The pharmaceutical arena grapples with a widespread challenge, as nearly 90% of newly developed Active Pharmaceutical Ingredients (APIs) exhibit low water solubility. Despite the existence of a multitude of pre-formulation and formulation strategies aimed at improving water solubility, a substantial 40% of these APIs encounter commercialization hurdles, primarily stemming from this inherent limitation1. The profound influence of solubility on drug effectiveness is indisputable. The solubility of a drug in water stands as a foundational characteristic that demands meticulous consideration2. In oral formulations, the amount of drug adsorption from the gastrointestinal tract into the systemic circulation, known as oral bioavailability, is crucial for ensuring sufficient efficacy3.The bioavailability of a pharmaceutical active is often characterized by two primary properties: permeability and solubility. The Food and Drug Administration, along with the pharmaceutical industry, commonly categorizes drugs based on these characteristics within a four-quadrant Biopharmaceutical Classification System (BCS). Presently, drugs exhibiting both high solubility and high permeability (Class I) constitute approximately 35% of the currently marketed drugs. However, only 10% of future drug candidates in the drug production line fall into Class I. In contrast, a substantial majority (around 80%) of upcoming drug candidates are anticipated to possess low aqueous solubility (Classes II and IV), and this has led to extensive efforts towards formulation strategies to improve water solubility4.The consequence of low solubility is more emphasized in oral drugs, where drugs with low solubility lead to a decrease in the presence of active pharmaceutical compounds in the systemic circulation.A significant proportion, approximately 30–40%, of drugs developed to date fall into the challenging category of being very difficult to dissolve in water, defined by the United States Pharmacopeia (USP) as less than 0.1 mg/ml. Examples of such drugs include drugs categorized as BCS class II such as danazol, nifedipine, and phenytoin, and drugs categorized as BCS class IV drugs like furosemide, taxol, and hydrochlorothiazide2.Various techniques are employed to address the issue of poor aqueous solubility of drugs. These techniques include, nanosuspension, particle size reduction, salt formation, hydrotropy, pH adjustment, solid dispersion, amorphous, and co-crystal compound formation5,6.Among these techniques, nanonization stands out as a widely employed method for enhancing solubility and bioavailability, as indicated by a substantial body of literature and the existence of authorized marketed products such as Rapamune®, Emend®, Triglide®, Tricor®, and Megace ES®7.Nanosuspension, defined as nanosized drug molecules prepared in an aqueous medium and stabilized by suitable stabilizers like surfactants and polymers, has emerged as a prominent approach8. The reduction in particle size is a well-established method for increasing dissolution rates and oral bioavailability. Beyond the advantages mentioned, nanocrystals offer easy transformation into solid forms such as tablets, capsules, and powders for redispersion. Researchers are expanding into nutraceuticals, utilizing nanocrystals to increase Maximum solubility and speed of dissolution while retaining the benefits of nanoformulation with the addition of a slight surfactant9. The advent of nanotechnology has revolutionized various fields, including chemical, physical, and life sciences, providing a new avenue for drug delivery in pharmaceuticals1,10.Nanosuspensions can be prepared employing two main methods: bottom-up and top-down. Stabilizing agents may consist of polymers like hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP K30), and surfactants such as ionic sodium lauryl sulfate (SLS) and nonionic polysorbate (Tween 80)11.PVA is biocompatible and non-toxic, making it safe for use in drug formulations. Its hydrophilic nature improves the wettability of poorly soluble drugs, enhancing their dispersion in aqueous environments. PVA is chemically stable and resistant to degradation, providing long-term stability to formulations. PVA can form hydrogen bonds with APIs, which can improve the stability and dispersion of nanosuspensions. These properties make PVA an effective stabilizer, ensuring the consistency, efficacy, and safety of pharmaceutical products12,13,14.The choice of stabilizers, a critical aspect of the bottom-up method, can be a tedious task, requiring considerable effort. The successful application of nanosuspensions has been demonstrated in improving the activity of various anti-infectives, including triclosan, ciprofloxacin, itraconazole, and miconazole10,15,16. Nanocrystals, in addition to improving drug dissolution, have shown promise in realizing sustained release and targeting specific tissues or organs. An important advantage of nanosuspensions is their administration routes, including oral, parenteral, ocular, and pulmonary delivery, which surpass traditional formulation products17.In contemporary pharmaceutical research, the utilization of Computer Aided Formulation Design (CAFD) methods has become widespread. These methodologies play a pivotal role in the selection of an optimal combination of stabilizers. Through the application of rational predictive CAFD