Ambroxol Hydrochloride (BANM, rINNM)Ambroksolihydrokloridi; Ambroksolio hidrochloridas; Ambroxol,chlorhydrate d’; Ambroxol hydrochlorid; Ambroxol-hidroklorid;Ambroxolhydroklorid; Ambroxoli hydrochloridum; Hidroclorurode ambroxol; NA-872 (ambroxol). trans-4-(2-Amino-3,5-dibromobenzylamino)cyclohexanol hydrochloride

Pharmacopoeias. In Chin. and Eur. (see p.vii).Ph. Eur. 6.2 (Ambroxol Hydrochloride). A white or yellowishcrystalline powder. Sparingly soluble in water; practically insolublein dichloromethane; soluble in methyl alcohol. A 1% solutionin water has a pH of 4.5 to 6.0. Protect from light.ProfileAmbroxol is a metabolite of bromhexine (p.1552) and is usedsimilarly as a mucolytic. It is given in a usual oral daily dose of

60 to 120 mg of the hydrochloride in 2 divided doses. Ambroxolhas also been given by inhalation, injection, or rectally.Adverse effects. HYPERSENSITIVITY. A report1 of contact allergyto ambroxol, but not bromhexine.1. Mancuso G, Berdondini RM. Contact allergy to ambroxol. ContactDermatitis 1989; 20: 154.Pharmacokinetics. References to pharmacokinetic studies ofambroxol.1. Hammer R, et al. Speziesvergleich in Pharmakokinetik und Metabolismusvon NA 872 Cl Ambroxol bei Ratte, Kaninchen,Hund und Mensch. Arzneimittelforschung 1978; 28: 899–903.2. Jauch R, et al. Ambroxol, Untersuchungen zum Stoffwechselbeim Menschen und zum quantitativen Nachweis in biologischenProben. Arzneimittelforschung 1978; 28: 904–11.3. Vergin H, et al. Untersuchungen zur Pharmakokinetik und Bioäquivalenzunterscheidlicher Darreichungsformen von Ambroxol.Arzneimittelforschung 1985; 35: 1591–5.Respiratory disorders. Mixed results1-3 were obtained whenambroxol was used in chronic bronchitis or chronic obstructivepulmonary disease (COPD—p.1112); in a randomised study, itwas no better than placebo in preventing acute exacerbations ofCOPD; however, in a subset of patients with more severe disease,ambroxol therapy reduced the number of exacerbations.4 Itwas ineffective5 when given to mothers for the prophylaxis ofneonatal respiratory distress syndrome (p.1508), although it maybe of modest benefit in the early treatment of established diseasein infants.6,7

Inhalation of ambroxol aerosol has also produced beneficial effectsin a patient with alveolar proteinosis who refused alveolarlavage.8For the use of mucolytics in productive cough see p.1547.1. Olivieri D, et al. Ambroxol for the prevention of chronic exacerbations:long-term multicenter trial: protective effect of ambroxolagainst winter semester exacerbations: a double-blind studyversus placebo. Respiration 1987; 51 (suppl 1): 42–51.2. Guyatt GH, et al. A controlled trial of ambroxol in chronic bronchitis.Chest 1987; 92: 618–20.3. Alcozer G, et al. Prevention of chronic bronchitis exacerbationswith ambroxol (Mucosolvan Retard): an open, long-term, multicenterstudy in 5,635 patients. Respiration 1989; 55 (suppl 1):84–96.4. Malerba M, et al. Effect of twelve-months therapy with oral ambroxolin preventing exacerbations in patients with COPD: double-blind, randomized, multicenter, placebo-controlled study(the AMETHIST Trial). Pulm Pharmacol Ther 2004; 17: 27–34.5. Dani C, et al. Antenatal ambroxol treatment does not prevent therespiratory distress syndrome in premature infants. Eur J Pediatr1997; 156: 392–3.6. Wauer RR, et al. Randomized double blind trial of Ambroxol forthe treatment of respiratory distress syndrome. Eur J Pediatr1992; 151: 357–63.7. Schmalisch G, et al. Changes in pulmonary function in preterminfants recovering from RDS following early treatment with ambroxol:results of a randomized trial. Pediatr Pulmonol 1999; 27:104–12.8. Diaz JP, et al. Response to surfactant activator (ambroxol) in alveolarproteinosis. Lancet 1984; i: 1023.Uricosuric action. A study1 was carried out in 48 young malehealthy subjects to examine the uricosuric effect of ambroxol.The minimum effective dose for lowering plasma-uric acid concentrationswas found to be between 250 and 500 mg daily givenin 2 divided doses. Although these doses are much higher thanthose used to treat bronchopulmonary disease, doses as high asl g daily were well tolerated.1. Oosterhuis B, et al. Dose-dependent uricosuric effect of ambroxol.Eur J Clin Pharmacol 1993; 44: 237–41.PreparationsProprietary Preparations (details are given in Part 3)Arg.: Ambril; Apracur Expectorante; Cortos; Graneodin Expectorante†;Mucosolvon; Tabcin Expectorante†; Tavinex Expectorante; Tavinex Expectotabs;Tosambrex; Austria: Ambrobene; Ambrohexal; Ambrolan; Ambrolos†;Ambronorm; Bisolangin†; Bisolaryn; Broxol; Mucoangin; Mucosolvan;Sekretovit; Belg.: Mucoangin; Surbronc; Braz.: Ambrizol†; Ambrol†; Ambroten;Ambrox†; Anabron; Broncoflux; Bronxol; Expectuss; Fluibron; Fluidin;Fluxol†; Mucibron; Mucoclean†; Mucolin; Mucosolvan; Mucoxolan; Neossolvan;Probec†; Pulmosolvan†; Surfactil†; Chile: Bronchopront†;

Broncot; Fluibron; Fluomit; Milbron†; Mintamox; Mucosolvan; Muxol; Tocalm;Cz.: Ambex; Ambrobene; Ambrosan; Ambrospray; Bronchopront†;Dignobroxol†; Dr Rentschler Hustenloser; Fervex†; Flavamed; Halixol; Mucosin;Mucosolvan; Neo-Bronchol; Solvolan; Denm.: Mucoangin; Fr.: Lysopadol;Muxol; Surbronc; Ger.: Ambril; Ambro; Ambro-Puren†; Ambrobeta;Ambrodoc; Ambrohexal; Ambroinfant†; Ambrolos†; Ambropp†; Bronchopront;Bronchowern; duramucal†; Expit; frenopect; Frubizin akut; LarylinHusten-Loser Pastillen; Larylin Husten-Loser Saft†; Lindoxyl; Muco-Aspecton†;Mucoangin; Mucobroxol†; Mucophlogat†; Mucosolvan; Neo-Bronchol†;Padiamuc; Pulmotin Hustenloser; Sigabroxol†; stas-Hustenloser†;tuss†; Gr.: Abrobion; Abrolen; Afrodor; Amboral; Ambrobion†; Ambromyc;Anavix; Aprinol; Auroxidol; Bunafon; Celibron; Dolcevin; Ebertuss; Effercet;Erosil; Fluibrox; Grenovix; Hivotex; Kriolen; Lextarol; Mavixan; Mucolin;Mucosolvan; Mucovix; Nibren; Olbenorm; Provixen-N; Puntol; Respirol;Saribal; Stefolant; Strubelin; Tevoril; Tosse; Tussefar; Zyrantol; Hong Kong:Amxol; Bronchopront; Marbroxol; Max; Medovent†; Mucosolvan; Qualisolvon;Hung.: Ambrobene; Ambrohexal; Bronchopront†; Halixol; Mucoangin;Solvolan; India: Acocontin; Acolyt; Ambrodil; Inhalex; Indon.:Ambril; Brommer; Bronchopront; Broncozol; Broxal; Epexol; Extropect;Gunapect; Interpec; Lapimuc; Molapect; Mucera; Mucolica; Mucopect; Mucos;Mucoxol; Nufanibrox; Silopect; Sohopect; Transbroncho; Transmuco;Ital.: Ambrotus; Amobronc; Atus; Broxol; Fluibron; Fluixol; Lintos; Lisopulm†;Muciclar; Mucoaricodil; Mucobron; Mucosolvan; Secretil; Surfactal;Tauxolo; Viscomucil; Jpn: Mucosal; Mucosolvan; Malaysia: Amxol; Axol;Mucosolvan; Shinoxol; Strepsils Chesty Cough; Mex.: Ambrofur; Amocol;Axol; Balsibron; Bionoxol; Boxolam; Brogal; Bronolban; Brosolan; Broxaquim;Broxofar; Broxoffler; Broxol; Broxolim; Cloxan; Ebromin; Euroxol

