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Pharmaceutical formulation EXAM > Suspensions 1 + 2 + 3 > Flashcards

Suspensions 1 + 2 + 3 Flashcards

1
Q

What are suspensions?

A
  • Suspensions are dispersions of solid particles in a vehicle
  • In pharmacy, the term “suspension” usually refers to a solid in a liquid dispersion
  • Oral, dermal (eg lotions), parenteral (eg IM injections), nasal, otic, ophthalmic, MDI, rectal suspensions.

> Solution (molecular dispersion) –> 1nm –> transparent

> Colloidal dispersion (1nm-1um) –> translucent

> Suspension (coarse dispersion) –> 0.5 um –> opaque

  • A suspension is formulated when the active ingredient is required in a concentration that exceeds its solubility in the desired vehicle.
  • The drug will dissolve up to its solubility and the rest will be in the form of undissolved particles.
  • A suspension is, therefore, a dispersion of undissolved drug in a saturated solution of the drug. (so don’t filter)
  • Key issue is ensuring that the medicament remains evenly dispersed – dose reproducibility (shake the bottle)
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2
Q

What are some reasons for suspension formulation?

A
  • Poor solubility precludes solution
  • Drug stability compared to solution
  • Ease of administration
  • Rapid effect compared to tablets
  • Palatability compared to solution
  • (Injection suspension formulation provide sustained release of drug)
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3
Q

What are mixtures? How are they related to suspensions?

A
  • Liquid preparations intended for oral administration
  • Oral Suspensions are a sub-group of mixtures
  • May be extemporaneously prepared or manufactured for long-term storage
  • Combinations of medicaments dissolved, diffused or suspended in an aqueous vehicle.
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4
Q

What are some reasons for mixtures?

A
  • Medicament may be more readily available (than solid oral dosage forms)
  • Reduced gastric irritation
  • Improved effectiveness
  • Overcome oesophageal retention
  • Ease of administration
  • Suspensions reduce unpleasant taste of solutions
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5
Q

What are diffusible solids? Give some examples.

A
  • Insoluble but easily wetted
  • Dispersible in water (without suspending agent)
  • Rare
  • May be a substance that is beyond its normal solubility

Eg Sodium bicarbonate 1-11, Caffeine citrate 1 - 32

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6
Q

What are indiffusible solids?

A
  • Medicaments do not easily disperse in water
  • Most drugs are hydrophobic – poorly wetted and dispersed
  • Eg. Internal: Paracetamol, Sulfonamides External: Calamine, sulfur, corticosteroids
  • Require wetting and use of a suspending agent to achieve a suspension.
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7
Q

Discuss the wetting of powders and contact angle.

A
  • Contact angle formed between a solid and a liquid (usually water) indicates how wettable it is.
  • decrease contact angle – more wettable
  • increase contact angle – not wettable
  • A layer of adsorbed air may prevent a solid being wetted by the vehicle.
  • Use of less polar liquids (eg glycerol, syrup) can displace the air and allow wetting by water.
  • Surfactants eg polysorbate may be required to achieve wetting. Surfactants should be used at concentration below CMC to avoid solubilisation effects.
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8
Q

What are suspensing agents? Provide some examples/

A

Indiffusible solids require a suspending agent to achieve even dispersion

Eg:

  • Pulv. Trag. Co
  • Tragacanth mucilage
  • Sodium CMC
  • Sodium alginate
  • Carbopol = carbomer
  • Bentonite (hydrophilic colloids)
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9
Q

How to compound oral suspennsions?

A

see attached image

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10
Q

What is required for long term storage of pharmaceutical suspensions?

A
  • remain suspended - very difficult in the long term
  • pour easily
  • re-disperse any sediment easily
  • maintain bioavailability - avoid crystal growth

Same principles apply for other suspension formulations

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11
Q

What are some important pharmaceutical principles?

A
  • Fine particle size required and work done in reducing the particle size
  • Increased free energy
  • Thermodynamic instability from the large surface area giving a tendency to flocculate or form a compacted cake
  • ΔG = γsl . ΔA
  • Hydrophobic drugs dispersed in water acquire a charge. Usually as a result of adsorption of OH- from water –> negative charge.
  • The electrical double layer is created around the charged particles (see colloids)
  • DLVO theory of lyophobic colloids can be applied to suspensions
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12
Q

What does a potential energy curve look like? DLVO theory of lyophobic colloids can be applied to suspensions.

