Molecular dynamics, viscoelastic properties and physical stability studies of a new amorphous dihydropyridine derivative with T-type calcium channel blocking activity

Knapik-Kowalczuk J., GÜNDÜZ M. G., Chmiel K., Jurkiewicz K., Kurek M., Tajber L., ...Daha Fazla

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, cilt.141, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 141
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.ejps.2019.105083
  • Dergi Adı: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Anahtar Kelimeler: Molecular dynamics, BDS, Physical stability, Amorphous APIs, Melt viscosity, Dihydropyridine, Calcium channel blocker, SOLUBILITY ADVANTAGE, TEMPERATURE-DEPENDENCE, RELAXATION DYNAMICS, SOLID DISPERSIONS, GLASSY STATES, DRUG, PHARMACEUTICALS, CRYSTALLIZATION, MOBILITY, LIQUID
  • Hacettepe Üniversitesi Adresli: Evet

Özet

One of the greatest problems of pre-clinical development of new chemical entities is their poor aqueous solubility. Herein, we focus our attention on MD20 - a novel calcium channel blocker that selectively blocks T-type calcium channel (Ca(v)3.2) over L-type calcium channel (Ca(v)1.2). To avoid future problems with limited solubility of this compound, an amorphous form of MD20 was obtained and thoroughly investigated by various experimental techniques. The thermal properties of both crystalline and amorphous MD20 were examined by differential scanning calorimetry and thermogravimetry. Dielectric spectroscopy studies of MD20 at T < T-g revealed that this compound possesses as many as four secondary relaxation processes. The molecular dynamics of the supercooled sample was investigated by dielectric and mechanical spectroscopies. In this paper, a comparison of the relaxation dynamics of supercooled MD20 obtained from both of these experimental techniques is presented. On the basis of the dielectric studies, the time of physical stability of the investigated material (at T=298 K) was predicted as 150 years. Finally, we have performed experimental long-term stability tests, which showed that amorphous MD20 did not reveal any signs of re-crystallization for at least 260 days.