methods, researchers can achieve desirable outcomes with a reduced number of experiments, expediting the attainment of results even before the initiation of actual laboratory experiments. The computational simulations contribute to comprehending the intermolecular interactions occurring at the molecular level among the formulation components. This understanding provides valuable insights into the observed physical and morphological changes within the formulation8.Molecular Dynamics (MD) is a computational method based on classical mechanics, which simulates the physical movements of atoms and furnishes atomic-scale information not easily attainable through experimental investigations. MD offers insights that can assist in the development of drug formulations in a cost-effective and time-efficient manner18.Styliari et al. and colleagues conducted an experimental and computational study on a method for coating drug nanoparticles with an amphiphilic polymer (mPEG-b-PCL) to enhance drug delivery. Their research found that after the evaporation of acetone, the polymer surrounds the drug molecules, resulting in a drug nanoparticle coated with the polymer with an efficiency of 99%19.The article by Tian et al. presents computational research on screening stabilizers and exploring stabilization mechanisms for irbesartan nanosuspensions, which improve the dissolution of poorly soluble irbesartan polymorphs. Soluplus-P407 and TPGS-HPMCE5 were identified as suitable stabilizers through spatial conformation and thermodynamic energy analyses. The prepared nanosuspensions enhanced dissolution at different pH values. The stabilization mechanism was analyzed using molecular docking, molecular dynamics simulations, FTIR, and Raman spectroscopy, suggesting decreased enthalpy and Gibbs free energy due to synergistic external and internal interactions contributing to stabilization20.Singh et al. utilized the emulsion solvent evaporation technique to create drug-loaded polymer nanoparticles for the oral formulation of tolbutamide using a biodegradable polymer (ε-caprolactone). The goal was to improve the bioavailability and therapeutic efficacy of tolbutamide by reducing its particle size to the nanoscale and achieving sustained drug release from the polymeric nanoparticles. Characterization techniques like FTIR, DSC, particle size analysis, zeta potential, and drug release studies were performed. The absence of new peaks or shifting of existing peaks in the FTIR spectra of the drug-excipient mixture compared to the pure drug indicates no chemical interaction and compatibility between the drug and polymers. DSC can detect any physical interactions or incompatibilities between the drug and excipients by analyzing changes in the melting endotherms, glass transition temperatures, or the appearance of new thermal events. The absence of any new thermal events or significant shifts in the melting/glass transition temperatures of the drug-excipient mixture, when compared to the pure drug, indicates that there are no physical interactions and that the components are compatible. The prepared drug-loaded poly(ε-caprolactone) nanoparticles were found to be in the nanometer size range with spherical morphology. The particle size was measured by dynamic light scattering using a Nicomp particle sizer. The zeta potential was measured to determine the stability of the nanoparticles. The prepared nanoparticles were found to be stable, with the zeta potential being influenced by the stabilizer type and concentration21.In this work, MD was employed to simulate the nanosuspension of four active pharmaceutical compounds: flurbiprofen, bezafibrate, miconazole, and phenytoin. These compounds, known using their low solubility in water, were simulated with a polyvinyl alcohol polymer stabilizer. The MD and subsequent analysis provided valuable insights at the molecular level. The examination of hydrogen bonding interactions, radial distribution functions, diffusion coefficients, and energy profiles permitted us to observe the virtual formation of particles.Flurbiprofen (C15H13FO2) and phenytoin (C15H12N2O2) both have functional groups, which are crucial for their pharmacological properties, and they are classified as class II drugs in the biopharmaceutics classification system BCS, indicating high permeability and low solubility4,22. Flurbiprofen’s structure includes a biphenyl system with a fluorine atom and a propanoic acid moiety, while phenytoin features an imidazolidine ring with carbonyl and phenyl groups.Miconazole (C18H14Cl4N2O) and bezafibrate (C19H20ClNO4) are also class II drug in the BCS23,24. Miconazole includes an imidazole ring with dichlorophenyl groups, a methoxy group, and an ethyl chain. Bezafibrate features two benzene rings, an amide group, a carboxylic acid group, and a chlorine substituent. The drug’s structure is shown in Fig. 1.Figure 1The initial structures of (A) flurbiprofen, (B) phenytoin, (C) miconazol, (D) bezafibrate.The molecular structures of flurbiprofen, phenytoin, miconazole, and bezafibrate differ owing to the presence of unique chemical groups and ring structures. These structural differences play a significant role in determining the pharmacological activities and therapeutic uses of the compounds.In this study, we used these drugs because of their low solubility and their placement in classification under BCS class II.
