Novel Bioequivalent Sitagliptin and Metformin Bilayer Tablet with Improved Chemical Stability

Abstract

Objectives: Fixed-dose combination tablets containing sitagliptin hydrochloride (SG) and metformin hydrochloride (MF) are a mainstay in the clinical management of type 2 diabetes. However, SG is highly susceptible to chemical degradation during storage, particularly in the presence of MF. Herein, a bilayer tablet in which SG and MF are physically separated into distinct layers was designed to enhance the chemical stability of SG while ensuring pharmacokinetic equivalence to the marketed reference product Janumet^®.

Methods: The compositions of individual SG and MF compartments were selected based on evaluations of their physical properties and dissolution profiles. Critical process parameters, including the pre- and main compression forces and coating levels of bilayer tablets, were fine-tuned to achieve dissolution characteristics comparable to those of the reference product.

Results: Under accelerated storage conditions (40 °C, 75% relative humidity), the optimized bilayer tablet exhibited superior stability, with total SG-related impurity levels of 0.18% compared with 0.86% in the reference product after six months. Furthermore, in a randomized bioequivalence study in healthy volunteers (n = 30), the SG/MF bilayer tablet was pharmacokinetically equivalent to the reference product, with all parameters falling within the Food and Drug Administration-mandated regulatory criteria.

Conclusions: In conclusion, this SG/MF bilayer tablet has better storage stability than the reference product and may be an alternative to conventional SG/MF combination tablets.

Introduction

Fixed-dose combination (FDC) therapy has emerged as a cornerstone in the clinical management of chronic diseases, particularly type 2 diabetes mellitus (T2DM), for which complex multidrug regimens are frequently necessitated. By consolidating multiple active pharmaceutical ingredients (APIs) into a single-dosage form, FDCs significantly mitigate “pill burden,” thereby enhancing patient treatment adherence and improving overall therapeutic outcomes [1]. Among the various synergistic combinations used for T2DM, the co-administration of a biguanide derivative and a dipeptidyl peptidase-4 (DPP-4) inhibitor is widely recognized for its superior glycaemic control and favourable safety profile [2].

Metformin hydrochloride (MF), a representative biguanide, remains the global gold standard first-line treatment for T2DM [3]. It exerts its antihyperglycemic effect by suppressing hepatic gluconeogenesis and increasing peripheral insulin sensitivity, while reducing the risk of hypoglycaemia and maintaining a weight-neutral profile [4]. MF has a high daily dose requirement (up to 2000 mg) and is primarily absorbed in the upper gastrointestinal tract, with a moderate oral bioavailability of 50–60% [5]. Sitagliptin hydrochloride (SG), a potent DPP-4 inhibitor, is frequently added to this regimen to improve glucose homeostasis by preventing the enzymatic degradation of incretin hormones, such as glucagon-like peptide-1 (GLP-1). This mechanism stimulates insulin secretion and suppresses glucagon release in a glucose-dependent manner [6]. Currently, several FDC products incorporating both of these agents into a monolithic matrix tablet are commercially available and widely utilized in clinical practice because SG/MF FDC tablets provide therapeutic convenience and have demonstrated bioequivalence to the concomitant administration of the individual components [7,8]. However, the formulation of these APIs into a conventional monolithic (single-layer) matrix presents significant pharmaceutical challenges, primarily regarding chemical stability while maintaining bioequivalent performance. SG is a chemically labile molecule; it is particularly prone to degradation under thermal and moisture stress [6]. In a shared matrix system including MF, the stability of SG is further compromised. This is due to the ability of MF, as a strongly basic biguanide, to elevate the local micro-environmental pH, which catalyses the deprotonation of the primary amine group of SG. This nucleophilic activation triggers deleterious drug–drug interactions and promotes the formation of various degradation products, such as N-acyl derivatives and cyclized adducts, during manufacturing and long-term storage [9,10,11]. In addition, SG stability is compromised by incompatibility with the lubricant sodium stearyl fumarate (SSF), which is commonly employed in MF/SG FDC tablets. Its primary amine undergoes a nucleophilic Michael addition with the fumarate moiety of SSF to form N-succinyl sitagliptin.