A

See attached image

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13
Q

Why do particles move?

A
  • Brownian motion – very few tiny particles (<1-2μm)
  • Thermal effects
  • Gravitational effects (>0.5 μm)
  • In response to shaking
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14
Q

Discuss the physical stability of suspensions

A
  • When repulsion is high (“like” charges) particles stay apart – deflocculated (peptised)
  • Gravity causes suspension particles to sediment eventually (Brownian motion has little impact)
  • Large particles sediment first and then small particles fill up gaps between them
  • Weight of the growing sediment forces particles closer together –> attraction in the primary minimum = caking (agglomeration of particles)
  • May be possible to redisperse, but only with considerable force
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15
Q

How are pharmaceutical suspensions different from hydrophobic colloids

A
  • Particles sediment
  • Include surfactant Vs effects
  • Flocculation in secondary minimum (reversible)
  • Flocculation is possible in primary minimum (reversible but not so for colloids)
  • Depth of primary minimum restricted by adsorbed layer (Vs) and fewer contact points from lower surface areas
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16
Q

What are some basic requirements to minimize irreversible caking?

A
  1. Controlled Flocculation
  2. Deflocculated with a structured vehicle
  3. Flocculation and structured vehicle
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17
Q

How is flocculated suspension achieved? How is flocculation different in colloids?

A
  • ​Aim to flocculate particles by trapping in a secondary minimum.
  • Particles are attracted to one another but remain separated
  • The large bulk of loosely flocculated sediment
  • Redispersible on shaking
  • Hence lack of caking

With suspensions (unlike colloids) “flocculation” may be achieved in the primary minimum as well as secondary minimum

> Flocs are more dense than in secondary minimum flocculation

> Size and irregular shape of particles reduces points of contact

> Presence of adsorbed surfactant prevents very close approach of particles

> Size of particles leads to significant kinetic energy on shaking –> redispersion

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18
Q

What are the differences between caking (deflocculated) vs flocculation

A

Caking = small volume of sediment, close packing of particles, difficult to redisperese

Flocculated= high volume of sediment, floc behaves like one giant particle, easily redispersed

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19
Q

How is the characteristics of sedimentation different over time between flocculation and caking (deflocculated)?

A

See attached image.

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20
Q

What is the equation of sedimentation? How is it measured?

A

F = Vu/Vo

  • F = sedimentation volume
  • Vu = ultimate volume of sediment
  • Vo = original volume of suspension

The greater the volume of sediment, the better

β = Vu/V∞

  • β is the degree of flocculation
  • Vu is the ultimate sedimentation volume of the flocculated suspension
  • V∞ is the ultimate sedimentation volume of the deflocculated suspension
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21
Q

How to control flocculation using electrolytes?

A
  • Flocculation can be achieved by reduction of zeta potential by use of counterions.
  • Decreasing ζ potential reduces the size of Vmax and increases the depth of the secondary minimum.
  • Use inorganic salts to flocculate drug particles of opposite charge

Eg: Sulfamerazine- + AlCl3 (Al+++) and Bismuth subnitrate+ + KH2PO4-

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22
Q

SHow how controlled flocculation works in a graph? What impact does zeta potential have with flocculation?

A

See attached image

  • As ζ potential approaches zero, suspension is flocculated with high sedimentation volume (no caking) and clear supernatant
  • At high magnitude ζ potential, suspension is deflocculated with caking and cloudy supernatant
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23
Q

Discuss the properties of a potential energy curve in suspensions

A
  • secondary minimum larger in suspensions
  • primary minimum shallower in suspensions
  • Particles trapped in secondary minimum = flocculation (esp if Vmax reduced, secondary minimum increased by use of electrolytes)
  • Particles with more energy than secondary minimum, but less than Vmax = deflocculated
  • Particles with more energy than Vmax = primary min –> caking = deflocculated particles sedimenting under gravity
  • Particles with low zeta potential AND surfactant = flocculation (may be in primary or secondary minimum)

VA + VR –> shape modified when Vs added

24
Q

How to use controlled flocculation using polymers? Why is concentration critical

A
  • Polymer bridging is an alternative method of producing flocculation.
  • Hydrophilic colloids used as suspending agents are hydrophilic macromolecules
  • They can adsorb onto particles
  • At suitable concentrations, each molecule can adsorb onto multiple particles forming “bridges” that join the particles into a floc

