Accessing Phase-Pure and Stable Acetaminophen Polymorphs by Thermal Gradient Crystallization

Abstract

We employ a simple and reproducible methodology based on thermal gradient crystallization to access forms I and II of acetaminophen. This methodology provides insight into the role of heat flux in the control over polymorphism and phase transitions. We report the crystallization of different polymorphs of acetaminophen as a function of the thermal gradient parameters (magnitude of the gradient, sample velocity) in a thin film geometry. The thin-film samples were displaced at well-defined velocities (1 ≤ v ≤ 75 μm/s) to control both the direction and the rate of crystal growth. We carried out a detailed structural analysis combining polarized optical microscopy and X-ray diffraction (specular and grazingincidence) to characterize the crystalline forms isolated by the thermal gradient technique. The resulting polymorphic forms have been found to exhibit high phase purity and remarkable stability over time. Figure 1. (a) Chemical structure of acetaminophen; (b) schematic representation of the thermal gradient setup. Communication pubs.acs.org/crystal

Directional crystallization of C8-BTBT-C8 thin films in a temperature gradient

“…Previous work has shown that the effective magnitude of the temperature gradient (G exp ) that forms between the hot and cold zones is less than the magnitude simply calculated by the equation G = (T h À T c )/x, where x = 2.0 mm is the gap between the hot and cold stages. [27][28][29][30] The calibration of the DT setup has been carried out as previously reported 30 and is detailed in the ESI, † (Table S1 and Fig. S1).…”

“…1). [27][28][29][30] This technique, also known as directional crystallization or solidification, is essentially an adaptation of the method of Percy Bridgman to thin films of molecular compounds using the set-up invented by Kenneth Jackson. 31 Although this technique has commonly been used for the study of organic compounds such as n-alkanes and m-nitroaniline, [32][33][34][35][36] it has not widely been applied to control the crystalline morphology of OSC thin films.…”

“…This technique presents several advantages: (i) nucleation and growth processes are decoupled, (ii) growth occurs preferentially through some selected crystallographic faces, (iii) uniaxial alignment takes place, and (iv) the number of molecules entering the crystal phase per unit time and through some crystallographic faces is externally controllable. [27][28][29][30] Up to now, the temperature gradient method has been applied to rather thick films (mm thick) sandwiched between two glass slides to avoid the unwanted dewetting of the melt state. 37 As a consequence, film thickness could hardly be controlled unless for OSCs exhibiting a smectic phase before the isotropization temperature (T iso ).…”

Controlling phase transformation during milling in the pre-formulation of Active pharmaceutical Ingredients

“…Meanwhile, thermal analysis requires less amount of the sample 2-4 mg with longer detection time 20-30 minutes or more depend on the targeted process with easier detection of the polymorphic mixture [22]. Other characterization methods are: Raman spectroscopy [36] , polarized light microscopy [37] , FTIR [38] and many others.…”

Distinguishing Cocrystals from Simple Eutectic Mixtures: Phenolic Acids as Potential Pharmaceutical Coformers

“…It is well-known that the pharmacokinetic properties of drugs are very closely related to the crystal form. Recently, extensive studies have been conducted to improve relevant properties of active pharmaceutical ingredients (APIs) via crystal engineering including polymorphism and crystal morphology control 1,2 and cocrystallization. 3−6 Cocrystals deserve particular attention, due to the wide range of potential coformers, which can be utilized for tuning the physicochemical properties of APIs.…”