1.1The design of dosage formsPeter YorkCHAPTER CONTENTSPrinciples of dosage form design 1Biopharmaceutical aspects of dosage formdesign 2Routes of drug administration 4Oral route 4Rectal route 5Parenteral route 5Topical route 5Respiratory route 6Drug factors in dosage form design 6Particle size and surface area 6Solubility 7Dissolution 7Partition coefficient and pKa 8Crystal properties; polymorphism 8Stability 9Organoleptic properties 10Other drug properties 10Therapeutic considerations in dosage formdesign 11Summary 11Bibliography 11PRINCIPLES OF DOSAGE FORMDESIGNDrugs are rarely administered as pure chemical sub-stances alone and are almost always given as formu-lated preparations or medicines.These can vary fromrelatively simple solutions to complex drug deliverysystems through the use of appropriate additives orexcipients in the formulations. The excipientsprovide varied and specialized pharmaceutical func-tions. It is the formulation additives that, amongother things, solubilize, suspend, thicken, preserve,emulsify, modify dissolution, improve the compress-ibility and flavour drug substances to form variouspreparations or dosage forms.The principal objective of dosage form design is toachieve a predictable therapeutic response to a drugincluded in a formulation which is capable of large-scale manufacture with reproducible productquality. To ensure product quality, numerous fea-tures are required: chemical and physical stability,suitable preservation against microbial contamina-tion if appropriate, uniformity of dose of drug,acceptability to users including both prescriber andpatient, as well as suitable packaging and labelling.Ideally, dosage forms should also be independent ofpatient to patient variation, although in practice thisis difficult to achieve. However, recent developmentsthat rely on the specific metabolic activity of individ-ual patients, or implants that respond, for example,to externally applied sound or magnetic fields totrigger a drug delivery function, are beginning toaccommodate this requirement.Consideration should be given to differences inbioavailability between apparently similar formula-tions, and the possible causes for this. In recent yearsincreasing attention has therefore been directedtowards eliminating variation in bioavailability char-acteristics, particularly for chemically equivalentproducts, as it is now recognized that formulation1

2. THE DESIGN OF DOSAGE FORMSsensitive drugs antioxidants can be included in theformulation and, as with light-sensitive materials,suitable packaging can reduce or eliminate theproblem. For drugs administered in liquid form, thestability in solution as well as the effects of pH overthe gastrointestinal pH range of 1-8 should beunderstood. Buffers may be required to control thepH of the preparation to improve stability, or whereliquid dosage forms are sensitive to microbial attack,preservatives are required. In these formulations,and indeed in all dosage forms incorporating addi-tives, it is also important to ensure that the compo-nents, which may include additional drug substancesas in multivitamin preparations, do not producechemical interactions themselves. Interactionsbetween drug(s) and added excipients, such asantioxidants, preservatives, suspending agents,colourants, tablet lubricants and packaging materi-als, do occur and must be checked for during for-mulation. Over recent years data from thermalanalysis techniques, particularlydifferential scanningcalorimetry (DSC), when critically examined havebeen found useful in rapid screening for possibledrug-additive and drug-drug interactions. Forexample, using DSC it has been demonstrated thatthe widely used tableting lubricant magnesiumstearate interacts with aspirin and should be avoidedin formulations containing this drug.Organoleptic propertiesModern medicines require that pharmaceuticaldosage forms are acceptable to the patient.Unfortunately, many drug substances in use todayare unpalatable and unattractive in their natural stateand dosage forms containing such drugs, particu-larly oral preparations, may require the addition ofapproved flavours and/or colours.The use of flavours applies primarily to liquiddosage forms intended for oral administration.Available as concentrated extracts, solutions,adsorbed on to powders or microencapsulated,flavours are usually composed of mixtures of naturaland synthetic materials. The taste buds of thetongue respond quickly to bitter, sweet, salt or acidelements of a flavour. In addition, unpleasant tastecan be overcome by using water-insoluble deriva-tives of drugs which have little or no taste. Anexample is the use of amitriptyline pamoate. In suchapproaches other factors, such as bioavailability,must remain unchanged. If an insoluble derivativeisunavailable or cannot be used, a flavour or perfumecan be used. Alternatively, unpleasant drugs can beadministered in capsules or prepared as coated par-ticles, or tablets may be easily swallowed avoidingthe taste buds.The selection of flavour depends upon severalfactors, but particularly on the taste of the drug sub-stance. Certain flavours are more effective at maskingvarious taste elements: for example, citrus flavoursare frequently used to combat sour or acid-tastingdrugs.The solubility and stability of the flavour in thevehicle are also important. The age of the intendedpatient should also be considered, as children, forexample, prefer sweet tastes, as well as the psycho-logical links between colours and flavours (e.g.yellowis associated with lemon flavour). Sweetening agentsmay also be required to mask bitter tastes. Sucrosecontinues to be used, but alternatives such as sodiumsaccharin, which is 200-700 times sweeter dependingon concentration, are available. Sorbitol is recom-mended for diabetic preparations.Colours are employed to standardize or improvean existing drug colour, to mask a colour change orcomplement a flavour. Although colours areobtained both from natural sources (e.g.carotenoids) and synthesized (e.g. amaranth), themajority used are synthetically produced. Dyes maybe aqueous (e.g. amaranth) or oil soluble (e.g. SudanIV) or insoluble in both (e.g. aluminium lakes).Insoluble colours are known as pigments. Lakes(which are generally water-insoluble calcium or alu-minium complexes of water-soluble dyes) are partic-ularly useful in tablets and tablet coatings because oftheir greater stability to light than correspondingdyes, which also vary in their stability to pH andreducing agents. However, in recent years the inclu-sion of colours in formulations has becomeextremely complex because of the banning of manytraditionally used colours in many countries. (Auseful summary on colours is given in Martindale,The Extra Pharmacopoeia).Other drugpropertiesAt the same time as ensuring that dosage forms arechemically and physically stable and are therapeuti-cally efficacious, it is also relevant to establish thatthe selected formulation is capable of efficient and,in most cases, large-scale manufacture. In additionto those properties previously discussed, such as par-ticle size and crystal form, other characteristics, suchas hygroscopicity, flowability and compressibility, areparticularly valuable when preparing solid dosageforms where the drugs constitute a large percentageof the formulation. Hygroscopic drugs can requirelow-moisture manufacturing environments and needto avoid water during preparation. Poorly flowing10 3. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNApplication of aerosols in pharmacy The use ofaerosols as a dosage form is particularly important inthe administration of drugs via the respiratorysystem. In addition to local effects, systemic effectsmay be obtained if the drug is absorbed into thebloodstream from the lungs. Topical preparations arealso well suited for presentation as aerosols.Therapeutic aerosols are discussed in more detail inChapter 31.BIBLIOGRAPHYAttwood, D. and Florence, A.T. (1983) Surfactant Systems,their Chemistry, Pharmacy and Biology. Chapman & Hall,London.Florence, A.T. and Attwood, D. (1998) PhysicochemicalPrinciples of Pharmacy, 3rd Edn. Palgrave, London.Rosen, M.J. (1989) Surfactants and Interfacial Phenomena,2ndEdn. John Wiley and Sons, New York.Shaw, D.J. (1992) Colloid and Surface Chemistry, 4th Edn.Butterworth-Heinemann, Oxford.100 4. THE DESIGN OF DOSAGE FORMSformulations may require the addition of flow agents(e.g. fumed silica). Studies of the compressibility ofdrug substances are frequently undertaken usinginstrumented tablet machines in formulation labora-tories to examine the tableting potential of the mate-rial, in order to foresee any potential problemsduring compaction, such as lamination or stickingwhich may require modification to the formulationor processing conditions.THERAPEUTIC CONSIDERATIONS INDOSAGE FORM DESIGNThe nature of the clinical indication, disease orillness against which the drug is intended is animportant factor when selecting the range of dosageforms to be prepared. Factors such as the need forsystemic or local therapy, the duration of actionrequired and whether the drug will be used in emer-gency situations, need to be considered. In the vastmajority of cases a single drug substance is preparedinto a number of dosage forms to satisfy both theparticular preferences of the patient or physician andthe specific needs of a certain clinical situation. Forexample, many asthmatic patients use inhalationaerosols from which the drug is rapidly absorbedinto the systematic circulation following deep inhala-tion for rapid emergency relief, and oral products forchronic therapy.Patients requiring urgent relief from angina pec-toris, a coronary circulatoryproblem, place tablets ofnitroglycerin sublingually for rapid drug absorptionfrom the buccal cavity. Thus, although systemiceffects are generally obtained following oral and par-enteral drug administration, other routes can beemployed as the drug and the situation demand.Local effects are generallyrestricted to dosage formsapplied directly, such as those applied to the skin,ear, eye and throat. Some drugs may be wellabsorbed by one route and not another, and musttherefore be considered individually.The age of the patient also plays a role in definingthe types of dosage forms made available. Infantsgenerally prefer liquid dosage forms, usually solu-tions and mixtures, given orally. Also, with a liquidpreparation the amount of drug administered can bereadily adjusted by dilution to give the required dosefor the particular patient, taking weight, age andpatients condition into account. Children can havedifficulty in swallowing solid dosage forms, and forthis reason many oral preparations are prepared aspleasantly flavoured syrups or mixtures. Adults gen-erally prefer solid dosage forms, primarily because oftheir convenience. However, alternative liquid prepa-rations are usually available for those unable to taketablets and capsules.Interest has grown recently in the design of for-mulations that deliver drugs to specific targets in thebody, for example the use of liposomes and nanopar-ticles, as well as providing drugs over longer periodsof time at controlled rates. Alternative technologiesfor preparing particles with required properties -crystal engineering - provide new opportunities.Supercritical fluid processing using carbon dioxide asa solvent or antisolvent is one such method, allowingfine-tuning of crystal properties and particle designand fabrication.Undoubtedly these new technologiesand others, as well as sophisticated formulations, willbe required to deal with peptide and protein drugs,the advent of gene therapy and the need to deliversuch labile macromolecules to specific cells in thebody. Interest is also likely to be directed to individ-ual patient requirements, such as age, weight andphysiological and metabolic factors, features that caninfluence drug absorption andbioavailability.SUMMARYThis chapter has demonstrated that the formulationof drugs into dosage forms requires the interpreta-tion and application of a wide range of informationfrom several study areas. Although the physical andchemical properties of drugs and additives need tobe understood, the factors influencing drug absorp-tion and the requirements of the disease to betreated also have to be taken into account whenidentifying potential delivery routes. The formula-tion and associated preparation of dosage formsdemand the highest standards, with careful examina-tion, analysis and evaluation of wide-ranging infor-mation by pharmaceutical scientists to achieve theobjective of creating high-quality and efficaciousdosage forms.BIBLIOGRAPHYAmidon, G.L., Lennernas, H., Shah,V.P., Crison, J.R.