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Solution formulation (2)

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cexoyahe's version from 2017-05-09 12:49

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Drug solubility - Cyclodextrins(1)• Cyclic saccharides produced from digestion of (corn) starch by the enzyme, glucosyltransferase to yield three types of oligosaccharide – α (6),β(7),γ(8) • Size of cavity increases through series • Polar groups on outside, apolar groups on inside • Can incorporate hydrophobic molecules in the cavity if small enough – “inclusion complex”
Drug solubility - Cyclodextrins(2)Can modify CD to improve solubility of CD e.g. hydroxypropyl cyclodextrin • Issues – toxicity of CD – release of drug from CD complex
Drug solubility (1)• Modification of the drug structure to improve physicochemical properties – Improved water solubility – Improved membrane partitioning – E.g. betamethasone vs. betamethasone sodium phosphate ester – Caution: chemical derivatisation creates a new chemical entity that must be re-tested
Drug solubility (2)• Sometimes it is impossible to achieve the necessary aqueous solubility – Alternative is non-aqueous solution – E.g. solution of drug in oil – Intramuscular injection of haloperidol formulated in sesame oil – Remains as globules in muscle and releases drug slowly – Others include: • Oral drops containing fat-soluble vitamins
Drug solubility (3)• What solvents are used in non-aqueous solutions? –Fixed (non-volatile) oils • Fatty acid esters of glycerol – Examples include: arachis oil, almond oil, olive oil, sesame oil, cottonseed oil –Alcohols • Ethanol and isopropyl alcohol are used widely in formulations for external application e.g. skin lotions
Considerations for vehicle acceptability• Quality – Pharmaceutical grade – Microbiological • Consider the route of administration: – Oral • Taste, – Topical • Volatility, irritancy, viscosity – Parenteral, ocular • Toxicity/irritancy,
WHAT ARE THE ACCEPTABLE pH VALUES FOR LIQUID FORMULATIONS?It depends on the intended route of administration…
pH values for liquid formulations• Oral– pH 3-9 for repeated dosing – pH 2-10 for occasional dosing
pH values for liquid formulations• Intravenous– Physiological pH (7.4) is preferable but: • Small volumes (<5mL) pH 5-9 • Larger volumes (>5mL) pH7-8 • If far from physiological pH then central vein administration is necessary to allow rapid dilution and distribution of formulation – Other injectable routes (e.g. intrathecal) • Aim for pH 7.4 • pH range is very narrow
pH values for liquid formulations• Ocular– Target: pH 7.4 – Very narrow range acceptable due to high irritability of ocular surface
pH values for liquid formulations• Nebuliser solutions– pH 6.5 is target – pH 6-7 is acceptable
pH values for liquid formulations• Nasal solutions– pH 6.8 is target – Limited range of acceptable pH
• Sterility is defined as:– “the absence of viable micro-organisms” – it is an absolute concept – something cannot be “almost sterile” – Sterility required for ocular, nebuliser and injectable formulations – Sterile formulations are tested for sterility using standardised tests stipulated by the Pharmacopoeia
Formulation sterility - what are the risks?• If site of administration is sterile then formulation should be sterile • Route of administration of aseptic products – Direct to bloodstream, lungs, ocular surface – Little or no mucosal defence to clear infection or block particulates – Microbes
Antimicrobial preservatives (1)• All formulations should be produced in clean or sterile environments as required • Preservatives should be added to prevent microbial spoiling when products are “in-use” • Single-use preparations: – Sterile solutions with no preservative – E.g. single-use eye drops, single-use injections, nebuliser solutions, all IV infusions, intra-spinal injections
Antimicrobial preservatives (2)• Preservatives are need in formulations that are used repeatedly • They must never be used to ‘clean-up” a product which is contaminated as a result of poor manufacturing – E.g. eye drops, nasal solutions, oral solutions, lotions, multidose vials of injectable solutions – Efficacy of preservatives in each formulation are tested individually
What types of preservatives are used in liquid formulations?• The preservative type depends largely on the type of formulation – E.g. high concentrations of sucrose in syrups are definitely not applicable to solutions for injection
Preservation of oral solutions• Sucrose– minimum 67 %w/v for efficacy – acts by hypertonicity and viscosity – Syrup BP = 67 %w/v in water – to maintain preservative activity, do not dilute – sweet taste – cariogenic – used orally in extemporaneously produced products – not generally used in proprietary products – not used for other rout
Preservation of oral solutions• Sorbic acid– Common preservative in liquid formulations (0.1- 0.2 %w/v) – Needs to be ionised to be effective (pKa ~4.5) therefore slightly acidic formulations are best
Preservation of oral solutions• Benzoic acid / Na + benzoate– Similar to sorbic acid i.e. • Common preservative in liquid formulations • Needs to be ionised to be effective (pKa ~4.5) therefore slightly acidic formulations are bes
Preservation of oral solutions@Parahydoxybenzoates (Parabens)• Alkyl esters (methyl, ethyl, propyl, butyl) of p-hydroxybenzoic acid • Very common preservatives • Good preservative activity across acid pH and up to pH8 (although diminishes above pH 7)) • Often used in combination e.g. Methylsoluble up to 0.25% and Propylsoluble up to 0.02% • Low toxicity is a strength but some problems with allergic reactions • Can be used e.g. oral liquids, eye drops, creams and injectables
Preservation of oral solutions• Chloroform(1)– 0.25 %v/v for oral use – used in extemporaneously produced products – not generally used in proprietary products – not used for other routes – available in a range of concentrations - be careful – has been associated with fatalities when e.g. double strength (0.5%) is confused with concentrated chloroform water (40x strength) – It is volatile and is readily lost by evaporation during manufacturing and use. – This results in only a 2 – 4 week “in use” shelf life being applied to products preserved with Chloroform.
Preservation of oral solutions • Chloroform(2)– It is however nephrotoxic and a recognised carcinogen; particularly toxic to babies (UK is almost unique in still using Chloroform), and has been associated with fatalities when e.g. double strength (0.5%) is confused with concentrated chloroform water (40x strength) – It is volatile and is readily lost by evaporation during manufacturing and use. This results in only a 2 – 4 week “in use” shelf life being applied to products preserved with Chloroform
• Chloroform formulations available– Chloroform water BP (single strength) • 0.25 %v/v chloroform in water – Chloroform water, double strength BP • 0.50 %v/v chloroform in water – Chloroform Spirit BP • 5.00%v/v chloroform in ethanol – Also available is Concentrated Chloroform Water • 10%v/v chloroform and 55% v/v ethanol in water • No longer in British Pharmacopoeia but sometimes seen
Preservation of oral solution; Issues with using chloroform in extemporaneous dispensing• Chloroform water, double strength BP – Use as half total volume to get correct concentration • Chloroform Spirit BP – Use 1/20 volume of final solution – Be aware of ethanol concentration for children • Concentrated Chloroform Water – Use 1/40 volume of final solution – Be aware of ethanol concentration for children
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