IR RAJ

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INFRARED SPECTROSCOPY: INTERPRETATION AND APPLICATION T.RAJKUMAR ASSISTANT PROFESSOR, DEPT OF PHARMACEUTICAL CHEMISTRY KOTTAM INSTITUTE OF PHARMACY IR AS A BENCH TOOL

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IR AS A BENCH TOOL Infra red spectrum is an important record, which gives sufficient information about the structure of a compound. Contrary to ultraviolet spectrum which comprises of relatively few peaks, this technique provides a spectrum containing a large number of absorption bands from which a wealth of information can be derived about the structure of an organic compound the absorption of I.R. radiations causes the various bonds in a molecule to stretch and bend with respect to one another.

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3 A PORTION OF THE ‘ELECTROMAGNETIC SPECTRUM SHOWING THE RELATIONSHIP OF THE VIBRATIONAL INFRARED TO OTHER TYPES OF RADIATION

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Principle of Infra red spectroscopy Infra red spectra is considered as vibrational-rotational spectra. All the bonds in a molecule are not capable of absorbing Infra red energy but only those bonds which are accompanied by change in dipole moment will absorb in the Infra red region. General theoretical aspects When the frequency of infrared radiations matches the natural vibrational frequencies of a bond with a dipole moment the radiation is absorbed increasing the amplitude of the vibrational motions of the covalent bonds. Infrared radiations are absorbed and connected by organic molecules with polar covalent bonds and dipole moments into energy of molecular rotation and molecular vibrations.

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V 1 V 0 PRINCIPLE OF IR

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A B A t o B S t r e t c h i n g v i b r a t i o n ( A ) ( B ) B e n d i n g v i b r a t i o n s Stretching: requires more energy than bonding.

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1. Scissoring: In this type, two atoms approach each other . Rocking: In this type the movement of the atoms takes place in the same direction.

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Wagging: Two atoms move 'up and down' with respect to the central atom. 4.Twisting: In this type, one of the atoms moves up the plane while the other moves down the plane with respect to the central atoms.

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VIBRATIONS IN IR

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Symmetrical stretching Asymmetrical stretching Scissoring Rocking Wagging Twisting

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13 FACTORS INFLUENCING VIBRATIONAL FREQUENCIES A) ELECTRONIC EFFECTS i) INDUCTIVE ii) RESONANCE/CONJUGATION B) EFFECT OF RING SIZE i) FOR ENDOCYCLIC DOUBLE BOND ii) FOR EXOCYCLIC DOUBLE BOND  -SUBSTITUENT EFFECT/FIELD EFFECT HYDROGEN BONDING EFFECT EFFECT OF HYBRIDISATION EFFECT OF VIBRATIONAL COUPLING G) EFFECT OF STRAIN

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Instrumentation

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Radiation source Nernst glower: composed of rareearthoxides of zirconia,yttriaand thoria. Globar source: is a rod of sintered silicon carbide Mercury arc: Monochromator Prism type Grating type

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Sample preparation Solids Solids run in solution Solid films Mull technique Pressed pellet technique Liquids Put into cells made up of Nacl,KBr or ThBr Gases

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Detertors Bolometers Thermo couple Thermisters Photoconductivity cell Semiconductor detector

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The IR spectrum A plot of transmittance on Y-axis V.S. frequency on X axis transmittance. (Apsorption intensity) transmittance (T) the ratio of the radiant power transmitted by a sample to the radiant power incident on sample. Absorbance (A) – A logarithm to base to the reciprocal of transmittance. A = log 10 (1/T)

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Frequency: The X axis is represented by two scales. 1.Wavelength – (2.5  to 25  ) 2.Wave number (4000 cm -1 to 650 bottom cm -1 ) Wave number are expressed in units of reciprocal centimeters i.e.). The reciprocal of wave length expressed in centimeters. Spectrum peak characteristics: High frequency region (functional group region) –1500 t0 1300 cm -1 Characteristic stretching frequencies of such group as = C–H, OH, NH, C=O, C-O, C = N C = C, C=C Finger print region = 1300 to 900 cm -1