Exabrol†; Expeflen; Fantrodol†; Ital-Ultra; Loexom; Loxibrin; Mucibron; Mucoangin;Mucosolvan; Mucovibrol; Mucovibrol T†; Mucoxol; Musalten; Musvan;Muxol†; Oxolvan; Prospec; Protitus; Randex; Rimoxol†; Sekretovit;Septacin; Seraxol-S; Softixol†; Solpat; Tobrin; Tradexol†; Trimexine; Tunitol-BX; Tusibron; Ulax-F; Viaxol; Weiscal; Neth.: Mucoangin; Philipp.: Ambrolex;Atrivex; Brocof; Bromace; Bromacef; Broxan; Broxifil; Broxil-M; Broxitrol;Broxolvan; Exolpen; Expel; Medibron; Mepebrox; Mucosolin; Mucosolvan;Mucovis; Phlemasol; Pontef; Pulmobrol; Venteze; Voxoll; Zobrixol;Pol.: Aflegan; Ambro; Ambrohexal; Ambroksol; Ambrosan; Ambrosol; Deflegmin;Flavamed; Mucoangin; Mucosolvan; Mukobron; Tussal Expectorans;Port.: Benflux; Bromax; Bronchopront†; Broncoliber; Bronxol; Drenoxol;Fluidox; Fluidrenol; Hipotosse; Mucodrenol; Mucosolvan; Mucotosse; Rus.:Ambrobene (Амбробене); Ambrohexal (Амброгексал); Ambrosan(Амбросан); Ambrosol (Амбросол); Bronchowern (Бронховерн); Halixol(Халиксол); Lasolvan (Лазолван); Medovent (Медовент); Suprima-Kof(Суприма-Коф); Singapore: Amxol; Axol; Bronchopront†; Max; Mucosolvan;Shinoxol; Spain: Ambrolitic; Dinobroxol; Motosol; Mucibron; Mucosan;Naxpa; Swed.: Mucoangin; Switz.: Fluibron†; Mucabrox; Mucoangin;Mucosolvon; Thai.: Ambrol†; Ambrolytic†; Ambrox†; Ambroxan;Ampromed; Amtuss; Amxol; Bronchopront†; Broncol; Broxol; Broxsa†;Max; Medovent; Misovan; Movent†; Mucodic; Mucolan; Mucolid; Mucomed;Mucopec; Mucosolvan; Mucoxine-F; Mucozan; Musocan; Nucobrox; Polibroxol;Simusol; Strepsils Chesty Cough; Streptuss-AX; Turk.: Ambreks;Fluibron; Mukoral; Pulmor; Sekrol; Tusilin; UAE: Mucum; Venez.: Ambril;Ambromuco; Ambrox; Benflux; Brocantol; Bronchopront; Litusix; Misulvan;Mucoangin; Mucorama; Mucosolvan; Muxen; Xolvax.Multi-ingredient: Arg.: Amoxi Respiratorio†; Amoxidal Respiratorio;Amoxidal Respiratorio Duo; Amoxigrand Bronquial; Amoxipenil Bronquial;Amoxitenk Respiratorio†; Aseptobron Respiratorio; Bronco Biotaer†;Bronquisedan; Bronquisedan Mucolitico; Cefacar Mucolitico†; CefacilinaBronquial; Gentiabron†; Letondal; Muco Cortos†; Muco Dosodos; MucoDosodos Biotic; Mucoprednibron; Mucosolvon Compositum; No-Tos Biotic;Nobactam Bronquial; Oxibron NF; Oximar Respiratorio; Pulmonix Plus;Toraxan; Trexirol NF†; Trifamox Bronquial Duo; Austria: Mucospas; Braz.:Penetro†; Chile: Ambrotos; Cz.: Doxycyclin Al Comp; Ger.: Ambrodoxy;Ambroxol AL comp; Ambroxol comp; Amdox-Puren†; Azudoxat comp†;Broncho-Euphyllin; Doxam; Doximucol; Doxy Comp; Doxy Lindoxyl; DoxyPlus; Doxy-Wolff Mucolyt†; Doxysolvat†; Jenabroxol comp†; Sigamuc†;Spasmo-Mucosolvan; Terelit†; India: Ambrodil Plus; Ambrodil-S; Amcof;Amcold; Asthalin AX; Axalin-AX; Axalin†; Kofarest; Mucaryl-AX†; NovamoxAX; Roxeptin-ME; Suprivent-A; Mex.: Acimox-Ex; Aeroflux; AlerfinEx; Alexing; Ambodil-C; Aminoefedrison; Balsibron-C; Biovicam Ex; Bisincof;Bolbamox†; Brogal Compositum; Brogal-T; Brogamax; Brominol-C; Bronar;Bronolban-M; Broquixol; Brosolan C; Broxofar Compuesto; BroxolAir; Broxol Plus; Broxolim-AM†; Broxolim-C; Brumax; Cefabroxil; Cibronal;Cobadex; Coricidin Expec; Dexol; Dexoltryn; Dofaxil; Doralan-Ax; EbrominP; Epicol NF†; Faribrox; Ferlex; Flamebin; Fludexol-CL; Fluvicil; Fluxibit;Fluxol; Fultac; Gimabrol; Histiacil NF; Laritol Ex; Linfarden; Loexom FC;Loexom FS; Loxorol; Mucoflux; Mucosolvan Compositum; MucovibrolAmoxi; Mucovibrol C; Musaldox; Neumyn-AS; Pentibroxil; Plexus; Ravotaf;Removil; Rezplen; Rombox; Salamflux; Sekretovit Amoxi; Sekretovit Ex;Sensibit XP; Septacin Amoxi; Septacin Ex; Seraxol; Serbol; Sermoxol;Sibilex; Solcibrol; Tadinar-C; Tavexyl; TheraFlu Tenalif; Torva; Toxol; Ulax-C;Vanmoxol; Port.: Clembroxol; Lactucol; Mucospas; Ventoliber; Rus.: ColdactBroncho (Колдакт Бронхо)†; Rinicold-Broncho (Риниколд Бронхо);Venez.: Aeroflux; Ambroclar; Ambromuco Compositum; Arbixil; Clenbuxol;Litusix Compositum; Mucolin; Mucosolvan Compositum.

