High-Temperature Stability | Do the Math for Shelf Life - Sterile ...

pharmaquality.com A P R I L I M A Y 2 0 1 1 V O L U M E 1 3 N U M B E R 2T E C H N O L O G Y A N D A P P L I C AT I O N SDoYou KnowSSO?Navigate the decisionpath for solid-stateoptimization in drugdevelopment10 DELIVERYGo Small to GetBig Results14 FORMULATIONPEG YourProteins22 QUALITY CONTROLDo the Math forShelf Life34 INGREDIENTSThe New CoatsAre Coming

QUALITY CONTROLCAPSULESwedish scientist Svante Arrhenius provided the first kinetic model to interpret the effect of temperature on reaction rate. Since then, pharmaceuticalscientists have often attempted to predict long-term chemical stability with insufficient understanding about the kinetic model, applyingthe practice in inappropriate situations. Understanding critical temperature relationships is the key to more accurately predicting long-term levelsfor a specific product.HIGH-TEMPERATURE STABILITYDo the Mathfor Shelf LifePredict stability usingdata collected at highertemperatures> By Michelle Duncan, PhD,and Irene Zaretsky, MSPharmaceutical scientists routinelypredict long-term chemicalstability at a lowertemperature using data generatedat a higher temperature over a shortertime period. The use of 40 degrees C chemicaldata (e.g., assay and related substances)to predict levels over long-term 25degrees C storage has become such commonpractice that the underlying theory isoverlooked or was never learned.There is disagreement about whetherthree months at 40 degrees C indicates expected25 degrees C levels for 12 monthsor for 24 months because of insufficientunderstanding or information about thekinetic model. More importantly, withoutsome theoretical understanding, thepractice is inappropriately applied to situationsthat do not fit the kinetic modelupon which it is based, resulting in erroneouspredictions.In addition to providing the backgroundof how these kinetic predictionswork, this paper will provide the key tounderstanding the temperature relationshipsand the ability to more accuratelypredict the expected long-term levels for aspecific product.Arrhenius Kinetics: WhereThis All BeganSwedish scientist Svante Arrhenius providedthe first kinetic model to interpret theeffect of temperature on reaction rate givenby Equation 1 (see info box). 1-3 The Arrheniusequation can be applied regardlessof the order (zero-order, first-order, etc.) ofthe reaction kinetics. 4 Equation 2 presentsthe linear form of the Arrhenius equationfor graphical presentation (y = mx + b).For many reactions, a linear relationshipcan be obtained between the inverse oftemperature (in degrees Kelvin) and thenatural log (Ln) of the measured rate constant(k), as shown in Figure 1.Figure 1.THE ARRHENIUS EQUATIONK = A exp (-Ea/RT) (Equation 1)k = reaction rate constantA = Arrhenius factor (y-intercept constant)Ea = the energy of activation for the reaction, cal/mole(1000 cal = 1 kcal)R = the ideal gas constant, 1.987 calories/deg moleT = the absolute temperature (degrees Kelvin), for 25° CT= 298° K and for 40°C T= 313° K)THIS EQUATION CAN BE WRITTEN IN SEVERALEQUIVALENT FORMS AS FOLLOWS:Ln k = -Ea/RT + Ln A (Equation 2, y = mx + b)Ln k2/k1 = -Ea/R*(1/T2-1/T1) (Equation 3)k2 = k1 * exp[-Ea/R*(1/T2-1/T1)] (Equation 4)The constants k1 and k2 are the rate constants at temperatureT1 and T2 (for example 25 degrees C and 40degrees C), respectively.Equation 3 presents a simplified formfor use with two temperatures. Equation 4expresses the relationship between thereaction rates and the corresponding temperatureswhen the activation energy (Ea)of the reaction is known. Equation 4 allowsfor the calculation of a reaction rate constantat a lower temperature when the activationenergy and the reaction rate at thehigher temperature are known.As shown by Figure 1, the Arrheniusmodel provides the ability to determine thereaction rate and, hence, predict stabilityat any temperature with knowledge of theactivation energy (Ea) and the reaction rateat another temperature.Limitations to Arrhenius’ ModelThe first requirement is a reaction (ongoing)where the reaction rate constant atArrhenius plot of Ln K against1/T. Slope = - Ea/R k = reactionrate constant, T = temperaturein degrees Kelvin Ea = activationenergy, R = ideal gas constant.© DREAMSTIME.COMPharmaceutical Formulation & Quality > April/May 2011

