Presentation on theme: "Goals of Preformulation"— Presentation transcript:
1Goals of Preformulation Establish the necessary physicochemical parameters of a new drug substance.Determine drug kinetic rate profile.Develop a stability indicating assay.Establish drug compatibility with common excepients.
2Goals of Preformulation Establish the necessary physicochemical parameters of a new drug substance.Determine drug kinetic rate profile.Develop a stability indicating assay.Establish drug compatibility with common excepients.
3Types of incompatibility Compatibility testsTypes of incompatibility?
4Which Drug/Excepient ratio Compatibility testsAim?Which excepientWhich Drug/Excepient ratio
5? Compatibility tests FDA Guidelines Methods Solid dosage form Liquid dosage formFDA Guidelines
6Compatibility test for solid dosage forms Stopper + WaxDrug + ExcepientRoom Temperature55oCWithout waterWith waterWithout waterWith waterCompare to drug stored under same conditions
7Compatibility test for solid dosage forms Stopper + WaxDrug + ExcepientRoom Temperature55oCVisual examinationAnalytical assayQuantitative relation of certain excepient character and interaction rate
8Compatibility test for liquid dosage forms Aqueous solutionNon-aqueous solutionParenteralOral
9Compatibility test for liquid dosage forms Aqueuos solution compatibilityParentralOralDrug + Excepient solution-Heavy metalsHeavy metals+chelating agentOxygen and nitrogen atmosphereAutoclavingDifferent blugs-EthanolGlycerinSucrosePreservativeBuffers
10Compatibility test for liquid dosage forms Aqueuos solution compatibilityParentralOralDrug + Excepient solutionVisual examinationAnalytical assay
11Compatibility tests ??? Drug : Excipient ratio The preformulation screening of drug-excipient interaction requires (1 : 1) Drug:excipient ratio, to maximize the likehood of observing an interaction.???Some researchers recommend ratios of :1:5 for diluents3:1 for binder & disintegrants5:1 for lubricant10:1 for colourant
15Compatibility tests Methods Chromatography TLC HPLC Advantages : Evidence of degradationSpots or peaks isolation.Quantification to obtain Kinetic data.Changes in the chromatograph such as appearance of NEW SPOT or Peak or change in Rf values or Rt means significant interaction.
16Compatibility testsMethodsThermal AnalysisIsothermal microcalorimetryDifferential scanning calorimetryThermogravimetric analysisCalorimetry is the science of heat. It is about how a given material responds to temperature changes on both the atomic and macroscopic level. It reveals important information about the arrangement and interaction of the atoms.
17Differential scanning calorimetry (DSC) Is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature.For solid state
18Applications Differential scanning calorimetry (DSC) It detects physical transformation such as melting, dehydration or crystallizationTemperatureHeat Flow-> exothermicGlassTransitionCrystallisationMeltingCrossLinking(Cure)
19Applications Differential scanning calorimetry (DSC) It detects physical transformation such as melting, dehydration or crystallizationPhase equilibrium diagrams of enantiomersCompatibility of drug with excepients
20Differential scanning calorimetry (DSC) DSC thermogram for API, Croscarmilose and physical mixture of both
21Differential scanning calorimetry (DSC) DSC thermogram for API, Lactose and physical mixture of both
22Heat conduction microcalorimetry Isothermal heat conduction microcalorimetry is an analytical method allowing determination of minute amounts of evolved or absorbed heat.The sensitivity is fold higher than the sensitivity of conventional differential scanning calorimetry (DSC).By microcalorimetry heat flow signals in the range of µW are detectable.The rate of heat flow is proportional to the rate of the process taking place.
23Heat conduction microcalorimetry Fig. 8. Concentration dependent drug-associated heat flow at 258C for a drug concentration of 8.7% NEA and various concentrations of E2-hemihydrate
24Heat conduction microcalorimetry For a reactionA + B = C + DFirst orderZero order
25Heat conduction microcalorimetry Time (days)12-101020Ø80oC75oCZero-order
26For liquid and solid state Heat conduction microcalorimetryApplicationsHeat conduction microcalorimetry detects chemical changes. BUT it gives no direct information about the chemical nature of the reactionFor liquid and solid state
28Thermogravimetric analysis Measures the amount and rate of change in the weight of a material as a function of temperature or time in a controlled atmosphere.Measurements are used primarily to determine the composition of materials and to predict their thermal stability at temperatures up to 1000°C.The technique can characterize materials that exhibit weight loss or gain due to decomposition, oxidation or dehydration. For solid state
30FT-IR SpectroscopyIs the absorption measurement of different IR frequencies by a sample positioned in the path of an IR beam.Different functional groups absorb characteristic frequencies of IR radiation.The main goal of IR spectroscopic analysis is to determine the chemical functional groups in the sample.
32FT-IR Spectroscopy Common Applications Identification of compounds by matching spectrum of unknown compound with reference spectrum (fingerprinting)Identification of functional groups in unknown substances.Identification of reaction components and kinetic studies of reactionsDetection of molecular impurities or additives present in small amounts .Analysis of formulations such as insecticides and copolymers
33Detects chemical interations For liquid and solid state FT-IR SpectroscopyDetects chemical interationsFor liquid and solid stateK. A.Mohammed, H. K. Ibrahim, M. M. Ghorab, Drug Deliv, 2014.
34X-ray diffractionX-rays interact with crystalline substances to give a diffraction pattern.The X-ray diffraction pattern of a pure substance is like a fingerprint of the substance.In a mixture of substances, each produces its pattern independently of the others.The powder diffraction method is thus ideally suited for characterization and identification of polycrystalline phases.
36Transdermal nonaqueuos solution compatibility -Compatibility with different excepients-Release and permeation characteristicsIn vitroIn vivoWith membrane(ex-vivo)Without membrane
37Nonaqueuos solution compatibility Time (units)612182490100110Amount releasedFlux of oily solution releaseFlux of solution+membrane releaseChein et al., Drug Dev Ind Pharm, 1983.
38Transdermal nonaqueuos solution compatibility -Compatibility with different excepients-Release and permeation characteristicsIn vitroIn vivoWith membrane(ex-vivo)Without membraneSacrifice
39Emulsion compatibility Preformulation is very formulation oriented:-Surfactant selection-Calculation of surfactant amount-Measuring CMC-Calculating the required HLB-pH stability profile of the surfactant in presence of other emulsion components