Three Strikingly Different Crystal Habits of Tadalafil: Design, Characterization, Pharmaceutical Performance, and Computational Studies

Abstract

The present study aims at improving the physicochemical properties of a widely used drug Tadalafil through crystal habit modification, without changing the polymorphic form. Three distinct types of crystal habits, namely, needle, plate, and block, were obtained under controlled crystallization protocols with optimized solvent compositions. Complete characterization of these three crystal habits was carried out using powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. Morphological features were studied by optical and scanning electron microscopy. Evaluation of the pharmaceutical performance of different crystal habits reveals significant improvement in compressibility and flow properties for the block-shaped crystals in comparison to the needle- and plate-shaped crystals. Also, a more linear tablet compression behavior was noted for the plate and block morphologies of the API compared to their needle counterpart. In vitro dissolution studies showed distinct release profiles for the same API form with different crystal habits, i.e., needle > plate > block. Insights into crystal growth mechanism and the role of solvents in affording the observed crystal habits are presented based on molecular dynamics simulations of intermolecular interactions with crystal facets, in conjunction with the experimental crystal face indexing of the single crystals of different habits. These observations were further supported by interaction topology analysis and the electrostatic features on different crystal facets.