Action and useMucolytic expectorant.Ph EurDEFINITIONtrans-4-[(2-Amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride.Content99.0 per cent to 101.0 per cent (dried substance).CHARACTERSAppearanceWhite or yellowish crystalline powder.SolubilitySparingly soluble in water, soluble in methanol, practically insoluble in methylene chloride.IDENTIFICATIONFirst identificationıB, D.Second identificationıA, C, D.ıA. Dissolve 20.0 mg in 0.05 M sulphuric acid and dilute to 100.0 ml with the same acid.Dilute 2.0 ml of the solution to 10.0 ml with 0.05 M sulphuric acid . Examined between 200nm and 350 nm (2.2.25), the solution shows two absorption maxima at 245 nm and 310 nm.

The ratio of the absorbance measured at 245 nm to that measured at 310 nm is 3.2 to 3.4.ıB. Infrared absorption spectrophotometry (2.2.24).Comparisonıambroxol hydrochloride CRS .ıC. Examine by thin-layer chromatography (2.2.27).Test solutionıDissolve 50 mg of the substance to be examined in methanol R and dilute to 5ml with the same solvent.Reference solutionıDissolve 50 mg of ambroxol hydrochloride CRS in methanol R and diluteto 5 ml with the same solvent.PlateıTLC silica gel F254 plate R.Mobile phaseıconcentrated ammonia R, 1-propanol R, ethyl acetate R, hexane R(1:10:20:70 V/V/V/V).Applicationı10 μl.DevelopmentıOver 2/3 of the plate.DryingıIn air.DetectionıExamine in ultraviolet light at 254 nm.ResultsıThe principal spot in the chromatogram obtained with the test solution is similar inposition and size to the principal spot in the chromatogram obtained with the referencesolution.ıD. Dissolve 25 mg in 2.5 ml of water R, mix with 1.0 ml of dilute ammonia R1 and allow to

stand for 5 min. Filter and acidify the filtrate with dilute nitric acid R. The filtrate givesreaction (a) of chlorides (2.3.1).

TESTSSolution SDissolve 0.75 g in methanol R and dilute to 15 ml with the same solvent.Appearance of solutionSolution S is clear (2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2,Method II).pH (2.2.3)4.5 to 6.0.Dissolve 0.2 g in carbon dioxide-free water R and dilute to 20 ml with the same solvent.Related substancesLiquid chromatography (2.2.29). Prepare the solutions immediately before use.Test solutionıDissolve 50.0 mg of the substance to be examined in water R and dilute to50.0 ml with the same solvent.Reference solution (a)ıDilute 5.0 ml of the test solution to 250.0 ml with water R. Dilute 1.0ml of this solution to 20.0 ml with the mobile phase.

vReference solution (b)ıDissolve 5 mg of the substance to be examined in 0.2 ml of methanolR and add 0.04 ml of a mixture of 1 volume of formaldehyde solution R and 99 volumes ofwater R. Heat at 60 °C for 5 min. Evaporate to dryness under a current of nitrogen. Dissolvethe residue in 5 ml of water R and dilute to 20 ml with the mobile phase.Column:ıı— size: l = 0.25 m, Ø = 4.0 mm,ı— stationary phase: octadecylsilyl silica gel for chromatography R (5 μm).Mobile phaseıA mixture of equal volumes of acetonitrile R and a solution prepared asfollows: dissolve 1.32 g of ammonium phosphate R in 900 ml of water R, adjust to pH 7.0 withphosphoric acid R and dilute to 1000 ml with water R.Flow rateı1 ml/min.DetectionıSpectrophotometer at 248 nm.Injectionı20 μl.SensitivityıReference solution (a).Run timeı3 times the retention time of the principal peak in the chromatogram obtained withthe test solution.System suitability:ı— resolution: minimum of 4.0 between the peaks due to impurity B and ambroxol in the

chromatogram obtained with reference solution (b).Limits:ı— any impurity: not more than the area of the principal peak in the chromatogram obtainedwith reference solution (a) (0.1 per cent),ı— total: not more than 3 times the area of the principal peak in the chromatogram obtainedwith reference solution (a) (0.3 per cent),ı— disregard limit: 0.1 times the area of the principal peak in the chromatogram obtainedwith reference solution (a).Heavy metals (2.4.8)Maximum 20 ppm.1.0 g complies with limit test C. Prepare the standard using 2 ml of lead standard solution (10ppm Pb) R.Loss on drying (2.2.32)Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C.Sulphated ash (2.4.14)Maximum 0.1 per cent, determined on 1.0 g.

ASSAYDissolve 0.300 g in 70 ml of alcohol R and add 5 ml of 0.01 M hydrochloric acid . Carry out apotentiometric titration (2.2.20), using 0.1 M sodium hydroxide. Read the volume addedbetween the two points of inflexion.1 ml of 0.1 M sodium hydroxide is equivalent to 41.46 mg of C13H19Br2ClN2O

STORAGEStore protected from light.

IMPURITIESıA. Ar-CH2OH: (2-amino-3,5-dibromophenyl)methanol,ıB. trans-4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)cyclohexanol,ıC. trans-4-[[(E)-2-amino-3,5-dibromobenzyliden]amino]cyclohexanol,ıD. cis-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol,ıE. Ar-CH=O: 2-amino-3,5-dibromobenzaldehyde.

Pharmaceutical solutionsfor oral administrationGeneral descriptionPharmaceutical solutions may be generallydefined as liquid preparations in which thetherapeutic agent and the various excipientsare dissolved in the chosen solvent system.Pharmaceutical solutions may contain arange of excipients, each with a definedpharmaceutical purpose. Examples of theseinclude:■ the vehicle, usually purified water■ co-solvents, e.g. propylene glycol,glycerin, alcohol■ agents specifically to enhance the solubility of the therapeuticagent in the vehicle, e.g. surface-active agents■ preservatives, e.g. parahydroxybenzoate esters (methylhydroxybenzoateand propylhydroxybenzoate), boric acid and boratesalts, sorbic acid and sorbate salts, phenolics■ sweeteners, e.g. glucose, saccharin, aspartame■ rheology (viscosity) modifiers, e.g. hydrophilic polymers(cellulose derivatives, alginic acid, polyvinylpyrrolidone)■ antioxidants, e.g. sodium formaldehyde sulphoxylate,butylated hydroxyanisole, butylated hydroxytoluene■ colours■ flavours■ buffers to regulate the pH of the formulation, e.g. citratebuffer.The specific roles of each of these formulation excipients will bedescribed later in this chapter.

Advantages and disadvantages of pharmaceuticalsolutions for oral administrationAdvantages■ Therapeutic agents can easily be administered orally toindividuals who have difficulty in swallowing, e.g. elderlypatients, infants.■ The therapeutic agent is dissolved in the formulation and istherefore immediately available for absorption. Providing thedrug does not precipitate within the gastrointestinal tract, thebioavailability of pharmaceutical solutions is greater than thatof oral solid-dosage forms.■ Taste-masking of bitter therapeutic agents may be readilyachieved.Disadvantages■ Pharmaceutical solutions for oral administration areunsuitable for therapeutic agents that are chemically unstablein the presence of water.■ The poor solubility of certain therapeutic agents may prohibittheir formulation as pharmaceutical solutions. The readershould note that certain techniques are available to enhancethe solubility of poorly soluble drugs. These will behighlighted later in this chapter.■ Pharmaceutical solutions are expensive to ship and are bulkyfor the patient to carry due to the associated mass of theproduct.

