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Pceut 531 > Midterm #2 > Flashcards

Midterm #2 Flashcards

1
Q

Dispersed systems: Definition

A
  • When one component is distributed more or less evenly throughout the second component
  • Ex: Drug in solvent (or medium)
  • Surfactants are often added
  • Classified on particle size
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2
Q

Molecular Dispersion

A
  • Ex: solutions
  • Usually a molecule
  • Diameter of particles <1.0 nm
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3
Q

Colloidal dispersion

A
  • Ex: aerosol preparation
    • dispersion of liquid or solid in gas
    • inhalation solutions
    • Fog (dispersion of liquid)
    • Smoke (dispersion of solid)
  • Diameter of particles: 1.0 – 500 nm
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4
Q

Coarse dispersion

A
  • Ex: emulsions and suspensions
    • Emulsion, oil dispersed in water (L/L)
    • Suspension is (S/L)
  • Diameter of particles: > 500 nm
  • The sizes of dispersions are a range, there might be some overlap
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5
Q

Pharmaceutical significance of dispersions which are not solutions

A
  • Solutions not always possible to formulate
    • Insoluable
    • Unstable
  • Solutions not required
    • Aesthetic reasons
    • Prolonged effect
    • Taste effect
    • Targeting effect
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6
Q

​Solutions not always possible to formulate

A
  • Drugs that are insoluble
  • Solution is not practical
  • Can add surfactants to stabalize dispersion system
  • Ex: Penicillin
    • Not stable in aqueous solutions
    • Hydrolysis
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7
Q

Solutions not required: Ointment or lotions vs. solution

A
  • “aesthetic reasons”
  • Solution not ideal for topical
    • spread out everywhere
  • Use emulsion products instead
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8
Q

Solutions not required: Prolonged effect

A
  • Ex: procaine-penicillin
  • IM suspension for injection
    • 13-24 hours in plasma
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9
Q

Solutions not required: Targeting effect

A
  • Ex: kaolin
    • Clay that absorbs toxins
    • Antidiarrehal
    • Oral suspension
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10
Q

Solutions not required: Taste effect

A
  • ​Ex: Cod Liver Oil
    • coating of cod liver oil in emulsion mask the taste​
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11
Q

Interactions in dispersed systems

A
  • In order to understand how drug molecules are dispersed, we must first consider drug-medium interactions.
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12
Q

Interactions in dispersed systems: Two phases

A
  • Ex: liquid-liquid; solid-liquid; gas-liquid
  • Phase separation
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13
Q

Examples of Cohesive and Adhesive Forces

A
  • Oil molecules
    • van der Waals forces
    • cohesive force
  • H20 molecules
    • Hydrogen bonding
    • cohesive force
  • Oil/Water
    • adhesive force
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14
Q

Cohesive Force Definition

A
  • interactions between like molecules
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15
Q

Adhesive Force definition

A
  • interactions between unlike molecules
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16
Q

interaction between oil/H2O molecules

A
  • little interaction
  • no adhesive force
  • oil pulls away from H2O and stay with other oil
  • contact between oil and water is reduced as much as possible
  • Cohesive force >>> adhesive force in this example…leads to no mixing
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17
Q

Cohesive and Adhesive and mixing

A
  • If cohesive > adhesive: no mixing
  • If adhesive > cohesive: mixing
    • prefer this in pharmaceutical preparations
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18
Q

Interfacial tension: Definition

A
  • owing to phase separation
  • tension between any two separated phases
  • the force acting at the right angles to a line 1 m in length along the interface
  • Maintain the interface and keep the phases separated
  • To mix, have to reduce the interfacial tension
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19
Q

Classification of Interphases: Gas/gas

A
  • No interface possible
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20
Q

Classification of Interfaces: Gas/liquid

A
  • Liquid surface, body of water exposed to atmosphere
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21
Q

Classification of Interfaces: Gas/solid

A
  • Solid surface, table top (ex: table and air interface, typically aerosol)
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22
Q

Classification of Interfaces: liquid/liquid

A
  • Liquid-liquid interface, emulsion
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23
Q

Classification of Interfaces: Liquid/solid

A
  • ​Liquid-solid, suspension
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24
Q

Classification of Interfaces: Solid/solid

A
  • Solid-solid interface
    • powder particles in contact
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25
Q

Surface tension: Definition

A
  • special type of interfacial tension
  • referring to the tension between gas/solid or gas/liquid
  • Water has the highest surface tension compared to any other pure liquids
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26
Q

Surface tensions of pure liquids and interface tensions against water: Trend

A
  • Lower interfacial tension, more hydrophilic, due to molecular structure
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27
Q

Surfactants: Definition and AKA

A
  • AKA: Surface active agents/amphiphiles
  • substances that can spontaneously collect at interfaces of solids, liquids or gases
    • thus lowering surface tensions or interfacial tensions
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28
Q

Surfactants Characteritic

A
  • two distinct regions in their chemical structure
    • hydrophilic and hydrophobic
  • amphipathic molecules
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29
Q

Critical Micelle Concentration (CMC)

A
  • When the concentration of a surfactant is greater than the concentration that can be accommodated by the surface or interface, micelles are formed
  • This cut-off concentration is called the critical micelle concentration
  • One application of surfactant is to help dissolve hydrophobic drugs in micelles formed by the surfactant
  • adding surfactant could increase drug solubility in aqueous solutions
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30
Q

Plot of Surface Tension against Surfactant Concentration

A
  • Surface tension decrease: @ some pt. surface tension does not change
  • No room for surfactants to go to interphase
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31
Q

Micelle Solution

A
  • Too hydrophilic, form micelle
  • Too hydrophobic, completely dissolve in oil
  • can form reverse micelle in oil phase
    • trap a water molecule
  • Micelle solution is not a true system
    • it is a dispersion system
  • cannot see with naked eye because transparent
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32
Q

Surfactant Classifications

A
  • By the nature of the polar head
  • Nonionic
  • H2O insoluable
  • H2O soluable
  • Anionic
  • Cationic
  • Zwitterionic
    *
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33
Q

Nonionic Surfactants

A
  • Most frequently used because
    • Stable
    • Low Toxicity
      • (less toxic than others such as cationic surfactants)
    • Compatible with most pharmaceuticals
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34
Q

H20 insoluble (hydrophobic) Surfactants

A
  • Ex: Spans
    • fatty acid esters of Sorbitan
    • Sorbitan monolaureate (Span 20)
    • Sorbitan trioleate (Span 80)
  • Have hydrophilic region and a hydrophilic chain
  • Example of nonionic surfactant
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35
Q

H20 soluble (hydrophilic) Surfactant

A
  • Example of nonionic surfactant
  • Ex: Tweens
    • derived from spans by adding polar polyoxyethylene glycol chains to non-esterified hydroxyls
    • Polyoxyethylene sorbitan monooleate (Tween 80), also known as polysorbate 80 (USP
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36
Q

Anionic Surfactant

A
  • negatively charged polar head usually contains a carboxylate (soap) and a sulfonate
  • Ex: Aerosol OT (bis (2-ethylhexyl) sodium sulfosuccinate)
  • not stable at pH < 10 as they are weak acids and unionized fatty acid is formed at this pH
  • weakly antibacterial
  • laxative and unpleasant soapy taste
  • incompatible with high concentration of electrolytes (salting out effect)
  • R - C00- Na+, K+, NH4+ - H20 soluble – Soft soaps
  • R - C00- Ca2+, Mg2+, A13+ - H20 insoluble – hard soaps
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37
Q

Cationic Surfactant

A

the positively charged polar head usually contains quaternary ammonium

  • [R4 N]+ C1- e.g., alkyl substituted pyridinium chlorides such as benzalkonium chloride in contact lens solutions
  • More often used as antibacterial preservatives than surfactants
  • Could be used in emulsion skin preparations due to antiinfective properties. The suitable pH range is 4 – 6.
    *
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38
Q

Mixing Anionic and Cationic Surfactants

A

Anionic and cationic surfactants are generally incompatible and should not be mixed.

