Franck Leveiller - Academia.edu (original) (raw)

Papers by Franck Leveiller

Studies in Surface Science and Catalysis, 2000

Drug Substance (DS) Specific Surface Area (SSA), porosity and Particle Size Distribution (PSD) ar... more Drug Substance (DS) Specific Surface Area (SSA), porosity and Particle Size Distribution (PSD) are important physical characteristics for pharmaceutical applications. For instance the DS surface area can greatly influence the dissolution rate which, in turn, might affect bioavailability. Several analytical methods can be used to characterise the DS and determine the powder SSA: measurements by gas adsorption (BET method) and

Studies in Surface Science and Catalysis, 2000

International journal of pharmaceutics, 1999

Mechanical treatments such as grinding, milling or micronization applied to crystalline drug subs... more Mechanical treatments such as grinding, milling or micronization applied to crystalline drug substances may induce changes such as the occurrence of crystal defects and/or amorphous regions. These changes are likely to affect the chemical and physical properties of the material as well as the corresponding drug product performances. Various analytical techniques such as standard differential scanning calorimetry, isothermal and solution microcalorimetry as well as dynamic vapour sorption can be used to characterise and possibly quantify the amorphous phase content of these materials. These techniques have been applied for the development of analytical methods based on temperature- or solvent-induced (including water) recrystallization of the amorphous phase in semi-crystalline drug substances and excipients and have sometimes allowed for detecting low amounts of amorphous phase. We have developed an alternative MTDSC method for the quantitation of the amorphous content in samples of...

The Journal of Physical Chemistry, 1992

Page 1. 10380 J. Phys. Chem. 1992,96, 10380-10389 Toward a Determination at Near Atomic Resolutio... more Page 1. 10380 J. Phys. Chem. 1992,96, 10380-10389 Toward a Determination at Near Atomic Resolution of Two-Dimensional Crystal Structures of Amphiphllk Molecules on the Water Surface. A Study Based on Grazkrg Incidence ...

The Journal of Physical Chemistry, 1993

ABSTRACT

Langmuir, 1994

Uncompressed arachidic acid films spread over 10-3 M cadmium chloride solution (pH 8.8 adjusted w... more Uncompressed arachidic acid films spread over 10-3 M cadmium chloride solution (pH 8.8 adjusted with ammonia) spontaneously form two-dimensional (2-D) crystalline clusters with coherence lengths of =loo0 A at 9 "C. Ten distinct low-order in-plane diffraction peaks and three high-order peaks were observed with grazing incidence X-ray diffraction (GID) using synchrotron radiation. Seven low-order peaks were attributed to scattering only from a crystalline cadmium layer and the remaining peaks to scattering primarily from the arachidate layer. The molecules in the arachidate layer arrange in a pseudorectangular unit cell with dimensions a = 4.60 A and b = 8.31 A and y = 93.4O with the chains tilted 1l0 along the b axis. The chains of the two crystallographically independent molecules in the unit cell are related by pseudoglide symmetry along the b axis yielding the herringbone motif. The reflections from the cadmium layer were indexed according to a supercell a, = 2a, b, = 3(-a + b)/2. Analysis of X-ray specular reflectivity measurements and the GID data indicated that the counterionic layer consists of a CdOH+ species, bound to the arachidate layer in a stoichometry close to 1:l. The probable formation of a cadmium-ammonia complex at the high pH = 8.8 was strongly suggested by the X-ray reflectivity measurements employing CH3NH2, (CH&NH, and (CH&N as alternative counterions. The arrangements of the arachidate chains and of the Cd ions were each determined to near atomic resolution by fitting the GID data, but the relative offset between the arachidate and Cd "lattices" was difficult to ascertain. (4) DeSimone, J. A.; Heck, G. L.; DeSimone, S. K. Electrical Double Layers in Biology; Plenum: New York, 1985. (5) Seimiya, T.; Miyasaka, H.; Kato, T.; Shirakawa, T.; Ohbu, K.; Iwakashi, M. Chem. Phys. Lipids 1987,43, 161. (6) Yazdanian, M.; Yu, H.; Zografi, G.; Kim, M. W. Langmuir 1992, 8,630. (7) Jacquemain, D.; Grayer Wolf, S.; Leveiller, F.; Deutach, M.; Kjaer, K.; Ale-Nielsen, J.; Lahav, M.; Leieerowitz, L. Angew. Chem. 1992,32, RisO National Laboratory. 130. J. J. Phys. Chem. 1992,96, 10380. (8) Leveiller,F.; Jacquemain,D.;Leiserowitz,L.;Kjaer,K.; Als-Nielsen, (9) Bosio, L.; Benatar, J. J.; Rieutord, F. Reu. Phys. Appl. 1987,22, "me I I D . (10) Richardson, R. M.; Roser, S. J. L~Q . Cryst. 1987,2, 797. 0143-1463/94/2410-0819~04.50/0 (14) Bloch, J. M. Phys. Rev. Lett. 1988, 61, 2941. (15) Dutta, P.; Peng, J. B.; Lm, B.; Ketterson, J. B.; Prakash, M.; (16) Leveiller,F.; Jacquemain, D.; Lahav, M.; Leieerowitz, L.; Deutach, Thin Solid F i l m 1988,160, 231. MBhwald, H.