PHARMAQUALITY.COMa given temperature can be determined.When monitoring the generation of a primarydegradation product, the presenceof a secondary degradation reaction canintroduce error to the calculation of the primaryrate constant and any attempted Arrheniusmodel predicted rates. Likewise,if a component is consumed to the extentthat the reaction equilibrium changes, thereaction rate will not remain constant. TheArrhenius kinetic model requires a reactionrate constant (k).Figure 2.The zero-order kinetic model for 10% drug lossover 24 months at 25 degrees C shown as thepercent of drug remaining as a function of timeat 25 degrees C.The Arrhenius kinetic model can be utilizedacross the temperature range where aconstant relationship between the effect oftemperature on the reaction rate is maintained,where the graph is linear. The reactionmechanism should not change over thetemperature range studied. Conformanceto the model (linearity) is often lost whencrossing a phase change, such as freezingand the glass-phase transition of proteinsand peptides. Reactions where the rate isdependent upon oxygen, light (photochemical),diffusion, or microorganism-baseddecomposition may not demonstrate Arrheniuskinetics over any temperature range.Figure 3.Table 1.Months at 40degrees C to reach10% drug loss63Relationship of reaction rates at 40 degrees C and activationenergy (Ea) for drug lossk40 (drug %labelclaim per month)-1.6667-3.3333Finding Ea for the ReactionThe activation energy (Ea) for a reactioncan be determined by conducting stabilitystudies at several different temperaturesand applying the Arrhenius kinetic model.The slope of the line formed with Equation2 contains Ea, as demonstrated in Figure 1.Higher temperatures (e.g., 55 degrees C,70 degrees C) and corresponding shortertimes (e.g., weeks, days) can be employedfor this determination provided the Arrheniuskinetic model remains valid (see Limitationsto Using Arrhenius Kinetic Model).The Ea for drug decomposition will usuallyfall in the range of 12 to 24 kcal/mole, witha typical value of 19 to 20 kcal/mole. 5 Theactivation energy can be approximatedbased upon prior knowledge of the drugdecomposition kinetics. Once the Ea isknown, it usually remains valid for usethrough small concentration changes orslight formulation changes.Importance of Ea: TheoreticalModel for Drug LossThe following discussion demonstrates the relationshipof drug degradation kinetics at 40degrees C and 25 degrees C, where drug lossis the shelf life-determining parameter. Forthis illustration, acceptable product stabilityis based upon a lower limit of 90% label claimk25 (drug %labelclaim per month)-0.4167-0.4167Ea (kcal/mole)activation energy1726and the expiration date set at exactly 90% labelclaim. For this exercise, a zero-orderdegradation kinetics model (Δdrug/Δtime =—k) is applied to determine the rate for 10%of drug loss occurrence over 24 months at 25degrees C (Figure 2). The slope was calculatedand is equal to —0.4167 drug %labelclaim/ month, which is the reaction rate constantat 25 degrees C (k25). Hence, for the drugto remain within acceptance criteria for 24months at 25 degrees C, the rate of degradationat 25 degrees C must be less than 0.4167drug %label claim/month.In a similar manner, drug loss can bemodeled at 40 degrees C accelerated temperaturefor the two scenarios of 10% drug lossoccurring at three months and at six months(Figure 3). The slopes, which represent thereaction rate constant at 40 degrees C (k40),were calculated to be —1.6667 drug %labelclaim/month for the six months limit scenarioand —3.3333 drug %label claim/month for thethree months limit scenario.Using the Arrhenius equation (Equation3) and the reaction rates at 