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Clement Brandel - One of the best experts on this subject based on the ideXlab platform.
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optimization of experimental conditions for the monitoring of nucleation and growth of racemic Diprophylline from the supercooled melt
Journal of Crystal Growth, 2017Co-Authors: Aurelien Lemercier, Clement Brandel, Yohann Cartigny, Samuel Petit, Quentin Viel, Eric Dargent, Gerard CoquerelAbstract:Abstract Since more and more pharmaceutical substances are developed as amorphous forms, it is nowadays of major relevance to get insights into the nucleation and growth mechanisms from supercooled melts (SCM). A step-by-step approach of recrystallization from a SCM is presented here, designed to elucidate the impact of various experimental parameters. Using the bronchodilator agent Diprophylline (DPL) as a model compound, it is shown that optimal conditions for informative observations of the crystallization behaviour from supercooled racemic DPL require to place samples between two cover slides with a maximum sample thickness of 20 µm, and to monitor recrystallization during an annealing step of 30 min at 70 °C, i.e . about 33 °C above the temperature of glass transition. In these optimized conditions, it could be established that DPL crystallization proceeds in two steps: spontaneous nucleation and growth of large and well-faceted particles of a new crystal form (primary crystals: PC) and subsequent crystallization of a previously known form (RII) that develops from specific surfaces of PC. The formation of PC particles therefore constitutes the key-step of the crystallization events and is shown to be favoured by at least 2.33 wt% of the major chemical impurity, Theophylline.
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prenucleation self assembly and chiral discrimination mechanisms during solution crystallisation of racemic Diprophylline
Chemistry: A European Journal, 2016Co-Authors: Clement Brandel, Yohann Cartigny, Gerard Coquerel, Joop H Ter Horst, Samuel PetitAbstract:The crystallisation behaviour of (RS)-Diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.
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measuring induction times and crystal nucleation rates
Faraday Discussions, 2015Co-Authors: Clement Brandel, Joop H. Ter HorstAbstract:A large variation is observed in induction times measured under equal conditions in 1 ml solutions. Ruling out experimental errors, this variation originates from the nucleation process. The induction time distribution is explained by the stochastic nature of nucleation if the number of nuclei formed is approaching 1 per vial. Accurate heterogeneous crystal nucleation rates were determined from the induction time distributions on a 1 ml scale for racemic Diprophylline in two solvents. The difference in nucleation behaviour in the two solvents originates from the energy barrier for nucleation, which is much higher in the solvent in which induction times are much longer. In addition the pre-exponential factor for the crystal nucleation rate in both solvents is rather low compared to predictions using Classical Nucleation Theory. Unfortunately, concentration and surface characteristics of the effective heterogeneous particles are not known which clouds a further molecular interpretation.
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impact of molecular flexibility on double polymorphism solid solutions and chiral discrimination during crystallization of Diprophylline enantiomers
Molecular Pharmaceutics, 2013Co-Authors: Clement Brandel, Youness Amharar, Judith M Rollinger, Ulrich J Griesser, Yohann Cartigny, Samuel Petit, Gerard CoquerelAbstract:The polymorphic behavior of racemic and enantiopure Diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformation...
Samuel Petit - One of the best experts on this subject based on the ideXlab platform.
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optimization of experimental conditions for the monitoring of nucleation and growth of racemic Diprophylline from the supercooled melt
Journal of Crystal Growth, 2017Co-Authors: Aurelien Lemercier, Clement Brandel, Yohann Cartigny, Samuel Petit, Quentin Viel, Eric Dargent, Gerard CoquerelAbstract:Abstract Since more and more pharmaceutical substances are developed as amorphous forms, it is nowadays of major relevance to get insights into the nucleation and growth mechanisms from supercooled melts (SCM). A step-by-step approach of recrystallization from a SCM is presented here, designed to elucidate the impact of various experimental parameters. Using the bronchodilator agent Diprophylline (DPL) as a model compound, it is shown that optimal conditions for informative observations of the crystallization behaviour from supercooled racemic DPL require to place samples between two cover slides with a maximum sample thickness of 20 µm, and to monitor recrystallization during an annealing step of 30 min at 70 °C, i.e . about 33 °C above the temperature of glass transition. In these optimized conditions, it could be established that DPL crystallization proceeds in two steps: spontaneous nucleation and growth of large and well-faceted particles of a new crystal form (primary crystals: PC) and subsequent crystallization of a previously known form (RII) that develops from specific surfaces of PC. The formation of PC particles therefore constitutes the key-step of the crystallization events and is shown to be favoured by at least 2.33 wt% of the major chemical impurity, Theophylline.
