Solutions - Pharmaceutical Sciences PDF

SOLUTIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Definition  A homogenous one-phase system consisting of two or more components  Solvent → phase in which the dispersion occurs  Solute → component which is dispersed as small molecules or ion...

SOLUTIONS Prof Thiru Govender Discipline of Pharmaceutical Sciences Definition  A homogenous one-phase system consisting of two or more components  Solvent → phase in which the dispersion occurs  Solute → component which is dispersed as small molecules or ions in the solvent Advantages (of Solutions as an Oral Dosage Form): 1. Easier to swallow → suitable for paediatrics and geriatics. 2. Immediately available for absorption → therefore there is is faster therapeutic response. 3. Drug is uniformly distributed in the formulation → promotes dose uniformity. 4. There is reduced gastro- intestinal irritation – since drug is not localized in one area. Disadvantages (of Solutions as an Oral Dosage Form): 1. Liquids are bulky – inconvenient to transport and store – there can be breakage → leading to loss of product. 2. Stability of substance in aqueous solution is often decreased → shelf-life is therefore shorter. 3. Promotes microbial growth → therefore require a preservative. 4. Accurate dose to be administered depends on patient. 5. Taste of drug → is more pronounced in solution. Aqueous Solutions  H2O- is most widely used solvent in pharmaceutical products → because of lack of toxicity, physiological compatibility and the ability to dissolve a wide range of materials.  Potable water can be used for oral solutions. Alternatively → purified water BP.  For parenterals → water for injection BP.  Some drugs → require water for injection BP free from CO2 and dissolved air.  Approaches to Improve Aqueous Solubility 1. Cosolvency 2. pH Control 3. Solubilization 4. Complexation 5. Chemical modification 6. Particle size control  1. Cosolvency  Solubility of a weak electrolyte or non-polar compound in H2O can be improved by the addition of a H2O miscible solvent in which the compound is also soluble.  Solubility of a given drug → maximal at a particular dielectric constant → can be used as a basis for selecting solvent blends.  Suitable blends should posses a dielectric constant of between 25-80.  Water/ ethanol → most commonly used.  Other suitable solvents → sorbitol, glycerol.  2. pH Control  If drug is a weak acid or weak base → solubility of drug in H2O can be influenced by pH of the system.  Solubility of a weak base can be increased by lowering the pH of its solution.  Solubility of a weak acid can be increased by raising the pH.  Substance with two pKa values exhibit more complex solubility profiles.  Chosen pH must not interfere with other product requirements e.g. chemical stability of drug, stability of dyes, preservatives or flavours.  pH of solutions for parenteral or ophthalmic use must be controlled → because extremes can cause pain and irritation.  Compromise must be reached to ensure that stability and solubility of excipients, physiological compatibility and bioavailability are adequate for intended purpose of product.  3. Solubilization  Solubility of substance in H2O can be improved by the addition of a surfactant - phenomenon known as → micellar solubilization.  Quantity of surfactant must be optimized.  Excess may be toxic and may affect bioavailability of drug.  Surfactants with HLB values > 15 are useful → must be non-toxic and non irritant, miscible with the solvent system, compatible with other ingredients in the formulation, free from disagreeable odour and taste, and non-volatile.  4. Complexation  Insoluble drug and soluble material may interact and form a soluble intermolecular complex.  Complex formation must be easily reversible so that free drug is released during or before contact with biological fluids e.g.  → iodine with 10-15% PVP  → salicylate with xanthines. 5. Chemical Modification  Involves chemical modification of a drug for production of water soluble derivative.  e.g.  → sodium phosphate salts of hydrocortisone  → chloramphenicol sodium succinate  6. Particle Size Control  Size and shape of particles can affect solubility.  ↓ particle size → leads to ↑ solubility.  Little application to solutions → relevant to suspensions.  Non-aqueous Solutions  Alternative Solvents  May be used when drug is unstable in aqueous solution/ incompletely dissolved → use non- aqueous system.  Can be used for depot effect e.g. I.M injection of testosterone.  