Effect of cyclodextrins on the solubility and stability of candesartan cilexetil in solution and solid state

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 54; no. 3; pp. 503 - 509
• Main Authors: Al Omari, Alaa’ A., Al Omari, Mahmoud M., Badwan, Adnan A., Al-Sou’od, Khaldoun A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 20-02-2011; Elsevier
• Subjects: Analysis; Analytical, structural and metabolic biochemistry; Antihypertensive Agents - analysis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Benzimidazoles - analysis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; beta-Cyclodextrins - analysis; beta-Cyclodextrins - chemistry; Biological and medical sciences; Biphenyl Compounds - analysis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Calorimetry, Differential Scanning; Candesartan cilexetil; Chromatography, High Pressure Liquid; Cyclodextrin; cyclodextrins; Cyclodextrins - analysis; Cyclodextrins - chemistry; differential scanning calorimetry; Drug Stability; enthalpy; entropy; Freeze Drying; Fundamental and applied biological sciences. Psychology; General pharmacology; high performance liquid chromatography; Humans; kneading; Medical sciences; Models, Molecular; Molecular modelling; Pharmacology. Drug treatments; Solubility; Solutions; Stability; Tablets; Tetrazoles - analysis; Tetrazoles - chemistry; Tetrazoles - pharmacology; Thermodynamics; X-radiation; X-Ray Diffraction; Candesartan cilexetil; Cyclodextrin; Stability; Molecular modelling; Solubility; Imidazole derivatives; Tetrazole derivatives; Cilexetil; Peptides; Candesartan; Peptide hormone; Solid state; Octapeptide; Renin angiotensin system; Biphenyl derivatives; Molecular model; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Angiotensin II; Inclusion compound; Physicochemical properties
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2010.09.027

Guest–host interactions of candesartan cilexetil (CAND) with cyclodextrins (CyDs) have been investigated using phase solubility diagrams (PSD), X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and molecular mechanical modelling (MM). Estimates of the complex formation constant (
K
11) show that the tendency of CAND (p
K
a
=
6.0) to complex with CyDs follows the order: β-CyD
>
HP-β-CyD
>
γ-CyD
>
α-CyD. Complex formation of CAND with β-CyD (Δ
G°
=
−31.5
kJ/mol) is largely driven by enthalpy change (Δ
H°
=
−32.8
kJ/mol) and slightly retarded by entropy change (Δ
S°
=
−4.6
J/mol
K). The HPLC results indicate that complex prepared by freeze drying method is chemically not stable due to the formation of amorphous CAND. Also it may suggest formulating CAND with β-CyD by kneading (dispersion) or co-evaporation (real inclusion complex) methods into capsule rather than compressed in tablets, where the compression enhances the instability of CAND. DSC thermograms for CAND/β-CyD complexes proved the formation of inclusion complexes with new solid phase. MM studies indicate the partial penetration of CAND into the β-CyD cavity.