Journal of the American Chemical Society, 1993

At low temperature (5-12 "C), uncompressed films of insoluble amphiphilic molecules C19H39XI wher... more At low temperature (5-12 "C), uncompressed films of insoluble amphiphilic molecules C19H39XI where the head group X contains one (CONH2, 1) or two ( C O N H C~H~C O N H Z , 2) amide groups, spontaneously form twodimensional (2D) crystalline clusters over aqueous subphases containing soluble amide or carboxylic acid molecules. These crystallites were detected and their structures were studied using grazing incidence X-ray diffraction (GID).

Journal of the American Chemical Society, 1992

ABSTRACT

Journal of the American Chemical Society, 1994

ABSTRACT The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic a... more ABSTRACT The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic alcohols (CnH2n+1OH, n=23, 30, 31, and C19H39CO2(CH2)(n)OH, n=9, 10) on pure water at a temperature of 5 degrees C have been determined to near-atomic resolution in order to understand the relative abilities of these monolayers to induce ice nucleation. The structures were solved making use of grazing incidence synchrotron X-ray diffraction (GID) data, complemented by lattice energy calculations. The GID data of the different monolayers within each of the two series (CnH2n+1OH, C19H39CO2CnH2nOH) are very similar. The molecules pack in a rectangular unit cell of average dimensions a=5.0 Angstrom, b=7.5 Angstrom for the normal alcohols CnH2n+1OH and a=5.7 Angstrom, b=7.5 Angstrom for C(19)H(39)CO(2)CnH(2n)OH. The plane group symmetry is essentially p1g1 for the normal alcohols The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic alcohols (CnH2n+1OH, n=23, 30, 31, and C19H39CO2(CH2)(n)OH, n=9, 10) on pure water at a temperature of 5 degrees C have been determined to near-atomic resolution in order to understand the relative abilities of these monolayers to induce ice nucleation. The structures were solved making use of grazing incidence synchrotron X-ray diffraction (GID) data, complemented by lattice energy calculations. The GID data of the different monolayers within eech of the two series (CnH2+1OH, C19H39CO2C(n)H(2n)OH) are very similar. The molecules pack in a rectangular unit cell of average dimensions a=5.0 Angstrom, b=7.5 Angstrom for the normal alcohols CnH2n+1OH and a=5.7 Angstrom, b=7.5 Angstrom for C19H39CO2CnH2nOH. The plane group symmetry is essentially p1g1 for the normal alcohols CnH2+1OH and essentially pllg for the other group. The molecular chains are tilted from the vertical by an average angle of 9 degrees, in the direction of the b axis, for CnH2n+1OH and by 29 degrees, in the direction of the a axis, for the other molecular type. The mclecular chains related by glide (g) symmetry are arranged in a herringbone pattern. The fit to the Bragg rod intensity data of CnH2n+1OH permitted a reliable estimate of 0.07 Angstrom(2) for the molecular mean-squared motion parallel to the water surface. The absolute orientations of the molecules C19H39CO2CnH2nOH were determined by lattice energy calculations. The anisotropic coherence lengths of the crystallites of C19H39CO2CnH2nOH derived from the widths of the two observed Bragg peaks have been correlated with the binding energies of molecules in different directions.CnH2+1OH and essentially p11g for the other group. The molecular chains are tilted from the vertical by an average angle of 90, in the direction of the b axis, for CnH2n+1OH, and by 29 degrees, in the direction of the a axis, for the other molecular type. The molecular chains related by glide (g) symmetry are arranged in a herringbone pattern. The fit to the Bragg rod intensity data of C,CnH(2+1)OH permitted a reliable estimate of 0.07 Angstrom(2) for the molecular mean-squared motion parallel to the water:r surface. The absolute orientations of the molecules C19H39CO2CnH2nOH were determined by lattice energy calculations. The anisotropic coherence lengths of the crystallites of C19H39CO2CnH2nOH derived from the widths of the two observed Bragg peaks have been correlated with the binding energies of molecules in different directions.