(1995). A theoretical basis for a biopharmaceutical drugclassification: the correlation of in vitro drug productdissolution and bioavailability. Pharmaceutical Research,12,413-420.Martindale,W. (1999) The Extra Pharmacopoeia., RoyalPharmaceutical Society of Great Britain, London.11 5. THE DESIGN OF DOSAGE FORMSModern Pharmaceutics,3rd edn. (1999) (Eds Banker, G.S.,Rhodes, C.T.) Marcel Dekker.Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thedn. (1999) (Eds Ansel, H.C., Allen, L.V., Popovitch,N.G.) Lippincott Williams &Wilkins, Philadelphia.Physical Pharmacy: Physical ChemicalPrinciples in thePharmaceutical Sciences, 4th edn. (1993) Martin A.N. andBustamanta, P. Lea and Febiger, Philadelphia.Physicochemical Principles of Pharmacy, 3rd edn.(1998) Florence, A.T. and Attwood, D., Macmillan,Basingstoke.Shekunov, B.Yu.,York,P. (2000) Crystallization processes inpharmaceutical technology and drug delivery design.Journal of Crystal Growth, 211, 122-136.Solid State Chemistry of Drugs, 2nd edn. (1999) Byrn, S.R.,Pfeiffer, R.R., Stowell, J.G., SSCI Inc., West Lafayette.12 6. SCIENTIFIC PRINCIPLESOF DOSAGE FORMDESIGN13PART ONE 7. This page intentionally left blank 8. 2Dissolution and solubilityMichael AultonCHAPTER CONTENTSDefinition of terms 16Solution, solubility 16Expressions of concentration 16Quantity per quantity 16Percentage 16Parts 17Molarity 17Molality 17Mole fraction 17Mitliequivalents and normal solutions 17The process of dissolution 17States of matter 17Energy changes 18Dissolution rates of solids in liquids 18Dissolution mechanisms 18Summary of factors affecting dissolution ratesIntrinsic dissolution rate 20Measurements of dissolution rates 21Beaker method 21Flask-stirrer method 21Rotating basket method 21Paddte method 21Rotating and static disc methods 21Solubility 23Methods of expressing solubility 23Prediction of solubility 23Physicochemical prediction of solubility 24Solubility parameter 24Solubility of solids in liquids 24Determination of the solubility of a solid in aliquid 2420Factors affecting the solubility of solids inliquids 25Temperature 25Molecular structure of solute 26Nature of solvent: cosolvents 26Crystal characteristics: polymorphism andsolvation 26Particle size of the solid 27pH 27Common ion effect 27Effect of indifferent electrolytes on the solubilityproduct 28Effect of non-electrolytes on the solubility ofelectrolytes 28Effect of electrolytes on the solubility of non-electrolytes 29Complex formation 29Solubilizing agents 29Solubility of gases in liquids 29Solubility of liquids in liquids 29Systems showing an increase in miscibitity withrise in temperature 30Systems showing a decrease in miscibility withrise in temperature 30Systems showing upper and lower criticalsolution temperatures 30The effects of added substances on criticalsolution temperatures 31Distribution of solutes between immiscibleliquids 31Partition coefficients 31Solubility of solids in solids 32References 32Bibliography 3215 9. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNSolutions are encountered extremely frequently inpharmaceutical development, either as a dosageform in their own right or as a clinical trials mater-ial. Equally importantly, almost all drugs function insolution in the body. This book therefore starts witha description of the formation of solutions and aconsideration of their properties.This chapter discusses the principles underlyingthe formation of solutions from solute and solventand the factors that affect the rate and extent of thedissolution process. It will discuss this process par-ticularly in the context of a solid dissolving in aliquid, as this is the situation most likely to beencountered during the formation of a drug solu-tion, either during manufacturing or during drugdelivery.Further properties of solutions are discussed inthe subsequent chapters in Part One of this book.Because of the number of principles and propertiesthat need to be considered, the contents of each ofthese chapters should only be regarded as introduc-tions to the various topics. The student is thereforeencouraged to refer to the bibliography at the end ofeach chapter in order to augment the present con-tents. The textbook written by Florence and Attwood(1998) is particularly recommended because of thelarge number of pharmaceutical examples that areused to aid an understanding of physicochemicalprinciples.DEFINITION OF TERMSThis chapter begins by clarifying a number of termsrelevant to the formation and concentration of solu-tionsSolution, solubilityA solution may be denned as a mixture of two ormore components that form a single phase which ishomogeneous down to the molecular level.The com-ponent that determines the phase of the solution istermed the solvent and usually constitutes thelargest proportion of the system. The other compo-nents are termed solutes, and these are dispersed asmolecules or ions throughout the solvent, i.e. theyare said to be dissolved in the solvent.The transfer of molecules or ions from a solid stateinto solution is known as dissolution.The extent towhich the dissolution proceeds under a given set ofexperimental conditions is referred to as the solu-bility of the solute in the solvent. Thus, the solubil-ity of a substance is the amount of it that passes intosolution when equilibrium is established betweenthe solution and excess (undissolved) substance. Thesolution that is obtained under these conditions issaid to be saturated.Because the above definitions are general onesthey may be applied to all types of solution involv-ing any of the three states of matter (gas, liquid,solid) dissolved in any of the three states of matter.However, when the two components forming asolution are either both gases or both liquids it ismore usual to talk in terms of miscibility ratherthan solubility.One point to emphasize at this stage is that therate of solution (dissolution) and amount which canbe dissolved (solubility) are not the same and are notnecessarily related, although in practice high drugsolubility is usually associated with a high dissolutionrate.Expressions of concentrationQuantity per quantityConcentrations are often expressed simply as theweight or volume of solute that is contained in agiven weight or volume of the solution. The majorityof solutions encountered in pharmaceutical practiceconsist of solids dissolved in liquids. Consequently,concentration is expressed most commonly by theweight of solute contained in a given volume of solu-tion. Although the SI unit is kg m~3the terms thatare used in practice are based on more convenient orappropriate weights and volumes. For example, inthe case of a solution with a concentration of 1 kgm 3the strength may be denoted by any one of thefollowing concentration terms, depending on thecircumstances:1 g L -1, 0.1 g per 100 mL, 1 mg mL-1,5 mg in 5 mL, or 1 fjig fjiL~l.PercentagePharmaceutical scientists have a preference forquoting concentrations in percentages. The concen-tration of a solution of a solid in a liquid is given by: n/ / weight of solute innconcentration in % w / v = x 100volume ofsolutionEquivalent percentages based on weight and volumeratios (% v/w,% v/v and % w/w expressions) can alsobe used for solutions of liquids in liquids and solu-tions of gases in liquids.16 10. DISSOLUTION AND SOLUBILITYIt should be realized that if concentration isexpressed in terms of weight of solute in a givenvolume of solution, then changes in volume caused bytemperature fluctuations will alter the concentration.PartsPharmacopoeias express some concentrations interms of the number of parts of solute dissolved in astated number of parts of solution. The use of thismethod to describe the strength of a solution of asolid in a liquid implies that a given number of partsby volume (mL) of solution contain a certain numberof parts by weight (g) of solid. In the case of solutionsof liquids in liquids, parts by volume of solute in partsby volume of solution are intended, whereas withsolutions of gases in liquids parts by weight of gas inparts by weight of solution are implied.MolarityThis is the number of moles of solute contained in1 dm3(or, more commonly in pharmaceuticalscience, 1 litre) of solution. Thus, solutions of equalmolarity contain the same number of solute mole-cules in a given volume of solution. The unit ofmolarity is mol L1(equivalent to 103mol m3if con-verted to the strict SI unit).MolalityThis is the number of moles of solute divided by themass of the solvent, i.e. its SI unit is mol kg-1.Although it is less likely to be encountered in phar-maceutical science than the other terms it does offera more precise description of concentration becauseit is unaffected by temperature.Mole fractionThis is often used in theoretical considerations and isdefined as the number of moles of solute divided bythe total number of moles of solute and solvent, i.e.:mole fraction of solute (xwhere n and n2 are the numbers of moles of soluteand solvent, respectively.Mill/equivalents and normal solutionsThe concentrations of solutes in body fluids and insolutions used as replacements for those fluids areusually expressed in terms of the number of milli-moles (1 millimole = one thousandth of a mole) in alitre of solution. In the case of electrolytes, however,these concentrations may still be expressed in termsof milliequivalents per litre. A milliequivalent (mEq)of an ion is, in fact, one thousandth of the gramequivalent of the ion, which is in turn the ionicweight expressed in grams divided by the valency ofthe ion. Alternatively,A knowledge of the concept of chemical equivalentsis also required in order to understand the use ofnormality as a means of expressing the concentra-tion of solutions, because a normal solution, i.e. con-centration = 1 N, is one that contains the equivalentweight of the solute, expressed in grams, in 1 litre ofsolution. It was thought that this term would disap-pear on the introduction of SI units, but it is stillencountered in some volumetric assay procedures.THE PROCESS OF DISSOLUTIONStates of matterThe kinetic theory of matter indicates that in con-densed phases the thermal motions of molecules arereduced sufficiently so that intermolecular forces ofattraction result in the formation of coherent massesof molecules, unlike the situation in gaseous phases,where the molecules move independently within theconfines of the container. In solid condensed phasesthe thermal motion of molecules (or ions) isvirtuallyrestricted to vibrations about mean positions and thecomponents tend to form three-dimensionalarrangements or crystal lattices (see Chapter 9), inwhich the intercomponent forces are best satisfiedand the potential energy of the system is minimized.In liquid condensed systems the thermal motions ofmolecules are greater than those in solids but lessthan those in gases.The structure of liquids is there-fore intermediate between that of solids and that ofgases.Thus, although the molecules can move withinthe confines of the liquid phase boundaries smallgroups of them tend to form regular arrangements ina transient manner. In addition, liquids are thoughtto contain a small amount of so-called free volumein the form of holes which, at a given instant, arenot occupied by the solvent molecules themselves(discussed further in Chapter 3).When a substance dissolves in a liquid the increasein volume of the latter is less than would be expected.17 11. