title: Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement.
abstract: The aim of the present work was to prepare a co-amorphous mixture (COAM) of Nateglinide and Metformin hydrochloride to enhance the dissolution rate of poorly soluble Nateglinide. Nateglinide (120 mg) and Metformin hydrochloride (500 mg) COAM, as a dose ratio, were prepared by ball-milling technique. COAMs were characterized for saturation solubility, amorphism and physicochemical interactions (X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR)), SEM, in vitro dissolution, and stability studies. Solubility studies revealed a sevenfold rise in solubility of Nateglinide from 0.061 to 0.423 mg/ml in dose ratio of COAM. Solid-state characterization of COAM suggested amorphization of Nateglinide after 6 h of ball milling. XRPD and DSC studies confirmed amorphism in Nateglinide, whereas FTIR elucidated hydrogen interactions (proton exchange between Nateglinide and Metformin hydrochloride). Interestingly, due to low energy of fusion, Nateglinide was completely amorphized and stabilized by Metformin hydrochloride. Consequently, in vitro drug release showed significant increase in dissolution of Nateglinide in COAM, irrespective of dissolution medium. However, little change was observed in the solubility and dissolution profile of Metformin hydrochloride, revealing small change in its crystallinity. Stability data indicated no traces of devitrification in XRPD of stability sample of COAM, and % drug release remained unaffected at accelerated storage conditions. Amorphism of Nateglinide, proton exchange with Metformin hydrochloride, and stabilization of its amorphous form have been noted in ball-milled COAM of Nateglinide-Metformin hydrochloride, revealing enhanced dissolution of Nateglinide. Thus, COAM of Nateglinide-Metformin hydrochloride system is a promising approach for combination therapy in diabetic patients.
authors: Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra, 400 056, India. sarikawairkar@gmail.com.
authors: Sarika
authors: http://orcid.org/0000-0002-0124-1741
authors: S
authors: Wairkar
authors: Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra, 400 056, India.
authors: Ram
authors: R
authors: Gaud
mesh_terms: D002626:Chemistry, Pharmaceutical; D003510:Cyclohexanes / Q000032:analysis* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004338:Drug Combinations; D008687:Metformin / Q000032:analysis* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D003510:Cyclohexanes; D004338:Drug Combinations; D000077715:Nateglinide; D010649:Phenylalanine; D008687:Metformin
keywords: COAM; Metformin hydrochloride; Nateglinide; dose ratio; improved Nateglinide dissolution