Liquid Dosage Form

What are liquid dosage forms? Solutions Suspensions Emulsions Suspensions and emulsions are examples of disperse systems What is the difference between each dosage form? A solution is a homogeneous dispersion of two or more substances on the molecular level A suspension is a coarse dispersion of solids in liquids An emulsion is a coarse dispersion of liquids in liquids What is a solution? A homogeneous dispersion/mixture of two or more substances on the molecular level (a one phase system). The solute is the compound dispersed as molecules or ions in the solvent The solutes include the APIs and the excipients The solute can be either solid or liquid, but in aerosols the solute is a gas- the propellant gas is dissolved in a solvent under pressure What is the solute and solvent in a soluThe solvent is the phase in which dispertion? sion occurs The solvent is generally present in a greater amount than the solute, however there are exceptions eg syrup The solvent is usually a liquid Water is the most common solvent. Organic solvents eg alcohol or oil, can be used on their own or combined with water What is miscibility? When the two components forming a solution are either both gases or both liquids, and they are able to mix without 1 / 11 separating So instead of saying one is soluble in the other, you say one is miscible in the other What are examples of solutions? • Oral solutions: mixtures, syrup, mouthwash, elixir (medicinal solution), linctus (syrup to relieve coughs and sore throats) • Parenteral solutions: injections which can be intravenous, subcutaneous, intramuscular, intraperitoneal, epidural, intrathecal • Topical-use solutions: antiseptic solutions, some types of lotions, collodions (a syrupy solution of nitrocellulose in a mixture of alcohol and ether, used to coat things) • Instilled into body cavities: eye drops/ ointments, ear drops, nasal drops/ sprays, enemas (injection of liquid into rectum to cause the intestines to empty) Why are solutions important? • When a drug is in solution form and taken orally, it is absorbed quicker and more readily than emulsions, suspensions or solid dosage forms since the drug doesn't need to undergo dissolution (eg when a tablet disintegrates) • Many drugs have a good solubility so can be readily made into a solution dosage form • Solutions are often used as specials, which is a category of unlicensed medicines that are manufactured specifically to meet the special clinical needs of an individual patient eg for paediatric use 2 / 11 What are advantages of solutions? When stating advantages, compare to other dosage forms • When a drug is in solution form and taken orally, it is absorbed quicker and more readily than emulsions, suspensions or solid dosage forms since the drug doesn't need to undergo disintegration/dissolution • Flexible dosing is possible eg 5ml, 10ml, based on the age/body weight, due to the dose uniformity of solution • Solutions can be designed for any route of absorption eg oral, parenteral • There is no difficulty in swallowing solutions so they can be used instead of solid dosage forms for oral administration for those who cannot take tablets eg children, elderly • Many drugs have a good solubility so can be readily made into a solution • Drugs are more likely to undergo reactions in solution and the reactions are likely to be faster • They are easier to manufacture compared to other liquid dosage forms • Solutions can be used as specials, which is a category of unlicensed medicines that are manufactured specifically to meet the special clinical needs of an individual patient • If the drug has a low solubility, it would be a challenge to formulate it into a solution • The drug stability can be reduced by hydrolysis in the aqueous phase, oxidation or microbial growth • Unpleasant tastes need to be masked when used for oral administration, especially for paediatric use. This means extra excipients eg flavourings/sweetening agents and colourants need to be added, 3 / 11 which requires more money and reduces amount of API that can be used. • Bulk of solutions makes them more expensive to transport and store, and less convenient for patients compared to What are disadvantages of solutions? more compact dosage forms • Because solutions have flexibility in dosage, accuracy is required to measure the dose when administrating for oral use. A measuring device should be used, rather than a kitchen spoon. What do we need to consider when formulating a solution? Solubility of the drug What is solubility? • The solubility of a solute is it's concentration in a saturated solution at a stated temperature and pressure • Solubility is expressed in the terms of maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature and at equilibrium (whereas concentration is the weight or volume of solute that is contained in a given mass or volume of solution) • When the solution is saturated, the concentration of drug dissolved at this point is called the equilibrium solubility. If the drug has an ionisable group, then the equilibrium solubility of the unionised form is called intrinsic solubility (S0) 4 / 11 What is a saturated solution? • A saturated solution is when the dissolved solute is in equilibrium with the solid solute (?) • Changes in conditions eg temperature, cause equilibrium to shift. As temperature increases, most solutes also increase in solubility, as most dissolution reactions are endothermic, although a few will experience a decrease in solubility. This means that if a solute is present at a concentration close to its solubility, a decrease in temperature could shift the equilibrium to cause it to become insoluble. It is not good practice to make solutions with a solute at a concentration close to its solubility. • To prepare a saturated solution, you either stir excess powdered solute in the solvent for several hours at a required temperature until an equilibrium is attained, or you warm the solvent with excess solute and then cool the mixture down to the required temperature then separate the undissolved solid out of the solution Why are some compounds soluble? • Solids are crystalline and have a rigid 3D arrangement of molecules • Liquid molecules are more mobile compared to solid molecules, and some liquids have a temporary local structure • Solids and liquids are condensed phases, and there is interaction between adjacent molecules of solid drug and liquid water • A drug will dissolve in water if drug-water interactions are more favourable energetically than average drug-drug and water-water interactions. This is determined by thermodynamic factors eg en5 / 11 thalpy change • The solubility of the drug in water is a result of a balance between lattice free energy, water free energy, and the free energy of hydration of the drug • During solution