25 degrees C and40 degrees C, the Ea can be calculated asshown in Table 1. The Arrhenius equationcan be applied regardless of the order of thereaction kinetics. For the kinetic model thatassumes 10% drug loss at 24 months at 25degrees C (k25 = —0.4167 drug %labelTable 2.Relationship of reaction rates at 40 degrees C and activationenergy (Ea) for impurity generationMonths at 40degrees C for impurityto reach 1%k40 (%w/wimpurity per month)k25 (%w/wimpurity per month)Ea (kcal/mole)activation energy60.16670.041717Zero-order kinetic models for 10% drug lossover three months and over six months at 40degrees C.30.33330.041726April/May > Pharmaceutical Formulation & Quality

QUALITY CONTROL | HIGH-TEMPERATURE STABILITYTable 3.Months at 25degrees C toreach 1.0% w/wdegradant limit(kinetic shelf life)241812claim/month) and 10% drug loss at threemonths at 40 degrees C (k40 = —3.3333 drug%label claim/month), the calculated Ea is 26kcal/mole. For the model that assumes 10%drug loss at 24 months at 25 degrees C (k25 =—0.4167 drug %label claim/month) and 10%drug loss at six months at 40 degrees C (k40= —1.6667 drug %label claim/month), thecalculated Ea is 17 kcal/mole.Knowledge of the Ea is key to the interpretationof accelerated data for predictionsat lower temperatures. If the Ea islow (less than or equal to 17 kcal/mole), theaccelerated 40 degrees C drug concentrationmust remain greater than 90% labelclaim for six months to achieve at least90% label claim for a shelf life of 24Table 4.Months at 25degrees C toreach 1.0% w/wdegradant limit(kinetic shelf life)2418129Relationship of rates and activation energy (Ea) for shelf-lifestability when limit is reached after six months at 40 degrees C.k25 (%w/w permonth) Rate ofdegradant growth at25 degrees Cthrough shelf life0.04170.05560.0834k40 (%w/w permonth) Rate ofdegradant growth at40 degrees C when1.0% w/w limit isreached at sixmonths0.16670.16670.1667Ea (kcal/mole)activation energy1714month at 25 degrees C. If the Ea is high(more than or equal to 26 kcal/mole), theaccelerated 40 degrees C drug concentrationmust remain greater than 90% labelclaim for only three months (and be 80%label claim at six months), and yet theproduct will remain at or above 90% labelclaim for a shelf life of 24 month at 25 degreesC. This application of Ea and Arrheniuskinetics to predict shelf life can beapplied to any drug level (limit) specified.Theoretical Model forImpurity/Degradant GenerationThe same approach can be used to understandand predict the generation of impurities/degradants.For this exercise, aRelationship of rates and activation energy (Ea) for shelf-lifestability when limit is reached after three months at 40 degrees C.k25 (%w/w permonth) Rate ofdegradant growth at25 degrees Cthrough shelf life0.04170.05560.08340.1111k40 (%w/w permonth) Rate ofdegradant growth at40 degrees C when1.0% w/w limit isreached at threemonths0.33330.33330.33330.33339Ea (kcal/mole)activation energy26221714zero-order degradation kinetics model(ΔImpurity/Δtime = —k) is applied to determinethe rates for an arbitrary 1% impuritygrowth at 25 degrees C and at 40degrees C. The calculated slope for growthfrom 0 to 1.0% w/w over 24 months at 25degrees C is equal to 0.0417% w/w permonth, which is the impurity generationrate constant at 25 degrees C (k25). In thesame manner, the impurity generationrate at 40 degrees C can be calculated forreaching 1.0% w/w after three months(0.3333% w/w per month) and for reaching1.0% w/w after six months storage (0.1667%w/w per month). Table 2 summarizes thecorresponding rates and Eas:Example calculationWhere:Ln k 2 /k 1 = -Ea/R*(1/T 2 -1/T 1 ) (Equation 3)Ln (k40/k25) = - [Ea/1.987*(1/313-1/298)]/1000cal/kcalk40 = 0.1667%w/w degradant/monthk25 = 0.0417%w/w degradant/monthSolving for Ea:Ea = - [Ln (0.1667/0.0417)*1.987]/[(1/313-1/298)*1000]Ea = 17 kcal/moleAs the Ea increases, the reaction rateat 40 degrees C increases. The degradantlevel at six months at 40 degrees C is predictiveof the degradant level to be reachedafter 24 months at 