Nonsteroidal anti-inflammatory drugs (NSAIDs) are characterized by poor aqueous solubility, often in the low microgram-per-milliliter range, which limits their dissolution rate and hence oral bioavailability. Flurbiprofen, a Biopharmaceutics Classification System (BCS) Class II arylpropionic acid NSAID (pKa – the negative logarithm of the acid dissociation constant ≈ 4.09), exhibits a free-acid solubility of only 0.011 mg/mL in water at 25 °C [1]. Such low solubility slows its release from solid dosage forms, leads to variable absorption, and contributes to inter- and intra-subject pharmacokinetic variability [2]. Strategies to improve solubility and dissolution are therefore critical to enhance systemic exposure and therapeutic consistency. Flurbiprofen itself is a potent cyclooxygenase (COX-1/COX-2) inhibitor used in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, dysmenorrhea, and various musculoskeletal pains [3]. Its molecular weight (244.27 g·mol⁻1) and lipophilicity (log P ≈ 4.2) favor tissue permeation but also contribute to the solubility constraints that define its BCS Class II profile.

Several research groups have synthesized amino-acid-based flurbiprofen prodrugs to mask the carboxyl group and modulate physicochemical properties. Mishra et al. prepared a series of ten flurbiprofen amide prodrugs with ethyl esters of amino acids such as glycine, L-phenylalanine, L-tryptophan, L-valine, L-alanine, and others, aiming to reduce gastrointestinal toxicity associated with the parent drug. Several compounds, particularly those based on L-valine (AR-2), L-aspartic acid (AR-9), and L-glutamic acid (AR-10), exhibited excellent pharmacological responses and promising hydrolysis profiles in both simulated intestinal fluid and 80% human plasma. Partition coefficient measurements indicated significant increases in lipophilicity (e.g., log P values > 4.0), which may contribute to improved membrane permeability. Interestingly, prodrugs with aromatic or branched aliphatic side chains showed enhanced partitioning but slightly lower hydrolysis rates, suggesting potential for sustained release behavior. Pharmacodynamic testing in rats confirmed that the prodrugs retained comparable anti-inflammatory and analgesic activity to flurbiprofen, despite delayed onset due to enzymatic activation. Importantly, all derivatives displayed substantially lower ulcerogenic indices compared to the parent drug, with some prodrugs reducing gastric lesions by over 70%. Overall, this study highlights that amidation with biocompatible amino acids offers a viable strategy for enhancing the therapeutic index of flurbiprofen by improving tolerability without compromising efficacy [4].

Baek and colleagues investigated the use of large-ring cycloamylose (CA) as a solubilizing excipient for flurbiprofen, preparing a 1:1 (w/w) solid dispersion by spray‐drying the drug with CA. Characterization by SEM (Scanning Electron Microscopy), DSC (Differential Scanning Calorimetry), and PXRD (Powder X-ray Diffraction) confirmed retention of the crystalline drug within the dispersions. The CA formulation exhibited a twelve-fold increase in aqueous solubility (from ≈5.12 µg/mL to 61.6 µg/mL) and a two-fold faster in vitro dissolution rate versus a commercial tablet. In rat pharmacokinetic studies, the dispersion delivered a six-fold higher AUC (area under curve) and significantly greater Cmax (maximum concentration) than the marketed product, without altering elimination half-life or Tmax, demonstrating that cycloamylose enables markedly improved oral absorption of flurbiprofen without altering its solid state [5].

Ionic-liquid and salt forms of flurbiprofen represent another promising avenue for improving the drug’s poor aqueous solubility and dissolution profile. A notable example is the ethylenediamine salt of flurbiprofen (FLU-EDA), synthesized in a 2:1 M ratio (two flurbiprofen anions per one divalent ethylenediamine cation). This salt was fully characterized by XRD, FT-IR, and DSC, revealing a well-defined crystalline structure and solid-state stability even under high humidity (75% RH (Relative Humidity), 35 °C, 20 days). Compared to native flurbiprofen, FLU-EDA exhibited a 57-fold increase in water solubility and a 32-fold increase in intrinsic dissolution rate (IDR) in aqueous media, demonstrating remarkable enhancement of dissolution behavior. While its solubility also increased in alkaline medium (pH 9.18), a slight reduction was observed in pH 6.86 phosphate buffer, highlighting its pH-dependent solubilization profile. Similarly, the IDR of the salt was significantly improved in water but was slightly lower than that of native FLU in buffered conditions. Nonetheless, FLU-EDA remained physically stable across all tested pH conditions without recrystallization, indicating good formulation robustness. These results support the potential of FLU-EDA as a new oral dosage form candidate for flurbiprofen, offering improved bioavailability and consistent performance, particularly in neutral or slightly alkaline environments [6].