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Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity
2017Co-Authors: Quentin Viel, Samuel Petit, Gérard Coquerel, Laurent Delbreilh, Eric DargentAbstract:A dielectric relaxation spectroscopy (DRS) study was performed to investigate the molecular mobility of amorphous chiral Diprophylline (DPL). For this purpose, both racemic DPL and a single enantiomer of DPL were considered. After fast cooling from the melt at very low temperature (−140 °C), progressive heating below and above the glass transition (Tg ≈ 37 °C) induces two secondary relaxations (γ- and δ-) and primary relaxations (α-) for both enantiomeric compositions. After chemical purification of our samples by means of cooling recrystallization, no γ-process could be detected by DRS. Hence, it was highlighted that the molecular mobility in the glassy state is influenced by the presence of theophylline (TPH), the main impurity in DPL samples. We also proved that the dynamic behavior of a single enantiomer and the racemic mixture of the same purified compound are quasi-identical. This study demonstrates that the relative stability and the molecular mobility of chiral amorphous drugs are strongly sensitive to chemical purity
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prenucleation self assembly and chiral discrimination mechanisms during solution crystallisation of racemic Diprophylline
Chemistry: A European Journal, 2016Co-Authors: Clement Brandel, Yohann Cartigny, Gerard Coquerel, Joop H Ter Horst, Samuel PetitAbstract:The crystallisation behaviour of (RS)-Diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.
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Crystallization from the Amorphous State of a Pharmaceutical Compound: Impact of Chirality and Chemical Purity
2016Co-Authors: Quentin Viel, Yohann Cartigny, Clément Brandel, Ermelinda M. S. Eusébio, João Canotilho, Valérie Dupray, Eric Dargent, Gérard Coquerel, Samuel PetitAbstract:The crystallization behavior and morphological features of particles obtained from amorphous Diprophylline (DPL) are reported. After fast cooling of the melt, progressive heating above the glass transition (Tg ≈ 37 °C) induces the nucleation and growth of well-shaped crystals: PC for primary crystals. The combination of differential scanning calorimetry, hot stage optical microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that these PC are kinetically favored and can form spontaneously in the supercooled melt whatever the enantiomeric composition, although their development and relative stability are influenced by the presence of theophylline, the main impurity in DPL samples. Specific crystal surfaces of the PC act as favorable areas and support for the subsequent formation of previously known metastable crystal forms consisting of solid solutions of the two DPL enantiomers. This study demonstrates the complex multistep mechanism that can occur during the temperature-induced crystallization of chiral amorphous drugs, and their strong sensitivity to enantiomeric composition and chemical purity
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impact of molecular flexibility on double polymorphism solid solutions and chiral discrimination during crystallization of Diprophylline enantiomers
Molecular Pharmaceutics, 2013Co-Authors: Clement Brandel, Youness Amharar, Judith M Rollinger, Ulrich J Griesser, Yohann Cartigny, Samuel Petit, Gerard CoquerelAbstract:The polymorphic behavior of racemic and enantiopure Diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformation...
Gerard Coquerel - One of the best experts on this subject based on the ideXlab platform.
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optimization of experimental conditions for the monitoring of nucleation and growth of racemic Diprophylline from the supercooled melt
Journal of Crystal Growth, 2017Co-Authors: Aurelien Lemercier, Clement Brandel, Yohann Cartigny, Samuel Petit, Quentin Viel, Eric Dargent, Gerard CoquerelAbstract:Abstract Since more and more pharmaceutical substances are developed as amorphous forms, it is nowadays of major relevance to get insights into the nucleation and growth mechanisms from supercooled melts (SCM). A step-by-step approach of recrystallization from a SCM is presented here, designed to elucidate the impact of various experimental parameters. Using the bronchodilator agent Diprophylline (DPL) as a model compound, it is shown that optimal conditions for informative observations of the crystallization behaviour from supercooled racemic DPL require to place samples between two cover slides with a maximum sample thickness of 20 µm, and to monitor recrystallization during an annealing step of 30 min at 70 °C, i.e . about 33 °C above the temperature of glass transition. In these optimized conditions, it could be established that DPL crystallization proceeds in two steps: spontaneous nucleation and growth of large and well-faceted particles of a new crystal form (primary crystals: PC) and subsequent crystallization of a previously known form (RII) that develops from specific surfaces of PC. The formation of PC particles therefore constitutes the key-step of the crystallization events and is shown to be favoured by at least 2.33 wt% of the major chemical impurity, Theophylline.
