Recent years, have been done huge advances in the quantification of different analytes in complex matrices [1]. Most of these methods suffer from several limitations due to the low concentration of model analytes and of possible disturbances in the sample matrices. Sample preparation processes were developed, to overcome this limitation [2]. As an efficacious sample preparation method, solid phase microextraction (SPME) was developed in 1990 by Pawliszyn et al. [3]. The mentioned method enjoys several advantages such as short extraction time and low solvent consumption, promoting its environmental compatibility [4]. The thin film microextraction (TFME) method was introduced by Pawliszyn et al. in 2003 as one of the SPME methods [5].

In the TFME method, a film with a high surface-to-volume ratio is used as the extracting phase [6]. Compared with SPME, the volume of the extractant phase increases, while the thickness of the extractant phase is constant or even reduced [7,8]. Different films such as ethylene-vinyl acetate film [9], polyaniline-nylon-6 [10], NiO nano worms [11], anodized aluminum [12] and cellulose paper [13,14] can be used for the TFME process. Although the use of different substrates to prepare thin film for the TFME method increased the extraction efficiency each of these compounds had relatively difficult synthesis routes. Therefore, renewable and environmentally friendly substrates are still highly desired. Among the mentioned functional substrates, celluloses are one of the most abundant natural polymers with proper renewability and also biodegradability [15].

Cellulosic materials are generally water insoluble, strong, recyclable, chemically stable, and biodegradable. These compounds are useful as one of the available and low-cost materials for the preparation of different functional materials [16]. Chemical modification of cellulose surface with suitable organic reagents makes it appropriate for extraction purposes [17]. So far, various compounds such as magnetite nanoparticles and activated carbon [18], zinc oxide nanoparticles [19], polydopamine-sulfobetaine [20] and metal-organic frameworks [21] have been used for surface modification of the celluloses of surface.

Metal–organic frameworks (MOFs) are a class of compounds comprising metal ions or clusters coordinated to organic ligands to form one, two, or three-dimensional structures [22]. First, by Yaghi et al. [23]. More than two thousand types of MOFs have been synthesized with different metals, such as Zn, Cr, Cu, Fe and Al [24]. The unique features of MOFs include, high surface area, purposeful synthesis and flexibility. MOFs have extensive applications in gas absorption and storage [25,26], catalysts [27], drug delivery [28], sensors [29] and as a sorbent in separation methods [30] due to their uniform and regular structures, adjustable porosity and different chemical properties. Recently, MOFs have been used in different extraction methods like SPME [31], HS-SPME [32], stir-bar sorptive extraction (SBSE) [33], magnetic solid phase extraction (MSPE) [34] and TFME [35,36].

Metal–organic framework −5 (MOF-5) is a cubic MOF compound with the formula of Zn4O(BDC)3, (BDC− =1,4-benzodicarboxylate) [37]. This compound was synthesized by Yaghi and et al. [22]. MOF-5 is notable for exhibiting one of the highest surface areas to volume ratios among the MOFs [38]. The first, MOF-5 was studied for hydrogen gas storage [39].Various methods including the solvothermal [40], the mechanical-chemical [41], the sonochemical [42] and the electrochemical method [43] have been developed for the synthesis of MOF-5. In the common solvothermal synthesis method, metal ions and organic ligands are mixed with a specific ratio in a specific solvent at a constant temperature. After the completion of the reaction, the obtained product is filtered and pure MOF crystals are obtained through the solvent evaporation method [44]. In this research, first the substrate (cellulose paper) was immersed in a certain concentration of organic ligand. Then, the modified cellulose paper was placed in an autoclave. During these stages, the MOF-5 is synthesized on the surface of the cellulose paper. This increases the surface-to-volume ratio, hence, improving the extraction efficiency. The modified substrate has been accommodated on the surface of cellulose paper to improve the ability of the sorbent. In addition, the method offers some advantages including low cost, simplicity, and short analysis time.

Non-steroidal anti-inflammatory drugs (NSAIDs) refer to a class of medications, designed to decreases inflammation, reduces pain, prevent blood clots, and decrease fever.‏ ‏This category of drugs is one of the most widely used medications, making it important to measure its content. Drug dose and its duration of use determine its side effects especially those affecting the kidneys or causing, heart attack, and raising risk of gastrointestinal ulcers and bleeding [45,46]. Moreover, these medications are also effective against critical disorders such as heart attacks and cancer. Despite their significant therapeutic properties, these drugs also have side effects, such as cardiovascular risks, gastrointestinal toxicity, high blood pressure, brain complications, kidney damage, and hepatotoxicity [47]. Regarding the increasing number of disorders due to the overdose of NSAIDs, monitoring the level of NSAIDs could immensely contribute to a simpler and better understanding of associated disorders while enabling early diagnosis. On the other hand, NSAID residues in the environment has drawn significant attention as they are not virtually eliminated from the sewage treatment plants and subsequently released into the ambient water sources in their native form or as metabolites [48]. Considering the low levels of NSAIDs in the complex matrices, suitable pretreatment methods are required for their determination [49]. Therefore, a quantitative measurement of NSAIDs, requires enrichment, pre-concentration and extraction methods such as in-tube-solid phase microextraction (IT-SPME) [50], MSPE [51], TFME [52], Hollow fiber (HF)-SPME [53], and Dispersive solid-phase extraction (DSPE) [54].

In the present study, an integrated film of MOF-5 was prepared using the solvothermal method. For this purpose, the cellulose filter paper was first immersed in the selected ligand solution. During this process, ligands were placed inside cellulose paper cavities. Next, the ligand-modified cellulose paper substrate was immersed in a solution containing the selected metal (Zn2+) and then placed in the autoclave for the solvothermal process. During this step, MOF-5 crystals were in situ, uniformly, and homogeneously formed on the cellulose thin film substrate. To the prepared sorbent was characterized, by various methods such as FT-IR, FE-SEM, EDX, elemental mapping, XRD, TGA and BET. It was then used for TFME of some non-steroidal anti-inflammatory drugs, including naproxen, aspirin, tolmetin, and celecoxib. Then, using a suitable eluent, selected drugs were eluted from the film and injected to HPLC-UV for their quantitative measurements. To achieve maximum extraction efficiency for the model analytes, various effective factors, including salt effect, extraction time, desorption volume, desorption time, stirring rate and sample pH were optimized by the response surface method. Additionally, the Plackett-Burman design (PBD) was used to screen the method was used. Then, the BBD method was employed to determine the optimal points for the effective parameters of the extraction. In the following, the figure of merit of the method was obtained under optimal conditions. Eventually, this method was utilized to extract target analytes in different urine samples. This work, thus, reports a highly capable, simple, fast, cost-effective, robust, and novel technique to extract and chromatographically determine selected analytes in urine complex matrices. The proposed TFME demonstrated a satisfactory reproducibility, low LOD and wide LDR.