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39
Q

Zwitterionic Surfactants

A
  • the polar head contains both positive and negative charges such as carboxylate (-), phosphate (-), quaternary ammonium (+)
  • Ex: natural products such as protein, lecithin, gelatin, and phosphatidylcholine
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40
Q

Hydrophilic Lipophilic Balance (HLB) classification

A
  • arbitrary scale of ratio of hydrophilicity to lipophilicity
  • Greater HLB means a greater hydrophollicity
  • The HLB value determines how a surfactant is used
  • Solubilizing agents work at >CMC
  • Detergents trap oil in micelles
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41
Q

Approximate HLB Values for a Number of Surfactants

A
  • Can search for surfactants that have certain HLB values
  • Span 85,b Arlacel 85b
    • HLB: 1.8
  • Span 80b
    • HLB: 4.3
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42
Q

Pharmaceutical applications of surfactants

A
  • Promote wetting by reducing the interfacial tension between liquid/solid
  • Antibacterial or antimicrobial
  • Stabilize colloids and foams
  • Stabilize emulsions (will be taught in “Emulsions”)
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43
Q

Surfactants promote wetting

A
  • reducing the interfacial tension between liquid/solid
  • wetting of solid (e.g., zinc oxide) by liquid: in the preparation of a suspension, you would wet powders, otherwise powders will float.
  • Void at surface of powder than are full of air. Surfactant introduces liquid into the void space
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44
Q

Degree of wetting by surfactants

A
  • The degree of wetting is determined by the contact angle (theta) which is a measure of the solvent’s ability to wet a solid. For example, for contact lenses, you want maximum wetting.
  • complete wetting: theta = 0°
  • ​incomplete wetting: 0° < theta < 90°
  • poor wetting: 90° < theta < 180°
  • no wetting: 180 degree angle
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45
Q

what are other methods that could be used to increase wetting of powders?

A
  • Ex: ethanol, because high affinity to hydrophobic powder
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46
Q

Antibacterial or antimicrobial property of surfactants

A
  • Cationic surfactants such as benzalkonium chloride.
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47
Q

Surfactant Stabilize colloids and foams

A
  • E.g., aerosol OT stabilizes foams when used in air-aerosol preparation. (Aerosol is a dispersion system with solid or liquid dispersed in air)
  • Ex: Nasal spray; dip tube into the bottom of the bottle, liquid and vapor phase, also a propellant added in both liquid and vapor phase, When open valve, liquid is dispersed
  • Foam: liquid that contains air, stabilize by increase concentration at liquid and air interface
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48
Q

Surfactant and Emulsions

A
  • Stabilize emulsions
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49
Q

Emulsion: Definition

A
  • at least two immiscible liquid phases, one of which is dispersed as globules (100 - 10,000 nm) in the other liquid phase
  • If globules are small (10 – 100 nm), the emulsion is defined as a colloidal emulsion or microemulsio
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50
Q

Examples of pharmaceutical emulsions

A
  • ointments, creams, lotions, liniments, vitamin E drop
  • Most of pharmaceutical emulsions are with droplets > 500 nm
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51
Q

Components of Emulsions

A
  • internal phase–dispersed, discontinuous, droplets, “the solute.”
  • external phase–dispersing medium, continuous, “the solvent.”
  • emulsifying agents–prevent droplets from contact or coalescing
  • emulsions are dynamically unstable
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52
Q

Types of Emulsions

A
  • Oil in Water (o/w) - oil as the droplets
  • Water in Oil (w/o) - water as the droplets
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53
Q

Pharmaceuticl Significance: o/w emulsions

A
  • water washable
  • convenient method of administering water insoluble liquids/solids
  • masks bad taste of oil-soluble drugs
  • increase absorption of oil-soluble drugs
  • increase stability of drugs which are easily hydrolyzed
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54
Q

Pharmaceutical use of o/w emulsion

A
  • oral, parenteral (e.g., IM injection), and external (e.g., o/w emulsions are common for creams and lotions) use
  • Ex: preparation of liquid paraffin, intralipid for total parenteral nutrition (for the delivery of oils and lipids)
  • Ex: o/w emulsions as delivery vehicles for hydrophobic drugs.
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55
Q

Pharmaceutical Significance w/o emulsions

A
  • convenient when administering water soluble liquids/solids
  • increase efficacy of percutaneously applied drugs
  • enables elegance and aesthetic appeal
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56
Q

Pharmaceutical Uses w/o emulsions

A
  • used almost exclusively for external applications
  • will remain on the skin longer and drugs in ointments take a longer time to be absorbed
  • Such onintments are usually very moisturizing, and thus good for dry skin
  • Note that both ointments and creams can be o/w or w/o
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57
Q

Theory of Emulsification and emulsifying agents

A
  • ∆F = W = gammaSL • ∆A ​
  • ∆F: surface free energy increase or the work done (W) to make an emulsion resulting in increase of surface area by 1m2.
  • ∆A: increase in total surface area of droplets. ∆A = Atotal droplets – Ainterface
  • GammaSL: Interfacial tension
  • the lesser work done (W), the more stable the emulsion.
  • spontaneous tendency for the droplets in an emulsion to coalesce so that ΔA is decreased and the emulsion reaches a more stable state.
    • all emulsions are thermodynamically unstable systems
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58
Q

Emulsifying agents (E.A.s) act by

A
  • gamma SL
  • preventing droplets from coalescing - physical barrier
  • surface charges cause repulsion between droplets
  • Not all E.A. are surface active agents
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59
Q

Surface active agents (surfactants): what they do

A
  • reduce interfacial tension, e.g. potassium laureate, Tweens
  • form monomolecular layer around the dispersed droplets (physical barrier)
  • may also cause surface charge if ionic surfactants are used
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60
Q

Surface Active Agents: Anionics

A
  • e.g., K+, Na+, NH4+ salts of lauric acid and oleic acid
  • Soluble in water
  • form o/w emulsions
  • Disagreeable taste and irritating to GIT (for external use only).
  • Not stable at pH < 10
  • divalent salts (Ca2+, Mg2+) are water insoluble and form w/o emulsions
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61
Q

When to determine whether on O/W or W/O emulsion will result

A
  • hydrophilic SAAs (with higher HLB values e.g., HLB 9-12) result in O/W emulsions
  • hydrophobic SAAs (with low HLB values e.g., HLB 3-6) result in W/O emulsions
  • type of emulsion is a function of the relative solubility of the SAA, and the phase in which it is more soluble being the continuous phase
    • rule of Bancroft
  • explained by the coalescence kinetics of the two liquid phases when they are shaken in the presence of an emulsifying agent
    • coalescence rate of oil globules or the coalescence rate of water globules
    • depending on which rate is greater
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62
Q

Cationics SAA

A
  • e.g., cethyltrimethylammonium bromide.
  • A quaternary ammonium compound
    • e.g., [R4N+]Br-
  • generally weak emulsifiers
  • used together with auxiliary emulsifying agents
    • such as cetostearyl alcohol, fatty acids and fatty esters that can thicken emulsions (by increasing viscosity
  • not very strong
    • usually combined with other emulsifying agents
  • do not mix with anions
  • optimal pH range 4 – 6
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63
Q

Nonionic SAA

A
  • e.g. Tweens, Myrjs (polyoxylethylene stearates
  • often used in combination
    • e.g. Tween 80 + Span 80
  • stable to pH changes and electrolytes.
  • most commonly used and compatible to most drugs
    *
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64
Q

Natural SAA

A
  • Can form o/w or w/o emulsions
  • Stable over a wide pH range
  • Physical barrier
  • O/W: acacia, gelatin (protein), and lecithin
  • W/O: cholesterol and lanolin
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65
Q

hydrophilic colloids

A
  • Acacia and gelatin
  • multimolecular layers around the dispersed droplets of oil in o/w emulsion
  • don’t lower surface tension much
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66
Q

Finely divided particles

A
  • form a film of particles
  • Physical barrier
  • e.g. zinc oxide, graphite, and magnesium hydroxide
  • powder wetted preferentially by water form o/w emulsions
  • powders wetted preferentially by oil form w/o emulsions
  • W/O: Calamine liniment (Calamine is a mixture of ZnO with 0.5% Fe2O3)
  • O/W: Magnesia Magma • Mineral oil
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67
Q

To be effective, emulsifying agents must

A

have some solubility in both phases (cannot be exclusively soluble in one phase).

