropy apply shear stress convert gel
  sol remove shear stress convert sol gel,
  means gel to sol to gel.
• Application - for stability of suspension
• e.g. conc. Parental suspension containing 40-70
  w/v of procaine penicillin G

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8. WETTABILITY

• (A) INTRODUCTION
• Wettability of a solid is an important property
  with regards to formulation of solid dosage form.
• Adsorption at solid surface is involved in
  wetting detergency.
• It may influence granulation of solid,
  penetration of dissolution fluid into tablet and
  granules adhesion of coating material to tablet.

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(B) METHOD OF DETERMINATION

• By contact angle
• The contact angle is the angle between a
  liquid droplet and the surface over which it
  spreads.
• Contact angle 00 complete wetting.
• Contact angle 1800 No wetting .
• By Draves test
• (C) IMPORTANCE
• Crystal structure can influence the contact
  angle.
• Problems associated with Wettability of powder
  are poor dissolution rate low adhesion of film
  coating.

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(C) IMPROVEMENT

• Mixing with hydrophilic excipient like Na CMC
  (water soluble) and bentonite, Al Mg silicate
  colloidal silica (water insoluble).
• Use of wetting agent (HLB value 6-9) which acts
  by lowering contact angle. It displaces air
  replace it with liquid phase.
• Wetting of powder by non aqueous solvent can be
  enhanced by certain lanolin derivative.

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9. SYRINGABILTY

• It is more mechanical property rather than
  pharmaceutical property.
• This phenomenon happens when a liquid dosage form
  passes through a syringe.
• The flow of material is dependant on size shape
  of crystals of material.
• Plates can easily move one over another .so, no
  friction observed can easily pass through the
  syringe.
• While in case of needles or cubes or prisms ,
  they cant pass through the syringe easily.
• So, we can arrange the degree of syringabilty in
  following way
• Plates gt Needles gt Cubes gt Prisms

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• Chemical Abstracts.

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