Terpenes, a large class of naturally occurring volatile hydrocarbons and their oxygenated derivatives (monoterpenes, sesquiterpenes, etc.), have been extensively studied as skin penetration enhancers (PEs) in transdermal drug delivery systems. These compounds are considered safer alternatives to synthetic PEs – such as azone or DMSO – as many are classified as GRAS (Generally Recognized As Safe) by regulatory agencies. Reviews have shown that terpenes can enhance percutaneous absorption of lipophilic small-molecule drugs by factors ranging from 90-fold, depending on the drug, skin model, and terpene type, with consistent improvement across different species, including human skin [7]. Among these, borneol has drawn attention due to its multifaceted enhancement mechanism and favorable safety profile. In comparative permeation studies using 5-fluorouracil (5‑FU) as a hydrophilic model drug and combining in vitro assays with coarse-grained molecular dynamics (CG MD), borneol demonstrated stronger enhancement than menthol – even though menthol is more hydrophobic (log P ∼ 3.2 vs. borneol ∼ 2.7) [8]. This indicates that lipophilicity alone does not fully explain permeation enhancement efficacy.

Mechanistically, borneol was found not only to disrupt the tightly packed lamellar structure of the stratum corneum (SC) as visualized by TEM imaging but also to significantly increase the diffusion coefficient of the drug within the lipid matrix. At higher concentrations (>10%), borneol induced the formation of transient aqueous pores through which 5‑FU could permeate – a behavior not observed with menthol. Moreover, CG MD revealed that borneol preferentially localizes near the hydrophilic head groups of ceramides, leading to deeper lipid disruption and facilitated partitioning of drug molecules [8]. Advanced computational molecular modeling approaches, akin to those employed by Ashraf et al. for flurbiprofen–antioxidant mutual prodrugs, have begun to be applied to terpene–lipid systems. Such simulations corroborate that borneol’s small size and amphiphilicity enable it to insert at key lipid head-group regions, dynamically destabilizing hydrogen-bond networks and transiently increasing water channel formation [9]. These combined mechanisms translate into enhancement ratios (ERs) that often exceed 10‑fold and, in some cases, reach over 30‑fold for drug permeation. Compounds such as borneol, nerolidol, carvacrol, and menthone consistently outperform synthetic PEs in ex vivo skin models, with borneol among the most effective natural enhancers [7]. Its effects are typically reversible and non‑irritating at moderate concentrations, supporting its suitability for topical and transdermal applications.

Transdermal drug delivery (TDD) offers a non-invasive route that combines many of the conveniences of oral administration with bioavailability approaching that of parenteral therapy. By bypassing gastrointestinal degradation and hepatic first-pass metabolism, TDD can produce more predictable plasma profiles with reduced inter- and intra-subject variability. It also enables sustained, near-zero-order release, maintaining therapeutic levels over extended periods without frequent dosing, which can improve adherence and minimize peak-related adverse effects. Moreover, painless self-administrable patches are particularly attractive for pediatric, geriatric, and needle-averse patients, and allow rapid discontinuation should intolerance occur. Despite these advantages, the stratum corneum remains the principal barrier to transdermal absorption. Consequently, a range of enhancement strategies has been developed, including chemical approaches (e.g., terpenes, surfactants, thermal/mechanical pretreatments), passive vesicular and nanoparticulate systems (e.g., liposomes, ethosomes, nanoemulsions, solid dispersions), and hybrid methods that combine chemical enhancers with physical techniques such as microneedles or iontophoresis. Each modality offers distinct merits – chemical enhancers like terpenes can reversibly fluidize lipid lamellae, whereas vesicles can encapsulate and protect labile drugs, and hybrid systems can further improve payload delivery – yet all must balance enhancement efficacy against potential irritation or safety concerns [10].

In light of the challenges posed by flurbiprofen’s poor aqueous solubility and the stratum corneum’s formidable barrier, a multipronged strategy emerges as essential. Structural modifications – ranging from amino-acid prodrugs and cycloamylose dispersions to ionic-liquid and salt forms – have demonstrably enhanced solubility, dissolution rate, and systemic bioavailability, while reducing gastrointestinal toxicity. Meanwhile, transdermal platforms, supported by safe chemical enhancers like borneol and advanced vesicular or hybrid technologies, offer controlled, non-invasive delivery that bypasses first-pass metabolism and improves patient compliance. Pursuing diverse formulation approaches and molecular redesigns is therefore critical not only to optimize therapeutic efficacy and tolerability but also to expand the clinical utility of NSAIDs such as flurbiprofen across varied patient populations and treatment contexts.

In this work, we report the synthesis, characterization, and functional evaluation of a novel ionic flurbiprofen conjugate: L-alaninium borneol ester flurbiprofenate (AlaOBor∙F). By integrating the biocompatibility of the amino acid L-alanine and the permeation-enhancing properties of borneol into a single cationic scaffold, we aimed to create a dual-function carrier system capable of improving both solubility and transdermal delivery of flurbiprofen. Two synthetic routes to the L-alaninium borneol ester hydrochloride precursor were explored and compared, and the final salt was obtained via direct ion pairing with flurbiprofen. The physicochemical properties of the resulting materials were thoroughly investigated using spectroscopic, thermal, and diffraction methods. Their aqueous solubility, lipophilicity, skin permeability, antioxidant potential, cytocompatibility, and anti-inflammatory activity were also assessed. This study seeks to demonstrate that structurally designed ionic flurbiprofenates incorporating terpene-based amino acid esters can overcome major delivery barriers while preserving or enhancing the drug's therapeutic profile.