Concentration is critical

  • excess can lead to deflocculation – if all binding sites on a particle have polymer adsorbed, bridging ceases and particles are separated by steric hindrance.
  • Less affected by the addition of electrolytes
  • Effectiveness depends on affinity for the particle surface, charge, size, and orientation of polymer in the continuous phase.
  • Commonly used suspending agents can have this effect in addition to increasing viscosity

At low concentrations of polymer: little bridging takes place –> relatively low sedimentation vol

At normal concentrations of polymer: maximal bridging occurs –> flocculation and high sedimentation vol

At high polymer concentrations: all sites on particle are full –> no opportunities for bridging –> steric stabilisation –> deflocculation and very low sedimentation vol.

25
Q

Name five characteristics of a flocculated suspension?

A
  • Larger secondary minimum
  • Shallower primary minimum
  • Flocculation may occur in the primary or secondary minimum
  • Larger sedimentation volume
  • No caking
  • Clear supernatant (within hours)
  • Rapid sedimentation (within hours)
26
Q

What effects do surfactants have on flocculation?

A
  • Surfactants are adsorbed onto particles and can produce flocculation
  • Adsorption of ionic surfactants affects zeta potential - counterions –> reduction similar to electrolyte addition. Possibility of bridging effects.
  • Adsorption of surfactants can also induce deflocculation – steric hindrance or ζ potential effects.
  • Concentration must not exceed CMC or solubilisation of the drug may occur
  • Surfactants often incorporated as wetting agents in low concentration – can affect flocculation status of product.
27
Q

Discuss the properties of deflocculated (peptised) suspensions. Why is deflocculated suspensions desired?

A
  • Want to limit the rate of sedimentation of particles to delay/avoid caking
  • Rate of sedimentation governed by Stokes’ Law
  • Can’t influence gravity
  • Limited opportunity to influence density
  • Can alter particle size or viscosity to reduce sedimentation rate
  • Decrease particle size by trituration to reduce sedimentation rate
  • Increase viscosity of continuous phase to reduce sedimentation rate – use of Structured Vehicles (suspending agents)
  • Can use knowledge of rheological properties of vehicles to advantage

Note: particle size also influences the rate of dissolution of the drug once it is taken –> affecting absorption

28
Q

What is the effect of particle size on sedimentation and suspensions?

A
  • Reduction in particle size reduces the magnitude of secondary minimum
  • Very small particles are subject to Brownian motion diffusion –> ∴ ↓ particle size to <1-2μm –> ↑diffusion –> separates particles
  • Smaller particles have reduced sedimentation rate
  • Smaller particle size –> greater free energy –> ↑ tendency to cake
  • Smaller particle size –> greater dissolution rate in body and in product during periods of elevated temperature
  • Narrow particle size distribution desirable – lower density flocs and less Ostwald ripening
29
Q

What are some rheological considerations for suspensions?

A
  • Suspensions undergo significant shearing forces when the bottle is shaken
  • Increasing viscosity using Newtonian fluids (eg Glycerol) –> difficulties shaking product to redisperse sediment and pouring the dose
  • Non-Newtonian fluids with shear thinning properties +/- thixotropy are advantageous.
30
Q

What suspending agents exhibit non-newtonian/pseudoplastic flow?

A
  • Tragacanth, Sodium Alginate, and Sodium Carboxymethylcellulose all show pseudoplastic flow.
31
Q

What properties do pseudoplastic vehicles have?

A

Pseudoplastic vehicles have high viscosity at low shear and low viscosity at high shear.

  • At rest (on the shelf) the suspension will have high viscosity to inhibit sedimentation.
  • When shaken the suspension becomes more fluid allowing redispersion of any sediment and easy pouring of dose.
32
Q

What is the ideal flow curve for suspension? What are some of the properties it exhibits?

A
  • System has a yield value which means that at rest it behaves like a solid. Shaking exceeds the yield value and viscosity reduces rapidly allowing redispersion and pouring of the dose.
  • Thixotropy allows time to pour dose, but allows viscosity to increase again at rest to impede sedimentation.
  • Flocculation itself results in plastic flow
33
Q

What does plastic flow without thixotropy look like?

