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The terms buffer, buffered solution, and buffer solution when used with reference to hydrogen-ion concentration or pH refer to the ability of a system, particularly an aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution with a solvent. Control of the formulation pH, could prevent large changes during storage and also ensure the physiological compatibility of the formulation with the biological fluid. Therefore, most formulation scientists utilize buffer solution to control potential changes in the pH of formulations.
The required amount of buffer capacity needed is generally between 0.01 and 0.1 M and a concentration between 0.05 and 0.5 M is usually sufficient. The selection of a suitable buffer should be based on
Buffer systems used in pharmaceutical dosage forms generally consist of either a mixture of a weak acid and its corresponding salt with a strong base or a mixture of a weak base and its corresponding salt with strong acid. Drug substance in solution may itself act as a buffer. If the drug is a weak electrolyte such as salicylic acid or ephedrine, the addition of base or acids, respectively will create systems in which the drug can act as a buffer.
It is worth noting that dilution of a drug product’s solution that has been formulated with a buffer system is likely to reduce the capacity (or the strength) of the buffer system, and consequently the ability of the buffer to resist the change in pH. Also, other factors such as amount and the type of co-solvents present, temperature and ionic strength may contribute to affect the pH of the formulation. For example, the pH of acetate buffers is known to increase with temperature, whereas the pH of boric acid buffers decreases with temperature.
The buffer may negatively affect the solubility of drugs substance and excipients. The effect depends on the polarity of the solute and salts when combined in the formulation. Non-polar solutes are solubilized (salted in) by weakly polar organic salts and are desolubilized (salted out) by polar salts. Conversely, polar solutes are solubilized by polar salts and desolubilized by organic salts.
The stabilizing effect of buffers that have multiple charged species in solution could also determine the potential reaction between drug substance and excipients. For example, buffers that use carbonates, tartrate, citrate, and various phosphate salts may precipitate with calcium ions by forming sparingly soluble salts; the precipitation being dependent on the pH of the solution. The activity of phosphate ions may be lowered due to interactions with other solution components.
Antioxidants are added to some liquid dosage forms to delay or inhibit the oxidation process of molecules. Antioxidants act by getting preferentially oxidized or by blocking an oxidative chain reaction. Examples antioxidants used in liquid dosage forms are shown in the table below.
| List of antioxidants generally used in liquid formulations | ||
| Oil Soluble | Slightly Water Soluble | Water Soluble |
| α-Tocopherol acetate | Acetone sodium bisulfite | Acetylcysteine |
| Ascorbic acid | Ascorbyl palmitate | Butylated hydroxyanisole (BHA) |
| Butylated hydroxytoluene (BHT) | Cysteine | Cysteine hydrochloride |
| d α-Tocopherol natural | d-α-tocopherol synthetic | Dithiothreitol |
| Monothioglycerol | Nordihydroguaiaretic acid | Propyl gallate |
| Sodium bisulfite | Sodium formaldehyde sulfoxylate | Sodium metabisulfite |
| Sodium sulfite | Sodium thiosulfate | Thiourea |
Chelating agents, also known as sequestrants, are molecules that protect drugs from catalysts that accelerate oxidative reaction. They function by forming stable complexes with metal ions particularly di-valent and tri-valent metal ions (including trace metals and heavy metals) thus inactivating their catalytic activity in oxidation of drug substances. Typical examples of this excipients include disodium edentate, calcium disodium edetate, edetic acid etc.
Sweeteners are employed in liquid pharmaceutical dosage forms intended for oral administration specifically to increase the palatability of the therapeutic agent. Examples include sucrose, sorbitol, mannitol, saccharin sodium, xylitol, high fructose corn syrup etc.
Sweetened, but sugar-free, preparations containing aspartame are suitable for diabetic patients and are not cariogenic.
Flavours are used to mask the taste of drugs, many of which have a very unpleasant taste. Flavours used in the formulation of pharmaceutical liquid dosage forms must be nontoxic, soluble (if used for a clear product like syrup, elixir), stable and compatible with the components of the formulation. Masking of few flavours is very difficult due to their complexity. A good example of such flavour is that of male fern extract which is initially sweet, then astringent and finally bitter.
