Hot melt extrusion-driven cocrystallization of aceclofenac with nicotinamide: A strategy to enhance solubility, bioavailability, and therapeutic effect

Abstract

Aceclofenac (ACF) is a commonly used non-steroidal anti-inflammatory drugs (NSAID) for numerous inflammatory conditions; however, its therapeutic potential is limited due to suboptimal solubility. Pharmaceutical cocrystals have demonstrated favorable and sustainable results in improving the physicochemical and biopharmaceutical characteristics of poorly soluble drugs. To enhance the solubility, dissolution rate, and bioavailability of ACF, we aimed to prepare cocrystals of this biopharmaceutics classification system (BCS) class II drug with a coformer including nicotinamide (NCT), using hot melt extrusion (HME) and liquid-assisted grinding (LAG) methods. ACF-NCT cocrystals synthesized using these methods were characterized using various methods and were further assessed for in vitro anti-osteoporotic and in vivo anti-arthritic activities. The results indicate that both LAG and HME cocrystals demonstrated significant improvement in solubility and dissolution profile compared to pure ACF. However, among these two methods, HME offered more advantages, including better solubility and dissolution profile, than the LAG method. The cocrystals achieved a remarkable 6.15-fold increase in solubility and ⁓3-fold enhancement in dissolution over pure ACF. The relative bioavailability of ACF-NCT HME cocrystal was 249.98% of pure ACF, indicating an improvement in oral bioavailability. The in vivo anti-arthritic activity also demonstrated significant improvement when compared to pure ACF. ACF-nicotinamide cocrystals prepared by hot melt extrusion achieved remarkable gains in solubility, bioavailability, and therapeutic efficacy, providing a promising strategy to overcome ACF’s clinical limitations.

Introduction

The introduction of high-throughput screening and combinatorial chemistry has made new drug discovery more efficient and accelerated. However, the challenge lies in the fact that these molecules are often lipophilic and bulky, which impacts their solubility and permeability.1 Over three-fourths of the new chemical entities and about 40% of the marketed drugs fall under the biopharmaceutics classification system (BCS) Class II and IV, which restricts their therapeutic efficacy due to limited absorption from the gastrointestinal tract, eventually interfering with the clinical application of the drug.2–5 Rather than searching for entirely new chemical entities, the current pharmaceutical approach prioritizes improving the solubility of existing, approved drugs. Various techniques have been explored for this purpose, each with its own set of merits and demerits. Among them, the cocrystal technique is gaining prominence due to its superior benefits compared to other methods, including improved solubility and stability while being a sustainable technique.3,4,6–9 Numerous research studies have cited successful applications of pharmaceutical cocrystals. For example, the solubility and oral bioavailability of quercetin in quercetin–caffeine cocrystals increase almost 14 times (1:1 water/ethanol medium) and 2.6 times, respectively, compared to pure quercetin.10 Similar successful results have been demonstrated in drug classes such as anti-tubercular agents, anticoagulants, anticancer, antifungal, and antihypertensive therapies to name a few.11–16

A cocrystal is a homogenous crystalline material composed of two or more compounds in a specific stoichiometric ratio, held together by non-covalent interactions such as van der Waals forces, hydrogen bonding, and π–π stacking interactions.2,4,17 Based on the principles of crystal engineering, an essential moiety of a cocrystal is the coformer, which is usually a water-soluble molecule.18,19 This supramolecular synthon approach of identifying specific motifs that engage in robust, non-covalent interactions enable the design of cocrystals with tailored physicochemical properties, including enhanced solubility and stability.20 Additionally, the United States Food and Drug Administration classifies pharmaceutical cocrystals as active pharmaceutical ingredient polymorphs, allowing approval via the 505(b)(2) pathway, which lowers development costs and speeds up commercialization.21,22

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used classes of drugs globally.23,24 Aceclofenac (ACF) suffers from poor aqueous solubility like the other drugs in this class. ACF, an aryl acetic acid analog, is a BCS Class II drug, making the low solubility a key factor in its absorption.25–27 Due to its low aqueous solubility, the drug concentration in the stomach and intestinal fluids remain low, resulting in limited absorption despite high intestinal permeability.24 ACF is used in numerous conditions, including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Based on the existing solubility, ACF 100 mg twice daily is required to achieve the therapeutic effects. The cocrystallization technique improves solubility, leading to increased bioavailability and allowing for dose reduction. Consequently, this technique can significantly lessen the hepatic and nephrotic burden associated with ACF administration.28 Therefore, we aimed to prepare ACF cocrystals to overcome solubility limitations and mitigate dose-dependent hepatic and renal risks.

Numerous published research data demonstrating the successful cocrystallization of ACF with various coformers, including nicotinamide (NCT), using the neat grinding method, solvent evaporation method, solution crystallization method, solvent drop grinding method, dry grinding method, and liquid-assisted grinding (LAG) method are available.29–34 While multiple techniques exist for cocrystal formation, hot melt extrusion (HME) offers a scalable, solvent-free, and industrially viable approach that is attractive for pharmaceutical applications.35,36 Given the widespread challenges of solubility and bioavailability in BCS Class II drugs, including ACF, this study aims to explore the potential of HME cocrystal to address these limitations. The LAG method, a modification of neat grinding known to enhance supramolecular selectivity in crystalline systems, was also employed for assessing the feasibility of cocrystal formation.37 To the best of our knowledge, the application of HME for preparing ACF cocrystal with NCT and subsequent in vitro and in vivo evaluation has not been reported previously. By utilizing the HME and LAG techniques, we aimed to enhance the solubility, dissolution rate, and bioavailability of ACF. Nicotinamide was selected as a coformer based on its GRAS status and excellent safety profile. Its strong hydrogen-bonding capability, favors stable cocrystal formation. Literature reports indicating that nicotinamide may support cellular metabolism and anti-inflammatory pathways, although it is not intended here as a primary therapeutic agent. Nicotinamide was used at sub-therapeutic levels, its role is structural and solubility-enhancing, rather than pharmacodynamically dominant.

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Materials

ACF, NCT, l-pyroglutamic acid, and l-Proline were obtained from Amoli Organics Pvt. Ltd., Jubilant Ingrevia Ltd., Sigma-Aldrich Chemicals Pvt. Ltd. and S.D. Fine Chem Ltd., respectively, in India. Indomethacin was obtained from CSPC Ouyi Pharmaceutical Co. Ltd., China. High-performance liquid chromatography (HPLC) grade acetonitrile and methanol, and Optima® liquid chromatography-mass spectrometry (LC-MS) grade methanol, acetonitrile, and formic acid (FA) were sourced from Fisher chemicals by Thermo Fisher Scientific Pvt. Ltd., India. Milli-Q water from the Milli-Q water purification system (Milli-Q®, HX 7040) was used for the preparation of buffers. Dulbecco’s modified eagle medium (DMEM), fetal bovine serum (FBS), and trypsin were sourced from Invitrogen-Thermo Fisher Scientific Pvt. Ltd., India. The MG63 cell lines were obtained from ATCC- The global bioresource center. Type II collagen and complete Freund’s adjuvant (CFA) were obtained from Sigma Aldrich Chemicals Pvt. Ltd., USA. All other chemicals were of analytical grade.

Govind S, Martis E, Shirsat V, Hot melt extrusion-driven cocrystallization of aceclofenac with nicotinamide: A strategy to enhance solubility, bioavailability, and therapeutic effect, Journal of Pharmaceutical Sciences, 2026; 115

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