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C X N O S H H H IMINO CARBONYL THIOCARBONYL AMINO HYDROXY ETHER SULFYHDRAL SULFIDE STRETCH AND BEND NOT DIAGNOSTIC (FINGER PRINT REGION) STRETCH – DIAGNOSTIC FUNCTIONAL GROUP REGION STRETCH- DIAGNOSTIC(FGR) BEND- NOT DIAGNOSTIC(FPR) STRETCH – DIAGNOSTIC (FGR) STRETCH- DIAGNOSTIC(FGR) INFORMATION FROM IR A. FUNCTIONAL GROUP IDENTIFICATION

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WAVE NO. SCALE 4000 cm -1 1300 cm -1 FUNTIONAL GROUP REGION 2500 cm -1 3700 cm -1 2800 cm -1 3300 cm -1 SBS N-H and O-H C-H 2500 cm -1 4000 cm -1 TBS 2500 cm -1 1950 cm -1 ALKENYL NITRILE DIAZONIUM SALT DBS 1950 cm -1 1300 cm -1 CARBONYL IMINE ALKYL 1300 cm -1 910 cm -1 FPR FINGER PRINT REGION BACK BONE STRETCH AND BEND C-C C-N C-O CHARECTERISTIC FOR A MOLECULE AR 910 cm -1 650 cm -1 AROMATIC REGION OUT OF PLANE BENDING (Ar/Het. Ar) C-H RING BENDING (Ar/Het. Ar) C-C C-X 4000 cm -1 400 cm -1 INFORMATION FROM IR C. MID IR AND GROUP FREQUENCIES

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A QUICK DIAGNOSTIC ASSESSMENT OF AN INFRARED SPECTRUM Diagnostic Step 1 : Overall Spectrum Appearance Diagnostic Step 2 : Testing for Organics and Hydrocarbons – Absorptions in the Region 3200–2700 cm -1 Diagnostic Step 3 : Testing for Hydroxy or Amino Groups – Absorptions in the Region 3650–3250 cm -1 Diagnostic Step 4 : Testing for Carbonyl Compounds – Absorptions in the Region 1850–1650 cm -1 Diagnostic Step 5 : Testing for Unsaturation – Weak to Moderate Absorption in the Region 1670–1620 cm -1 Diagnostic Step 6 : Testing for Aromatics – Well-defined Absorptions in the Region 1615–1495 cm -1 Diagnostic Step 7 : Testing for Multiple Bonding (Often with a Bond Order of 2 or Higher) – Absorption in the Region 2300–1990 cm -1 􀀀

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Principal frequently bonds (from left to right in spectrum) OH + 3600 cm ‑1 (Acids alcohols) N-H + 3300 – 3500 cm -1 (1-2 peaks, 2-1, 3-0) NO 2 + 1450 – 1650 cm -1 (2 absorptions) C = N + 2250 cm -1 (Nitrile) C = C + 2150 cm -1 (Acetylene) C=O + 1685 – 1725 cm -1 (Carboxyl) C=C + 1650 cm -1 (Alkene 2 Absorption) C=C + 1450 – 1600 cm -1 (Aromatic 4 Absorption) CH 2 + 1450 cm -1 CH 3 + 1375 cm ‑1 C–O + 900 – 1100 cm -1 (Alcohol acid ester ether anhydride)

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Uses: IR can be used to distinguish one compound from another. Absorption of IR energy by organic compounds will occur in a manner characteristic of the types of bonds and atoms in the functional groups present in the compound,thus infrared spectrum gives structural information about a molecule. Finger print region can be subdivided into three regions as follows: 1500 – 1350 cm _1 1350 – 1000 cm -1 and Below 1000 cm -1

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1500 1400 1300 1200 1100 1000 900 800 700 C-O –CH = CH – (Trans) Gem dimethyl O–H Monosubsituted benzene Ortho disubstituted benzene disustituted benzene disubstituted 6.25 10 14.26  Wavelength in Microns Fig. Characteristic absorptions in the Finger print region.

