Formation and Solid-State Characterization of a Salt-Induced Metastable Polymorph of Flufenamic Acid

Abstract

Using additives is one of more recent and special methods to obtain a desirable polymorph. However, for pharmaceuticals, additives are usually limited to structurally related organic compounds. In this study, we have shown the potential of using a salt additive to induce crystallization of the metastable polymorph V of flufenamic acid (FFA). Additionally, it was found that FFA V undergoes a rapid interface mediated polymorphic transformation. Therefore, the slow evaporation method which can decrease the contact of the solvent during crystallization was chosen to delay the polymorphic transformation. It can be concluded that understanding the system is a prerequisite for using additives to obtain the desired polymorph.

Strong Additive–Surface Interaction Leads to the Unusual Revival of Growth at Solvent-Poisoned Faces ofdl-Alanine Crystal

“…Surprisingly, our experimental results show that all the inorganic salts used in this study revive the water-poisoned dead growth at both the polar COO − -rich −c end and NH 3 + -rich +c end of DL-alanine seed crystals, contrary to one's usual understanding that a strong additive−surface (or solvent− surface) interaction is supposed to block the active sites at the crystal face hence inhibit the face growth. 1,5,8 All the interesting findings will be presented and discussed.…”

Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association

“…Recent efforts have been devoted to the development of consistent and reliable crystallization processes for producing desirable polymorphs, including on-line, spectroscopy-based monitoring designs of crystal growth in solution (3)(4)(5). Polymorphic formation is known to be affected by a wide variety of growth conditions, such as type of solvent (6)(7)(8), supersaturation (4,9), temperature (10), and use of additives (11,12). Despite considerable efforts studying crystallization mechanism, understanding of kinetic factors that govern polymorphic formation in solution largely remains limited (13).…”

Nonamorphism in Flufenamic Acid and a New Record for a Polymorphic Compound with Solved Structures

“…8 Elucidation of the first crystal structure (form III) occurred in 1973, 9 and nearly ten years later the structure of a second form (form I) was reported. 10 The existence of polymorphism in this compound has offered a challenge for methodologies developed for polymorph discovery and control from the use of soluble additives 11 to epitaxy 12 and now polymer-induced heteronucleation (PIHn). 13 Furthermore, outside the potential significance of polymorphism for influencing the bioavailability of this drug, its supramolecular chemistry is of considerable interest to test within the fenamic acid series the concept of the polymorphophore: a structural element that when incorporated into a compound favors the formation of polymorphic crystals.…”