Polymorphism of paracetamol: Relative stabilities of the monoclinic and orthorhombic phases inferred from topological pressure-temperature and temperature-volume phase diagrams (original) (raw)
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Journal of pharmaceutical sciences, 2017
Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L = 535 ± 10 K and PI-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of t...
DSC and adiabatic calorimetry study of the polymorphs of paracetamol
Journal of Thermal Analysis and Calorimetry, 2004
Monoclinic (I) and orthorhombic (II) polymorphs of paracetamol were studied by DSC and adiabatic calorimetry in the temperature range 5 - 450 K. At all the stages of the study, the samples (single crystals and powders) were characterized using X-ray diffraction. A single crystal → polycrystal II→ I transformation was observed on heating polymorph II, after which polymorph I melted
Journal of Thermal Analysis and Calorimetry, 2007
The thermodynamic relationship between crystal modifications of paracetamol was studied by alternative methods. Temperature dependence of saturated vapor pressure for polymorphic modifications of the drug paracetamol (acetaminophen) was measured and thermodynamic functions of the sublimation process calculated. Solution calorimetry was carried out for the two modifications in the same solvent. Thermodynamic parameters for sublimation for form I (monoclinic) were found: DG sub 298 =60.0 kJ mol -1 ; DH sub 298 =117.9±0.7 kJ mol -1 ; DS sub 298 =190±2 J mol -1 K -1 . For the orthorhombic modification (form II), the saturated vapor pressure could only be studied at 391 K. Phase transition enthalpy at 298 K, DH tr 298 (I®II)=2.0±0.4 kJ mol -1 , was derived as the difference between the solution enthalpies of the noted polymorphs in the same solution (methanol). Based on DH tr 298 (I®II), differences between temperature dependencies of heat capacities of both modifications and the vapor pressure value of form II at 391 K, the temperature dependence of saturated vapor pressure and thermodynamic sublimation parameters for modification II were also estimated (DG sub 298 =56.1 kJ mol -1 ; DH sub 298 =115.9±0.9 kJ mol -1 ; DS sub 298 =200±3 J mol -1 K -1 ). The results indicate that the modifications are monotropically related, which is in contrast to findings recently reported found by classical thermochemical methods.
Stabilisation of metastable polymorphs: the case of paracetamol form III
Chemical communications (Cambridge, England), 2016
The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of β-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph.
Physical Chemistry Chemical Physics, 2011
The properties of the intermolecular hydrogen bonds in the monoclinic (Form I) and the orthorhombic (Form II) polymorphs of paracetamol, C 8 H 9 NO 2 , have been studied by single crystal polarized Raman spectroscopy (40 to 3700 cm À1 ) in a wide temperature range (5 K o T o 300 K) in relation to the dynamics of methyl-groups of the two forms. A detailed analysis of the temperature dependence of the wavenumbers, bandwidths and integral intensities of the spectral bands has revealed an essential difference between the two polymorphs in the strength and ordering of OHÁ Á ÁO and NHÁ Á ÁO hydrogen bonds. The compression of intermolecular hydrogen bonds is interrelated with crystal packing and the dynamics of methyl-groups. On structural compression of the orthorhombic polymorph on cooling, a compromise is to be sought between the shortening of OHÁ Á ÁO and NHÁ Á ÁO bonds, attractive CHÁ Á ÁO and repulsive CHÁ Á ÁH contacts in the crystal structure. As a result of a steric conflict at temperatures below 100 K, N-HÁ Á ÁO hydrogen bonds become significantly disordered, and an extended intramolecular transition from the conformation ''staggered'' with respect to the CQO bond to the one ''staggered'' with respect to the NH bond is observed. In most of the studied crystals this transition was only about 60% complete even at 5 K, but in some of the crystals the orientation of all the methyl-groups became staggered with respect to the NH bond at low temperatures. This complete transition was coupled to a sharp shortening of the OHÁ Á ÁO and NHÁ Á ÁO hydrogen bonds at o100 K, the appearance of new additional positions of the protons in these H-bonds, and a slight strengthening of the C-HÁ Á ÁO bonds formed by methyl-groups. The same conformational transition has been observed also in the monoclinic polymorph at T o 80 K. The crystal packing in Form I prevents the O-HÁ Á ÁO hydrogen bonds from adopting the optimum geometry, and they are significantly disordered at all the temperatures, especially at r200 K. The packing of molecules in Form I is also not favourable to form C-HÁ Á ÁO hydrogen bonds involving methyl-groups. One can conclude from the comparison of diffraction and spectroscopic data that the higher stability of Form I results not from a larger strength of individual OHÁ Á ÁO and NHÁ Á ÁO hydrogen bonds, but is a cumulative effect: all the hydrogen bonds together stabilize the structure of the monoclinic polymorph more than that of the orthorhombic polymorph.