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68
Q

Type of emulsifying agents

A
  • Surfactants
  • Finely divided solid particles
  • Hydrophilic colloids
  • Auxiliary emulsifying agents
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69
Q

Methods for determining the type of unknown emulsions

A
  • use water soluble dyes
    • Ex: amaranth, a water soluble dye gives color to o/w emulsions, but not to w/o emulsions
    • Oil soluble dyes would be used for w/o emulsions;
  • dilute with the appropriate solvent
    • water is added to w/o emulsions, it will not be mixed
    • Oil mixes well
  • measure conductance (based on the electrical conductivity of aqueous solutions)
    • If the current is passed, it is o/w and if is not passed, it is w/o.
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70
Q

How to choose emulisifying agents

A

* hydrophilic emulsifying agent, if o/w

  • hydrophobic emulsifying agent, if w/o
  • often used in combination
    • e.g. Na lauryl S04 + Stearyl alcohol in Hydrophilic ointment USP –caution incompatibility
  • note instability of agents at various pH’s
  • choose a nontoxic compound. Tweens and spans are not toxic.
  • take care of taste
  • take care of odor
  • should be chemically stable.
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71
Q

Physical Stability of Emulsions

A
  • ​important for maintenance of elegance, odor, color
  • Physical instability caused by:
    • movement of droplets ­increasing– creaming for O/W emulsions
    • movement of droplets decreasing – sedimentation for W/O emulsion
  • movements of droplets are reversible and can be reversed by shaking
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72
Q

Stokes Law

A

v=(d2(ps-po)g/18no =terminal velocity (cm/sec)

  • d: diameter of droplet
  • ps and po: densities of dispersed phase and dispersing medium, respectively
  • g: gravitational force
  • no: viscosity of dispersing medium
  • To decrease V
    • decrease d, make ps=po
    • increase viscosity
  • Hard to decrease d, so usually increase viscosity
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73
Q

Cracking of Emulsions

A
  • aggregation and coalescence of droplets to form separate phases – cracking
  • This process is irreversible.
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74
Q

Inversion of Emulsions

A
  • Brought about by
    • electrolytes
      • ex:sodium stearate + CaC12 ® Ca stearate (lipophilic) make o/w go to w/o
    • ​change in phase-volume ratio
      • ​add water to w/o to get o/w
      • best to make emulsions such that the dispersed phase (droplets) is not greater than 50% v/v
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75
Q

Changing Temperature of Emulsions

A
  • w/o at high temperature, but o/w at low temperature
  • due to temperature-dependent changes in aqueous solubility of emulsifying agents
  • Surfactants are associated with water (hydration)
  • Dehydration will occur at high temperature and thus surfactants become less water soluble
    • caution should be taken when a long-term storage of emulsions in a refrigerator is needed
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76
Q

Chemical Stability of Emulsions

A

hydrolysis; oxidation, etc.

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77
Q

Microbial stability of Emulsions

A
  • add preservatives
    • Ex: parabens – especially acacia containing emulsion
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78
Q

Emulsions Beyond Use Date

A
  • In general, emulsions for internal use have 14 day beyond-use date
  • External use products: 1 month beyond-use date
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79
Q

An example of emulsion

A
  • Clobetasol propionate, a synthetic corticosteroid, for topical dermatologic use.
  • Clobetasol ointment (w/o): each gram of the 0.05% ointment contains clobetasol propionate 0.5 mg in a base of propylene glycol, sorbitan sesquioleate, and white petrolatum (this is an oil base)
  • Clobetasol cream is o/w emulsion with a water base
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80
Q

Wet gum (English) method of making emulsion

A
  • oil added to water
  • make mucilage by triturating 2 parts of water with one part of gum (e.g., acacia)
  • add 4 parts of oil (and oil miscible ingredients) gradually in increments with trituration to form the primary emulsion
  • then add water gradually to volume with trituration
  • add ingredients miscible with external phase (water) before making up to volume
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81
Q

Example of a preparation of an emulsion by Dry gum (Continental) method

A
  • the oil:water:acacia ratio (4:2:1) is the same as wet gum
  • order of mixing acacia and oil is different for preparation of a primary emulsion
  • dissolve or mix any necessary ingredients in oil
  • mix 1 part of E.A. (acacia) with 4 parts of oil
  • add 2 parts of water all at once while triturating rapidly until the primary emulsion is complete
  • add external phase (water) and other water miscible ingredients gradually to volume while triturating
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82
Q

Suspensions: Definitions

A

Suspensions are liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble.

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83
Q

Oral Suspensions

A
  • e.g., aluminum suspension as antacid, Tylenol suspension
  • have already been prepared (ready-to-use), usually for stable drugs. A manufactured oral suspension should be used if available
  • Oral suspensions for unstable drugs, e.g., penicillin are often available as dry powders and need to be reconstituted before use by adding vehicle
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84
Q

Topical suspensions

A
  • application to the skin for a local effect
  • which have already been prepared (ready-to-use), usually for stable drugs. A manufactured topical suspension should be used if available.
  • Topical suspensions for unstable drugs are available as dry powders and need to be reconstituted before use. Some physicians like to create their own unique suspensions for patients with particular skin conditions
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85
Q

Sterile suspensions for injection

A

e.g., IM suspensions for penicillin.

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86
Q

Pharmaceutical significance of suspensions

A
  • Easy use for patients (very sick patients, children and infants) unable to swallow solid dosage forms such as whole tablets or capsules.
  • Making insoluble drugs palatable, e.g., pediatric suspensions with flavorings to mask disagreeable taste.
  • Because bioavailability of drugs in a suspension is comparable to that in a solution, suspensions are often used as experimental formulations in new drug development.
  • For aesthetic appeal, e.g., dermatological pastes.
  • For prolonged therapeutic effect, e.g., IM suspensions of penicillin and insulin.
  • For stability reason of certain drugs. Some drugs may be more stable when present as a solid, e.g., penicillin.
  • Suspensions are much easier to prepare and use than solid dosage forms.
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87
Q

Formulation consideration and desired properties of suspensions

A
  • Solid articles in suspensions should settle slowly (a physical stability issue)
  • Suspensions should be easily resuspended by shaking:
  • Chemical stability: For example, drug hydrolysis in water.
  • Microbiological stability: Antimicrobial preservatives can be added if necessary.
  • Physical changes:
  • Wetting
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88
Q

Suspensions should be easily resuspended by shaking

A
  • Solid particles in suspensions should not form a hard “cake” on the bottom of the bottle upon standing.
  • Suspensions should not be too viscous so that redispersion is difficult.
  • Suspensions are thermodynamically unstable, and therefore one aspect of physical stability of suspensions is concerned with keeping the particles uniformly distributed throughout the dispersion.
  • two major physical stability considerations: 1) how to control sedimentation; 2) how to prevent particles from caking?
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89
Q

Sedimentation Rate of Suspension Manipulation

A
  • Particle size (d) should be small enough
    • achieved through choice of drug form and proper compounding equipments/techniques
    • Particle size should not be too small (easy to cake) or too large (easy to settle).
  • ps and po should be equal (ideally)
  • the density of the vehicle can be increased by adding sucrose, glycerin, sorbitol or other soluble or water-miscible additives
  • Glycerin has a density of 1.25, Syrup NF has a density of 1.313, and Sorbitol 70% has a density of 1.285.
  • The viscosity (ηo) of the liquid may be increased to decrease the sedimentation rate (v) by adding a viscosity agent (e.g., structure vehicles).
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90
Q

Structured vehicles

A
  • aqueous solutions of polymers
  • pseudoplastic or plastic property, that is, the viscosity of the liquid can be decreased upon shaking, but the suspensions can maintain a high viscosity on standing, which is desired for pharmaceutical suspensions
  • A dilatent fluid will increase its viscosity upon shaking (e.g., a cornstarch/water mixture). Such dilatent fluids should never be used in pharmaceutical suspensions.
  • Polymers used as structured vehicles include sodium carboxymethylcellulose, acacia, tragacanth, and bentonite. Note some of such polymers are anionic, and thus not compatible with charged drugs.
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91
Q

Physical Changes of Suspensions

A
  • Solid particles must remain unchanged in size and form. Crystal growth can lead to changes in particle size. Polymorphic, amorphous-to-crystalline, and degree of hydration of drugs can also change the form and size of particles.
  • There should be no physical changes in other suspension ingredients (i.e., sugar crystallization). Crystallization should be prevented.
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92
Q

Wetting Suspensions

A
  • If the liquid vehicle (e.g., glycerin) is one with a low surface tension, this is usually not a problem; the liquid can easily wet the solid.
  • In most situations, water constitutes all or part of the dispersing vehicle. Since water has a high surface tension and does not easily wet many solids, especially hydrophobic drugs, we need to consider the following
    • If the powders are hydrophilic, they will be wet easily by water or any other polar solvents. In this case, no special additives are necessary. Two common examples of such powders are ZnO and Calamine.​
    • If the powders are hydrophobic, either a water-miscible liquid with a low surface tension or a wetting agent must be added. Such water-miscible liquids include glycerin, alcohol, propylene glycol, or polyethylene glycol. The wetting agent can be a surfactant such as sodium stearate, sodium lauryl sulfate, docusate sodium, and Tween 80. Note that all additives must be approved for internal use if suspensions are to be used internally
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93
Q

