pH-dependent Solubility Research Articles

Functionalisation of chitosan with methacryloyl and crotonoyl groups as a strategy to enhance its mucoadhesive properties

Mucoadhesive polymers are crucial for prolonging drug retention on mucosal surfaces. This study focuses on synthesising and characterising novel derivatives by reacting chitosan with crotonic and methacrylic anhydrides. The structure of the resulting derivatives was confirmed using proton-nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. It was established that the degree of substitution plays a crucial role in the pH-dependent solubility profiles and electrophoretic mobility of the chitosan derivatives. Spray-drying chitosan solutions enabled preparation of microparticles, whose mucoadhesive properties were evaluated using fluorescence flow-through studies and tensile test, demonstrating improved retention on sheep nasal mucosa for modified derivatives. Acute toxicity studies conducted in vivo using planaria and in vitro using MTT assay with the Caco-2 cell line, a model of the mucosal epithelium in vitro, showed that the novel derivatives are not cytotoxic. These findings emphasise the potential of tailored chitosan chemical modifications for enhancing transmucosal drug delivery.

Effect of Hydroxyapatite Nanoparticle Crystallinity and Colloidal Stability on Cytotoxicity.

Hydroxyapatite nanoparticles (nHA) have gained attention as potential intracellular drug delivery vehicles due to their high binding affinity for various biomolecules and pH-dependent solubility. Yet, the dependence of nHA cytocompatibility on their physicochemical properties remains unclear since numerous studies have revealed starkly contrasting results. These discrepancies may be attributed to differences in size, shape, crystallinity, and aggregation state of nHA, which complicates fundamental understanding of the factors driving nHA cytotoxicity. Here, we hypothesize that nHA cytotoxicity is primarily driven by intracellular calcium levels following the internalization of nHA nanoparticles. By investigating the cytotoxicity of spherical nHA with different crystallinity and dispersity, we find that both lower crystallinity and increased agglomeration of nHA raise cytotoxicity, with nanoparticle agglomeration being the more dominant factor. We show that the internalization of nHA enhances intracellular calcium levels and increases the production of reactive oxygen species (ROS). However, only subtle changes in intracellular calcium are observed, and their physiological relevance remains to be confirmed. In conclusion, we show that nHA agglomeration enhances ROS production and the associated cytotoxicity. These findings provide important guidelines for the future design of nHA-containing formulations for biomedical applications, implying that nHA crystallinity and especially agglomeration should be carefully controlled to optimize biocompatibility and therapeutic efficacy.

Discovery of alkaline laccases from basidiomycete fungi through machine learning-based approach

BackgroundLaccases can oxidize a broad spectrum of substrates, offering promising applications in various sectors, such as bioremediation, biomass fractionation in future biorefineries, and synthesis of biochemicals and biopolymers. However, laccase discovery and optimization with a desirable pH optimum remains a challenge due to the labor-intensive and time-consuming nature of the traditional laboratory methods.ResultsThis study presents a machine learning (ML)-integrated approach for predicting pH optima of basidiomycete fungal laccases, utilizing a small, curated dataset against a vast metagenomic data. Comparative computational analyses unveiled the structural and pH-dependent solubility differences between acidic and neutral-alkaline laccases, helping us understand the molecular bases of enzyme pH optimum. The pH profiling of the two ML-predicted alkaline laccase candidates from the basidiomycete fungus Lepista nuda further validated our computational approach, showing the accuracy of this comprehensive method.ConclusionsThis study uncovers the efficacy of ML in the prediction of enzyme pH optimum from minimal datasets, marking a significant step towards harnessing computational tools for systematic screening of enzymes for biotechnology applications.Graphical

Mesoporous silica-based amorphous solid dispersions to enhance the oral bioavailability of Neratinib maleate

Neratinib maleate (NM) used in the treatment of breast cancer, has a low and variable oral bioavailability due to its pH-dependent solubility and gut-wall metabolism-restricted permeability. Mesoporous silica based solid dispersion of NM (SD-NM-MSi) was designed to improve its solubility and dissolution rate. SYLOID XDP 3050 was selected as a mesoporous silica carrier based on its higher drug loading (15.7 %) and good flow properties. The extensive surface area of the Mesoporous silica offered a suitable site for drug adsorption. Thermal and diffractometry analysis indicated that NM was adsorbed in an amorphous form. In vitro dissolution studies revealed that the optimized SD-NM-MSi showed a higher rate and extent of drug dissolution compared to plain NM in pH 3.0, pH 4.5, and 6.8, respectively. Similarly, an oral pharmacokinetic study (10 mg/kg) resulted in significantly higher plasma exposure for SD-NM-MSi compared to plain NM, with a 73 % (P < 0.01) increase in the relative oral bioavailability of NM.

