Concentrations that are effective but not toxic Sufficiently soluble in water o Commonly used: Alcohol (5%-10%) Propylene glycol (10%) Parabens Combinations of these are synergistic Organic acids – benzoic acid, sorbic acid Only the free acid form of the preservative is effective o Therefore the pH of the solution matters - Anti-oxidants o Suicide substrates with better affinity for oxygen than the API o i.e. abscrobic acid, sodium bisulphite, butylated hydroxytoluene - Viscosity-enhancing agents o Organoleptic property o Ensures adequate measurement of volume dispensed o i.e. cellulose derivatives, sodium carboxymethylcellulose, sodium alginate Types of non-oral liquid solutions - Parenteral – sterile solutions for injection or infusion - Pulmonary – inhalation solutions administered by pressurized metered dose inhalers or by nebulizers for local or systemic effect - Nasal – designed to be administered to the nasal passage in drops or sprays - Ophthalmic – to be administered within conjunctival sac - Optic – applied to external auditory canal - Mouthwashes & gargles – for prevention and treatment of mouth and throat infections - Rectal – enemas or rectal injections to evacuate bowel or exert local or systemic therapeutic effect - Topical skin/nail/hair – solution applied to skin for local and/or systemic effect
Solubility & Dissolution Phenomena Drug solubility - To be in solubility, drug has to be molecularly dispersed – complete separation with no cohesive forces between molecules o 100% interaction with the solvent - Immediately around the particle surface is where you have the most concentrated solution o Called diffusion or particle layer - Diffusion – movement from high solute concentration to low solute concentration o Reaches equilibrium when there is uniform distribution and equal concentration of solute molecules throughout the solvent - Different polymorphs have different solubilities & melting points o Solubility & melting point are inversely related Higher melting point = lower solubility & vice versa o Also true for structural analogs, such as sulfa drugs - Substituents have their own classifications o Methyl – hydrophobic o Carboxylic acid – slightly hydrophilic Esters (carboxylic acid derivative) can be used to increase permeability o Amine – hydrophilic Improves permeability o Alcohol – very hydrophilic Used when feel the need to introduce hydrophilicity o Help us determine whether a drug will be soluble by looking at the OVERALL structure o On their own, weak acids are very slightly soluble - Ex. Pentobarbital is practically insoluble in water; what can you do formulation-wise? o Cosolvent Solubilize in alcohol, PEG, etc. Typically see 10-fold improvement o Buffers Works if you have an ionizable group but still limited gain 5-fold or 6-fold o Salts If you have an ionizable group WILL GIVE YOU BIGGEST GAIN Usually far superior to cosolvent Becomes a new molecule & if you’re already into trials when you figure this out, have to start all over o Micellization Very rare & only in select cases Precipitation pH calculations -
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- Fall '09