Physicochemical Properties Of Drug Research Articles

Temperature-Based Topological Indices and QSPR Analysis of COVID-19 Drugs

COVID-19 is a disease caused by a novel coronavirus that is quickly spreading over the world. There is no specific medicine for the treatment of COVID-19, and it is being treated with existing drugs. To treat this condition, new medication research is being conducted. A topological index is a form of molecular descriptor that simply establishes numerical values associated with a compound’s molecular structure and is efficiently employed in modeling several physico-chemical aspects in numerous quantitative structure-property/activity relationship (QSPR/QSAR) investigations. In this article, we compute some general temperature topological indices of chloroquine, hydroxychloroquine, theaflavin, lopinavir, ritonavir, and arbidol molecular structures. In addition, QSPR analysis of the relevant topological indices is presented, and it is established that these topological indices are highly correlated with the physico-chemical properties of COVID-19 drugs. This theoretic approach may aid chemists and others working in the pharmaceutical sector in predicting the qualities of COVID-19 drugs before experimenting.

Erythrocyte membrane encapsulated gambogic acid nanoparticles as a therapeutic for hepatocellular carcinoma

Gambogic acid (GA) is a potential clinical anticancer drug that can exert antitumor effects via various molecular mechanisms. Notwithstanding, GA's low water solubility, poor stability, short half-life, and unavoidable toxic side effects have significantly hampered its clinical application. Erythrocyte membrane-coated nanoparticles (RBCM-NPs) improve drug's physicochemical properties, biocompatibility, and pharmacokinetic behaviors, allowing for long-term drug circulation and passive targeting. In this study, a novel biomimetic drug delivery system (DDS) against hepatocellular carcinoma was prepared by covering RBCM on GPP-NPs (GA-loaded mPEG-PLA NPs) to develop the RBC@GPP-NPs. In comparison to RBCM-free nanoparticles and free GA, RBC@GPP-NPs improved the drug's water solubility, stability, safety, and anti-tumor activity in vivo. We expect that this bionic nanoparticle composite can expand the clinical applicability of GA and provide a feasible solution for the research and development of GA's nano-formulation.

Evaluation of Some Sulfonamide Derivatives as a Potential Inhibitors of The Carbonic Anhydrase IX/XII by ADME and Molecular Docking Method

Molecular docking is a simulation technique that calculates the binding score of the molecules of interest to protein structures and visualizes the bond structure. It is a widely used technique for foresight because it helps to determine bond relationships between molecular structures before laboratory applications in the development of new drugs. ADME studies also provide clues for the determination of the molecules analyzed by the molecular docking method to be drug candidates. In this study, inhibition of CA IX and CA XII enzymes by sulfonamide derivatives synthesized in our previous study was investigated using molecular docking method. The CA enzyme family has an important role in the survival and spread of cancer cells. Therefore, we aimed to find new drug candidates that inhibit these enzymes. We found that the sulfonamide derivative named 6 binds to the active sites of both CA IX and CA XII enzymes with -7.44 kcal/mol and -6.39 kcal/mol energy, respectively, closest to the binding of the reference molecule acetazolamide. In addition, the compatibility of all compounds used in the study with drug-like properties was investigated using the ADME method. In conclusion, it can be said that the sulfonamide derivatives named 1-9 generally have the characteristic features of a drug (physicochemical and structural properties) and oral bioavailability.

A Drug–Drug Multicomponent Crystal of Metformin and Dobesilate: Crystal Structure Analysis and Hygroscopicity Property

A drug–drug multicomponent crystal consisting of metformin (MET) and dobesilate (DBS) was prospectively connected by solvent cooling and evaporating co-crystallization using the multicomponent crystal strategy, not only to optimize the physicochemical properties of single drugs, but also to play a role in the cooperative effect of DBS with the potential vascular protective effects of MET against diabetic retinopathy (DR). The crystal structure analysis demonstrated that MET and DBS were coupled in a 3D supramolecular structure connected by hydrogen-bonding interactions with a molar ratio of 1:1. Almost all hydrogen bond donors and receptors of MET and DBS participated in the bonding, which hindered the combination of remaining potential hydrogen bond sites and water molecules, resulting in a lower hygroscopicity property than MET alone.

