Antonijevic, Milan

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Is There a Simple Relationship Between Different Phases, Phase Transitions and Stability of Drugs?Milan D. AntonijevicSchool of Science, University of Greenwich at MedwayIntroductionResearch InterestsExamples of a solid state characterisation using conventional thermo-analytical instrumentationThermally Stimulated Current Spectroscopy (TSC) as a new mean of characterising materialsConclusionsTA Instruments, London 2009Educational BackgroundBSc Chemistry – 1997, University of BelgradeOver 4 years – QA/QC, Pharmaceutical Industry, Serbia PhD in Pharmaceutical Materials Science – 2005, Queens University BelfastAcademia (Lecturer in Pharmaceutical Analysis) University of East Anglia (2004-2006)University of Greenwich (2006-present)TA Instruments, London 2009Research InterestsSolid-State characterisationUnderstanding relationship between phase transitions and stability of different formsPhoto and thermal stabilityDevelopment of TSC as a new tool for characterisation of small (pharmaceutically important) moleculesTA Instruments, London 2009AspirinNice model drugCheap, non hazardousSignificant information availableGaps in knowledge TA Instruments, London 2009TGA ResultsStability in solid-stateTA Instruments, London 2009DSC ResultsAspirin (25to210°C/210to-30°C/-30to210°C@10)TA Instruments, London 2009DSC ResultsAspirinTA Instruments, London 2009DSC ResultsSalicylic AcidTA Instruments, London 2009DSC ResultsSalicylic Acid + Acetic AcidTA Instruments, London 2009DSC ResultsCorrelation between presence of Acetic Acid and temperature of a phase transitions1st heating 2nd heating25-155/-55/155 Melting Point (°C) Tg (°C) Exo (°C) Endo (°C)Crimped panscooling@5141.2±0.6 -38.2±0.6 58.4±0.2 94.8±1.3cooling@10141.2±0.7 -38.2±0.6 58.5±0.4 94.4±1.2TA Instruments, London 2009cooling@20140.6±0.5 -38.9±0.3 42.5±1.2 92.7±0.5Pinhole panscooling@5141.0±0.4 -20.4±0.4 69.3±0.5 109.7±0.4cooling@10140.9±0.3 -24.5±0.8 61.2±1.3 102.8±0.6cooling@20140.6±0.4 -25.7±0.3 58.2±1.2 100.8±0.5CaffeinePolymorphic transitionForm II is stable at room temperatureForm I is stable above 150°CXanthine alkaloid (theophylline, theobromine)TA Instruments, London 2009Caffeine Form II – DSC Results1st heatingTA Instruments, London 2009Caffeine Form II – DSC ResultscoolingTA Instruments, London 2009Caffeine Form II – DSC Results2nd heatingTA Instruments, London 2009Caffeine Form I – DSC Results1st heatingTA Instruments, London 2009Caffeine Form I – DSC ResultscoolingTA Instruments, London 2009Caffeine Form I – DSC Results2nd heatingTA Instruments, London 2009Caffeine Form I – DSC ResultsMelting of caffeine in1st and 2nd heatingTA Instruments, London 2009Theophylline - DSC1st heatingTA Instruments, London 2009TheophyllinecoolingTA Instruments, London 2009Theophylline2nd heatingTA Instruments, London 2009TheophyllineTA Instruments, London 2009Theobromine1st heatingTA Instruments, London 2009TheobrominecoolingTA Instruments, London 2009Theobromine2nd heatingTA Instruments, London 2009Caffeine, Theophylline, TheobromineCaffeine and Theobromine – sublime rapidly Melting point (°C) Phase Transition (°C) Recystallisation (°C)Caffeine ~ 235 ~ 145 ~ 235Theophylline ~ 271 ~ 220 ~ 260Theobromine ~ 346 - ~ 333TA Instruments, London 2009NifedipineExists in several polymorphic formsMay exist in amorphous formPhoto sensitiveTA Instruments, London 2009NifedipineAs received – 1st heatingTA Instruments, London 2009NifedipineAs received – 2nd heatingTA Instruments, London 2009NifedipineUV irradiated – 1st heatingTA Instruments, London 2009NifedipineUV irradiated – 2nd heatingTA Instruments, London 2009NifedipineAmorphous – 1st heatingTA Instruments, London 2009NifedipineAmorphous – 2nd heatingTA Instruments, London 2009NifedipineAmorphous UV irradiated – 1st heatingTA Instruments, London 2009NifedipineAmorphous UV irradiated – 2nd heatingTA Instruments, London 2009ConclusionCrystalline Nifedipine more prone to photo degradation compare to amorphous Less stable crystalline form may be formed upon the exposure of crystalline Nifedipine to the UV lightTA Instruments, London 20091st heating 2nd heatingTg (°C) Tc (°C) PT (°C) Tm (°C) Tg (°C) Tc (°C) PT (°C) Tm (°C)Crystalline ~ 172 ~ 45 ~ 100 ~ 135 ~ 166Crystalline-UVTm - 72 ~ 159 ~ 37 ~ 135 ~ 154Amorphous ~ 36 ~ 91 ~ 102 ~ 160 ~ 37 ~ 99 ~ 158Amorphous-UV~157 ~ 40 ~ 120 ~157Thermally Stimulated Current Spectroscopy (TSC)TSC is a general term applied to themeasurement of current generated bytemperature-activated relaxation of moleculardipoles in response to the application of a staticelectric field• 1936, Frei and Grotzinger• electrets, ionic crystals • waxes, resins• ceramics, plasticTA