ATM kinase phosphorylates Ser15 of p53 in a pH-dependent manner

The phosphorylation of Ser15 in the transactivation domain (TAD) of the tumor suppressor protein 53 (p53) by ataxia-telangiectasia mutated (ATM) kinase is a crucial step in the tumor suppressor function of p53. An understanding of the factors that affect the rate of Ser15 phosphorylation may provide new strategies for the manipulation of the ATM-p53 pathway in cancer therapy. In this study, the effect of electrostatic interactions between ATM and p53 was investigated by measuring the phosphorylation of Ser15 at varying pH ranges from 5 to 9. To achieve this, two different kinase assay methods were utilized: the ELISA technique, which directly quantifies the phosphorylated Ser15, and the Universal Kinase Assay, which assesses the formation of ADP. The results revealed that Ser15 phosphorylation was pH-dependent, with higher phosphorylation rates observed in the alkaline range. To ascertain whether the lower phosphorylation rates observed at acidic pH were due to protein denaturation, a pH-dependent solubility profile was generated using the CamSol server. The obtained results demonstrated comparable solubility rates within the pH range of the kinase assays performed. Furthermore, the significance of negatively charged residues in TAD1-39 was evaluated by substituting Asp and Glu residues with hydrophobic and uncharged hydrophilic residues in TAD1-39 using ChimeraX and subsequently comparing their interactions with the ATM using the protein-protein docking server HADDOCK2.4. The results of the docking simulations indicated that the alteration of negatively charged residues with uncharged ones resulted in a reduction in the efficiency of the interaction between the ATM and TAD1-39. In conclusion, it can be stated that electrostatic interactions between the ATM and TAD are important for optimal Ser15 phosphorylation.

Formulation Variables Influencing the Development of Ketoconazole Gastroretentive Drug Delivery System

Background: Ketoconazole (KZ) is categorized as class II according to the Biopharmaceutics Classification System (BSC) classification, which shows a strong pH-dependent solubility where its solubility is enhanced under an acidic medium (pH below 3). This strong pH dependence results in unpredictable absorption and a wide range of bioavailabilities. Objective: To prolong the gastric residence time of KZ’s tablet to enhance KZ’s solubility and hence its bioavailability for better therapeutic activity. Methods: To prepare mucoadhesive tablets, we use both direct and wet granulation methods. We employed various evaluation tests to assess the prepared tablets. These tests encompass a range of assessments, including weight variation, hardness, thickness, friability, disintegration test, swelling study, mucoadhesive strength study, and in vitro drug release studies. Results: The study found that polymer viscosity, as well as polymer concentration, have a significant effect on mucoadhesive strength and drug release, whereas diluent type has a non-significant influence on drug release. We selected Formula 7, which employs xanthan gum as a mucoadhesive polymer in a 1:1 drug polymer ratio, as the optimum formula because it provides an accepted physico-mechanical property and releases 87% of the drug over 8 hours. Conclusions: Gastric mucoadhesive tablets may be an effective method of delivering active ingredients, as they provide a favorable environment that enhances their dissolution by extending their duration in the stomach, thereby increasing their bioavailability.

