Analytical Techniques for Characterization of Solid State

7/31/2019 Analytical Techniques for Characterization of Solid State

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Submitted by :-Ramneek Singh


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Polymorphism - the ability ofa compound to crystallise inmore than one crystal form

Pseudopolymorphic forms

(solvated forms) - crystallinesolids containing solventmolecules as an integral partof their crystal structure

Amorphism - the absence of

regular or crystalline structurein a body solid; amorphousmaterials do not possessthree-dimensional long-rangemolecular order

Polymorph A Polymorph B

Solvate A Solvate B


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Verifying that the solid is the expectedchemical compound.

Characterizing the internal structure. Describing the habit of the crystal.

Therefore , comprehensive characterization of all

preformulation bulk lots is necessary to avoid

misleading prediction of stability or solubility , which

depends on a particular crystalline form .


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Active pharmaceutical ingredients (API, drugs) Mainly solids (crystalline, amorphous or semi-

crystalline)

Organic molecules, peptides, proteins Single components

Excipients (additives, fillers etc.) Organic, inorganic

Solids or liquids

Formulations (dosage forms, delivery systems) Mixtures of APIs and excipients

Packaging materials


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1.Bulk and Biopharmaceutical PropertiesFlowability, CompressabilitySolubility and dissolution (Bioavailability)

2.Chemical PropertiesStability / Reactivity

3.Regulatory issuesQuality, Efficacy and Safety

4.Intellectual Property

Patents.5.Processing factorsBulk and mechanical propertiesEase of isolation, filtration and dryingDegree of purity


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For thermodynamic properties:1. Thermal analysis

2. Microcalorimetry3. Vapour pressure determination4. Solubility determination

For particle and bulk properties:1. Microscopy

2. Micromeritics


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For structural properties:1. X-ray diffraction method

powdersingle crystal2. Spectroscopy

UV

IRRamanSolid state NMR


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IUPAC definition - a group of techniques in which aphysical property is measured as a function oftemperature, while the sample is subjected to a

controlled temperature programme (heating, coolingor isothermal). A range of techniques e.g.: Differential Thermal Analysis (DTA) temperature

Differential Scanning Calorimetry (DSC) energy

Thermogravimetric Analysis (TGA) mass

Thermomechanical Analysis (TMA) dimensions

Dielectric Analysis (DEA) dielectric/electric properties


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Modern instrumentation used for thermal analysisusually consists of the following parts:

sample holder/compartment for the sample

sensors to detect/measure a property of the sample andthe temperature

an enclosure within which the experimental parameters

(temperature, speed, environment) may be controlled a computer to control data collection and processing

sample

sensors

temperaturecontrol (furnace)

PC


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Most popular thermal technique DSC measures the heat absorbed or liberated during

the various transitions in the sample due totemperature treatment Differential: sample relative to reference Scanning: temperature is ramped Calorimeter: measures heat

DSC measurements are both qualitative and

quantitative and provide information about physicaland chemical changes involving: Endothermic processes sample absorbs energy Exothermic processes sample releases energy Changes in heat capacity


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Power Compensation DSC

High resolution / high sensitivity research studies Absolute specific heat measurement Very sensitive to contamination of sample holders

Heat Flux DSC

Routine applications Near / at line testing in harsh environments Automated operation

Cost-sensitive laboratories


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Melting points crystalline materials Desolvation adsorbed and bound solvents Glass transitions amorphous materials

Heats of transitions melting, crystallisation Purity determination contamination,

crystalline/amorphous phase quantification Polymorphic transitions polymorphs and

pseudopolymorphs Processing conditions environmental factors Compatibility interactions between components Decomposition kinetics chemical and thermal

stability


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40 60 80 100 120 140 160 180 200 220 240 260 280 300

20

mW

temperature [oC]

^exo

Exothermic upwardsEndothermic downwards

Y-axis heat flow

X-axis temperature (and time)

DESOLVATIONGLASS TRANSITION

CRYSTALLISATIONMELTING

DECOMPOSITIONH2O


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40 60 80 100 120 140 160 180 200 220 240 260 280 300

20

mW

^exo

temperature [oC]

DSC scan of a crystalline material one polymorphic form

MELTING

Onset = melting point (mp)

Heat of fusion (melting) = integration of peak


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40 60 80 100 120 140 160 180 200 220 240 260 280 300

20

mW

temperature [oC]

^exo

DSC scan of a crystalline material polymorphic transition

METASTABLEFORM

TRANSITION

STABLEFORM


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40 60 80 100 120 140 160 180 200 220 240 260 280 300

20

mW

^exo

temperature [o

C]DSC scan of a hydrate

MELTING

DEHYDRATION


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40 60 80 100 120 140 160 180 200 220 240 260 280 300

temperature [C]

1 mW

DEHYDRATION

GLASS TRANSITION

Midpoint = glass transition (Tg)

Polyvinylpyrrolidone (PVP) co-processed with hydroflumethiazide


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Purity of phenacetin Source: TA Instruments, Cassel RB,Purity Determination and DSC Tzero Technology


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Source: Schmitt E et al.Thermochim Acta 2001, 380 , 175 183


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Conventional linear temperature (cooling,heating) programme

Fast scan DSC very fast scan rates (also linear)

MTDSC (modulated temperature DSC) morecomplex temperature programmes, particularlyuseful in the investigation of glass transitions(amorphous materials)

HPDSC (high pressure DSC) stability of materials,oxidation processes


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Pharma applications:

