DOSAGE FORM DESIGN PARAMETERS

SOLID-STATE CHARACTERIZATION AND PHYSICAL BEHAVIOR

Nalini Shastri
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SPECTROSCOPY
Luminence spectroscopy Vibrational spectroscopy Solid state NMR

LUMINESCENCE SPECTROSCOPY
spontaneous emission of EMR
Hydrated Erythromycin-B hydrochloride Dehydrated Erythromycin-B hydrochloride

The excitation spectra (open circle) were obtained using an analyzing emission at wavelength of 465 nm, while the emission spectra were obtained upon excitation at 350 nm(solid square) and at 390 nm(solid circle).
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LUMINESCENCE SPECTROSCOPY

Excitation spectra of diflunisal, Form-III (solid trace) and Form-IV (dashed trace)
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VIBRATIONAL SPECTROSCOPY
IR spectroscopy
NIR Mid IR Far IR

Raman spectroscopy

VIBRATIONAL SPECTROSCOPY
Intermolecular interactions in solid materials Polymorphism Drug Excipient/container/storage vessel interactions Mapping of tablets Online reaction monitoring biopharmaceutical applications
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CHECK YOUR KNOWLEDGE

Importance of degrees of freedom in vibrational spectroscopy Harmonic oscillator selection rule Anharmonic Oscillator Model Overtone Vibrational Spectroscopy

POLYMORPHS
The vibrational bands associated with OH, NH and C=O bonds are usually strong in the IR spectrum making this an ideal technique for studying hydrogen bonding The frequency of vibration will be altered when hydrogen bonds are formed due to changes in the electronic density within the bond Amide groups are commonly found in drug molecules and the position of the NH and C=O stretching modes in the IR spectrum may be used to infer the inter- and intra-molecular hydrogen bonding pattern

POLYMORPHS
polymorphic systems - electrostatic micro-environment of the functional groups may vary between forms Differences in H bonding (inter- or intra-molecular) Steric forces within the molecule may also alter due to conformational or crystal-packing changes. frequencies of some, or all, of the vibrational modes will probably differ between solid-state forms. In addition, changes in symmetry, due to conformational or packing effects, can alter the appearance of the spectrum by causing band splitting or relative intensity changes. Band splitting may also be due to an asymmetric unit cell containing more than one molecule.
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POLYMORPHS
Burgers rules, the highest frequency OH or NH stretching band will be associated with the form least stable at absolute zero since the highest frequency will be associated with the form containing the weakest hydrogen bonding. Useful in Raman spectra also The low frequency region of the vibrational spectrum of solids, between 10 and 150 cm1, contains bands attributable to lattice vibrations (or phonons) which are extremely sensitive to structural changes in the solid state.
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HYDRATES
The strong vibrations of the OH functional group in IR for characterizing hydrates. The exact position of the bands will depend on the extent of hydrogen bonding the lower the (OH) frequency, the stronger the hydrogen bonding. More than one bond may be observed for higher hydrates giving multiple vibrational bands Water is a weak scatterer of light and so does not give a strong Raman spectrum However, the Raman spectra of hydrates will show variation due to the steric and polar influences of the water on the molecular and crystal structure.
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AMORPHOUS
amorphous phase - there is no long-range order in the material a characteristic spectral fingerprint obtained Can be used for identification and quantification
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IR SPECTROSCOPY
Sensitive to the structure, conformation and environment of organic compounds Traditionally used aid in structure elucidation Qualitative and quantitative Typically nondestructive in nature Recovery for further characterization Complimentary to other techniques TG-IR, LC-IR
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IR SPECTROSCOPY- SAMPLING
Alkali halide Mull DRIFTS ATR Photoacoustic spectroscopy (PAS) Fiber Optics IR microspectroscopy TG-IR
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IR SPECTROSCOPY- SAMPLING
Diffuse reflectance IR FT spectroscopy Sample analyzed as such/halide dilution Minimal sample preparation, Non destructive 10-400mg sample cups available Variable temp & humidity for phase transitions quantitative purposes Limitation
results are sometimes affected by the particle size problem in quantitative analysis
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IR SPECTROSCOPY- SAMPLING
Attenuated total reflectance IR radiation is passed through a crystal at an angle less than the critical angle Causes the light to undergo total internal reflection Internally reflected energy will be attenuated at those frequencies corresponding to changes in molecular vibrational states Minimal sample preparation and handling Suitable for study of polymorphs and solvatomorphs Scrupulous in the cleaning of the crystal surface between analyses in order to avoid cross contamination sampling depth range of 510 mm- poor penetration
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FTIRATR
fingerprint region of benzoic acid (solid trace) and sodium benzoate (dashed trace)

carbonyl band frequency shift from free acid =1678 cm-1 to salt =1595 cm-1

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IR - ANHYDROUS GLISENTIDE
I Polymorphism crystal packing rather than conformational differences
I cm-1 urea carbonyl S=O stretching band aromatic carbonyl 1635, 1545 1157 II cm-1 1620, 1545 1165