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNThe process of dissolution may therefore be consid-ered to involve the relocation of a solute moleculefrom an environment where it is surrounded by otheridentical molecules, with which it forms intermolecu-lar attractions, into a cavity in a liquid, where it is sur-rounded by non-identical molecules, with which itmay interact to different degrees.Energy changesIn order for this process to occur spontaneously at aconstant pressure the accompanying change in freeenergy, or Gibbs free energy (AG), must be negative.The free energy (G) is a measure of the energy avail-able to the system to perform work. Its valuedecreases during a spontaneously occurring processuntil an equilibrium position is reached when nomore energy can be made available, i.e. AG = 0 atequilibrium.This change in free energy is defined by the gen-erally applicable thermodynamic equation:where AH, which is known as the change in theenthalpy of the system, is the amount of heatabsorbed or evolved as the system changes its ther-modynamic state, i.e. in this case when dissolutionoccurs T is the thermodynamic temperature and ASis the change in the so-called entropy, which is ameasure of the degree of disorder or randomness inthe system.The entropy change (AS) is usually positive forany process, such as dissolution, that involves mixingof two or more components. In an ideal solutionthere is, by definition, no net change in the inter-molecular forces experienced by either solute orsolvent when dissolution occurs. In such circum-stances AH - 0. Thus, the free energy change AGduring the formation of an ideal solution is dictatedsolely by the term TAS.In most real systems dissolution is accompaniedby a change in the intermolecular forces experiencedby the solute and the solvent before and after theevent. A change in enthalpy will therefore accom-pany dissolution in such systems. Equation 2.2 indi-cates that the likelihood of dissolution will dependon the sign of AH and, if this sign is positive, on thevalue of AH relative to that of.TAS. In other words,it follows from Eqn 2.2 that as TAS is usually posi-tive then dissolution will occur if AH is either nega-tive, zero or very slightly positive (i.e. it must be lessthan the value of TAS).The overall change in enthalpy of dissolution AHcan be regarded as being made up of the changeresulting from the removal of a solute molecule fromits original environment plus that resulting from itsnew location in the solvent. For example, in the caseof a crystallinesolid dissolving in a liquid these con-tributions can be described by Eqn 2.3:where the change in crystal lattice enthalpy (AHci) isthe heat absorbed when the molecules (or ions) ofthe crystalline solute are separated by an infinite dis-tance against the effects of their intermolecularattractive forces. The enthalpy of solvation (AHsolv) isthe heat absorbed when the solute molecules areimmersed in the solvent.AHci is always positive and Affsolv is most com-monly negative.Thus, in most cases AHcl > AHsolv, sothat AH is also positive. In these cases heat isabsorbed when dissolution occurs and the process isusually defined as an endothermic one. In somesystems, where marked affinity between solute andsolvent occurs, the negative AHsolv is so great that itexceeds the positive AHcl. The overall enthalpychange then becomes negative, so that heat isevolved and the process is an exothermic one.DISSOLUTION RATES OF SOLIDS INLIQUIDSDissolution mechanismsThe dissolution of a solid in a liquid may beregarded as being composed of two consecutivestages.1. First is an interfacial reaction that results in theliberation of solute molecules from the solidphase. This involves a phase change, so thatmolecules of solid become molecules of solute inthe solvent in which the crystal is dissolving. Thesolution in contact with the solid will besaturated (because it is in direct contact withundissolved solid). Its concentration will be Cs, asaturated solution.2. After this, the solute molecules must migratethrough the boundary layers surrounding thecrystal to the bulk of the solution, at which timeits concentration will be C.This step involves thetransport of these molecules away from thesolid-liquid interface into the bulk of the liquidphase under the influence of diffusion orconvection. Boundary layers are static or slow-moving layers of liquid that surround all wettedsolid surfaces (see Chapter 4 for further details).18 12. DISSOLUTION AND SOLUBILITYMass transfer takes place more slowly throughthese static or slow-moving layers, which inhibitthe movement of solute molecules from thesurface of the solid to the bulk of the solution.The concentration of the solution in theboundary layers changes therefore from beingsaturated (Cs) at the crystal surface to beingequal to that of the bulk of the solution (C) at itsoutermost limit.These stages are illustrated in Figure 2.1.Like any reaction that involves consecutive stages,the overall rate of dissolution will depend onwhichever of these steps is the slowest (the rate-determining or rate-limiting step). In dissolution theinterfacial step ((1) above) is virtually instantaneousand so the rate of dissolution will be determined bythe rate of the slower step ((2) above), of diffusion ofdissolved solute across the static boundary layer ofliquid that exists at a solid-liquid interface.The rate of diffusion will obey Picks law of diffu-sion, i.e. the rate of change in concentration of dis-solved material with time is directly proportional tothe concentration difference between the two sidesof the diffusion layer, i.e.,where the constant k is the rate constant (s"1).In the present context AC is the difference in con-centration of solution at the solid surface (C) andFig. 2.1 Diagram of boundary layers and concentration changesurrounding a dissolving particle.the bulk of the solution (C2). At equilibrium, thesolution in contact with the solid (C1) will be satu-rated (concentration = Cs), as discussed above.If the concentration of the bulk (C2) is greaterthan this, the solution is referred to as supersatu-rated and the movement of solid molecules will be inthe direction of bulk to surface (as during crystal-lization), and if C2 is less than saturated the mole-cules will move from the solid to the bulk (as duringdissolution).An equation known as the Noyes-Whitney equa-tion was developed to define the dissolution from asingle spherical particle. The rate of mass transferof solute molecules or ions through a static diffu-sion layer (dm/dt) is directly proportional to thearea available for molecular or ionic migration (A),the concentration difference (AC) across theboundary layer, and is inversely proportional to thethickness of the boundary layer (h). This relation-ship is shown in Eqn 2.6, or in a modified form inEqn 2.7.where the constant k1 is known as the diffusioncoefficient, D, and has the units of m2/s.If the solute is removed from the dissolutionmedium by some process at a faster rate than itpasses into solution, then the term (Cs - C) in Eqn2.7 may be approximated to Cs. Alternatively, if thevolume of the dissolution medium is so large that Cis not allowed to exceed 10% of the value of Cs, thenthe same approximation may be made in particular.In either of these circumstances dissolution is said tooccur under sink conditions, and Eqn 2.7 may besimplified toIt should be realised that such sink conditions mayarise in vivo when a drug is absorbed from its solu-tion in the gastrointestinal fluids at a faster rate thanit dissolves in those fluids from a solid dosage formsuch as a tablet.If solute is allowed to accumulate in the dissolu-tion medium to such an extent that the aboveapproximation is no longer valid, i.e. whenC > Cs/10, then non-sink conditions are said to bein operation.When C = Cs it is obvious from Eqn 2.7that the overall dissolution rate will be zero, as thedissolution medium is saturated with solute.19or 13. THE DESIGN OF DOSAGE FORMSfactors can influence their therapeutic performance.To optimize the bioavailability of drug substances itis often necessary to carefully select the most appro-priate chemical form of the drug. For example, suchselection should address solubility requirements,drug particle size and physical form, and considerappropriate additives and manufacturing aidscoupled to selecting the most appropriate adminis-tration route (s) and dosage form(s). Suitable manu-facturing processes and packaging are also required.There are numerous dosage forms into which adrug substance can be incorporated for the conve-nient and efficacious treatment of a disease. Dosageforms can be designed for administration by alterna-tive delivery routes to maximize therapeuticresponse. Preparations can be taken orally orinjected, as well as being applied to the skin orinhaled, and Table 1.1 lists the range of dosage formsthat can be used to deliver drugs by the variousadministration routes. However, it is necessary torelate the drug substance to the clinical indicationbeing treated before the correct combination of drugand dosage form can be made, as each disease orillness often requires a specific type of drug therapy.In addition, factors governing the choice of adminis-tration route and the specific requirements of thatroute which affect drug absorption need to be takeninto account when designing dosage forms.Many drugs are formulated into several dosageforms of varying strengths, each having selected phar-Tabte1.1 Dosage forms available for differentadministration mutesAdministration route Dosage