25 degrees C when the Eais 17 kcal/mole. Degradants with reactionmechanisms with high activation energies(greater than 17 kcal/mole) can exhibitlevels exceeding 1.0% w/w by six monthsat 40 degrees C, yet have 25 degrees C valuesbelow the 1.0% w/w limit.Shelf Life, Rates, andActivation EnergyTo demonstrate the importance of Ea inpredicting long-term shelf life at 25 degreesC from 40 degrees C rates, the Arrheniuskinetic equation was used to demonstratethe relationship of reaction rates and Ea. Therelationships are demonstrated in Table 3for the scenario where the degradantreaches the 1.0% w/w limit at six monthsat 40 degrees C and the zero-order rateconstant (k40) is equal to 0.1667% w/wdegradant/month.Table 4 demonstrates these relationshipsfor the scenario where the degradantreaches the 1.0% w/w limit at three monthsat 40 degrees C and the zero-order rateconstant (k40) is equal to 0.3333% w/wPharmaceutical Formulation & Quality > April/May 2011

PHARMAQUALITY.COMCASE STUDYPredict Dextrose DegradationIt is widely reported that dextrose in solution degrades to form 5-hydroxymethylfurfural(5-HMF) during heating (terminal sterilization) and overtime. 6-8 According to the dextrose injection monograph in the USP, thelimit for 5-HMF and related substances is not more than 0.25 absorbanceunits at 284 nm wavelength. 9The multiple pathway formation of 5-HMF by dehydration of dextrose isdepicted in Figure A. 10 The overall kinetic scheme, involving an intermediate,Figure A.Possible mechanism of 5-HMF formation in dextrose solutions(reference 10).Figure B.Simplified reaction scheme for 5-HMF formation.Substances and Products, requires long-term testing over 12 months atroom temperature (25 degrees C or 30 degrees C) and over six months ataccelerated conditions of 40 degrees C at the time of submission. The document’sObjections of the Guidance section states: “The guidance exemplifiesthe core stability data package for new drug substances and products,but leaves sufficient flexibility to encompass the variety of different practicalsituations that may be encountered due to specific scientific considerationsand characteristics of the materials being evaluated. Alternative approachescan be used when there are scientifically justifiable reasons.” 12The known chemistry of dextrose degradation to 5-HMF as presentedhere represents a justifiable reason for submitting a shorter time period ofaccelerated data. The kinetic model with known activation energy indicatesthat submission of two months at 40 degrees C data is sufficient and moreappropriate than six months at 40 degrees C data to estimate the level of5-HMF at 25 degrees C and to support a requested 24 months at 25 degreesC expiration dating period. nwith definable rate constants for formation andreaction, has been published by at least threegroups. 11 The Eas for k 1 and k 2 of the reactionscheme shown in Figure B, as determined bySturgeon and colleagues, are 32.6 kcal/mole and12.3 kcal/mole, respectively. Previously, Heimlichand Martin determined the Ea for 5-HMF formationfrom dextrose to be 31.2 kcal/mole and 31.8kcal/mole, dependent upon the method used todetermine the first-order rate constant. 11Before appreciable formation of 5-HMF canoccur, a reasonably high steady state level of theintermediate must first be established. Thus, theoverall generation of 5-HMF will be dependent uponthe k 1 with an activation energy of 32.6 kcal/mole.Using Table 5 and the Ea of 31 kcal/mole listing, thelast column indicates that 5-HMF levels measuredafter two months at 40 degrees C will be predictiveof 24 months at 25 degrees C. The production of5-HMF is proceeding at least 12 times faster at 40degrees C than at 25 degrees C. The level of 5-HMFafter six months at 40 degrees C will be three timeshigher than the level reached at 24 months at25 degrees C.The U.S. Food and Drug Administration/InternationalConference on Harmonisation Guidance forIndustry, Q1A(R2), Stability Testing of New DrugTable 5.Ea(kcal/mole)activationenergy9141720222631Stability predictions based upon the ratio of rates (Ea) at 40degrees C and 25 degrees C.Ratio (R)k40 to k25(k40 =R*k25)23456812Requiredmonths at 40degrees Cto reach levelequivalent to12 months at25 degrees C6432.521.51Requiredmonths at 40degrees Cto reach levelequivalent to18 months at25 degrees C964.53.632.251.5Requiredmonths at 40degrees Cto reach levelequivalent to24 months at25 degrees C12865432April/May > Pharmaceutical Formulation & Quality