II

cm-1
1720 1720 broadened

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POLYMORPHISM
Unit cell contents of acetaminophen

Monoclinic

Orthorhombic

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Acetaminophen polymorphs

Hydrogen bond lengths and angles

Orthorhombic

Monoclinic

H(5)O(2) H(6)O(1) O(1)-H(5)O(2) N(1)-H(6)O(1)

1.852(26) A0 2.072(28) A0

1.772(20) A0 2.007(18) A0

170.80(2.35) A0 166.15(1.75) A0 163.52(2.19) A0 163.93(1.51) A0

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IR IDENTIFICATION & QUANTIFICATION

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FTIR-ATR FOR SOLVATOMORPHIC SYSTEMS

1068 cm-1

3522 cm-1

lactose monohydrate (solid trace) lactose anhydrate (dashed trace)

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FTIR-ATR FOR PHASE TRANSFORMATION

3522 cm-1

lactose anhydrate (dotted trace) lactose monohydrate 50% (solid trace) 23 lactose monohydrate (dashed trace)

DRUG-EXCIPIENT INTERACTION
40oC and 75% RH for 14 days

Omeprazole + SA (1:1)

SA

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IR LYOPHILIZATION STABILITY
The secondary structure of proteins is reflected in the amide-I (16001700 cm-1), amide-II (15001600 cm-1), and amide-III (12251300 cm-1) These are primarily associated with the stretching vibrations of peptide carbonyl groups a-chymotrypsin in aqueous (dashed trace) and dried solid (solid trace) state

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RAMAN SPECTROSCOPY
inelastic scattering of laser radiation by nonabsorbing medium with loss of vibrational energy by a sample Raman active when change in the polarizability during the vibration Symmetric modes tend to be Raman-active

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RAMAN SPECTROSCOPY
IR and Raman are complementary techniques Same bands observed in the IR absorption spectrum will also be observed in the Raman spectrum. Fundamentally different nature of the selection rules associated with the Raman effect leads to the observation of significant differences in peak intensity between the two methods. Symmetric vibrations and nonpolar groups yield the most intense Raman scattering bands (C=S, S=S) Antisymmetric vibrations and polar groups (C=O,N-H) yield the most intense IR absorption bands.

DR-IR

FT-Raman

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RAMAN VS FT-IR

CHLORAMPHENICOL PALMITATE

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RAMAN- POLYMORPHISM
C=C stretching CN stretching NH deformation Variation in lattice structure 1624 1250 1600 50-150 Different packing arrangements Altered chemical configuration in substituent groups of molecule

I - carbamzepine

III - carbamzepine
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RAMAN- SOLVATES
1 and 2 good correlation indicating that the structure of the solvate is similar to that of the parent molecule The lattice vibration modes of 1 shifted to lower frequency Due to expansion of the griseofulvin lattice to accommodate the CHCl3 molecules The expansion reduces interactions between drug molecules - decreasing the frequency of the lattice vibrations No correlation between 1 and 3 different structures

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RAMAN- MIXING EFFICIENCY

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RAMAN - STABILITY

FT-Raman spectra of a theophylline tablet, showing the effect of storage at 75% RH on the solid-state form of the drug. Conversion into the monohydrate form 32 can be seen from the increase in intensity of the band at 1685 cm1

RAMAN IDENTIFICATION IN TABLETS

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RAMAN CONTERFEIT TABLETS

digoxin tablet

Pure digoxin

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NIR SPECTROSCOPY
NIR correspond to harmonics and overtones of the fundamental frequencies detected in IR or Raman NIR spectrum more difficult to interpret spectrum region (4000 to 13,350 cm-1)

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NIR SPECTROSCOPY
Greatest utility - functional groups that contain unique hydrogen atoms Characteristic -OH band, usually observed around 5170 cm-1. Studies of water in solids Determination of hydrate species in an anhydrous matrix

