(<i>S</i>)-3-(Ammoniomethyl)-5-methylhexanoate (pregabalin)

Nalivela, Venu; Vishweshwar, Peddy; Thaimattam, Ram; Devarakonda, Surya; Bhattacharya, Apurba

doi:10.1107/s0108270107016952

Cited by 10 publications

(6 citation statements)

References 6 publications

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“…Among them, (S)-3-isobutyl--aminobutyric acid, or Pregabalin (SPG), is an anticonvulsant blockbuster drug. In the anhydrous P2 1 2 1 2 1 crystal, which has the refcode CIDDEZ (Venu et al, 2007) in the CSD (Groom et al, 2016), the zwitterion dipoles pack along the b axis generating a double layer that is coplanar to the (110) plane. The structure is supported by a 2D network of charge-assisted hydrogen bonds between the ammonium and carboxylate groups [ Fig.…”

Section: Resultsmentioning

confidence: 99%

Plasticity in zwitterionic drugs: the bending properties of Pregabalin and Gabapentin and their hydrates

Khandavilli

Lusi

Frawley

2019

Int Union Crystallogr J

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The investigation of mechanical properties in molecular crystals is emerging as a novel area of interest in crystal engineering. Indeed, good mechanical properties are required to manufacture pharmaceutical and technologically relevant substances into usable products. In such endeavour, bendable single crystals help to correlate microscopic structure to macroscopic properties for potential design. The hydrate forms of two anticonvulsant zwitterionic drugs, Pregabalin and Gabapentin, are two examples of crystalline materials that show macroscopic plasticity. The direct comparison of these structures with those of their anhydrous counterparts, which are brittle, suggests that the presence of water is critical for plasticity. In contrast, structural features such as molecular packing and anisotropic distribution of strong and weak interactions seem less important.

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Section: Resultsmentioning

confidence: 99%

Plasticity in zwitterionic drugs: the bending properties of Pregabalin and Gabapentin and their hydrates

Khandavilli

Lusi

Frawley

2019

Int Union Crystallogr J

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“…Samples of the solids were gently ground into a fine powder and measured on a PANalytical EMPYREAN diffractometer using Bragg–Brentano geometry and an incident beam of Cu Kα radiation (λ = 1.5406 Å). Scans were performed at room temperature on a spinning silicon sample holder with a step size of 0.013° 2θ and a step time of 68 s. An XPRD pattern from a reported single X-ray structure (CSD code CIDDEZ) of pregabalin was used as a reference . Single-crystal data of the anhydrate (CSD code CIDDEZ) as well as the two similar hydrate forms (CCDC numbers 1879470 and 1879471) was used to illustrate the proposed dehydration mechanism, as shown in Figure .…”

Section: Methodsmentioning

confidence: 99%

Solution versus Crystal Hydration: The Case of γ-Amino Acid Pregabalin

Steendam

Khandavilli

Keshavarz

et al. 2019

Crystal Growth & Design

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Understanding the link between solution chemistry and nucleation is essential to control crystallization processes, in particular regarding pharmaceutical compounds. In the present work, the link between the solution hydration state and crystallization of the γ-amino acid pregabalin is presented. Pregabalin is a blockbuster pharmaceutical drug having broad therapeutic effects. Using induction time experiments in combination with the classical nucleation theory, we show that the ease of nucleation increases with solubility and water fraction of the solvent. Water was found to enhance both the kinetic and thermodynamic processes of forming a nuclei. As a result, larger clusters which represent the hydrate form were measured using dynamic light scattering in pure water. Once in the solid state, the hydrate form of pregabalin was found to be physically unstable, as it rapidly converted back into its anhydrate form, as rationalized using in-line Raman spectroscopy. Thus, the hydration and nucleation of pregabalin in solution is highly favored, as opposed to the solid-state situation, where the anhydrate is the stable form. Despite these differences, a solution–crystallization link could still be established in our work. Knowledge of the solution chemistry and structural landscape of pharmaceutical compounds is essential for the development of manufacturing routes and patent protections, and we foresee that the presented approach can be used to further reveal relationships among self-association in solution, crystallization, and hydration of a wide range of organic compounds.

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“…( S )-Pregabalin has a thermodynamically stable anhydrous form 44,45 produced worldwide and two recently discovered monohydrates. 46,47 ( S )-PG hydrates can nucleate in water-containing solvents, but they are unstable in solid state and transform to anhydrate rapidly.…”

Section: Introductionmentioning

confidence: 99%

“…40 The less bioactive (R)enantiomer can be racemized and recycled or used as a resolving agent to produce other asymmetric chemicals. [41][42][43] (S)-Pregabalin has a thermodynamically stable anhydrous form 44,45 produced worldwide and two recently discovered monohydrates. 46,47 (S)-PG hydrates can nucleate in watercontaining solvents, but they are unstable in solid state and transform to anhydrate rapidly.…”

Section: Introductionmentioning

confidence: 99%