Drug solubilityIn pharmaceutical solutions both the therapeutic agent and theexcipients are legally required to be present in solution over theshelf-life of the formulated product. As a result pharmaceuticalsolutions are termed homogeneous. One of the major challengesto the pharmaceutical scientist is the attainment of homogeneityin the formulation, due primarily to, in many cases, the limitedaqueous solubility of the therapeutic agent. Initially there arepossible scenarios regarding the formulation of pharmaceuticalsolutions of a therapeutic agent for oral administration:■ The aqueous solubility of the therapeutic agent is high at theselected pH of the formulation. Under these circumstancesthe therapeutic agent may be readily incorporated into thevehicle and formulated as an oral solution.■ The aqueous solubility of the therapeutic agent is moderate atthe selected pH of the formulation, i.e. the aqueous solubilityis less than the requested concentration of therapeutic agent.Under these circumstances the solubility of the therapeutic

agent in the formulation must be enhanced using co-solventsand related methods.■ The aqueous solubility of the therapeutic agent is low at theselected pH of the formulation. The difference between theaqueous solubility of the therapeutic agent and the requiredconcentration is too great to be bridged by the use of cosolventsand related methods or the concentration of cosolventsor surfactants in the solubilised formulation may betoxic when administered orally. The drug may therefore beformulated as an alternative-dosage form, e.g. a suspension.Prior to discussing the solubility of therapeutic agents andformulation strategies to modify this property, it is worthconsidering the process of drug dissolution. The dissolution of atherapeutic agent in water involves several key molecular steps:the removal of a molecule of the drug from the solid state, theformation of a cavity within the solvent and the accommodationof the drug molecule into the formed cavity. This process involvesthe breakage of solute–solute and solvent–solvent bonds(endothermic processes) and the formation of a bond between thesolute and the solvent (with the subsequent liberation of energy).Dissolution occurs whenever the Gibb’s free energy (_G) of theprocess is negative and involves a balance between the enthalpyof dissolution (_H) and the associated entropy (_S) at thetemperature of dissolution (T), as defined below:_G _ _H _ T_SFactors affecting the solubility of therapeutic agentsThe solubility properties of drug molecules in a particular solventsystem are sometimes difficult to predict and have been reportedto be dependent, at least in part, on several physicochemicalproperties, including molecular weight, volume, radius ofgyration, density, number of rotatable bonds, hydrogen bonddonors and hydrogen bond acceptors. Furthermore, the propertiesof the solid state, e.g. crystal habit, crystalline/amorphousproperties, will also affect the solubility of the therapeutic agent.There are some empirical relationships between thephysicochemical properties and the solubility of therapeuticagents that influence formulation strategies, as follows:■ The solubilities of a chemically related series of therapeuticagent are inversely related to their melting points. Therefore,as the melting point of the therapeutic agent is increased, thesolubility would be expected to decrease.■ The solubility of a therapeutic agent is directly affected byboth the type of chemical substituent groups and the

substituent position. The solubility of therapeutic agents

containing hydrophilic groups (e.g. OH, COO_, ammoniumion) will accordingly be greater than those containinglipophilic substituent groups, e.g. methyl, ethyl, ethoxy orchlorine groups.■ The solubilities of therapeutic agents that are either acids orbases (representing the vast majority of drug substances) arepH-dependent. The solubility of acids and bases increases asthe degree of ionisation increases and may be easily calculatedusing the following equation (where S refers to the solubilityof the drug and So is the intrinsic solubility, i.e. the solubilityof the unionised form of the drug).pK _ pKa _ log

(S _ So for acids So )pH _ pKa _ log

S( o for bases S _ So)From these equations two invaluable conclusions may bedrawn:– At pH values above the pKa, the solubility of acidic drugsincreases.– At pH values below the pKa, the solubility of basic drugsincreases.In simple terms the solubility of acidic compounds increasesas the pH of the solution is increased (above the pKa) and thesolubility of basic compounds increases as the pH is loweredbelow the pKa.Determination of the solubility properties of zwitterioniccompounds, i.e. those that exhibit both acidic and basicproperties, is more complicated than for simple acids or bases.However, in common with simple acids and bases, the solubilityof zwitterionic therapeutic agents is affected by pH. At basic pHvalues the therapeutic agent behaves primarily as an acid whereasat low pH values the molecule behaves as a base. The pH range atwhich the therapeutic agent exhibits minimal solubility liesbetween the pKa values of the acidic and basic groups.Formulation methods to enhance/optimise the solubilityof therapeutic agentsThe information described below may be employed to optimisethe formulation of pharmaceutical solutions, remembering that theprerequisite for pharmaceutical solutions is the exclusivepresence of dissolved therapeutic agent.

Appropriate selection of drug saltThe reader will be aware that the majority of therapeutic agentsare commercially available to the pharmaceutical scientist in arange of salt forms, each form exhibiting a different aqueoussolubility. The differences in solubility may be accredited, at leastin part, to the crystal properties of the salt, which, in turn, affectthe energy required to dissociate solute–solute bonds. Therefore,unless a specific salt form is specified or in the absence of apharmaceutical approved salt of a therapeutic agent, theformulation scientist should select the salt that provides therequired solubility in the dosage form.Optimisation of the pH of the formulationAs mentioned above, the solubility of an ionised therapeuticagent is a function of both the pKa of the compound and the pHof the formulation. Importantly, the acceptable pH range of

solutions for oral administration is large, ranging from circa 5 to8 pH units. Therefore, a common formulation strategy involvesthe selection of a pH value for the formulation that optimises theionisation and hence solubility of the therapeutic agent. Controlof the pH in the formulation is achieved using a buffer that doesnot adversely affect the solubility of the therapeutic agent.Use of co-solventsCo-solvents are primarily liquid components that are incorporatedinto a formulation to enhance the solubility of poorly solubledrugs to the required level. In the formulation of pharmaceuticalsolutions for oral administration, aqueous solutions are preferreddue to the lack of toxicity of water as the vehicle. However, if thesolubility of the therapeutic agent renders this approachinappropriate, the incorporation of co-solvents within theformulation offers a pharmaceutically acceptable approach.Commonly employed co-solvents include glycerol, propyleneglycol, ethanol and poly(ethylene glycol), details of which areprovided in subsequent sections.Prediction of the solubility of therapeutic agents in mixedsolvent systems (the vehicle, water and the chosen co-solvent) isdifficult, due to the effects of many variables on the solubility (asdescribed previously). In practice the pharmaceutical scientistshould measure the solubility of the chosen therapeutic agent in aseries of mixed solvents to determine the most suitable solventsystem for the given purpose. The final choice of the co-solventsystem for a particular formulation involves consideration of thesolubility of the therapeutic agent in the vehicle, the toxicity of thevehicle and the cost of the formulation. Indeed, it should be notedthat the range of concentrations of each co-solvent used in oralformulations is primarily limited by concerns regarding toxicity.