Factors to consider → toxicity, irritancy, sensitizing potential, flammability, stability, compatibility with other excipients. a) Fixed oils of vegetable origin - Non-volatile oils which consist mainly of fatty acid esters of glycerol e.g. Almond oil, arachis oil, ethyl oleate, coconut oil b) Alcohols - Ethyl alcohol → widely used solvent. - External application → evaporates rapidly and has cooling effect. - Isopropyl alcohol used externally. c) Polyhydric alcohols - Propylene glycol used in conjunction with H2O or glycerol as a cosolvent - Polyethylene glycols used in external preparations as ointment bases - Glycerol → widely used for oral preparations as a cosolvent d) Dimethyl sulphoxide - Highly polar compound → used as penetration enhancer - Used as solvent in veterinary preparations e) Ethyl ether - May be used as a cosolvent with alcohol for colloidions - Not used on its own in pharmaceuticals f) Liquid Paraffin - Used as a solvent for topical application of drugs - Not to be used in nasal preps g) Other solvents - Isopropyl myristate and palmitate used in cosmetics → non-greasy - Xylene in ear drops Formulation Additives 1. Buffers 2. Colours 3. Flavours and perfumes 4. Preservatives 5. Antioxidants 6. Sweetening agents 1. Buffers  Materials when dissolved in solvent will enable it to resist any changes in pH should acid/ alkali be added.  Depends on pH and buffering capacity required.  Must be compatible with other excipients and have a low toxicity. Common pharmaceutical buffer → carbonates, citrates, lactates, phosphates, tartrates.  Borates have been used in external preps.  Injections, eye drops, nasal drops → buffered at pH 7.4. 2. Colours  To improve attractiveness of prep  Must complement flavour used  Also used to mask degradation → if no effect on therapeutic outcome.  Natural and synthetic colours are available → synthetics more widely used  E.g. amaranth (FD & C red no. 2) 3. Flavours & Perfumes  The use of sweetening agents only may not be sufficient to render a product palatable.  Useful in paediatric formulations → to improve patient compliance.  May be natural or synthetic.  Natural → fruit juices, aromatic oils, peppermint and lemon oils.  Synthetic → cheaper and more readily available. 4. Preservatives  Adsorption of preservative from product onto container must not occur.  pH of solution must not affect preservative efficacy.  Must not interact with excipients e.g. parabens can be adsorbed onto micelles of non-ionic surfactants.  Microbial challenge test to assess efficacy of preservative system ( refer to suspensions and emulsions) should be done. 5. Antioxidants  Decomposition of solutions in which drug undergoes oxidation can be controlled by the addition of antioxidants.  6. Sweetening Agents  Low molecular weight carbohydrates widely used.  In particular sucrose is most widely used.  Advantage – colourless, very soluble in H2O, stable over pH range 4-8, masks taste of salty and bitter drugs.  Polyhydric alcohols → sorbitol, mannitol, glycerol used as sweeteners → included in diabetic preparations.  Hydrogenated glucose syrup, isomalt, fructose and xylitol are also used.  Artificial sweetners → can be used in combination with sugars and alcohols or on their own.  Require small quantities because hundreds or thousands times sweeter than sucrose.  Used in concentrations not greater than 0.2% e.g. sodium or calcium saccharin.  Highly water soluble and chemically and physically stable over wide pH range.  Disadvantage - impart bitter or metallic after taste. 1) Mixtures and draughts - Mixture → aqueous preparation mostly manufactured on a small scale with a shelf-life of a few weeks. - Draughts → mixtures of which only one or two large doses of ± 50mL are given. 2) Elixirs - Clear, sweetened hydroalcohol liquids for oral use: Contains flavouring substances/ Drug 3) Linctuses - A viscous preparation usually prescribed for the relief of cough. - Usually contains simple solution of active in a high concentration of sucrose. - Should be sipped slowly and should not be diluted prior to administration. 4) Mouth washes & gargles - Aqueous solutions for the prevention and treatment of mouth and throat infections. - Contains antiseptics, analgesics and/or astringents. 5) Nasal products - Small volume solutions in an aqueous vehicle - pH should be 6.8 - Has to be isotonic - Should be made viscous 6) Ears drops - Simple solutions of drugs in water, glycerol, propylene glycol or alcohol/water mixtures 7) Enemas - Aqueous or oily solutions for rectal administration - For cleansing, diagnostic or therapeutic effect. 8) Preparations for External Use - Lotions - formulated as solutions - applied to skin without friction. - Liniments - intended to be massaged into skin. - Paints - to obtain film of drug on skin. Manufacturing of Solutions  For both small and large scale-only equipment required is suitable mixing vessels, a means of agitation and a filtration system to ensure clarity.  Size of materials can be reduced-solute simply added to solvent in a mixing vessel. Stirred until complete dissolution. May use heat.  Volatile substances e.g. perfume added after cooling.  Filtered to ensure clarification.  Stability of Solutions  Chemical and physical stability in intended containers is important.  Must retain clarity, colour, odour, taste, viscosity for duration of shelf-life.  Clarity and colour assessed by visual examination or spectrophotometrically.  Viscosity assessed by rheological assessment.  Stability of flavours and perfumes more difficult to assess → chromatography/ panel of assessors.  Active Drug → assessed by HPLC etc.