Controlling the Polymorphic Outcome of 2,6-Dimethoxybenzoic Acid Crystallization Using Additives

Abstract

In this study, 2,6-dimethoxybenzoic acid (2,6MeOBA) was used as a model substance to investigate the use of additives to control the polymorphic outcome of crystallization. 2,6MeOBA exists as three polymorphs. Two of the 2,6MeOBA polymorphs, I and III, obtained in most of the crystallization experiments, were characterized by thermal analysis, and their relative thermodynamic stability was determined. Forms I and III are enantiotropically related, where form III is the high-temperature form. Pure form II was very difficult to obtain. Crystallization of 2,6MeOBA was explored under different conditions by performing evaporation and cooling crystallization from different solvents. Surfactants, polymers, and different molecular compounds with diverse possibilities for the formation of intermolecular interactions were tested as additives. The additives facilitating the crystallization of the metastable forms were additionally studied under different crystallization conditions. The effect of additives polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) on the thermodynamic stability and solvent-mediated phase transition (SMPT) kinetics was evaluated. HPC and PEG showed the potential to favor the formation of form III in crystallization from water.

Polymorphism, phase transition, and physicochemical property investigation of Ensifentrine

“…Understanding various crystallisation conditions [50][51][52][53][54] is also important for managing polymorph formation. Aside from the reactive crystallisation process, we employed a variety of solvents and crystallisation environments (Table 1).…”

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

“…They can significantly widen the metastable zone, elongate induction time, or completely stabilize the supersaturated solution . Overall, additive-controlled crystallization has already been successfully employed as a technological tool for polymorphic, , size and habit control of APIs, ,,, as well as for process stability enhancement and simplification of downstream formulation procedure. , Most of these additives are well-known formulation additives with low or no toxic effects on humans; therefore, the industrial application of such crystallization technologies should give no rise for regulatory holdbacks. All at the same, there are numerous examples of additive-controlled crystallization which are dominantly performed in batch mode, and only a few publications discuss the adaptation of continuous technologies.…”

Crystallization of Metastable Isonicotinamide Polymorphs and Prevention of Concomitant Crystallization by Additives

“…Therefore, common crystallization approaches often cannot provide crystallization of a pure polymorph. In such cases, other crystallization methods or approaches are introduced: antisolvent crystallization, ultrasound-assisted crystallization, laser-induced nucleation, crystallization in gels, , and in the presence of additives (including tailor-made or structurally related additives, , polymers , and surfactants) and templates (self-assembled monolayer − or other templates). Structurally related additives have been used to obtain metastable forms of paracetamol, − para -aminobenzoic acid, benzamide, etc.…”