Excipients used in pharmaceutical solutions fororal administrationExcipients in pharmaceutical formulations are physiologicallyinert compounds that are included in the formulation to facilitatethe administration of the dosage form, e.g. pourability,palatability, to protect the formulation from issues regardingphysical and chemical stability and to enhance the solubility ofthe therapeutic agent. Pharmaceutical solutions commonlycontain a wide range of excipients, the details of which areprovided below.The vehicleThe preferred and most commonly used vehicle in solutions fororal administration is Purified Water USP, due to the low cost andlow toxicity of this ingredient. Under normal circumstances tap(drinking) water should not be used due to the possibility ofchemical imcompatibities within the formulation. The mainfeatures of Purified Water USP are as follows:■ It is prepared by distillation, ion exchange methods or byreverse osmosis.■ The solid residue (obtained after evaporation) is less than1 mg per 100 ml of evaporated sample.■ It must not be used for the preparation of parenteralformulations.In the case of parenteral formulations Water for Injections BPmust be used, the specifications and use of which are describedin Chapter 5.Co-solventsAs defined previously, co-solvents are employed to increase thesolubility of the therapeutic agent within the formulation. Themain co-solvents that are used in the formulation of oral solutionsare detailed below.

GlycerolGlycerol (also termed glycerin) is an odorless, sweet liquid thatis miscible with water and whose co-solvency properties aredue to the presence of three hydroxyl groups (termed a triol)(Figure 1.1). It has similar co-solvency properties to ethanol.

Alcohol USP (CH3CH2OH)Alcohol USP contains between 94.9 and 96.0% v/v ethyl alcohol(ethanol) and is commonly used as a co-solvent, both as a singleco-solvent and with other co-solvents, e.g. glycerol. The knownpharmacological and toxicological effects of this co-solvent havecompromised the use of alcohol in pharmaceutical preparations.As a result there are both labelling requirements for preparationsthat contain alcohol and upper limits with respect to theconcentration of alcohol that may be used in formulations.Propylene Glycol USPPropylene Glycol USP is an odourless, colourless, viscous liquiddiol that contains two hydroxyl groups (Figure 1.2). It is used inpharmaceutical preparations as a co-solvent, generally as areplacement for glycerin.Poly(ethylene glycol) (PEG)PEG (Figure 1.3) is a polymer composed of repeating units of themonomer ethylene oxide (in parenthesis). The physical state ofthe polymer is dependent on the number of repeat units (n) andhence on the molecular weight. Lower-molecular-weight grades(PEG 200, PEG 400) are preferred as co-solvents inpharmaceutical solutions.Miscellaneous agents used to enhance the solubility oftherapeutic agentsIn addition to the use of co-solvents, other pharmaceuticalstrategies are available to the pharmaceutical scientist to increasethe solubility of therapeutic agents in the chosen vehicle. Theseinclude the use of surface-active agents and complexation, asdetailed below.

Surface-active agentsSurface-active agents are chemicals that possess both hydrophilic(water-liking) and hydrophobic (water-disliking) regions. At diluteconcentrations surface-active agents will orient at the interfacebetween two phases (e.g. water/oil, water/air), with thehydrophilic and hydrophobic regions of the molecule beingpositioned to the hydrophilic and hydrophobic phases,respectively. As the concentration is increased, the interface willbecome saturated with surface-active agent and the molecules thatare present in the bulk aqueous phase will orient themselves inan attempt to shield the hydrophobic regions of the surface-activeagent. This orientation is referred to as a micelle and theconcentration of surface-active agent at this occurs is termed thecritical micelle concentration (CMC).For further details regarding the physicochemical propertiesof surfactants, the reader should consult the companion text byDavid Attwood and Alexander T Florence (FASTtrack: PhysicalPharmacy (London: Pharmaceutical Press; 2008). The use ofsurface-active agents for the solubilisation of poorly solubledrugs occurs exclusively in the presence of micelles and henceat concentrations of surface-active agents in excess of the CMC.In this the core of the micelle represents a hydrophobic regioninto which the poorly water-soluble drugs may partition. Thelocation in the micelle is related to the chemical structure ofthe drug. For example, if the therapeutic agent is poorly solublethe molecule will locate exclusively within the micelle, whereasif the drug is water-insoluble but contains polar groups, the

molecule will orient within the micelle, with the polar groups atthe surface of the micelle and the hydrophobic region of themolecule located within the hydrophobic core of the micelle. Inso doing the drug is solubilised within the colloidal micelles;due to their small size, the resulting solution appearshomogeneous to the naked eye.

ComplexationComplexation refers to the interaction of apoorly soluble therapeutic agent with anorganic molecule, e.g. surface-active agents,hydrophilic polymers to generate a solubleintermolecular complex. One particularconcern regarding the use of solution of drugcomplexes is the ability of the complex todissociate following administration. This isparticularly important in situations wherethe complexing agent is a hydrophilicpolymer, as the high molecular weight of the drug–polymer complex would prevent drug absorption acrossbiological membranes

Common excipients in pharmaceutical solutionsThere are several excipients that are commonly employed in theformulation of pharmaceutical solutions. These include: (1)buffers; (2) sweetening agents; and (3) viscosity-enhancing agents.BuffersBuffers are employed within pharmaceutical solutions to controlthe pH of the formulated product and, in so doing, optimise thephysicochemical performance of the product. Typically pHcontrol is performed:■ to maintain the solubility of the therapeutic agent in theformulated product. The solubility of the vast number ofcurrently available drugs is pH-dependent and, therefore, thesolubility of the therapeutic agent in the formulation may becompromised by small changes in pH■ to enhance the stability of products in which the chemicalstability of the active agent is pH-dependent.The concentration (and hence buffer capacity) of buffer saltsemployed in the formulation of oral solutions should be selectedto offer sufficient control of the pH of the formulation but yetshould be overcome by biological fluids following administration.This latter property is particularly appropriate for parenteralformulations to ensure that there is no irritation or damagefollowing injection.Examples of buffer salts used in pharmaceutical solutionsinclude:■ acetates (acetic acid and sodium acetate): circa 1–2%■ citrates (citric acid and sodium citrate): circa 1–5%■ phosphates (sodium phosphate and disodium phosphate):circa 0.8–2%.It must be remembered that the buffer system used in solutionformulations should not adversely affect the solubility of thetherapeutic agent, e.g. the solubility of drugs may be affected inthe presence of phosphate salts.Sweetening agentsSweetening agents are employed in liquid formulations designedfor oral administration specifically to increase the palatability ofthe therapeutic agent. The main sweetening agents employed inoral preparations are sucrose, liquid glucose, glycerol, sorbitol,saccharin sodium and aspartame. The use of artificial sweeteningagents in formulations is increasing and, in many formulations, saccharin sodium is used either as the sole sweetening agent or in

combination with sugars or sorbitol to reduce the sugarconcentration in the formulation. The use of sugars in oralformulations for children and patients with diabetes mellitus is tobe avoided.