Analytical Methods for Estimation of Curcumin in Bulk, Pharmaceutical Formulation and in Biological Samples

Curcumin natural chemical constituents extracted from Curcuma longa has been extensively studied because of its various pharmacological properties, such as anti-inflammatory, antioxidant, anti-proliferative, antitumor, antibiotic, antiprotozoal, immunomodulatory and anticarcinogenic effects. Analytical methods play an important role to describe physicochemical properties of drug. Several techniques for estimating curcumin in turmeric powder and pharmaceutical formulations have been developed to improve the demand for analytical methods of curcumin. Various analytical methods for estimating curcumin (spectrophotometric, chromatographic, capillary electrophoresis, and biosensor approaches) have been fully reviewed and discussed in this study.

Statistical Methods in the Study of Protein Binding and Its Relationship to Drug Bioavailability in Breast Milk.

Protein binding (PB) is indicated as the factor most severely limiting distribution in the organism, reducing the bioavailability of the drug, but also minimizing the penetration of xenobiotics into the fetus or the body of a breastfed child. Therefore, PB is an important aspect to be analyzed and monitored in the design of new drug substances. In this paper, several statistical analyses have been introduced to find the relationship between protein binding and the amount of drug in breast milk and to select molecular descriptors responsible for both pharmacokinetic phenomena. Along with descriptors related to the physicochemical properties of drugs, chromatographic descriptors from TLC and HPLC experiments were also used. Both methods used modification of the stationary phase, using bovine serum albumin (BSA) in TLC and human serum albumin (HSA) in HPLC. The use of the chromatographic data in the protein binding study was found to be positive —the most effective application of normal-phase TLC and HPLCHSA data was found. Statistical analyses also confirmed the prognostic value of affinity chromatography data and protein binding itself as the most important parameters in predicting drug excretion into breast milk.

Topological Indices of Novel Drugs Used in Diabetes Treatment and Their QSPR Modeling

A topological index is a real number obtained from the chemical graph structure. It is helpful to calculate the physicochemical and biological properties of numerous drugs. This is done through degree-based topological indices. In this paper, acarbose, tolazamide, miglitol, prandin, metformin, and so on used to treat diabetes are discussed, and the purpose of the QSPR study is to determine the mathematical relation between the properties under investigation (e.g., boiling point and flash point) and different descriptors related to the molecular structure of the drugs. In this study, it is observed that topological indices (TIs) applied to said drugs have a good correlation with physicochemical properties in this course.

Challenge and Development Strategy for Colon-Targeted Drug Delivery System

Colon-Targeted Drug Delivery System (CTDDS) is able to improve local therapeutic effects in the treatment of colon-specific diseases, such as Crohn’s disease, Ulcerative Colitis (UC), and Irritable Bowel Syndrome (IBS). A colon can also be a suitable site for systemic delivery of drugs susceptible to extreme gastric pH, such as peptides and protein therapeutics. The physiological conditions of the gastrointestinal tract and the physicochemical properties of drugs are being considered to develop strategies and approaches to overcome emerging challenges. This review will discuss factors, challenges, strategies, and approaches to developing a colon-targeted drug delivery system.

Machine learning approaches and their applications in drug discovery and design.

This review is focused on several machine learning approaches used in chemoinformatics. Machine learning approaches provide tools and algorithms to improve drug discovery. Many physicochemical properties of drugs like toxicity, absorption, drug-drug interaction, carcinogenesis, and distribution have been effectively modeled by QSAR techniques. Machine learning is a subset of artificial intelligence, and this technique has shown tremendous potential in the field of drug discovery. Techniques discussed in this review are capable of modeling non-linear datasets, as well as big data of increasing depth and complexity. Various machine learning-based approaches are being used for drug target prediction, modeling the structure of drug target, binding site prediction, ligand-based similarity searching, de novo designing of ligands with desired properties, developing scoring functions for molecular docking, building QSAR model for biological activity prediction, and prediction of pharmacokinetic and pharmacodynamic properties of ligands. In recent years, these predictive tools and models have achieved good accuracy. By the use of more related input data, relevant parameters, and appropriate algorithms, the accuracy of these predictions can be further improved.

Ionic Liquids: Promising Approach for Oral Drug Delivery.

Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems.This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed. This article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers.

New Perspectives in Drug Delivery Systems for the Treatment of Tuberculosis.

