Development Of New Chemical Entities Research Articles

Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study

Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.

Preparation, characterization, in-vitro and toxicological evaluation of carbopol based nanogels for solubility enhancement of Valsartan

Solubility is an essential criterion for attaining desired concentration of the drug within the systemic circulation to ensure intended pharmacological action. The main setback for the formulation development of new chemical entities and generic drugs is their lower aqueous solubility. Therefore, a drug carrier system is needed which not only enhances the solubility of low aqueous soluble drugs but also maintains a constant pharmacological action of drugs within predetermined intervals of time. For this purpose, authors prepared carbopol 934-co-poly(itaconic acid) (CPcPIA) nanogels by the free radical polymerization technique for the solubility enhancement of Valsartan. The polymeric nanogels were characterized and studied for further evaluation. FTIR studies indicated no interactions between the drug and nanogel contents. SEM showed a porous and sponged structure of particles without any agglomeration. Similarly, higher thermal stability was detected for the fabricated nanogel compared to its constituents, while reduction in crystallinity of the drug and excipients was shown by XRD analysis, indicating the amorphous nature of the polymeric nanogels. Average particle size and zeta potential of prepared nanogels were found 290.32 nm and –8.32 mV, respectively. Furthermore, various studies such as sol-gel fraction, dynamic swelling, drug loading, in-vitro drug release studies, solubility, and toxicity study were conducted for the developed nanogels. A significant increase in the solubility of Valsartan (2.002, 2.976, and 3.543 mg/mL) was observed by polymeric nanogels in pH 1.2, deionized distilled water, and pH 7.4 as compared to reference product. Toxicity study indicated no toxic effect of prepared nanogels on rabbit's species. Thus, it can be demonstrated from the results that synthesized nanogels are not only limited to a specific class of drug but the solubility of all low aqueous soluble drugs can be enhanced by the prepared networks of nanogels.

Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aβ) aggregation inhibitors

Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aβ) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aβ peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aβ peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aβ peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aβ peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aβ peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aβ peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.

Concept of Drug Metabolism and Pharmacokinetics with Special Focus on Herbal-Drug Interaction

The study of how xenobiotics undergo the process of absorption, distribution, metabolism, and excretion (ADME) is conceptualized as pharmacokinetics. An understanding therefore of the PK properties is crucial and plays an important contribution in the drug discovery and development of new chemical entities. Drug metabolism is linked to the metabolic breakdown of drugs (xenobiotic metabolism) by enzyme or living organisms. The pathway involved in this process can lead to the bio-transformations that occurs in most living organisms. The drug metabolic action facilitates the detoxification process except in special circumstances where the metabolites (break down products) can lead to toxic effects. Under such circumstances the study of drug metabolism is termed as pharmacokinetics, which constitutes an important discipline as a branch of pharmacology. Herbal natural products have been used to prevent and treat diseases worldwide since the creation of mankind. However, the efficacy, safety and quality of herbal bioactive metabolites depends on the multiple components absorbed in the body and their pharmacokinetics. This review attempts to give an insight into the concept of drug metabolism and pharmacokinetics with special consideration on PK drug-herbal interactions, mechanisms, metabolizing enzymes involved and transporters implicated in the determination of the PK of xenobiotics.

Design, Synthesis, Molecular Docking, ADMET, and Biological Studies of Some Novel 1,2,3-Triazole Linked Tetrazoles as Anticancer Agents.