Journal of Pharmaceutical Sciences, 2005

The thermodynamic relationships between the two known polymorphs of paracetamol have been investi... more The thermodynamic relationships between the two known polymorphs of paracetamol have been investigated, and the subsequent pressure-temperature and temperature-volume phase diagrams were constructed using data from crystallographic and calorimetric measurements as a function of the temperature. Irrespective of temperature, monoclinic Form I and orthorhombic Form II are stable phases at ordinary and high pressures, respectively. The I and II phase regions in the pressure-temperature diagram are bordered by the I-II equilibrium curve, for which a negative slope (dp/dT & À0.3 MPa Á K À1 ) was determined although it was not observed experimentally. This curve goes through the I-II-liquid triple point whose coordinates (p & 234 MPa, T & 505 K) correspond to the crossing point of the melting curves, for which dp/dT values of þ3.75 MPa Á K À1 (I) and þ3.14 MPa Á K À1 (II) were calculated from enthalpy and volume changes upon fusion. More generally, this case exemplifies how the stability hierarchy of polymorphs may be inferred from the difference in their sublimation curves, as topologically positioned with respect to each other, using the phase rule and simple inferences resorting to Gibbs equilibrium thermodynamics. ß

Le Journal de Physique IV, 2001

ABSTRACT

European Journal of Pharmaceutical Sciences, 2007

Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailabilit... more Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8-12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2001

Following the synthesis steps, the isolation steps (filtration, drying, milling,...) applied on a... more Following the synthesis steps, the isolation steps (filtration, drying, milling,...) applied on a drug substance (DS) may largely impact its textural properties (porosity, particles surface state, granulometry), hence its performances such as, for instance, flowability or compression behavior. We present here the changes of the texture of a DS agglomerates induced during the last steps of the manufacturing process (including grinding, densification, polymorphic conversion induced by temperature and relative humidity) as studied by mercury intrusion porosimetry (MIP). Initial and final samples have been also studied by gas adsorption (B.E.T. method), and scanning electron microscopy (SEM) techniques. SEM observation and interpretation of MIP curves demonstrate that the initial batch presents two types of open intra-granular pores (cone-shaped pores and pores between elementary particles). The change between the initial and final textural properties of the powdered samples was also followed by MIP analysis performed on intermediate samples. The sample obtained after the final stage of the process did not present conic pores, which have totally disappeared from the surface of the agglomerates probably because of the granulation induced during polymorphic conversion due to humidity and mechanical rotation of the reactor.