formsOralRectalTopicalParenteralRespiratoryNasalEyeEarSolutions, syrups, suspensions,emulsions, gels, powders, granules,capsules, tabletsSuppositories, ointments, creams,powders, solutionsOintments, creams, pastes, lotions,gels, solutions, topical aerosolsInjections (solution, suspension,emulsion forms), implants, irrigationand dialysis solutionsAerosols (solution, suspension,emulsion, powder forms)inhalations, sprays, gasesSolutions, inhalationsSolutions, ointments, creamsSolutions, suspensions, ointmentscreamsmaceutical characteristics suitable for a specific appli-cation. One such drug is the glucocorticoid pred-nisolone, used in the suppression of inflammatory andallergic disorders. Through the use of different chem-ical forms and formulation additives a range of effec-tive anti-inflammatory preparations are available,including tablet, enteric-coated tablet, injections, eyedrops and enema. The extremely low aqueous solubil-ity of the base prednisolone and acetate salt makesthese forms useful in tablet and slowly absorbed intra-muscular suspension injection forms, whereas thesoluble sodium phosphate salt enables a soluble tabletform, and solutions for eye and ear drops, enema andintravenous injection to be prepared. The analgesicparacetamol is also available in a range of dosageforms and strengths to meet specific needs of the user,including tablets, dispersible tablets, paediatricsoluble tablets, paediatric oral solution, sugar-free oralsolution, oral suspension, double-strength oral sus-pension and suppositories.It is therefore apparent that before a drug sub-stance can be successfully formulated into a dosageform many factors must be considered. These can bebroadly grouped into three categories:1. Biopharmaceutical considerations, includingfactors affecting the absorption of the drugsubstance from different administration routes;2. Drug factors, such as the physical and chemicalproperties of the drug substance;3. Therapeutic considerations, includingconsideration of the clinical indication to betreated and patient factors.High-quality and efficacious medicines will be for-mulated and prepared only when all these factors areconsidered and related to each other. This is theunderlying principle of dosage form design.BIOPHARMACEUTICAL ASPECTS OFDOSAGE FORM DESIGNBiopharmaceutics can be regarded as the study of therelationship between the physical, chemical and bio-logical sciences applied to drugs, dosage forms anddrug action. Clearly, understanding the principles ofthis subject is important in dosage form design, par-ticularly with regard to drug absorption, as well asdrug distribution, metabolism and excretion. Ingeneral, a drug substance must be in solution formbefore it can be absorbed via the absorbing mem-branes and epithelia of the skin, gastrointestinal tractand lungs into body fluids. Drugs are absorbed in two2 14. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNSummary of factors affecting dissolutionratesThese factors may be derived from a considerationof the terms that appear in the Noyes-Whitney equa-tion (Eqn 2.7) and a knowledge of the factors that inturn affect these terms. Most of the effects of thesefactors are included in the summary given in Table2.1. It should be borne in mind that pharmacists areoften concerned with the rate of dissolution of adrug from a formulated product such as a tablet or acapsule, as well as with the dissolution rates of puresolids. Later chapters in this book should be con-sulted for information on the influence of formula-tion factors on the rates of release of drugs into solu-tion from various dosage forms.Intrinsic dissolution rateBecause the rate of dissolution is dependent on somany factors, it is advantageous to have a measure ofthe rate of dissolution which is independent of rate ofagitation, area of solute available etc. In the lattercase this will change greatly in a conventional tabletformulation, as the tablet breaks up into granulesand then into primary powder particles as it comesinto contact with water.Table 2.1 Factors affecting in vitro dissolution rates of solids in liquidsTerm in Noyes-Whitney equation Affectedby CommentsA, surface area ofundissolved solidCs solubility of solid indissolution medium.C, concentration of solute insolution at time tk, dissolution rate constantSize of solid particlesDispersibility of powderedsolid in dissolution mediumPorosity of solid particlesTemperatureNature of dissolution mediumMolecular structure of soluteCrystalline form of solidPresence of other compoundsVolume of dissolution mediumAny process that removesdissolved solute from thedissolution mediumThickness of boundary layerDiffusion coefficient of solutein the dissolution mediumA c 1/particle size. Particle size will change duringdissolution process, because large particles will becomesmaller and small particles will eventually disappear.Compacted masses of solid may also disintegrate intosmaller particlesIf particles tend to form coherent masses in thedissolution medium then the surface area available fordissolution is reduced. This effect may be overcome bythe addition of a wetting agentPores must be large enough to allow access ofdissolution medium and outward diffusion of dissolvedsolute moleculesDissolution may be an exothermic or an endothermicprocessSee previous comments on solubility parameters,cosolvents and pH.See previous comments on sodium salts of weak acidsand esterificationSee previous comments on polymorphism and solvationSee previous comments on common ion effect, complexformation and solubilizing agentsIf volume is small C will approach Cs if volume is large Cmay be negligible with respect to Cs i.e. apparent sinkconditions will operateFor example, adsorption on to an insoluble adsorbent,partition into a second liquid that is immiscible with thedissolution medium, removal of solute by dialysis or bycontinuous replacement of solution by fresh dissolutionmediumAffected by degree of agitation, which depends, in turn,on speed of stirring or shaking, shape, size and positionof stirrer, volume of dissolution medium, shape and sizeof container, viscosity of dissolution mediumAffected by viscosity of dissolution medium and size ofdiffusing molecules.20 15. DISSOLUTION AND SOLUBILITYThis is known as the intrinsic dissolution rate(IDR), which is the rate of mass transfer per area ofdissolving surface and typically has the units of mgcrrr2mirr1. IDR should be independent ofboundarylayer thickness and volume of solvent (if sink condi-tions are assumed).Thus:Thus IDR measures the intrinsic properties of thedrug only as a function of the dissolution medium,e.g. its pH, ionic strength, counter ions etc).Techniques for measuring IDR are discussed brieflybelow and in more detail in Chapter 8.Measurement of dissolution ratesMany methods have been described in the literature,particularly in relation to the determination of therate of release of drugs into solution from tablet andcapsule formulations, because such releasemay havean important effect on the therapeutic efficiency ofthese dosage forms (see Chapters 17, 27, 29 and 30).Attempts have been made to classify the methods fordetermining dissolution rates. These classificationsare based mainly on whether or not the mixingprocesses that take place in the various methodsoccur by natural convection arising from density gra-dients produced in the dissolution medium, or byforced convection brought about by stirring orshaking the system. The following brief descriptionsare given as examples of the more commonly usedmethods that are illustrated in Figure 2.2.Beaker methodThe methodology of Levy and Hayes forms the basisof this technique. In their initial work they used a400 cm3beaker containing 250 dm3of dissolutionmedium, which was agitated by means of a three-bladed polyethylene stirrer with a diameter of 50mm. The stirrer was immersed to a depth of 27 mminto the dissolution medium and rotated at 60 rpm.Tablets were dropped into the beaker and samples ofthe liquid were removed at known times, filtered andassayed.Flask-stirrer methodThis is similar to the previous method except that around-bottomed flask is used instead of a beaker.The use of a round-bottomed container helps toavoid the problems that may arise from the forma-tion ofmounds of particles in different positions onthe flat bottom of a beaker.Rotating basket methodThis method is described in most pharmacopoeiasfor the determination of the dissolution rates ofdrugs from tablets and capsules. Details of the appa-ratus and methods of operation are given in theseofficial compendia. Basically these methods involveplacing the tablet or capsule inside a stainless steelwire basket, which is rotated at a fixed speed whileimmersed in the dissolution medium, which is con-tained in a wide-mouthed cylindrical vessel, thebottom of which is either flat or spherical. Samplesof the dissolution medium are removed at specifiedtimes, filtered and assayed.Paddle methodThis is another official method. The dissolutionvessel described in the rotating basket method, i.e.the cylindrical vessel with the spherical bottom, isalso used in this method. Agitation is provided by arotating paddle and the dosage form is allowed tosink to the bottom of the dissolution vessel beforeagitation is commenced.Rotating and static disc methodsIn these methods the compound that is to beassessed for rate of dissolution is compressed into anon-disintegrating disc which is mounted in a holderso that only one face of the disc is exposed. Theholder and disc are immersed in the dissolutionmedium and either held in a fixed position (staticdisc method) or rotated at a given speed (rotatingdisc method). Samples of the dissolution mediumare removed after known times, filtered and assayed.In both methods it is assumed that the surface areafrom which dissolution can occur remains constant.Under these conditions the amount of substance dis-solved per unit time and unit surface area can be deter-mined. This is the intrinsic dissolution rate andshould be distinguished from the measurementobtained from the previously described methods. Inthese latter methods the surface area of the drug thatis available for dissolution changes considerably duringthe course of the determination because the dosageform usually disintegrates into many smaller particles,and the size of these particles then decreases as disso-lution proceeds.As these changes are not usually mon-itored the dissolution rate is measured in terms of thetotal amount of drug dissolved per unit time.It should be appreciated from a consideration ofthe comments made in Table 2.1 that not only willdifferent dissolution rate methods yield different21 16. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGN(a) Beaker method (b) Flask-stirrermethod(c) Rotating basketmethod(d) Paddle method(e) Rotating disc methodStatic disc methodFig. 