Tuberculosis is a chronic respiratory disease caused by Mycobacterium tuberculosis. The common treatment regimens of tuberculosis are lengthy with adverse side effects, low patient compliance, and antimicrobial resistance. Drug delivery systems (DDSs) can overcome these limitations. This review aims to summarize the latest DDSs for the treatment of tuberculosis. In the first section, the main pharmacokinetic and pharmacodynamic challenges posed by the innate properties of the drugs are put forth. The second section elaborates on the use of DDS to overcome the disadvantages of the current treatment of tuberculosis. We reviewed research articles published in the last 10 years. DDSs can improve the physicochemical properties of anti-tuberculosis drugs, improving solubility, stability, and bioavailability, with better control of drug release and can target alveolar macrophages. However, more pre-clinical studies and robust bio-relevant analyses are needed for DDSs to become a feasible option to treat patients and attract investors.

A New Approach for β-cyclodextrin Conjugated Drug Delivery System in Cancer Therapy.

Natural cyclodextrins (CDs) are macrocyclic starch molecules discovered a decade ago, in which α-, β-, and γ-CD were commonly used. They originally acted as pharmaceutical excipients to enhance the aqueous solubility and alter the physicochemical properties of drugs that fall under class II and IV categories according to the Biopharmaceutics Classification System (BPS). The industrial significance of CDs became apparent during the 1970s as scientists started to discover more of CD's potential in chemical modifications and the formation of inclusion complexes. CDs can help in masking and prolonging the half-life of drugs used in cancer. Multiple optimization techniques were discovered to prepare the derivatives of CDs and increase their complexation and drug delivery efficiency. In recent years, due to the advancement of nanotechnology in pharmaceutical sectors, there has been growing interest in CDs. This review mainly focuses on the formulation of cyclodextrin conjugated nanocarriers using graphenes, carbon nanotubes, nanosponges, hydrogels, dendrimers, and polymers to achieve drug-release characteristics specific to cells. These approaches benefit the discovery of novel anti-cancer treatments, solubilization of new drug compounds, and cell specific drug delivery properties. Due to these unique properties of CDs, they are essential in achieving and enhancing tumor-specific cancer treatment.

Enhancement of Stability profile of Aspirin through Cocrystallization Technique

Cocrystallization process is a well-known technique for altering the pharmaceutical properties of drugs without modifying their actual pharmacological actions. Availability of a number of potential coformers make this technique more useful for implementation in pharmaceutical research area on newer and older API’s having pharmaceutical issues like poor solubility, stability profiles etc. Aspirin is a long-known antipyretic and anti-inflammatory drug belonging to BCS Class II having poor aqueous solubility. This API undergoes hydrolysis at higher temperature and in humid environment with the resultant degradation products being salicylic acid and acetic acid. Cocrystalization technique could be useful for improving its stability profile as the physicochemical properties of drugs get modified by their cocrystallization with coformers having better thermal stability as well higher solubility profile than API’s. In this study, aspirin and benzoic acid have been cocrystallized in a fixed stochiometric ratio (1:2) for improving its stability issues. Differential Scanning Calorimetry (DSC), Infra-Red spectroscopy technique (FTIR) and X-ray Diffraction (XRD) technique were used for analysis of cocrystals. Dissolution study was performed which revealed an improved dissolution profile of cocrystals compared to pure drug aspirin. Accelerated stability study was performed as per ICH guidelines for 6 months and stability profile of drug and cocrystals were compared by using HPLC technique, which exhibited a better stability profile of cocrystals compared to pure drug.

