Transcript Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007 Slide.

Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
Slide 1.
April 2007
Pharmaceutical Development
Excipients
Presenter:
Simon Mills
Email:
[email protected]
Slide 2.
April 2007
Introduction
 Overview of Excipients commonly used in Oral dosage forms
 Role of Key Tablet Excipients
– Diluents (fillers, bulking agents), Disintegrants, Binders, Lubricants, Glidants
 Role of Key Oral Liquid/Suspension Excipients
– Solvents/co-solvents , Buffering agents, Preservatives, Anti-oxidants,
Wetting agents, Anti-foaming agents, Thickening agents, Sweetening
agents, Flavouring agents, Humectants
 Paediatric Issues with Excipients and Excipient Quality
Slide 3.
April 2007
Excipients
 Drug products contain both drug substance (commonly referred to as active pharmaceutical
ingredient or API) and excipients.
 The resultant biological, chemical and physical properties of the drug product are directly
affected by the excipients chosen, their concentration and interactions with the API.
 Excipients are sub-divided into various functional classifications, depending on the role that
they are intended to play in the resultant formulation.
 Certain excipients can have different functional roles in different formulation types.
e.g. lactose; widely used as:
– a diluent, filler or bulking agent in tablets and capsules
– a carrier for dry powder inhalation products.
 In addition, individual excipients can have different grades, types and sources depending on
those different functional roles….
Slide 4.
April 2007
Tablet Excipients
 ….for example, there are various grades of lactose commercially available that
have different physical properties, e.g. flow characteristics & particle size
distribution. This permits selection of what is considered the most suitable
grade for a particular need, e.g. with tablet development:
– Usually, fine grades of lactose are utilised when manufacturing tablets by the wet granulation
route, as it utilises the binder more efficiently and permits better mixing and granule quality.
– In contrast, spray dried lactose is used for direct compression tablets, as it flows better and is
more compressible.
 In tablets, the key excipient types include:
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Diluents, e.g. lactose, microcrystalline cellulose
Disintegrants, e.g. sodium starch glycolate, croscarmellose sodium
Binders, e.g. PVP, HPMC
Lubricants, e.g. magnesium stearate
Glidants, e.g. colloidal SiO2
Slide 5.
April 2007
Tablet Diluents (Fillers)
 Bulking agent
– To make tablet weight practical for the patient: minimum tablet weight is typically
~50mg. Actual API doses can be as low as ~20µg, e.g. for oral steroids.
 Compression aid
– Deform readily to facilitate production of a robust tablet product.
 Flow aid
– Good flow of bulk powders is very important in tablet manufacture. Lactose can
exhibit poor flow characteristics, so is often supplemented with microcrystalline
cellulose in wet granulation tablets, or is used as the spray dried version
(particularly with direct compression formulations).
Slide 6.
April 2007
Tablet Disintegrants

As an aid to de-aggregation of compacted tablets. Disintegrants cause rapid
break up (disintegration) of the tablet compact upon exposure to moisture.

Generally, disintegration is viewed as the first stage in the dissolution
process, although dissolution does occur simultaneously with disintegration.

Mode of action:
– In many cases water uptake alone will cause disintegration, by rupturing the
intra-particle cohesive forces that hold the tablet together and resulting in
subsequent disintegration.
– If swelling occurs simultaneously with water uptake, the channels for penetration
are widened by physical rupture and the penetration rate of water into the tablet
increased.
Slide 7.
April 2007
Tablet Binders
 Binders act as an adhesive to ‘bind together’ powders or granules
– As a powder in dry granulation (roller compaction, slugging)
– As a solution in wet granulation. Binder can be added either dry with other
excipients for granulation or already dissolved in the granulating fluid; water is
the most common granulating fluid, very occasionally in a co-solvent system
with, e.g. ethanol.
 Binders can be:
– Insoluble in water, e.g. starch
– Soluble in water e.g. HPMC
– Soluble in water and ethanol e.g. Povidone
Slide 8.
