Cocrystallization and amorphization induced by drug–excipient interaction improves the physical properties of acyclovir

• Published in: International journal of pharmaceutics Vol. 422; no. 1; pp. 160 - 169
• Main Authors: Masuda, Takaaki, Yoshihashi, Yasuo, Yonemochi, Etsuo, Fujii, Kotaro, Uekusa, Hidehiro, Terada, Katsuhide
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 2012
• Subjects: absorption; Acyclovir; Acyclovir - administration & dosage; Acyclovir - chemistry; Acyclovir - metabolism; Administration, Cutaneous; Amorphous; Animals; antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; citric acid; Citric Acid - chemistry; Cocrystal; Crystallization; Crystallography, X-Ray; Dissolution rate; Drug Compounding; drugs; Drug–excipient interactions; Excipients - chemistry; high performance liquid chromatography; Hydrogen-Ion Concentration; Kinetics; Male; Mice; Mice, Hairless; Models, Molecular; Ointments; physical properties; polyethylene glycol; Polyethylene Glycols - chemistry; Powder Diffraction; screening; Skin - metabolism; Skin Absorption; Solubility; Spectroscopy, Fourier Transform Infrared; Synchrotrons; tartaric acid; Tartrates - chemistry; Technology, Pharmaceutical - methods; Thermogravimetry; Transdermal absorption; X-radiation; Amorphous; Drug–excipient interactions; Transdermal absorption; Acyclovir; Dissolution rate; Cocrystal
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.10.046

Packing diagram along the
ab plane for ACV–TA cocrystal (a) and the
bc plane for ACV–TA cocrystal (b).
Although acyclovir is one of the most important antiviral drugs used today, there are several problems with its physical properties. The aim of this study is to prepare cocrystals or amorphous complex of acyclovir using drug–excipient interactions to improve the physical properties of the drug, especially its dissolution rate and transdermal absorption. Screening for formation of cocrystals and the presence of amorphous acyclovir was conducted with various pharmaceutical excipinents, with the use of the solution-crystallization method and liquid-assisted cogrinding. The potential cocrystalline phase and the amorphized complex were characterized by PXRD, TG/DTA, IR, DSC and HPLC techniques. The screening indicated that acyclovir formed novel cocrystals with tartaric acid and was amorphized with citric acid. The acyclovir–tartaric acid cocrystal (ACV–TA cocrystal) structure was determined from synchrotron X-ray powder diffraction data.
T
g of the amorphous acyclovir–citric acid compound (ACV–CA amorphous) was determined by DSC. The initial dissolution rate of the ACV–TA cocrystals was considerably faster than that of anhydrous acyclovir.
In vitro skin permeation of ACV–CA amorphous from polyethylene glycol (PEG) ointment was remarkably higher than that of the crystalline acyclovir. We successfully improved the physical properties of acyclovir by the cocrystallization and amorphization techniques, using pharmaceutical excipients.