Formulation and Evaluation of Apremilast Co-Crystals Loaded in Gel

Apremilast has low solubility and irritant effect in GIT can cause ulcerative colitis with bleeding. In this study, pharmaceutical cocrystals were designed to efficiently deliver Apremilast (APR) by topical administration to overcome this issue. Cocrystallization of drug with conformer is an immense approach used to explore the physicochemical properties of drug. Formulation and evaluation of APR co-crystals by solvent evaporation method for solubility enhancement were the objective of the current research. All the prepared formulations were evaluated by powder Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dissolution, and solubility studies. Dissolution and solubility studies of the formulations confirmed that solubility enhanced as compared to the solubility of the available market drugs. From all these studies, it can be concluded that the co-crystallization technique enhanced the solubility of APR by using the solvent evaporation method. The cocrystals of APR were prepared in 1:1 molar ratio with urea. APR cocrystals showed the improvement in solubility and dissolution as compared to pure APR. The formation of cocrystals was confirmed from change in endothermic peak of DSC and from shifting of FTIR spectra of cocrystals. The topical gel of APR cocrystals was formulated using Carbapol-940 and hydroxypropyl methylcellulose (HPMC) as a gelling agent. The cocrystals with altered physicochemical properties of APR were prepared with Urea and formulated as a topical gel to overcome the problems related to oral administration. F2 formulation was found to be optimized batch and selected variables show a significant effect on the responses that are drug release and spread ability.

Understanding the Impact of Age-Related Changes in Pediatric GI Solubility by Multivariate Data Analysis.

The aim of this study was to understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in newborns and young infants in comparison to adults. Multivariate statistical analysis was used to understand drug solubilization as a function of drug’s physicochemical properties and the composition of gastrointestinal fluids. The solubility of seven poorly soluble compounds was assessed in adult and age-specific fasted and fed state biorelevant media. Partial least squares regression (PLS-R) was used to assess the influence of (i) drug physicochemical properties and (ii) age-related changes in simulated GI fluids, as well as (iii) their interactions, on the pediatrics-to-adult solubility ratio (Sp/Sa (%)). For five out of seven of the compounds investigated, Sp/Sa (%) values fell outside of the 80–125% limits in at least one of the pediatric media. Lipophilicity was responsible for driving drug solubility differences between adults and children in all the biorelevant media investigated, while drug ionization was most relevant in the fed gastric media, and the fasted/fed intestinal media. The concentration of bile salts and lecithin in the fasted and fed intestinal media was critical in influencing drug solubility, while food composition (i.e., cow’s milk formula vs. soy formula) was a critical parameter in the fed gastric state. Changes in GI fluid composition between younger pediatric patients and adults can significantly alter drug luminal solubility. The use of pediatric biorelevant media can be helpful to identify the risk of altered drug solubilization in younger patients during drug development.

Local delivery of usnic acid loaded Rhamnolipid vesicles by gelatin / tragacanth gum / montmorillonite/ vanillin cryogel scaffold for expression of osteogenic biomarkers and antimicrobial activity

Treatment of osteomyelitis as a destructive disease with strong, systemic, and high-dose antibiotics always faces tough challenges and severe side effects. The present study aimed to design dual-purpose cryogel nanocomposite scaffolds with antibacterial and bone regenerative properties. The gelatin/tragacanth gum/montmorillonite/vanillin cryogel scaffold (GTM/V) was prepared and enriched with Usnic acid (UA) encapsulated in Rhamnolipid (RH) biosurfactant nanoparticles as a dispersing agent with antioxidant and antimicrobial properties. The physicochemical properties of drug loaded nanoparticles, mechanical, rheological, and biological properties of the cryogel were evaluated. Biological evaluations, including cell proliferation (by MTT assay), cell attachment (by SEM), osteogenic activity (by Alizarin Red staining and alkaline phosphatase assay), and osteogenic gene expression (by quantitative real-time polymerase chain reaction) were studied using MG-63 cells. The antibiofilm effect of the cryogel was studied on Staphylococcus aureus. The results showed the mechanical profile of UA/RH loaded GTM/V scaffold was 3.08 ± 0.20 MPa compressive strength at 70% strain and the elastic modulus was 19.69 ± 1.57 MPa. Biocompatible UA/RH containing cryogel scaffolds showed osteogenic effect through increasing the ALP activity, and the Alizarin-red staining on days 7 and 14 compared to the control group (P < 0.05). The relative increase in expression of bone repair markers, including COL1A1, BGLAP, and SPP1F were shown by RT-PCR. The scaffold had strong antibacterial effects on S. aureus, with an inhibition zone of 1.40 ± 0.21 cm and antibiofilm activity of 43.76 ± 1.65%. In conclusion, our findings support the application of UA/RH loaded GTM/V scaffold for the treatment of osteomyelitis and bone regeneration.

Challenges and Perspectives in the Discovery of Dengue Virus Entry Inhibitors.