April 2007
Tableting Lubricants
 Lubricants prevent adherence of granule/powder to punch die/faces and to
promote smooth ejection from the die after compaction
– Magnesium stearate is by far the most extensively used tableting lubricant
– There are alternatives, e.g. stearic acid, sodium stearyl fumarate, sodium behenate
Just to illustrate the need for effective lubrication; high speed tablet presses can operate at:
– 360,000 tablets/hour ≡ 6000 tablets/min
– 30 stations ≡ 200 tablets/min/station ≡ ca. 3 tablets/second/station
 Lubricants tend to be hydrophobic, so their levels (typically 0.3 – 2%) need to
be optimised:
– Under-lubricated blends tend to flow poorly and show compression sticking problems
– Over-lubricated blends can adversely affect tablet hardness and dissolution rate
Slide 9.
April 2007
Tablet Glidants
E.g. colloidal silicon dioxide
 Improve flow by reducing intra-particulate friction
 Very low levels required (ca. <0.1%)
 Very low bulk density (0.03 – 0.04g/cm3)
– Difficult to work with (very voluminous)
– Issues with dust exposure
Slide 10.
April 2007
Excipients For Oral Suspension Products
 Again, excipients are sub-divided into various functional classifications,
depending on the role that they play in the resultant formulation.
 In Oral Liquid/Suspension products, the possible types of excipients include:
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Solvents/co-solvents e.g. Aqueous Vehicle, Propylene Glycol, Glycerol
Buffering agents, e.g. Citrate, Gluconates, Lactates
Preservatives, e.g. Na Benzoate, Parabens (Me, Pr and Bu), BKC
Anti-oxidants, e.g. BHT, BHA, Ascorbic acid
Wetting agents, e.g. Polysorbates, Sorbitan esters
Anti-foaming agents, e.g. Simethicone
Thickening agents, e.g. Methylcellulose or Hydroxyethylcellulose
Sweetening agents, e.g. Sorbitol, Saccharin, Aspartame, Acesulfame
Flavouring agents, e.g. Peppermint, Lemon oils, Butterscotch, etc.
Humectants, e.g. Propylene Glycol, Glycerol, Sorbitol
Slide 11.
April 2007
Solvents/Co-Solvents
 Water is the solvent most widely used as a vehicle due to:
– Lack of toxicity, physiological compatibility, and good solubilising power (high dielectric constant), but
• Likely to cause instability of hydrolytically unstable drugs
• Good vehicle for microbial growth
 Sorbitol, dextrose, etc. are often added as solubilisers, as well as base sweeteners
– Similar pros and cons
 Water miscible co-solvents are used to:
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Enhance solubility, taste, anti-microbial effectiveness or stability
Reduce oral dose volume?
Or, conversely, optimise insolubility (if taste of API is an issue)
Examples: propylene glycol, glycerol, ethanol, low mol wt PEGs
 Water immiscible co-solvents, e.g.
– Emulsions / microemulsions using fractionated coconut oils
Slide 12.
April 2007
Buffering Agents
 Necessary to maintain pH of the formulation, thereby
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Ensure physiological compatibility
Maintaining/optimising chemical stability
Maintaining/optimising anti-microbial effectiveness
Optimise solubility (or insolubility if taste is an issue)
• But, optimum pH for chemical stability, preservative effectiveness and
solubility (or insolubility) may not be the same
 Compromises need to be made
Slide 13.
April 2007
Preservatives
 Preservatives used in multi-use cosmetic/pharmaceutical products (particularly
paediatric formulations)
– prevents an increased risk of contamination by opportunistic microbial pathogens (from excipients or
introduced externally), resulting in potential health consequences
 Ideally targeted for microbial cells - showing no toxicity/irritancy towards
mammalian cells
– In reality, the majority of effective GRAS preservatives are active against both microbial and
mammalian cells (non-specific cytoplasmic poisons)
 There is a limited number of approved preservatives available for multi-use oral
products, and options are even more limited for other routes of administration.
 This restricted number can be further reduced by dose, pH-solubility profiles,
incompatibilities, adsorption, toxicity and other relevant physico-chemical factors.
Slide 14.
