Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Comparative studies of the effects of novel excipients amino acids with cyclodextrins on enhancement of dissolution and oral bioavailability of the non-ionizable drug carbamazepine Heba A. Abou-Taleb a , Zeinab Fathalla b , Hamdy Abdelkader b,c, ⁎ a Department of Pharmaceutics and industrial pharmacy, Faculty of Pharmacy, Nahda University (NUB), Beni-suef, Egypt b Pharmaceutics Department, Faculty of Pharmacy, Minia University, Minia, Egypt c Department of Pharmaceutics, Faculty of Pharmacy, Deraya University, New Minia City, Minia, Egypt ARTICLE INFO Keywords: Solubility Dissolution rate Amino acids Molecular docking Comparative bioavailability Carbamazepine BCS Class II ABSTRACT Despite significant innovations in pharmaceutical industries, low water solubility is still a common bio- pharmaceutics-related problem that encounters 40% of marketed pharmaceutical products and results in erratic oral absorption and low bioavailability. Poorly soluble non-ionizable drugs pose additional challenges for en- hancing solubility of this class of drugs. The effects of small molecular weight carriers such as amino acids (glycine, L-threonine; L-lysine and aspartic acid) on solubilization and enhancing bioavailability of Carbamazepine (Car) were investigated and compared to the more known excipients cyclodextrins (β-CD, HPβ- CD and γ-CD). Drug-carrier PM and Coppt in 1:1 molar ratio were prepared; characterized for docking, solubility, DSC, FTIR, XRD and dissolution rate; and evaluated for their oral bioavailability. Molecular docking calcula- tions, spectral and thermal analysis confirmed Car-Amino acids ion pair complexes and Car-CDs inclusion complexes. While dissolution rate enhancement factors recorded for both CDs and amino acids were up to 12- times; additional permeation enhancing mechanism could explain superior relative bioavailability by approxi- mately 170% for Car: Amino acid complexes and 166% for Car: CDs compared with Car alone. This study warrants the use of amino acids as a promising small molecular weight and versatile water-soluble carrier for enhancing solubility/permeability and bioavailability for this non-ionizable drug. This might endow the for- mulator flexibility in the design and dosage form with less bulky economic and more patient friendly solid platform for those epileptic patients and/or elderly patients that can experience difficulty in swallowing and need rapid onset of action. 1. Introduction Drugs with low water-solubility are likely to show incomplete ab- sorption, inconsistent bioavailability and variability in therapeutic re- sponses. Notwithstanding substantial endeavours made by formulation scientists to optimize and overcome such pharmaceutical problems (poor aqueous solubility and dissolution rates), approximately 40% of currently marketed compounds and a majority (> 90%) of drug de- velopment candidates remain poorly water-soluble (Khoder et al., 2016; Kalepu and Nekkanti, 2015). Several formulation approaches including pH alterations, cosolvents, salt formation, particle size re- duction, surfactants, polymorphic modification, co-crystals, amorphi- zation and solubilization by macromolecules (CDs, polyethylene glycols and polyvinyl pyrrolidone) and liposomes have been investigated and adopted in pharmaceutical industries (Kalepu and Nekkanti, 2015; Loftsson, 2017; Abdelkader et al., 2007; Abdelkader et al., 2014). Non-ionizable drugs are those drugs that show pH-independent so- lubility and their water solubility is uniformly unaffected by the wide physiological gastrointestinal (GI) pH range (pH 1.2 to ≈ pH 7), hence; if this class of drugs showed poor solubility, the solubility would be likely to remain quite low across the GI anatomical parts and the total bioavailability would be affected, as well (Khoder et al., 2018). Stra- tegies that depend on pH changes or salt formation are not working with this class of drugs and that might pose additional challenges ahead of researchers in the field towards the developing of a viable pharma- ceutical product (Shah et al., 2014). amongst effective strategies for https://doi.org/10.1016/j.ejps.2020.105562 Received 14 July 2020; Received in revised form 8 September 2020; Accepted 17 September 2020 Abbreviations: BCS, Biopharmaceutics classification system; CDs, Cyclodextrins; Coppt, Coprecipitated dispersions; DSC, Differential scanning calorimetry; FTIR, Fourier transform infrared spectroscopy; PM, Physical mixtures; SEM, Scanning electron microscopy; XRD, X-ray diffraction ⁎ Corresponding author at: Pharmaceutics Department, Faculty of Pharmacy, Minia University, Minia, Egypt. E-mail address: h.abdelkader@mu.edu.eg (H. Abdelkader). European Journal of Pharmaceutical Sciences 155 (2020) 105562 Available online 20 September 2020 0928-0987/ © 2020 Elsevier B.V. All rights reserved. T