The intricate process of protein binding orchestrates crucial drug interactions within the bloodstream, facilitating the formation of soluble complexes. This research endeavours to improve the dissolution and oral bioavailability of Rifampicin (RMP) by strategically manipulating drug-protein binding dynamics and the hydrophobic characteristics of human serum albumin (HSA). Various precipitation techniques leveraging methanol, ammonium sulfate, and heat treatment were meticulously employed to tailor the properties of colloidal albumin (HSA NPs). The resultant complexes underwent comprehensive characterization encompassing evaluations of hydrophobicity, size distribution, surface charge, and structural analyses through FTIR, TG-DSC, XRD, and morphological examinations. The findings revealed a significant binding affinity of 78.07 ± 6.6% with native albumin, aligning with prior research. Notably, the complex RMP-HSA NPs-M13, synthesized via the methanolic precipitation method, exhibited the most substantial complexation, achieving a remarkable 3.5-fold increase, followed by the ammonium sulfate (twofold) and heat treatment (1.07-fold) methods in comparison to native albumin binding. The gastric simulated media exhibited accelerated drug release kinetics, with maximal dissolution achieved within two hours, contrasting with the prolonged release observed under intestinal pH conditions. These findings translated into significant improvements in drug permeation, as evidenced by pharmacokinetic profiles demonstrating elevated Cmax, AUC, t1/2, and MRT values for RMP-HSA NPs-M13 compared to free RMP. In summary, this innovative approach underscores the potential of precipitation methods in engineering stable colloidal carrier systems tailored to enhance the oral bioavailability of poorly soluble drugs, offering a pragmatic and scalable alternative to conventional surfactants, polymers, or high-energy methods for complex formation and production.

Layered double hydroxides (LDHs) are highly effective drug delivery systems, owing to their capacity to intercalate or adsorb biomaterials, flexible structure, swelling property, high stability, good biocompatibility, and ease of synthesis. Phenytoin (PHT) is an antiseizure BCS (Biopharmaceutics Classification System) class II drug, presenting low aqueous solubility. Therefore, the current study aimed at increasing its solubility, dissolution, and bioavailability. PHT was intercalated to the MgAl-LDH formed in situ and successful intercalation to form MgAl-PHT-LDH was confirmed by FTIR, PXRD, DSC, and TGA. Examination of particle size and morphology (by photon correlation spectroscopy and electron microscopy, respectively) confirmed the formation and intercalation of nanostructured LDH. Intercalation enhanced the saturation solubility of PHT at 25°C in 0.1N HCl and phosphate buffer (pH 6.8) by 6.57 and 10.5 times respectively. The selected drug excipient powder blend for the formulation of MgAl-PHT-LDH tablets exhibited satisfactory properties in both pre-compression parameters (angle of repose, bulk density, tapped density, Carr\'s index, and Hausner ratio) and tablet characteristics (weight variation, thickness, hardness, friability, content uniformity, and disintegration time). MgAl-PHT-LDH tablets showed better dissolution of PHT compared to unprocessed PHT tablets at all time points. Oral bioavailability of MgAl-PHT-LDH tablets and unprocessed PHT tablets was tested in two groups of Sprague Dawley rats based on analysis of serum levels of both forms of PHT by UPLC-ESI-MS/MS serum. MgAl-PHT-LDH tablets demonstrated a relative bioavailability of 130.15% compared to unprocessed PHT tablets, confirming a significantly higher oral bioavailability of MgAl-PHT-LDH. In conclusion, MgAl-PHT-LDH could provide a strategy for enhancing solubility, dissolution, and thereby bioavailability of PHT, enabling the evaluation of theclinical efficacy of MgAl-PHT-LDH tablets for the treatment of seizures at lower PHT doses.

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made.

The poor water solubility of orally administered drugs leads to low dissolution in the GI tract, resulting to low oral bioavailability. Traditionally, in vitro dissolution testing using the compendial dissolution apparatuses I and II has been the gold-standard method for evaluating drug dissolution and assuring drug quality. However, these methods don\'t accurately represent the complex physiologies of the GI tract, making it difficult to predict in vivo behavior of these drugs. In this study, the in vivo predictive method, gastrointestinal simulator alpha (GIS-α), was used to study the dissolution profiles of commercially available BCS Class II drugs, danazol, fenofibrate, celecoxib, and ritonavir. This biorelevant transfer method utilizes multiple compartments alongside peristaltic pumps, to effectively model the transfer of material in the GI tract. In all cases, the GIS-α with biorelevant buffers gave superior dissolution profiles. In silico modeling using GastroPlusTM yielded better prediction when utilizing the results from the GIS-α as input compared to the dissolution profiles obtained from the USP II apparatus. This gives the GIS-α an edge over compendial methods in generating drug dissolution profiles and is especially useful in the early stages of drug and formulation development. This information gives insight into the dissolution behavior and potential absorption patterns of these drugs which can be crucial for formulation development, as it allows for the optimization of drug delivery systems to enhance solubility, dissolution, and ultimately, bioavailability.

