Drug Physical Properties Research Articles

Hydrofluoroether Synthesis through One‐Pot Anodic Iodoalkoxylation of Alkenes

AbstractThe incorporation of carbon‐fluorine bonds can profoundly influence the chemical and physical properties of drugs, agrochemicals, and materials. Different methods allow the installation of CF3, CF2H units and C−F bonds including trifluoro‐ and difluoromethoxylations, reflecting the limited diversity of reactions available to synthetic chemists. We introduce the 2,2,2‐trifluoroethoxy group through an electro‐oxidative iodination of alkenes as a versatile substituent for fluorine chemists. An iodoarene serves as an unusual iodine source facilitating the 1,2‐iodoalkoxylation of a broad range of industrially relevant aliphatic alkenes in high yields (31–98%) showing high Markovnikov regioselectivity.

General Randić Index of Unicyclic Graphs and Its Applications to Drugs

In this work, we determine the maximum general Randić index (a general symmetric function of vertex degrees) for η0≤η<0 among all n-vertex unicyclic graphs with a fixed maximum degree Δ and the maximum and the second maximum general Randić index for η0≤η<0 among all n-vertex unicyclic graphs, where η0≈−0.21. We establish sharp inequalities and identify the graphs attaining the inequalities. Thereby, extremal graphs are obtained for the general Randić index, and certain open gaps in the theory of extremal unicyclic graphs are filled (some open problems are provided). We use computational software to calculate the Randić index for the chemical trees up to order 7 and use the statistical (linear regression) analysis to discuss the various applications of the Randić index with the physical properties of drugs on the said chemical trees. We show that the Randić index is better correlated with the heat of vaporization for these alkanes.

Amorphization of different furosemide polymorphic forms during ball milling: Tracking solid-to-solid phase transformations

Ball milling is used, not only to reduce the particle size of pharmaceutical powders, but also to induce changes in the physical properties of drugs. In this work we prepared three crystal forms of furosemide (forms Ⅰ, Ⅱ, and Ⅲ) and studied their solid phase transformations during ball milling. Powder X-ray diffraction and modulated differential scanning calorimetry were used to characterize the samples after each milling time on their path to amorphization. Our results show that forms Ⅰ and III directly converted into an amorphous phase, while form Ⅱ first undergoes a polymorphic transition to form Ⅰ, and then gradually loses its crystallinity, finally reaching full amorphousness. During ball milling of forms Ⅰ and Ⅱ, the glass transition temperature (Tg) of the amorphous fraction of the milled material remains almost unchanged at 75 °C and 74 °C, respectively (whilst the amorphous content increases). In contrast, the Tg values of the amorphous fraction of milled form III increase with increasing milling times, from 63 °C to 71 °C, indicating an unexpected phenomenon of amorphous-to-amorphous transformation. The amorphous fraction of milled forms I and II samples presented a longer structural relaxation (i.e., lower molecular mobility) than the amorphous fraction of milled form III samples. Moreover, the structural relaxation time remained the same for the increasing amorphous fraction during milling of forms I and II. In contrast, the structural relaxation times were always shorter for the amorphous fraction of form III, but increased with increasing amorphous content during milling, confirming amorphous-to-amorphous transformation.

The Mechanism of Drug Carryover in Feed Manufacturing as a Function of Drug Properties and Equipment Design—A Brief Review

This paper thoroughly reviews the mechanism of veterinary drug carryover in feed manufacturing facilities, factors resulting in varying concentrations of drug carryover in processing equipment, the impact of chemical and physical properties of drugs, and the effect of equipment type and design. The Google Scholar database (from 1998 to 2023) was searched with words and phrases such as drug carryover, feed manufacturing, equipment cleaning and validation, food allergen control, sources of drug carryover, and process parameters in drug carryover. Some papers were from the Iowa State University Library database and PubMed. Drug carryover is a function of ingredients, nature of drugs, equipment type, process parameters, and cleaning procedures. The gaps are the lack of commercial feed mills data on the role and interaction of nanomaterials, molasses, equipment type, and process parameters in drug carryover in animal feed. Modification of process parameters, e.g., airflow in bucket elevators and the interaction of feed ingredients, composition, equipment type, and design, need to be investigated in the commercial setting to address drug carryover. Rhetorically, can big data facilitate the standardization of cleaning procedures at feed mills? The findings can result in drug carryover prevention/control in animal feed and animal-based human food.

