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Low‐molecular‐weight gelators (LMWGs) are an important class of soft materials that offer various potential applications including drug delivery. Structural diversities of the reported LMWGs and lack of molecular‐level understanding of the self‐assembly process of gelation make it difficult to design a gelator a priori. Most often gelators are discovered in a serendipitous manner and second‐generation gelators are designed by modifying known gelling scaffolds. Since gel network within which the solvent molecules are immobilized is often found to be crystalline, a supramolecular synthon approach in the context of crystal engineering is demonstrated to be quite effective in designing LMWGs for various applications including therapeutics. Self‐drug‐delivery systems, wherein the need for a delivery vehicle does not exist, are becoming an effective alternative to conventional drug delivery systems. In the form of a simple gel (for non‐invasive topical application) or injectable gel (for invasive subcutaneous applications), LMWGs derived from drugs provide an effective way to develop self‐drug‐delivery systems. This review article encompasses the early development of LMWG research, describes gradual transition from discovering just a gelator to a gelator having potential material applications including drug delivery, and highlights the merit of supramolecular synthon approach in designing LMWGs for self‐drug‐delivery applications.

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well-known non-steroidal anti-inflammatory drug (NSAID) ibuprofen. A well-studied gel-inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts (S1-S7) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single-crystal and powder X-ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts (S2, S3, S6, and S7) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE2 assays) revealed that all of the salts (except S3 and S7) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6, displayed anti-inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self-delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.

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Following a structural rationale, a series of simple organic salts derived from mafenide (a drug for treating burn wounds) and n-alkyl carboxylic acids (Me–(CH2)n–COOH; n = 1–3, 10–15) and various nonsteroidal anti-inflammatory drugs (NSAIDs), namely, indomethacin (IND), diclofenac (DIC), meclofenamic acid (MEC), tolfenamic acid (TOL), and flufenamic acid (FLU) (designated as salts 1–14, respectively) were synthesized as potential hydrogelators. Gelation studies revealed that mafenide n-alkyl carboxylates with n = 11–14, i.e., salts 5–8, and the indomethacin salt of mafenide, i.e., salt 10, were hydrogelators. The corresponding hydrogels, namely, 5­(HG)–8­(HG) and 10­(HG), were characterized by table-top and dynamic rheology and high-resolution transmission electron microscopy (HR-TEM). Single-crystal structures of the nongelator salts 1–3 and the gelator salt 10 were determined by X-ray diffraction. The results obtained from various studies, which included the solubility, biostability, biocompatibility (MTT assay), and anti-inflammatory (PGE2 assay) response of salt 10, the antibacterial response (zone inhibition assay) of salt 10, its components, and 10(HG), and the release of salt 10 in vitro from the corresponding hydrogel bed to the bulk solvent at 37 °C in 24 h, suggested their plausible use in developing multidrug-derived topical hydrogels for self-delivery applications.