In September 2018, the First European Workshop on Metal Phosphonates Chemistry brought together some prominent researchers in the field of metal phosphonates and phosphinates with the aim of discussing past and current research efforts and identifying future directions. The scope of this perspective article is to provide a critical overview of the topics discussed during the workshop, which are divided into two main areas: synthesis and characterisation, and applications. In terms of synthetic methods, there has been a push towards cleaner and more efficient approaches. This has led to the introduction of high-throughput synthesis and mechanochemical synthesis. The recent success of metal–organic frameworks has also promoted renewed interest in the synthesis of porous metal phosphonates and phosphinates. Regarding characterisation, the main advances are the development of electron diffraction as a tool for crystal structure determination and the deployment of in situ characterisation techniques, which have allowed for a better understanding of reaction pathways. In terms of applications, metal phosphonates have been found to be suitable materials for several purposes: they have been employed as heterogeneous catalysts for the synthesis of fine chemicals, as solid sorbents for gas separation, notably CO₂ capture, as materials for electrochemical devices, such as fuel cells and rechargeable batteries, and as matrices for drug delivery.

In this paper we report drug delivery systems that are based on phosphonate MOFs. These employ biologically-acceptable metal ions (e.g. Ca²⁺ and Mg²⁺) and several anti-osteoporosis bisphosphonate drugs (etidronate, pamidronate, alendronate and neridronate), as the organic linkers. These materials have been synthesized, structurally characterized, and studied for the self-sacrificial release (by pH-driven dissolution) of the bisphosphonate active ingredient. They exhibit variable release rates and final % release, depending on the actual structure of the metal-bisphosphonate material. Their cytotoxicity profiles match those of the active ingredients.

(Poly)phosphonic acids constitute an exciting family of phosphorus compounds. One of the attractive attributes of these molecules is the rich chemistry of the phosphonate moiety, and, in particular, its high affinity for metal ions and mineral surfaces. Whether the phosphonate group belongs to a “small” molecule or to a polymeric matrix, phosphonate-containing compounds have found a phalanx of real-life applications. Herein, we address a special category of phosphorus compounds called bisphosphonates (BPs, a.k.a. “-dronates”) and also phosphonate containing polymers. The success of BPs in mitigating osteoporosis notwithstanding, these “-dronate” drugs present a number of challenges. Nevertheless, the main drawback of BPs is their limited oral bioavailability. It is, therefore, imperative to design and fabricate “smart” systems that allow controlled delivery of the active BP agent. Here, easy-to-prepare drug delivery systems are presented based on silica gels. These have been synthesized, characterized, and studied as hosts in the control release of several BP drugs. They exhibit variable release rates and final % release, depending on the nature of bisphosphonate (side-chain length, hydro-philicity/-phobicity, water-solubility), cations present, pH and temperature. These gels are robust, injectable, re-loadable and re-usable. Furthermore, alternative drug delivery systems are presented that are based on metal-organic frameworks (MOFs). In these biologically acceptable inorganic metal ions have been incorporated, together with BPs as the organic portion. These materials have been synthesized, characterized, and studied for the self-sacrificial release (by pH-driven dissolution) of the BP active ingredient. Several such materials were prepared with a variety of bisphosphonate drugs. They exhibit variable release rates and final % release, depending on the actual structure of the metal-bisphosphonate material. Lastly, we will present the use of phosphonate-grafted polymers as scale inhibitors for water treatment applications.

Bisphosphonates (BPs) constitute a class of drugs used for the treatment of calcium- and bone-related disorders, including osteoporosis, Paget’s disease, etc. The presence of the anionic phosphonate groups endows them with the ability to act as ligands to metal ions. As a result, the synthesis of complexes or coordination polymers of various structural motifs can be accomplished. In this work, the 3rd generation BP drug risedronate (RIS) was combined with biologically acceptable alkaline earth metal ions (e.g., Ca²⁺ and Sr²⁺) in an effort to synthesize new materials. These metal–RIS compounds can operate as controlled delivery systems (CDSs) when exposed to appropriate experimental conditions, such as the low pH of the human stomach. CDS networks containing Ca²⁺ or Sr²⁺ and RIS were physicochemically and structurally characterized and were evaluated for their ability to release the free RIS drug during an acid-driven hydrolysis process. Due to the low solubility of RIS at low pH, cationic additives (linear polyethyleneimine and amine-terminated polyaminoamide dendrimer) were utilized as drug solubilizers. Based on the drug release results of this study, there was an attempt to correlate the drug release efficiency with the structural features of these CDSs.

Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr²⁺ and Ba²⁺) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr²⁺ or Ba² and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs.

Bisphosphonate drugs constitute the primary treatment for bone diseases such as Paget’s disease and osteoporosis. Despite their effectiveness, they also exhibit severe drawbacks, such as rapid excretion and limited oral bioavailability. High doses are usually administered to counterbalance these drawbacks. Subsequently, side effects are triggered, such as osteonecrosis of the lower jaw and esophageal cancer. Controlled drug release systems may be viable candidates to overcome those issues. Herein, we present novel functionalized silica-based hydrogels loaded with the osteoporosis drug etidronate (1,1-hydroxyethylidene-diphosphonate) used to control the release profile of the drug. Various methodologies were evaluated to control the initial release rate and the final released concentration of the drug. These included the gel density, by systematically increasing the initial concentration of silicate used to prepare the hydrogels, the presence of metal cations (Ca²⁺ and Cu²⁺), and the internal surface functionalization of the gel with silane-based grafting agents (with anionic, cationic, and neutral groups). This study also contributes to our continuous effort to develop new a priori programmable drug-loaded gels for the controlled release of osteoporosis drugs.