Crystallisation of a salt hydrate with a complex solid form landscape

Abstract

Different approaches were utilized to assess the thermodynamic stability relationship between four distinct hemihydrates of sitagliptin L-tartrate (SLT). These phases are true polymorphs, having the same chemical composition and molar ratio of water, but different arrangement in the crystal lattice. The general approaches (Burger and Ramberger rules) have only limited applicability, but indicated a monotropic relationship between Phase 1 and Phase 2. The crystallisation and transformation behaviour of the polymorphs was strongly influenced by the solvent composition. As the stability thereof was found to be solvent-dependent, the application of the van't Hoff plot or the solvent-mediated transformation did not unambiguously reveal the relative stability of the forms. Experiments were carried out in an endeavour to determine the most suitable concentration trajectory for cooling crystallisation of the selected candidate and prevent concomitant crystallisation. The application of in situ monitoring techniques, such as FTIR-ATR and FBRM, offered great potential for process optimization and control.

Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways, and Thermodynamic Stability

“…Under slurry conditions, the solute−solvent interactions diminish the nucleation barrier and accelerate the nucleation and growth rate of the stable phase, leading to a spontaneous form I → form II transition at a w > 0.26. A similar phenomenon has been recently described by Tieger et al 52 for different polymorphic forms of sitagliptin L-tartrate, the stability order of which altered depending on the a w value of the water/organic solvent mixture.…”

Solid-State Characterization of Different Crystalline Forms of Sitagliptin

“…Sitagliptin (7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3- (trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine) is an effective anti-glycemic drug used for the treatment of type 2 diabetes mellitus (T2DM) [3]. The original product is marketed by Merck & Co., under the trade name Januvia, as sitagliptin phosphate monohydrate, approved in 2006 by the Food and Drug Administration (FDA) [4,5].…”

“…The hydrate formation is of great importance in the pharmaceutical industry, considering the ubiquity of water vapor, because hydrates are frequently more stable [5]. Thus, the presence of solvates and hydrates influences the physicochemical properties of the crystals.…”

“…The characterization of solid-state properties is a prerequisite in the development of new pharmaceutical solid dosage forms [5]. Thus, the characterization and differentiation of different crystalline forms of sitagliptin is required so that the physical properties of complex solvates and hydrates can be determined.…”