Pain remains as a major clinical problem which affects about 20 % of the adult population worldwide (Zhuang et al., 2021). However, the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, including persistent inflammatory pain (Goldberg and McGee, 2011). In clinic, multimodal analgesia is highly recommended to improve analgesic effect and reduce adverse effects (O'Neill and Lirk, 2022). In addition, the development of drug-drug salts based on hydrogen-bonded organic frameworks (Gao et al., 2022) has been reported to have great significance in improving drug solubility, intrinsic dissolution rate, stability, and exerting synergistic effects, such as norfloxacin-sulfathiazole (Gopi et al., 2016), lamotrigine-tolfenamic acid (Li et al., 2022), tranexamic acid-salicylic acid (Nechipadappu et al., 2019), and levetiracetam-ibuprofen (Machado et al., 2017). Hence, drug-drug salts may result in improved clinical benefits than individual drugs or their combinations.

Recently, metformin (MET, Scheme 1), a widely used antihyperglycemic drug for treating type 2 diabetes mellitus (Acebedo-Martínez et al., 2023), has been reported to possess analgesic effects for inflammatory and neuropathic pain (Dasuni Wasana et al., 2022, Pecikoza et al., 2022). MET can activate adenosine monophosphate-activated kinase (AMPK) which has been suggested to play a role in regulating pain transmission (Russe et al., 2013, Price and Dussor, 2013). Recent studies have indicated that MET can synergize with analgesics to alleviate hyperalgesia in an inflammatory pain model (Pecikoza et al., 2017).

Inflammatory pain is among the most prevalent forms of acute and chronic pain (Machelska et al., 2004). NSAIDs (nonsteroidal anti-inflammatory drugs), such as ibuprofen (IBU, Scheme 1) and naproxen (NAP, Scheme 1), are cyclooxygenase (COX) enzyme inhibitors which exhibit anti-inflammatory, antinociceptive, and antipyretic effects (Cashman, 1996). However, many NSAIDs are poorly water-soluble drugs and have some side effects, such as gastrointestinal damage (García-Rayado et al., 2018), nephrotoxicity (Baker and Perazell, 2020), hepatotoxicity (Aithal, 2011). Many adverse reactions of NSAIDs were related to high dosage and irregular medication intake (Grosset and Grosset, 2007). Drug-drug salt crystals are a well-established strategy for preparing new phase(s) and optimizing the physicochemical properties of drugs (Putra et al., 2016). Therefore, drug-drug salt crystals of MET with IBU and NAP may not only improve the solubility of IBU and NAP, but also achieve synergistic antinociceptive effects for inflammatory pain, the thus reducing their dose-dependent side effects.

Up to present, several drug-drug salt crystals of MET and NSAIDs (such as diclofenac, mefenamic acid, and flurbiprofen) have been reported to improve the physicochemical properties of MET or NSAIDs (Feng et al., 2021, Acebedo-Martínez et al., 2023). The synergistic analgesic effects of drug-drug salts of MET and NSAIDs have not been reported. In present work, we prepared two new drug-drug salt crystals of MET with IBU or NAP by the solvent evaporation method. The obtained crystals MET-IBU and MET-NAP were characterized by X-ray diffraction (SCXRD and PXRD), Hirshfeld surface (HS), thermal analysis (DSC and TG), and Fourier transform infrared spectroscopy (FT-IR) techniques. Equilibrium solubility determination and intrinsic dissolution rate (IDR) tests were used to evaluate their solubility and dissolution rate. Their physicochemical stability was evaluated by the accelerated stability test and stressing test. Finally, a model of λ-Carrageenan-induced inflammatory pain in mice was performed to evaluate the analgesic effects of MET-IBU and MET-NAP. This study aimed to improve the solubility, dissolution rate of NSAIDs (IBU and NAP), and achieve synergistic antinociceptive effects with MET for inflammatory pain by developing drug-drug salt crystals, which may provide a new strategy for pain treatment.