Angewandte Chemie, 1992

... Von Didier Jacquemain, Sharon Grayer Wolf, Franck Leveiller, Moshe Deutsch, Kristian Kjaer*, ... more ... Von Didier Jacquemain, Sharon Grayer Wolf, Franck Leveiller, Moshe Deutsch, Kristian Kjaer*, Jens Als-Nielsen", Meir Lahav" und Leslie ... hinaus lassen sie sich auch zur Induktion der Bil-dung von Keimen fur das Wachstum organischer und anor-ganischer dreidimensionaler ...

Angewandte Chemie International Edition in English, 1992

The advent of well-collimated, high-intensity synchrotron X-ray sources and the consequent develo... more The advent of well-collimated, high-intensity synchrotron X-ray sources and the consequent development of surface-specific X-ray diffraction and fluorescence techniques have recently revolutionized the study of Langmuir monolayers at the air-liquid interface. These methods allowed for the first time the determination of the in-plane and vertical structure of such monolayers with a resolution approaching the atomic level. We briefly describe these methods, including grazing incidence X-ray diffraction, specular reflectivity, Bragg rods, standing waves, and surface fluorescence techniques, and review recent results obtained from them for Langmuir films. The methods have been successfully applied in the elucidation of the structure of crystalline aggregates of amphiphilic molecules such as alcohols, carboxylic acids and their salts, a-amino acids, and phospholipids at the water surface. In addition, it became possible to monitor by diffraction the growth and dissolution of the crystalline self-aggregates as well as structural changes occurring by phase transitions. Furthermore, the surface X-ray methods shed new light on the structure of the underlying ionic layer of attached solvent or solute species. Examples are given where singly or doubly charged ions bound to the two-dimensional (2D) crystal form either an ordered or diffuse counterionic layer. Finally, the surface diffraction methods provide data on transfer of structural information from 2D clusters to 3D single crystals, which had been successfully accomplished by epitaxial-like crystallization both in organic and inorganic crystals.

Acta Crystallographica Section A Foundations of Crystallography, 2000

Studies in Surface Science and Catalysis, 2000

Drug Substance (DS) Specific Surface Area (SSA), porosity and Particle Size Distribution (PSD) ar... more Drug Substance (DS) Specific Surface Area (SSA), porosity and Particle Size Distribution (PSD) are important physical characteristics for pharmaceutical applications. For instance the DS surface area can greatly influence the dissolution rate which, in turn, might affect bioavailability. Several analytical methods can be used to characterise the DS and determine the powder SSA: measurements by gas adsorption (BET method) and

Studies in Surface Science and Catalysis, 2000

International journal of pharmaceutics, 1999

Mechanical treatments such as grinding, milling or micronization applied to crystalline drug subs... more Mechanical treatments such as grinding, milling or micronization applied to crystalline drug substances may induce changes such as the occurrence of crystal defects and/or amorphous regions. These changes are likely to affect the chemical and physical properties of the material as well as the corresponding drug product performances. Various analytical techniques such as standard differential scanning calorimetry, isothermal and solution microcalorimetry as well as dynamic vapour sorption can be used to characterise and possibly quantify the amorphous phase content of these materials. These techniques have been applied for the development of analytical methods based on temperature- or solvent-induced (including water) recrystallization of the amorphous phase in semi-crystalline drug substances and excipients and have sometimes allowed for detecting low amounts of amorphous phase. We have developed an alternative MTDSC method for the quantitation of the amorphous content in samples of...

The Journal of Physical Chemistry, 1992

Page 1. 10380 J. Phys. Chem. 1992,96, 10380-10389 Toward a Determination at Near Atomic Resolutio... more Page 1. 10380 J. Phys. Chem. 1992,96, 10380-10389 Toward a Determination at Near Atomic Resolution of Two-Dimensional Crystal Structures of Amphiphllk Molecules on the Water Surface. A Study Based on Grazkrg Incidence ...