2.2 Methods of measuringdissolutionrates.results, but also changes in the experimental vari-ables in a given method are likely to lead to changesin the results.This latter point is particularly impor-tant, as dissolution rate tests are usually performedin a comparative manner to determine, for example,the difference between two polymorphic forms of thesame compound, or between the rates of release of adrug from two formulations. Thus, standardizationof the experimental methodology is essential if suchcomparisons are to be meaningful.Finally, it should also be realized that although themajority of dissolution testing is concerned with22 17. DISSOLUTION AND SOLUBILITYpure drugs or with conventional tablet or capsuleformulations, knowledge of the rates of drug releasefrom other types of dosage form is also important.Reference should be made therefore to later chaptersin this book for information on the dissolutionmethods applied to these other dosage forms.SOLUBILITYThe solution produced when equilibrium is estab-lished between undissolved and dissolved solute in adissolution process is termed a saturated solution.The amount of substance that passes into solution inorder to establish the equilibrium at constant temper-ature and pressure and so produce a saturated solutionis known as the solubility of the substance. It is possi-ble to obtain supersaturated solutions but these areunstable and the excess solute tends to precipitatereadily.Methods of expressing solubilitySolubilities may be expressed by means of any of thevariety of concentration terms that are defined at thebeginning of this chapter. They are expressed mostcommonly, however, in terms of the maximum massor volume of solute that will dissolve in a given massor volume of solvent at a particular temperature.Pharmacopoeias give information on the approx-imate solubilities of official substances in terms ofthe number of parts by volume of solvent requiredto dissolve one part by weight of a solid, or one partby volume of a liquid. Unless otherwise specified,these solubilities apply at a temperature of 20C.They also use the expression parts in defining theapproximate solubilities that correspond to descrip-tive terms such as freely soluble and sparinglysoluble.Prediction of solubilityProbably the most sought-after information aboutsolutions in formulation problems is what is thebest? or what is the worst? solvent for a givensolute.Theoretical prediction of precise solubilities isan involved and occasionallyunsuccessful operation,but from a knowledge of the structure and propertiesof solute and solvent an educated guess can bemade. This is best expressed in subjective terms,such as very soluble or sparingly soluble. Often(particularly in pre- or early formulation) this is allthe information that the formulator requires. TheTable 2.2 Descriptive solubilitiesDescriptionVery solubleFreely solubleSolubleSparingly solubleSlightly solubleVery slightly solublePractically insolubleApproximate weight of solvent (g)necessary to dissolve 1 g of solute< 1Between 1 and 10Between 10 and 30Between 30 and 100Between 100 and 1000Between 1000 and 10 000> 10 000interrelationships between such terms and approxi-mate solubilities are shown in Table 2.2.Speculation on what is likely to be a good solventis usually based on the like dissolves like principle,that is, a solute dissolves best in a solvent with similarchemical properties. The concept traditionallyfollows two rules:1. Polar solutes dissolve in polar solvents.2. Non-polar solutes dissolve in non-polar solvents.In the context of solubility, a polar molecule has adipole moment. Chemical groups that confer polarityto their parent molecules are known as polar groups.To rationalize the above rules, consider the forcesof attraction between solute and solvent molecules. Ifthe solvent is A and the solute B and the forces ofattraction are represented by A-A, B-B and A-B,one of three conditions will arise:1. IfA-A A-B, i.e. the affinity of a solventmolecule for its own kind is markedly greaterthan its affinity for a solute molecule, the solventmolecules will be attracted to each other andform aggregations from which the solute isexcluded. As an example, benzene is almostcompletely insoluble in water. Attractionbetween water molecules is very strong, so thatwater exists as aggregates, which have a similarform to ice, floating in a matrix of freemolecules. It may be visualized as icebergsfloating in a sea of free water molecules.Molecules are continually moving from sea toicebergs and from icebergs to sea.The attractionbetween benzene molecules arises from weak vander Waals forces, so that although very littleenergy is required to disperse benzenemolecules, discrete benzene molecules areunable to penetrate the closely bound wateraggregates.23 18. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGN2. If B-B A-A, the solvent will not be able tobreak the binding forces between solute moleculesand disperse them. This situation would applyifyou tried to dissolve sodium chloride in benzene.The sodium chloride crystal is held together bystrong electrovalent forces which cannot be brokenby benzene. A conducting solvent, such as water,would be required to overcome the attractionbetween solute molecules.3. If A-B > A-A or B-B, or the three forces are ofthe same order, the solute will disperse and forma solution.The above is a simplified overview of the situation.The rest of this chapter will attempt to explain thebasic physicochemical properties of solutions thatlead to such observations.Physicochemical prediction of solubilitySimilar types of interrnolecular force may contributeto solute-solvent, solute-solute and solvent-solventinteractions. The attractive forces exerted betweenpolar molecules are much stronger, however, thanthose that exist between polar and non-polar mole-cules, or between non-polar molecules themselves.Consequently, a polar solute will dissolve to a greaterextent in a polar solvent, where the strength of thesolute-solvent interaction will be comparable to thatbetween solute molecules, than in a non-polarsolvent, where the solute-solvent interaction will berelatively weak. In addition, the forces of attractionbetween the molecules of a polar solvent will be toogreat to facilitate the separation of these moleculesby the insertion of a non-polar solute between them,because the solute-solvent forces will again be rela-tively weak.Thus, solvents for non-polar solutes tendto be restricted to non-polar liquids.The above considerations are often expressed verygenerally as like dissolves like, i.e. a polar substancewill dissolve in a polar solvent and a non-polar sub-stance will dissolvein a non-polar solvent. Such a gen-eralization should be treated with caution, because theinterrnolecular forces involved in the process of disso-lution are influenced by factors that are not obviousfrom a consideration of the overall polarity of a mole-cule; For example, the possibility of interrnolecularhydrogen-bond formation between solute and solventmay be more significant than polarity.Solubility parameter Attempts have been made todefine a parameter that indicates the ability of a liquidto act as a solvent. The most satisfactory approach isbased on the concept that the solvent power of a liquidis influenced by its interrnolecular cohesive forces andthat the strength of these forces can be expressed interms of a solubility parameter. The initially intro-duced parameters, which are concerned with thebehaviour of non-polar, non-interacting liquids, arereferred to as Hildebrand solubility parameters.Although these provide good quantitative predictionsof the behaviour of a small number of hydrocarbons,they only provide a broad qualitativedescription of thebehaviours of most liquids because of the influence offactors such as hydrogen-bond formation and ioniza-tion. The concept has been extended, however, by theintroduction of partial solubility parameters, e.g.Hansen parameters and interaction parameters, thathave improved the quantitative treatment of systems inwhich polar effects and interactions occur.Solubility parameters, in conjunction with theelectrostatic properties of liquids, e.g. dielectric con-stant and dipole moment, have often been linked byempirical or semiempirical relationships either tothese parameters or to solvent properties. Studies onsolubility parameters are sometimes reported in thepharmaceutical literature.The use of dielectric con-stants as indicators of solvent power has alsoreceived attention, but deviations from the behaviourpredicted by such methods may occur.Mixtures of liquids are often used as solvents. Ifthe two liquids have similar chemical structures, e.g.benzene and toluene, then neither tends to associatein the presence of the other, and the solvent proper-ties of a 50:50 mixture would be a mean of those ofeach pure liquid. If the liquids have dissimilar struc-tures, e.g. water and propanol, then the molecules ofone of them tend to associate with each other and soform regions of high concentration within themixture.The solvent properties of this type of systemare not so simply related to its composition as in theprevious case.Solubility of solids in liquidsSolutions of solids in liquids are the most commontype encountered in pharmaceutical practice. Thepharmacist should therefore be aware of the generalmethod of determining the solubility of a solid in aliquid and the various precautions that should betaken during such determinations.Determination of the solubility of a solid in aliquidThe following points should be observed in all solu-bility determinations:1. The solvent and the solute must be pure.24 19. DISSOLUTION AND SOLUBILITY2. A saturated solution must be obtained beforeany solution is removed for analysis.3. The method of separating a sample of saturatedsolution from undissolved solute must besatisfactory.4. The method of analysing the solution must bereliable.5. Temperature must be adequately controlled.A saturated solution is obtained either by stirringexcess powdered solute with solvent for several hoursat the required temperature until equilibrium hasbeen attained, or by warming the solvent with anexcess of the solute and allowing the mixture to coolto the required temperature. It is essential that someundissolved solid should be present at the comple-tion of this stage in order to ensure that the solutionis saturated.A sample of the saturated solution is obtained foranalysis by separating it from the undissolved solid.Filtration is usually used, but precautions should betaken to ensure that:1. it is carried out at the temperature of thesolubility determination, in order to prevent anychange in the equilibrium between dissolved andundissolved solute; and2. loss of a volatile component does not occur.The filtration process has been simplified by theintroduction of membrane filters that can be used inconjunction with conventional syringes fitted withsuitable inline adapters.The amount of solute contained in the sample ofsaturated solution may be determined by a varietyofmethods, e.g. gravimetric or volumetric analysis,electrical conductivity measurements, ultraviolet(UV) spectrophotometry and chromatographicmethods. The selection of an appropriate method isaffected by the natures of the solute and the solventand by the concentration of the solution.Factors affecting the solubility of solids in liquidsKnowledge of these factors, which are discussedbelow together with their practical applications, is animportant aspect of the pharmacists expertise.Additional information, which shows