Enhancement of Valsartan Solubility by Amorphous solid Dispersion Ternary System: An Optimization and Characterization

Valsartan has poor water solubility, particularly at a pH below 5 due to its pH-dependent solubility. This limits its bioavailability. To enhance the solubility and dissolution rate of valsartan solid dispersion, we prepared it using the spray drying technique in a ternary system. Kollidon VA64 and Kolliphor P407 were utilized in various ratios for its preparation. Drug solubility, crystallography, and dissolution of Val-ASD were evaluated to examine the effect of formulation on its physicochemical characteristics. The molecular interactions between the drug, polymer, and surfactant, as well as amorphization, were analysed using FTIR, DSC, and XRD. Optimisation was conducted utilising the full factorial design approach with a confidence level of 95%. Valsartan was prepared as a solid dispersion that showed a 39-fold increase in solubility compared to its pure form. Furthermore, the formulation was found to accelerate the rate of dissolution. The X-ray diffraction (XRD) and differential scanning calorimetry (DSC) profiles indicated complete amorphization, while the Fourier transform infrared (FTIR) profile displayed hydrogen bonding and hydrophobic interactions between the drug and matrix, which collectively contribute to its enhanced characteristics. Solubility and dissolution were improved in a dependent manner with respect to Kollidon VA64 and Kolliphor P407.

Improved preclinical drug metabolism and pharmacokinetics of pibothiadine (HEC121210), a novel hepatitis B virus capsid assembly modulator

Pibothiadine (PBD; HEC121120) is a novel hepatitis B virus capsid assembly modulator based on GLS4 (morphothiadine) and has inhibitory activities against resistant strains. To assess the overall preclinical drug metabolism and pharmacokinetics (DMPK) properties of PBD, in vivo pharmacokinetics studies in rats and dogs have been performed along with a series of in vitro metabolism assays. The oral bioavailability of PBD in rats and dogs might be related to its medium permeability in Caco-2 cells and largely be impacted by the pH-dependent solubility. PBD was highly distributed to the liver where the local exposure was 16.4 fold of the system exposure. PBD showed relatively low metabolic rate in recombinant human cytochrome P450 enzymes, whereas low to moderate in vitro clearance in liver microsomes and low (dog) to moderate (rat) in vivo clearance. Furthermore, β-oxidation and dehydrogenation were proposed as the primary metabolic pathways of PBD in rats. Compared to GLS4, the higher systemic exposure of PBD might be attributed to its improved oral absorption and metabolic stability. In addition, the enhanced liver/plasma exposure ratio could further increase the local exposure around the target. These improved DMPK properties might indicate better development of PBD in the clinical phase.

Biopharmaceutical profiling of anti-infective sanggenons from Morus alba root bark for inhalation administration

Mulberry Diels-Alder-type adducts (MDAAs), isolated from Morus alba root bark, exhibit dual activity against viral and bacterial pathogens but show sobering efficacy following oral administration. Inhalation administration may overcome issues with oral bioavailability and improve efficacy for the treatment of respiratory infections. To assess the suitability of MDAAs for inhalation administration, physicochemical (e.g. pH, pKa, logP, pH-dependent solubility) and biopharmaceutical (epithelial cytotoxicity, permeability, and uptake) properties of two bioactive MDAA stereoisomers sanggenon C (SGC) and sanggenon D (SGD) were evaluated as isolated natural compounds and within parent extracts (MA21, MA60). Despite their structural similarity, SGD exhibited a 10-fold higher solubility than SGC across pH 1.2–7.4, with slight increases at neutral pH. Both compounds were more soluble in isolated form than in the parent extracts. The more lipophilic SGC was found to be more cytotoxic when compared to SGD, indicating a better cellular penetration, which was confirmed by uptake studies. Nonetheless, SGC and SGD exhibited no measurable permeability across intact Calu-3 monolayers, highlighting their potential for increased lung retention and improved local anti-infective activity following inhalation administration. Results suggest that SGC and SGD in isolated form, rather than as extracts, are promising candidates for pulmonary drug delivery to treat lung infections.

New mathematical model from dynamic dissolution rate tests

In vitro dissolution experiments are becoming increasingly complex attempting to replicate in vivo behavior. The objective of these new methods is to explore the behavior of low-solubility drugs. This is more relevant for drugs classified in subclasses 2a, 2b and 2c of the BCS, considering their pH-dependent solubility and dissolution characteristics.A novel mathematical approach using a modified double Weibull equation is proposed to model the dissolution and precipitation kinetics observed in two-stage and transfer dissolution experiments (dumping test). This approach demonstrates a high level of accuracy in fitting experimental data for two drugs BCS class 2a and two BCS class 2b, providing valuable insights into their dissolution behavior under different conditions.The results highlight the versatility of the proposed model in capturing complex dissolution phenomena, including rapid dissolution, precipitation, and redissolution. The ease of implementation in Excel, using the Solver tool, makes it a practical and accessible tool for pharmaceutical researchers.Overall, the study contributes to the development of more effective in vitro dissolution testing methods, facilitating the formulation and optimization of pharmaceutical products and potentially aiding in the establishment of in vitro-in vivo correlations (IVIVC).