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Type of vibration Frequency (cm -1 ) Intensity C–H Alkanes (stretch) 3000-2850 s –CH 3 (bend) 1450 and 1375 m –CH 2 (bend) 1465 m Alkenes (stretch) 1300-3000 m (out of plane bend) 1000-650 s Aromatics (stretch) 3150-3050 s (out of plane bend) 900-690 s Alkyne (stretch) ca. 3300 s Aldehyde 2900-2800 w 2800-2700 w C–C Alkane Not interpretatively useful C=C Alkene 1680-1600 m-w Aromatic 1600 and 1475 m-w C  C Alkyne 2250-2100 m-w C=C Aldehyde 1740-1720 s Ketone 1725-1705 s Carboxylic acid 1725-1700 s Ester 1750-1730 s Amide 1680-1630 s Anhydride 1810 and 1760 s Acid chloride 1800 s C–O Alcohols, ethers, esters, carboxylic acids, anhydrides 1300-1000 s O–H Alcohols, phenols Free 3650-3600 m H-bonded 3400-3200 m Carboxylic acids 3400-2400 m N–H Primary and secondary amines and amides (stretch) 3500-3100 m (bend) 1640-1550 m-s C–N Amines 1350-1000 m-s C=N Imines and oximes 1690-1640 w-s C  N Nitriles 2260-2240 m X=C=Y Allenes, ketenes, isocyanates, isothiocyanates 2270-1940 m-s N=O Nitro (R-NO 2 ) 1550 and 1350 s S–H Mercaptans 2550 w S=O Sulfoxides 1050 s Sulfones, sulfonyl chlorides, sulfonamides 1375-1300 and 1350-1400 s C-X Fluoride 1400-1000 s Chloride 785-540 s Bromide, iodide <667 s

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Analyzing the spectrum Steps: Step 1 Check the presence of the carbonyl group (C=O) in the range 1660-1820 cm -1 . If the carbonyl group is present one of the following types of compounds is present. Carboxylic acid Ester Amide Anydride Aldehyde Ketone If the molecule is conjugated (alternating double and single bond) the strong (C=O) absorption will be shifted to the right by ~ 30 cm -1 . Step 2 Check for the presence of saturated Alkane compounds containing methyl and methylene groups produce generally simple IR spectra. CH – sp 3 absorption is a stretch in range 3000 – 2840 cm -1 . Note: It is important to remember that the alkane (sp 3 ) stretch occurs on right side of 3000 cm ‑1 mark in the IR spectrum and that alkene and aromatic sp 2 stretches occurs on left side of the 3000 cm ‑1 mark. CH 3 Methyl groups have characteristic bending at approximately 1375 cm -1 . CH 2 Methylene groups have characteristic bending at approximately 1465 cm ‑1 .

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Step 3 Check for presence of unsaturated = C–H (sp 2 ) structure.  C-H (sp 2 ) absorption is a stretch in the range 3000 – 3100 cm -1 i.e. left side of the 3000 cm -1 mark on X-axes scale. Check or determine whether the = C-H bond is alkene, aromatic or both. Alkene = C–H bond Look for C=C stretch at 1600-1650 cm -1 usually an unequal pair of absorptions. Out of plane (OPD) bending at 650-1000 cm -1 Step 4 – (Con't) Aromatic = C-H band Look for C=C stretch at 1475 – 1600 cm -1 usually 2 pairs. Overtone / concentration bands appear between 1667 & 2000 cm -1 . Out of plane bending 650-1000 cm -1 Note: The substitution pattern informs in the overtone area and OOP area is duplicate. Use both tables to confirm substitution pattern. Step 5 Carbonyl compounds (Carboxylic acid) Strong bond of C=O group appears in range 1700-1725 cm -1 . Very broad absorption band of OH group in the range 2400-3400 cm -1 This broad band will usually obscure the alkane C-H stretch bands from 2849-3000 cm -1 . Medium intensity C–O stretch as in (C-OH) ranges 1210- to 1320 cm -1 .

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Step 6 Carbonyl compounds (esters) C=O stretch appears in range 1730-1750 cm -1 . Check for two or more C–O stretch bands one stronger and broader than the other in the range 1100-1300 cm -1 . e.g. – C 8 H 8 O 2 Step 7 Carbonyl compounds (Anhydrides) 2 C=O stretch bands 1740-1755 cm -1 & 1800 – 1830 cm -1 . Conjugation will move these bands to lower frequency. Multiple C–O stretch bands in the range 900-1300 cm -1 . e.g. – Propanoic anhydride

