Topic 5

• Examples of semisolid dosage forms:

  • Ointment: single-phase basis with dispersed solids or liquids
  • Cream: multiphase preparation with lipophilic and aqueous phases
  • Gels: liquids gelled by suitable gelling agents
• Examples of semisolid dosage forms:

  • Paste: semi-solid preparations for cutaneous application with large proportions of solids dispersed in the basis
  • Poultices: hydrophilic heat-retentive basis with solid or liquid active substances dispersed, spread thickly on a dressing and heated before skin application
• Examples of semisolid dosage forms:

  • Medicated plasters: flexible preparations with active substances for skin application, designed to maintain contact with the skin for slow absorption or as protective/keratolytic agents
• Ointment:

  • Greasy, for external skin application
  • Contains dissolved or dispersed medicaments
  • Non-medicated ointment can act as protectants, emollients, and lubricants
  • Bases are needed to make ointments
• Ointment Bases:

  • Hydrocarbon bases
  • Fats and fixed oil bases
  • Absorption bases
  • Emulsifying bases
  • Water-soluble bases
• Hydrocarbon Bases:

  • Oily bases derived from petroleum, insoluble in water
  • Emollient effect, occlusive dressings, protective to water labile drugs
  • Examples: Paraffin (Petrolatum) bases, Yellow/White Soft Paraffin, Hard Paraffin, Liquid Paraffin
• Hydrocarbon Bases:

  • Yellow/White Soft Paraffin: widely used ointment bases, semi-solid mixtures of hydrocarbons from petroleum
  • Both have similar properties with a melting point range of 38–56°C
  • White Soft Paraffin BP: highly refined and decolourised, used for products with colourless or pale ingredients
• Hydrocarbon Bases:

  • Liquid Paraffin: reduces viscosity in ointment bases
  • Example formulation: Paraffin Ointment BP with Hard Paraffin BP, White Soft Paraffin BP, White Beeswax BP, and Cetostearyl Alcohol BP

  Hard Paraffin BP

  •As a stiffening agent in ointment bases

  •It is a mixture of solid hydrocarbons obtained from petroleum or shale oil

  • It has a solidifying point of 50–57°C

  • Because of its relatively high melting point it is also added to other paraffins to increase the melting point of a product and therefore increase its suitability for use in warm climates
• Absorption Bases:

  • Can absorb water and aqueous solutions to form water-in-oil emulsions
  • Include paraffins with emulsifying agents like Beeswax, Wool fat (lanolin)-can absorb about 50% of its weight of water, Wool alcohols-The emulsifying component of wool fat obtained by fractionation

  eg: Wool Alcohols Ointment BP and Simple Ointment BP
• Emulsifying Bases:

  • Anhydrous bases with sufficient emulsifying agents to make them miscible with water hence washable
  • Types: Anionic-emulsifying oint, Cationic-cetrimide , Non-ionic-cetomacrogol
• Water-soluble Bases:

  • Polyethylene glycols (PEG) or macrogols are stable, hydrophilic substances that are non irritant to the skin
  • Solid grades (MW 1000 abv) used as ointment bases
  • Combining numerous M.W. of macrogols - a product with the consistency of an ointment can be produced
  • Examples: Macrogol Ointment BP
• Water-soluble Bases Advantages

  • Macrogols are water miscible, easily washed off, non-occlusive, non-staining, non-irritant, do not hydrolyse or support mould growth
• • Yellow Soft Paraffin has been used when an ointment includes dark coloured ingredients
  • White Soft Paraffin → for products with colourless, white or pale ingredients
  • White Soft Paraffin produce products that are more ‘pleasing to the eye’
  • •However, the unbleached form, Yellow Soft Paraffin BP, is less likely to cause sensitivity reactions in susceptible patients
• Example of formulation:

  •Paraffin Ointment BP

  Hard Paraffin BP

  White Soft Paraffin BP

  White Beeswax BP

  Cetostearyl Alcohol BP
• Cetostearyl Alcohol BP is added to the hydrocarbon base to increase its emollient properties

  •White Beeswax BP is added to help stiffen the ointment

  •These ingredients help to produce a homogeneous mixture of the Hard Paraffin BP and the White Soft Paraffin BP
• Selection of Ointment Bases

  •Solubility characteristics of drug and desired rate of release

  •Typical properties of variousointment bases:

  • Water washability and• Tendency for skin occlusion
• Antioxidants• Trace metal contaminants catalyse oxidative reaction• Antioxidants can prevent rancidity of hydrophobic compounds• E.g. of antioxidants• BHT or butylated hydroxytoluene• BHA or butylated hydroxyanisole
• MANUFACTURE OF OINTMENTS

  •Objective: uniformly distribute the medicinal agent in a base.