The Journal of Physical Chemistry, 1993

ABSTRACT

Langmuir, 1994

Uncompressed arachidic acid films spread over 10-3 M cadmium chloride solution (pH 8.8 adjusted w... more Uncompressed arachidic acid films spread over 10-3 M cadmium chloride solution (pH 8.8 adjusted with ammonia) spontaneously form two-dimensional (2-D) crystalline clusters with coherence lengths of =loo0 A at 9 "C. Ten distinct low-order in-plane diffraction peaks and three high-order peaks were observed with grazing incidence X-ray diffraction (GID) using synchrotron radiation. Seven low-order peaks were attributed to scattering only from a crystalline cadmium layer and the remaining peaks to scattering primarily from the arachidate layer. The molecules in the arachidate layer arrange in a pseudorectangular unit cell with dimensions a = 4.60 A and b = 8.31 A and y = 93.4O with the chains tilted 1l0 along the b axis. The chains of the two crystallographically independent molecules in the unit cell are related by pseudoglide symmetry along the b axis yielding the herringbone motif. The reflections from the cadmium layer were indexed according to a supercell a, = 2a, b, = 3(-a + b)/2. Analysis of X-ray specular reflectivity measurements and the GID data indicated that the counterionic layer consists of a CdOH+ species, bound to the arachidate layer in a stoichometry close to 1:l. The probable formation of a cadmium-ammonia complex at the high pH = 8.8 was strongly suggested by the X-ray reflectivity measurements employing CH3NH2, (CH&NH, and (CH&N as alternative counterions. The arrangements of the arachidate chains and of the Cd ions were each determined to near atomic resolution by fitting the GID data, but the relative offset between the arachidate and Cd "lattices" was difficult to ascertain. (4) DeSimone, J. A.; Heck, G. L.; DeSimone, S. K. Electrical Double Layers in Biology; Plenum: New York, 1985. (5) Seimiya, T.; Miyasaka, H.; Kato, T.; Shirakawa, T.; Ohbu, K.; Iwakashi, M. Chem. Phys. Lipids 1987,43, 161. (6) Yazdanian, M.; Yu, H.; Zografi, G.; Kim, M. W. Langmuir 1992, 8,630. (7) Jacquemain, D.; Grayer Wolf, S.; Leveiller, F.; Deutach, M.; Kjaer, K.; Ale-Nielsen, J.; Lahav, M.; Leieerowitz, L. Angew. Chem. 1992,32, RisO National Laboratory. 130. J. J. Phys. Chem. 1992,96, 10380. (8) Leveiller,F.; Jacquemain,D.;Leiserowitz,L.;Kjaer,K.; Als-Nielsen, (9) Bosio, L.; Benatar, J. J.; Rieutord, F. Reu. Phys. Appl. 1987,22, "me I I D . (10) Richardson, R. M.; Roser, S. J. L~Q . Cryst. 1987,2, 797. 0143-1463/94/2410-0819~04.50/0 (14) Bloch, J. M. Phys. Rev. Lett. 1988, 61, 2941. (15) Dutta, P.; Peng, J. B.; Lm, B.; Ketterson, J. B.; Prakash, M.; (16) Leveiller,F.; Jacquemain, D.; Lahav, M.; Leieerowitz, L.; Deutach, Thin Solid F i l m 1988,160, 231. MBhwald, H.

Journal of the American Chemical Society, 1993

At low temperature (5-12 "C), uncompressed films of insoluble amphiphilic molecules C19H39XI wher... more At low temperature (5-12 "C), uncompressed films of insoluble amphiphilic molecules C19H39XI where the head group X contains one (CONH2, 1) or two ( C O N H C~H~C O N H Z , 2) amide groups, spontaneously form twodimensional (2D) crystalline clusters over aqueous subphases containing soluble amide or carboxylic acid molecules. These crystallites were detected and their structures were studied using grazing incidence X-ray diffraction (GID).