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Step 8 Carbony compounds (Amides) C=O stretch at approximately 1640-1700 cm -1 . N–H stretch (Medium Absorption) near 3500 cm -1 . Primary Amino (-NH 2 ) 2 peaks & 3180-3350. Secondary Amino (-NH) 1 peak (3300). N-H scissoring - 1550-1670 cm -1 N-H bend - 800 cm -1 Benzamide C 7 H 7 NO Step 9 Carboxyl compound (Aldehydes) C=O stretch – 1720 – 1740 cm -1 2 weak aldehyde C–H stretch absorptions near 2850 & 2750 cm -1 .] e.g. Nonanol

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Step 10 Carbonyl compound (Ketones) C=O stretch occurs at approximately 1705-1725 cm -1 Ketones are confirmed when the other five compound types containing a carbonyl group have been eliminated. Ketone IR spectra can sometimes be confused with ester spectra because of an absorption in the 1100-1300 cm -1 range similar to the location of the C–O stretch in esters usually however, the ester will have 2 or more of the C–O stretch absorptions. The ketones structure produces a medium to strong, absorption in the 1100-1300 cm -1 range due to coupled stretching and bending absorption. e.g. Propargyl alcohol (2-propy-1-ol) C 3 H 4 O Benzonitrile

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Alcohols & phenols Broad absorption near 3600 – 3300 cm -1 confirm presence of C–O (C–OH) near 1000 – 1300 cm -1 . e.g. – C 10 H­ 9­ O 2 Naphthol in CCl 4 solution 2 Naphthol in KBr Disc. OH – broad (distinct) = C–H stretch Aromatic ring absorption –C=C–C–O OH C–H (Aliphatic) CH 3 CH 2 The stronger the bond the greater will be the amount of energy to stretch it. C  C C=C C–C 2200 cm -1 1650 cm -1 1200 cm -1 sp sp 2 sp 3

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36 TABLE 2-7 The C-O and O-H Stretching Vibration in Alcohols and Phenols Compound C-O Stretch, cm -1 (  ) O-H Stretch, cm -1 ( )  Phenols D 1220 (8.20) I 3610.(2.77) E N 3  Alcohols (saturated) C 1150 (8.70) C 3620 (2.76) R R 2 Alcohols (saturated) E 1100 (9.09) E 3630 (2.755) A A 1 Alcohols (saturated) S 1050 (9.52) S 3640 (2.75) E E Unsaturation on adjacent carbons or a cyclic structure lowers the frequency of C-O absorption

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 1: OVERALL SPECTRUM APPEARANCE <5 absorbtion bands/peaks: Low molecular wt organic/inorganic: Crystalline with high mp- Inorganic Amorphous with low mp- Organic Mobile, volatile, liquid- Organic Broad bands: Hydrogen bond Organic: hydroxy and amino containing Inorganic: hydrates No. of bands less/more Nature of band simple/complex narrow/broad

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 2: TESTING FOR ORGANICS AND HYDROCARBONS – ABSORPTIONS IN THE REGION 3200–2700 cm -1 3000 3200 2700 >3000cm-1 unsaturated or aromatic [isolated peak at 3010 or 3040 cm-1: olefinic] <3000cm-1 aliphatic [additional peak at 1470 and 720 cm-1: long linear aliphatic chain] 1470 720

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 3: TESTING FOR HYDROXY OR AMINO GROUPS – ABSORPTIONS IN THE REGION 3650–3250 cm -1 3650 3250 Broad: Hydrogen bounded Relatively sharp: Non-hydrogen bounded or sterically hindered- Alcoholic or Phenolic Broad, overlapping –C-H streching Vibration- Carboxylic

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 3: TESTING FOR HYDROXY OR AMINO GROUPS – ABSORPTIONS IN THE REGION 3650–3250 cm -1 3650 3250 Sharp and split- Primary amino group Often close to –C-H streching region Sharp and unsplit- Secondary amino group Often close to –C-H streching region Acetylinic C-H strech Acetylinic triple bond strech 3300 2200

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 4: TESTING FOR CARBONYL COMPOUNDS – ABSORPTIONS IN THE REGION 1850–1650 cm -1 Simple carbonyl: Ketone, aldehyde, carboxylic acid Or ester 1750-1700 Amide or lactum Reactive carbonyl: Halogenated carbonyl, Anhydride Strained ring lactones Corbonyl group conjugated With a double bond or aromatic ring Imino and Azo 1850 1650 1650 1550