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prenucleation self assembly and chiral discrimination mechanisms during solution crystallisation of racemic Diprophylline
Chemistry: A European Journal, 2016Co-Authors: Clement Brandel, Yohann Cartigny, Gerard Coquerel, Joop H Ter Horst, Samuel PetitAbstract:The crystallisation behaviour of (RS)-Diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.
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impact of molecular flexibility on double polymorphism solid solutions and chiral discrimination during crystallization of Diprophylline enantiomers
Molecular Pharmaceutics, 2013Co-Authors: Clement Brandel, Youness Amharar, Judith M Rollinger, Ulrich J Griesser, Yohann Cartigny, Samuel Petit, Gerard CoquerelAbstract:The polymorphic behavior of racemic and enantiopure Diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformation...
Chris Vervaet - One of the best experts on this subject based on the ideXlab platform.
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hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding
International Journal of Pharmaceutics, 2016Co-Authors: G Verstraete, J Van Renterghem, P J Van Bockstal, Sabah Kasmi, B G De Geest, T De Beer, J P Remon, Chris VervaetAbstract:Hydrophilic aliphatic thermoplastic polyurethane (Tecophilic™ grades) matrices for high drug loaded oral sustained release dosage forms were formulated via hot melt extrusion/injection molding (HME/IM). Drugs with different aqueous solubility (Diprophylline, theophylline and acetaminophen) were processed and their influence on the release kinetics was investigated. Moreover, the effect of Tecophilic™ grade, HME/IM process temperature, extrusion speed, drug load, injection pressure and post-injection pressure on in vitro release kinetics was evaluated for all model drugs. 1H NMR spectroscopy indicated that all grades have different soft segment/hard segment ratios, allowing different water uptake capacities and thus different release kinetics. Processing temperature of the different Tecophilic™ grades was successfully predicted by using SEC and rheology. Tecophilic™ grades SP60D60, SP93A100 and TG2000 had a lower processing temperature than other grades and were further evaluated for the production of IM tablets. During HME/IM drug loads up to 70% (w/w) were achieved. In addition, Raman mapping and (M)DSC results confirmed the homogenous distribution of mainly crystalline API in all polymer matrices. Besides, hydrophilic TPU based formulations allowed complete and sustained release kinetics without using release modifiers. As release kinetics were mainly affected by drug load and the length of the PEO soft segment, this polymer platform offers a versatile formulation strategy to adjust the release rate of drugs with different aqueous solubility.
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thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding
European Journal of Pharmaceutics and Biopharmaceutics, 2015Co-Authors: Bart Claeys, T De Beer, J P Remon, Anouk Vervaeck, Xander Hillewaere, Sam Possemiers, Laurent Hansen, Chris VervaetAbstract:Abstract This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions – crystalline API in a crystalline carrier – at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24 h, whereas a complete release of Diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65 wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM.
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release characteristics of polyurethane tablets containing dicarboxylic acids as release modifiers a case study with Diprophylline
International Journal of Pharmaceutics, 2014Co-Authors: Bart Claeys, T De Beer, J P Remon, Laurent Hansen, Sander De Bruyn, Chris VervaetAbstract:The influence of several dicarboxylic acids on the release characteristics of polyurethane tablets with a high drug load was investigated. Mixtures of Diprophylline (Dyph) and thermoplastic polyurethane (TPUR) (ratio: 50/50, 65/35 and 75/25 wt.%) were hot-melt extruded and injection molded with the addition of 1, 2.5, 5 and 10% wt.% dicarboxylic acid as release modifier. Incorporating malonic, succinic, maleic and glutaric acid in the TPUR matrices enhanced drug release, proportional to the dicarboxylic acid concentration in the formulation. No correlation was found between the water solubility, melting point, logP and pKa of the acids and their drug release modifying capacity. Succinic and maleic acid had the highest drug release modifying capacity which was linked to more intense molecular interactions with Dyph. A structural fit between the primary and secondary alcohol of Dyph and both carboxylic groups of the acids was at the origin of this enhanced interaction.
