Polymorphs of Pridopidine Hydrochloride

Abstract

Pridopidine hydrochloride (Huntexil, Neuro-Search A/S, Ballerup, Denmark) is a dopaminergic stabilizer, currently in development for the treatment of motor symptoms associated with Huntington's disease. In this study, two polymorphic forms are characterized, forms I and II. The crystal structures of both polymorphs contain Nand the polymorphism can be viewed as alternative orientations (parallel or antiparallel) of comparable molecular columns while retaining theForms I and II have melting points of 199 and 210 °C, respectively. Following melting of form I, a kinetically controlled crystallization to form II is observed. The polymorphs are enantiotropically related, form I being stable at ambient conditions and form II being stable above 127 °C. At around 180 °C, the differential scanning calorimetry thermogram of a mixture of forms I and II shows a solid-state transition from form I to form II, which is not observed for pure form I samples. Transformation of form II to form I below the transition temperature is solution-mediated. Because of the thermodynamic relation and the propensity for transformations, the safety, quality, and efficacy of pridopidine hydrochloride is not affected by the existence of form II.

Solvates of the antifungal drug griseofulvin: structural, thermochemical and conformational analysis

“…This suggests that the 2:1 solvate is thermodynamically more stable than the 1:1 solvate at room temperature. Interestingly, while solvent mediated polymorphic phase transformations are well known in the literature (Thirunahari et al, 2009;Maher et al, 2012;Prohens et al, 2012;Zimmermann et al, 2012;Gomez et al, 2012), examples of phase transformation of a solvate to another solvate (of the same solvent) with different stoichiometry are seldom reported. A recent precedent of this kind has been reported by Tanaka et al (2005): an organic host, 2,3-bis-fluoren-9-ylidene succinic acid, forms a 1:1 solvate (needles) with ethanol which completely transforms to 1:2 solvate (prisms) in the solvent.…”

Pseudopolymorphs of LB30870, a Direct Thrombin Inhibitor: One-Dimensional Solvent Channel Structures Explain Reversible Hydration/Dehydration

“…Pharmaceutical solids can exist in several subphases, such as polymorphs, solvates, hydrates, and cocrystals. − Different solid forms (at different free energy states) of the same molecule often show different physical properties including solubility, melting point, particle size, dissolution rate, hygroscopicity, and others. Phase transitions such as polymorph interconversion, desolvation of solvates, formation of hydrate, and conversion of crystalline to amorphous form may occur during various chemical and pharmaceutical processes. − In particular, hydrates are frequently found and may be classified as stoichiometric or nonstoichiometric. − Stoichiometric hydrates have well-defined water content with step-shaped isotherms and a different crystal structure than the anhydrous drug or other hydrates.…”

Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery

“…We calculated the values of r , φ 1 , φ 2 , and θ from the X-ray data for the compounds 20 ·HCl, 13a , 14a , and 14b (from this work), as well as piperidine derivatives 25 – 28 (described in the literature) − (Table ). Analysis of the data obtained using EVP (Figure ) showed that 3,6-disubstituted 3-azabicyclo[3.2.0]­heptane scaffolds (3,6-ABH, r = 3.11–3.34 Å) were larger than both 1,3- and 1,4-disubstituted piperidines ( r = 2.50–2.52 Å and 2.89–2.94 Å, respectively).…”