Double‐Layered Polyvinylpyrrolidone–Poly(methyl vinyl ether‐alt‐maleic acid)‐Based Microneedles to Deliver Meloxicam: An In Vitro, In Vivo, and Short‐Term Stability Evaluation Study

AbstractThis study aims to explore the use of polymeric microneedles (MNs) for the transdermal delivery of drugs, a noninvasive and convenient method that avoids first‐pass metabolism and gastrointestinal complications. Specifically, a double‐layered MN formulation is developed using polyvinylpyrrolidone and cross‐linked poly(methyl vinyl ether‐alt‐maleic acid), comprising a dissolvable layer and a hydrogel‐forming layer. Meloxicam serves as the model drug, and no organic solvents are employed in the manufacturing process to reduce toxicity. Coherent anti‐Stokes Raman spectroscopy (CARS) is utilized to confirm that the manufacturing process does not alter the drug's physical properties. In vitro and ex vivo studies demonstrate that the double‐layered MN formulation exhibits faster drug release in the first few hours, followed by a slower release. This results in extended bioavailability in vivo compared to the commercial oral formulation of meloxicam. Preliminary results indicate that the MN formulation is also effective in pain relief and inflammation reduction. The short‐term stability of the MN formulation is also confirmed, including its mechanical properties, sustained skin permeability, drug physical properties and distribution within MNs using CARS microscopy. Overall, these results suggest that the double‐layered MN formulation holds significant potential for transdermal drug delivery, offering a safer and more effective alternative to traditional oral administration.

Mesoporous Drug Delivery System: From Physical Properties of Drug in Solid State to Controlled Release.

Mesoporous materials, which exhibit great potential in the control of polymorphs and delivery of poorly water-soluble drugs, have obtained considerable attention in the field of pharmaceutical science. The physical properties and release behaviors of amorphous or crystalline drugs may be affected by formulating them into mesoporous drug delivery systems. In the past few decades, an increasing amount of papers have been written about mesoporous drug delivery systems, which play a crucial role in improving the properties of drugs. Herein, mesoporous drug delivery systems are comprehensively reviewed in terms of their physicochemical characteristics, control of polymorphic forms, physical stability, in vitro performance, and in vivo performance. Moreover, the challenges and strategies of developing robust mesoporous drug delivery systems are also discussed.

Topological Indices of Drugs Used in Rheumatoid Arthritis Treatment and Its QSPR Modeling

A topological index is a molecular descriptor derived from the molecular structure of a chemical substance. These indices can be used to analyze mathematical values and predict various physical properties of drugs. This article discusses tofacitinib, leflunomide, upadacinib, baricitinib, filgotinib, methotrexate, and other drugs used to treat rheumatoid arthritis, and the goal of the QSPR study is to calculate the relationship between the properties under investigation (e.g., boiling point, polarity, and molar volume) and molecular descriptors. Topological indices (TIs) were imposed on said drugs to calculate the correlation with physicochemical properties in this course.

Physical Characteristics of Cilostazol–Hydroxybenzoic Acid Cocrystals Prepared Using a Spray Drying Method

The cocrystal formation of pharmaceuticals can improve the various physical properties of drugs, such as solubility, without the need for chemical modification of the drug substances. In the present study, we prepared cocrystals of cilostazol and additive coformers (derivatives of hydroxybenzoic acid) using a spray drying method. Based on the preparation of the cocrystals of cilostazol and the coformers as reported previously, the characteristics of the cilostazol cocrystals prepared using solvent evaporation, slurry, and spray drying methods were compared. The physical characterization revealed that the spray drying method successfully produced cilostazol–4-hydroxybenzoic acid and cilostazol–2,4-dihydroxybenzoic acid cocrystals, whereas samples of cocrystals of cilostazol and 2,5-dihydroxybenzoic acid produced via the spray drying process appeared to contain coformer polymorphs. The dissolution of cilostazol was improved using the spray-dried cocrystal samples composed of coformers compared to samples prepared using cilostazol alone or a physical mixture. The present results provide useful information regarding the manufacture of cilostazol cocrystals and pharmaceutical cocrystals via spray drying in large-batch production.

