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When are bioavailability-bioequivalence studies necessary?
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DRUG IDENTIFICATION USING THE MAJOR 2ND DERIVATIVE NEAR-INFRARED PEAKS R. D. Jee P. R. Khan and A. C. Moffat &&%fo; PharmaceuticalAnalysis, The School of Pharmacy,University of London. Brunswick Square. London, WClN 1AX. UK
FREE ENERGY PREDICTION OF THE HOST-GUEST COMPLEXATION OF VARIOUS CYCLODEXTRINS
TraditIonally mid-infrared spectra have Table 1. been used for identification of pure drug Peaks Number of pairs substances by simple comparison wth 0 34253 authentic spectra or lists of malor peak 1 9596 positions(1). Near-infrared reflectance 2 1179 spectra are also rich in chemical information 3 103 and much simpler to measure. However, 4 14 identifications using NIR have in the past 5 5 involved relatively complex chemometric 6 0 methods such as Mahalonobis distances, princtpal component analysis and correlation in wavelength space. We have investigated the
application of peak positions to second derivative NIR spectra. The reflectance spectra of some 300 powdered compounds were recorded over the wavelength range 1100to 2500 nm using a Foss NIRSystems 6500 spectrophotometer fitted with a Rapid Content Analyser. A data base of the positions of the major negative peaks in the second derivative (log l/R) spectra was set up and validated by comparing all the possible different pairs of compounds (approx. 45 000 pairs). Even without making any use of the relative peak intensity information. it was possible to differentiate between all compounds with just 6 peaks. Table 1 shows the number of different pairs of compounds giving 0, 1 etc peak matches. Increasing the number of peaks. and/or calculating a score which takes the relative peak intensities into account, improved the discrimination further. This simple method was superior to the commonly used correlation in wavelength space and demonstrates that NIR is as good a!
mid-IR for identifications. 1. Clarke’s Isolation and Identification of Drugs, 2nd edition, 1986 Pharmaceutical Press UK.
C.T. Klein, D. Polheim, B.
and P. Wolschann Institut fir Theoretische Chemie und Strahlenchemie, Wiihringer St&e 17, A-1090 Wien Institut filr PharmazeutischeTechnologie, Althanstr. 14, A-1090 Wien
Cyclodextrin inclusion complexes play an important role in pharmaceutical technology, because the inclusion into the hosts cavity influences the different molecular properties like solubility, bioavailibility, reactivity or spectra of the guest drastically. The physicochemicalbehaviour of such associationcomplexes are therefore of high interest in respect to the association constant and the corresponding thermodynamic parameters. The knowledge of the complexation afinity of the cyclodextrins and guest molecules is necessary for the selection of proper cyclodextrins and suitable complexation conditions for specific applications. A procedure for the theoretical estimationof free energies of host-guestcomplexation, based on a multivariant regression analysis was therefore developed. For the prediction model around 80 compoundswere considered.As descriptors of the various molecular properties were used e.g. the molecular surface, the ovality, which is connected to the molecular shape and the partition coefficients. Other descriptors are e.g. the electrotopological index, based on the electronegativity of the atoms and the number of the heteroatoms.The model was evaluated by the program TSAR from the Oxford Molecular Simulation Package. From several developed models the best fitting one was further refined and shows a high predictive power and is statistically significant. Individual models are calculated for c(-, p and y-cyclodcxtrins. The models are tested for a number of guest molecules, for which the association constants were estimated spectrophotometrically.A different influence of the various parameters used in the model is observed for the three cyclodextrins,caused by the different mobility of the cyclodextrin ring system and the fact that an
association of a guest molecule into the CD’s cavity makes the complex geometries more rigid.
68 pH-METRIC METHOD AS A POWERFUL TOOL TO INVESTIGATE DRUG MOLECULAR PHYSICOCHEMICAL DESCRIPTORS G. Care@‘, R. Fruttero’, A. Pagliara”, P.-A. Carrupt”, A. Gasco’ and B Testa” *Dipartimento di Scicnza e Tecnologia de1 Farmaco, Via P. Giuria, 9, 10125 Torino, Italy “Institut de Chimie Th&peutique, BEP, Universiti de Lausanne, CH-1015 Lausanne Ionisation and lipophilicity are molecular descriptors that have a marked influence on the biodistribution of drugs. A number of experimental techniquesare nowadays available to measure ionization constantsand distributioncoefficients(log D). The potentiometrictitrator GlpKa (Sirius Analytical Instruments Ltd, Forrest Row, East Sussex, UK) is a modem instrumentable to measure ionisation umstauts in water
@Ka), in the presence of a \Me.r-miscible solvent @sKa) and also in biphasic systems (poKa). Thus the iouisaticm profile of a given solute is calculated from its pKa (or psKa) whereas its distribution profile @H vs log D) is obtained from the extent of the diffcrena between pKa and p&a. The GlpKa instrument is fuI1~ automated and the graphical/mathematical approach implemented m the software. allows pKa, psti, poKa to be obtaineddirectly from the Bjemun differenceplot through an iterative least squaresprocedure. Optimized protocolsfor the pH-metric techniquewere recentlyusedby someof us to characterizethe acid-base behavior of zwitterionic drugs, to investigate the changes in
isotropic hpophilicity associated with the oxidation state of the sulfiu atom of drugs and to ration&e the lipophilici@ of a series of (p-meth~lbenql)alk~~-amines in liposomal anisotropic system.