Viscosity-enhancing agentsThe administration of oral solutions to patients is usuallyperformed using a syringe, a small-metered cup or a traditional5-ml spoon. The viscosity of the formulation must be sufficientlycontrolled in order to ensure the accurate measurement of thevolume to be dispensed. Furthermore, increasing the viscosity ofsome formulations may increase the palatability. Accordinglythere is a viscosity range that the formulation should exhibit tofacilitate this operation. Certain liquid formulations do notrequire the specific addition of viscosity-enhancing agents, e.g.syrups, due to their inherent viscosity.The viscosity of pharmaceutical solutions may be easilyincreased (and controlled) by the addition of non-ionic or ionichydrophilic polymers. Examples of both of these categories areshown below:■ non-ionic (neutral) polymers– cellulose derivatives, e.g.:● methylcellulose● hydroxyethylcellulose● hydroxypropylcellulose– polyvinylpyrrolidone■ ionic polymers– sodium carboxymethylcellulose (anionic)– sodium alginate (anionic).Full details of the physicochemical properties of these polymersare provided in later chapters.AntioxidantsAntioxidants are included in pharmaceutical solutions toenhance the stability of therapeutic agents that are susceptible tochemical degradation by oxidation. Typically antioxidants aremolecules that are redox systems which exhibit higher oxidativepotential than the therapeutic agent or, alternatively, arecompounds that inhibit free radical-induced drug decomposition.Typically in aqueous solution antioxidants are oxidised (andhence degraded) in preference to the therapeutic agent, therebyprotecting the drug from decomposition. Both water-soluble andwater-insoluble antioxidants are commercially available, thechoice of these being made according to the nature of theformulation. Examples of antioxidants that are commonly used for aqueous formulations include: sodium sulphite, sodiummetabisulphite, sodium formaldehyde sulphoxylate and ascorbicacid. Examples of antioxidants that may be used in oil-basedsolutions include: butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA) and propyl gallate. Typically antioxidantsare employed in low concentrations (_ 0.2% w/w) and it isusual for the concentration of antioxidant in the finishedproduct to be markedly less than the initial concentration, dueto oxidative degradation during manufacture of the dosage form.Antioxidants may also be employed in conjunction withchelating agents, e.g. ethylenediamine tetraacetic acid, citricacid, that act to form complexes with heavy-metal ions, ions thatare normally involved in oxidative degradation of therapeuticagents.PreservativesPreservatives are included in pharmaceutical solutions to controlthe microbial bioburden of the formulation. Ideally, preservativesshould exhibit the following properties:

■ possess a broad spectrum of antimicrobial activityencompassing Gram-positive and Gram-negative bacteria andfungi■ be chemically and physically stable over the shelf-life of theproduct■ have low toxicity.A wide range of preservatives is available for use inpharmaceutical solutions for oral use, including the following(values in parentheses relate to the typical concentration rangeused in oral solutions):■ benzoic acid and salts (0.1–0.3%)■ sorbic acid and its salts (0.05–0.2%)■ alkyl esters of parahydroxybenzoic acid (0.001–0.2%).Usually a combination of two members of this series isemployed in pharmaceutical solutions, typically methyl andpropyl parahydroxybenzoates (in a ratio of 9:1). Thecombination of these two preservatives enhances theantimicrobial spectrum.Factors affecting preservative efficacy in oral solutionsThe activity of a preservative is dependent on the correct form ofthe preservative being available in the formulation at the requiredconcentration to inhibit microbial growth (termed the minimuminhibitory concentration: MIC). Unfortunately, in many solutionformulations, the concentration of preservative within theformulation may be affected by the presence of other excipientsand by formulation pH. Factors that directly affect the efficacy of preservatives in oral solutions include: (1) the pH of theformulation; (2) the presence of micelles; and (3) the presence ofhydrophilic polymers.The pH of the formulationIn some aqueous formulations the use of acidic preservatives, e.g.benzoic acid, sorbic acid, may be problematic.The antimicrobial properties are due to the unionised form of thepreservative; the degree of ionisation being a function of the pHof the formulation. The activity of the unionised form of the acidin this respect is due to the ability of this form to diffuse acrossthe outer membrane of the microorganism and eventually into thecytoplasm. The neutral conditions within the cytoplasm enablethe preservative to dissociate, leading to acidification of thecytoplasm and inhibition of growth.The fraction of acidic preservative at a particular pH may becalculated using a derived form of the Henderson–Hasselbalchequation, as follows:The use of this equation may be illustrated in the followingexample:

Worked exampleExample 2.1Assuming that the MIC for the unionised form of an acidicpreservative (pKa 4.2) is 0.0185 mg/ml, calculate the requiredconcentration to preserve an oral solution that has been bufferedto pH 4.7.The Henderson–Hasselbalch equation may be employed, asdescribed above, to determine the fraction of unionised acidwithin the formulation.12 Pharmaceutics – Dosage Form and DesignOOH(a) (b)3HC OHFigure 1.4 Structural formulaof (a) benzoic acid and(b) sorbic acid.

Fraction _ ( 1 ) (1_10pH_pKa)

Fraction _ ( 1 ) _ 0.24

The required concentration is then calculated by dividing theMIC for the unionised form of the preservative by the fraction ofunionised preservative present, i.e.0.0185

( _ 0.07 mg/ml. 0.24 )In practice an overage is added and therefore the actualconcentration of preservative required would be 0.1–0.15 mg/ml.As the reader will observe, the pKa of the preservative is avital determinant within the above calculations. Organic acids,e.g. benzoic acid, sorbic acid, have pKa values that are circa 4.2and therefore, in solution formulations whose pH is neutral, ahigh concentration of preservative will be required to ensure thatthe required concentration of the unionised species is obtained.If the above calculation is repeated for an oral solution at pH 7.2,the following result is obtained:Therefore, the required preservative concentration is

( 0.0185 0.00001)_ 1850 mg/ml.

Importantly, the preservative efficacies of parabens (alkylesters of parahydroxybenozoic acid) and the phenolics aregenerally not affected by formulation pH (within a pH rangebetween 4.0 and 8.0) due to the high pKa of the organichydroxyl group. The structures of these preservatives are shownin Figure 1.5.The presence of micellesThe role of micelles for the solubilisation of lipophilictherapeutic agents was described above. If the preservativeexhibits lipophilic properties (e.g. the unionised form of acidicpreservatives, phenolics, parabens), then partition of these speciesinto the micelle may occur, thereby decreasing the available(effective) concentration of preservative in solution. Anequilibrium is established, as depicted in Figure 1.6.

To correct this problem, the preservative concentration mustbe increased to ensure that the free concentration within theformulation is _ MIC of the preservative.The presence of hydrophilic polymersIt has been shown that the free concentration of preservative inoral solution formulations is reduced in the presence ofhydrophilic polymers, e.g. polyvinylpyrrolidone, methylcellulose.This is due to the ability of the preservative to interact chemicallywith the dissolved polymer. As described above, this problem isaddressed by increasing the concentration of preservative in theformulation. In certain circumstances the preservative may beincompatible with hydrophilic polymers in the formulation dueto an electrostatic interaction. Therefore, cationic hydrophilicpolymers should not be used in conjunction with acidicpreservatives in oral solution formulations.Flavours and colourantsUnfortunately the vast majority of drugs in solution areunpalatable and, therefore, the addition of flavours is oftenrequired to mask the taste of the drug substance. Taste-masking

using flavours is a difficult task; however, there are someempirical approaches that may be taken to produce a palatableformulation.■ The four basic taste sensations are salty, sweet, bitter andsour. It has been proposed that certain flavours should beused to mask these specific taste sensations. In particular:– Flavours that may be used to mask a salty taste include:● butterscotch● apricot● peach● vanilla● wintergreen mint.– Flavours that may be used to mask a bitter taste include:● cherry● mint● anise.14 Pharmaceutics – Dosage Form and DesignHA HA A_

Figure 1.6 Diagrammatic illustrationof the equilibrium of an acidicpreservative in the presence ofmicelles. HA and A_ refer to theunionised and ionised states of thepreservative.