1,2,3-Triazole-tetrazoles have received substantial attention because of their unique bioisosteric properties and an extraordinarily broad spectrum of biological activity, making them interesting for the drug design, and synthesis of a delightful class of widely investigated heterocyclic compounds. To address major health concerns, it is consequently important to devote ongoing effort to the identification and development of New Chemical Entities (NCEs) as possible anticancer medicines. We began our initial investigation of the reaction between 5-(azidomethyl)-1H-pyrrolo[ 2,3-b]pyridine and 1-phenyl substituted-5-(prop-2-yn-1-ylthio)-1 H-tetrazole under click chemistry to give the corresponding triazole precursors and screened for their cytotoxicity reported by variations in therapeutic actions of the parent molecule. All of the prepared scaffolds were characterized by proton, carbon resonance spectroscopy, IR, and mass spectral techniques. When tested for in vitro antitumor activity the prepared compounds 7e, 7h had a significant anticancer activity against human adenocarcinoma Hs766T cell line with IC50 = 5.33, 4.92 μg/mL and Hs460 cell line with IC50 = 4.82, 6.15 μg/mL respectively. Final scaffolds 7f, 7h, and 7j acquire the highest potential drug binding scores ΔG = -10.42, -8.80, -9.37 Kcal/, with amino acids residues Ala A:11 (2.195 A˚), Asp A:119 (1.991 A˚), Thr A:58 (1.890 A˚), Lys A:16 (1.253 A˚), Asp A:38 (2.013 A˚), Lys A:117 (2.046 A˚) respectively and process Lipinski's rule of five as good agents for oral bioavailability. The molecular framework for the synthesis of novel Aza indole 1,2,3-triazole scaffolds coupled to tetrazole core was discovered in our study and evaluated for their anticancer activity.

Design and Synthesis of Michael Acceptor‐Based Peptidyl β‐Nitrostyrenes as 3CLpro Inhibitors of SARS‐CoV‐2

AbstractSevere Acute Respiratory Syndrome coronavirus 2 main protease was found to be one of the most attractive anti‐viral targets for the development of new chemical entities to combat coronavirus and Michael acceptors were found to be appropriate 3‐chymotrypsin‐like protease inhibitors of Severe Acute Respiratory Syndrome coronavirus 2. In this regard, a series of Michael acceptor‐based peptidyl β‐nitrostyrenes were synthesized and evaluated for their Severe Acute Respiratory Syndrome coronavirus 2 3‐chymotrypsin‐like protease inhibitory potentials using a 3‐chymotrypsin‐like protease of Severe Acute Respiratory Syndrome coronavirus 2 assay kit. Among the compounds evaluated, (E)‐N‐(2‐morpholino‐2‐oxo‐1‐phenylethyl)‐2‐(4‐(2‐nitrobut‐1‐en‐1‐yl)phenoxy)acetamide demonstrated better inhibition with an effective concentration (EC50) of 58 μM. In silico ADME predictions showed that the majority of these compounds have drug‐like properties. Furthermore, free energy calculation (ΔG Bind) and docking results demonstrate the suitable fitting of most active compound at the active site of the enzyme. Based on the in vitro and in silico studies, peptidyl β‐nitrostyrene based Michael acceptors could serve as an excellent ligand for the inhibition of 3‐chymotrypsin‐like protease of Severe Acute Respiratory Syndrome coronavirus 2 and may be used as a potential template for further development of bioactive ligands to treat CORONA VIRUS Disease of 2019.

Chemogenomics: Is A Promising Area for Drug Target and Discovery

The latest tools of genomics and chemistry and applies them to target and drug discovery is chemogenomoics. It is defined as the analysis of class of organic compound libraries against families of functionally related proteins called as receptor. chemogenomoics help to investigate biological target for the new drug entities. This deals with the systematic investigation of chemical-biological interactions. Study of chemogenomoics is the very important tool in medicinal chemistry for the development of new chemical entities) The main goal of chemogenomics is to identify the newer drugs and the targets because of number of chemical entities ware present so it is very difficult to identify the targets of said chemical compounds. The chemogenomic approach is the interaction of possible drug molecules with all probable targets In this regards we have reported significance and application of chemogenomoics.

Quinoline Hydrazide/Hydrazone Derivatives: Recent Insights on Antibacterial Activity and Mechanism of Action.