Enhanced Oral Efficacy of Semaglutide via an Ionic Nanocomplex with Organometallic Phyllosilicate in Type 2 Diabetic Rats.

This study aimed to develop an effective oral formulation of semaglutide, a glucagon-like peptide-1 receptor agonist, using an organometallic phyllosilicate-based colonic delivery system. The core nanocomplex (AMP-Sema) of 3-aminopropyl-functionalized magnesium phyllosilicate (AMP) and semaglutide was prepared via electrostatic interactions. Subsequently, AMP-Sema was coated with a polymer showing pH-dependent solubility (Eudragit® S100) for preferential colonic delivery. The surface-coated nanoparticles (EAMP-Sema) showed a narrow size distribution, and the encapsulated semaglutide maintained its conformational stability. The pH-dependent drug release property of EAMP-Sema yielded around 20% and 62% drug release at pH 1.2 and 7.4, respectively. The nanoparticles exhibited significantly decreased size and surface charge at pH 7.4, which indicated the pH-dependent dissolution of the coating layer. Furthermore, EAMP-Sema effectively improved the membrane permeability and metabolic stability of semaglutide in the gastrointestinal tract. It protected the encapsulated drugs from proteolysis in simulated intestinal fluids and increased drug transport by 2.5-fold in Caco-2 cells. Consequently, orally administered EAMP-Sema (equivalent to 8 mg/kg of semaglutide) showed significant therapeutic benefits, yielding effective glycemic control and weight loss in high-fat diet/streptozotocin (40 mg/kg)-induced type 2 diabetic rats. These results demonstrate that EAMP-Sema could improve the efficacy of orally administered semaglutide by enhancing the GI stability and cellular uptake of protein drugs.

A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Formulation and Evaluation of pH-Modulated Amorphous Solid Dispersion-Based Orodispersible Tablets of Cefdinir.

Cefdinir (CEF) is a semi-synthetic third-generation broad-spectrum oral cephalosporin that exhibits poor solubility at lower pH values. Considering this, pH-modulated CEF solid dispersions (ASDs) were produced by solvent evaporation method employing various hydrophilic carriers and alkalizers. Among different carriers, ASDs produced using PEG 6000 with meglumine as alkalizer were found to significantly increase (p < 0.005) the drug solubility (4.50 ± 0.32 mg/mL) in pH 1.2. Fourier transform infrared spectrophotometry confirmed chemical integrity of CEF while differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) indicated CEF was reduced to an amorphous state in ASD8. Antimicrobial assay performed by well diffusion method against Staphylococcus aureus (MTCC96) and Escherichia coli (MTCC118) demonstrated significantly superior (p < 0.001) efficacy of CEFSD compared to CEF. The porous orodispersible tablets (ODTs) of ASD8 (batch F5) were developed by incorporating ammonium bicarbonate as a subliming agent by direct compression, followed by vacuum drying displayed quick disintegration (27.11 ± 1.96 s) that met compendial norms and near-complete dissolution (93.85 ± 1.27%) in 30 min. The ODTs of ASD8 appear to be a promising platform to mitigate the pH-dependent solubility and dissolution issues associated with CEF in challenging physiological pH conditions prevalent in stomach. Thus, ODTs of ASD8 are likely to effectively manage various infections and avoid development of drug-resistant strains, thereby improving the curing rates.

Highly Soluble Dacarbazine Multicomponent Crystals Less Prone to Photodegradation.

