Preformulation

• From Molecule to Patient

  1. Discovery/

  2. Literature serve

  3. Research and Development

  4. Approval

  5. Manufacture

  6. Distribution

  7. Therapeutic Target

  8. Final Dosage form

  9. Patient
• Pharmaceutical Industry
• Main Customers


  • Medicines
  • Return
  • Documents
  • Patient
  • Regulatory Agencies
• Dosage Forms are the means by which drug molecules are delivered to sites of action within the body
• General Considerations in Dosage Form Design

  • Effectiveness
  • Safety
  • Reliability
  • Stability (Physical, Chemical, Microbiological)
  • Pharmaceutical elegance (Appearance, Organoleptic properties)
  • Convenience (Ease of use, Dosing frequency, Consumer acceptance)
• Necessity/Need of dosage forms

  • Mechanism for safe and convenient delivery of accurate dosage
  • Protection of drug from atmosphere or increasing shelf-life of drugs, human anatomy factors
  • Masking taste and odour
  • Optimal drug action or Improving ADME of the drugs
  • Delivering the drugs within body tissues/specific site
  • Sustained release medication
  • Controlled release medication
• Factors Affecting Drug Presentation to the Body

  • Administration route
  • Physical form of the drug product
  • Design and formulation of the product
  • Method of manufacture of the product
  • Physicochemical properties of the drug and excipients
  • Control and maintenance of location of drug at the absorption site
  • Control of the release rate of the drug from the drug product
  • Physiological factors/ Physiological state of patient
• Preformulation


  Phase of research and development in which pre-formulation scientist characterize physical & chemical 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
• Direct Benefits of Preformulation


  • Gives direction for development of formulation in choice of dosage form, excipients, composition, physical structure
  • Helps in adjustment of Pharmacokinetics [ADME] and biopharmaceutical [ionizability, pKa, partition coefficient]properties
  • Support for process development of drug substance (yield, filtration etc)
  • Produce necessary and useful data for development of analytical methods
• Preformulation Process


  1. Receive new drug substance

  2. Obtain all available information

  3. If not available, do the literature search

  4. Determine physical property of the new API

  5. Macroscopic and Microscopic examination

  6. Determine polymorphs, solvates and hydrates

  7. Stability testing at normal and exaggerated condition

  8. Determine their solubility, partition co-efficient, pKa, dissolution rate

  9. If poor bioavailability test results due to solubility, pKa, P, etc. make new salt or ester

  10. If satisfactory, check lot to lot uniformity

  11. Select most stable, active form for bioavailability testing

  12. Check API stability with excipients

  13. Prepare worksheet and final preformulation report and issue to product development dept
• Physicochemical Properties Characterized in Preformulation

  • Physical Characteristics (Bulk Characteristics, Solubility Analysis, Stability Analysis)
  • Chemical Characteristics (Oxidation, Hydrolysis, Photolysis, Racemization, Polymerization, Isomerization, Decarboxylation, Enzyme Decomposition)
• Preliminary Evaluation


  • Compound identity
  • Formula and molecular weight
  • Structure
  • Therapeutic indications (Probable human dose, Desired dosage form(s), Bioavailability model, Competitive products)
  • Potential hazards
  • Initial bulk lots (Lot number, Crystallization solvent(s), Particle size range, Melting point, % volatiles)
  • Analytical methods (HPLC assay, TLC assay, UV/ Visible spectroscopy)
• Color


  Generally a function of a drug's inherent chemical structure relating to a certain level of unsaturation. Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores.
• Odour


  The substance may exhibit an inherent odor characteristic of major functional groups present. Odor greatly affects the flavor of a preparation or food stuff.
• Taste


  If taste is considered as unpalatable, consideration is to be given to the use of a less soluble chemical form of the drug. The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product.
• Methods to Determine Melting Point

  • Capillary Melting
  • Hot Stage Microcopy
  • Differential scanning calorimetry or thermal Analysis
• Differential Scanning Calorimetry and thermal analysis

  Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate. DSC is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition.
• Purity


