Burcu Mesut

Historically, pharmaceutical formulation development relied heavily on trial-and-error experimentation, which was useful for empirical progress but often provided limited mechanistic understanding and insufficient efficiency for increasingly complex drug products. The introduction of Design of Experiments (DoE) and Quality by Design (QbD) established a more systematic framework for studying formulation variables, manufacturing parameters, and Critical Quality Attributes (CQAs). Approaches such as factorial designs, response-surface methodology, and mixture designs have therefore become central to modern pharmaceutical development because they improve experimental efficiency and support the definition of design space. However, as formulations become more nonlinear, high-dimensional, and multi-objective, these classical approaches may no longer be sufficient on their own. This review examines the evolution of experimental design in pharmaceutical research, from one-factor-at-a-time experimentation to structured DoE/QbD strategies, and then to emerging intelligent optimization methods. Its central objective is to clarify when conventional DoE/QbD remains appropriate and when it should be complemented by machine learning, Bayesian optimization, digital twins, and closed-loop experimental systems. The review first summarizes the foundations and strengths of classical experimental design; then, it discusses its practical limitations in complex formulation settings, and finally evaluates how data-driven and hybrid approaches can extend pharmaceutical development. Evidence from tablets, capsules, nanocarriers, transdermal patches, and biotherapeutic systems suggests that intelligent optimization can improve predictive performance and experimental efficiency when used alongside, rather than instead of, established pharmaceutical development principles.

Background/Objectives: Canagliflozin (CFZ) is the first sodium glucose co-transporter 2 (SGLT-2) inhibitor and is characterized by poor water solubility and permeability, resulting in low oral bioavailability. In this study, a CFZ nanosuspension (CFZ-NS) was converted into a solid form to improve the physical stability of CFZ nanocrystals (CFZ-NCs) and to enable formulation as a tablet dosage form. Methods: To achieve adequate redispersibility of dried CFZ-NCs, fluid bed granulation and spray-drying methods were employed, and the effects of critical process parameters were investigated. The stability of spray-dried nanocrystal tablets (NCs-SD-TAB) was evaluated over a three-month period under storage conditions of 25 ± 2 °C with 60 ± 5% relative humidity (RH) and 40 ± 2 °C with 75 ± 5% RH. Results: The highest redispersibility index (94%) was obtained using the spray-drying method. Tablets prepared with spray-dried NCs-SD-TAB exhibited a significantly higher in vitro dissolution rate under non-sink conditions compared with control tablets prepared using unprocessed CFZ with the same excipients, as well as the marketed product. NCs-SD-TAB showed an approximately three-fold increase in drug release at 15 min in 0.1 N HCl, with a pH 4.5 acetate buffer and pH 6.8 phosphate buffer, which simulate gastrointestinal pH conditions, relative to the marketed product. Conclusions: Overall, these results indicate that nanocrystal technology represents a promising approach for CFZ as an improved oral drug-delivery system, primarily due to its solubility enhancement capabilities.

Background: This work aimed to enhance the solubility of Tadalafil (TDL), a BCS Class II drug, by preparing Type IV lipid-based formulations. Methods: Type IV formulations were prepared using surfactants and/or hydrophilic co-surfactants, resulting in oil-free systems. Results: Based on the solubility test, Transcutol^® HP exhibited the highest solubility for TDL (48.33 ± 0.004 mg/mL) and was selected as the co-surfactant. Among surfactants, Kolliphor^® PS80 (42.74 ± 2.29 mg/mL), Kolliphor^® EL (41.87 ± 2.50 mg/mL), Kollisolv^® PEG 400 (40.70 ± 0.30 mg/mL), and Kolliphor^® HS15 (31.40 ± 3.63 mg/mL) demonstrated high solubilization capacity. These were used to prepare formulations without the addition of an oil phase. The developed formulations resulted in a system with a nano-droplet size (® (2:1) exhibited a significantly higher dissolution of over 95% within 5 min compared to the marketed product. The in vitro lipolysis studies demonstrated that F2 formulation maintained TDL in a supersaturated state throughout digestion, with limited enzymatic degradation of the excipients. Cytotoxicity evaluation using the MTT assay in Caco-2 cells confirmed the biocompatibility of both drug-free and TDL-loaded formulations, with IC₅₀ values of 19.55 µg/mL and 17.55 µg/mL, respectively. Conclusions: The overall results suggested that the developed solid Type IV lipid formulations can improve the dissolution rate of TDL, which would potentially lead to an improvement in its oral bioavailability and, consequently, a reduction in the treatment dose as a safe delivery system.