Instruments, London 2009TSC originExperimental variables:• Temperature of polarization• Time of polarization• Polarization field• Cooling rate• The lowest temperature• Time at lowest temperature• Heating rate• Final temperature• Temperature of stabilizationTA Instruments, London 2009TSC spectrumTA Instruments, London 2009Main parts of the instrumentThermostated sample holderVacuum systemHeating and Cooling unitDC generatorCurrent detector (10-4 to 10-16 A)Recording unitTA Instruments, London 2009Glass transition is characterised by:Heat capacity change (DSC)Amorphous MaterialsVisco-elastic changes (TSC)TA Instruments, London 2009TW-TSDC0.81.01.21.41.61.82.0TSDCTp=242KTp=239KTp=236KTp=233KTp=230KTp=227KTp=224KCurrent (x10-13A)190 200 210 220 230 240 250 260 270 280-0.4-0.20.00.20.40.6 Tp=221KCurrent (x10Temperature (K)TA Instruments, London 2009TSC PEG 4000 - Aldrich0.40.60.81.01.2Global TSDCTp = 223 KTp = 220 KTp = 217 KTp = 214 KTp = 211 KTp = 208 KTp = 205 KTp = 202 KT  = 199 KCurrent (10-13 A)TA Instruments, London 2009160 170 180 190 200 210 220 230 240 250 260-0.20.00.2pCurrent (10Temperature (K)TSC PEG 6000 - BDH0.81.01.21.41.61.82.0 Global TSDCTp = 242 KTp = 239 KTp = 236 KTp = 233 KTp = 230 KTp = 227 KTp = 224 KTp = 221 KCurrent (x10-13A)TA Instruments, London 2009190 200 210 220 230 240 250 260 270 280-0.20.00.20.40.6 Tp = 218 KCurrent (x10Temperature (K)TSC PEG 20000 - Clariant0.40.60.81.0Global TSDCTp = 253 KTp = 250 KTp = 247 KTp = 244 KTp = 241 KTp = 238 KTp = 235 KTp = 232 KTp = 229 KCurrent (10-13 A)TA Instruments, London 2009190 200 210 220 230 240 250 260 270 280 2900.00.2Tp = 226 KTp = 223 KCurrent (10Temperature (K)TSC PEG 4000/6000/20000TA Instruments, London 2009TSC PEG 4000/6000/20000PEG 4,000 PEG 6,000 PEG 20,000Melting T (K) 326 - 331 328 - 333 333- 340TW Tg1 (K) 205 227 235TW Tg2 (K) 220 236 247TA Instruments, London 2009TSDC Tg (K) 205.8 223.2 237.1∆H TW Tg1 (kJmol-1) 111.25 134.91 112.43∆H TW Tg2 (kJmol-1) 111.46 116.96 113.64Fragility index Tg1 28.3 31.0 25.0Fragility index Tg2 26.5 25.9 24.0TSC PEG 6000 – Lancaster/BDH200 210 220 230 240 250 260 270 280 290-10123456789 PEG (Tg)Vectran (β relaxation)Tp = 263 KTp = 261 KTp = 258 KTp = 256 KTp = 253 KTp = 251 KTp = 248 KTp = 245 KTp = 243 KTp = 237 KTp = 235 KTp = 233 KCurrent (10-13 A)Temperature (K)1.82.0 Global TSDCT  = 242 KTA Instruments, London 2009190 200 210 220 230 240 250 260 270 280-0.20.00.20.40.60.81.01.21.41.6pTp = 239 KTp = 236 KTp = 233 KTp = 230 KTp = 227 KTp = 224 KTp = 221 KTp = 218 KCurrent (x10-13A)Temperature (K)HS Microscopy PEG 6000 –Lancaster/BDHTA Instruments, London 2009Caffeine - TSDC ResultsForm I                              Form IITA Instruments, London 2009α-process 139ºC Form II only - polymorphic transitionγ-process -8ºC Forms I and II - orientation of side groupβ1-process 91ºC Form IIβ2-process 107ºC Form I - orientation/mobility of sub-unitCaffeine - SDC ResultsForm I - negative peak at -8ºC and 112ºCForm II - negative peak at 52ºCTA Instruments, London 2009Kinetic Parameters - TSC MethodTSDC                                      SDCTA Instruments, London 2009Validation CharacteristicsTSC MethodSignal-to-NoiseTotal Charge under the peak ( C ) versus the strenght of applied electrical fieled ( V/mm ) for the γ−process in Caffeine Form II  y = 0.0056x + 0.0372R2 = 0.99212.533.500.511.520 100 200 300 400 500 600Electrical Field (V/mm)Charge (e-10C)TA Instruments, London 2009ConclusionsTSC technique:• Appears as a powerful technique for thedetection of the polymorphs and polymorphictransitions, weak glass transitions and secondorder transitions in materials.• Ability to detect movements of side groupsmakes this thermal technique potentiallyapplicable in the field of structural analysis,and could even expand its thermodynamicuse.TA Instruments, London 2009ConclusionsThere have been well established correlations betweenphases and phase transitions such as:Stability of amorphous phase (Tg – 50°C)Stability of pseudo-polymorphs (solvent-drug inter.)Stability of polymorphs (difference in energy)Poorly understood relationships:Width of the phase transition processImportance of second order transitions (β and γ)TA Instruments, London 2009AcknowledgmentsMSc studentsRahul PatilAmit NarayankarAbdul SyedIESTE studentIvana LazarevicErasmus studentInmaculada Andres TomeTA Instruments, London 2009

Is there a simple relationship between different phases, phase transitions and stability of drugs?

http://gala.gre.ac.uk/4429/1/Milan_Antonijevic_%2D_TA_Instruments.pdf

Is there a simple relationship between different phases, phase transitions and stability of drugs?

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