Bedaquiline’s solubility problem: advanced formulation strategies for optimized tuberculosis therapy

Tuberculosis remains one of the deadliest infectious diseases on the planet, and the rise of multidrug-resistant and extensively drug-resistant strains has made an already formidable public health challenge even harder. In 2024 alone, roughly 1.23 million people died from tuberculosis and 10.7 million new cases were diagnosed, including 1.2 million children. Against this backdrop, bedaquiline, a diarylquinoline compound approved by the US Food and Drug Administration in 2012 under the brand name Sirturo, has emerged as the first genuinely new anti-tuberculosis drug in four decades. It targets mycobacterial ATP synthase, an enzyme essential for energy production in Mycobacterium tuberculosis, and is now recommended by the World Health Organization as part of first-line therapy for drug-resistant tuberculosis. Yet a team of pharmaceutical scientists led by Pragya Yadav and Poonam Parashar at Amity Institute of Pharmacy in Lucknow, India, publishing in Discover Chemistry, argues that bedaquiline’s clinical promise is being throttled by a deceptively simple problem: the drug barely dissolves in water.

The physicochemical profile of bedaquiline explains why. With a log P value of 7.1, the compound is extraordinarily lipophilic, and its aqueous solubility sits at roughly 0.000193 milligrams per milliliter, among the lowest of any marketed antimycobacterial agent. These properties place it firmly in Class II of the Biopharmaceutics Classification System, where dissolution rate, not permeability, is the bottleneck for oral absorption. Because the drug dissolves so poorly, higher doses are needed to reach therapeutic plasma concentrations, which in turn drives dose-dependent adverse effects and prolonged tissue retention. Bedaquiline’s long terminal half-life of approximately 5.5 months, a consequence of extensive tissue distribution, compounds concerns about accumulation, QT interval prolongation, and hepatotoxicity. The review by Yadav and colleagues systematically evaluates the advanced formulation strategies now being deployed to overcome these barriers, from solid dispersions and salt formation to polymeric micelles, solid lipid nanoparticles, nanoemulsions, and inhalable nanoparticulate systems.

Solid dispersions represent one of the most practical and industrially scalable approaches. The technique disperses a crystalline drug within a hydrophilic polymeric carrier, converting it into an amorphous or microcrystalline state with higher free energy than the original crystal lattice. When the carrier dissolves in the gastrointestinal tract, the drug is released in a molecularly dispersed form, dramatically increasing the effective surface area available for dissolution. The evolution of solid dispersion technology spans four generations, from early crystalline carriers such as urea and sugars to modern systems combining hydrophobic polymers like hydroxypropyl methylcellulose acetate succinate with surfactants such as poloxamer 407, Tween 80, and tocopheryl polyethylene glycol succinate, alongside co-solvents like polyethylene glycol 400 and Transcutol P. These advanced formulations not only boost saturation solubility but also stabilize the amorphous phase through anti-plasticization and drug-polymer hydrogen bonding interactions that inhibit nucleation and crystal growth during storage.

Recent experimental work with bedaquiline fumarate demonstrates the tangible gains achievable through solid dispersion. Pardhi and colleagues prepared solid dispersions using polyethylene glycol and polyvinylpyrrolidone via solvent evaporation, achieving solubility increases of 6.4-fold and 13.44-fold respectively. The polyvinylpyrrolidone-based dispersion enhanced relative bioavailability by 173 percent in fasted conditions and 154 percent in fed conditions compared with a bedaquiline suspension, confirming improved performance in both in vitro dissolution and in vivo pharmacokinetic studies. A separate investigation employing tocopheryl polyethylene glycol 1000 succinate and poloxamer 188 as dispersing matrices boosted saturation solubility by 5.68-fold for binary dispersions and 7.46-fold for ternary dispersions. Interestingly, the binary system showed faster drug release due to a parachute effect, wherein the polymer and surfactant slow precipitation and sustain elevated drug concentrations during the supersaturation phase. Kaur and coworkers further revealed that drug-polymer interactions, rather than amorphization alone, can be the decisive factor governing release performance, with a strong insoluble bedaquiline-polymer ionic complex forming at pH 6.0 and dissolution behavior shifting dramatically across biorelevant media.