WHEN ARE EIOAVAILABILITY-BIOEQUIVALENCE STUDIES NECESSARY7 H.H. BioChem. Karlsruhe.Germany The assessment of efficacyand safety as WBIIas the documentationof an appropriate (blo)pharmaceuticalqwllty are esa&ial mqulrementa in the drug regiatratll process. For solid oral dosage forms with new molecular entitles (NME) the charactwlsatlon of both, pharmacoklnelicpropertiesof the drug substance and bioavailablllty(BA) of Ihe drug product are mandatorynot only after single and multipledose administrationsbut also in special aihfations(e.g. fetiated. renal failure, hepatic insufliciency).In contrast. for generic veraions an Abtxwiatecl New Drug Application (ANDA) procedure is accepted by regulatoryagencies for the assessment of efficacy and safety. Basls for such an ANDA is the investigationof bioequlvalenca (BE) of the generic formulation in comparison with an appropriate reference (innovator) product with Yull” clinical documentation. However, the regulatoryrequirementa concerningthe necessity of BRIBE studisa differ from region to region. While In some countries such invest&&na are requested for drug regis!raUon of all products, particularlygenerics. in others there requiratnentsare dafined on a case by case basis. In this context pharrn8cuJynarnlcand pharmacoklnetlc aspects are considered for dedsion rnakkrg. e.g. a narrow thsmpeullc index or non-linear pharmacoklnetlcs. h&oover, also the physiwchemical drug substance prop&lies and blophwmaceuficalaspect of Ihe dosage f&n rue relevant. The fundamental question is how far a formulationmay affect the rate and extent of absorptirx~of the active dNg ingredient from the product into the body. Only in cases where the (in viva) release of the drug from the pharmaceuticalform is the rate limiting step BA willdepend on the dosage form jwopertleaat all. In contrast,A the permeation process through the gut wall is rate limiting for drug absorption rm aignlflcent eff8ct of the gale&al form on BA may be expected. Consequently,BA atudii should b mandatoryfor all dosage f0nll5 with ~mcdlfred release dmraclerlstka whlla they may be waived In cases when the pwmeatll process through the gut wall membrane is rate lfmlling,e.g. in cases of compoundsof ‘high” solub#ity and low” pwmeabilll in immediate release forms.
65
67
DRUG IDENTIFICATION USING THE MAJOR 2ND DERIVATIVE NEAR-INFRARED PEAKS R. D. Jee P. R. Khan and A. C. Moffat &&%fo; PharmaceuticalAnalysis, The School of Pharmacy,University of London. Brunswick Square. London, WClN 1AX. UK
FREE ENERGY PREDICTION OF THE HOST-GUEST COMPLEXATION OF VARIOUS CYCLODEXTRINS
TraditIonally mid-infrared spectra have Table 1. been used for identification of pure drug Peaks Number of pairs substances by simple comparison wth 0 34253 authentic spectra or lists of malor peak 1 9596 positions(1). Near-infrared reflectance 2 1179 spectra are also rich in chemical information 3 103 and much simpler to measure. However, 4 14 identifications using NIR have in the past 5 5 involved relatively complex chemometric 6 0 methods such as Mahalonobis distances, princtpal component analysis and correlation in wavelength space. We have investigated the
application of peak positions to second derivative NIR spectra. The reflectance spectra of some 300 powdered compounds were recorded over the wavelength range 1100to 2500 nm using a Foss NIRSystems 6500 spectrophotometer fitted with a Rapid Content Analyser. A data base of the positions of the major negative peaks in the second derivative (log l/R) spectra was set up and validated by comparing all the possible different pairs of compounds (approx. 45 000 pairs). Even without making any use of the relative peak intensity information. it was possible to differentiate between all compounds with just 6 peaks. Table 1 shows the number of different pairs of compounds giving 0, 1 etc peak matches. Increasing the number of peaks. and/or calculating a score which takes the relative peak intensities into account, improved the discrimination further. This simple method was superior to the commonly used correlation in wavelength space and demonstrates that NIR is as good a!
mid-IR for identifications. 1. Clarke’s Isolation and Identification of Drugs, 2nd edition, 1986 Pharmaceutical Press UK.