– Flavours that may be used to mask a sweet taste include:● vanilla● fruit and berry.– Flavours that may be used to mask a sour taste include:● citrus flavours● raspberry.■ Usually a combination of flavours is used to achieve theoptimal taste-masking property.■ Certain excipients may be added to oral solutionformulations, referred to as flavour adjuncts (e.g. menthol,chloroform) that add flavour to the formulation but, inaddition, act to desensitise the taste receptors. In so doingthese agents augment the taste-masking properties ofconventional flavours.Colours are pharmaceutical ingredients that impart the preferredcolour to the formulation. When used in combination withflavours, the selected colour should ‘match’ the flavour of theformulation, e.g. green with mint-flavoured solutions, red forstrawberry-flavoured formulations. Although the inclusion ofcolours is not a prerequisite for all pharmaceutical solutions,certain categories of solution (e.g. mouthwashes/gargles) arenormally coloured.

Types of pharmaceutical solutionsPharmaceutical solutions for oraladministrationThere are three principal types of solutionformulations that are administered orally:oral solutions, oral syrups and oral elixirs. Inaddition, other solution formulations areemployed for a local effect, e.g.mouthwashes/gargles and enemas. Details ofthese are provided in the following sections.Oral solutionsOral solutions are administered to the gastrointestinal tract toprovide systemic absorption of the therapeutic agent. Due to theresilience of the gastrointestinal environment, oral solutions maybe formulated over a broad pH range. However, unless there areissues regarding the solubility or stability of the therapeutic agent,

the usual pH of oral solutions is circa 7.0. Typically the followingclasses of excipients are used in the formulation of oral solutions:■ buffers (e.g. citrate, phosphate)■ preservatives (e.g. parabens, benzoic acid, sorbic acid)

■ antioxidants (water-soluble antioxidants are used, e.g. sodiummetabisulphite 0.01–1.0% w/w)■ flavours and colours (the colour should be selected tocomplement the flavour of the formulation)■ viscosity-modifying agents (to affect the pourability of theformulation. For this purpose hydrophilic polymers are used,e.g. sodium alginate, hydroxyethylcellulose).The reader should note that, to be classified as a solution, allcomponents of the formulation (including the therapeutic agent)should be soluble, with no evidence of precipitation.

Oral elixirsAn elixir is a clear, hydroalcoholic solution that is formulated fororal use. The concentration of alcohol required in the elixir isunique to each formulation and is sufficient to ensure that all ofthe other components within the formulation remain in solution.For this purpose other polyol co-solvents may be incorporatedinto the formulation. The presence of alcohol in elixirs presents apossible problem in paediatric formulations and, indeed, for thoseadults who wish to avoid alcohol. The typical components of anelixir are as follows:■ Purified water.■ Alcohol. This is employed as a co-solvent to ensure solubilityof all ingredients. As highlighted above, the concentration ofalcohol varies depending on the formulation. Generally theconcentration of alcohol is greater than 10% v/v; however, insome preparations, the concentration of alcohol may begreater than 40% v/v.■ Polyol co-solvents. Polyol co-solvents, e.g. propylene glycol,glycerol, may be employed in pharmaceutical elixirs toenhance the solubility of the therapeutic agent and associatedexcipients. The inclusion of these ingredients enables the concentration of alcohol to be reduced. As before, theconcentration of co-solvents employed is dependent onthe concentration of alcohol present, the type of co-solventused and the solubility of the other ingredients in thealcohol/co-solvent blend. The reader is directed to thepharmacopoeial monographs to observe the concentration ofco-solvents in specific examples of the pharmaceutical elixirs.Two examples in the USP that illustrate the range ofconcentrations of co-solvents are Phenobarbital Elixir andTheophylline Elixir (Tables 1.1 and 1.2).

■ Sweetening agents. The concentration of sucrose in elixirs isless than that in syrups and accordingly elixirs require theaddition of sweetening agents. The types of sweetening agentsused are similar to those used in syrups, namely syrup,sorbitol solution and artificial sweeteners such as saccharinsodium (Figure 1.8).It should be noted, however, that the high concentration ofalcohol prohibits the incorporation of high concentrations ofsucrose due to the limited solubility of this sweetening agentin the elixir vehicle. To obviate this problem, saccharin sodium, an agent which is used in small quantities and whichexhibits the required solubility profile in the elixir, isemployed.

■ Flavours and colours. All pharmaceutical elixirs containflavours and colours to increase the palatability and enhancethe aesthetic qualities of the formulation. The presence ofalcohol in the formulation allows the pharmaceutical scientistto use flavours and colours that may perhaps exhibitinappropriate solubility in aqueous solution. For example, itmay be observed that in the two formulations cited above,essential oils were used as the flavouring agents. As before,the selected colour should optimally match the chosenflavour.■ Ancillary comments– Preservatives are not required in pharmaceutical elixirs thatcontain greater than circa 12% v/v alcohol, due to theantimicrobial properties of this co-solvent.– Due to the volatile nature of some of the components ofelixirs, elixirs should be packaged in tight containers and notstored at high temperatures.– The addition of viscosity-enhancing agents, e.g. hydrophilicpolymers, may be required to optimise the rheologicalproperties of elixirs.

Miscellaneous oral solutionsIn addition to conventional solutions, syrupsand elixirs, there are other solution-baseddosage forms that are administered orally, inparticular linctuses and mouthwashes/gargles. These two subcategories are brieflydescribed below.LinctusesLinctuses are viscous preparations thatcontain the therapeutic agent dissolved in avehicle composed of a high percentage ofsucrose and, if required, other sweeteningagents. These formulations are administered orally and are primarily employed for the treatment of cough, dueto their soothing actions on the inflamed mucous membranes.Linctuses may also be formulated as sugar-free alternatives inwhich sucrose is replaced by sorbitol and the requiredconcentration of sweetening agent.Mouthwashes and garglesMouthwashes/gargles are designed for the treatment of infectionand inflammation of the oral cavity. Formulations designed forthis purpose employ water as the vehicle, although a co-solvent,e.g. alcohol, may be employed to solubilise the active agent. Theuse of alcohol as a co-solvent may act to enhance theantimicrobial properties of the therapeutic agent. Otherformulation components are frequently required to enhance thepalatability and acceptability of the preparation. These includepreservatives, colours, flavouring agents and non-cariogenicsweetening agents.EnemasEnemas are pharmaceutical solutions that are administeredrectally and are employed to ensure clearance of the bowel,usually by softening the faeces or by increasing the amount ofwater in the large bowel (osmotic laxatives). Enemas may beaqueous or oil-based solutions and, in some formulations, thevehicle is the agent that promotes bowel evacuation, e.g. arachisoil retention enema. Aqueous formulations usually contain salts(e.g. phosphates) to alter the osmolality within the rectum,thereby increasing the movement of fluid to the rectal contents.Viscosity-enhancing agents, e.g. glycerol, may be included to aidretention of the formulation within the rectum and to reduce theincidence of seepage