Salt formation offers a complementary strategy rooted in pH modulation of the diffusion layer microenvironment. Bedaquiline is a weakly basic drug with one tertiary amine group and one quinoline ring nitrogen, making acidic counterions suitable for salt generation. The marketed form, bedaquiline fumarate, already exhibits higher aqueous solubility than the free base. Zhang and colleagues synthesized a novel saccharin salt and demonstrated in beagle dogs that food-dependent absorption variability dropped from 7.2-fold with the fumarate salt to 3.2-fold with the saccharin salt, a significant improvement in diet-independent absorption that could enhance patient compliance. Okezue and Byrn systematically characterized four additional salt forms, including benzoate, nicotinate, hydrochloride, and malonate, prepared at 1:1 molar ratios and evaluated under accelerated stability conditions of 40 degrees Celsius and 75 percent relative humidity for six months. The benzoate salt emerged as the most promising candidate, exhibiting the lowest chemical degradation tendency, non-hygroscopic behavior, and stability as a hydrate without polymorphic transformation, though regulatory approval as a new molecular entity remains pending.

Polymeric micelles have garnered considerable attention as nanotechnology-driven platforms for delivering hydrophobic drugs like bedaquiline. These core-shell nanostructures self-assemble from amphiphilic block copolymers in aqueous solution, with the hydrophobic core serving as a reservoir for poorly soluble compounds while the hydrophilic shell stabilizes the particle in physiological environments. Krishnapal and colleagues developed bedaquiline-encapsulated Soluplus micelles using thin film hydration, achieving particle sizes of 73.30 nanometers with 98.65 percent entrapment efficiency. The micelles enhanced solubility by 25-fold and intestinal permeability by 3.5-fold compared with free drug solution, with dose-dependent cellular uptake confirmed in Caco-2 cells and acceptable viability profiles. Soria-Carrera and coworkers demonstrated that alginate-coated polypeptidic micelles prevented burst release and provided controlled, sustained delivery while protecting bedaquiline from premature degradation in simulated gastric and intestinal fluids. In a zebrafish embryo model infected with Mycobacterium marinum, Bhandari and colleagues showed that bedaquiline-loaded micellar nanoparticles significantly reduced bacterial burden compared with naive drug, with correlative light and electron microscopy confirming nanoparticle accumulation inside endothelial cells and a 10 percent improvement in embryo survival at a maximum dose of 8.3 nanograms per embryo.

Solid lipid nanoparticles offer another versatile colloidal carrier system, combining biocompatibility, biodegradability, and facile surface engineering with the ability to encapsulate both lipophilic and hydrophilic payloads. De Matteis and colleagues fabricated two distinct lipid-based nanocarriers for bedaquiline, including lipid nanoparticles and nanoemulsion-based chitosan nanocapsules, both demonstrating substantial antimicrobial activity against the H37Rv tuberculosis strain while remaining non-cytotoxic in A549, HepG2, and THP-1 cell lines. Najib Ullah and coworkers optimized bedaquiline-loaded solid lipid nanoparticles using Capmul MCM C10, Poloxamer 188, and PL90G, achieving a particle size of 144 nanometers with 92.05 percent entrapment efficiency and 13.33 percent drug loading. The formulation released 98.19 percent of payload over 12 hours in phosphate buffer at pH 7.2, following first-order kinetics, and demonstrated superior pharmacodynamic effects including reduced tumor volume and restored antioxidant enzyme levels. Okezue and team extended this work to oral administration, exploring the effects of lecithin, Tween 80, and polyethylene glycol concentrations on particle size distribution and zeta potential, with dissolution studies confirming enhanced drug release compared with free base powder.

