Orthorhombic paracetamol, crystal

Fig. 4.5 Phase transformation of Form II orthorhombic paracetamol to the monoclinic Form I. At 25 °C (left photo), the crystal in the center of the field is extinguished under crossed polarizers. The conversion takes place at 110 °C along a front which moves from lower left to upper right. The conversion is approximately 50 per cent completed in the middle photo, and essentially complete in the right hand one. (From Nichols 1999, with permission see also Nichols 1998.)...

Nichols, G. and Frampton, C. S. (1998). Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J. Pharm. ScL, 87, 684-93. [113, 144f]... 

Paracetamol is a compound with a significant usage in the pharmaceutical industry. It is already known that the paracetamol crystal exhibits a polymorphism. Three polymorphs of paracetamol have been reported a thermodynamically stable monoclinic form I, a metastable orthorhombic form II, and a very unstable form III. The monoclinic form I is the form used commercially due to its thermodynamic stability at room temperature. In the current work, we investigate both forms I and II to underline the difference in their chemical behavior and to point out that it is not possible to gain understanding about one form based upon the knowledge on another form. 

The poor compression of paracetamol was addressed through the preparation of a new orthorhombic form [55]. Owing to its well-known poor compressional properties, commercially available paracetamol materials for direct compression are compounds of paracetamol with gelatin, polyvinylpyrrolidone, starch, or starch derivatives. Since a chemically pure paracetamol that could be used for direct compression would constitute a better compendial article, a new polymorph was produced. The new form was recrystallized from dioxane, and its crystals were found to consist of sliding planes that led to good compressibility. However, the orthorhombic form is metastable with respect to the monoclinic form phase conversion was observed if the raw material contained greater than 20% of the monoclinic phase. However, the dissolution rates for the two forms were found to be similar, and therefore any questions as to the relative bioavailability of the two forms would probably be meaningless. 

Mechanochemical co-crystallisation has also been exploited in the synthesis of readily compressible and thermodynamically stable forms of the API paracetamol (Figure 8.8(b)). While tablet formation using the thermodynamically stable polymorph of paracetamol is difficult, the metastable orthorhombic polymorph yields tablets much more readily due to its layered crystal structure. Consequently, it was expected that co-crystals of paracetamol with a similar layered structure would also be readily compressible. Screening by LAG revealed four co-crystals of paracetamol with improved ability to compress into tablets. Structural characterisation and Density Functional Theory (DFT) calculations revealed that enhanced compressibility was related to the formation of a sheet-like structure reminiscent of the second polymorph of paracetamol (Figure 8.8(c)-(e)). ... 

For these reasons we have performed investigations by means of linear-dichroic infrared (IR-LD) spectroscopy analysis of oriented solids on both monoclinic and orthorhombic polymorphs of Paracetamol by the orientation technique as a liquid crystal (LC) suspension. The conventional IR spectral analysis of Paracetamol in solution has been previously danonstraled [351-355]. However, here for the presented CS-NLC orientation technique, IR-LD analysis leads to (a) detailed vibrational assignment of characteristic bands of both polymorphs and (b) the supramo-lecular solid-state structural characterization at room temperature and atmospheric pressure. It also avoids the phase transition and guarantees the study of the different forms. A quantitative approach to the yield determination of monoclinic form I in mixtures with the orthorhombic modification was also illustrated. 

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