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    Pre Formulation

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    Diana
    Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

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    Pre Formulation

    Uploaded by

    Diana
    21 views25 pages
    Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

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    Preformulation Techniques and Formulation Selections

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    Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    21 views25 pages

    Pre Formulation

    Uploaded by

    Diana
    Preformulation testing involves investigating a drug's physical and chemical properties alone and when combined with excipients. This helps formulators develop stable, bioavailable dosage forms. Key tests include determining solubility, dissolution behavior, partition coefficient, ionization constant, and solid state properties. Solubility and dissolution are especially important to ensure the drug is in solution and can be absorbed. These techniques provide critical information to guide formulation selection and development.

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    of 25

    Preformulation Techniques

    and
    Formulation Selection
    Pharmaceutical sciences :
     Stage I : screen compounds and select drug candidates

     Stage II : select salts and solid forms

     Stage III : evaluate drug properties


    Critical physical chemical properties
    1. Drug should be in SOLUTION
    2. Must be BIOAVAILABLE
    3. Must be MANUFACTURABLE
    Preformulation is :
     Preformulation testing is the first step in the rational
    development of dosage forms of a drug substance
     It can be defined as an investigation of physical and
    chemical properties of a drug substance alone and when
    combined with excipients.
     The overall objective of preformulation testing is to
    generate information useful to the formulator in
    developing stable and bioavailable dosage forms which
    can be mass-produced
    Preformulation
    is a case of LEARNING before DOING
    Dissolution
    Behavior

    Partition
    Solubility
    coefficient

    Material
    Ionization
    Stability
    constant

    Solid state
    properties
    SOLUBILITY
     Importance of solubility
    Drug should be in solution to be absorbed
    Drug candidates are becoming lipophilic and poorly soluble

     How soluble is soluble enough ?


    Dependent on dose and permeability
    Biopharmaceutical classification system
    BCS of Drugs
    How to determine solubility
     Semiquantitative determination
    Solvent Vigorously Examine
    (fixed volume) shaking visually

    Adding solute in small


    incremental amounts
    Undissolved
    solute particles ?

    No Yes
    “LAW OF MASS ACTION”
    Estimated solubility Total amount
    added up
     Quantitative determination
    Shaking at constant
    Excess drug powder Ampul/vial temperature
    150 mg/ml (15 %) (2-5 ml) (25 or 37 oC)
    + solvent 2 - 8 oC ?
    The first few ml’s of the filtrates should be
    discarded due to possible filter adsorption 48 hr

    Determine the drug Membrane filter


    concentration in the 0.45 m
    filtrate
    72 hr
    Same Determine the drug Membrane filter
    concentration ? concentration in the 0.45 m
    filtrate
    ? hr
    Solubility
    Determine the drug Membrane filter
    concentration in the 0.45 m
    filtrate
    Solubility and Dissolution improvement
     Salts
     Cosolvent, oils, emulsions and microemulsion
     Surfactants
     Complexes (eg. cyclodextrin)
     Solvates
     More soluble polymorphs
     Amorphous
     Pro-drugs
     Micronization
     Nanosizing
     Super critical fluid technologies
    Log aqueous solubility (mol) 5

    Indomethacin
    4 (weak acid)

    3 Chlorpromazine
    (weak base)
    2

    1 Oxytetracycline
    (amphoteric)

    2 4 6 8 10 12 14

    pH
    Dissolution behavior
     Dissolution rate for poorly soluble compounds may often
    be the rate limiting step to absorption
     Bio relevant dissolution media should be the most
    important consideration
    How to determine dissolution of actives ?
     Nelson constant surface method

    Dissolution
    medium
    Rotating
    Paddle
    Harden wax
    or paraffin Tablet surface
    Partition coefficient
     Like biological membrane in general, the GI membranes
    are largely lipoidal in character.
     The rate and extent of absorption decreased with the
    increasing polarity of molecules.
     Partition coefficient (distribution coefficient): the ratio in
    which a solute distributes itself between the two phases
    of two immiscible liquids that are in contact with each
    other (mostly n-octanol/water).
     Partition coefficient can be modified via prodrug approach
    Ionization Constant
     The unionized species are more lipid-soluble and hence
    more readily absorbed.
     The GI absorption of weakly acidic or basic drugs is
    related to the fraction of unionized drug in solution.
     Factors affecting absorption:
    - pH at the site of absorption
    - Ionization constant
    - Lipid solubility of unionized species
    “pH-partition theory”
    Henderson-Hasselbalch equation
    For acids:
    pH = pKa + log [ionized form]/[unionized form]
    For bases:
    pH = pKa + log [unionized form]/[ionized form]

    Determination of Ionization Constant


    1. Potentiometric pH-Titration
    2. pH-Spectrophotometry Method
    3. pH-Solubility Analysis
    Solid state properties
     Organoleptic (color, particle size, flow)
     Particle shape and size  specific surface area
     Polymorphism
     Melting point
     Hygroscopicity
     Compressibility
     Density
    Particle size & Surface area
     Microscopy
     Shieving
     Particle size analyzer (light / laser / electrical conductivity)
     Surface area based on BET theory of absorpsion
    Polymorphism by XRD
    Stability
     Solid state stability
     Solution state stability
     Compatibility studies : stability in presence of excipients
    Solid state Stability
     In general solid state reaction more slower and more
    difficult to interpret compared to solution.
     Use stressed condition :
     High temperature
     Use 40, 50, 60oC. Use 5oC as control
     Stable in 60oC for 30 days
     High humidity
     Use desiccator with various salts
     Oxidative stability
     Use chamber with Oxygen (usually 40% )
     Photolytic stability
     Use ICH guideline
    Solution State Stability
     Identification condition necessary to form stable solution
     Consider :
     Effect of pH
     Effect of temperature
     Effect of solvents
     Effect of light
     Effect of Oxygen

     Use Arrhenius law


    Compatibility Studies
     Compatibility studies of new drug should consider two or
    more excipients of the same class.
     Mixture in specific ratio, use 5 % water if needed.
     Three techniques commonly use :
     TLC
     DTA/DSC
     Diffuse reflectance spectroscopy

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