Paracetamol polymorphs, crystallization

Nichols, G. Frampton, C.S. Physicochemical characterization of the orthorhombic polymorph of paracetamol 160. crystallized from solution. J. Pharm. Sci. 1998, 87 (6),... 

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. 

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. 

Di Rrofio, G., Tucci, S., Curcio, E. and Drioli, E. 2007b. Controlling polymorphism with membrane-based crystallizers Application to form I and II of paracetamol. Chem. Mater. 19 2386-2388. 

The final product flowabilily, compressabilty, and compaction depend on the mechanical properties and morphologies of the crystalline form. The fact that these properties are different for different polymorphs suggests that the manufacturability of a drug product depends on the polymorphic state. The effect of polymorphism on tableting of ibuprofen and acetaminophen has been studied. It was found that crystal habit affects drug flowability. Polymorphs of paracetamol show different compressability. Form II being easier to compress as a tablet. 

Database analyses have been carried out to estimate the percentage of crystal structures that contain solvent molecules in the crystal lattice. In a database study performed a decade ago, Nangia and Desiraju found that about 15% of organic crystals are solvated. The dioxane solvates of paracetamol significantly impact its physicochemical properties. The structural interrelationship and reversible phase transformations between the two polymorphs were studied. Interestingly, desolvation of either form generates the stable polymorph of paracetamol. 

Vibrational spectra are mainly governed by vibrations within the molecule. But since these vibrations are influenced by the environment of the molecule and hence the crystal packing, thqr will also diEFer for diflerent polymorphs of the same molecule. The diEFerences will in general not be as obvious as for XRPD, but nevertheless the specificity of spectroscopic and diffraction methods with respect to the differentiation of polymorphs is similar. Figure 8.3 a shows the Raman spectra of the same two polymorphs of paracetamol, as given in Figure 8.2. While the spectra look essentially similar, dear line shifts, for example, can be observed between 1700 and 1200 cm (Figure 8.3b). In some cases, such as isomorphous solvates (solvates which are identical in structure, except that diEFerent solvents occupy a certain lattice space), the specificity of IR and Raman is often superior to XRPD. 

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)). ... 

A variation of these parameters leads to a manipulation of the size and the morphology of the crystallized PCM crystals. Irrespective of parameters such as pressure or concentration, the same polymorphic form of paracetamol is always produced for pure solvents. When generating PCM particles from mixmres of ethanol and acetone, two different crystal forms were detected depending on the ratio between the solvents. 

Willock, D. J. Price, S. L. Leslie, M. Catlow, C. R. A. The relaxation of molecular crystal structures using a distributed multipole electrostatic model, J. Comp. Chem. 1995,16, 628-647 Price, S. L. Applications of realistic electrostatic modeling to molecules in complexes, sohds and proteins, J. Chem. Soc. Faraday Trans. 1996, 92, 2997-3008 Beyer, T. Day, G. M. Price, S. L. The prediction, morphology, and mechanical properties of the polymorphs of paracetamol, J. Am. Chem. Soc. 2001,123,5086-5094. 

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. 

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