April 2007
Anti-Oxidants
 Used to control oxidation of API, e.g. lovastatin, preservative, e.g. K sorbate
or vehicle, e.g. oils or fats susceptible to β-oxidation
 Sacrificial (more oxidisable than API, preservative, etc). Levels will reduce
with time…. need to be monitored by specific assay
 Need to assess regulatory acceptability (differs in different countries)
 Efficacy can be affected by:
– Compatibility with other excipients
– Partitioning into micelles (from surfactants)
– Adsorption onto surfaces (container, thickening agent and suspended particles)
– Incompatibilities, e.g. with metal ions
Slide 15.
April 2007
Wetting Agents
 To aid ‘wetting’ and dispersion of a hydrophobic API, preservative or
antioxidant
– Reduces interfacial tension between solid and liquid
– Encourages deflocculation (stable colloidal dispersion)
 Examples include
– surface active agents, e.g. polysorbates, sorbitan esters
• But can cause excessive foaming (see anti-foaming agents)
– hydrophilic colloids e.g. bentonite, tragacanth, alginates, cellulose derivative
Slide 16.
April 2007
Anti-Foaming Agents
 Foaming can be caused by the presence of surfactants and
thixotropic thickening agents (which can entrap air in ‘gel-like’
structure) in the liquid formulation.
 A typical example is Simethicone (polydimethylsiloxane-silicon
dioxide), which is used at levels of 1-50ppm
Slide 17.
April 2007
Thickening Agents
 Suspension stabilisers: prevent settling/sedimentation (particularly if a
wetting agent present)
 They usually modify viscosity and are often thixotropic (where viscosity
is dependent on applied shear and exhibits ‘shear thinning’)
• Easily poured when shaken
• Quickly reforms ‘gel-like’ structure
• Can impact on flocculation
 Work by entrapment of solid particles, e.g. API, in a viscous or even
‘gel-like’ structure
– Can be either water soluble, e.g. methylcellulose or hydroxyethylcellulose
– Or water insoluble, e.g. microcrystalline cellulose
Slide 18.
April 2007
Sweetening Agents
 Natural sweeteners
– Sucrose; soluble in water (vehicle), colourless, stable (pH 4-8), increases viscosity
– Sorbitol (non-cariogenic - appropriate for paediatric formulations)
 Artificial sweeteners
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Regulatory review required
Much more intense sweeteners compared with sucrose
As a consequence the levels are much lower (<0.2%)
Can impart a bitter or metallic after-taste (hence used in combination with natural sweeteners),
e.g.
• Saccharin, and it’s salts
• Aspartame
• Acesulfame -K
Slide 19.
April 2007
Flavouring Agents
 Supplements and compliments sweetening agent
– Ensures patient compliance (especially in paediatric formulations – a big issue)
– Can be natural, e.g. peppermint, lemon oils,
– Or artificial e.g. butterscotch, ‘tutti-frutti’ flavour
For instance:
– If the product tastes salty then peach, apricot or liquorice can be used
– If the product tastes bitter then mint, cherry or anise can be used
– If the product tastes too sweet then vanilla can be used
– If the product tastes sour then raspberry or liquorice can be used
 Taste appreciation has a genetic element….. So it is difficult to formulate for
global use
– One person’s acceptable taste is another’s unacceptable taste
 Regulatory acceptability of flavours needs to be checked
– Different sources, different compositions, different flavour, e.g. there are >30 different “strawberry flavours”!
Slide 20.
April 2007
Humectants
 Hygroscopic excipients that are added to prevent cap-locking caused by
evaporation of formulation and subsequent condensation onto neck of
container-closure, e.g. of a bottle after first opening
 Retard evaporation of aqueous vehicle of dosage form
 Examples include
– propylene glycol
– glycerol
– sorbitol
Slide 21.
April 2007
Paediatric Safety Issues
with Common Excipients
Slide 22.