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 5: TESTING FOR UNSATURATION – WEAK TO MODERATE ABSORPTION IN THE REGION 1670–1620 cm -1 3040 3010 Unsaturated -C-H stretch 1000 880 -C-H bend 1670 1620 Narrow, weak to Moderate band -C=C- stretch

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 6: TESTING FOR AROMATICS – WELL-DEFINED ABSORPTIONS IN THE REGION 1615–1495 cm -1 Weak to moderate -C-H stretch Out of plane bend 3150 3000 1225 950 1615 1495 In plane bend Weak to moderate Single or split -C=C-C- stretch

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WAVE NO. SCALE 3700 cm -1 700 cm -1 DIAGNOSTIC STEP 7: TESTING FOR MULTIPLE BONDING (OFTEN WITH A BOND ORDER OF 2 OR HIGHER) – ABSORPTION IN THE REGION 2300–1990 cm -1 3320 3310 Acetylinic -C-H stretch Acetylinic -C-C stretch 2300 1990

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FT-IR : INSTRUMENTATION Michelsion Interferometer Replaces dispersive devices Interferogram Data of radiation intensity of combined beam as a function of position of movable mirror ( as a function of time) Fourier transformation Data acquired in time domain is converted in to frequency domain, as spectra. Reflectance spectroscopy Modern FTIR works on principle of reflectance Michelsion Interferometer Transmittance Spectroscopy Reflectance Spectroscopy

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TRANSMITTANCE SPECTROSCOPY REFLECTANCE SPECTROSCOPY SAMPLE PREPARATION TIME CONSUMING TIME SAVING STRONGLY ABSORBING SAMPLES NOT A PREFFERED METHOD PREFFERED METHOD BIOLOGICAL SAMPLES NOT A PREFFERED METHOD CONVINIENTLY STUDIED IN THEIR NATIVE ENVIRONMENT REAL TIME ANALYSIS NOT POSSIBLE POSSIBLE REFLACTANCE VS TRANSMITTANCE SPECTROSCOPY

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FTIR- REFLECTANCE SPECTROSCOPY SPECULAR REFLECTANCE: Reflection is from sample with smooth surface Sample must be reflective or on reflective surface Information provided is from thin layer DIFFUSE REFLECTANCE Reflection is from samples with rough surface Solid and powders, diluted in IR transparent matrix if needed Information provided is from the bulk matrix ATTENUATED TOTAL REFLECTANCE Reflection is from surface thick layer of the sample IR beam reflects from interface via Total Internal Reflectance Sample must be in optical contact with ATR Crystal Information provided is from the surface

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ATTENUATED TOTAL REFLECTANCE –FTIR (ATR-FTIR) Single Bounce Multiple Bounce (HATR) Sample is placed in optical contact against ATR Crystal, which is composed of material with high index of refraction (ZnSe). Angle of Incidence of IR beam should be greater than Critical angle( θ c ), which is function of refractive indices of ATR Crystal (n 1 ) and sample(n 2 ) θ c = sin -1 (n 2 /n 1 ) Penetration depth (d p )of evanescent wave determines the quality of ATR spectra, which is function of critical angle ( θ c ) and wavelength of incident radiation ( λ ). d p = λ /2 π (n 1 2 sin 2 θ - n 2 2 ) 1/2 Single bounce ATR is sufficient for qualitative and quantitative analysis major components and for minor component analysis multiple bounce ATR is required, Which actually increases effective path length (EPL)

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ATTENUATED TOTAL REFLECTANCE CRYSTALS

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ATR-FTIR APPLICATION Characterize structure and the properties of biological systems such as stratum corneum. Study drug release from semisolid formulations non-invasively. Investigate drug penetration into appropriate acceptor system artificial and biological Membranes. Measure drug diffusion from relevant pharmaceutical system such as polymer, film etc . Characterize interaction between drugs and synthetic, semisynthetic and native macromolecules.