Antibiotics are becoming gradually ineffective due to drug resistance, leading to greater difficulty in the treatment of infectious diseases. Therefore, the development of new chemical entities with different mechanisms of action is essential in the fight against resistant microorganisms. Various studies have shown that quinoline hydrazide/hydrazone derivatives possess several biological activities, such as antimalarial, antitubercular, anticancer, anti-inflammatory, and antimicrobial. Among these activities, the antibacterial activity of quinoline hydrazide/hydrazone derivatives is noteworthy. The synthetic flexibility of the quinoline ring has led to the development of a wide range of structurally diverse quinoline hydrazide/hydrazone derivatives, which can act at various bacterial targets such as DNA gyrase, glucosamine-6-phosphate synthase, enoyl ACP reductase, and 3-ketoacyl ACP reductase. This review emphasizes the antibacterial potential of various reported quinoline hydrazide/hydrazone derivatives based on substitution in the quinoline ring. The antibacterial activity of various metal-quinoline hydrazide/hydrazone complexes is also discussed. The aim of this review is to assemble and scrutinize the latest reports in this promising area of drug development.

Preclinical Drug Development Process: Formulation and Development Aspects

Drug discovery and development process aims to make available new pharmacological entities to prevent, treat, mitigate or cure disease in a safe and effective manner. It involves rigorous testing and optimization of selected compounds to identify the drug that is most effective. Drug development starts with a target identification and validation, followed by drug candidate (hits) discovery, and lead drug (compound with favourable pharmaceutical, safety, efficacy and pharmacokinetic profile) selection and optimization then preclinical research, clinical research, FDA drug review, FDA post-market drug safety monitoring. In the stage of preclinical study, pharmaceutical preformulation and development and toxicity studies are the major concerns. The chapter focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. During preformulation studies the parameters evaluated are: solubility in different media and solvents, dissolution of the active pharmaceutical ingredient (API), accelerated stability studies under various conditions, solid state properties (polymorphs, particle size, particle shape, etc.), formulation development of new chemical entity (NCE),optimization of existing formulations, process development for selected dosage form, novel formulations for improved delivery of existing dosage forms, controlled release and sustained release formulations, micro and nano formulations, partition coefficient, pKa determination. It also emphasizes on Pharmacokinetic studies. The chapter also provides detailed information related to a vast pool of excipients available which is of immense help in designing preclinical formulations. A light is thrown on key aspects of preclinical formulation development by cited examples.

An Overview of Pharmacovigilance and Adverse Drug Reaction Monitoring of Drugs and Vaccines during the COVID-19 Pandemic

Once a drug is approved in phase III of clinical trials, pharmacovigilance (PV) becomes very important for the surveillance of drug, vaccine or medical devices. PV constitutes part of the phase IV approval, which involves a study for collecting, detecting, and monitoring adverse events in any population that the drug is used. The adverse events that are reported must be assessed to ascertain the causal effects and prevent or avoid unanticipated side effects on the population. With the advent of the coronavirus disease 2019 (COVID-19) pandemic, vaccination has been the motor for the management of the pandemic, and through intensive health sensitization, more people are vaccinated in a short period leading to greater challenges to the PV taskforce and the PV operating centrers. Global partnerships including the international society of pharmacovigilance (ISOP), the French national agency for medicines and health products safety (ANSM), and a multitude of others are working in synergy towards putting in place a continuous collaboration work package with many sensitization, education, capacity building, and research initiatives. This is within the framework of identifying the safety and efficacy of vaccines in order to provide solutions to emerging challenging ethical questions.
 Through PV, signal detection is in progress for the identification of adverse events. The unanticipated emergence and negative impact of COVID-19, caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2) has significantly compelled global pharmacists and drug actors to collectively play an important role in the management of COVID-19. This has to be done within the framework of therapeutic strategies and guaranteed safety, efficacy and quality of new and old xenobiotics. In the current treatment COVID-19 has created health-related challenges and a shift in paradigm in drug discovery and development of new chemical entities (NCE), for vaccine or drug repurposing for different levels of treatment interventions. The accelerated interest in dynamic research and innovation have led to different approaches of treatment and this has come with potential side effects, which has led to the call for post marketing surveillance and monitory. PV is therefore a key component for phase IV study for the drugs and vaccines approved for global use. This paper gives an insight into the global PV monitoring and surveillance of new chemical entities (drugs and vaccines) and new technologies targeting the management of COVID-19.

