Dimorphism of the prodrug l‐tyrosine ethyl ester: Pressure–temperature state diagram and crystal structure of phase II

• Published in: Journal of pharmaceutical sciences Vol. 100; no. 11; pp. 4774 - 4782
• Main Authors: Rietveld, Ivo B., Barrio, Maria, Tamarit, Josep‐Lluís, Nicolaï, Béatrice, Van de Streek, Jacco, Mahé, Nathalie, Ceolin, René, Do, Bernard
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.11.2011; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: Biological and medical sciences; calorimetry (DSC); Calorimetry, Differential Scanning; Chemical Sciences; crystal polymorphism; crystal structure; Crystallization; General pharmacology; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; polymorphism; Powder Diffraction; Pressure; Prodrugs - chemistry; stability; Temperature; thermal analysis; thermodynamics; Tyrosine - analogs & derivatives; Tyrosine - chemistry; X-ray powder diffractometry; calorimetry (DSC); crystal polymorphism; X‐ray powder diffractometry; crystal structure; thermodynamics; polymorphism; stability; thermal analysis; Tyrosine; Differential scanning calorimetry; Temperature; Stability; Pharmaceutical technology; Prodrug; Pressure; Powder; Ester; Thermodynamics; Aminoacid; X-ray powder diffractometry; Thermal analysis; X ray diffractometry; Physicochemical properties; Polymorphism; Crystalline structure
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.22672

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, P212121 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. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4774–4782, 2011