Despite great effort made by our human beings, cancers still seriously threaten our health and life [1]. To avoid the severe side effects of traditional radiotherapy and chemotherapy, molecular targeted therapy featured by interfering with specific molecules in cancers has been developed to inhibit the growth and metastasis of cancer cells [2]. Among them, epidermal growth factor receptor (EGFR) attracts much attention due to its critical role in the pathogenesis of different types of carcinomas [3]. Erlotinib hydrochloride (ERL), a selective and potent EGFR tyrosine kinase inhibitor, is approved by FDA as a frontline drug for the treatment of lung cancer and pancreatic cancer [4]. However, the poor water solubility of ERL leads to low dissolution rate and thus low oral bioavailability, while increasing the oral dose of ERL may cause several dose-related side effects like skin rashes and intestinal disorders [5,6]. Therefore, improving the water solubility of ERL can not only enhance the antitumor effects but also alleviate the undesired side-effects.

In recent years, amorphous technology has attracted much attention because it can effectively improve the solubility and dissolution of insoluble drugs by destroying their crystal lattice [7]. Unfortunately, application of amorphous systems suffers from the thermodynamical instability ascribed to their high Gibbs free energy, which can result in the phase transition from amorphous to crystalline form [8]. Although the polymer-assisted amorphous solid dispersion technology has potential in improving the physical stability of amorphous drugs, the added polymer may not only absorb moisture and facilitate the recrystallization of the amorphous drugs, but also lead to low drug loading and large dosage of drugs [9]. In contrast, the co-amorphous system, formed by the combination of the active drug with a co-former (e.g., small molecule excipients or another active ingredients), is a uniform single-phase amorphous system with favorable physical stability [10]. Furthermore, the added co-former can produce synergistic therapeutic effects and fewer side effects when the co-former is a pharmacologically relevant active ingredient [11]. Therefore, it's a critical issue to select an appropriate co-former for the preparation of the co-amorphous system.

Up to now, many low molecular weight compounds have been utilized as co-formers for co-amorphous drug delivery systems [12]. Among them, natural products, such as sugars (sucrose, mannitol, and glucose), organic acids (benzoic acid and citric acid), amino acids (tryptophan, theanine, and arginine), and alkaloids (oxymatrine and piperine), are considered as promising co-formers in the co-amorphous systems due to their natural environmental protection, non-toxic side effects, and good biocompatibility [13]. More importantly, some of those natural products also possess multiple favorable pharmacological activities. Gallic acid (GA), chemically known as 3, 4, 5-trihydroxybenzoic acid, is one of the simplest natural organic acid compounds, which has antioxidant, antitumor, anti-inflammatory, anti-free radical, and antibacterial bioactivities [14]. It has been reported that addition of GA can enhance the antitumor effects of many anticancer drugs [15,16]. Furthermore, GA possesses great potential in forming co-amorphous systems by virtue of the existence of multiple hydroxyl groups in GA that can function as hydrogen bond donors [17].

In this study, GA was utilized as a bioactive co-former, and the ERL-GA co-amorphous system (ERL-GA CM) was constructed for not only the enhanced solubility and bioavailability of ERL, but also the synergistic antitumor effects (Fig. 1). ERL-GA CM was prepared by solvent evaporation method and verified by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The intermolecular interactions in ERL-GA CM were studied via Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy, and then further verified through molecular dynamics (MD) simulations. Subsequently, the solubility, dissolution behavior, and physical stability of ERL-GA CM were measured. Finally, the pharmacokinetic and antitumor efficacy of ERL-GA CM were evaluated in vivo.