A

Plastic flow without thixotropy can be useful also – has yield value, but lacks the time delay before rethickening

34
Q

Use carbopol 934 as an example of a structure vehicle as an alternative to pulv trag co or Na carboxymethylcellulose

A

Carbopol 934 produces plastic or pseudoplastic dispersions without significant thixotropy.

> (Also found to show little variation in apparent viscosity at temperatures between 10oC and 50oC)

35
Q

What is the relationship between rate of sedimentation and viscosity (structured vehicles)?

A

Relationship between rate of sedimentation and viscosity can be complicated:

  • suspensions do not follow Stokes’ Law exactly
  • the nature of the structured vehicle itself can have direct effects on the particles (polymer bridging)
36
Q

How does a ideal formulation combine controlled flocculation with a structured vehicle?

A
  1. Disperse the particles
  2. Flocculate the particles
  3. Add lyophilic colloid as a structured vehicle
37
Q

How to formulate suspensions based on previous question?

A
38
Q

What are some other oral suspension excipients?

A
  • Formulation will require other excipients, including flavouring, sweeteners, colouring, preservative, buffer, antioxidant etc.
  • Ionic status/surface activity of excipients in a formulation will influence flocculation of suspension
  • Some will influence sedimentation characteristics via density and/or viscosity changes
  • Plan full formulation, before controlling flocculation

See attached image for examples of excipients

39
Q

What are clay water systems? What are some examples and their uses?

A

Clays used as suspending agents and/or therapeutic agents

Includes:

  • Kaolin (treat diarrhoea)
  • Bentonite (flocculating/ suspending agent)
  • Hectorite (cosmetics)

All form thixotropic colloidal dispersions in water

40
Q

What are some properties of kaolin? (clay-water systems)

A

Only weakly hydrophilic, so difficult to disperse in water (use glycerol or syrup to wet). Kaolin has mixed charge and forms crystalline hydrates that swell and form gel or mucilage structure by electrostatic attraction.

  • Used in mixtures for diarrhoea – still available commercially overseas as Kaopectate
  • Kaolin is very prone to caking in suspensions
  • Early formulations of Kaolin and Opium Mixture used 2% Light Magnesium Carbonate to partially flocculate the Kaolin.

MgCO3 ↔ Mg2+ (flocculate clay) + CO3-

Problem: MgCO3 only partially soluble. Only Mg2+ in solution that was flocculating. More Mg2+ released to replace it and caused excessive flocculation – gel formation

> Replaced with Potash Alum (soluble) for better control of flocculation.

41
Q

What are some other examples of clay-water systems

A
  • Aluminium Hydroxide Mixture with Kaolin was an APF preparation that used Sodium Citrate as a deflocculating agent to control flocculation to make the product pourable.
  • Calamine Lotion APF also includes Sodium Citrate to deflocculate bentonite.
  • Chlorhexidine added to Calamine Lotion –> semi-solid

Sometimes can overdo flocculation

42
Q

What are some terms used to evaluate suspensions?

A
  • Zeta Potential: electrophoretic methods. ζ potential near zero indicates flocculation.
  • Redispersibility: number of inversions required to redisperse settled suspension indicates degree of flocculation/caking
  • Sedimentation Volume: F = Vu/Vo – well flocculated suspension has ratio close to one
  • Rheological Studies : Can be used to investigate structured vehicles – difficult to interpret.
43
Q

What does crystal growth in suspensions indicate?

A
  • Crystal growth in suspensions is a form of physical instability and may alter bioavailability of drug
  • Crystal growth will promote sedimentation and caking
  • Crystal growth is like a reverse dissolution process (Noyes-Whitney) – transport of molecules to surface and addition to the crystal lattice.
  • Take steps to minimise this occurring
44
Q

What are some crystal growth mechanisms?

A
  • Ostwald Ripening: growth of large particles at the expense of small particles (change in particle size distribution towards larger particles)

> small particles dissolve into molecules which diffuses into a larger particle which crystallises on larger particle

  • Polymorphism: drug may change from metastable form to more stable polymorph. Metastable polymorphs are more soluble, so as change occurs supersaturation leads to deposition on larger particles.
  • Solvation – Drug may convert into another solvated form on storage. Eg Anhydrous crystal may become a hydrate of lower solubility.
45
Q

What is the formula of crystal growth?