Journal of the American Chemical Society, 1992

ABSTRACT

Journal of the American Chemical Society, 1994

ABSTRACT The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic a... more ABSTRACT The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic alcohols (CnH2n+1OH, n=23, 30, 31, and C19H39CO2(CH2)(n)OH, n=9, 10) on pure water at a temperature of 5 degrees C have been determined to near-atomic resolution in order to understand the relative abilities of these monolayers to induce ice nucleation. The structures were solved making use of grazing incidence synchrotron X-ray diffraction (GID) data, complemented by lattice energy calculations. The GID data of the different monolayers within each of the two series (CnH2n+1OH, C19H39CO2CnH2nOH) are very similar. The molecules pack in a rectangular unit cell of average dimensions a=5.0 Angstrom, b=7.5 Angstrom for the normal alcohols CnH2n+1OH and a=5.7 Angstrom, b=7.5 Angstrom for C(19)H(39)CO(2)CnH(2n)OH. The plane group symmetry is essentially p1g1 for the normal alcohols The two-dimensional (2D) crystal structures of self-aggregated clusters of amphiphilic alcohols (CnH2n+1OH, n=23, 30, 31, and C19H39CO2(CH2)(n)OH, n=9, 10) on pure water at a temperature of 5 degrees C have been determined to near-atomic resolution in order to understand the relative abilities of these monolayers to induce ice nucleation. The structures were solved making use of grazing incidence synchrotron X-ray diffraction (GID) data, complemented by lattice energy calculations. The GID data of the different monolayers within eech of the two series (CnH2+1OH, C19H39CO2C(n)H(2n)OH) are very similar. The molecules pack in a rectangular unit cell of average dimensions a=5.0 Angstrom, b=7.5 Angstrom for the normal alcohols CnH2n+1OH and a=5.7 Angstrom, b=7.5 Angstrom for C19H39CO2CnH2nOH. The plane group symmetry is essentially p1g1 for the normal alcohols CnH2+1OH and essentially pllg for the other group. The molecular chains are tilted from the vertical by an average angle of 9 degrees, in the direction of the b axis, for CnH2n+1OH and by 29 degrees, in the direction of the a axis, for the other molecular type. The mclecular chains related by glide (g) symmetry are arranged in a herringbone pattern. The fit to the Bragg rod intensity data of CnH2n+1OH permitted a reliable estimate of 0.07 Angstrom(2) for the molecular mean-squared motion parallel to the water surface. The absolute orientations of the molecules C19H39CO2CnH2nOH were determined by lattice energy calculations. The anisotropic coherence lengths of the crystallites of C19H39CO2CnH2nOH derived from the widths of the two observed Bragg peaks have been correlated with the binding energies of molecules in different directions.CnH2+1OH and essentially p11g for the other group. The molecular chains are tilted from the vertical by an average angle of 90, in the direction of the b axis, for CnH2n+1OH, and by 29 degrees, in the direction of the a axis, for the other molecular type. The molecular chains related by glide (g) symmetry are arranged in a herringbone pattern. The fit to the Bragg rod intensity data of C,CnH(2+1)OH permitted a reliable estimate of 0.07 Angstrom(2) for the molecular mean-squared motion parallel to the water:r surface. The absolute orientations of the molecules C19H39CO2CnH2nOH were determined by lattice energy calculations. The anisotropic coherence lengths of the crystallites of C19H39CO2CnH2nOH derived from the widths of the two observed Bragg peaks have been correlated with the binding energies of molecules in different directions.