DSC study and phase diagrams calculation of binary systems of paracetamol
The study reports a DSC investigation of solid-liquid equilibria in three binary mixtures of paracetamol, namely with caffeine, ascorbic acid and citric acid. All these systems reveal simple eutectic behavior and eutectic temperatures and temperatures of liquidus were determined. Further, assessed eutectic and liquidus temperatures together with data for pure components were used for evaluation of parameters of the Redlich-Kister equation for the excess Gibbs energy of binary melts. Finally, binary T-x phase diagrams of the above mentioned systems were calculated using the FactSage software.
Journal of Pharmaceutical Sciences, 2013
Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients and this is problematic for the development of a suitable dose form. Rimonabant, an API developed by Sanofi and discontinued due to side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure--temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does.
Thermal analysis of paracetamol polymorphs by FT-IR spectroscopies
Journal of Pharmaceutical and Biomedical Analysis, 2011
A simple IR spectroscopy based methodology in routine screening studies of polymorphism is proposed. Reflectance and transmittance temperature-dependent IR measurements (coupled with the 2D-IR data presentation and the baseline analysis) offer a positive identification of each polymorphic phase, therefore allowing simple and rapid monitoring of the measured system. Applicability and flexibility of the methodology was demonstrated on the measurement of the model polymorphic compound paracetamol under various conditions (including geometric constraints and elevated pressure). The thermal behavior of paracetamol strongly depends on slight variations in experimental conditions that can result in formation of various phases (three polymorphs and the amorphous form). The amorphous phase can crystallize during heating into either Form II or Form III within almost identical temperature range. Likewise, the crystal transformations II → I and III → II also can proceed within almost identical temperature range. Furthermore, the thermal behavior is even more diverse than that, and includes the crystallizations of Forms I, II and III from the melt, and the high temperature II → I transition. The variety of the temperatures of the transformations is a major obstacle for unambiguous identification of a particular phase by DSC and a major reason for the implementation of these IR methods.
Acta Crystallographica Section C Structural Chemistry, 2018
Paracetamol [N-(4-hydroxyphenyl)acetamide, C8H9NO2] has several polymorphs, just like many other drugs. The most stable polymorphs, denoted Forms I and II, can be obtained easily and their crystal structures are known. Crystals of the orthorhombic, less stable, room-temperature Form III are difficult to grow; they need a special recipe to crystallize and suffer from severe preferred orientation. A crystal structure model of Form III has been proposed and solved from a combination of structure prediction and powder X-ray diffraction (PXRD) [Perrinet al.(2009).Chem. Commun.22, 3181–3183]. The finalRwpvalue of 0.138 and the corresponding considerable residual trace were reasons to check its validity. A new structure determination of Form III using new high-resolution PXRD data led to a finalRwpvalue of 0.042 and an improvement of the earlier proposed model. In addition, a reversible phase transition was found at 170–220 K between the orthorhombic Form III and a novel monoclinic Form II...
Prediction of Polymorphic Transformations of Paracetamol in Solid Dispersions
Journal of Pharmaceutical Sciences, 2014
A novel approach employing variable-temperature X-ray powder diffraction (VTXRPD) was used to exploit its suitability as an off-line predictive tool to study the polymorphic transformations of paracetamol (PMOL) in melt-extruded hydrophilic polymer matrices. Physical mixtures (PMs) and extruded formulations of PMOL with either polyvinyl caprolactam graft copolymer (Soluplus R ) or vinylpyrrolidone-vinyl acetate copolymer (Kollidon R ) in the solid state were characterized by using differential scanning calorimetry, hotstage microscopy, and scanning electron microscopy. The experimental findings from VTXRPD showed that the stable Form I (monoclinic) of PMOL transformed to the metastable polymorph Form II (orthorhombic) at temperatures varying from 112 • C to 120 • C, in both the PMs and extrudates suggesting an effect of both temperature and identity of the polymers. The findings obtained from VTXRD analysis for both the PMs and the extruded formulations were confirmed by in-line near-infrared (NIR) monitoring during the extrusion processing. In the NIR study, PMOL underwent the same pattern of polymorphic transformations as those detected using VTXPRD. The results of this study suggest that VTXRPD can be used to predict the polymorphic transformation of drugs in polymer matrices during extrusion processing and provides a better understanding of extrusion processing parameters. C