Application of In Silico Filtering and Isothermal Titration Calorimetry for the Discovery of Small Molecule Inhibitors of MDM2.

The initial discovery phase of protein modulators, which consists of filtering molecular libraries and in vitro direct binding validation, is central in drug discovery. Thus, virtual screening of large molecular libraries, together with the evaluation of binding affinity by isothermal calorimetry, generates an efficient experimental setup. Herein, we applied virtual screening for discovering small molecule inhibitors of MDM2, a major negative regulator of the tumor suppressor p53, and thus a promising therapeutic target. A library of 20 million small molecules was screened against an averaged model derived from multiple structural conformations of MDM2 based on published structures. Selected molecules originating from the computational filtering were tested in vitro for their direct binding to MDM2 via isothermal titration calorimetry. Three new molecules, representing distinct chemical scaffolds, showed binding to MDM2. These were further evaluated by exploring structure-similar chemical analogues. Two scaffolds were further evaluated by de novo synthesis of molecules derived from the initial molecules that bound MDM2, one with a central oxoazetidine acetamide and one with benzene sulfonamide. Several molecules derived from these scaffolds increased wild-type p53 activity in MCF7 cancer cells. These set a basis for further chemical optimization and the development of new chemical entities as anticancer drugs.

IBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease.

Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a potential source of therapeutic options. The present study describes the biological activity of two new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazole-imidazoline previously identified, using structure–activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC50 > 100 µM) besides potent activity against trypomastigotes (0.4–2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, 2c also stands out, with greater potency against intracellular amastigotes (pIC50 = 5.85). The selected pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids system, but did not sustain parasite clearance in a washout assay. The compounds’ mechanism of action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its biological activity to identify new drug candidates for Chagas disease therapy.

Development and Characterization of Eudragit® EPO-Based Solid Dispersion of Rosuvastatin Calcium to Foresee the Impact on Solubility, Dissolution and Antihyperlipidemic Activity.

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.

Alternatingly Amphiphilic Antimicrobial Oligoguanidines: Structure–Property Relationship and Usage as the Coating Material with Unprecedented Hemocompatibility

With the emergence of antibiotic resistance in recent years, the combat against bacteria is becoming more difficult and critical in human healthcare. In addition to the development of new chemical entities and derivatives of antibiotics and disinfectants, the antimicrobial surface is recognized as a potential way to prevent healthcare-associated infections, particularly those caused by medical devices such as implants and various catheters. However, traditional ways of engineering antimicrobial surfaces using coated metal nanostructures or blended-in antibiotics inevitably face the problem of metal ion or antibiotic leakage, leading to surface deactivation, toxicity, and antibiotic resistance. A new strategy developed in recent years involves the use of coated cationic antimicrobial polymers, which serve as resistance-resistant, surface-anchored antibacterial agents, but they also usually come with hemolytic activity resulting from their membrane-disrupting-type mechanism of action. In this report, we show that the combinatorial approach can be highly useful for the selection of alternatingly amphiphilic oligomers, which are essentially molecular nanorods as revealed by molecular dynamic simulations. The combinatorial process allowed the structure–property relationship of these molecular nanorods to be revealed and yielded oligoguanidine hit with high antimicrobial activity, fast killing kinetics, and extremely low hemolytic activity through assay screening. We demonstrate that the covalent conjugation of such a prescreened oligoguanidine nanorod to glass slides or polycaprolactone films could produce antimicrobial surfaces with excellent performance. A catheter prototype made using such a modified polycaprolactone film could transport bacteria-contaminated liquid, efficiently removing all bacteria without causing lysis of red blood cells.

PET as a Translational Tool in Drug Development for Neuroscience Compounds.

In central nervous system drug discovery programs, early development of new chemical entities (NCEs) requires a multidisciplinary strategy and a translational approach to obtain proof of distribution, proof of occupancy, and proof of function in specific brain circuits. Positron emission tomography (PET) provides a way to assess in vivo the brain distribution of NCEs and their binding to the target of interest, provided that radiolabeling of the NCE is possible or that a suitable radioligand is available. PET is therefore a key tool for early phases of drug discovery programs. This review will summarize the main applications of PET in early drug development and discuss the usefulness of PET microdosing studies performed with direct labelling of the NCE and PET occupancy studies. The purpose of this review is also to propose an alignment of the nomenclatures used by drug metabolism and pharmacokinetic scientists and PET imaging scientists to indicate key pharmacokinetic parameters and to provide guidance in the performance and interpretation of PET studies.

Development and Validation of Stability-Indicating Assay Method for a Novel Oxazolidinone (PH-192) with Anticonvulsant Activity by Using UHPLC-QToF-MS.

The treatment of seizure disorders with currently available pharmacotherapeutic agents is not optimal due to the failure of some patients to respond, coupled with occurrences of side effects. There is therefore a need for research into the development of new chemical entities as potential anticonvulsant agents, which are different structurally from the existing class of drugs. We recently identified a novel triazolyl-oxazolidinone derivative, PH-192, as a potential anticonvulsant agent. PH-192 demonstrated protection comparable to phenytoin against both chemically- and electrically-induced seizures in rodents with little or no central nervous system side effects. However, PH-192 did not exhibit protection beyond 30 min; therefore, we decide to investigate a stability-indicating assay of PH-192 in plasma and other solutions. A reliable and validated analytical method was developed to investigate the stability of PH-192 for 90 min in human plasma, acidic, basic, and oxidative conditions, using a Waters Acquity ultra high-performance liquid chromatography (UHPLC) system with a quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-192 was stable in human plasma after 90 min at 37 °C, with more than 90% successfully recovered. Moreover, stress stability studies were performed, and degradants were identified using LC-QToF-MS under acidic, basic, and oxidative simulated conditions.

Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease.

The identification of effective pharmacological tools for Alzheimer’s disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a C. elegans model of AD based on the overexpression of Aβ42 and improves learning abilities in the 5XFAD mouse model of AD. Further, in vitro ADME-Tox profiling and toxicological studies in zebrafish confirmed the low toxicity of this compound, which represents a chemical starting point for AD drug development.

Machine Learning for In Silico ADMET Prediction.

ADMET (absorption, distribution, metabolism, excretion, and toxicity) describes a drug molecule's pharmacokinetics and pharmacodynamics properties. ADMET profile of a bioactive compound can impact its efficacy and safety. Moreover, efficacy and safety are considered some of the major causes of clinical attrition in the development of new chemical entities. In past decades, various machine learning or quantitative structure-activity relationship (QSAR) methods have been successfully integrated in the modeling of ADMET. Recent advances have been made in the collection of data and the development of various in silico methods to assess and predict ADMET of bioactive compounds in the early stages of drug discovery and development process.

Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. A success of formulation development depends on how efficiently it makes the drug available at the site of action. Poorly soluble and dissolution profile creates problem in pharmaceutical industry for development of dosage form. The ability to increase aqueous solubility can thus be a valuable aid to increasing efficiency and/or reducing side effects (Adverse drug reaction) for drugs. This is true for parenterally, topically and orally administered solutions. Biopharmaceutical classification system (BCS) highlights the dissolution as rate limiting step for oral absorption of BCS class II and class IVdrugs. BCS class II and class IV drugs have low solubility.Increasing dissolution directly correlated to bioavailability of drug at site of action or systemic circulation. In this article we discuss, concept of dissolution, factors affecting dissolution,different techniques used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation with hydrophilic excipients.