Multiple choice questions1. Regarding weakly acidic drug molecules, which of thefollowing statements are true?a. The solubility of weak acids increases as the pH isdecreased.b. The solubility of weak acids increases as the pH is increased.c. The solubility of weak acids in pharmaceutical formulationsmay be affected by the presence of counterions.d. All weakly acidic therapeutic agents exhibit an isoelectricpoint.2. Regarding weakly basic drug molecules, which of thefollowing statements are true?a. The solubility of weak bases increases as the pH isdecreased.

b. The solubility of weak bases increases as the pH is increased.c. The solubility of weak bases in pharmaceutical formulationsmay be affected by the presence of counterions.d. All weakly basic therapeutic agents exhibit an isoelectricpoint.3. Regarding the following drug substance, which of thefollowing statements are true?a. The solubility of the above drug increases as the pH isdecreased from pH 9 to pH 4.b. The solubility of the above drug increases as the pH isincreased from 7 to 9.c. The above drug may be susceptible to oxidation.d. The above drug exhibits an isoelectric point.4. Regarding buffers for pharmaceutical solutions for oraladministration, which of the following statements are true?a. Citrate buffer is commonly used as a buffer forpharmaceutical solutions.b. Buffers are required solely to control the stability oftherapeutic agents.c. Buffer salts may affect the solubility of therapeutic agents.d. The buffer capacity of a buffer system is increased as theconcentration of buffer components is increased.5. Regarding the use of antioxidants in pharmaceuticalsolutions for oral administration, which of the followingstatements are true?a. Antioxidants are required in all solution formulations.b. Antioxidants reduce the rate of oxidation of the therapeuticagent.c. BHT and BHA are examples of antioxidants that are includedin aqueous solutions.d. The efficacy of antioxidants may be improved in the presenceof ethylenediaminetetraacetic acid (EDTA).

6. Regarding the use of co-solvents for the formulation ofpharmaceutical solutions for oral administration, which ofthe following statements are true?a. Co-solvents are required in all pharmaceutical solutionformulations.b. Alcohols are commonly used as co-solvents in pharmaceuticalsolutions.c. Glycerol may directly affect the pH of the formulation.d. Co-solvents may affect the viscosity of the solutionformulation.7. Regarding the use of preservatives in pharmaceuticalsolutions for oral administration, which of the followingstatements are true?a. Preservatives are required in all pharmaceutical solutionformulations.

b. Preservatives are not required if the solution is manufacturedunder sterile conditions.c. Esters of parahydroxybenzoic acid are used as preservativesfor pharmaceutical solutions for oral administration.d. Preservatives render pharmaceutical solutions for oraladministration sterile.8. Regarding pharmaceutical elixirs, which of the followingstatements are true?a. Preservatives are required in all elixir formulations.b. Elixirs generally require the addition of sweetening agents.c. Elixirs generally contain _ 10% alcohol USP.d. Colours are required for all elixir formulations.9. Regarding pharmaceutical linctuses, which of the followingstatements are true?a. Preservatives are required in all linctus formulations.b. Linctuses generally require the addition of syntheticsweetening agents.c. Linctus formulations may contain high concentrations ofsucrose.d. Colours are required for all linctus formulations.10. Regarding oral syrups, which of the following statements aretrue?a. Preservatives are required in all oral syrups.b. In certain syrups the concentration of sucrose may be _ 80%w/w.c. Sugar-free syrups require the inclusion of a viscositymodifyingagent.d. Colours are required for all oral syrups.

HANDBOOK YANG LAIN

8.4.4 ExcipientsMcRorie (1996) suggests that, in general, one-time doses of medications withpreservatives pose no risk of toxicity to even the tiniest premature neonate.However, multiple doses of the medicine (and preservative) can lead to lifethreateningtoxicity. In 1981 and 1982, the US Food and Drug Administration(FDA) received reports of 16 deaths in neonates attributed to benzyl alcoholfound in sodium chloride flush solution (McRorie, 1996). Benzyl alcohol syndrome has since become a recognised event in premature infants (Brownet al., 1982). The normal metabolic pathways for benzyl alcohol in adults areimmature in premature infants, leading to the accumulation of benzyl alcoholand benzoic acid.Chloroform is known to be hepatotoxic, renally toxic and potentiallycarcinogenic; its use as a preservative has been prohibited in the USA since1976 (Hanson, 2003). However, many of the newer alternative preservativesare ineffective if the pH is above 7; therefore chloroform is still in use in somepreparations in the UK (Hanson, 2003).One of the more common preservative systems used is a combination ofhydroxybenzoates (also known as ‘parabens’). This preservative system canworsen asthma and has also been shown to promote hypersensitivity reactions(Golightly et al., 1988).Although propylene glycol is generally acknowledged to be safe in smallquantities (Ruddick, 1972), larger amounts may cause side-effects such ashyperosmolarity, seizures, lactic acidosis and cardiac toxicity (in both childrenand adults) (Martin and Finberg, 1970; Arulanatham and Genel,1978; Cate and Hedrick, 1980; Glasgow et al., 1983). Propylene glycolmay also act as an osmotic laxative. Preparations that contain large quantitiesmay not therefore be suitable for neonates and young children.Ethanol is known to have a CNS depressant effect, and its use is avoidedwherever possible in extemporaneous preparations. However, limited quantitiesof ethanol may be justifiable under some circumstances, in order toprevent the use of other co-solvent systems associated with known toxicities.Limits for the inclusion of ethanol in paediatric formulations have beenproposed in the USA (American Academy of Pediatrics Committee onDrugs, 1984; Anon, 1993).Use of preparations that contain sugars, especially sucrose, are associatedwith the formation of dental cavities, particularly with long-term use.These examples highlight the need for careful consideration of preservativesystems and other excipients in extemporaneous formulations, particularlywhere young children are concerned. The Handbook of PharmaceuticalExcipients contains useful information for accountable pharmacists, and a listof excipients of known effect is available from the European MedicinesAgency (EMEA).

8.4.5 ConcentrationA change in concentration can either enhance or reduce stability. Oxidationand photodegradation, typically following zero-order kinetics, tend to bemore significant at lower concentrations. Therefore, stability data may notbe transferable from one concentration to another.

8.4.6 DilutionAlthough dilution of more concentrated liquids may be possible in manyinstances, this can lead to potential calculation errors and may also reducestability (see above) and impair preservative efficacy.8.4.7 Ionic strength and pHThe degradation rate is often influenced by the ionic strength of the medium.For example, the rate of either acid- or base-catalysed hydrolysis of ampicillinin aqueous solution at constant pH is proportional to the concentration of theion used as a buffer.The rate of hydrolysis of many drugs is dependent on pH, with the reaction

rate commonly increasing at either extreme of the scale.8.4.8 VehicleCertain vehicles may be incompatible with some drugs, causing precipitationor degradation (e.g. polar solvents). Highly viscous liquids may poseissues pertaining to patient acceptance and difficulties in measuring dosesaccurately.8.4.9 StorageConsideration ought to be given to the nature of the container used to store theformulation. For instance, some substances may adsorb to plastic containers,leading to reduced homogeneity and potential degradation and, hence, inaccuratedoses. Some drugs are sensitive to light, and as such may undergosignificant photodegradation if not protected from it.The amount of headspace in the final container should be limited, particularlyfor drugs prone to oxidation.Conditions of storage will be determined by the nature of the drug and theformulation. Unpreserved formulations are generally stored in the fridge inorder to minimise the risk of microbiological contamination, unless this isknown to have an adverse effect on the formulation (e.g. inappropriateincrease in viscosity or precipitation).