Multilayer tablets, including bilayer tablets (BLTs), represent an advanced solid oral dosage form that consolidates two distinct formulations into a single cohesive unit through a sequential compaction process. Beyond the primary benefit of reducing pill burden, the BLT architecture serves as a sophisticated engineering solution for managing complex drug–drug and drug–excipient interactions [12]. Furthermore, BLT systems enable the independent modulation of drug release profiles by targeting the individual layers [13]. Recent studies have demonstrated that the performance of BLTs is strongly governed by layer-specific formulation design, structural configuration, and process optimization, including Quality by Design (QbD)-based formulation strategies and hybrid manufacturing approaches [14,15]. Despite these advantages, BLTs are susceptible to mechanical failures, such as lamination or interfacial separation, which are often driven by differences in the elastic recovery and plastic deformation characteristics of the materials constituting the two layers during decompression [16]. To ensure structural integrity, it is paramount to adjust the pre-compression force (PRE-F) and main compression force (MAIN-F) accordingly. Precise modulation of PRE-F is required to facilitate sufficient granule fragmentation and provide a receptive surface for the second layer, while the MAIN-F predominantly affects the hardness, porosity, and release profile of multilayer tablets [17]. Beyond these mechanical constraints, establishing dual-drug compatibility to minimize physical or chemical interactions through a bilayer architecture, while simultaneously achieving pharmacokinetic bioequivalence of both active ingredients compared to their monolithic counterparts, remains highly challenging. Due to the substantial dose asymmetry between SG and MF, coupled with the restricted absorption of MF in the upper small intestine (the ‘absorption window’), achieving in vivo bioequivalence requires sophisticated formulation study [10]. While a previous study has documented a sitagliptin phosphate and MF bilayer formulation [11], the crucial influence of compaction force on mechanical strength, drug release behavior, and the chemical stability of BLT was not investigated. Consequently, critical insights into these formulation–process–performance interrelationships remain to be elucidated.

This study aimed to develop an SG/MF BLT with enhanced chemical stability and a bioequivalent pharmacokinetic (PK) profile compared with that of a monolithic matrix tablet (MRP; Janumet® 50/1000 mg, Merck, Rahway, NJ, USA). To achieve this, the SG and MF compartments were separately prepared via direct compression and wet granulation, respectively, aligning their dissolution profiles with those of the MRP. These two compartments were subsequently consolidated into a BLT system, where the PRE-F, MAIN-F, and film-coating levels were fine-tuned to ensure adequate mechanical properties and achieve target release profiles. The chemical stability of the optimized BLT was evaluated under accelerated conditions (40 °C/75% RH) for 6 months. Furthermore, a randomized, crossover PK design and bioequivalence between BLT and MRP were evaluated in healthy adult subjects, with validated LC-MS/MS analysis.

Download the full article as PDF here Novel Bioequivalent Sitagliptin and Metformin Bilayer Tablet with Improved Chemical Stability

or continue reading here

Materials

SG hydrochloride and MF hydrochloride were obtained from Korea Biochem Pharm. Co., Ltd. (Sejong, Republic of Korea) and ABHILASHA PHARMA (Ankleshwar, India), respectively. The D90 (the particle diameter at which 90% of the cumulative volume is smaller than this value) values of SG and MF powder were 130.8 and 38.2 μm, respectively, as measured using a laser diffraction particle size analyzer (Mastersizer 3000; Malvern Panalytical, Malvern, UK). Microcrystalline cellulose (MCC; HEWETEN® 102 and VIVAPUR® 200) and SSF (PRUV®) were obtained from JRS Pharma (Rosenberg, Germany). Dicalcium phosphate dihydrate (DCPD; Di-Tab®) was obtained from Innophos (Cranbury, NJ, USA). Povidone K30 (Kollidon® 30) was obtained from BASF (Ludwigshafen, Germany), and hydroxypropyl cellulose (HPC-L) was obtained from Nippon Soda (Tokyo, Japan). Croscarmellose sodium (Primellose®) was obtained from DFE Pharma (Goch, Germany), colloidal silicon dioxide (Aerosil® 200) was obtained from Evonik (Essen, Germany), and magnesium stearate was obtained from Faci (Carasco, Italy). The film-coating material Tabshield Brown 21B907 was composed of polyvinyl alcohol (40.0%), titanium dioxide (17.6%), polyethylene glycol 3350 (20.2%), talc (14.8%), red iron oxide (6.0%), and yellow iron oxide (1.4%) and was obtained from Copitek (Suwon, Republic of Korea). The MRP, Janumet® 50/1000 mg tablets (Merck, Rahway, NJ, USA), was purchased from Shindeok Pharmaceutical Co., Ltd. (Seoul, Republic of Korea; lot No. T035331 and U009951) and used for comparative dissolution and bioequivalence analyses. All solvents were of high-performance liquid chromatography grade.

Yang, I.G.; Han, J.-Y.; Jeong, M.Y.; Seo, D.-W.; Kang, M.J.; Kim, S.H. Novel Bioequivalent Sitagliptin and Metformin Bilayer Tablet with Improved Chemical Stability. Pharmaceutics 2026, 18, 1066. https://doi.org/10.3390/pharmaceutics18091066

Are you looking for excipients in commercial quantities?