Control of flocculation in suspensions

A
  • prevent formation of a compact “hard” cake of particles that is difficult to redisperse
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94
Q

Attractive forces between particles in suspensions

A
  • Van der Waals interactions or induced dipole-induced dipole interactions
  • Dipole-dipole interactions
  • Molecular bridging provided by including surfactants or polymers in suspensions
  • Adsorption of surfactants and/or polymers onto surface of particles in suspensions causes molecular interactions between surfaces bearing adsorbed surfactants and/or polymers, with the relatively long carbon chains in surfactants or polymers.
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95
Q

Repulsive forces between particles in suspensions

A
  • Electrical repulsion between particles carrying the same charges.
  • Adsorption of ions present in suspensions onto surface of particles. The sources of ions can be impurities, ionic surfactants, and electrolytes.
  • Ionization of molecules situated on the surface of particles, depending on pH and pKa values of the molecules.
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96
Q

Flocculated suspensions

A
  • formation of light, fluffy groups of particles held together by attractive forces which are predominant
  • present as large flocs and form loose scaffold-like structure.
  • These particles settle rapidly because they form the large flocs, but do not cake, and can always be resuspened with gentle shaking as particles do not bond tightly to each other.
  • clear supernatant boundary
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97
Q

Deflocculated suspensions

A
  • repulsive forces between particles are predominate
  • Particles repel and present as discrete, separate entities.
  • Particles in deflocculated suspension settle very slowly as each particle settles separately and the size of particle is small, but ultimately form dense sediment (cake) which is difficult to resuspend.

No clear boundary after precipitation

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98
Q

Why “hard” cake?

A
  • Downward movement due to gravity and the lateral motion due to Brownian movement facilitate tight packing of larger particles with the smaller particles filling the void spaces.
  • Particles at the bottom of the cake are gradually pressed together by the weight of the ones above.
99
Q

Flocculation in pharmaceutical solutions

A

Good pharmaceutical suspensions are best achieved through the formation of a stable floc which resists the tendency toward deflocculation.

100
Q

How to control flocculation practically?

A
  • Addition of electrolytes to reduce repulsive forces to bring particles together to from loose flocs. See the example shown in the figure below.
  • Use of surfactants in suspensions. In addition to promoting wetting, ionic surfactants adsorbed onto the surface of particles can cause surface charges, if the surfactants used are ionic surfactants. Surfactants adsorbed onto the surface of particles can also build up molecular bridging to bring particles together
101
Q

How to determine if a suspension is a flocculated or deflocculated suspension?

A
  • Flocculated suspensions: There is a distinct boundary between the sediment and the supernatant liquid; the liquid above the sediment is clear because even small particles present in the systems are associated with the flocs.
  • Deflocculated suspensions: No clear boundary is formed, and the supernatant remains turbid for a considerably longer period of time.
  • The supernatant is clear or turbid during the initial stages of setting is a good indication that the suspension is flocculated or deflocculated, respectively.
102
Q

Caking Diagram

A

y axis is measure of surface charge

103
Q

Steps to compounding a suspension

A
  1. Reduction of particle size, wetting and dispersion of the active ingredient
  2. Stabilization of the dispersed solid powder
  3. Preparation of the vehicle
  4. Addition and dispersion of active ingredients in vehicle
  5. Addition of remaining ingredients and final mixing
104
Q

Step 1 of compounding a suspension: Reduction of particle size, wetting and dispersion of the active ingredient

A
  • Use dry mill to achieve target particle size and particle size range. In pharmacy, mortar nd pestle are used for particle size reduction (grind or levigation).
  • Drug powder may be treated with a water miscible material such as glycerin to aid in wetting. A surfactant is frequently added to the water to aid in wetting and displacement of air. Additives such as preservatives and buffers are frequently added at this solid dispersion stage.
105
Q

Step 2 of compounding a suspension: Stabilization of the dispersed solid powder

A

If necessary, addition of electrolytes (as flocculating agent) to neutralize surface charges of solid particles. From a practical aspect, this is not effective except where particles are in the relative small size range (i.e. < 1 μm).

106
Q

Step 3 of compounding a suspension: Preparation of the vehicle

A

Prepare structured vehicle that can stabilize the dispersion by limiting particle movement due to its high viscosity.

107
Q

Step 4 of compounding a suspension: Addition and dispersion of active ingredients in vehicle

A

Active ingredient is then added to the vehicle with trituration. The mixture is then homogenized to ensure uniform dispersion of the ingredients. Any high energy process (e.g., a high-speed blender or homogenizer) which has a tendency to incorporate air into the suspension should be done with care since these mixtures may contain surface active compounds which promote foaming, and the viscosity of suspensions makes it difficult to remove air bubbles from the suspensions.

108
Q

Step 5 of compounding a suspension: Addition of remaining ingredients and final mixing

A
  • Sensitive ingredients such as flavours are added after the high energy step. Finally, water is added to bring the suspension to its target volume.
109
Q

Antacid oral suspension: Sorbitol solution role

A

increasing density

110
Q

Antacid oral suspension: Syrup (sucrose) role

A

increasing density and viscosity

111
Q

Antacid oral suspension: Glycerin role

A

wetting, levigating agent

112
Q

Antacide Oral Suspension: Methylparaben and Propylparaben role

A

antimicrobial preservative

113
Q

Evaluation of Suspension: F value

A
  • F is Vu/Vo
  • Vu is volume of the sediment after a suspension reaches equilibrium
  • Vo is the original volume of a suspension before setting
  • Vu is usually smaller than Vo. For pharmaceutical suspensions, 0 < F < 1. A good pharmaceutical suspension would have a F value close to 1.0.
114
Q

Evaluation of Suspension

A
  • F Values
  • Suspensions should be redispersed with less than 20 shakes.
  • Stable over time?
115
Q

Evalution of Suspension: Stable over time?

A
  • Beyond-use dates should be conservative.
  • Oral: If the drug is stable, 1 month beyond-use date.If stability of the drug is unknown, 7-14 days beyond-use date and storage in a refrigerator if appropriate.
  • Topical: If the stability of the drug is known to be long, 2-6 months beyond-use date. Use shorter beyond-use date for other products (consult literature).
116
Q

Tablet Definition

A

Solid dosage forms containing drug substances with or without suitable diluents and prepared either by compression or molding.

117
Q

Tablet Compression vs. Molding

A
  • Compression – large scale
  • Molding – small scale: dampened tab material in mold -> ejected -> allow to dry
118
Q

Compressed Tablets

A
  • Prepared by single compression with no special coating.
  • Most commonly done – tableting machine exerts pressure, combining diluents, binders, fillers used to promote adhesion of particles
119
Q

Multiple Compressed Tablet

A
  • Made by more than one compression cycle; results in multilayered tablet.
  • Purpose is 2-stage release of a drug such as 2 drugs that are incompatible, e.g. Hyzaar, Entex-PSE
120
Q

Sugar Coated Tablet

A
  • Compressed tablet covered with a water soluble, usually colored sugar coat
  • protects drug from air and humidity and may help overcome objectionable drug taste
  • Coating may be up to 50% of size (sometimes undesirable) à more difficult to swallow, e.g. Dimetapp
121
Q

Film Coated Tablet

A
  • Compressed tablet covered with a thin water soluble polymer coating; durable protection
  • To mask taste, e.g. Bayer Aspirin
122
Q

Enteric Coated Tablet

A
  • Compressed tablet with a film coat that resists dissolution in acidic environment of the stomach
  • used to delay tablet disintegration
  • Weak acid coatings resist disintegration in stomach pH, therefore minimize GI irritation, e.g. Ecotrin, Erythromycin
123
Q

Controlled Release Tablet

A
  • Tablet formulated to release drug at a controlled rate
  • e.g. Theo-dur
124
Q

Chewable Tablet

A
  • Compressed tablet designed for smooth rapid disintegration when chewed or swallowed
  • usually flavored
  • Desirable for children, flavor is important, e.g. Children’s chewable Tylenol
125
Q