Dengue virus (DENV) disease has become one of the major challenges in public health. Currently, there is no antiviral treatment for this infection. Since human transmission occurs via mosquitoes of the Aedes genus, most efforts have been focused on the control of this vector. However, these control strategies have not been totally successful, as reflected in the increasing number of DENV infections per year, becoming an endemic disease in more than 100 countries worldwide. Consequently, the development of a safe antiviral agent is urgently needed. In this sense, rational design approaches have been applied in the development of antiviral compounds that inhibit one or more steps in the viral replication cycle. The entry of viruses into host cells is an early and specific stage of infection. Targeting either viral components or cellular protein targets are an affordable and effective strategy for therapeutic intervention of viral infections. This review provides an extensive overview of the small organic molecules, peptides, and inorganic moieties that have been tested so far as DENV entry direct-acting antiviral agents. The latest advances based on computer-aided drug design (CADD) strategies and traditional medicinal chemistry approaches in the design and evaluation of DENV virus entry inhibitors will be discussed. Furthermore, physicochemical drug properties, such as solubility, lipophilicity, stability, and current results of pre-clinical and clinical studies will also be discussed in detail.

Polyrotaxane-Based Supramolecular Material for Improvement of Pharmaceutical Properties of Protein Drugs

Pharmaceutical excipients, such as surfactants, amino acids, and polymers, have often been used to improve the physicochemical properties of protein drugs. However, the effects of these additives are limited because of factors such as their weak interactions with protein drugs. In the present study, we evaluated the application of a supramolecular polymer, aminated polyrotaxane (NH2-PRX), which can strongly interact with protein drugs via its dynamic and transformable properties, as a new pharmaceutical excipient for these agents. As a conventional control polymer with low mobility and average complexation ability, aminated dextran (NH2-DEX) was also prepared. NH2-PRX significantly reduced the aggregation of antibodies induced by shaking, compared with NH2-DEX. The adsorption of insulin onto glass and polypropylene containers was also reduced by the addition of NH2-PRX. In addition, the in vivo bioactivity of insulin was completely retained in the presence of NH2-PRX. Moreover, severe adverse effects were not observed following the administration of NH2-PRX. These findings indicate the potential use of NH2-PRX as a transformable pharmaceutical excipient for protein drugs.

Understanding the role of electrostatic interactions on the association of 5-fluorouracil to chitosan-TPP nanoparticles

Judicious design strategies should be considered powerful tools to better control the properties of chitosan (CS) and tripolyphosphate (TPP) particles. This study focused on understanding the role of the charge properties of 5-fluorouracil (5-FU) on the formation and properties of CS-TPP nanoparticles. The effect of synthesis variables of CS-TPP nanoparticles (CS to TPP ratio and order of addition) under pH 4.5 and 5.5 was evaluated, where CS and TPP were charged, and 5-FU had two different charges (positive and negative), maximizing the interactions between them for the formation of nanoparticles. The order of addition and drug location resulted in changes in the interaction forces, influencing the particle size and size distribution. 5-FU addition into CS resulted in stronger interactions, favoring the formation of smaller particles. The pH of reactional medium and CS to TPP ratio affected the properties of particles, in terms of size and potential zeta, which led to greater 5-FU entrapment. These results demonstrated that the particle properties still depends of the synthesis factors, but the physicochemical properties of drug also influence the reactions/interactions involved in the formation of CS-TPP nanoparticles.

Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models.

Concerns over maternal and fetal drug exposures highlight the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modeling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiologic changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared with the observed data. Fully bottom-up fetoplacental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in nonpregnant subjects and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed pharmacokinetic data reported in nine maternal (five fetoplacental) studies for cefuroxime, 10 maternal (five fetoplacental) studies for cefazolin, and six maternal (two fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability, facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively used for maternal-fetal risk assessment after maternally administered drugs or unintended exposure to environmental toxicants. SIGNIFICANCE STATEMENT: This study investigates the performance of an integrated maternal-placental-fetal PBPK model to predict maternal and fetal tissue exposure of renally eliminated antibiotics that cross the placenta through a passive diffusion mechanism. The transplacental permeability clearance was predicted from the drug physicochemical properties. Results demonstrate that the PBPK approach can facilitate the prediction of maternal and fetal drug exposure simultaneously at any gestational age to support its use in the maternal-fetal exposure assessments.