An Experiment in Physical Chemistry: Polymorphism and Phase Stability in Acetaminophen (Paracetamol)

Large-Scale Crystallization of a Pure Metastable Polymorph by Reaction Coupling

“…Since each polymorph is a unique material with its physicochemical properties, the discovery, the selection, and the production of a desired polymorph at large-scale are essential in many high-valued industries . They are especially so in the pharmaceutical arena . Metastable polymorphs can often be recrystallized in a small-scale through swift cooling and rapid solvent evaporation by suddenly raising the relative supersaturation, S , and/or broadening of the metastable zone width (MZW), or through the solvent effect by altering the shape of the solubility curve and MZW, or through heterogeneous nucleation by lowering the interfacial energy and/or S …”

“…Many have reported that the melting point of Form II is ranging from 155° to 160 °C without prior conversion to Form I. ,, However, the differential scanning calorimetry (DSC) scan in our present work (Figure ) displays that the melting point of Form II is at 151 °C, the molten Form II recrystallizes at 154 °C and becomes Form I solids with a melting point of 170 °C. Since acetaminophen is a monotropic system ,, based on thermodynamic rules for polymorph transitions according to Burger and Ramberger, , the likelihood for the direct transition from Form II to Form I in the presence of Form I nuclei without going through the melting of Form II can be totally dismissed. The purity of Form II crystals without any trace of Form I crystals is further examined by X-ray diffraction (XRD) (Figure and Figure S5 in the Supporting Information) and IR (Figure S6 in the Supporting Information).…”

“…3 They are especially so in the pharmaceutical arena. 4 Metastable polymorphs can often be recrystallized in a small-scale through swift cooling 5 and rapid solvent evaporation 6 by suddenly raising the relative supersaturation, S, 7 and/or broadening of the metastable zone width (MZW), 8 or through the solvent effect 9 by altering the shape of the solubility curve and MZW, 10 or through heterogeneous nucleation 11 by lowering the interfacial energy and/or S. 12 However, unlike biological environments where a bulk material with a metastable modification can be cleverly induced, confined, and stabilized through the layering and tiling of the organic nucleation templates and nanosized crystals of metastable polymorph, 13 large-scale crystal production of metastable polymorph for industrial applications is more difficult to achieve because of the interplay among the four key factors: (1) the time delay in temperature change over the large heat capacity of the solution volume in a vessel even with a good mixing which, in turn, can affect the temperature-dependent equilibrium saturation concentration, C*, and the initial S 0 = C 0 /C*, where C 0 is the initial concentration, (2) the Ostwald's rule of stages 14 that metastable polymorphs are prone to be formed and then transformed rapidly into only one thermodynamically stable polymorph, (3) the nucleation of thermodynamically stable polymorph when S at later times is lower than the initial S 0 , and (4) instead of going through recrystallization, realistically, the process usually undergoes crystallization immediately after a chemical reaction.…”

Влияние Температуры На Ромбическую Форму Молекулярных Кристаллов Парацетамола

“…Фор-ма III крайне неустойчива и поэтому ее кристаллическая структура пока достоверно не определена. Молекуляр-ные кристаллы ромбической модификации получают, как правило, из растворов [7][8][9][10][11][12][13][14][15][16][17][18]. Нам удалось синтезиро-вать кристаллы ромбической модификации путем ваку-умной сублимации порошка кристаллов моноклинной модификации [19,20].…”