QUALITY CONTROL | HIGH-TEMPERATURE STABILITYFigure 4.Predicteddegradant formationat 25 degreesC when 1% w/wdegradation isreached afterthree months at40 degrees C fordifferent activationenergies (Ea).Figure 5.Kinetic model for1% w/w degradantformation afterthree months at40 degrees C.degradant/month. The zero-orderdegradant generation rates at 25 degreesC (k25) are calculated for reaching 1.0%w/w at different expiry time intervals: 12,18, and 24 months (Tables 3 and 4). Forthese examples, the initial time zero startinglevel is set to 0% w/w. As shown in Tables3 and 4, each of these differentshelf-life scenarios has a reaction mechanismwith a different Ea.As the Ea decreases, the reaction rateat 25 degrees C increases relative to therate at 40 degrees C. The temperature sensitivityof the reaction decreases with decreasedactivation energy, as indicated bythe decreased proportionality betweenthe rates (k40 α k25). When the activationenergy is 9 kcal/mole (very low), evenwhen remaining within the limit of 1.0%w/w degradation through six months at40 degrees C, a maximum of 12 months at25 degrees C shelf life can be projected.In comparison, when activation energyis 17 kcal/mole with 1.0% w/w degradationthrough six months at 40 degreesC, 24 months elapses before the same1.0% w/w degradant level is reached at25 degrees C. If the Ea is known to be 17kcal/mole or greater, then 40 degrees Cvalues at six months of 1.0% w/w (or less)can kinetically support a shelf life, for thisdegradant limit, of 24 months at 25 degreesC. (This article does not address dataaccuracy—variability of the analyticalmethodology and/or the product samples—orthe use of confidence intervals,Editor’s Choice1. Weiss WF IV, Young TM, Roberts CJ. Principles, approaches, and challenges for predicting protein aggregation rates and shelf life.J Pharm Sci. 2009;98(4):1246-1277.2. Zahn M, Kållberg PW, Slappendel GM, et al. A risk-based approach to establish stability testing conditions for tropical countries.J Pharm Sci. 2006;95(5):946-965.3. Waterman KC, Adami RC. Accelerated aging: Prediction of chemical stability of pharmaceuticals. Inter J Pharm. 2005;293:101-125.4. Beaman J, Whitlock M, Wallace R, et al. The scientific basis for the duration of stability data required at the time of submission.J Pharm Sci. 2010;99(6):2538-2543.5. Bauer M. Stability of drug substances and drug products: Considerations on the stability of drug substances and formulation inthe pharmaceutical industry domain. STP Pharma Pratiques 2005;15(3):232-246.Pharmaceutical Formulation & Quality > April/May 2011

PHARMAQUALITY.COMFigure 6.Figure 7.Degradant reached 1%w/w at 40 degrees C; each model predicts thesame level at 25 degrees C.Degradant level at 25 degrees C for the three activation energymodels in Figure 6.which should also be incorporated whenestablishing product shelf life.)Because many drugs demonstrate Easof 19-20 kcal/mole, this is the basis for thepractice of comparing six month 40 degreesC values against the specification limit as apredictor of meeting that specificationthrough a shelf life of 24 months at 25 degreesC. The proportionality of six monthsstorage at 40 degrees C as predictive of 24months at 25 degrees C is predicated uponan activation energy of at least 17 kcal/mole.Some reactions proceed relatively fastat higher temperatures, as demonstrated inTable 4 and Figure 4. In this example, thedegradant growth at 40 degrees C reachesthe product limit (assigned here as 1.0%w/w) after three months storage (k40 =0.3333%w/w degradant per month). Theusual response is