how some ofthese factors may be used to improve the solubilitiesand bioavailabilities of drugs, is given in Chapters 21and 17,respectively.Temperature Earlier discussion centred on Eqn2.2 shows that the free energy change (AG) thataccompanies dissolution is dependent on the valueand sign of the change in enthalpy (AH). The addi-tional comments that referred to Eqn 2.3 indicatethat when AH is positive the dissolution process isusually an endothermic one, i.e. heat is normallyabsorbed when dissolution occurs. If this type ofsystem is heated it will tend to react in a way that willnullify the constraint imposed upon it, e.g. the rise intemperature. This tendency is an example of LeChateliers principle.Thus, a rise in temperature willlead to an increase in the solubility of a solid with apositive heat of solution. Conversely, in the case ofthe less commonly occurring systems that exhibitexothermic dissolution, an increase in temperaturewill give rise to a decrease in solubility.Plots of solubility versus temperature, which arereferred to as solubility curves, are often used todescribe the effect of temperature on a given system.Some examples are shown in Figure 2.3. Most of thecurves are continuous; however, abrupt changes inslope may be observed with some systems if a changein the nature of the dissolving solid occurs at aspecific transition temperature. For example, sodiumsulphate exist as the decahydrate Na2SO4,10H2O upto 32.5C, and its dissolution in water is anendothermic process. Its solubility thereforeincreases with rise in temperature until 32.5C isreached. Above this temperature the solid is con-verted into the anhydrous form Na2SO4, and the dis-solution of this compound is an exothermic process.The solubility therefore exhibits a change from apositive to a negative slope as the temperatureexceeds the transition value.Fig. 2.3 Solubility curves for various substances in water25 20. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNMolecular structure of solute It should be appreci-ated from the previous comments on the predictionof solubility that the natures of the solute and thesolvent will be of paramount importance in deter-mining the solubility of a solid in a liquid. It shouldalso be realized that even a small change in the mole-cular structure of a compound can have a markedeffect on its solubility in a given liquid. For example,the introduction of a hydrophilic hydroxyl group canproduce a large improvement in water solubility, asevidenced by the more than 100-fold difference inthe solubilities of phenol and benzene.In addition, the conversion of a weak acid to itssodium salt leads to a much greater degree of ionicdissociation of the compound when it dissolves inwater. The overall interaction between solute andsolvent is markedly increased and the solubility con-sequently rises. A specific example of this effect isprovided by a comparison of the aqueous solubilitiesof salicylic acid and its sodium salt, which are 1:550and 1:1, respectively.The reduction in aqueous solubility of a parentdrug by its esterification may also be cited as anexample of the effects of changes in the chemicalstructure of the solute. Such a reduction in solubilitymay provide a suitable method for:1. masking the taste of a parent drug, e.g.chloramphenicol palmitate is used in paediatricsuspensions rather than the more soluble andvery bitter chloramphenicol base;2. protecting the parent drug from excessivedegradation in the gut, e.g. erythromycinpropionate is less soluble and consequently lessreadily degraded than erythromycin;3. increasing the ease of absorption of drugs fromthe gastrointestinal tract, e.g. erythromycinpropionate is also more readily absorbed thanerythromycin.Nature of solvent: cosolvents The importance of thenature of the solvent has already been discussed interms of the statement like dissolves like, and inrelation to solubility parameters. In addition, thepoint has been made that mixtures of solvents maybe employed. Such mixtures are often used in phar-maceutical practice to obtain aqueous-based systemsthat contain solutes in excess of their solubilities inpure water.This is achieved by using cosolvents suchas ethanol or propylene glycol, which are misciblewith water and which act as better solvents for thesolute in question. For example, the aqueous solu-bility of metronidazole is about 100 mg in 10 mL.Chien (1984) has shown, however, that the solubilityof this drug can be increased exponentially by theincorporation of one or more water-miscible cosol-vents, so that a solution containing 500 mg in 10 mLand suitable for parenteral administration in thetreatment of anaerobic infection, can be obtained.Crystal characteristics: polymorphism and salvationThe value of the term AHcl in Eqn 2.3 is determinedby the strength of the interactions between adjacentmolecules (or ions) in a crystal lattice. These inter-actions will depend on the relative positions and ori-entations of the molecules in the crystal. When theconditions under which crystallization is allowed tooccur are varied, some substances produce crystalsin which the constituent molecules are aligned in dif-ferent ways with respect to one another in the latticestructure. These different crystalline forms of thesame substance, which are known as polymorphs,consequently possess different lattice energies, andthis difference is reflected by changes in other prop-erties; for example, the polymorphic form with thelowest free energy will be the most stable and possessthe highest melting point. Other less stable (ormetastable) forms will tend to transform into themost stable one at rates that depend on the energydifferences between the metastable and the stableforms. Polymorphs are explained more fully inChapter 9.The effect of polymorphism on solubility is partic-ularly important from a pharmaceutical point ofview, because it provides a means of increasing thesolubility of a crystalline material and hence its rateof dissolution by using a metastable polymorph.Although the more soluble polymorphs aremetastable and will convert to the stable form therate of such conversion is often slow enough for themetastable form to be regarded as being sufficientlystable from a pharmaceutical point of view. Thedegree of conversion should obviously be monitoredduring storage of the drug product to ensure that itsefficacy is not altered significantly. In addition, con-version to the less soluble and most stable poly-morph may contribute to the growth of crystals insuspension formulations.Many drugs exhibit polymorphism, e.g. steroids,barbiturates and sulphonamides. Examples of theimportance of polymorphism with respect to thebioavailabilities of drugs and to the occurrence ofcrystal growth in suspensions are given in Chapters17 and 23, respectively.The absence of crystalline structure that is usuallyassociated with a so-called amorphous powder (seeChapter 9) may also lead to an increase in the solubil-ity of a drug compared to that of its crystalline form.In addition to the effect of polymorphism the latticestructures of crystalline materials may be altered by26 21. DISSOLUTION AND SOLUBILITYthe incorporation of molecules of the solvent fromwhich crystallization occurred. The resultant solidsare called solvates; the phenomenon is referred tocorrectly as salvation and sometimes incorrectly andconfusingly as pseudopolymorphism. The alter-ation in crystal structure that accompanies solvationwill affect AHcl so that the solubilities of solvated andunsolvated crystals will differ.If water is the solvating molecule, i.e. if a hydrateis formed, then the interaction between the sub-stance and water that occurs in the crystal phasereduces the amount of energy liberated when thesolid hydrate dissolves in water. Consequently,hydrated crystals tend to exhibit a lower aqueous sol-ubility than their unhydrated forms. This decrease insolubility can lead to precipitation of drugs fromsolutions.In contrast to the effect of hydrate formation, theaqueous solubilities of other, i.e. non-aqueous, sol-vates are often greater than those of the unsolvatedforms. Examples of the effects of solvation and theattendant changes in solubilities of drugs on theirbioavailabilities are given in Chapter 17.Particle size of the solid The changes in interfacialfree energy that accompany the dissolution of parti-cles of varying sizes cause the solubility of a sub-stance to increase with decreasing particle size, asindicated by Eqn 2.10:where S is the solubility of small particles of radius r,S0 is the normal solubility (i.e. of a solid consistingof fairly large particles), y is the interfacial energy, Mis the molecular weight of the solid, p is the densityof the bulk solid, R is the gas constant and T is thethermodynamic temperature.This effect may be significant in the storage ofpharmaceutical suspensions, as the smaller particlesin such a suspension will be more soluble than thelarger ones. As the small particles disappear, theoverall solubility of the suspended drug will decreaseand the larger particles will grow.The occurrence ofcrystal growth by this mechanism is of particularimportance in the storage of suspensions intendedfor injection (Winfield and Richards, 1998).The increase in solubility with decrease in particlesize ceases when the particles have a very smallradius, and any further decrease in size causes adecrease in solubility. It has been postulated that thischange arises from the presence of an electricalcharge on the particles and that the effect of thischarge becomes more important as the size of theparticles decreases.pH If the pH of a solution of either a weaklyacidic drug or a salt of such a drug is reduced thenthe proportion of unionized acid molecules in thesolution increases. Precipitation may therefore occurbecause the solubility of the unionized species is lessthan that of the ionized form. Conversely, in the caseof solutions of weakly basic drugs or their salts pre-cipitation is favoured by an increase in pH. Suchprecipitation is an example of one type of chemicalincompatibility that may be encountered in the for-mulation of liquid medicines.This relationship between pH and the solubilityofionized solutes is extremely important with respectto the ionization of weakly acidic and basic drugs asthey pass through the gastrointestinal tract and expe-rience pH changes between about 1 and 8. This willaffect the degree of ionization of the drug molecules,which in turn influences their solubility and theirability to be absorbed. This aspect is discussed insome detail, elsewhere in this book and the reader isreferred to Chapters 3 and 17 in particular.The relationship between pH and the solubilityand pKa value of an acidic drug is given by Eqn 2.11,which is a modification of the Henderson-Hasselbalch equation (Eqn 3.12):where S is the overall solubility of the drug and SUis the solubility of its unionized form, i.e. S = S0 +solubility of ionized form (SI). If the pH of the solu-tion is known then Eqn 2.11 may be used to calcu-late the solubility of an acidic drug at that pH.Alternatively, the equation allows determination ofthe minimum pH that must be maintained in orderto prevent precipitation from a solution of knownconcentration.In the case of basic drugs the correspondingrelationship is given by Eqn 2.12:Common ion effect The equilibrium in a saturatedsolution of a sparingly soluble salt in contact withundissolved solid may be represented by:From the Law of Mass Action the equilibriumconstant K for this reversible reaction is given byEqn 2.14:27 22. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNwhere the square brackets signify concentrations ofthe respective components. As the concentration of asolid may be regarded as being constant, thenwhere Ks is a constant which is known as the solu-bility product of compound AB.If each molecule of the salt contains more thanone ion of each type, e.g. Ax+By-, then in thedefinition of the solubility product the concentrationof each ion is expressed to the appropriate power,i.e.:These equations for the solubility product are onlyapplicable to solutions of sparingly soluble salts.If Ks is exceeded by the product of the concen-tration of the ions, i.e. [A+][B-], then the equilibriumshown above, (Eqn 2.13) moves towards the left inorder to restore the equilibrium, and solid AB is pre-cipitated. The product [A+] [B~]will be increased bythe addition of more A+ions produced by the disso-ciation of another compound, e.g. AX > A++ X ,where A+is the common ion. Solid AB will be pre-cipitated and the solubility of this compound istherefore decreased. This is known as the commonion effect. The addition of common B~ions wouldhave the same effect.The precipitating effect of common ions is, in fact,less than that predicted from Eqn 2.15. The reasonfor this is explained below.Effect of indifferent electrolytes on the solubility productThe solubility of a sparingly soluble electrolyte maybe increased by the addition of a second electrolytethat does not possess ions common to the first, i.e. adifferent electrolyte.The definition of the solubility product of a spar-ingly soluble electrolyte in terms of the concentra-tion of ions produced at equilibrium, as indicated byEqn 2.15, is only an approximation from the moreexact thermodynamic relationship expressed by Eqn2.16:where Ks is the solubility product of compound ABand aA+and aB~ are known as the activities of therespective ions. The activity of a particular ion maybe regarded as its effective concentration. Ingeneral this has a lower value than the actual con-centration, because some ions produced by dissocia-tion of the electrolyte are strongly associated withoppositely charged ions and do not contribute soeffectively as completely unallocated ions to theproperties of the system.At infinite dilution the wideseparation of ions prevents any interionic associa-tion, and the molar concentration (CA+)and activity(aA+) of a given ion (A+) are then equal, i.e.:As the concentration increases, the effects of interi-onic association are no longer negligible and theratio of activity to molar concentration becomes lessthan unity i.e.:orwhere/A+ is known as the activity coefficient of A+. Ifconcentrations and activity coefficients are usedinstead of activities in Eqn 2.16, thenThe product of the concentrations, i.e. (CA+-CB_), willbe a constant (/Cs) as shown by Eqn 2.15, and(/A+-/B_) may be equated to /A+B_, where /A+B^ is themean activity coefficient of the salt AB, i.e.BecausefA+B_ varies with the overall concentration ofions present in solution (the ionic strength), and asKs is a constant, it follows that Ks must also varywith the ionic strength of the solution in an inversemanner to the variation of fA+B . Thus, in a systemcontaining a sparingly soluble electrolyte without acommon ion, the ionic strength will have an appre-ciable value and the mean activity coefficient fA+B_will be less than 1.From Eqn 2.17 it will be seen that Ks will there-fore be greater than Ks. In fact, the concentrationsolubility product Ks will become larger and largeras the ionic strength of the solution increases. Thesolubility of AB will therefore increase as the con-centration of added electrolyte increases.This argument also accounts for the fact that if noallowance is made for the variation in activity withionic strength of the medium, the precipitating effectof common ions is less than that predicted from theLaw of Mass Action.Effect of non-electrolytes on the solubility of electrolytesThe solubility of electrolytes depends on the dissoci-ation of dissolved molecules into ions. The ease ofthis dissociation is affected by the dielectric constantof the solvent, which is a measure of the polar natureof the solvent. Liquids with a high dielectric constant(e.g. water) are able to reduce the attractive forces28 23. DISSOLUTION AND SOLUBILITYthat operate between oppositely charged ions pro-duced by dissociation of an electrolyte.If a water-soluble non-electrolyte such as alcoholis added to an aqueous solution of a sparinglysoluble electrolyte, the solubility of the latter isdecreased because the alcohol lowers the dielectricconstant of the solvent and ionic dissociation of theelectrolyte becomes more difficult.Effect of electrolytes on the solubility of non-electrolytesNon-electrolytes do not dissociate into ions inaqueous solution, and in dilute solution the dissolvedspecies therefore consists of single molecules. Theirsolubility in water depends on the formation of weakintermolecular bonds (hydrogen bonds) between theirmolecules and those of water.The presence of a verysoluble electrolyte (e.g. ammonium sulphate), the ionsof which have a marked affinity for water, will reducethe solubilityof a non-electrolyte by competing for theaqueous solvent and breaking the intermolecularbonds between the non-electrolyte and the water.Thiseffect is important in the precipitation of proteins.Complex formation The apparent solubility of asolute in a particular liquid may be increased ordecreased by the addition of a third substance whichforms an intermolecular complex with the solute.The solubility of the complex will determine theapparent change in the solubility of the originalsolute. Use is made of complex formation as an aidto solubility in the preparation of solution of mer-curic iodide (HgI2). The latter is not very soluble inwater but is soluble in aqueous solutions of potas-sium iodide because of the formation of a water-soluble complex, K2(HgI4).Solubilizing agents These agents are capable offorming large aggregates or micelles in solutionwhen their concentrations exceed certain values. Inaqueous solution the centre of these aggregatesresembles a separate organic phase and organicsolutes may be taken up by the aggregates, thus pro-ducing an apparent increase in their solubilities inwater. This phenomenon is known as solubiliza-tion. A similar phenomenon occurs in organic sol-vents containing dissolved solubilizing agents,because the centre of the .aggregates in these systemsconstitutes a more polar region than the bulk of theorganic solvent. If polar solutes are taken up intothese regions their apparent solubilities in theorganic solvents are increased.Solubility of gases in liquidsThe amount of gas that will dissolve in a liquid isdetermined by the natures of the two componentsand by temperature and pressure.Provided that no reaction occurs between the gasand liquid then the effect of pressure is indicated byHenrys law, which states that at constant tempera-ture the solubility of a gas in a liquid is directly pro-portional to the pressure of the gas above the liquid.The law may be expressed by Eqn 2.18:where w is the mass of gas dissolved by unit volume ofsolvent at an equilibrium pressure p and k is a pro-portionality constant. Although Henrys law is mostapplicable at high temperatures and low pressures,when solubility is low it provides a satisfactorydescription of the behaviour of most systems atnormal temperatures and reasonable pressures, unlesssolubility is very high or reaction occurs. Equation2.18 also applies to the solubility of each gas in a solu-tion of several gases in the same liquid, provided thatp represents the partial pressure of a particular gas.The solubility of most gases in liquids decreases asthe temperature rises. This provides a means ofremoving dissolved gases. For example, water forinjections free from either carbon dioxide or air maybe prepared by boiling water with minimal exposureto air and preventing the access of air during cooling.The presence of electrolytes may also decrease thesolubility of a gas in water by a salting out process,which is caused by the marked attraction exertedbetween electrolyte and water.Solubility of liquids in liquidsThe components of an ideal solution are miscible inall proportions. Such complete miscibility is alsoobserved in some real binary systems, e.g. ethanoland water, under normal conditions. However, if oneof the components tends to self-associate becausethe attractions between its own molecules are greaterthan those between its molecules and those of theother component, i.e. if a positive deviation fromRaoults law occurs, the miscibility of the compo-nents may be reduced. The extent of the reductiondepends on the strength of the self-association and,therefore, on the degree of deviation from Raoultslaw. Thus, partial miscibility may be observed insome systems, whereas virtual immiscibility may beexhibited when the self-association is very strongand the positive deviation from Raoults law is great.In cases where partial miscibility occurs undernormal conditions the degree of miscibility is usuallydependent on the temperature. This dependency isindicated by the phase rule, introduced by J.Willard Gibbs, which is expressed quantitatively byEqn 2.19:29 24. THE DESIGN OF DOSAGE FORMSgeneral ways, by passive diffusion and by specializedtransport mechanisms. In passive diffusion, which isthought to control the absorption of most drugs, theprocess is driven by the concentration gradient thatexists across the cellular barrier, with drug moleculespassing from regions of high to those of low concen-tration. Lipid solubilityand the degree of ionization ofthe drug at the absorbing site influence the rate of dif-fusion. Several specialized transport mechanisms arepostulated, including active and facilitated transport.Once absorbed, the drug can exert a therapeutic effecteither locally or at a site of action remote from that ofadministration. In the latter case the drug has to betransported in body fluids (Fig. 1.1).When the drug is administered from dosage formsdesigned to deliver via the buccal, respiratory, rectal,intramuscular or subcutaneous routes, it passesdirectly into the blood-stream from absorbing tissues,but the intravenous route is the most direct ofall.When delivered by the oral route the onset of drugaction will be delayed because of the required transittime in the gastrointestinal tract, the absorptionprocess and hepatoenteric blood circulation features.The physical form of the oral dosage form will alsoinfluence absorption rate and onset of action, withsolutions acting faster than suspensions, which in turngenerally act faster than capsules and tablets. Dosageforms can thus be listed in order of time of onset oftherapeutic effect (Table 1.2). However, all drugs, irre-Table 1 .2 Variation in time of onset of action fordifferent dosageformsTime of onset of actionSecondsMinutesMinutes to hoursSeveral hoursDaysVariesDosage formsi.v. injectionsi.m. and s.c. injections,buccal tablets, aerosols, gasesShort-term depot injections,solutions, suspensions,powders, granules, capsules,tablets, modified-releasetabletsEnteric-coated formulationsDepot injections, implantsTopical preparationsFig. 