Buccal and Sublingual tablet

A
  • Flat, compressed tablets intended to be dissolved in the buccal pouch and under the tongue, respectively.
  • Not intended to be chewed
  • Buccal tabs are a little thicker than sublingual tabs to produce a slower rate of absorption
    • e.g. Nitroglycerin (NTG) sublingual tablets Fentanyl buccal tablets
  • ​ODT – orally disintegrable tablets, “melt” when placed in mouth, e.g. Prevacid, Zydis, Zofran
126
Q

Effervescent Tablet

A
  • Contain Sodium bicarbonate and an organic acid such as tartaric or citric; when placed in water these ingredients react liberating carbon dioxid
    • e.g. Alka Seltzer
127
Q

Regular vs. Enteric tablet

A
  • Regular: dissolve fast, immediate effect, chest pain
  • Enteric: for platelet, better for maintain, less irritation
128
Q

Compressed Tablets contain fillers and excipients

A

done by punch and die method

129
Q

Tablet Characteristics – all measured at time of production

A
  1. Thickness
  2. Weight
  3. Hardness to resist chipping but soft enough to disintegrate
  4. Disintegration
  5. Dissolution – in vitro test measuring percent of drug dissolved at a specific time
  • uncoated – 30 minutes
  • coated – up to 2 hours
  • sublingual – 3 minutes
130
Q

Tablet Ingredients

A
  • All need to be compatible
  1. Diluents – add bulk, e.g. lactose
  2. Binders – promote adhesion of particles, e.g. starch, gelatin
  3. Lubricants – enhance flow of material into dyes
  4. Glidants – more flowable than lubrican
  5. Colorants- for esthetics, or product ID
  6. Flavorants – taste, e.g. mannitol, sucrose
  7. Disintegrants – help to break up the tablet by absorbing water, e.g. starch, cellulose
131
Q

Method of Production: Direct Compression

A
  • Used when the drug exits as a granular material with inherent free flowing as well as cohesive properties.
  • Poweder to tablet
132
Q

Method to Production: Granulation Techniques

A
  • Must be used to convert the powdered drug mixture into granules with the desired properties of flow and cohesion.
  • Powder to Granules to Tablets
133
Q

Dry Granulation

A
  • Used when the drug is moisture sensitive; slugging, by double compression, resulting in a larger tablet.
    1. Mixture compressed into slugs.
    • Drug + Binder
  1. ​​Slugs broken up and sized by and screening
  2. Lubricants added and tablets compressed
134
Q

Wet Granulation

A
  • Most widely used 10-20% corn starch 25-50% glucose solution, molasses, cellulose, acacia, gelatin
    1. ​Ingredients weighed and mixed with water.
    2. Wet granules or damp mass screened into pellets or granules, and dried at high temperature
    3. Granules sized by screening.
    4. Lubricants added and tablets compressed

Other wet granulation techniques: fluid-bed, spray-drying, Congealing, spheronization

135
Q

Compressed Suppositories or Inserts

A

more popular than vaginal suppositories because they are less messy, e.g. vaginal inserts product local effect

136
Q

Troches

A
  • compressed tablets, dissolve slowly,e.g. Mycelex
  • Put on tongue to treat thrush
137
Q

Cachets

A

made up with flour and water (not in U.S.)

138
Q

Pills

A
  • round solid oral dosage forms, usually made by hand
  • Not as common
139
Q

Sugar Coating Process

A
  • oldest method, least used today
  • Multistep Process
    • usually single compression, finishing, coloring, waterproofing, sealing, subcoating, smoothing, rounding
  • Problems time consuming, expensive, tablets are large and convex
140
Q

Film Coating Process

A
  • water soluble coat, thin, with raised or Depressed monogram
141
Q

Components of Coat

A
  • Polymer, e.g. methylcellulose, water soluble
  • Plasticiser for flexibility, elasticity, durability, e.g. cellulose, PEG
  • Colorant - esthetic
  • Solvent, e.g. water
142
Q

Problems with Coats

A
  • flaking, uneven coloring, rough, bridging (monogram is filled)
143
Q

Air Suspension Coating

A
  • sprayed on powder or granule suspended in air
144
Q

Compression Coating used to make multi layered tablets

A
  • e.g. Meclizine (Antivert)
  • Problem is tablets are friable and degradable
145
Q

Gelatin Coating (gelcap)

A
  • gelatin coated
  • Ingredient to make smaller sized tablet (up to 1/3)
146
Q

Modified Release Technology

A

delayed-release

147
Q

Enteric Coatings: Mechanism

A
  • to avoid GI irritation
  • Strong acid environment of the stomach (pH 1) maintains the weaker acid groups of the coating (pka 5) in the protonated, uncharged state and therefore insoluble.
  • Coating is a weak acid:
    • Low pH – protonated to unionized to insoluble
    • High pH – unprotonated to ionized to soluble
    • e.g. Ery-tabs, coating is phthalic acid coat,

pH 4-6

* **Erythromycin capsules, enteric coating is over the granules of capsules**
148
Q

Modified Release Technology: Polyacid polymers used

A
  • Cellulose acetate phthalate
  • Polyvinyl acetate phthalate, more moisture stable
  • Hydroxypropylmethylcellulose phthalate
149
Q

Controlled Release versus Sustained Release

A

Controlled release dosage form results in sustained release drug action

  • Controlled release refers to the drug delivery system that precisely controls the rate at which drug is released to the site of absorption.
  • The result of controlled release technology is drug release and action that is referred to as sustained, prolonged, extended, timed or slow.
150
Q

Extended-release technology and coating: Coated beads, granules or microspheres

A

Drug is coated onto inert beads (sugar, starch or microcrystalline cellulose). Then, the beads are coated with a lipid material (e.g. beeswax, ethylcellulose etc.). Mixtures of coated, less coated and uncoated granules produce the desired controlled release of the drug e.g. dexedrine (dextroamphetamine) spansules (Smith Kline Beecham) used to treat obesity.

151
Q

Extended-release technology and coating: Microencapsution

A

The “wall” material (e.g. gelatin) is first dissolved in water. To this is added the material to be encapsulated, and then a second material, usually acacia, is added to concentrate the gelatin into tiny liquid droplets. These droplets coat the particles of the drug to be encapsulated e.g. Micro-K, extended release KCI. Different rates of drug release may be obtained by changing the core: wall ratio.

152
Q

Extended-release technology and coating: Embedding drug in slowly eroding matrix

A

Drug granules are made with a material (lipid or cellulosic) which slowly erodes in body fluids, thus resulting in granules which progressively release the drug for absorption. Combination of drug granules and drug-excipient granules provide extended release action. The granules may be tableted or formulated as a capsule. In the body, the tablet (or capsule material) is wetted and the polymer forms a gel layer around the tablet. The drug diffuses through this layer. As the outer gel layer becomes completely hydrated, it erodes and a new gel layer will form with any polymer still remaining in the tablet. E.g. Valrelease (15mg slow release valium) is equivalent to conventional 5 mg Valium taken three times daily). Multilayered tablets can be prepared with one layer containing the uncombined drug for immediate release and the other layer having the drug embedded in a hydrophilic matrix for extended release.

153
Q

Extended-release technology and coating: Embedding drug in inert plastic matrix

A

Drug is granulated with an inert plastic material e.g. polyethlene, polyvinyl acetate or polymethacrylate and then compressed into tablets. Drug is slowly released from the plastic matrix by leaching into the body fluids e.g. Gradumet, methamphetamine from Abbott.

154
Q

Extended-release technology and coating: Ion exchange

A

A resin-drug complex is granulated and then tableted, encapsulated or suspended in an aqueous vehicle. The release of the drug from the complex is dependent on pH and the electrolyte concentration in the GI tract e.g. Tussionex, chlorpheniramine polistirex suspension.

In the stomach:

  • Drug resinate + HCI <-> acidic resin + drug hydrochloride
  • Resin salt + HCI <-> resin chloride + acidic drug

In the intestine:

  • Drug resinate + NaCI <-> sodium resinate + drug hydrochloride
  • Resin salt + NaCl <-> resin chloride + sodium salt of drug.
155
Q

Extended-release technology and coating: Osmotic Pump

A

Oros system developed bv Alza. The core tablet is surrounded by a semipermeable membrane with a laser produced 0.4 mm diameter hole. The core tablet has two layers, the drug layer and an osmotically active layer. The latter draws water from the GI tract through the membrane. As pressure within the tablet increases, a solution of the drug is ejected out through the 0.4mm orifice. The rate of influx of water depends on the osmotic layer and the thickness and composition of the membrane. Pfizer has a similar system for Glucotrol extended release tablets and Procardia XL extended release tablets.

