Highly Crystalline Forms of Valsartan with Superior Physicochemical Stability

Single crystal structures of blockbuster antihypertensive drug Valsartan are revealed the first time in this report. Two new highly crystalline forms, named form E and an ethanol solvate form F, were discovered and fully characterized by PXRD, Raman, IR, TG, DSC, and DVS. Conformational flexibility and single crystal structures are discussed in detail. Physicochemical properties, such as hygroscopicity, chemical stability, crystallinity, and dissolution behaviors, are compared with the marketed solid-state form (amorphous state). The results show that the newly discovered highly crystalline form E presents a remarkably different dissolution behavior and superior chemical stability.

[1]  A. Bond,et al.  Polymorphs of Pridopidine Hydrochloride , 2012 .

[2]  A. Matzger,et al.  Structural and Physicochemical Aspects of Dasatinib Hydrate and Anhydrate phases. , 2012, Crystal growth & design.

[3]  Han‐Gon Choi,et al.  Novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes. , 2012, International journal of pharmaceutics.

[4]  Jaehoon Kim,et al.  Dissolution rate improvement of valsartan by low temperature recrystallization in compressed CO2: Prevention of excessive agglomeration , 2011 .

[5]  Lawrence X. Yu,et al.  The BCS, BDDCS, and Regulatory Guidances , 2011, Pharmaceutical Research.

[6]  J. Rantanen,et al.  Towards effective solid form screening. , 2010, Journal of pharmaceutical sciences.

[7]  Hyo-Kyung Han,et al.  Improved pH-independent dissolution and oral absorption of valsartan via the preparation of solid dispersion , 2010, Archives of pharmacal research.

[8]  R. Sinisterra,et al.  Pharmaceutical Composition of Valsartan: β-Cyclodextrin: Physico–Chemical and Characterization Anti-Hypertensive Evaluation , 2010, Molecules.

[9]  V. Kadam,et al.  Study of inclusion complexes of valsartan with β-cyclodextrin and hydroxypropyl β-cyclodextrin , 2010 .

[10]  Miranda L. Cheney,et al.  Effects of Crystal Form on Solubility and Pharmacokinetics: A Crystal Engineering Case Study of Lamotrigine , 2010 .

[11]  S. Rohani,et al.  Polymorphism and crystallization of active pharmaceutical ingredients (APIs). , 2009, Current medicinal chemistry.

[12]  Leonard J. Chyall,et al.  New solid-state chemistry technologies to bring better drugs to market: knowledge-based decision making , 2007, Expert opinion on drug discovery.

[13]  Rolf Hilfiker,et al.  POLYMORPHISM , 1945 .

[14]  A. Miro,et al.  Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin , 2006 .

[15]  Lawrence X. Yu,et al.  Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs). , 2004, Advanced drug delivery reviews.

[16]  W. Curatolo,et al.  Drug polymorphism and dosage form design: a practical perspective. , 2004, Advanced drug delivery reviews.

[17]  Michael J Cima,et al.  High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids. , 2004, Advanced drug delivery reviews.

[18]  Lawrence X. Yu,et al.  Scientific Considerations of Pharmaceutical Solid Polymorphism in Abbreviated New Drug Applications , 2003, Pharmaceutical Research.

[19]  M. Davies,et al.  The Qualitative and Quantitative Analysis of Chlorpropamide Polymorphic Mixtures by Near-Infrared Fourier Transform Raman Spectroscopy , 1993, Pharmaceutical Research.

[20]  M. Burnier,et al.  Angiotensin II Type 1 Receptor Blockers , 2001, Circulation.

[21]  P. Thürmann,et al.  Valsartan: a novel angiotensin Type 1 receptor antagonist , 2000, Expert opinion on pharmacotherapy.

[22]  G. Flesch,et al.  Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man , 1997, European Journal of Clinical Pharmacology.