Rapid shelf life estimation using non-isothermal ...
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Rapid shelf life estimation using non-isothermal treatments by DSC Andrea ARTEAGA-ROBALINO 1 , Robert ALCOCER-VALLEJO 1 , Javier SANTAMARÍA-AGUIRRE 1 and Luis CASTILLO- CABAY 1 1 Universidad Central del Ecuador. [email protected] , [email protected] Arteaga, A. (2017). Estimación rápida del tiempo de vida útil del ácido acetil salicílico mediante tratamientos no isotermales empleando calorimetría diferencial de barrido. Quito: Universidad Central del Ecuador. This project was possible by the support from Proyecto Semilla of Universidad Central del Ecuador and Académie de Recherche et D̓̓ Enseignement Supérieur (ARES) from Belgium. The traditional methods for determining the shelf life of drugs are isothermal, they require long periods of time for their execution and do not consider the kinetics of the solid state. The dynamics of industrial production require that decisions regarding stability should be taken quickly without neglecting the safety, efficacy and quality inherent in medicines. Therefore, rapid, sensitive and safe methods are needed to estimate the shelf life of raw materials and pharmaceutical forms. The use of non-isothermal techniques, like differential scanning calorimetry (DSC), reduce the time required for the assay, from months or years, to a few days. Main objective: Estimate the shelf life of acetylsalicylic acid (ASA) manufactured in different years and ASA/salicylic acid (SA) binary mixtures using DSC and the Kissinger method. § Preexponential factor and activation energy, calculated with the Kissinger equation, for the raw material and the binary mixtures show there is not significant difference between them. So, these samples can be characterized by an isokinetic point where the degradation kinetic is the same for all. Besides, the remaining shelf life changes with specific surface area because particles with less area available for the reaction degrade more slowly than the other ones. § The used non-isothermal method is a fast tool for the shelf life estimation and it is sensitive enough to detect activation energy differences possibly related to variations in composition, production process or storage. Introduction Raw material and binary mixtures analyzed by HPLC Quantification of ASA DSC Assay Heating rate (β): 5, 10, 20 °C/min Tm Kissinger method Microscopic Assay # 2 ( = * /− = − ⁄ = ( AR ⁄ ) Temperature range: 90 – 300 °C Atmosphere: Nitrogen Flow: 25 mL/ min Figure 1. DSC thermograms of ASA Figure 2. Kissinger plot ASA/SA binary mixtures were prepared to simulate a natural degradation degree and to compare with the raw materials results obtained by DSC. The maximum reaction temperature (Tm) depends to the heating rate, this significant effect is used by Kissinger equation to calculate kinetic parameters like preexponential factor (A) and activation energy (Ea). RM 1 RM 2 RM 3 Mixture 1 Mixture 2 Mixture 3 Activation energy [KJ/mol] 107,43 ± 5,38 118,57 ± 2,12 112,54 ± 14,39 95,67 ± 6,51 125,41 ± 10,35 102,91 ± 9,99 Pre-exponential factor [min -1 ] 1,29 x 10 12 2,46 x 10 13 5,98 x 10 12 5,38 x 10 10 1,48 x 10 14 3,84 x 10 11 Degradation constant (25°C) [min -1 ] 1,94 x 10 -7 4,15 x 10 -8 1,15 x 10 -7 9,32 x 10 -7 1,58 x 10 -8 3,59 x 10 -7 Remaining shelf life, t 95 [months] 2,73 14,14 2,71 0,96 33,69 2,54 Table 1. Degradation kinetic parameters Figure 3. ASA crystals: (a) RM 1; (b) RM 2 and (c) RM 3 A 1 , mm 2 V 2 , mm 3 SSA 3 , mm -1 RM 1 1,58 0,099 17,85 RM 2 1,88 0,139 15,99 RM 3 1,58 0,100 17,20 1 Area, 2 Volume, 3 Specific Surface Area Table 2. Specific Surface Area of ASA Methods Results Conclusions References SA solution sprinkled over ASA crystals Kissinger equation: Preparation of binary mixtures Tm Ea and A characterize the degradation kinetics of each sample and they are used to get the degradation constant (K) from Arrhenius equation. The remaining shelf life (t) to reach a degradation (D) of 5% is calculated with the parameters below by the following equation: = − ’1 − 100 * − To establish a relationship between kinetic parameters of the ASA naturally degraded and the artificial mixtures, the activation energies were compared by simple ANOVA and there is no statistically significant difference between them. The complex behavior of the ASA kinetic involved physical processes related to the shape and the particle size of the samples. So, the specific surface area was determined to explain the degradation level (Table 2).
Transcript of Rapid shelf life estimation using non-isothermal ...
Rapid shelf life estimation using non-isothermal treatments by DSC
AndreaARTEAGA-ROBALINO1,RobertALCOCER-VALLEJO1,JavierSANTAMARÍA-AGUIRRE1andLuisCASTILLO-CABAY1
[email protected],[email protected]
Arteaga, A. (2017). Estimación rápida del tiempo de vida útil del ácido acetilsalicílico mediante tratamientos no isotermales empleando calorimetríadiferencialdebarrido.Quito:UniversidadCentraldelEcuador.
ThisprojectwaspossiblebythesupportfromProyectoSemillaofUniversidadCentraldelEcuadorandAcadémiedeRechercheetD ̓̓ EnseignementSupérieur(ARES)fromBelgium.
The traditionalmethods fordetermining theshelf lifeofdrugsare isothermal, they require longperiodsof time for theirexecutionanddonotconsider the kinetics of the solid state. Thedynamicsof industrial production require that decisions regarding stability shouldbe takenquicklywithoutneglectingthesafety,efficacyandqualityinherentinmedicines.Therefore,rapid,sensitiveandsafemethodsareneededtoestimatetheshelflifeofrawmaterialsandpharmaceuticalforms.Theuseofnon-isothermaltechniques,likedifferentialscanningcalorimetry(DSC),reducethetimerequiredfortheassay,frommonthsoryears,toafewdays.
Mainobjective:Estimatetheshelflifeofacetylsalicylicacid(ASA)manufacturedindifferentyearsandASA/salicylicacid(SA)binarymixturesusingDSCandtheKissingermethod.
§ Preexponential factor and activation energy, calculated withthe Kissinger equation, for the raw material and the binarymixtures show there is not significant difference betweenthem.So,thesesamplescanbecharacterizedbyanisokineticpoint where the degradation kinetic is the same for all.Besides,theremainingshelf lifechangeswithspecificsurfaceareabecauseparticleswithlessareaavailableforthereactiondegrademoreslowlythantheotherones.
§ Theusednon-isothermalmethodisafasttoolfortheshelflifeestimation and it is sensitive enough to detect activationenergy differences possibly related to variations incomposition,productionprocessorstorage.
Introduction
RawmaterialandbinarymixturesanalyzedbyHPLC QuantificationofASA
DSCAssay
Heatingrate(β):5,10,20°C/min
Tm
Kissingermethod
MicroscopicAssay
𝑙𝑛 #𝛽𝑇𝑚2( = 𝑙𝑛 *
𝐴𝑅𝐸𝑎/ −
𝐸𝑎𝑅𝑇𝑚
𝑏 = −𝐸𝑎 𝑅⁄ 𝑎 = 𝑙𝑛 (AR 𝐸𝑎⁄ )
Temperaturerange:90–300°CAtmosphere:NitrogenFlow:25mL/min
Figure1.DSCthermogramsofASA
Figure2.Kissingerplot
ASA/SA binary mixtures were prepared to simulate a natural degradationdegreeandtocomparewiththerawmaterialsresultsobtainedbyDSC.Themaximum reaction temperature (Tm) depends to the heating rate, thissignificanteffectisusedbyKissingerequationtocalculatekineticparameterslikepreexponentialfactor(A)andactivationenergy(Ea).
RM1 RM2 RM3 Mixture1 Mixture2 Mixture3
Activationenergy [KJ/mol] 107,43±5,38 118,57±2,12 112,54±14,39 95,67±6,51 125,41±10,35 102,91±9,99
Pre-exponentialfactor [min-1] 1,29x1012 2,46x1013 5,98x1012 5,38x1010 1,48x1014 3,84x1011
Degradationconstant(25°C) [min-1] 1,94x10-7 4,15x10-8 1,15x10-7 9,32x10-7 1,58x10-8 3,59x10-7
Remainingshelflife,t95 [months] 2,73 14,14 2,71 0,96 33,69 2,54
Table1.Degradationkineticparameters
Figure3.ASAcrystals:(a)RM1;(b)RM2and(c)RM3
A1,mm2 V2,mm3 SSA3,mm-1RM1 1,58 0,099 17,85RM2 1,88 0,139 15,99RM3 1,58 0,100 17,20
1Area,2Volume,3SpecificSurfaceArea
Table2.SpecificSurfaceAreaofASA
Methods Results
Conclusions
References
SAsolutionsprinkledoverASAcrystals
Kissingerequation:
Preparationofbinarymixtures
Tm
EaandAcharacterizethedegradationkineticsofeachsampleandtheyareused to get the degradation constant (K) from Arrhenius equation. Theremainingshelflife(t)toreachadegradation(D)of5%iscalculatedwiththeparametersbelowbythefollowingequation:
𝑡𝐷 =−𝑙𝑛 '1 − 𝐷
100*
𝐴𝑒−𝐸𝑎𝑅𝑇
Toestablisha relationshipbetweenkineticparametersof theASAnaturallydegradedandtheartificialmixtures,theactivationenergieswerecomparedbysimpleANOVAandthereisnostatisticallysignificantdifferencebetweenthem.ThecomplexbehavioroftheASAkineticinvolvedphysicalprocessesrelatedtotheshapeandtheparticlesizeofthesamples.So,thespecificsurfaceareawasdeterminedtoexplainthedegradationlevel(Table2).