Nanoemulsions and self-emulsifying systems represent soft nanocarriers distinguished by thermodynamic stability and globule sizes typically below 200 nanometers. Ajayi and colleagues developed a self-emulsifying nanoemulsion employing Span 20, Tween 80, and ethanol for bedaquiline encapsulation, achieving 97.5 percent drug release where the naive suspension showed no detectable release under identical conditions. The release kinetics followed a Weibull model with a beta value of 3.266, indicating a sigmoidal pattern of slow initial release followed by acceleration. Jahan and coworkers formulated a bedaquiline-loaded self-nanoemulsifying drug delivery system using caprylic acid, propylene glycol, and Transcutol-P, achieving globule sizes of 98.88 nanometers, 93 percent in vitro release over 12 hours, and stability across accelerated storage conditions, with cell viability assays in A549 cells confirming safety. Pardhi and colleagues further developed a bedaquiline microemulsion with thermodynamic stability, an optimum globule size of 26.50 nanometers, and gel-sol-gel rheological behavior, demonstrating cytocompatibility in Caco-2 cells at concentrations up to 500 micrograms per milliliter alongside significantly higher cellular uptake than control.

Inhalable and targeted particulate systems push the boundaries of bedaquiline delivery beyond conventional oral dosing. Rawal and colleagues developed a dry powder inhaler formulation of bedaquiline-loaded chitosan nanoparticles, exploiting the drug’s high lipophilicity for targeted pulmonary delivery. The optimized lyophilized nanoparticles exhibited good flow properties with a Hausner ratio of 1.25, content uniformity within the desired 85 to 115 percent range, and a fine particle fraction of 5.38 percent with a mass median aerodynamic diameter of 3.98 micrometers. Cell viability assays in J774 macrophages revealed 90 percent survival at all doses for the freeze-dried nanoparticles, compared with toxicity at 125 micrograms per milliliter for naive bedaquiline and conventional dry powder inhaler formulations. In vivo pharmacokinetic studies demonstrated a 1.65-fold increase in maximum concentration in lung tissue, alongside significant increases in half-life and area under the curve, with histopathological examination confirming negligible peribronchial infiltration, hyperplasia, and interalveolar septal thickening. Nesalin and Kumar developed bedaquiline-encapsulated microspheres using ethyl cellulose and chitosan via solvent evaporation and ionic gelation, achieving particle sizes between 243 and 486 nanometers with sustained release of 67.33 to 84.8 percent over 24 hours following Fickian diffusion kinetics.

The industrial translation of these laboratory advances demands careful attention to equipment requirements, batch reproducibility, stability profiles, economic viability, Good Manufacturing Practice compliance, and regulatory clearance. Amorphous systems such as solid dispersions stringently require protective packaging with blister systems, desiccants, and nitrogen flushing to prevent moisture invasion, particularly in tropical regions classified under ICH climatic zone IVb where high humidity accelerates recrystallization risks. Among the evaluated technologies, self-nanoemulsifying drug delivery systems and solid dispersions have emerged as the most Good Manufacturing Practice-acceptable platforms for bedaquiline commercialization, owing to facile scale-up, well-characterized excipient availability, and regulatory acceptance. The incorporation of Generally Recognized as Safe-listed polymers such as polyvinylpyrrolidone, hydroxypropyl methylcellulose, poloxamers, and polyethylene glycol, alongside lipid excipients, can streamline dossier compilation and accelerate approval pathways. Quality by Design frameworks must be executed to optimize critical quality attributes including particle size, polydispersity index, amorphous fraction, and zeta potential, screening critical material attributes and process parameters to ensure robust process design. Looking forward, the integration of artificial intelligence-assisted formulation design, targeted macrophage delivery systems, inhalable bedaquiline platforms, and long-acting delivery technologies promises to further bridge the gap between laboratory feasibility and industrially relevant strategies, ultimately improving therapeutic efficacy and global access to this vital drug for tuberculosis control.

Subject of Research: Pharmaceutical Sciences

Article Title: Enhancing bedaquiline solubility with advanced approaches for optimized tubercular therapy

Article References: Yadav, P., Dubey, A., Jaruat, S., Singh, S., Srivastava, V., & Parashar, P. (2026). Enhancing bedaquiline solubility with advanced approaches for optimized tubercular therapy. Discover Chemistry, 3(1), Article 583. https://doi.org/10.1007/s44371-026-01040-6

Image Credits: AI Generated

DOI: 10.1007/s44371-026-01040-6

Keywords: bedaquiline, tuberculosis, MDR-TB, drug solubility, solid dispersion, polymeric micelles, solid lipid nanoparticles, nanoemulsion, drug delivery, pharmaceutical formulation, Enhancing, solubility