to assume that only a 12-month shelf life at 25 degrees C can beachieved. In reality, the levels of degradantreached at 25 degrees C are dependent uponthe Ea of the reaction as shown in Figure 5.The proportionality of the level measuredafter three months at 40 degrees C aspredictive of the level for 12 months at 25degrees C is valid only for an Ea of 17kcal/mole. If the activation energy is knownto be 22 kcal/mole or greater, then 40 degreesC values at three months up to 1.0%w/w can kinetically support a shelf life,for this degradant limit, of 18 months at25 degrees C. This application of Ea andArrhenius kinetics to the prediction ofshelf life can be applied to any degradantlevel specified.Stability Prediction Made EasyNow that the relationship of reaction ratesto Ea is understood, it becomes easier topredict values over longer time periods atlower storage temperatures, like 25 degreesC, from values obtained at higher(accelerated degradation) temperatures,such as 40 degrees C.The Ea is the proportionality factor betweenreaction rates at different temperatures(k40 α k25). The Arrhenius equation(Equation 4) can be solved for the exactrelationship between reaction rates at 40degrees C and 25 degrees C for any activationenergy Ea. This proportionality canbe used to predict levels and shelf life, aspresented in Table 5. When the activationenergy is 17 kcal/mole, the same degradantlimit is reached at six months at 40 degreesC and at 24 months at 25 degrees C.Table 5 can be used as a guide to interpret40 degrees C kinetic prediction of 25degrees C shelf life. As data is collectedover time at 40 degrees C, the results ateach test interval can be used to predict thelevel and, hence, the shelf life at 25 degreesC. When the activation energy is greaterthan 17 kcal/mole, samples stored at 40 degreesC and tested at six months will exhibitlevels greater than what will be actuallyreached over 24 months at 25 degrees C. Ifthe activation energy is 26 kcal/mole, thelevel measured at three months at 40 degreesC represents the expected level for24 months at 25 degrees C, and the levelmeasured at six months at 40 degrees Cwill actually represent twice the expectedlevel for 24 months at 25 degrees C.The concept presented in Table 5 isshown in Figures 6 and 7. Figure 6 showsthree different rate scenarios for the monthsat 40 degrees C to reach 1% w/w degradant.When the Ea for the reaction is 26 kcal/moleor greater, although the 1% w/w level isreached by three months at 40 degrees C(k40 = 0.3333% w/w degradant/month), thedegradant growth at 25 degrees C will notreach 1%w/w until 24 months or beyond,as represented in Figure 7.When the Ea for the reaction is 22 kcal/mole and at four months at 40 degrees Cthe 1% w/w level is reached (k40 = 0.2500%w/w degradant/month), the degradantgrowth at 25 degrees C will again not reach1%w/w until 24 months, as represented inFigure 7. An Ea of 17 kcal/mole and a sixmonths 40 degrees C degradant level of1% w/w (k40 = 0.1667% w/w degradant/month) likewise corresponds to a projectionof 24 months at 25 degrees C to reach1% w/w. Thus, as demonstrated, differentrates at 40 degrees C can project to thesame or similar stability at 25 degrees C.Additionally, as indicated in Table 5, forthe same activation energy of 17 kcal/mole,when the degradation rate at 40 degrees Cis faster, reaching 1% w/w by three months(k40 = 0.3333% w/w degradant/month),the 1%w/w level is projected to be reachedby 12 months at 25 degrees C (Figures 4and 5). A shelf life of 12 months is kineticallysupported. Consequently, if the activationenergy is lower than 17 kcal/molefor this same k40 rate of reaching 1% w/wApril/May > Pharmaceutical Formulation & Quality