To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (Smax) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (P app ) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10-6 cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (Cmax) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC0-24) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications.

Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11-19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.

Predictive performance assays are crucial for the development and approval of nanomedicines and their bioequivalent successors. At present, there are no established compendial methods that provide a reliable standard for comparing and selecting these formulation prototypes, and our understanding of the in vivo release remains still incomplete. Consequently, extensive animal studies, with enhanced analytical resolution for both, released and encapsulated drug, are necessary to assess bioequivalence. This significantly raises the cost and duration of nanomedicine development. This work presents the development of a discriminatory and biopredictive release test method for liposomal prednisolone phosphate. Using model-informed deconvolution, we identified an in vivo target release. The experimental design employed a discrete L-optimal configuration to refine the analytical method and determine the impact of in vitro parameters on the dosage form. A three-point specification evaluated the key phases of in vivo release: early (T-5%), intermediate (T-20%), and late release behavior (T-40%), compared to the in vivo release profile of the reference product, NanoCort®. Various levels of shear responses and the influence of clinically relevant release media compositions were tested. This enabled an assessment of the effect of shear on the release, an essential aspect of their in vivo deformation and release behavior. The type and concentration of proteins in the medium influence liposome release. Fetal bovine serum strongly impacted the discriminatory performance at intermediate shear conditions. The method provided deep insights into the release response of liposomes and offers an interesting workflow for in vitro bioequivalence evaluation.

The growing co-consumption of botanical natural products with conventional medications has intensified the need to understand potential effects on drug safety and efficacy. This review delves into the intricacies of intestinal pharmacokinetic interactions between botanical natural products and drugs, such as alterations in drug solubility, permeability, transporter activity, and enzyme-mediated metabolism. It emphasizes the importance of understanding how drug solubility, dissolution, and osmolality interplay with botanical constituents in the gastrointestinal tract, potentially altering drug absorption and systemic exposure. Unlike reviews that focus primarily on enzyme and transporter mechanisms, this article highlights the lesser known but equally important mechanisms of interaction. Applying the Biopharmaceutics Drug Disposition Classification System (BDDCS) can serve as a framework for predicting and understanding these interactions. Through a comprehensive examination of specific botanical natural products such as byakkokaninjinto, green tea catechins, goldenseal, spinach extract, and quercetin, we illustrate the diversity of these interactions and their dependence on the physicochemical properties of the drug and the botanical constituents involved. This understanding is vital for healthcare professionals to effectively anticipate and manage potential natural product-drug interactions, ensuring optimal patient therapeutic outcomes. By exploring these emerging mechanisms, we aim to broaden the scope of natural product-drug interaction research and encourage comprehensive studies to better elucidate complex mechanisms.

In this work, an automated dissolution system (dissoBOT) was used for dissolution testing for the first time. Carry-over (CO) of the dissoBOT was determined for paracetamol (PA) and diclofenac sodium (DS), which are active pharmaceutical ingredients (APIs). Initially, partial method validation of the UV-VIS spectrophotometry method for PA and DS determination was performed by defining the limit of detection (LOD), the limit of quantification (LOQ), linear concentration range, accuracy, and precision. The LODs and LOQs were less than 0.01 mg/L for both APIs. The determined linear concentration ranges were from 1.00 mg/L to 30.00 mg/L for PA and from 0.50 mg/L to 3.50 mg/L for DS (the square of the correlation coefficient was greater than 0.9990, and the quality coefficient was less than 1.00 % for both APIs). The accuracy of the method was evaluated by calculating the recovery (Re) of the solutions of standards with known concentrations. The method for both APIs was deemed to be accurate (the average Re for PA and DS were 99.81 % and 101.43 %, respectively). Precision was evaluated by calculating the relative standard deviation (RSD). The method for PA and DS was deemed to be precise, as the RSD value for PA was 0.13 %, and for DS was 0.38 %. The volume (V) of the washing medium in both cleaning cycles performed by the dissoBOT system, as well as the medium dispensing V, were established, where the medium dispensing V was in accordance with the United States Pharmacopeia requirements. The CO of the dissoBOT system, using tap water as the washing medium, was determined to be less than 1.00 % for both APIs. The CO values for one cleaning cycle of the sampling station with a V of 2 mL was in the range of 1.24-1.54 %, for V of 5 mL was in the range of 0.78-0.93 %, and for V of 10 mL was in the range of 0.27-0.36 %. In addition, the CO of the dissoBOT, when employing two cleaning cycles of the sampling station (each V of 10 mL) was reduced (CO <0.20 %). Finally, the dissoBOT was successfully employed for the dissolution PA and DS tables.

Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent. In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM). It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC. By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions. By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption.