Predicting crystal form stability under real-world conditions.

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2-4. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid-solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1-2 kJ mol-1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control5.

Complementarity of mDSC, DMA, and DRS Techniques in the Study of Tg and Sub-Tg Transitions in Amorphous Solids: PVPVA, Indomethacin, and Amorphous Solid Dispersions Based on Indomethacin/PVPVA.

Recently, glasses, a subset of amorphous solids, have gained attention in various fields, such as polymer chemistry, optical fibers, and pharmaceuticals. One of their characteristic features, the glass transition temperature (Tg) which is absent in 100% crystalline materials, influences several material properties, such as free volume, enthalpy, viscosity, thermodynamic transitions, molecular motions, physical stability, mechanical properties, etc. In addition to Tg, there may be several other temperature-dependent transitions known as sub-Tg transitions (or ß-, γ-, and δ-relaxations) which are identified by specific analytical techniques. The study of Tg and sub-Tg transitions occurring in amorphous solids has gained much attention because of its importance in understanding molecular kinetics, and it requires the combination of conventional and novel characterization techniques. In the present study, three different analytical techniques [modulated differential scanning calorimetry (mDSC), dynamic mechanical analysis (DMA), and dielectric relaxation spectroscopy (DRS)] were used to perform comprehensive qualitative/quantitative characterization of molecular relaxations, miscibility, and molecular interactions present in an amorphous polymer (PVPVA), a model drug (indomethacin, IND), and IND/PVPVA-based amorphous solid dispersions (ASDs). This is the first ever reported DMA study on PVPVA in its powder form, which avoids the contribution of solvent to the mechanical properties when a self-standing polymer film is used. A good correlation between the techniques in determining the Tg value of PVPVA, IND, and IND/PVPVA-based ASDs is established, and the negligible difference (within 10 °C) is attributed to the different material properties assessed in each technique. However, the overall Tg behavior, the decrease in Tg with increase in drug loading in ASDs, is universally observed in all the above-mentioned techniques, which reveals their complementarity. DMA and DRS techniques are used to study the different sub-Tg transitions present in PVPVA, amorphous IND, and IND/PVPVA-based ASDs because these transitions are normally too weak or too broad for mDSC to detect. For IND/PVPVA-based ASDs, both techniques show a shift of sub-Tg transitions (or secondary relaxation peaks) toward the high-temperature region from -140 to -45 °C. Thus, this paper outlines the usage of different solid-state characterization techniques in understanding the different molecular dynamics present in the polymer, drug, and their interactions in ASDs with the integrated information obtained from individual techniques.

Impact of sodium chloride on the expansion of a liquid-liquid miscibility gap in an API/water system. Case study of Brivaracetam.

Brivaracetam, or (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide, is an active pharmaceutical ingredient designed for the treatment of epilepsy. During the development of the IV administration mode, a liquid-liquid miscibility gap has been observed with pure water, isotonic and hypertonic solutions (vehicle at 0.9% w/w and 5%w/w NaCl respectively). The study reveals that the NaCl concentration has a direct impact on the extent of the demixing domain; from a sub-micronic demixing in pure water towards a macroscopic miscibility gap in hypertonic aqueous solutions. The thorough exploration of these heterogeneous equilibria led to define experimental parameters for safe IV injections without risk of liquid - liquid miscibility gap at 37°C.

Solid-liquid phase diagrams for the determination of the solid state nature of both polymorphs of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide.

This work focuses on the determination of the solid state nature of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide (Etiracetam), the racemic intermediate of (S)-2-(2-oxo-pyrrolidin-1-yl)-butyramide, an Active Pharmaceutical Ingredient, marketed under the name Levetiracetam(®). It is show how this information can easily be extracted from solid-liquid phase diagrams of the racemic system. As two polymorphs of Etiracetam are known (Forms I and II), the analyses have been performed considering both polymorphs. The solid-liquid phase diagrams are determined experimentally, using Differential Scanning Calorimetry, and theoretically, using the Prigogine-Defay and Schroeder-Van Laar equations. Only the phase diagram involving the polymorph stable at higher temperatures (Form II) can be constructed experimentally. The theoretical phase diagram involving this polymorph compares well with the experimental one, thus allowing the use of theoretical equations for the prediction of the solid-liquid phase diagram involving Form I, which is meta-stable above 30.5 °C. Our findings confirm that both polymorphs are racemic compounds, which is also confirmed by XRPD analysis.

Combining piracetam and lithium salts: ionic co-crystals and co-drugs?

Mechanochemical reaction of solid piracetam with the inorganic salts LiCl and LiBr yields ionic co-crystals which are also co-drugs, characterized by markedly different thermal properties with respect to pure components, also depending on the method for preparation and/or conditions of measurements; single crystal and powder X-ray diffraction at variable temperatures, DSC, TGA, hot stage microscopy (HSM) and intrinsic dissolution rate have been used to fully characterize the solid products.