156
Q

Immediate release vs. Controlled release graph

A
  • Immediate release will have a short but quick peak
  • Controlled release will be more sustained but not as quick.
157
Q

Immediate Release

A
  • conventional dosage forms
  • Rapid onset of action, within minutes
  • Short duration of action, minutes to 1-2 hours in general
  • Examples: sugar coated, film coated, gelatin coated, air suspension, chewable, buccal, sublingual, troches, water soluble –> all can be crushed
158
Q

Modified release

A
  • Drug release features based on time, course, and/or location.
    *
159
Q

extended release:

A

FDA – dosage forms allow reduction of dosing frequency.

160
Q

delayed release:

A
  • Dosage forms release drug at a time other than promptly after administration.
  • Maybe time based or based on environment (GI pH).
161
Q

Repeat action:​

A

Contain two single doses of medication, one for immediate release (IR) and the second, delayed release (DR). eg. two layer tablet.

162
Q

Target release:

A
  • Drug release directed toward isolating or concentrating a drug in a body region, tissue, or site of absorption or for drug action. eg. vancomycin oral solution.
163
Q

Features of E.R. products:

A

1) released at a predetermined rate.
2) Dissolve in GI fluids.
3) Maintain a sufficient time in GI blood level.
4) Absorbed at rate that will replace the amount of drug being metabolized and excreted.

164
Q

Benefits of ER products

A
  1. neither very slow nor very fast rates of absorption and excretion.
  2. Uniformly absorbed from GI tract.
  3. Relatively good margin of safety.
  4. Used in the treatment of chronic rather than acute conditions.
  5. Improvement of therapeutic efficacy.
  6. Enhance patient adherence, i.e. convenience.
  7. Minimize toxicity due to predictable continuous blood levels.
165
Q

Disadvantages of ER products

A
  1. Drug not easily retrieved if there is any adverse reaction.
  2. Release pattern cannot be modified to meet individual needs
  3. Expensive.
166
Q

Hydrocarbon (Oleaginous) Ointment

A
  • Characteristics
    • Insoluble in water
    • Not water-washable
    • Anhydrous
    • Will not absorb water
    • Emollient
    • Occlusive
    • Greasy
  • Example:
    • White Petrolatum
    • White Ointment
    • Vegetable shortening
    • Vaseline®
167
Q

Water-in-Oil Emulsion Absorbtion Ointment

A
  • Characteristics
    • Insoluble in water
    • Not water-washable
    • Contains water
    • Can absorb water (limited)
    • Emollient
    • OcclusiveGreasy
  • Example
    • Hydrous Lanolin
    • Cold Cream Rose water oint
    • Eucerin®
    • Hydrocream®
168
Q

Anhydrous Absorption Ointment

A
  • Characteristics
    • Insoluble in water
    • Not water-washable
    • Anhydrous
    • Can absorb water
    • Emollient
    • Occlusive
    • Greasy
  • Examples:
    • Hydrophilic Petrolatum
    • Lanolin
    • Aquaphor®
    • Aquabase®
    • Polysorb®
169
Q

Water-Removable (Oil-in-Water Emulsion) Ointment

A
  • Characteristics
    • Insoluble in water
    • Water washable
    • Contains water
    • Can absorb water
    • Non-occlusive
    • Non-greasy
    • Lipid-free
  • “Creams”
  • Examples:
    • Hydrophilic Ointment
    • Vanishing Cream
    • Dermabase®
    • Velvachol®
    • Unibase®
170
Q

Water soluable “Gels”

A
  • Characteristics
    • Water soluable
    • Water washable
    • May contain water
    • Can absorb water (limited)
    • Non-occlusive
    • Non-greasy
    • Lipid Free
  • Examples
    • Polyethylene Glycol
    • Ointment
171
Q

Absorption bases have two subgroups

A

(1) Anhydrous absorption bases
* These are hydrocarbon bases that contain an emulsifier or emulsifiers that form water-in-oil emulsions when water is added.
(2) Water-in-oil emulsions
* These are absorption bases that contain water, the amount depending on the base.

172
Q

Incorporation prep of ointment

A
  • Mixing all ingredients of ointment together
    • a. Reduce particle size of powder
    • b. Mix ingredients by geometric addition

*

173
Q

Sulfur Ointment

A
  • Levigate Sulfur to a smooth paste with liq. Pet. And incorporate into white Pet.
  • Place final product in white oint jar. Make swirl. Clean edge of container. Make sure oint does not touch inside of the lid.
  • Sulfur – insoluble in H2O
        Hydrophobic

    Scabicide/Insecticide
  • White Pet – Hydrocarbon from petroleum
                Insoluble in water and alcohol

            Soluble in oils

            Emollient

            Vehicle for other ointment preps
  • Therapeutic use of Sulfur ung:
  • Treatment for scabies (old time)
  • Anti-pruritic effect
174
Q

Fusion prep of ointment

A
  • Melting ingredients – cooling with constant stirring →solid
  • Rosewater ointment
175
Q

Rose water ointment (cold cream)

A

​1) Melt Spermaceti and white wax

2) Add Liq. Pet. And continue to heat until 70°C
3) Dissolve Na Borate in water and rose water in a separate beaker
4) Add to melted mixture, stirring rapidly and continuously until temp ↓~ 45°C
5) Add rose oil (color optional)
6) Fill jar – label

176
Q

Cetyl Esters

A
  • Spermaceti: (from head of sperm whale)
  • Saturated fatty alcohols and saturated fatty acids
  • Melts @ 43-47°C
  • Insoluble in water – Soluble in boiling alcohol, ether and chloroform
  • Used for its consistency and texture to ointments
177
Q

White wax:

A
  • Insoluble in water
  • Soluble in chloroform, ether, oils, hydrocarbons
  • Used as a stiffening agent in ointments
178
Q

Na Borate: Na2 B4 O7

A
  • -Used to produce a white and creamy cold cream by SAPONIFICATION of FA in white wax at high temp
  • -Yields an emulsifying agent that supports the formation of a w/o emulsion
179
Q

Therapeutic use of rose water ung:

A
  • (recipe from a famous roman physician – pharmacist Galen 1st of AD)
  • Ceratum Refrigerans
  • -Emollient
  • -Cleansing cream
  • -Ointment base
180
Q

Gel formation with Carbopol

A
  • Carbopol: water soluble polymers made up of acrylic acids
  • Anionic due to – COOH groups
  • Forms salts – COO –Na+
  • Aqueous solution pH 2.8-3.2

Carbopol resin (presolvated) state is tightly coiled. Dispersed in water, the molecule is hydrated and uncoils to produce a certain viscosity. To generate high viscosity, the molecule must be uncoiled and extended by neutralizing with a base (Trolamine)

181
Q

Ointments Definition

A
  • Semi solid preps intended for external application to the skin or mucous membranes, with or without medicinal subs.
    *
182
Q

Creams Definition and Uses

A
  • viscous liquid or semi solid emulsions of either o/w or w/o
           Uses: emollients, after administration, water evaporates leaving   behind a thin residue film (external is water, internal is oil)
183
Q

Pastes: Defintion and Uses

A
  • Differ from oints. Contain large (20%) of solid material. Thicker, stiffer than oints.

Generally more absorptive and less greasy e.g. TAC dental paste. Uses: Use: on acute lesions that tend to crust or ooze.

184
Q

Lotions: Defintions and Uses

A
  • finely powdered subs that are insoluble in the dispersion medium – Prepared as emulsions. Their fluidity permits rapid and uniform application over a wider area *shake* e.g. Calamine lotion
185
Q

Hydrocarbon Bases

A
  • good (best) for lipophilic drugs (because mixes) Nonpolar, unionized, hydrophobic not destroyed by water. Do not dry out.
    a) Petrolatum USP – a mixture of semisolid hydrocarbon from petroleum- aka yellow petrolatum
    b) White petrolatum USP – decolorized petrolatum - aka white petrolatum jelly (Vaseline ®)
    c) Yellow ointment – petrolatum 95%, yellow wax 5% (from honeycomb) - aka simple ointment
    d) Mineral oil – Liquid petrolatum – Paraffin -> Mixture of liquid hydrocarbons from petroleum. Good levigating agent e.g. zinc oxide salicylic acid
186
Q

Stratum Corneum

A

primary barrier to absorption of drugs to produce systemic effect. Outer layer dead skin cells (surface film)

187
Q

Absorption bases (w/o)

A

Absorb (more) water to become w/o (oil/water) emulsion. If they are already w/o emulsions, they will absorb more water. – Hydrophilic, anhydrous or partially hydrous.