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DRUG RELEASE FROM SEMISOLID FORMULATIONS Drug release from suspension is a stepwise process involving the dissolution of the solid drug particles in the liquid phase of the vehicle, characterized by the dissolution coefficient , and the diffusion of the dissolved drug through the heterogeneous vehicle, described by an effective diffusion coefficient . Two ATR experiments independent from each other is required. Inverted Donor – Acceptor arrangement was utilized. B.D. Hanh, R. Neubert, S. Wartewig, Investigations of drug release from suspensions using FTIR-ATR technique: Part I. Determination of effective diffusion coefficient of drugs, Int. J. Pharm. 204 (2000) 145– 150. B.D. Hanh, R. Neubert, S. Wartewig, Investigations of drug release from suspensions using FTIR-ATR technique: Part II. Determination of effective dissolution coefficient of drugs, Int. J. Pharm. 204 (2000) 151– 158.

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DRUG PENETRATION INTO APPROPRIATE ACCEPTOR SYSTEM ARTIFICIAL AND BIOLOGICAL MEMBRANES FTIR-ATR is now a well-established technique employed to monitor the penetration of drugs into membranes and the permeation of drugs across membranes as well as to determine diffusion coefficients of the diffusants In the simplest case of such experiments, an appropriate artificial or natural membrane acting as acceptor is sandwiched between an impermeable ATR crystal and a reservoir of penetrant, the donor Disadvantages Difficult to ensure optimal contact with ATR Crystal Permeation of vehicle alters biophysical properties of membrane which may affect membrane IR band absorbtion These two causes less defined acceptor in the mathematical model

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DRUG PENETRATION INTO APPROPRIATE ACCEPTOR SYSTEM ARTIFICIAL AND BIOLOGICAL MEMBRANES (FRANZ TYPE CELL) Experimental set-up with a well-defined acceptor Can be achieved using Franz-type diffusion cell. Appropriate liquid as acceptor ensures the contact of the system with the ATR crystal It is also advantageous that the calibration of the IR spectra of the liquid/drug solution can be performed in a separate experiment. Marcus Hartmann, Bui Duc Hanh, Helmut Podhaisky, Jo¨rg Wensch, Jerzy Bodzenta, Siegfried Wartewig and Reinhard H. H. Neubert, A new FTIR-ATR cell for drug diffusion studies, Analyst, 2004, 129, 902–905.

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DRUG DIFFUSION FROM RELEVANT PHARMACEUTICAL SYSTEM (ATR-FTIR SPECTROSCOPIC IMAGING) IR imaging is performed using Focal-Plane Arrays (FPA) as multichannel detectors, available in 64x64 or 128x128 pixels format. Thousands of spatially encoded interferograms are collected simultaneously from analytes distributed within the sample and are subsequently transformed to the same number of spectra. Combination of spectral analysis, chemometric analysis, and digital image analysis provides real time images.

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DRUG DIFFUSION FROM RELEVANT PHARMACEUTICAL SYSTEM (ATR-FTIR SPECTROSCOPIC IMAGING) Macro ATR-IR images of PEG/sodium benzoate showing distribution of sodium benzoate (top row) and PEG (bottom row) as a function of time. S.G. Kazarian, K.L.A. Chan, “Chemical photography” of drug release, Macromolecules 36 (2003) 9866–9872.

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Near Infrared Spectroscopy in Pharmaceutical Manufacturing: An Introduction Herschel discovered the near-infrared (NIR) (780–2500 nm) The pharmaceutical industry has used Near Infrared Spectroscopy (NIRS) in laboratory based applications for several decades primarily to inspect incoming raw materials and testing of finished product, and more recently for on-line and in-line measurements during production. NIRS can be used to monitor moisture and solvents during drying, powder blend uniformity, particle size, coating thickness, as well as other properties. The information obtained can be used to determine end-points of several unit operations like blending, drying and coating. NIRS is non-invasive, fast and provides real-time data for improved process understanding and control.

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The FDA has recognized the need for the pharmaceutical industry to implement real time analysis and control in various stages of manufacturing of pharmaceutical products. In a new initiative, “PAT-A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance” , the FDA has outlined the direction that it would like the manufacturing side of the pharmaceutical industry to move towards. This new guidance encourages the use of modern process analytical technologies (PATs) in pharmaceutical production and quality control which will help move the industry away from empirical, and towards science based standards for manufacturing control. Control Development, Inc. has developed and is developing on-line and in-line NIR based instrumentation for several manufacturing unit operations, such as: Blending • Drying • Coating (Pan coaters and Wurster ) • Wet and dry granulation • Content Uniformity Analysis for Tablets • Crystallization