April 2007
Solvents/Sweeteners
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Need for oral liquid preparations (that children typically find easiest to swallow) often
necessitates:
– Taste-masking; which often relies on sweeteners
– Addition of co-solvents to improve drug solubility
Most commonly used solvent/sweeteners are
– Propylene glycol
– Glycerine (Glycerol)
However, there are many historical precedence’s of adulteration of these excipients (e.g. with
diethylene glycol: used in anti-freeze, brake and transmission fluids), often with tragic
consequences:
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Sulphanilamide Elixir Tragedy (1935)
New low solubility antibiotic (sulphanilamide)
Need for a ‘child-friendly’ oral dosage form
Formulators used novel excipient, diethylene glycol
Impetus for formation of US Food & Drugs Administration
Federal Food, Drug and Cosmetic Act (1938) required toxicological testing for all new drugs
Genesis of cGMP’s
Slide 23.
April 2007
Sweeteners
Aspartame Toxicity
– Aspartame is used as an intense sweetener in beverages, food products, and in
pharmaceutical preparations
– It enhances flavour systems and can be used to taste-mask unpleasantly bitter tasting
characteristics of common drugs
– A number of adverse events have been reported following the consumption of large quantities
of aspartame in beverages (Golightly et al, 1988; Butchko and Kotsonis, 1989)
– Although, aspartame has been blamed for hyperactivity in children; a double-blind study of 48
pre-school children who were dosed with diets containing 38±13mg/kg body weight of
aspartame for 3-weeks, showed no appreciable adverse behaviour or impact on cognitive
function (Wolraich et al, 1994)
Slide 24.
April 2007
Solvents
Ethanol Toxicity
– Widely used as a co-solvent to aid solubility
– In US, maximum permitted quantities in OTC products:
• 0.5% for children under 6-years
• 5% for children 6-12-years
• 10% for children over 12-years
– May cause adverse symptoms of intoxication, lethargy, stupor, coma, respiratory depression and
cardiovascular collapse
Peanut Oil Toxicity
– Peanut oil is used as a food additive and as a solvent in intra-muscular injections
– Some workers have suggested that the use of peanut oil in childhood (infant formula and topical
preparations) can lead to later episodes of hypersensitivity, and therefore should be discontinued
Slide 25.
April 2007
Solvents/Preservatives
Propylene Glycol Toxicity
–The development of multi-dose oral liquid and parenteral preparations also
necessitates the requirement for preservative(s) to prevent microbial
contamination as serious microbial infections in the very young can often be
fatal
–Propylene glycol is a general solvent and antimicrobial preservative used in a
wide range of pharmaceutical preparations including oral liquid, topical and
parenteral preparations
–In addition to risks associated with adulteration, its use in large volumes in
children is discouraged, and it has been associated with CNS adverse events,
especially in neonates
Slide 26.
April 2007
Preservatives
Benzyl Alcohol toxicity in neonates
–Widely used as a preservative in cosmetics, foods and pharmaceuticals
(including injectables and oral liquids)
–Toxic syndrome was attributed to the practice of “flushing out” umbilical
catheters with solutions containing benzyl alcohol, because of trace levels of
benzaldehyde that were present
–FDA recommended discontinuation of practice and the use of medicinal
products containing preservatives in neonates (1982)
Slide 27.
April 2007
Preservatives
Na Benzoate toxicity
– Widely used as a preservative in cosmetics, foods and pharmaceuticals (including injectables
and oral liquids)
– Injectable combinations of Na Benzoate and Caffeine should not be used in neonates
– Found to elicit non-immunological contact reactions, including urticaria
– Needs to be taken into account when formulating paediatric products
Thimerosal toxicity
– Formerly widely used as a preservative in cosmetics, in soft contact lens solutions and
pharmaceuticals (including eye drops and vaccines)
– Link with toxicity in eye drops
– Strong links with toxicity in paediatric vaccines
– Banned by EMEA and FDA in 1999 in paediatric vaccines
– Linked with childhood autism, but not substantiated by EMEA (2004) and FDA (2006)
Slide 28.