Unani concept of drug substitution (therapeutic interchange) and its validation on scientific parameters

BackgroundUnani concept of therapeutic interchange, despite having immense practical aspect, has not been touched upon in a coherent way by most of the Unani scholars except Razi (Rhazes 865–925 AD), who took the concept plausibly and framed rules for alternate drug prescription at the time of unavailability of the drugs of choice. ObjectiveThe Unani concept of therapeutic interchange is based on similarity in action, temperament and physical properties of drugs mainly botanicals, which are already established and need no further discussion; however, phytochemistry has not been considered a basis for substitution. Therefore, objective of this study was evaluation of the concept on phytochemical parameters as actions of most drugs are due to phytoconstituents. Material and methodsClassical Unani literature pertaining to therapeutic interchange and ethnobotanical literature for uses and phytoconstituents of three botanicals and their respective substitutes were reviewed. Ethnobotanical literature was collected from well known search engine viz., PubMed, Google Scholar, Scopus and Science direct. In view of exploring the concept on scientific basis, physicochemical, phytochemical and analytical (HPLC, GC–MS) studies were also conducted. ResultsThe study exhibited similarity in phytoconstituents in main and substitute botanicals with insignificant differences. Direct relation between doses, actions, intensity of actions, temperament and chemical constituents of main and substitute botanicals was observed. ConclusionThe study, however, seemed to validate the concept on the basis of phytoconstituents, further pharmacological studies on the basis of properties and activities is required to strengthen the concept.

Recent Trends in Nanocrystals for Pharmaceutical Applications.

As the quick development of modern methods and technologies currently, more and more drugs have been invented with a better efficiency. However, the poor water solubility has limited the drugs' pharmaceutical application. Tremendous research has been put in the design and development of nanocrystals for pharmaceutical applications over the past few decades. The nanocrystals not only have the chance to solve the poor solubility problem, but also could conquer the bioavailability and even the specific delivery problems. The physical properties of drugs can be changed dramatically due to the change of their size in a nanodimension. Therefore, the nanocrystals have great potential to overcome the challenge to design and development of new drugs for pharmaceutical applications. In this review, we provide an overview of the recent trends in nanocrystals for pharmaceutical applications. The current technologies including top-down, bottom-up, and combinative technologies for nanocrystals were fully examined. Most importantly, the emphasis is put on the pharmaceutical applications including their formulation, administration methods, safety, and toxicity. The commercial status, limitations, challenges, and future trends of the nanocrystals for pharmaceutical applications were also discussed.

Efficient modeling of drug solubility in supercritical carbon dioxide

Development of new models and correlations to determine the drug solubility in supercritical fluids, i.e., supercritical CO2, helps us to avoid time-consuming computations with poor outcomes while improving the supercritical technology. In this communication, a supervised technique, namely, the least square support vector machine (LSSVM) was employed to estimate the solubility of 33 different drug compounds in supercritical CO2. The corresponding solubility was determined as a function of temperature, pressure, density of supercritical CO2, and two physical properties of drug, i.e. molecular weight and melting point. The results obtained from the employed LSSVM model were compared with eight correlations. The obtained average absolute relative deviation and the square of regression coefficient for the testing group of LSSVM model were found to be 5.61% and 0.9975, respectively. Therefore, the model developed in this work can be reliably applied to the studied drugs by only knowing their physical properties.

Effects of varying the 6-position oxidation state of hexopyranoses: a systematic comparative computational analysis of 48 monosaccharide stereoisomers.

