Paracetamol polymorphism

This procedure is illustrated by using the case studies of aspirin (nonpolymorphic system) and paracetamol (polymorphic system), both widely used as antipyretic (fever suppressant) and analgesic (painkiller) drugs. 

Fig. 4.18 X-ray powder diffraction patterns for the two polymorphs of paracetamol. (From Nichols and Frampton 1998, with permission.)...

Fig. 4.40 (See also colour plates.) Comparison of optical and SEM images of polymorphs of paracetamol grown from IMS. Upper, optical photomicrographs of Form 1 (left, scale bar = 250 p.m) and Form II (right, scale bar = 100 p.m). (From Nichols 1998, with permission.) Lower, SEM images of Form 1 (left), and Form 11 (right). (From Nichols and Frampton 1998, with permission.)...

Nichols, G. (1998). Optical properties of polymorphic forms I and II of paracetamol. Microscope, 46, 117-22. [lOOf]... 

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]... 

Our second example of a drug exhibiting polymorphism is paracetamol (II). This dmg is known to exist in two polymorphic forms, monoclinic (Form 1) and orthorhombic (Form 2), of which Form 1 is the more thermo-... 

Figure 1.12 Photomicrographs showing the solution phase polymorphic conversion of orthorhombic paracetamol (needles) to monoclinic paracetamol (prisms and plates). Micrograph (a) was taken at t=0 and (b) was taken at t= 30 min. Scale bars = 250 pm.

The importance of polymorphism within crystal engineering is substantial and in the area of pharmaceutical crystals has proven to be of great importance financially (Chapter 3.3). Studies using pressure as a variable have been applied recently to the studies of pharmaceutical or related compounds to explore more widely potential polymorphism in such compounds. The examples of glycine and paracetamol are discussed below. 

The majority of the crystallization literature deals with inorganic crystals, and the organic chemistry literature mainly covers small organic molecules with few degrees of freedom such as glutamic acid, phenytoin, or paracetamol. The reality in the pharmaceutical industry is often much more complicated— molecular weights above 1000 g/mole are common, and complex molecular structures have an effect on nucleation and growth kinetics as well as on the likelihood of polymorph formation. 

In the production of solid pharmaceutical preparations, it is important to be aware of the identities of polymorphs that might be formed during the drying process, or during any later processing steps, e.g. milling, compression, extrusion. The pressure-induced formation of specific solvates with superior stabilities has also been reported, e.g. for paracetamol. ... 

Benghiat FS, Charbonnier LM, Vokaer B, De Wilde V, Le Moine A (2009) Interleukin 17-producing T helper cells in alloimmunity. Transplant Rev (Orlando) 23 11-18 Bernal W, Donaldson P, Underhill J, Wendon J, Williams R (1998) Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure. 

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. 

Fig. 6.11 Optical appearance and Raman spectra of (a) paracetamol Form III (b) paracetamol Form II, and (c) paracetamol Form I. Reproduced with permission from M. Szelagiewicz etal., In Situ Characterisation of Polymorphic Forms [83] published by Akademiai Kiado Rt. 1999.

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