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Challenges in geochemical modelling of metal(loid) solubility and binding mechanisms along a soil profile at a multi-contaminated site

Recognising the need for robust models in predicting groundwater contamination risks from metal(loid)s in contaminated topsoil, this study focuses on the geochemical behaviour of As, Cd, Cu, Pb, Sb and Zn in one of Sweden's most heavily contaminated areas. Samples were collected from the waste zone and underlying subsoil down to 5 m and batch experiments were carried out to assess pH-dependent solubility. The results indicate that Cd, Cu, Pb and Zn are efficiently immobilized in the waste zone, while As(V) and Sb(V) are more easily leached. With the exception of Pb and Cu at high pH, the mobilized metals appear to be predominantly in a truly dissolved state, as confirmed by ultrafiltration at 10 kDa.Speciation modelling using Visual MINTEQ did not suggest a significant role of precipitates such as Zn or Pb arsenates and phosphates, although their involvement could not be ruled out. To better understand sorption/desorption patterns, a multi-surface geochemical model was established, drawing on the Stockholm Humic and CD-MUSIC models for organic matter and Fe/Al (hydr)oxide sorption. However, when default parameters were used, the model consistently overestimated the solubility of Cd, Cu, Pb and Zn in both the waste zone and the uncontaminated subsoil. In contrast, As(V) solubility was generally underestimated, also when the reactive surface area of the Fe- and Al (hydr)oxides was decreased in the model. The model's performance was better for Sb(V), though not without imperfections. When the parameters for organic matter were adjusted such that 100% of the solid-phase organic matter was active with respect to ion binding, but only 25% of the dissolved organic matter, the model description improved considerably for Pb and Cu in the upper soil layers. The model revealed distinct differences in the adsorption behaviour of the metal cations, with Pb being sorbed mostly to Fe/Al (hydroxides), whereas a considerable part of Cu was sorbed to organic matter, particularly in the waste zone.Possibly, the dissolution of easily weatherable metal-containing mineral phases may have contributed to the poor model performance for Cd, Zn and for Cu in the deeper soil layers, although other factors, such as a contribution of hydrous SiO2 or Mn oxides to metal binding, could not be ruled out. Metal sorption to carbonate phases may also have been a contributing factor in the waste zone. Lastly, the reactivity of Fe- and Al (hydr)oxides may have been overestimated by oxalate extraction when default parameters for high-surface-area ferrihydrite were applied.These findings provide valuable insights for environmental management and underscore the need for a more detailed characterization of metal(loid) sorption in contaminated soils, as well as the development of improved modelling strategies to enhance solubility predictions.

Investigation into the role of carboxylic acid and phenolic hydroxyl groups in the plant biostimulant activity of a humic acid purified from an oxidized sub-bituminous coal.

Humic substances (HS) are increasingly being applied as crop plant biostimulants because they have been shown to increase plant productivity, especially under environmentally stressful conditions. There has been intense interest in elucidating the HS molecular structures responsible for eliciting the plant biostimulant response (PBR). The polar and weakly acidic carboxylic (COOH) and phenolic hydroxyl (ArOH) functional groups play major roles in the acid nature, pH dependent solubilities, conformation, and metal- and salt-binding capabilities of HS. Reports on the role played by these groups in the PBR of HS found growth parameters being both positively and negatively correlated with COOH and ArOH functionalities. To investigate the role of COOH and ArOH in HS biostimulant activity we used a humic acid (HA), purified from an oxidized sub bituminous coal to prepare HAs with COOH groups methylated (AHA), ArOH groups acetylated (OHA), and with both COOH and ArOH groups methylated (FHA). The original HA was designated (NHA). The four HAs were subjected to elemental, 13C-NMR, FTIR, and EPR analyses and their antioxidant properties were assessed using the trolox equivalents antioxidant capacity assay (TEAC). 13C-NMR and FTIR analysis revealed significant alkylation/acetylation. To determine the effects of alkylating/acetylating these functional groups on the HA elicited PBR, the HAs were evaluated in a plant bioassay on corn (Zea mays L.) seedling under nutrient and non-nutrient stressed conditions. Treatments consisted of the four HAs applied to the soil surface at a concentration of 80 mg C L-1, in 50 ml DI H2O with the control plants receiving 50ml DI H2O. The HA-treated plants, at both fertilization rates, were almost always significantly larger than their respective control plants. However, the differences produced under nutrient stress were always much greater than those produced under nutrient sufficiency, supporting previous reports that HA can reduce the effects of stress on plant growth. In addition, for the most part, the HAs with the alkylated/acetylated groups produced plants equal to or larger than plants treated with NHA. These results suggests that COOH and ArOH groups play a limited or no role in the HA elicited PBR. Alternatively, the HA pro-oxidant to antioxidant ratio may play a role in the magnitude of the biostimulant response.