Yohann Cartigny - One of the best experts on this subject based on the ideXlab platform.
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optimization of experimental conditions for the monitoring of nucleation and growth of racemic Diprophylline from the supercooled melt
Journal of Crystal Growth, 2017Co-Authors: Aurelien Lemercier, Clement Brandel, Yohann Cartigny, Samuel Petit, Quentin Viel, Eric Dargent, Gerard CoquerelAbstract:Abstract Since more and more pharmaceutical substances are developed as amorphous forms, it is nowadays of major relevance to get insights into the nucleation and growth mechanisms from supercooled melts (SCM). A step-by-step approach of recrystallization from a SCM is presented here, designed to elucidate the impact of various experimental parameters. Using the bronchodilator agent Diprophylline (DPL) as a model compound, it is shown that optimal conditions for informative observations of the crystallization behaviour from supercooled racemic DPL require to place samples between two cover slides with a maximum sample thickness of 20 µm, and to monitor recrystallization during an annealing step of 30 min at 70 °C, i.e . about 33 °C above the temperature of glass transition. In these optimized conditions, it could be established that DPL crystallization proceeds in two steps: spontaneous nucleation and growth of large and well-faceted particles of a new crystal form (primary crystals: PC) and subsequent crystallization of a previously known form (RII) that develops from specific surfaces of PC. The formation of PC particles therefore constitutes the key-step of the crystallization events and is shown to be favoured by at least 2.33 wt% of the major chemical impurity, Theophylline.
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prenucleation self assembly and chiral discrimination mechanisms during solution crystallisation of racemic Diprophylline
Chemistry: A European Journal, 2016Co-Authors: Clement Brandel, Yohann Cartigny, Gerard Coquerel, Joop H Ter Horst, Samuel PetitAbstract:The crystallisation behaviour of (RS)-Diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.
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Crystallization from the Amorphous State of a Pharmaceutical Compound: Impact of Chirality and Chemical Purity
2016Co-Authors: Quentin Viel, Yohann Cartigny, Clément Brandel, Ermelinda M. S. Eusébio, João Canotilho, Valérie Dupray, Eric Dargent, Gérard Coquerel, Samuel PetitAbstract:The crystallization behavior and morphological features of particles obtained from amorphous Diprophylline (DPL) are reported. After fast cooling of the melt, progressive heating above the glass transition (Tg ≈ 37 °C) induces the nucleation and growth of well-shaped crystals: PC for primary crystals. The combination of differential scanning calorimetry, hot stage optical microscopy, powder X-ray diffraction, and Raman spectroscopy revealed that these PC are kinetically favored and can form spontaneously in the supercooled melt whatever the enantiomeric composition, although their development and relative stability are influenced by the presence of theophylline, the main impurity in DPL samples. Specific crystal surfaces of the PC act as favorable areas and support for the subsequent formation of previously known metastable crystal forms consisting of solid solutions of the two DPL enantiomers. This study demonstrates the complex multistep mechanism that can occur during the temperature-induced crystallization of chiral amorphous drugs, and their strong sensitivity to enantiomeric composition and chemical purity
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impact of molecular flexibility on double polymorphism solid solutions and chiral discrimination during crystallization of Diprophylline enantiomers
Molecular Pharmaceutics, 2013Co-Authors: Clement Brandel, Youness Amharar, Judith M Rollinger, Ulrich J Griesser, Yohann Cartigny, Samuel Petit, Gerard CoquerelAbstract:The polymorphic behavior of racemic and enantiopure Diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformation...
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Impact of Molecular Flexibility on Double Polymorphism, Solid Solutions and Chiral Discrimination during Crystallization of Diprophylline Enantiomers
2013Co-Authors: Clément Brandel, Youness Amharar, Judith M Rollinger, Ulrich J Griesser, Yohann Cartigny, Samuel Petit, Gérard CoquerelAbstract:The polymorphic behavior of racemic and enantiopure Diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization