title: Clarifying the mechanism of aggregation of particles in high-shear granulation based on their surface properties by using micro-spectroscopy.
abstract: The present study aimed to clarify, by means of micro-spectroscopy, the mechanism of aggregation of particles into granules during high-shear granulation. We used two types of pharmaceutical granules prepared by high-shear granulator, one containing mefenamic acid and the other containing flavoxate hydrochloride as poorly soluble active pharmaceutical ingredients (APIs). Lactose, cornstarch, and microcrystalline cellulose were used as excipients; and hydroxypropyl cellulose (HPC) was used as the binding agent. The distributions of components in granules were visualized by mapping cross-sections of individual granules with techniques utilizing mid-infrared spectroscopy at the SPring-8 synchrotron radiation facility and micro-Raman spectroscopy. In the distribution maps of mefenamic acid granules, distributions of mefenamic acid, cornstarch, and microcrystalline cellulose overlapped; in flavoxate hydrochloride granules, on the other hand, distributions of flavoxate hydrochloride and lactose overlapped. Assessment of the surface free energy of each component found that ingredients with overlapping distribution had similar surface properties. Therefore, it was revealed that in high-shear granulation, in addition to the granulator operating conditions and general properties of the formulation itself (such as the solubility and particle size of each ingredient), the surface properties of the ingredients and their interrelationships were also factors that determined the aggregation behavior of the particles.
authors.affiliation: Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan; Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. Electronic address: kanoh.takeo12@chugai-pharm.co.jp.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kano
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshihashi
authors.affiliation: Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 148-8501, Japan.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Yonemochi
authors.affiliation: Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004339:Drug Compounding / Q000379:methods; D005079:Excipients / Q000737:chemistry*; D005422:Flavoxate / Q000008:administration & dosage* / Q000737:chemistry; D007785:Lactose / Q000737:chemistry; D008528:Mefenamic Acid / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013059:Spectrum Analysis, Raman / Q000379:methods; D013213:Starch / Q000737:chemistry; D013499:Surface Properties
chemical_list: D005079:Excipients; D008528:Mefenamic Acid; D005422:Flavoxate; D002482:Cellulose; D013213:Starch; C008079:hydroxypropylcellulose; D007785:Lactose; C109691:microcrystalline cellulose
keywords: Aggregation; Distribution map; High-shear granulation; Micro-spectroscopy; Surface free energy