# Stability of Paracetamol Amorphized by Co-Melting with Various Cellulose Derivatives
## 4 Discussion  
The melting point of paracetamol obtained in DSC studies confirms that the substance used in the research was the I crystalline form [28]. For all physical mixtures, enthalpy of melting indicates a partial reduction in paracetamol crystallinity as a result of homogenization in the solid phase with polymers, which is consistent with the literature data and the results of previous studies [24,29]. The lack of a crystallization peak during rapid cooling shows that paracetamol does not crystallize during rapid cooling, neither single substance nor in a mixture. Additionally, a fold on the 2 nd heating of paracetamol DSC curve at approximately 23 \({}^{\circ}\)C, characteristic of a glass transition shows full paracetamol amorphization after melting and rapid cooling. An exothermic crystallization peak starting at approximately 76 \({}^{\circ}\)C corresponds to recrystallization II which melts at 158 \({}^{\circ}\)C. This information is consistent with the literature data [23,24,30]. Signals above 130 \({}^{\circ}\)C in the DSC curves of mixtures containing 75% paracetamol with various HPMCs indicate the formation of metastable form III. Subsequently, paracetamol re-crystallizes to form II, as indicated by the melting point of approximately 154 \({}^{\circ}\)C (slightly lower than form II of paracetamol without the addition of polymers). In the case of the mixture with HPMC 86, these signals were the highest in intensity. The DSC curve of 2 nd heating of a mixture containing 75% paracetamol and MC indicates the formation of a small amount of form I paracetamol, which confirms the melting peak at a temperature slightly below 170 \({}^{\circ}\)C [29,30]. The lack of recrystallization and melting peak in the DSC curves of mixtures containing 50% and 25% paracetamol shows that no metastable form III or form II was formed in these mixtures immediately after melting. At the same time, this means that paracetamol has completely amorphized after co-melting in these mixtures. Analysis of co-melting samples after 2 and 4 months makes it possible to check whether paracetamol crystallization occurs when the mixtures are stored at room temperature. The purpose of the analyses is to determine whether the amorphization of paracetamol after fusion with polymers is stable and whether it depends on the type of polymer in the mixture and the proportion of components. Broadened melting peak starting above 140 \({}^{\circ}\)C on DSC curves of the mixture containing 75% paracetamol with HPMC 86 analyzed after 2 and 4 months correspond to form II. The signal of formation of metastable form III observed for this mixture immediately after co-melting was in this curve practically invisible. Thus, the formation of the II form of paracetamol occurs not only during heating, but also during storage of the mixture. The  
Figure 6: UHPLC chromatograms of paracetamol (a) and mixtures after 4 months of co-melting, containing 50% of paracetamol with HPMC 86 (b), HPMC 90 (c), HPMC 120 (d) and MC (e). melting enthalpy of form II after 2 and 4 months is also higher than immediately after co-melting the mixture. For a mixture containing 50% paracetamol with HPMC 86, a small, strongly broadened DSC peak increasing over time indicates a small amount of form II. However, crystallization was not noticeable in the mixture containing 25% paracetamol. The results indicate progressive crystallization of paracetamol after co-melting paracetamol with HPMC 86 if the content of the active ingredient in the mixture was min. 50%. A strong endothermic peak at approximately 130 \({}^{\circ}\)C in the DSC curves of mixtures containing 75% and 50% paracetamol with HPMC 90 and HPMC 120 tested after 2 and 4 months indicates the formation of metastable form III, which then crystallizes to form II. However, the fact that the crystallization of form II preceded the formation of form III indicates that form II was not formed earlier, during storage of the co-melting mixtures.