Design of quetiapine fumarate loaded polyethylene glycol decorated graphene oxide nanosheets: Invitro-exvivo characterization

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R2: 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF.

Hydroxyl-terminated triazine dendrimers mediated pH-dependent solubility enhancement of glipizide across dendritic generations: A comparative investigation

A huge challenge for the pharmaceutical industry is hydrophobic compounds, which affect aqueous solubility, an important measure of a medicine’s efficacy. Several approaches have been used; dendrimers are particularly noteworthy because of their long-term viability, nanoscale size, large payload capacity, and adaptable end functional groups. The unique architecture of dendrimers allows for modified medication delivery and solubility profiles, making them a powerful tool for improving the solubility of hydrophobic drugs. This marks the beginning of a new era in pharmaceutical formulations. A new era in drug formulations has begun with this. As part of this study, we synthesized third-generation hydroxyl-terminated triazine-based dendrimers by meticulously reducing chlorine groups following Michael’s addition. We intend to methodically examine the effects of various concentrations of these dendrimers on the solubility behavior of glipizide, a pharmaceutical agent with intrinsic hydrophobicity, across the first, second, and third generations (the full generation). A stimulating tale of solubility improvement emerged from our research. Glipizide’s solubility was positively correlated with the concentration and generational progression of the dendrimers. The solubility of hydrophobic drugs in water can be dramatically altered by dendrimers based on hydroxyl-terminated triazine. This field of study benefits from adding new dendrimers with each generation.

Biowaiver as a Bioequivalence Study Option

SCIENTIFIC RELEVANCE. Biowaiver is a procedure for establishing the bioequivalence of generic and reference products without in vivo studies. Regulatory requirements for this procedure, as described in a variety of documents, differ in certain features and aspects. These differences need to be analysed.AIM. The aim was to compare international and Russian regulatory approaches to the Biopharmaceutics Classification System-based biowaivers, provide recommendations on comparative dissolution testing, and outline opportunities for streamlining the regulatory framework of the Eurasian Economic Union (EAEU).DISCUSSION. In this article, the authors analyse biowaiver requirements and describe procedures for assessing the permeability and pH-dependent solubility of medicines, comparing dissolution profiles in various media that simulate the gastrointestinal environment, and interpreting test results. This paper shows the role of excipients in the solubility and permeability of an active substance.CONCLUSIONS. The authors recommend a methodological approach to the biowaiver procedure for replacing in vivo bioequivalence studies with in vitro tests under the current EAEU regulatory framework and list the characteristics of medicines that limit the applicability of the procedure. In conclusion, this article provides a rationale for harmonising the existing guidelines and requirements.

Enhancement of Physicochemical and Pharmacokinetic Characteristics of Ranolazine drug substance using Cocrystalization Technique

Biopharmaceutical Classification System II drug, Ranolazine exhibits pH-dependent solubility and thus shows variable absorption along the gastrointestinal tract. Due to poor aqueous solubility particularly in basic pH, an attempt has been made to improve solubility through the cocrystallization technique. Cocrystals of Ranolazine with Nicotinamide have been synthesized at different molar ratios (1:1, 1:2, 1:3 2:1, and 3:1) through solvent-assisted grinding, slurry preparation, and solvent evaporation method and subsequently characterized by different analytical methodologies. Conformational characterization studies have been performed using techniques like melting point analysis, powder X-ray diffraction, and differential scanning calorimetry. Saturation solubility of Ranolazine alone along with cocrystals prepared in different molar ratios was conducted in water and buffers of different pH (1.2, 4.5, and 6.8) to establish enhancement in solubility. Ranolazine: Nicotinamide 1:2 cocrystals were found to be stable in accelerated and long-term stability conditions. In-vivo study performed in rats to demonstrate enhanced bioavailability. Ranolazine cocrystals with Nicotinamide were shown to have enhanced solubility in basic pH and improved peak plasma concentration, the area under the curve, and relative bioavailability by 2-folds.