Enhanced analysis of polymorphism

Detection of low level amorphous content Suppression of decomposition true melting

points

Detection of low energy transitions

Characterisation close to processing conditions

Separation of overlapping events


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This technique uses composite heating profile: determines heat capacityand separates heat flow into the reversible and non-reversiblecomponents

Benefits

Increased sensitivity for detecting weak transitions especially glasstransition

Separation of complex events into their:

heat capacity (reversible) e.g. glass transition, melting and

kinetic components (non-reversible) e.g. evaporation,crystallization, decomposition

Disadvantages

Slow data collection

Risk of sample transformation


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A technique measuring thevariation in mass of a sampleundergoing temperaturescanning in a controlled

atmosphere Thermobalance allows for

monitoring sample weight asa function of temperature

The sample hangs from thebalance inside the furnaceand the balance is thermallyisolated from the furnace

balance

sample

furnacepurge gas


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Desolvation adsorbed and bound solvents,

stoichiometry of hydrates and solvates

Decomposition chemical and thermal stability

Compatibility interactions between components


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0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320

2

mg

temperature [oC]

TGA curves of crystalline and amorphous substance


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0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 3400

^exo

20

mW

temperature [oC]

2

mg

DSC and TGA scans of lactose monohydrate


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Anhydrous/dihydrate mixture was prepared by dry blending. Heating rate was 50/min


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Thermal techniques alone are insufficient to provethe existence of polymorphs and solvates

Other complementary techniques are used e.g.

microscopy, diffraction and spectroscopy Types:

DSC-TGA

DSC-XRD DSC coupled with X-ray diffraction

TGA-MS TG system coupled with a mass spectrometer

TGA-FTIR TG system coupled with a Fourier Transform

infrared spectrometer

TGA -MS or -FTIR - evolved gas analysis (EGA)


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All substances that are transparent ,when examinedunder a microscope that has crossed polarizing filters

are either

Isotropic -Which have a single refractive index, thesedo not transmit light and they apper black

(amorphous ,supercooled glasses and non crystalline

or cubic crystal lattice substance ).

Anisotropic -Which have more than one refractiveindex and appear bright with brilliant colors

(birefringence) against the black polarized light.


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Owing to the many possible crystal habitsand their appearances at different

orientations , these methods require a well-trained optical crystallographer tocharacterize fully even simple biaxialsystems.


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Is arguably an irreplaceable tool for the analysisof pharmaceutical solids and widely-recognizedas the most powerful technique when structural

characterization and identification of crystallinephases (e.g., polymorphs, solvates) is needed. Unlike other analytical techniques with limited

potential for structure characterization and phaseidentification, X-ray diffraction provides an

unparalleled access to the intimate building ofthe crystalline motif, which makes it the mostreliable tool for crystal form identification.


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X-rays are diffracted by crystals just as visiblelight is dispersed into a color spectrum by a ruledgrating.

This is due to the fact that X-rays havewavelengths of about the same magnitude asthe distance between the atoms or molecules.

X-ray source is hot cathode tube with either amolybdenum anode or copper anode.


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sin2dn

Braggs equation assumes:

Crystal is perfect and infinite

Incident beam is perfectly parallel and monochromatic

Braggs Equation:-

Where n= any positive integer

d=interplanar distance


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X-ray

intensity(fromdetector)

c

dn

2sin c

Measurement of critical

angle, c, allowscomputation of planar

spacing, d.

Incoming X-rays diffract from crystal planes.

reflections mustbe in phase fora detectable signal

spacingbetweenplanes

d

extradistance

travelledby wave 2


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determination of bond angles and inter-atomic

distances.

study of crystallattice by diffraction angles.


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Schematic of 4-circle diffractometer; theangles between the incident ray, thedetector and the sample.


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Film may be replaced with detector

POWDER METHOD

Different cones for different reflections


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Is characterization technique for understandingthe nature and the effect of water (or solvent)activity on solids (e.g., bound/non-bound water,hygroscopicity, solvation, phase transition,

wettability, etc.). Vapor sorption kinetics measurements are used

in establishing handling and/or processingconditions for sensitive APIs, excipients and drug

products. In a similar approach, the design ofpackaging materials can benefit from themoisture vapor transmission rate (MVTR) datagenerated using this analytical technique.


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Spectroscopy displays the short-range structureof molecular solid (electronic environment ofmolecular function) and is thus complementary

to long range structural information obtainedfrom X-rays diffractometery. Various techniques used are :-

Raman (regular and micro) FTIR (transmission, reflection, micro) UVIS LiquidNMR(1H, 13C, 15N, 19F, 27Al, 29Si,31P, 51V, 59Co, 63Cu

, 77Se, 113Cd, 195Pt, two dimensional NMR) Solid state NMR (13C, 23Na, 27Al, 29Si, 31P,195Pt)


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For characterization of solid materials With respect to the structural information

solid state NMR techniques probe the

local environment around a specificnucleus.

Thus, such methods can be used for thedetermination of the local order in solidmaterials. This is particular importance foramorphous materials where othermethods quite often fail.


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=54.74

B0

In solid state NMR, we tilt the sample to themagic angle, which is 54.74 relative to B0.

And then we spin it around that angle at very high

frequency. Thus the name of this type of NMR Magic Angle Spinning.


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APPLICATIONS:

Identification of crystal forms based on their individual

chemical shifts.

Determination of phase purity.

Information about structural charecteristics in crystalforms.

Detection of solvent present in solvates and itsinteraction

with lattice.

Analysis of molecular mobility in crystal forms.


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Analytical Techniques for Characterization of Solid State

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