C.T. Klein, D. Polheim, B.
and P. Wolschann Institut fir Theoretische Chemie und Strahlenchemie, Wiihringer St&e 17, A-1090 Wien Institut filr PharmazeutischeTechnologie, Althanstr. 14, A-1090 Wien
Cyclodextrin inclusion complexes play an important role in pharmaceutical technology, because the inclusion into the hosts cavity influences the different molecular properties like solubility, bioavailibility, reactivity or spectra of the guest drastically. The physicochemicalbehaviour of such associationcomplexes are therefore of high interest in respect to the association constant and the corresponding thermodynamic parameters. The knowledge of the complexation afinity of the cyclodextrins and guest molecules is necessary for the selection of proper cyclodextrins and suitable complexation conditions for specific applications. A procedure for the theoretical estimationof free energies of host-guestcomplexation, based on a multivariant regression analysis was therefore developed. For the prediction model around 80 compoundswere considered.As descriptors of the various molecular properties were used e.g. the molecular surface, the ovality, which is connected to the molecular shape and the partition coefficients. Other descriptors are e.g. the electrotopological index, based on the electronegativity of the atoms and the number of the heteroatoms.The model was evaluated by the program TSAR from the Oxford Molecular Simulation Package. From several developed models the best fitting one was further refined and shows a high predictive power and is statistically significant. Individual models are calculated for c(-, p and y-cyclodcxtrins. The models are tested for a number of guest molecules, for which the association constants were estimated spectrophotometrically.A different influence of the various parameters used in the model is observed for the three cyclodextrins,caused by the different mobility of the cyclodextrin ring system and the fact that an
association of a guest molecule into the CD’s cavity makes the complex geometries more rigid.
68 pH-METRIC METHOD AS A POWERFUL TOOL TO INVESTIGATE DRUG MOLECULAR PHYSICOCHEMICAL DESCRIPTORS G. Care@‘, R. Fruttero’, A. Pagliara”, P.-A. Carrupt”, A. Gasco’ and B Testa” *Dipartimento di Scicnza e Tecnologia de1 Farmaco, Via P. Giuria, 9, 10125 Torino, Italy “Institut de Chimie Th&peutique, BEP, Universiti de Lausanne, CH-1015 Lausanne Ionisation and lipophilicity are molecular descriptors that have a marked influence on the biodistribution of drugs. A number of experimental techniquesare nowadays available to measure ionization constantsand distributioncoefficients(log D). The potentiometrictitrator GlpKa (Sirius Analytical Instruments Ltd, Forrest Row, East Sussex, UK) is a modem instrumentable to measure ionisation umstauts in water
@Ka), in the presence of a \Me.r-miscible solvent @sKa) and also in biphasic systems (poKa). Thus the iouisaticm profile of a given solute is calculated from its pKa (or psKa) whereas its distribution profile @H vs log D) is obtained from the extent of the diffcrena between pKa and p&a. The GlpKa instrument is fuI1~ automated and the graphical/mathematical approach implemented m the software. allows pKa, psti, poKa to be obtaineddirectly from the Bjemun differenceplot through an iterative least squaresprocedure. Optimized protocolsfor the pH-metric techniquewere recentlyusedby someof us to characterizethe acid-base behavior of zwitterionic drugs, to investigate the changes in
isotropic hpophilicity associated with the oxidation state of the sulfiu atom of drugs and to ration&e the lipophilici@ of a series of (p-meth~lbenql)alk~~-amines in liposomal anisotropic system.
WHEN ARE EIOAVAILABILITY-BIOEQUIVALENCE STUDIES NECESSARY7 H.H. BioChem. Karlsruhe.Germany The assessment of efficacyand safety as WBIIas the documentationof an appropriate (blo)pharmaceuticalqwllty are esa&ial mqulrementa in the drug regiatratll process. For solid oral dosage forms with new molecular entitles (NME) the charactwlsatlon of both, pharmacoklnelicpropertiesof the drug substance and bioavailablllty(BA) of Ihe drug product are mandatorynot only after single and multipledose administrationsbut also in special aihfations(e.g. fetiated. renal failure, hepatic insufliciency).In contrast. for generic veraions an Abtxwiatecl New Drug Application (ANDA) procedure is accepted by regulatoryagencies for the assessment of efficacy and safety. Basls for such an ANDA is the investigationof bioequlvalenca (BE) of the generic formulation in comparison with an appropriate reference (innovator) product with Yull” clinical documentation. However, the regulatoryrequirementa concerningthe necessity of BRIBE studisa differ from region to region. While In some countries such invest&&na are requested for drug regis!raUon of all products, particularlygenerics. in others there requiratnentsare dafined on a case by case basis. In this context pharrn8cuJynarnlcand pharmacoklnetlc aspects are considered for dedsion rnakkrg. e.g. a narrow thsmpeullc index or non-linear pharmacoklnetlcs. h&oover, also the physiwchemical drug substance prop&lies and blophwmaceuficalaspect of Ihe dosage f&n rue relevant. The fundamental question is how far a formulationmay affect the rate and extent of absorptirx~of the active dNg ingredient from the product into the body. Only in cases where the (in viva) release of the drug from the pharmaceuticalform is the rate limiting step BA willdepend on the dosage form jwopertleaat all. In contrast,A the permeation process through the gut wall is rate limiting for drug absorption rm aignlflcent eff8ct of the gale&al form on BA may be expected. Consequently,BA atudii should b mandatoryfor all dosage f0nll5 with ~mcdlfred release dmraclerlstka whlla they may be waived In cases when the pwmeatll process through the gut wall membrane is rate lfmlling,e.g. in cases of compoundsof ‘high” solub#ity and low” pwmeabilll in immediate release forms.