High-Pressure Studies of Pharmaceuticals:  An Exploration of the Behavior of Piracetam

Abstract

The structural response of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) to both direct compression and high-pressure recrystallization from aqueous solution is reported. Crystals obtained by these methods have been characterized in situ by single-crystal X-ray diffraction. Compression of form II between pressures of 0.45-0.70 GPa caused a reversible, singlecrystal to single-crystal transition to give a new polymorph, form V. Crystallization from a dilute aqueous solution of piracetam at a pressure of 0.6 GPa via crystallization of high-pressure ice-VI resulted in the formation of a previously unreported dihydrate. The molecular packing arrangements of these new structures are compared with the known polymorphs and hydrates of piracetam. This study highlights how the systematic variation of pressure is a powerful method for the exploration of polymorphism and solvate formation and has the potential to add a further dimension to polymorph screening of pharmaceuticals.

Stability hierarchy between Piracetam forms I, II, and III from experimental pressure–temperature diagrams and topological inferences

“…In this paper, it will be demonstrated how the stability hierarchy can be inferred from experimental pressure-temperature diagrams. (Table 1 and Table S1 in the Supporting Information), and two more forms as well as two hydrates have been obtained under pressure: form IV (monoclinic, P21/c), 7 form V (triclinic, P-1), 8 a monohydrate, 7 and a dihydrate 8 . From the data in Table 1, it can be inferred that form III is the denser form, while form I is the less dense one.…”

“…10 and clearly The use of specific volumes obtained at ordinary pressure is validated by a reported density increase of approximately 5 % between 0 and 0.5 GPa for form II. 8 Triple point I-II-III is found at about 0.1 GPa, thus it can be safely assumed that the decrease in the specific volumes of the three solid phases is in the order of 1%.…”

Multicomponent organic crystals at high pressure

“…Solvation -desolvation on compression and decompression is a promising topic that awaits a systematic research. The first examples of studies in this direction show already that high-pressure seems to favour the formation of solvates [63,[103][104][105][106][107][108][109], even of those compounds that were never obtained as solvates at ambient pressure, for example of L-alanine [63]. Very high degrees of hydration were reported for the high-pressure phases of some molecular compounds, such as GABA [107], or 1,4-diazabicyclo[2.2.2]octane hydroiodine [108].…”

“…The formation of hydrates/solvates seems to be kinetically controlled, i.e. strongly dependent on the exact procedure of compression -decompression, and only on the value of pressure and temperature eventually reached [5,63,104,105]. For example, Lalanine in a MeOH-EtOH mixture forms no solvates if compressed rapidly to a pressure value above 6 GPa and preserved at this pressure.…”

Raman and terahertz spectroscopical investigation of cocrystal formation process of piracetam and 3-hydroxybenzoic acid

“…Piracetam is a cyclic derivative of GABA (c-aminobutyric acid), with chemical name 2-oxo-1-pyrrolidine acetamide. It is widely used for the treatment of post-stroke aphasia, epilepsy, cognitive decline following heart and brain surgery, and dementia [7]. Based on the tendency of hydrogen bonding motifs between amides and carboxylic acids, piracetam (as API) and 3-hydroxybenzoic acid (3-hBA, as CCF) are chosen as suitable model molecules in this study to investigate the formation of corresponding pharmaceutical cocrystal with chemical-green grinding method.…”