2011LamPharmacotherapyFormulationsoralantineoplastic

180PHARMACOTHERAPY Volume 31, Number 2, 2011The rate of these reactions can be affected by140, 141, 143temperature and pH. For example, whenhydroxyurea oral solution 100 mg/ml wasextemporaneously prepared with mildly heatedwater at 41 o C in an attempt at facilitatingdissolution, the mild heating of the water statisticallysignificantly reduced the chemical stabilityby 40% compared with the preparation usingroom-temperature sterile water. 4 Azathioprine ismore rapidly hydrolyzed to -mercaptopurine atalkaline pH than under acidic or neutralconditions. 147 Temozolamide is stable at acidicpH less than 5 and labile at pH greater than 7,and it is rapidly hydrolyzed to an active metaboliteat neutral and alkaline conditions. 99Melphalan is insoluble in water; rapid hydrolysisoccurs when the drug is prepared in water, whereasthe rate of reaction slows down in an acidic condition.It was observed that the melphalan75, 148, 1492-mg/ml oral suspension prepared in methylcelluloseand simple syrup or wild cherry syrupstarted to decompose between time of preparationand time of assay. 25 More than 80% of thedrug decomposed within 24 hours at roomtemperature, whereas more than 50% decomposedwithin 7 days at 5 o C. 25 It is unknown if thepotency remains within the USP-specified limitswhen the liquid formulation is administeredimmediately after preparation, or if the stabilitymay last longer when the drug is prepared with amore acidic excipient and/or vehicle, or at adifferent concentration. Therefore, the practiceof mixing crushed tablets or emptying contentsof capsules with any solution without knowingstability data is discouraged.The selection of appropriate excipients anddetermination of the optimum pH range arecrucial steps during the compounding process tomaintain the stability or to extend the shelf-life ofa final product. An acidic pH of 5– is usuallyrequired to maintain optimal stability for mosthydrolyzable drugs. 141 Some pharmaceuticalexcipients may be used to increase the stability tominimize the hydrolytic and oxidative processes. 141For example, when temozolamide oral suspensionis prepared, it is essential to add povidone K-30in the suspension to prevent crystal growth so asto make the formulation more soluble and stablewith an extended shelf-life. 100Another example is that mercaptopurine isknown to undergo oxidation in alkaline solutions.The addition of ascorbic acid as an25, 78antioxidant at a concentration of 0.1% (weight/volume) to the standard formulation of mercaptopurinehas been shown to increase the suspension’sshelf-life at room temperature from 5 weeksto 11 weeks. 79 Other commonly used antioxidantsused in aqueous preparations include sodiumsulfite, sodium bisulfite, and hypophosphorus acid. 141One should note that the stability of two oralliquid formulations using the same activeingredient but prepared extemporaneously withdifferent vehicles, different final concentrations,excipients, water content, and/or the changes oflight or temperature condition may be differentfrom each other. For example, the potency ofchlorambucil 2-mg/ml oral suspension decreasesto less than 90% in less than 24 hours at roomtemperature, but remains stable for 7 days whenit is kept refrigerated in a light-resistant container. 25Another example is that the chemical stability ofcyclophosphamide oral suspension prepared at afinal concentration of 2 mg/ml in aromatic elixiris 14 days when refrigerated, 39 but at least 5days at the same temperature when it is preparedat a concentration of 20 mg/ml in simple syrup or40, 41Ora-Plus. Therefore, any liquid preparationthat can maintain its stability only at a specifiedtemperature or light condition should beproperly labeled on the prescription bottle toavoid a loss of potency and to minimize drugwaste. It is also important to note that theexcipients found in commercially availabletablets or capsules may reduce the chemicalstability of the extemporaneously prepared oralliquid by changing the pH to a value that maycause the rate of degradation to increase. 143An unpleasant or foul odor and the presence ofturbidity in an oral liquid may result frommicrobial growth that could also adversely affectits appearance and palatability. 140–143 After anextemporaneous oral liquid formulation isprepared, the pharmacist should examine anychange in the color, odor, or texture of theformulation. A good suspension should haveuniform particle-size distribution and viscosity. 143If caking, difficulty in resuspending, crystalgrowth, microbial growth, or discoloration isobserved, it may indicate instability, and the141, 143product should be discarded.If no published stability data are found, oneshould consult the pharmaceutical companies orlarge research centers since they may be able toprovide some useful unpublished stability informationor share their own institutional experiences.BioavailabilitySince the bioavailability of most oral anticancerdrugs is known to be substantially variable, 150 the