1.1 Pathways a drug may take following the administration of a dosage form by differentroute.3 25. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNwhere P and C are the numbers of phases and com-ponents in the system, respectively, and F is thenumber of degrees of freedom, i.e. the number ofvariable conditions such as temperature, pressureand composition that must be stated in order todefine completely the state of the system at equilib-rium.The overall effect of temperature variation on thedegree of miscibility in these systems is usuallydescribed by means of phase diagrams, which aregraphs of temperature versus composition at con-stant pressure. For convenience of discussion of theirphase diagrams the partiallymiscible systems may bedivided into the following types.Systems showing an increase in miscibility withrise in temperatureA positive deviation from Raoults law arises from adifference in the cohesive forces that exist betweenthe molecules of each component in a liquidmixture. This difference becomes more marked asthe temperature decreases, and the positive deviationmay then result in a decrease in miscibility sufficientto cause the separation of the mixture into twophases. Each phase consists of a saturated solution ofone component in the other liquid. Such mutuallysaturated solutions are known as conjugatesolutions.The equilibria that occur in mixtures of partiallymiscible liquids may be followed either by shakingthe two liquids together at constant temperature andanalysing samples from each phase after equilibriumhas been attained, or by observing the temperatureat which known proportions of the two liquids, con-tained in sealed glass ampoules, become miscible, asshown by the disappearance of turbidity.Systems showing a decrease in miscibility withrise in temperatureA few mixtures, which probably involve compoundformation, exhibit a lower critical solution tempera-ture (GST), e.g. triethylamine plus water, paralde-hyde plus water. The formation of a compoundproduces a negative deviation from Raoults law, andmiscibility therefore increases as the temperaturefalls, as shown in Figure 2.4.The effect of temperature on miscibility is of usein the preparation of paraldehyde enemas, whichusually consist of a solution of paraldehyde innormal saline. Cooling the mixture during prepara-Fig. 2.4 Temperature-composition diagram for the triethylamine-water system (at 101 325 kPa, standard atmospheric pressure).tion allows more rapid solution, and storage of theenema in a cool place is recommended.Systems showing upper and lower criticalsolution temperaturesThe decrease in miscibility with increase in temper-ature in systems having a lower GST is notindefinite. Above a certain temperature, positivedeviations from Raoults law become important andmiscibility starts to increase again with further risesin temperature. This behaviour produces a closed-phase diagram, as shown in Figure 2.5, which repre-sents the nicotine-water system.Fig. 2.5 Temperature-composition diagram for the nicotine-water system (at 101 325 kPa; standard atmospheric pressure).30 26. DISSOLUTION AND SOLUBILITYIn some mixtures where an upper and lower CSTare expected, these points are not actually observed,as a phase change by one of the components occursbefore the relevant CST is reached. For example, theether-water system would be expected to exhibit alower CST, but water freezes before the temperatureis reached.The effects of added substances on criticalsolution temperaturesIt has already been stated that a CST is an invariantpoint at constant pressure. These temperatures arevery sensitive to impurities or added substances. Ingeneral, the effects of additives may be summarizedby Table 2.3.The increase in miscibility of two liquids causedby the addition of a third substance is referred to asblending.The use of propylene glycol as a blending agent,which improves the miscibility of volatile oils andwater, can be explained in terms of a ternary phasediagram.This is a triangular plot which indicates theeffects of changes in the relative proportions of thethree components at constant temperature and pres-sure, and it is a good example of the interpretationand use of such phase diagrams.Distribution of solutes betweenimmiscible liquidsPartition coefficientsIf a substance which is soluble in both componentsof a mixture of immiscible liquids is dissolved insuch a mixture, then, when equilibrium is attained atconstant temperature, it is found that the solute isdistributed between the two liquids in such a waythat the ratio of the activitiesof the substance in eachliquid is a constant.This is known as the Nernst dis-tribution law, which can be expressed by Eqn 2.20:where aA and aB are the activitiesof the solute in sol-vents A and B, respectively. When the solutions aredilute, or when the solute behaves ideally,the activi-ties may be replaced by concentrations (CA and CB):where the constant K is known as the distributioncoefficient or partition coefficient. In the case ofsparingly soluble substances K is approximatelyequal to the ratio of the solubilities (SA and .SB) ofthe solute in each liquid, i.e.:In most other systems, however, deviation from idealbehaviour invalidates Eqn 2.22. For example, if thesolute exists as monomers in solventA and as dimersin solvent B, the distribution coefficient is given byEqn 2.23, in which the square root of the concentra-tion of the dimeric form is used:If the dissociation into ions occurs in the aqueouslayer, B, of a mixture of immiscible liquids, then thedegree of dissociation (a) should be taken intoaccount, as indicated by Eqn 2.24:The solvents in which the concentrations of thesolute are expressed should be indicated when parti-tion coefficients are quoted. For example, a partitioncoefficient of 2 for a solute distributed between oiland water may also be expressed as a partitioncoefficient between water and oil of 0.5. This can berepresented as /Coilwater = 2 and KwateToil = 0.5. Theabbreviation K0.,,is often used for the former.Table 2.3 The effects of additives on critical solution temperature (CST)Type of CST Solubility of additive in each componentUpperUpperLowerLowerApprox. equally soluble in both componentsReadily soluble in one component but not in otherApprox. equally soluble in both componentsReadily soluble in one component but not in otherEffect on CSTLoweredRaisedRaisedLoweredEffect on miscibilityIncreasedDecreasedIncreasedDecreased31 27. SCIENTIFIC PRINCIPLES OF DOSAGE FORM DESIGNSolubility of solids in solidsIf two solids are either melted together and thencooled or dissolved in a suitable solvent, which isthen removed by evaporation, the solid that is rede-posited from the melt or the solution will either be aone-phase solid solution or a two-phase eutecticmixture.In a solid solution, as in other types of solution,the molecules of one component (thesolute) aredis-persed molecularly throughout the other component(the solvent). Complete miscibility of two solidcom-ponents is only achieved if:1. the molecular size of the solute is the same asthat of the solvent, so that a molecule of theformer can be substituted for one of the latter inits crystal lattice structure; or2. the solute molecules are much smaller than thesolvent molecules, so that the former can beaccommodated in the spaces of the solventlattice structure.These two types of solvent mechanism are referred toas substitution and interstitial effects, respectively. Asthese criteria are only satisfied in relatively fewsystems, partial miscibility of solids is more commonlyobserved. Thus, dilute solutions of solids in solids maybe encountered in systems of pharmaceutical interest,for example when the solvent is a polymeric materialwith large spaces between its intertwined moleculesthat can accommodate solute molecules.Unlike a solution, a simple eutectic consists of anintimate mixture of the two microcrystalline compo-nents in a fixed composition. However, both solidsolutions and eutectics provide a means of dispersinga relatively water-insoluble drug in a very fine form,i.e. as molecules or microcrystalline particles, respec-tively, throughout a water-soluble solid. When thelatter carrier solid is dissolved away the molecules orsmall crystals of insoluble drug may dissolve morerapidly than a conventional powder because thecontact area between drug and water is increased. Therate of dissolution and, consequently, the bioavailabil-ities of poorly soluble drugs may therefore beimproved by the use of solid solutions or eutectics.REFERENCESChien,Y.W. (1984) J. ParenteralSci. Tech., 38, 32-36.Noyes, A.A. and Whitney,W.R. (189T).J.Am. Chem. Soc., 19,930.Winfield, AJ. and Richards, R.M.E. (1998) PharmaceuticalPractice, 2nd edn., Churchill Livingstone, Edinburgh.BIBLIOGRAPHYBarton, A.P.M. (1983) Handbook of Solubility Parametersandother Cohesion Parameters.CRC Press Inc., Boca Raton,Florida.Beerbower, A.,Wu, PL. and Martin, A. (1984), J. Pharm.Sci., 73, 179-188.British Pharmacopoeia (latest edition), HMSO. London.Florence, A.T. and Attwood, D. (1998)PhysicochemicalPrinciples of Pharmacy, 3rd edn, Macmillan, London.Pharmaceutical Handbook, 3rd edn (1999) (Ed.A. Wade).Pharmaceutical Press, London.Rowlinson, J.S. and Swinton, F.L. (1982) Liquids and LiquidMixtures, 3rd edn, Butterworths, London.United States Pharmacopeia and National Formulary (latestedition) United States Pharmacopeial Convention Inc.,Rockville, MD.32 28. 3Properties of solutionsMichael AultonCHAPTER CONTENTSIntroduction 33Types of solution 33Vapour pressures of solids, liquids andsolutions 33Ideal solutions: Raoults law 34Real and non-ideal solutions 35lonization of solutes 35Hydrogen ion concentration and pH 36Dissociation (or ionization) constants and pK"a 36Buffer solutions and buffer capacity 38INTRODUCTIONColligative properties 38Osmotic pressure 38Osmolality and osmolarity 39Iso-osmotic solutions 39Isotonic solutions 39Diffusion in solution 39Bibliography 40The main aim of this chapter is to provide informa-tion on certain principles that relate to the applica-tions of solutions in pharmaceutical science. It dealsmainly with the physicochemical properties of solu-tions that are important with respect to pharmaceu-tical systems.These aspects are covered in sufficientdetail to introduce the pharmaceutical scientist tothese properties. Much is published elsewhere in fargreater detail and any reader requiring this addi-tional information is referred to the bibliography atthe end of the chapter.TYPES OF SOLUTIONSolutions may be classified according to the physicalstates (i.e.gas,solid or liquid) of the solute(s) and thesolvent. Although a variety of different types can exist,solutions of pharmaceutical interest .virtually allpossess liquid solvents. In addition, the solutes arepre-dominantly solid substances. Consequently, most ofthe comments made in this chapter are made wi