April 2007
Preservatives
Lactic Acid toxicity (immature metabolism)
–Lactic acid is used in beverages, food, cosmetics and pharmaceuticals
–In topical cosmetics it is used as a skin softener
–In food and beverages it is used as a preservative
–It is usually present as the racemate (RS); but in some cases the S-isomer
predominates
–Lactic acid is the naturally occurring endpoint of anaerobic metabolism of
carbohydrates; so is usually viewed as being non-toxic at the levels used in
typical formulations
–However, there is evidence that neonates have difficulty metabolising the
R-isomer; and hence this isomer and the racemate, should not be used in
infant formulas for children less than 3 months old (WHO, 1974)
Slide 29.
April 2007
Diluents/Fillers
 Lactose toxicity (immature metabolism)
– Lactose occurs widely in dairy products and is used in infant feed formulas
– In pharmaceutical preparations it is widely used as a diluent in tablets and capsules, in lyophilised
powders, and as a carrier in dry powder inhalation products
– Lactose intolerance occurs when there is a deficiency in the intestinal enzyme lactase
– This enzyme is normally present at high levels at birth, declining rapidly in early childhood
– Hypolactasia (malabsorption of lactose) can thus occur at an early age (4-8 years) and varies among
different ethic groups (Suarez and Saviano, 1997)
– It is unlikely that severe gastrointestinal adverse events could result from ingestion of medicinal
products in adults, but it is less clear if this is equally applicable in infants
Slide 30.
April 2007
Anti-oxidants
 Propyl Gallate toxicity
–Used as an anti-oxidant in cosmetics, food and wide range of pharmaceuticals
–Strong sensitising potential in animals
–Few reports of adverse events in humans; but do include methemoglobinemia
(met-Hb) in neonates (Nitzan et al, 1979)
Slide 31.
April 2007
Suspending and Surfactant Agents
– Carrageenan is a naturally occurring gel base or suspending agent derived
from seaweed extracts
• Generally considered to be non-toxic and non-irritating, except in parenteral preparations
• UK Food Advisory Committee did recommend the removal of carrageenan as an additive
in infant food formulas.. because of its ability to induce inflammatory responses in animals
(MAFF, 1992)
– Docusate sodium, an anionic surfactant, is widely used in pharmaceutical
preparations as a wetting agent, dissolution aid and as laxative and faecal
softeners.
• Levels of docusate sodium should be strictly controlled in medicinal products to prevent
diarrhoea, especially in infants. The adult dose (500mg) is over six times the amount
administered to children of 6-months (75mg), and older (Guidott, 1996)
Slide 32.
April 2007
Wetting Agents
– Polyoxyethylene sorbitan fatty acid esters (polysorbates 20, 40 and 60) are
used as emulsifying agents, non-ionic surfactants, solubilising agents,
wetting, dispersing and as suspending agents
• Polysorbates are generally regarded as non-toxic and non-irritant materials
• However, they have been associated with serious adverse events, including some deaths,
in neonates who were administrated with vitamin E intravenous preparations (Alade et al,
1986; Balistreri et al, 1986)
Slide 33.
April 2007
Colorants
Tartrazine toxicity
– Oral Liquid formulations are often complementarily coloured and flavoured to aid in paediatric
patient acceptance and long term compliance.
– For instance, a paediatric formulation might be taste-masked using banana flavour (a particular
favourite of many young children), which would be complemented by the addition of a yellow
colorant.
– One such colorant (FD&C Yellow No. 5 or tartrazine) has long been the subject of much
controversy centred around its safety profile, and its possible link with hives and hyperactivity in
children.
– In the US, any prescription drug containing tratrazine, is labelled:
“This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic reactions (including
bronchial asthma) in certain susceptible persons.”
– Generally speaking, concerns over the safety profile of colorants in pharmaceuticals and foods are
associated with hypersensitivity and hyperactivity.
Slide 34.
April 2007
Lubricants
Talc toxicity
–Talc is commonly used as a dusting powder; and historically has been used as
both a glidant and lubricant
• Although, generally regarded as non-toxic when orally ingested, inhalation
of talc causes irritation and severe respiratory distress in children
Slide 35.
April 2007
Summary
 Overview of Excipients used in Tablets and Oral
Liquid/Suspension dosage forms
– Functional role(s)
– Paediatric Issues with Excipients
ANY QUESTIONS PLEASE?
Slide 36.
April 2007