The document details a training workshop on pharmaceutical development focusing on pediatric formulations, highlighting the roles and types of excipients in both oral dosage forms like tablets and liquids. It discusses the importance of excipient quality, formulation interactions, and specific issues related to pediatric safety and toxicity of common excipients. Key topics include the functional classifications of excipients, their roles in formulations, and historical concerns regarding safety in pediatric preparations.

1. 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 Pharmaceutical Development

2. Pharmaceutical Development Excipients Presenter: Simon Mills Email: [email_address]

3. 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

4. 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….

5. 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: 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 SiO 2

6. 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 ~20 µg, 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).

7. 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.

8. 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

9. 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

10. 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/cm 3 ) Difficult to work with (very voluminous) Issues with dust exposure

11. 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: 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

12. 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: 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

13. Buffering Agents Necessary to maintain pH of the formulation, thereby 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

14. 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.

15. 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

16. 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

17. 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

18. 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

19. 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 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

20. 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”!

21. 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

22. Paediatric Safety Issues with Common Excipients

23. Solvents/Sweeteners 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: 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

24. 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)

25. 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

26. 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

27. 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)

28. 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)

29. 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)

30. 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

31. 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)

32. 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)

33. 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)

34. 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.

35. 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

36. Summary Overview of Excipients used in Tablets and Oral Liquid/Suspension dosage forms Functional role(s) Paediatric Issues with Excipients ANY QUESTIONS PLEASE?