  •Base forms the body of ointment

  
  

  •Major Unit Operations:

  • Particle Size Reduction or Milling•

  Mixing
• 1. Impact:
  2. • Instantaneous force perpendicular to particle surface
  3. • Particle-to-particle or particle-to-mill surface collision•
  4. 2. Attrition:• Force parallel to the particle surface•
  5. 3. Compression:
  6. • Force applied slowly to particle surface toward centre of particle
  7. • 4. Cutting:• Shearing force with a sharp edge
• Equipment for Particle Size Reduction

  • Fluid Energy Mills

  • High speed particle-to-particle impact or attrition

  • Impact Mills• Hammer

  • Cutting Mills

  • Knives

  • Compression Mills

  • Roller Mills

  • Tumbling Mills
• • Mixing Convection
  • Mixing•
  • Repeated cycling of material from top to bottom
  • • Mixer is usually a jacketed vessel to facilitate heat transfer
  • • Anchor or Impeller
  • • Static Mixing
  • • Materials passes through a tube with stationary baffles
• Components that can be melted are combined and melted together

  Mixture is stirred while cooling

  The heat labile and volatile components are mixed toward the end of the ointment preparation

  Forms of substances which can be added to congealing mixture:

  Solution

  Insoluble powder levigated with a portion of the base

  Carried out in large steam jacketed vessels
• Order of heating during ointment making fusion:

  • Start with material with the highest melting point
  • Not all materials are exposed to the highest temperature

  OR

  • Start with material with the lowest melting point
  • Melted components exert solvent action on the subsequent components
  • Sufficient for melting at lower temperature
• Rheology is the study of the flow anddeformation properties of matter
• Viscosity is an expression of the resistance of a fluid to flow.The higher the viscosity, the greater is the resistance
• The difference of velocity (dv)between two planes of liquid separated by an infinitesimal distance (dr) is the velocity gradient or rate of shear
• The force per unit area (F′/A) required to bring about flow is called the shearing stress and is given the symbol F The higher the viscosity of a liquid, the greater is the force per unit area(shearing stress) required to produce acertain rate of shear
• Non-Newtonian behaviour is exhibited by heterogeneous dispersions of liquid and solid
• Explain plastic flow

  The previous rheogram represents a bingham body that exhibits plastic flow

  • Plastic flow curves do not pass through the origin but intersect the shearing stress axis at a particular point → this point is referred to as the yield value

  A Bingham body does not begin to flow until a shearing stress corresponding

  to the yield value is exceeded

  •At stresses below the yield value, the

  substance acts as an elastic material
• Yield value is an important property of certain dispersions .The slope (∆G/∆F) of the rheogram is known as the mobility which is analogous to fluidity in Newtonian systems
• Plastic flow is associated with the presence of flocculated particles in concentrated suspensions• A continuous structure is set up throughout the system• A yield value exists because of the contacts between adjacent particles which must be broken down before flow can occur• Yield value is an indication of force of flocculation:• The more flocculated the suspension, the higher the yield value• Frictional forces between moving particles can also contribute to yield value
• • As the yield value is exceeded, any furtherincrease in shearing stress (i.e., F - f) bringsabout a directly proportional increase in rate ofshear (G) → a plastic system resembles aNewtonian system at shear stresses aboveyield value
• Pseudoplastic:• Liquid dispersions of natural & synthetic gums(e.g. tragacanth, sodium alginate,methylcellulose & sodium carboxymethylcellulose) exhibit pseudoplastic flow• Pseudoplastic flow is typically exhibited by polymers in solution
• Why does viscosity decrease when shearing stress increases in psedoplastic

  
  

  As shearing stress is increased, normally disarranged molecules begin to align their long axes in the direction of flow

  This orientation reduces internal resistance of the material and allows a greater rate of shear at each successive shearing stress

  Moreover, some of the solvent associated with the molecules may be released,resulting in lowering of both concentration and size of the dispersed molecules →decrease apparent η
• Dilatant Flow

  
  

  • Certain suspensions with a high percentage of dispersed solids exhibit an increase in resistance to flow with increasing rates of shear

  • Such systems actually increase in volume when sheared and are hence termed dilatant

  -Also known as a shear thickening system

  -N is always less than 1 and decreases as degree of dilatancy increases .As N approaches 1, the

  system becomes increasingly Newtonian
• Substances possessing dilatant flow properties are:

  -suspensions containing a high concentration (about 50% or greater) of small, deflocculated particles

  Particulate systems / suspension that are flocculated would be expected to possess plastic, rather than dilatant, flow characteristics
• Dilatant behaviour can be explained as follows: (1)

  At rest, particles are closely packed with minimal interparticle volume (voids) The amount of vehicle in the suspension is sufficient to fill voids and permits particles to move relative to one another at low rates of shear. Thus, a dilatant suspension can be poured from a bottle because under these conditions (at relatively low rate shear stress) it is reasonably fluid• As shear stress is increased, the bulk of the system expands or dilates• The particles, in an attempt to move quickly past each other, take on an open form of packing
• Dilatant behaviour can be explained as follows:

  Such arrangement leads to a significant increase in interparticle void volume. The amount of vehicle remains constant and, at some point, becomes insufficient to fill the increased voids between particles.Accordingly, resistance to flow increases because particles are no longer completely wetted, or lubricated, by the vehicle .Eventually, the suspension will set up as a firm paste
• Why should precaution be taken up when using dilatant material ?

  Processing of dispersions containing solid particles is mostly by high-speed mixers,blenders or mills• Dilatant materials may solidify under these conditions of high shear, thereby overloading and damaging processing equipment