A
  • See attached imaage
  • Reduction of interfacial tension (with surfactant) may limit this effect
46
Q

What are some factors influencing crystal growth?

A
  • Concentration: more drug means that particles are closer and crystal growth is more likely
  • Solubility-Temperature Relationship: the stronger the relationship the greater the chance of crystal growth with temperature fluctuations. A “flat” temperature-solubility profile is ideal
  • Agitation: Crystal growth in sediment less likely if product is agitated frequently (BUT if the suspension is very dilute may promote growth)
  • Frequency of Temperature Fluctuations: the more often the temp changes, the greater the chance of crystal growth.
  • Viscosity: increased viscosity reduces the extent of crystal growth
  • Adsorbed substances: surface active agents can reduce crystal growth by 3 mechanisms:

> Decreased interfacial tension

> Increase S∞ by solubilization effect

> Interfere with nucleation: coating particles to inhibit crystal growth. Surfactants may form a net-like cover over particle:

  • Surfactant protect 010,110,001 face of acid crystals
  • C00- groups favour adsorption by cationic surfactants
  • Hydrocarbon and COOH groups favours anionic surfactant adsorption
47
Q

What is the formulation of dry syrups (powder for reconstitution)?

A
  • Dry Syrups are Suspensions that are supplied as a powder that is reconstituted immediately prior to supply or administration
  • Paediatric antibiotic mixtures frequently formulated this way
  • Dry syrup formulations are an option for products that would be too unstable for long-term storage as liquid suspensions
48
Q

What are some examples of formulation types of dry syrups?

A
  • Powder for reconstitution by pharmacist - dispensed to the patient as a prepared suspension – short shelf-life, often refrigerated
  • Sachets – for reconstitution by patient or carer immediately prior to use. Dose controlled by sachet size
  • Bulk product - dose measured by patient prior to reconstitution eg bulk laxative Metamucil
49
Q

What are some advantages of dry syrups?

A
  • Chemical stability – good for drugs that are very unstable (eg undergo hydrolysis)
  • Physical stability – No issues with caking or crystal growth until reconstituted and short shelf-life makes these problems negligible
  • More palatable – Extra option of microencapsulation to disguise taste. Aqueous vehicle more palatable than oily vehicle.
  • Reduced transport weight – cheaper to transport
50
Q

How are dry syrups physically presented?

A
  • Powder admixture: simplest method, but problems with homogeneity. Random mixing or Ordered mixing (small drug particles attach to large excipient particles).
  • Granulation: powder is moistened and granulated as for tablets. Fewer problems with segregation, better flow. Sucrose is good granulator – offers sweetness and viscosity. Drug must be stable to granulation and drying. Flavouring agents may be damaged.
  • Partial Granulation: Granulate drug and some of the excipients and dry blend others in powder form. Blend flavours in powder form to avoid damage by granulation. Part of the diluent (eg sucrose) can be added this way
51
Q

What does a typical formulation of dry syrup consist of?

A
  • Drug
  • Flavouring
  • Sweetener
  • Wetting agent
  • Antifoaming agent

See rest in attached image

52
Q

Compare dry syrups with regular suspensions

A

Some issues face with regular suspensions are eliminated in dry syrups:

  • Control of sedimentation and caking
  • Preservative – may not be required if used immediately (sachets)

BUT some new formulation challenges arise:

  • Need excipients that will dissolve rapidly when product is reconstituted with cold water.
  • Avoid foaming when product reconstituted – incorporate antifoaming agents.
53
Q

What are some viscosity-increasing agents and preservatives used in dry syrups?

A

Visocity increasing agents

  • Acacia
  • PVP
  • Sodium carboxymethlycellulose
  • Tragacanth

Preservatives

  • Potassium sorbate
  • Sodium benzoate
  • Sodium hydroxybenzoate
  • Scurose
54
Q

What are some dry syrup examples

A
55
Q

Hw to achieve sustained release suspension?

A
  • MS Contin® Controlled Release Suspension (Granules for reconstitution)
  • Achieved sustained release from a liquid product
  • Drug is in ion exchange resin beads and is slowly released over 12 hours
  • Reconstituted by the patient immediately prior to administration
  • Must not chew granules –> dose dumping

See attached image for ingredients

Pharmaceutical formulation EXAM (9 decks)

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