title: Investigation of salt formation between memantine and pamoic acid: Its exploitation in nanocrystalline form as long acting injection.
abstract: In the present work, we prepared memantine-pamoic acid (MEM-PAM) salt by counter ion exchange in the aqueous phase to reduce the water solubility of MEM hydrochloride (native form) to make it suitable for long acting injection. The ratio of MEM to PAM in salt formation was optimized to maximize the loading efficiency and complexation efficiency. The 2:1 molar ratio of MEM to PAM salt form displayed nearly 95% complexation efficiency and 50% drug loading. The solubility was decreased by a ∼1250 folds. Thermo Gravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction Analysis (PXRD) studies revealed the formation of new solid phase. Additionally, Nuclear Magnetic Resonance (NMR) spectroscopy confirmed the anhydrous nature of the salt form. Through Fourier transformation infrared spectroscopy (FT-IR) we identified the molecular interactions. Further, the microcrystals of the salt were transformed into nanocrystals (NCs) using high pressure homogenization. The particle size distribution and atomic force microscopy confirmed the monodispersed and spherical shape of the NCs. The in vitro dissolution studies were performed under sink condition in phosphate buffer saline pH 6.8. The results of MTT assay in murine fibroblast 3T3 cell line show that the NCs were less cytotoxic and more tolerable than plain MEM HCl. The in vivo performance of NCs administered as i.m. injection at three different doses in female Sprague-Dawley rats showed that the plasma levels lasted till the 24th day of the study. The pharmacokinetic parameters AUC0-∞ and Cmax increased linearly with increasing dose. Therefore, the results suggest that injectable NCs could represent a therapeutic alternative for the treatment of AD.
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Naresh
authors: N
authors: Mittapelly
authors: Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Ramakrishna
authors: R
authors: Rachumallu
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Gitu
authors: G
authors: Pandey
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Shweta
authors: S
authors: Sharma
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Abhishek
authors: A
authors: Arya
authors: Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India.
authors: Rabi Shankar
authors: RS
authors: Bhatta
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-CDRI Campus, Lucknow, India. Electronic address: mishrapr@hotmail.com.
authors: Prabhat Ranjan
authors: PR
authors: Mishra
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002460:Cell Line; D005260:Female; D007267:Injections / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008559:Memantine / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008855:Microscopy, Electron, Scanning / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009284:Naphthols / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000008:administration & dosage / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D009284:Naphthols; D012492:Salts; C004368:pamoic acid; D008559:Memantine
keywords: Extended release; High pressure homogenization; Hydrophobic salt formation; Long acting injection; Memantine; Nanocrystals; Pharmacokinetic modeling