188
Q

Hydrophilic petrolatum

A

absorbs water to form w/o emulsions Aquaphor ®. Can absorb 3 times its weight in water. Good for water soluble drugs in an oleaginous base.

189
Q

Anhydrous lanolin

A

Fat like substance from the wool of sheep with less than 25% H2O.

Absorbs water to form w/o aka refined wool fat.

190
Q

Lanolin

A

contains 25-30% water as w/o emulsions will absorb more H2O

191
Q

Cold cream

A

forms w/o because water content is less than 45%. White w/o emulsion. Sodium soap emulsifier is formed from sodium borate and fatty acids in waxes during fusion, Eucerin®

192
Q

Water removable bases (o/w)

A

aka “water washable”. Non occlusive, non-greasy, resemble creams. Therapeutically they can absorb serous discharge – offer drying effect. Banishing cream – o/w 60-75% H2O. Hydrophilic oint USP

193
Q

Water-soluble bases

A

contain only water soluble ingredients.

     PEG 3350 (solid)  400g        PEG

     PEG  400 (liquid)  600g        oint

Gels: can also make a water-soluble base using water, PEG and some gelling agent – either a carbomer or cellulose derivative.

194
Q

Selection of appropriate base

A

Hydrophilic Hydrophobic

     Ionized                         Nonionized

     Polar                             Nonpolar

a) Drug stability – must be put in a compatible phase
b) Vehicle type depends upon location and condition of skin

195
Q

Desirable properties of oint bases:

A
  1. Chemically and physically stable under normal conditions of use and storage.
  2. Non reactive and compatible with a wide variety of drugs and auxiliary agents.
  3. Free from objectionable odor.
  4. Nontoxic, nonsensitizing and nonirritating.
  5. Aesthetically appealing, easy to apply and nongreasy (face).
  6. Remains in contact with the skin until removal is desired then is removed easily.
196
Q

General Principals of Choosing Vehicle

A
  • Wet wound, want hydrophilic base, water removable base
  • Rash (dry wound), promote moisture, use lipophilic base , occlusive base
  • Thick skin, need occlusive

Creams–> moist lesions

Pastes–>Areas needed to be protected

Lotion–>large areas

197
Q

Percutaneous Absorption

A
  • The absorption of substances from outside the skin to positions beneath the skin.

Ointments/Creams/Lotions/Gels/Pastes

Patches

198
Q

Anatomy of Skin

A

Largest, heaviest organ, 2 square meters (BSA-have to calculate this on NAPLEX without calculator)

Used as a route of drug administration for local, regional and systemic effects

199
Q

Surface film of Skin

A

thin film, pH 4-6.5, made up of sebum from hair follicles, sweat, dead cells

200
Q

Epidermis of skin

A

outermost layer of stratified squamous epithelial cells

a. Stratum corneum – (primary barrier) 15-30 layers of keratinized cells
b. Stratum germinativum – layer from which new cells are germinated

2 layers:

  • stratum spinosum
  • stratum basale: cell division
201
Q

Dermis of Skin

A

fibrous protein matrix of collagen and elastin

  • where all the nerves and muscles are
  • supports the epidermis
  • contains blood vessels and nerves
202
Q

Factors affecting penetration of the skin by drugs

A

Composition and condition of the skin

 \*\*Nature of the drug (including nature of the vehicle)

**surface film is no barrier**

203
Q

Stratum corneum

This is the major obstacle:

A
  • acts as physical and chemical barrier, it limits penetration of UV light, microorganisms and toxic substances
    *
204
Q

Strateum Corneum Composition

A
  • Composition: 40% protein (keratin)
  • 40% water makes skin supple (water and lipids)
  • **20% lipids
  • Composition and thickness vary depending on the areas
  • ear < axillary < scalp<trunk> &lt;&gt;</trunk>
205
Q

Strateum Corneum Condition:

A

hydration ­ penetration

Stratum corneum is hygroscopic but relativelynon-permeable to water. As hydration increases, percutaneous absorption (PA) increases,

e.g. vehicle, bandage absorbs water (ex: baby skin is developing, so apply sparingly, give reduced amount of drug)

Male and female skin is the same in composition.

206
Q

Occlusive

A

increase hydration because it forms a barrier to moisture loss –> ointment (lipid soluble topical, best for lips when skiing, NOT chap-stick, wax that doesn’t melt)

207
Q

Solubility – drug in the vehicle

A

Oleaginous –>oil soluble (oints) –> good vehicle for lipophilic drugs ********

Aqueous –> water soluble (creams) –> good vehicle for hydrophilic drugs

208
Q

Nature of the drug

A

Drugs pass through the semi permeable membrane by diffusion down their concentration gradient

209
Q

Concentration : ­ increase penetration

A

As the concentration in the vehicle increases, the rate and the extent of PA increases

210
Q

Solubility: hydrophilic and lipophilic characteristic desirable.

A

Drugs must have some degree of solubility in both water and oil for effective PA

In general, aqueous solubility determines its concentration presented to the absorption site and lipid solubility influences its rate of transport across the absorption site

211
Q

Absorption enhancers – to increase absorption and penetration

A

May work indirectly to release drugs from the vehicle (propylene glycol) or by directly affecting the structure of the stratum corneum or combination of both

  • Water **
  • Alcohol, ethanol **
  • Propylene glycol **
  • Dimethylsulfoxide (DMSO), toxic –> dermal and ocular effects ** can cause brain damage in high concentration, cancer and eye dryness
212
Q
A

Most of these effects overlap from one level to the next

213
Q

Surface – effects can be classified into 3 areas:

A

a. Cleansing, e.g., antimicrobials soaps for acne, e.g. Betadine, chlorhexidine (ICU patients get chlorhexidine bath and treat nose for MRSA)
b. Protective, e.g. sun blockers (Zinc oxide not block UV damage, only protective, need sunscreen for UV protection)
c. Occlusive – form a barrier to moisture loss, promote water retention, e.g. Vaseline, lanolin, cocoa butter

214
Q

Stratum corneum- absorption, some degree of systemic effects

A
  • Protective, e.g., sunblockers containing benzophenone or octyl methoxycinnamate, topical antibiotics containing bacitracin, neomycin (polysporin has 2 antibiotic and good enough, some people have neomycin allergy)
  • Moisturizing – include humectants, substances that attract and hold water, e.g. glycerin or propylene glycol
  • Emollient – soften skin
    • Urea –>keratolytic, humectant
    • Lactic acid
    • Allantoin –> softens keratin
  • Keratolytic – acne, psoriasis
    • Remove keratinized layers
    • Acne products –> promote sebaceous duct pathway
    • Psoriasis products –> remove cell aggregates
215
Q

Dermis – Systemic Effects

A
  • Anesthetics – benzocaine, lidocaine Topical anesthetics
  • Antipruritics – (antiitch) e.g., hydrocortisone, diphenhydramine
  • Counterirritants – e.g., methyl salicylate, Ben-gay
216
Q

TDDS Transdermal Delivery System

A

passage of drug substances from surface of skin to systemic circulation (useful for drugs with wide therapeutic range. Ex: Nitroglycerin, but not digoxin)

217
Q

2 types:TDDS

A

Monolithic: DRUG –MATRIX layer

Matrix controls rate of drug release

Membrane-controlled:

Release of drug in the reservoir through the controlling membrane is constant

218
Q

TDDS: Special considerations:

A
  • Apply to dry, clean area of the skin (shaven if applicable)
  • Remove old patch before applying new, fresh patch
  • Absorption varies with sites of application (ex: testoderm vs. androderm)
  • Should not cut patches- liquid spill out of reservoir (consult with Manufacturer
219
Q

TDDS: Disadvantages:

A
  1. Allergy to adhesive material. Contact dermatitis.
  2. Absorption varies with medical condition, e.g. fever causes vasodilation thus increases absorption of drug from patch
  3. Esthetics
  4. Skin irritation/rash
220
Q

TDDS: Advantages

A
  1. Avoid GI toxicity, degradation, interaction with food
  2. Can be used as alternative to oral when N/V, diarrhea (NPO)
  3. Avoid parenteral admin (peripheral vein loss, muscle decrease, thrombocytopenia)
  4. Can be used as an alternative drug delivery system
  5. Drug effect terminated by removal of patch
  6. Convenient, multiple dosing with a single administration
  7. Easily identify by markings and physical features of patch
221
Q

USP (795) - Compounding non sterile preparations General principles:

A
  1. Personnel are capable and qualified to perform their assigned duties.
  2. Ingredients used in compounding have their expected identity, quality and purity.
  3. Compounded preparations are of acceptable strength, quality, and purity, with appropriate packaging and labeling, and prepared in accordance with good compounding practices, official standards and relevant scientific data and information. Tailored to needs (ex: 12.5mg oxycodone that is not commercially available)
  4. Critical processes are validated to ensure that procedures, when used, will consistently result in the expected qualities in the finished preparation.
  5. The compounding environment is suitable to the intended purpose.
  6. Appropriate stability evaluation is performed or determined from the literature for establishing reliable beyond-use dating to ensure that the finished preparations have their expected potency, purity, quality, and characteristics, at least until the labeled beyond-use date.
  7. There is assurance that processes are always carried out as intended or specified and are under control.
  8. Compounding procedures and conditions are adequate for preventing errors.
    • Ability to troubleshoot errors
  9. Adequate procedures and records exist for investigating and correcting failures or problems in compounding, testing, or in the preparation itself.
222
Q

Suppositories Definition

A
  • Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften or dissolve and exert localized or systemic effect.

