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Dimorphism of the prodrug L-tyrosine ethyl ester: pressure-temperature state diagram and crystal structure of phase II

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Ivo B Rietveld
  • Maria Barrio
  • Josep-Lluís Tamarit
  • Béatrice Nicolaï
  • Jacco Van de Streek
  • Nathalie Mahé
  • René Ceolin
  • Bernard Do
Polymorphism is important in the field of solid-state behavior of drug molecules because of the continuous drive for complete control over drug properties. By comparing different structures of a series of L-tyrosine alkyl esters, it became apparent that the ethyl ester possesses dimorphism. Its structure was determined by powder diffraction and verified by density functional theory calculations; it is orthorhombic, P2(1) 2(1) 2(1) with a = 12.8679(8) Å, b = 14.7345(7) Å, c = 5.8333 (4) Å, V = 1106.01(11) Å, and Z = 4. The density of phase II is in line with other tyrosine alkyl esters and its conformation is similar to that of l-tyrosine methyl ester. The hydrogen bonds exhibit similar geometries for phase I and phase II, but the H-bonds in phase I are stronger. The solid II-solid I transition temperature is heating-rate dependent; it levels off at heating rates below 0.5 K min(-1), leading to a transition temperature of 306 ± 4 K. Application of the Clapeyron equation in combination with calorimetric and X-ray data has led to a topological diagram providing the relative stabilities of the two solid phases as a function of pressure and temperature; phase II is stable under ambient conditions.
OriginalsprogEngelsk
TidsskriftJournal of Pharmaceutical Sciences
Vol/bind100
Udgave nummer11
Sider (fra-til)4774-82
Antal sider9
ISSN0022-3549
DOI
StatusUdgivet - 2011
Eksternt udgivetJa

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