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NIR BULK WATER

37 NIR absorption spectrum of bulk water

NIR IDENTIFICATION & QUANTIFICATION

1610 nm results from a N-H moiety being strongly hydrogen bonded in form II of SMX

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NIR SOLVATES

NIR spectra for loracarbef 2-propanolate samples desolvated to various isopropyl alcohol concentrations during drying to loracarbef anhydrate
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NIR IDENTIFICATION
THROUGH BLISTER PACKED TABLETS

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NIR-PROCESSING

1680 1180

NIR spectra of coated solid dosage tablets. Tablets were coated for four different times: 0, 20, 40, and 44 minutes

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FAR - IR
Far-IR region considered an extension of mid-IR region Far-IR region 400 to 10 cm-1 Investigate fundamental vibrational modes of heavy atoms like metalligand bonds Study intermolecular vibrations of crystalline materials, polymorphism The motion of molecules relative to one another gives rise to lattice modes referred to as external modes. These low-frequency modes are very sensitive to changes in conformation or structure of a molecule (usually in the range of 200 to 10 cm-1)
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FAR - IR
Not popular Require nontraditional optical windows, such as PE/PP Alkali halide windows do not transmit in this region spectral quality also is compromised due to the existence of relatively poor sources and insensitive detectors
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SOLID STATE NMR

probes atomic environments based on the different resonance frequencies exhibited by nuclei in a strong magnetic field commonly used for structure elucidation characterizing the crystal forms Not for routine analysis Sensitive technique, Minimal sample preparation Non invasive, non destructive, Qualitative or quantitative Provide structural data - identity of solvents bound in a crystal
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SOLID STATE NMR

1H NMR spectrum - peaks that are usually too broad to provide useful chemical shift information

13C,31P, 15N, 25Mg, and 23Na

SSNMR spectrum of these nuclei, the samples spun at high speeds at an angle of 54.7o with respect to the static magnetic field for highresolution Cross polarization-magnetization of abundant nuclei such as 1H to dilute nuclei such as 13C
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SSNMR-APPLICATIONS

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SOLID STATE NMR

The crystallography of compounds related by polymorphism is such that nuclei in the two structures are magnetically nonequivalent Resonances of these nuclei are not equivalent. SS NMR spectra used to deduce the nature of polymorphic variations, especially when the polymorphism is conformational in nature

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13C

CPMAS spectra

five polymorphs of sulfathiazole

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13CPMAS

SOLID-STATE & SOLUTION SPECTRA

tedisamil dihydrochloride

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Solid-state 13C-NMR spectra

polymorphism associated with different conformations on side chain
Form A

Form B

fosinopril sodium
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SSNMR PRESENCE OF EXCIPIENTS

crystalline prednisolone, 2-ms contact time

7.7% (w/w) dispersion of prednisolone in Captisol, contact times of 2 ms

7.7% (w/w) dispersion of prednisolone in Captisol, contact times of 15 ms

13C

CPMAS-SSNMR, MAS rate rate 5.0 kHz

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estradiol

MeOH

EtOH

IPA

Acetone
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SSNMR-QUANTIFICATION

13C CPMAS NMR spectrum of neotame polymorphic Form A +Form G (1:1)

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13C

CPMAS-SSNMR

paracetamol monoclinic

melt crystallised paracetamol

difference spectrum
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13C

CPMAS-PROCESSING

piroxicam polymorphs. (A)(E) show A) Form-I, B) Form-II, C) Form-I cryoground for 60 minutes, D) Form-II cryoground for 60 minutes, E) piroxicam monohydrate

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INTEGRATED CHARACTERIZATION STRATEGY

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SEM and SSNMR

Crystalline lactose

Spray dried lactose

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TG-IR FOR SOLVATOMORPHS

i) absorption bands at 2972 and 1066 cm-1 an organic species containing aliphatic C-H and C-C-O moieties from evolved gas ii) spectral library matching of IR revealed ethanol solvate 58

MICROSCOPY-FTIR
Indomethacin

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HSM-RAMAN
(

R,S)-proxyphylline polymorphs and super cooled melt

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INTEGRATED TECHNIQUES
DL Proline Are they crystalline or amorphous is the DL-proline a racemic compound (a new crystal form containing both D and L enantiomers of proline) or a racemic conglomerate (a physical mixture of D and L crystal forms)

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DSC-XRD

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SSNMR

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