QUALITY CONTROL | HIGH-TEMPERATURE STABILITYby three months (k40 = 0.3333% w/wdegradant/ month), levels at 25 degrees Cwill reach 1% w/w before 12 months, and ashelf life of 12 months is not kineticallysupported. The information in Table 5 canbe used to estimate shelf life based uponthe Ea and stability at 40 degrees C.The practice of predicting long-termchemical stability at a lower temperatureusing data generated at a higher temperatureover a shorter time period is basedupon application of the Arrhenius kineticmodel. The Arrhenius equation can beapplied regardless of the order of the reactionkinetics. By using the Ea with theexperimental level of drug or degradantobtained at a higher temperature (40degrees C), the expected level of drug ordegradant over long-term storage at alower temperature (25 degrees C) can bemore accurately predicted and the kineticshelf life estimated. The proportionalityof six months storage at 40degrees C as predictive of 12 months at25 degrees C is predicated upon an activationenergy of 9 kcal/mole. The proportionalityof six months storage at 40degrees C as predictive of 24 months at25 degrees C is predicated upon an activationenergy of 17 kcal/mole. As theactivation energy increases, the temperaturesensitivity of the reaction increases,resulting in a greaterdifference in the rates at different temperatures.The information in Table 5can also be used to estimate shelf life at25 degrees C based upon the activationenergy and the stability at 40 degreesC. As presented, the Arrhenius kineticmodel can be applied to specific drugchemistry to scientifically justify appropriatemonths at accelerated 40 degreesC condition for submission. nREFERENCES1. Martin A. Physical Pharmacy: PhysicalChemical Principles in the PharmaceuticalSciences. 4 th ed. Philadelphia: Lea &Febiger; 1993: Chapter 12, Kinetics, pages284-323.2. Lachman L, Lieberman HA, Kanig JL. TheTheory and Practice of Industrial Pharmacy.3 rd ed. Philadelphia: Lea & Febiger;1986:765-767.3. Wigent RJ. Chemical kinetics. In: GennaroAR, ed. Remington: The Science and Practiceof Pharmacy. 20 th ed. Philadelphia:Lippincott Williams & Wilkins; 2000.4. Carstensen JT. Drug Stability: Principles andPractices. New York: Marcel Dekker;1990:29-34.5. Conners KA, Amidon GL, Stella VJ. ChemicalStability of Pharmaceuticals: A Handbook forPharmacists. 2 nd ed. New York: John Wiley &Sons; 1986:24.6. Brönsted JN, Guggenheim EA. Contributionto the theory of acid and base catalysis: themutarotation of glucose. J Am Chem Soc.1927;49(10):2554-2584.7. Taylor RB, Jappy BM, Neil JM. Kinetics ofdextrose degradation under autoclaving conditions.J Pharm Pharmacol. 1972;24(2):121-129.8. Sturgeon RJ, Athanikar NK, Hartison HA, etal. Degradation of dextrose during heatingunder simulated sterilization. J Parenter DrugAssoc. 1980;34(3):175-182.9. U.S. Pharmacopeia–National Formulary. Dextroseinjection monograph. Available at:www.uspnf.com.10. Hryncewicz CL, Koberda M, Konkowski MS.Quantitation of 5-hydroxymethylfurfural (5-HMF) and related substances in dextroseinjections containing drugs and bisulfite. JPharm Biomed Anal. 1996;14(4):429-434.11. Heimlich KR, Martin AN. A kinetic study ofglucose degradation in acid solution. J AmPharm Assoc. 1960;49(9):592-597.12. U.S. Food and Drug Administration. Centerfor Drug Evaluation and Research. Center forBiologics Evaluation and Research. Guidancefor Industry: Q1A(R2) Stability Testing of NewDrug Substances and Products. Washington,D.C.: U.S. Food and Drug Administration;2003.Michelle Duncan is an associate director in global research and development withBaxter Healthcare. She holds a bachelor’s in biochemistry and molecular biology fromNorthwestern University and earned her PhD in pharmaceutics from the University ofTexas at Austin. She specializes in the formulation development of parenteral products and hasled numerous injectables through FDA approval (NDA and ANDA routes) and to successful commercialization.Irene Zaretsky is a research associate with Baxter, supporting analytical andformulation development. She earned her master’s in chemistry from the Institute of Technologyin Minsk, Belarus, and has worked more than 13 years in the U.S. pharmaceutical industry.BaxterBioPharmaSolutions.comContact us at biopharmasolutions@baxter.comReprinted with permission from PFQ Magazine April/May 2011.