Suppositories –>from the latin word “supponere”–> to place under

223
Q

Suppository vs Oral Dose

A

Dose can be greater, lesser or equal than that of oral depending on

1) nature of the drug
2) ability of absorption,
3) capacity of releasing the drug

224
Q

Pharmaceutical Significance: Suppositories

A
  • Localized action, e.g. hemorrhoidal pain, inflammation and itching, e.g. Preparation H; constipation, e.g. glycerin,bisacodyl
  • Systemic action,
  • e.g. aminophylline for asthma control
                      promethazine – antiemetic relief

                   oxymorphine – pain control

                   ergotamine – to treat migraines
225
Q

Suppositories Advantages

A
  1. avoids inactivation by pH or enzyme activity of the stomach or intestines
  2. avoids irritation to the stomach, e.g. aspirin
  3. avoids first pass effect, liver metabolism, e.g.albuterol, progesterone.
  4. difficulty in swallowing, e.g. children – aminophylline
  5. nausea and vomiting, e.g. prochlorperazine
  6. when a rapid action is needed, e.g. aspirin, actaminophen
226
Q

Types of Suppositories: Rectal

A

(a) Adult–tapered at one or both ends, about 2g each 1.5 inch, shape –> bullet or torpedo

Gloves when inserting rectal suppositories

(b) Infant 1g each
* * ½ size, ½ weight, pencil shape**

  • Weights based on when cocoa butter (theobroma oil) is used as a base
  • used for systemic (e.g. acetaminophen) and local effect (e.g. glycerin for lubricating effect)
227
Q

Types of Suppositories: Vaginal

A
  • Vaginal (pessaries)–USP specification: globular or oviform, weighing about 5g each (cocoa butter as the base)
  • Inserted with special insertion appliance
  • Weight and size may vary depending on manufacturer

PEG or glycerinated gelatin is the preferred base since cocoa butter leaks. Also slow release sometime desirable. Wear a pad because it leaks

228
Q

Urethral Suppository

A
  • Urethral (bougies) - rarely encountered

4g, pencil shape, 3-6 mm diameter, 140 mm in length

male urethral suppositories are longer than the female urethral suppositories

229
Q

Nasal and Aural Supositories

A

Not Used Anymore

230
Q

Rectum

A
  • 150 mm long, has abundant vascularization
  • No villi/microvilli on rectal mucosa
  • small amount of fluid of low buffering capacity —> 2-3 ml of inert mucus
  • pH 7.2
  • epithelium lipoidal in rectum
  • lower, middle and upper hemorrhoidal vein
  • only upper hemorrhoidal vein empties into the portal system (i.e., liver) and the lower and middle veins empty into the vena cava
231
Q

Factors affecting drug absorption: in rectum

A
  1. colonic content
  2. pH
  3. diarrhea
  4. tissue dehydration
  5. lack of buffering capacity of rectal fluids
  6. colonic obstruction (e.g. tumors, ileus)
232
Q

Suppository Bases

A

base can be active or inactive (vehicle). Should be stable, nonirritating, inert, compatible with drugs, and not interfere with the release of drugs.

Two main bases: important characteristics include melting, softening,

dissolving to release the drug and do not interact with the active drug.

233
Q

Fatty, e.g. cocoa butter (theobroma oil), suppository base

A

needs to melt to release drug.

            * *Fat soluble drugs in cocoa butter (CB) remain in oil, immiscible in aqueous physiologic fluids**
             - If drug is too soluble in base, it will not be readily released for absorption.
234
Q

Coca butter (theobroma oil) suppository base

A
  • melts to form a non-viscous, bland oil
  • yellow solid, faint chocolate odor
  • mixture of triglycerides
  • immiscible with water
  • pleasing property b polymorphic form melts at ≈ 35°
  • (body temperature 36.9°)
  • **keep this in mind when compounding**:
    • do not melt too rapidly or at high temperature ( > 40-50°C) or cool too quickly to avoid formation of a polymorphic form which melts at room temperature
  • *This is a good base for water-soluble drugs**
235
Q

** CB: desirable base for relief of imflammation or irritation**

A
  • Polymorphism properties; CB exists in several different crystallineforms:
    • beta form – more stable, higher melting point 34-35C
    • alpha form - melting point 22C
    • **gamma form – melting point – 18C **
  • **alpha and gamma are unstable forms **
236
Q

Fattibase:

A

Stable, non-irritating, melting point 35-37°C, opaque-white. Composed of triglycerde from palm, palm kernel and coconut oils with self-emulsifying glyceryl monostearate.

237
Q

Wecobee and Witepsol

A

Stable, excellent mold release characteristics. Witepsol – wide range of melting points, can contain emulsifiers, hence can incorporate limited quantity of water.

238
Q

Water soluble, e.g. polyethylene glycols (PEG’s), glycerinated gelatin, polybase

A
  • dissolve in mucous; hygroscopic –> takes up water;
  • no temperature problem for storage but dehydrates and irritates tissue. Avoid irritation by wetting before insertion. Release rate slower than cocoa butter because dissolves slowly
  • moisten suppository by dipping in water (lukewarm water so that it has some hydration)
  • should contain preservatives, eg. parabens
239
Q

Types of water soluble bases: Suppositories

A
  • Glycerinated gelatin - [glycerin (70% w/w), gelatin (20% w/w) and H2O plus drug (10% w/w)]
    • usually vaginal suppositories since they exert an osmotic effect and defecation reflex.​
  • olyethylene glycols - - (CH2 - 0 - CH2)x - x= mol. wt.
    • Polymers of ethylene oxide and water, prepared to various chain lengths, molecular weights and physical states
      • e.g., PEG 200 - 600 colorless liquid
      • PEG 1000 - 8000 white waxy solids
    • use various combination of PEG’s to obtain required degree of consistency and hardness
240
Q

Rate of Drug Release Suppositories

A
  • Cocoa butter base liquefies in 3-7 minutes
  • Glycerinated gel liquefies in 30-40 minutes
  • PEG liguefies in 30-50 minutes
  • Oil soluble drug - oily base ® slow release, poor escaping tendency
  • Water soluble drug - oily base ® rapid release desirable
  • Oil soluble drug - water miscible base ® rapid release rate desirable
  • Water miscible drug - water miscible base ® moderate release, based on diffusion, all water soluble.
241
Q

Suppository making: By hand

A
  • hand rolling and shaping
    • avoids heat and need of a mold
    • ​requires skill
    • not uniform in size, shape and contents –> problem
242
Q

Suppository making: Molding/fusion

A

most common method, mold after melting. Molds are made of stainless steel, brass, aluminum or plastic

  1. Disperse or dissolve drug in melted suppository base - care with cocoa butter with the respect to temperature. Do not heat cocoa butter to > 40-50°C. Should heat to creamy-hazy appearance not to a clear yellow state. PEG can be heated to melt at 60°C.
  2. Add lubricant [e.g., mineral oil (water soluble bases), Tincture of Green Soap (oil soluble bases)] to a clean (unscratched) mold
  3. Pour base and drug into the mold, keeping any drug in suspension by constant stirring
  4. Cool at room temperature or in a refrigerator
  5. Slice off excess suppository
  6. Open mold and avoid scraping the mold
243
Q
A

Pceut 531 (3 decks)

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