Journal of Pharmaceutical Sciences, 2005

The thermodynamic relationships between the two known polymorphs of paracetamol have been investi... more The thermodynamic relationships between the two known polymorphs of paracetamol have been investigated, and the subsequent pressure-temperature and temperature-volume phase diagrams were constructed using data from crystallographic and calorimetric measurements as a function of the temperature. Irrespective of temperature, monoclinic Form I and orthorhombic Form II are stable phases at ordinary and high pressures, respectively. The I and II phase regions in the pressure-temperature diagram are bordered by the I-II equilibrium curve, for which a negative slope (dp/dT & À0.3 MPa Á K À1 ) was determined although it was not observed experimentally. This curve goes through the I-II-liquid triple point whose coordinates (p & 234 MPa, T & 505 K) correspond to the crossing point of the melting curves, for which dp/dT values of þ3.75 MPa Á K À1 (I) and þ3.14 MPa Á K À1 (II) were calculated from enthalpy and volume changes upon fusion. More generally, this case exemplifies how the stability hierarchy of polymorphs may be inferred from the difference in their sublimation curves, as topologically positioned with respect to each other, using the phase rule and simple inferences resorting to Gibbs equilibrium thermodynamics. ß

Le Journal de Physique IV, 2001

ABSTRACT

European Journal of Pharmaceutical Sciences, 2007

Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailabilit... more Poor water solubility a b s t r a c t Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8-12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2001

Following the synthesis steps, the isolation steps (filtration, drying, milling,...) applied on a... more Following the synthesis steps, the isolation steps (filtration, drying, milling,...) applied on a drug substance (DS) may largely impact its textural properties (porosity, particles surface state, granulometry), hence its performances such as, for instance, flowability or compression behavior. We present here the changes of the texture of a DS agglomerates induced during the last steps of the manufacturing process (including grinding, densification, polymorphic conversion induced by temperature and relative humidity) as studied by mercury intrusion porosimetry (MIP). Initial and final samples have been also studied by gas adsorption (B.E.T. method), and scanning electron microscopy (SEM) techniques. SEM observation and interpretation of MIP curves demonstrate that the initial batch presents two types of open intra-granular pores (cone-shaped pores and pores between elementary particles). The change between the initial and final textural properties of the powdered samples was also followed by MIP analysis performed on intermediate samples. The sample obtained after the final stage of the process did not present conic pores, which have totally disappeared from the surface of the agglomerates probably because of the granulation induced during polymorphic conversion due to humidity and mechanical rotation of the reactor.

Angewandte Chemie, 1992

... Von Didier Jacquemain, Sharon Grayer Wolf, Franck Leveiller, Moshe Deutsch, Kristian Kjaer*, ... more ... Von Didier Jacquemain, Sharon Grayer Wolf, Franck Leveiller, Moshe Deutsch, Kristian Kjaer*, Jens Als-Nielsen", Meir Lahav" und Leslie ... hinaus lassen sie sich auch zur Induktion der Bil-dung von Keimen fur das Wachstum organischer und anor-ganischer dreidimensionaler ...

Angewandte Chemie International Edition in English, 1992

The advent of well-collimated, high-intensity synchrotron X-ray sources and the consequent develo... more The advent of well-collimated, high-intensity synchrotron X-ray sources and the consequent development of surface-specific X-ray diffraction and fluorescence techniques have recently revolutionized the study of Langmuir monolayers at the air-liquid interface. These methods allowed for the first time the determination of the in-plane and vertical structure of such monolayers with a resolution approaching the atomic level. We briefly describe these methods, including grazing incidence X-ray diffraction, specular reflectivity, Bragg rods, standing waves, and surface fluorescence techniques, and review recent results obtained from them for Langmuir films. The methods have been successfully applied in the elucidation of the structure of crystalline aggregates of amphiphilic molecules such as alcohols, carboxylic acids and their salts, a-amino acids, and phospholipids at the water surface. In addition, it became possible to monitor by diffraction the growth and dissolution of the crystalline self-aggregates as well as structural changes occurring by phase transitions. Furthermore, the surface X-ray methods shed new light on the structure of the underlying ionic layer of attached solvent or solute species. Examples are given where singly or doubly charged ions bound to the two-dimensional (2D) crystal form either an ordered or diffuse counterionic layer. Finally, the surface diffraction methods provide data on transfer of structural information from 2D clusters to 3D single crystals, which had been successfully accomplished by epitaxial-like crystallization both in organic and inorganic crystals.

Acta Crystallographica Section A Foundations of Crystallography, 2000