Mechanism of Nanoparticle Formation from Ternary Coground Phenytoin and Its Derivatives

• Published in: Journal of pharmaceutical sciences Vol. 101; no. 9; pp. 3413 - 3424
• Main Authors: Moribe, Kunikazu, Ogino, Akiko, Kumamoto, Takuya, Ishikawa, Tsutomu, Limwikrant, Waree, Higashi, Kenjirou, Yamamoto, Keiji
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.09.2012; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: AFM; Biological and medical sciences; Chemistry, Pharmaceutical; Crystallization; Drug Stability; General pharmacology; grinding; interaction; Magnetic Resonance Spectroscopy; Medical sciences; Methylation; Microscopy, Atomic Force; nanoparticle; Nanoparticles; Nanotechnology; NMR; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; phenytoin; Phenytoin - analogs & derivatives; Phenytoin - chemistry; physicochemical; physicochemical; solid state; NMR; Povidone - chemistry; Sodium Dodecyl Sulfate - chemistry; solid state; Spectroscopy, Fourier Transform Infrared; Technology, Pharmaceutical - methods; Water - chemistry; NMR; grinding; interaction; AFM; nanoparticle; phenytoin; physicochemical; solid state; Pharmaceutical technology; Nanoparticle; Interaction; Grinding(comminution); Anticonvulsant; Nuclear magnetic resonance imaging; Solid state; Microparticle; Formation mechanism; Phenytoin
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.23141

The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and 13C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association.