Flavouring agents such as vanilla, raspberry, orange oil, lemon oil are used for oral solutions. Menthol is used in both oral and nasal solutions. Certain flavours appeal to certain patient populations and certain parts of the world; this must be borne in mind by the formulation scientist. For example, fruit and bubble gum flavours are acceptable to children, whilst mint flavour is not.
Colourants (colouring agents) are largely incorporated into pharmaceutical products to standardize or improve an existing drug colour, to mask a colour change and improve appearance and/ or sometimes to complement a flavour or match the colour of a medicine with its taste. Examples being the addition of red colour with cherry flavour, yellow with lemon, green with mint, purple with blackcurrant, etc.
Whilst colours are obtained both from natural sources (e.g. carotenoids) or synthesized (e.g. amaranth), the majority used are synthetically produced. Like flavouring agents, colour preference varies between cultures.
Antifoaming agents are excipients that prevent foam formation during manufacturing processes or when reconstituting liquid dosage forms. They do so by lowering surface tension and cohesive binding of the liquid phase.
The term deforming and antifoaming are like two faces of a coin, utilizing the same type of material for their prevention but differing slightly in their mechanism of foam prevention. Deforming indicates breaking, rapid knockdown and controlling of pre-existing foam. Foam inhibition or antifoaming on the other hand implies preventing the foam from forming in the first place.
Examples of excipients used as antifoaming agents include simethicone (polymethylsiloxane), paraffin oils, organic phosphates, alcohols etc.
Humectants, such as propylene glycol, glycerol, polyethylene glycol and sorbitol are hygroscopic excipients used at ~5% in liquid dosage forms (e.g., aqueous suspensions and emulsions for external application) to retard the evaporation of aqueous vehicle from dosage forms during storage and use. However, high concentrations may also remove moisture from the skin, causing dryness.
Emulsifying agents adsorb at the interface or on the surface of the suspended droplets, reducing the interfacial tension and preventing droplet coalescence. Examples include sodium lauryl sulphate, cetrimide, macrogols etc.
These are neutral electrolytes that are capable of preventing caking of suspended solids. They act by reducing the zeta potential of suspended charged particles to zero and thus cause aggregation or floc formation of the particles.
The optimal concentration of flocculating agents necessary to produce the flocculated state can be quantified using Schulze-Hardy rule, which states that of the valence of ions having a charge opposite to that of the hydrophobic particles appears to determine the effectiveness of the electrolyte in aggregating the particles. The aggregating value or efficiency increases with the valency of the ions. Divalent ions are ten times as effective as monovalent ions. Also, trivalent ions are thousand times as effective as monovalent ions. This rule is only valid for systems where the aggregating electrolyte does not undergo any chemical interaction with the ions of double layer of the particle surface.
In case of weakly charged, water-insoluble, organic non-electrolytes, monovalent ions including sodium or potassium chloride in small concentration (0.01 – 1.00 %), are often adequate to induce flocculation while in case of insoluble, highly charged, polyelectrolyte species, water-soluble divalent or trivalent ions such as aluminium chloride, calcium salts, citrates, sulphates, and potassium biphosphates at concentrations 0.01 – 1.00 % may be required for floc formation depending on the particle charge.
The floccules exhibit a porous loose structure in which the dispersion medium can easily flow through during sedimentation, allowing a greater entrapment of the liquid phase. The flocs formed are easily redispersible on moderate agitation. Flocculated particles form a type of lattice which resists complete settling of particles and are thus, less prone to compaction and cake formation. The supernatant in the case of flocculated suspensions quickly becomes clear due to rapid settling of large flocs formed.
Excipients serve different and specialized pharmaceutical purposes in dosage forms. They come in direct contact with drug substance(s) and therefore, can undergo chemical reactions and physical interactions under favourable conditions producing less active or inactive and toxic by-products with adverse reactions.
In order to avoid the use of incompatible excipients and to assure safety and stability, excipients used in the manufacture of liquid dosage forms must be evaluated to identify all forms of drug-excipient interactions which could alter the safety and stability of a dosage form.
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