Excipients PDF

MPharm Programme Excipients Dr Paul Carter MPharm  Excipients Drug often minor component of a dosage form (levothyroxine) Excipients are not therapeutically active, but are present for a purpose Care – excipients control behaviour of dosage...

MPharm Programme Excipients Dr Paul Carter MPharm  Excipients Drug often minor component of a dosage form (levothyroxine) Excipients are not therapeutically active, but are present for a purpose Care – excipients control behaviour of dosage form i.e. can affect bioavailability e.g. tablets Facilitate manufacture/administration/identification Promote consistent drug release/bioavailability Improve stability/protect drug against degradation MPharm  Excipient – ideal properties Stable & reproducible No unintended interaction with drug Pharmacologically inert Give desired function Cost effective Pharma grade – comply with BP, PhEur, or USP-NF (US pharmacopoeia) & manufactured under GMP. MPharm  Excipients - Role Aid in the processing of the drug delivery system during its manufacture Protect, support, or enhance stability, bioavailability, or patient acceptability, Assist in product identification, and enhance any attribute of the overall safety Assist in the effectiveness and/or delivery of the drug in use Assist in maintaining the integrity of the drug product during storage MPharm  Excipients - safety Late 1960s, phenytoin capsules. The calcium sulfate diluent was replaced by lactose giving an increase in the mean serum phenytoin concentration by a factor of 4.5. The drug had a narrow therapeutic index. Lactose is freely soluble in water, whereas the calcium sulphate was slightly soluble. So, the calcium sulphate acted as a matrix and prolonged the release of the drug, whereas lactose gave an immediate and large release of phenytoin (above the toxic threshold). J Neurologic Sci. 1972, 16(4): p. 481-487 In 2007, pharmaceutical manufacturers in Panama used diethylene glycol, instead of glycerin, for the formulation of a cough syrup. Diethylene glycol (antifreeze) is nephrotoxic and hepatotoxic. MPharm  Excipients – adverse effects Excipients can occasionally be the cause of a medicine's side effects. A few examples: Excipient Linked with Glucose and sucrose Obesity, and tooth decay if taken orally Benzyl alcohol A gasping syndrome in neonates Ethanol CNS effects Aspartame A source of phenylalanine in patients with phenylketonuria Polyoxyl castor oils Severe anaphylactoid reactions Propylene glycol CNS effects especially in neonates and children under 4 yrs Colourants (e.g. tartrazine) Hypersensitivity and behavioural disturbances MPharm  Tablet compression/compaction MPharm  Tablet excipients Diluents or bulking agents added to make adequate sized tablet, handling Lactose (α-lactose monohydrate) – pleasant taste good solubility/dissolution low hygroscopicity Inert Spray dried lactose – used for direct compression (DC) Microcrystalline cellulose also good for DC Mannitol for chewable tablets MPharm  Tablet excipients Lubricants Prevent powder/metal adherence – ensure smooth ejection from die Enhance flow properties Magnesium stearate (up to 1 % w/w), hydrophobic Prolong disintegration time, reduce drug dissolution, reduce tablet strength Sodium stearyl fumarate – hydrophilic MPharm  Tablet excipients Binding agents Adhesives to bind particles together during granulation Either added as dry powder during dry granulation or as a solution for wet granulation Starch Polyvinylpyrrolidone (PVP) Glidants Improve flow of powders or granules Reduce interparticulate friction – smooth surface irregularities Colloidal silica MPharm  Tablet excipients Disintegrating agents Cause tablet to disintegrate – increases surface area Swell in contact with water – burst open tablet e.g. starch, croscarmellose sodium (known as a ‘superdisintegrant’) Some work by capillary action, drawing liquid up through pores which disrupts bonds between particles e.g. pregelatinised starch Lyophilised tablets disintegrate with 5 s (orodispersible tablets), mainly sucrose Dyes and flavouring agents Coatings Film or sugar coat Enteric coatings e.g. cellulose acetate phthallate, or polymers (Eudragits) Polymers for M/R release e.g. HPMC (hydroxypropylmethyl cellulose), xanthan gum MPharm  Excipients for Liquid Preparations Water Most widely used – physiologically non-toxic and compatible Good at dissolving ingredients BUT – supports microbiological growth and care with drugs prone to hydrolysis Water miscible co-solvents Enhance solubility, taste and stability Propylene glycol, glycerol, ethanol MPharm  Excipients for Liquid Preparations Buffers Control pH to enable physiological compatibility, microbial and chemical stability and solubility (or insolubility if taste is an issue) Antimicrobial agents Preservatives – prevent growth of opportunistic microbes (from excipients or externally introduced) Anti-oxidants Control oxidation of drug, preservative, other excipients Concentration decreases with time since they oxidise first MPharm  Excipients for Liquid Preparations Wetting agents Decrease interfacial tension Surface active agents (e.g. Cetrimide, SLS), hydrophilic colloids (e.g cellulose derivatives, tragacanth – also act as suspending agents) Antifoaming agents Simeticone Thickening agents Stabilise suspensions – give high viscosity, often thixotropic methylcellulose MPharm  Excipients for Liquid Preparations Sweetening agents Natural – sucrose Artificial – saccharin Flavouring agents Natural – peppermint Artificial – butterscotch Humectants Hygroscopic excipients for external preparations (suspensions, emulsions) e.g. glycerol, PEGs Reduce evaporation of water/aqueous vehicle – prevents drying after application and during product life MPharm