  • Designed to estimate the levels of all known & significant impurities & contaminates in the drug substance under evaluation. It is another parameter which allows for comparison with subsequent batches. Occasionally, an impurity can affect stability.
• Particle Size


  • Can influence dissolution rate, suspendability, uniform distribution, penetrability, lack of grittiness
• Methods to Determine Particle Size

  • Sieving
  • Microscopy
  • Sedimentation rate method
  • Light energy diffraction
  • Laser holography
  • Cascade impaction
  • Coulter counter method
• Sieving method

  Range: 50 - 150 μm. Simple, inexpensive. If powder is not dry, the apertures get clogged.
• Microscopy


  Range: 0.2 - 100 μm. Particle size can be determined by the use of calibrated grid background. Most direct method. Slow & tedious method.
• Sedimentation method


  Range: 1 - 200 μm. Andreasen pipette is used. Particle size is calculated by Stoke's law.
• Light energy diffraction


  Range: 0.5 - 500 μm. Particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone. Quick & fast.
• Laser holography


  Range: 1.4 - 100 μm. A pulsed laser is fired through an aerosolized particle spray & photographed in three dimensional with holographic camera, allowing the particles to be individually imaged & sized.
• Cascade impaction


  The principle that a particle driven by an air stream will hit a surface in its path, provide that its inertia is sufficient to overcome the drug force that tends to keep in it in airstream.
• Particle Shape


  • Particle shape will influence the surface area, flow of particles, packing & compaction properties of the particles. A sphere has minimum surface area per unit volume.

  
• Surface Area


  Particle size & surface area are inversely related to each other. Smaller the drug particle, greater the surface area. Specific surface is defined as the surface area per unit weight (Sw) or unit volume (Sv) of the material.
• Crystal Properties and Polymorphism


  • Shows more than one crystalline form with different space lattice arrangements. Polymorphs have different melting points, x-ray diffraction patterns and solubility even though they are chemically identical. Only one form is thermodynamically stable at a given temperature and pressure. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving form may be utilized to improve the rate and extent of bioavailability.
• Hygroscopicity


  Hygroscopicity is the tendency of material to absorb moisture from atmosphere & be dynamic equilibrium with water in the atmosphere. Deliquescent is the hygroscopic substance which absorb moisture from air and they can be liquefied by partially or wholly forming solution. Efflorescent is a substance which loses water to form a lower hydrate or become anhydrous.
• Examples of Hygroscopic, Deliquescent and Efflorescent Substances

  • Hygroscopic & Deliquescent: Ephedrine, Hyoscyamine, Phenobarbital, Pilocarpine, Physostigmine
  • Efflorescent: Atropine, Cocaine, Codeine, Scopolamine, Caffeine
• Methods of Determining Hygroscopicity

  Sample of compound are accurately weighed into container and placed at various humid condition for period of up to 2 weeks. If Weight gain - Deliquescent or Hygroscopic, If Weight loss - Efflorescent. Also determined by TGA, GC, & KF titration.
• Importance of Hygroscopicity


  • It affects the flow property, compression characteristics, granulation & hardness of the final tablet. Important in aerosol. Affects the chemical stability of hydrolysable drugs.
• Methods of Improving Hygroscopicity

  • 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.

  
• Electrostatic Charge


  Electrostatic charges are the consequence of classic attraction & repulsion effect between the charges. Electrostatic charge is produced by separation of positive & negative charge, mechanical impact, friction between two surface, rupturing of particle, separation of solid & liquid surface. Pharmaceutical processing procedures can induce static charge.
• Factors Affecting Static Charge

  • Effect of particle shape, Effect of tablet excipient, Effect of Particle size, Effect of moisture
• Importance of Electrostatic Charge

  • In pre-formulation of suspension, Affects flow property of powder, Affects mixing process, For thermal stability of emulsions, May damage tablet machine, May affect compression coating
• Wettability


  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.
• Method of Determining Wettability

  By contact angle: The contact angle is the angle between the solid surface and the tangent to the liquid surface at the point of contact.