The advancement of efficient drug delivery systems continues to pose a significant problem in pharmaceutical sciences, especially for compounds with limited water solubility. Lipid-based systems, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), have emerged as viable options owing to their biocompatibility, capability to safeguard labile chemicals, and potential for prolonged release. Nonetheless, the encapsulation efficiency (EE) and release dynamics of these carriers can be enhanced by including cyclodextrins (CDs)—cyclic oligosaccharides recognized for their ability to form inclusion complexes with hydrophobic compounds. This article offers an extensive analysis of CD-modified SLNs and NLCs as multifunctional drug delivery systems. The article analyses the fundamental principles of these systems, highlighting the pre-complexation of the drug with cyclodextrins before lipid incorporation, co-encapsulation techniques, and surface adsorption after formulation. Attention is concentrated on the physicochemical interactions between cyclodextrins and lipid matrices, which influence essential factors such as particle size, encapsulation efficiency, and colloidal stability. The review includes characterization techniques, such as particle size analysis, zeta potential measurement, drug release studies, and Fourier-transform infrared spectroscopy (FT-IR)/Nuclear Magnetic Resonance (NMR) analyses. The study highlights the application of these systems across many routes of administration, including oral, topical, and mucosal, illustrating their adaptability and potential for targeted delivery. The review outlines current formulation challenges, including stability issues, drug leakage, and scalability concerns, and proposes solutions through advanced approaches, such as stimuli-responsive release mechanisms and computer modeling for system optimization. The study emphasizes the importance of regulatory aspects and outlines future directions in the development of CD-lipid hybrid nanocarriers, showcasing its potential to revolutionize the delivery of poorly soluble drugs.

Drug targeting for brain malignancies is restricted due to the presence of the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB), which act as barriers between the blood and brain parenchyma. Certainly, the limited therapeutic options for brain malignancies have made notable progress with enhanced biological understanding and innovative approaches, such as targeted therapies and immunotherapies. These advancements significantly contribute to improving patient prognoses and represent a promising shift in the landscape of brain malignancy treatments. A more comprehensive understanding of the histology and pathogenesis of brain malignancies is urgently needed. Continued research focused on unraveling the intricacies of brain malignancy biology holds the key to developing innovative and tailored therapies that can improve patient outcomes. Lipid nanocarriers are highly effective drug delivery systems that significantly improve their solubility, bioavailability, and stability while also minimizing unwanted side effects. Surface-modified lipid nanocarriers (liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, lipid nanocapsules, lipid-polymer hybrid nanocarriers, lipoproteins, and lipoplexes) are employed to improve BBB penetration and uptake through various mechanisms. This systematic review illuminates and covers various topics related to brain malignancies. It explores the different methods of drug delivery used in treating brain malignancies and delves into the benefits, limitations, and types of brain-targeted lipid-based nanocarriers. Additionally, this review discusses ongoing clinical trials and patents related to brain malignancy therapies and provides a glance into future perspectives for treating this condition. Graphical Abstract (Created by using Biorender.com licenced version).

This mini-review theoretically illustrates the in silico methods used in the pharmacy field to enhance drug discovery and development and reduce preclinical studies. It is shown that in silico methods are computational-based approaches that study the structure, properties, and activities of molecules using computer simulations and mathematical algorithms. These results highlight the importance of obtaining data that can affect the prediction of in vivo results. Artificial intelligence and machine learning development enhance in silico methods such as quantitative structure-activity relationship, molecular placement, and physiological-based pharmacokinetics, which are usually used. This approach not only saves time and costs but also offers ease of application. Studies conducted to evaluate the use of in silico methods in areas such as pharmacology, toxicology, and pharmaceuticals are provided as examples. It was concluded that over time, in silico methods usage and development increased due to their ability to predict the in vivo performance of the drug.

One of the crucial approaches to managing the low solubility and weak bioavailability of drugs is via nanocrystal technology. Through this technology, drug particles have an increased solubility and a faster dissolution rate due to high surface free energy, which requires an appropriate stabilizer(s) to prevent instabilities during the manufacturing process and storage of the nanosuspension. This study aimed to establish a scientific predictive system for properly selecting stabilizers or to reduce the attempts on a trial-and-error basis in the wet-milling method. In total, 42 experiments were performed to examine the effect of critical material attributes on the wettability of the drug, the saturation solubility in the stabilizer solutions or combinations thereof and the dynamic viscosity of stabilizer solutions. All data were evaluated by Minitab 19^® and an optimization study was performed. The optimized formulation at a certain concentration of stabilizer combination was ground by Dyno Mill^® with 0.3 mm beads for one hour. The optimized nanosuspension with a particle size of 204.5 nm was obtained in short milling time and offered 3.05- and 3.51 times better dissolution rates than the marketed drug product (Invokana^® 100 mg) in pH 4.5 and pH 6.8 as non-sink conditions, respectively. The formulation was monitored for three months at room temperature and 4 °C. The parameters were 261.30 nm, 0.163, −14.1 mV and 261.50 nm, 0.216 and −17.8 mV, respectively. It was concluded that this approach might indicate the appropriate selection of stabilizers for the wet-milling process.