formulation, solid-solid bonds must be broken, while the solvent-solvent bonds must be broken and replaced by solute-solvent bonds. The drug molecules become solvated (undergo solvation) • Enthalpy is the most important contribution to free energy • ”H= ”H1 + ”H2 + ”H3 where ”H1 is the separation of the solute (endothermic), ”H2 is the separation of the solvent (endothermic) and ”H3 is the solute-solvent interactions (exothermic) What is the enthalpy change of drug dis- • Usually (”H1 + ”H2) > ”H3 therefore ”H solving in water? is usually positive/ endothermic for most compounds • A positive value of H ” does not necessarily mean that a solution will not form, as it also depends on the total energy change (Gibbs free energy) 1. Removal of individual molecules from a solid lattice crystal (”H1- separation of the solute) This is endothermic so heat is absorbed therefore this step requires energy. When the solute is an ionic solid, ”H1 What are the steps to forming a solution? corresponds to the lattice energy that must be overcome to form a solution (the higher the charge of the ions in an ionic solid, the higher the lattice energy). The higher the charge of the ions in an ionic solid, the high the lattice energy. 2. Creation of cavity in solvent (”H2- sep6 / 11 aration of the solvent) This is endothermic so heat is absorbed therefore this step requires energy. 3. Free solute molecule enters solvent cavity (”H3- solute-solvent interactions) This is exothermic so heat is evolved therefore this step releases energy. G = H - TS where G is Gibbs free energy change, H is the enthalpy change of the What is the Gibbs free energy equation? process, T is the absolute temperature (in K) and S is the entropy change of process What is a solubility curve? • The relationship between solubility and temperature plotted on a graph • Solubility (g/100g of water) would be on the Y axis and temperature (°C) on the X axis What is dissolution? • The process of solid molecules or ions forming a solution • The dissolution rate is how quickly the solute dissolved to form a solution, and this can affect the bioavailability of the solution • Dissolution rate is given by the Noyes-Whitney equation, which is initially derived for spherical particles where diffusion is an important part of the process • It is important in manufacturing solutions, and also for drug absorption and action if the drug is given in solid dosage form • Dissolution is affected by - temperature, hence why heat may be used when making a solution to promote the dissolution rate (not to increase solubility) - surface area, so a large surface area 7 / 11 would give us a quicker dissolution rate • High solubility is associated with a high dissolution rate. However there are some exceptions eg film forming polymer HPMC • A high dissolution rate increases bioavailability of oral use liquid dosage forms dM/dt = D.A (Cs - C) /h OR dM/dt = kA(Cs - C) dM/dt- rate of diffusion (dissolution rate) D- diffusion coefficient What is the Noyes-Whitney equation? A- surface area of particles Cs- saturation concentration of drug C- concentration of drug in bulk phase h- thickness of diffusion layer k- dissolution rate constant • G must be negative in order for the process of dissolution to occur spontaneously at a constant pressure. This is not usual • In most cases, heat is absorbed so H is positive. This means that for dissolution to occur spontaneously, TS must increase, to ensure that TS > H Will dissolution occur spontaneously? - increasing T will promote solution formation (heating increases ability of solute to dissolve in solvent) - increasing S means solute molecules become more randomly distributed in solution which encourages dissolution (stirring decreases time taken for solute to dissolve) 8 / 11 • As the dissolution process is usually endothermic (heat is taken in), increasing temperature (supplying heat) will increase the solubility of a solid. • For exothermic process eg reaction between NaOH and water, heat is given out so increasing temperature decreases the solubility of a solid • Changing temperature is a good way of increasing rate of dissolution as it speeds up processes. What is the effect of temperature on sol• However, there is no point in heating a ubility? solution to encourage dissolution when developing medicines, because most solutions taken for oral use are stored in a room temperature environment, so there is no more heat and this could cause a risk of the drug coming out of solution eg precipitation. Also, a patient cannot take a hot solution. Therefore you need to consider the storage and patient use when trying to make a drug dissolve in a solvent. • Solubility is the maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature and at equilibrium • Concentration is the weight or volume of solute that contains in a given mass or volume of solution What is the difference between solubility • The units of concentration can be and concentration? - percentages eg %w/w, %w/v, %v/v - quantity per quantity eg 50mg/5ml - parts eg 20 parts - molarity eg M, mol/L - molality eg ml/kg - mole fraction However some of these units are also used for solubility eg quantity per quanti9 / 11 ty • When the solution is saturated, the concentration of the drug dissolved at this point is called the equilibrium solubility • If the drug has an ionisable group, then the equilibrium solubility of the unionised form is called intrinsic solubility (S0) What is a suspension? A coarse dispersion of solids in liquids, in which particles can be seen and easily separated by settling or filtration • Improved taste so encourages children What are advantages of suspensions? to take it • Resistant to degradation effects (?) What are disadvantages of suspensions? • Become unstable over time • Inconvenient to carry as they are bulky • Can be difficult to administer the correct dosage as they are not a unit dosage form unlike with tablets What is an emulsion? A coarse dispersion of liquids in liquids eg oil in water What are formulation methods to enhance solubility of the API? • Optimisation of the pH of the formulation • Selection of appropriate salt form • Use of co solvents • Use of surfactants • Most drugs are either weak acids, weak bases or salts of one of these, and they are ionisable but completely. The ionised form is more soluble in aqueous solution compared to the unionised form. pH determines the extent of ionisation of How does pH affect solubility of a drug? weak acids and weak bases so affects the absorption of the drug in different parts of the body. • Acidic APIs, eg non-steroidal anti-inflammatory agents, are less soluble in acidic solutions than in alkaline solutions. 10 / 11 This is because most of the acidic API would be unionised in the acidic solution so is less able to interact with water molecules. 11 / 11