Antonijevic, Milan

Greenwich Academic Literature Archive

Understanding molecular mobility of pharmaceutically important materials/systems – current knowledge and challenges Milan D. AntonijevićVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsOverview of presentationChallenge 1• Molecular mobility studied by TSC• Examples (amorphous, polymorphs, co-crystals)Challenge 2• Thermal Analysis by Structural Characterisation• Thermal Dissolution Analysis (TDA)Challenge 3• Consumers careVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014AcknowledgmentsPhD students:Samuel Owusu-WareAnthony CherryColleagues:Mike Reading, CyversaMichael Morton, CyversaAndrew Lacey, Heriot-Watt UniversityDave Grandy and Douglas Hourston, Loughborough UniversityVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Challenge 1VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014TSC is a general term applied to the measurement of currentgenerated by temperature-activated relaxation of moleculardipoles in response to the application of a static electric field• 1936, Frei and Grotzinger• electrets, ionic crystals • waxes, resins• ceramics, plastic• small organic moleculesVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsIntroduction to TSCACAIII 30/09/2014Potential drugsIntroduction to TSCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsPharmaceutical Applications• Amorphous materials• Polymorphs• Batch-to-batch control• Co-crystals VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Global glass relaxation processDifferent relaxation modes contributing to overall processTW outputsVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Defining Ea - (TW)Tp(°C) Tmax(°C)Ea (kJ/mol)ΔH‡(kJ/mol)12 35 90 8714 37 93 9016 38 104 10118 39 112 10920 41 126 12322 42 135 13224 43 145 14226 43 157 15428 44 171 16930 45 190 18832 45 208 20534 46 225 22236 46 246 24438 47 259 25740 48 273 27042 50 298 295𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭𝑭 𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰𝑰 (𝒎𝒎) = 𝟏𝟏𝟐𝟐.𝟑𝟑𝟑𝟑𝟑𝟑 𝟏𝟏𝑬𝑬𝑭𝑭 (𝑻𝑻𝑭𝑭)𝑹𝑹𝑻𝑻𝑭𝑭VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsPharmaceutical Applications• Amorphous materials• Polymorphs• Batch-to-batch control• Co-crystals VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014CaffeineExists in two polymorphic forms:Form I, unstable at room T, TrigonalForm II, stable at room T, MonoclinicTransition point: 141 ± 2°CMelting Point: 236 - 243°C (British Pharmacopoeia)VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Caffeine - TSDC ResultsForm I                            Form IIα-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-unitVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Kinetic Parameters - TSC MethodTSDC                                      SDCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsPharmaceutical Applications• Amorphous materials• Polymorphs• Batch-to-batch control• Co-crystals VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014-100 -80 -60 -40 -20 0 20 40 60 80 100 120 140 160-1.00E-013-5.00E-0140.00E+0005.00E-0141.00E-0131.50E-0132.00E-013Current (A)Temperature (0C)-100 -80 -60 -40 -20 0 20 40 60 80 100 120 140 160-1.00E-013-5.00E-0140.00E+0005.00E-0141.00E-0131.50E-0132.00E-013Current (A)Temperature(0C)Batch to Batch variationsVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Batch to Batch variationsVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsPharmaceutical Applications• Amorphous materials• Polymorphs• Batch-to-batch control• Co-crystals VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugs• 1:1 molar ratio co-crystal (CC) of salicylic acid (SA) and benzamide (BA)• 1:1 molar ratio physical mixture (PM)SA/BA co-crystal systemPrimary transitions:BA = 128oCSA = 159oCCC = 119oCPM = 110oCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsSA/BA co-crystal systemVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsSA/BA co-crystal systemTc:CC-A = 125oCCC-B = 119oCPM= 110oCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugs• Thermal Analysis by Structural Characterisation (TASC)• Thermal Dissolution Analysis (TDA)Challenge 2VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014TASC consists of imposing a pattern on the surface of a sampleor exploiting pre-existing structure, then characterizing howthat pattern changes as the sample is heated; in this caseOptical Microscopy was used but it can be applied to otherforms of microscopy such as electron microscopy and AtomicForce Microscopy.heatVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014The TASC algorithm scans an areaand tries to identify whether adesignated structure exists andwhere it is located. Top right there isa schematic of an indentation,underneath this is the result of aTASC analysis.Right is a 3D representation of theoutput of the TASC analysis. The apexof the cone provides the location ofthe featureVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014This is graph showing a co-plot of DSC and TASC data.The flow event happens after the glass transition asmeasured by DSC as expected.00.20.40.60.811.21.41.60 50 100 150Temp. /oCNormalisedValuesVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014-0.200.20.40.60.8130 50 70 90 110 130 15090oCTemp. /oCNormalised TASCAn ideal form of microscopy isAtomic Force Microscopy. Below is acomparison of an AFM result(circles), on an indentation 500nm indiameter with one obtained usingoptical microscopy on an indentation200μm in diameter (squares).130oCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Potential drugsPart 2• Thermal Analysis by Structural Characterisation (TASC)• Thermal Dissolution Analysis (TDA)VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Right is an image of a collectionof sugar crystals in water in a DSCcrucible. The TASC algorithm canfollow their disappearance.In the graph shown right; it canbe seen that small crystals D, Fand G disappear much fasterthan the large crystal I.VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014BACDETemp / 0CThermal Dissolution AnalysisTASC is used to track the dissolution of the salicylic acidcrystals in the field of view of the microscope. Thetemperature program was 5oC/min.VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Thermal Dissolution AnalysisTASC is used to track the dissolution of the objects in thefield of view of the microscope. The temperature programwas 5oC/min.Fraction dissolvedTemp. /oCVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/201400.10.20.30.40.50.60.70 500 1000 1500Thermal Dissolution AnalysisFraction dissolvedSurface area /auTemp. /oCThe dissolution behavior clears falls into two categoriesshown as red and green.gradientVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/201400.10.20.30.40.50.60.70 500 1000 1500Thermal Dissolution AnalysisgradientSurface area /auThe objects in the field can be allocated to the twocategories.VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/201400.10.20.30.40.50.60.70.80.9125 35 45Temp. /oCNormalised TASCi)ii)iii)iv)CIDAFiltered i) from solvent; iii) from residueBy appropriate chemical analysis the ‘red’ and‘green’ materials can be identified.Glucose Salicylic AcidVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Surface area a.u.Slope of kinetic plot a.u.00.10.20.30.40.50.60.70 200 400 600 800 1000 1200 1400sucrosecaffinesalicylic acidindomethacinIt is typically the case that different material have differentdissolution kinetics.VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Thermal Dissolution AnalysisTGA-GC-MS Mass Loss ChromatographyChromatography‘Volume’ LossTDA-HPLCTemp. /oCTotal Volume Lost /auVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Challenge 3Do customers get what they pay for?VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014VI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014ConclusionsChallenges are all around us some are new, some oldThey are often complexthereforeThoughtful approach and joint effort, often involving innovative intellect, is requiredto solve themInnovation often faces challenges and challenges in one area drive innovation in anotherVI Congress of Serbian Pharmacists - New Challenges in Drug Analysis                       16/10/2014Keeping your attention was my challenge for todayThank you!!!

Understanding molecular mobility and solubility of pharmaceutically important materials/systems - current knowledge and challenges

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Understanding molecular mobility and solubility of pharmaceutically important materials/systems - current knowledge and challenges

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