Knowledge of multi-dimensional carbohydrate structure is essential when delineating structure-function relationships in the development of analytical techniques such as ion mobility-mass spectrometry and of carbohydrate-based therapeutics, as well as in rationally modifying the chemical and physical properties of drugs and materials based on sugars. Although monosaccharides are conventionally presumed to adopt the canonical 4C1 chair conformation, it is not well known how altering the substituent identity around the pyranose ring affects the favored conformational state. This work provides a comprehensive and systematic computational comparison of all eight aldohexose isomers in the gas phase with reduction and oxidation at the C-6 position using density functional theory (M05-2X/cc-pVTZ(-f)//B3LYP/6-31G**) to determine the conformational and anomeric preference for each sugar in the gas phase. All 6-deoxyhexose and aldohexose isomers favored the 4C1 chair conformation, while oxidation at C-6 showed a shift in equilibrium to favor the 1C4 chair for β-alluronic acid, β-guluronic acid, and β-iduronic acid. The anomeric preference was found to be significantly affected by a remote change in oxidation state, with the alternate anomer favored for several isomers. These findings provide a fundamental platform to empirically test steric and electronic effects of pyranose substituents, with the goal of formulating straightforward rules that govern carbohydrate reactivity and drive quicker, more efficient syntheses. Graphical abstract A systematic comparative conformational analysis of all eight aldohexose isomers using DFT methods (M05-2X/cc-pVTZ(-f)) reveals changes in anomeric and ring conformational preference upon reduction or oxidation at the C-6 position for several sugars.

Virtual screening of coformers and solubility test for glibenclamide cocrystallization

Background: The therapeutic effectiveness of active pharmaceutical ingredients (API) depends on their solubility. API, which has poorly soluble drugs, can cause low bioavailability. According to the biopharmaceutical classification system (BCS), glibenclamide is classified under BCS Class II drugs), which has low solubility and high permeability. Cocrystallization is one method to enhance the physical properties of drugs, especially the solubility. Aims and Objectives: In this study, we apply the approach to the solid state to estimate the probability of cocrystal formation using virtual screening, and then, study the solubility and dissolution test of one of the best coformers. Materials and Methods: We used virtual screening of coformers for glibenclamide by employing the molecular docking method. AutoDock was used for docking, and the type and energy (Ei) of interaction were observed. The work was continued by the cocrystallization process using dry grinding. Solubility and dissolution tests have referred to the Higuchi and Connor methods using the ultraviolet spectrophotometer. Results: Based on molecular docking, the best of three from coformers were oxalic acid (Ei = −1.6 kcal/mol), benzoic acid (Ei = −2.6 kcal/mol), and ascorbic acid (Ei = −2.1 kcal/mol). The result of the solubility test showed that glibenclamide oxalic acid increases by 81.6% compared to pure glibenclamide at 24 h. The result of the dissolution test showed that glibenclamide oxalic acid has a better curve (77.3% in 60 min) that pures glibenclamide (44.52% in 60 min). Conclusion: This study indicated that oxalic acid as a coformer can increase the dissolution profile of glibenclamide by the approach cocrystalization method.

ENHANCEMENT OF BIOAVAILABILITY THROUGH INCREASE IN DRUG PERMEATION, STABILITY AND RETENTION TIME

The rate and extent to which an unchanged drug reaches the systemic c irculation is called as bioavailability (BA). Bioavailabili ty, a subcategory of absorption is one of the principal pharmacokinetic parameter determined for an active substance form a pharmaceutical product. It also indicates the fractional extent to which a dose of drug reaches its site of action or biological fluid from which the drug has access to its site of action. Physical properties of drug, drug formulation, route of administration, gastric emptying rate etc. are several factors affect the bioavailab ility of drug from its drug product. Poor solubility, enzymatic and transporters barrier, drug stability and short retention of the drug in stomach due to peristaltic movement are several factors decrease t he bioavailability of the drug. This review deals with the bioavailability improvements techniques from poor permeation, lesser stability and short retention of the drug in stomach. Lipid based formulations; ion pairing and use of permeation enhancer are different methods to enhance the bioavailability th rough increase in permeation. Enteric coating, complexation and metabolism inhibitors lead to increase in drug stability. Bioadhesive polymers in formulation improve the gastro retention time serve as improved bioavailable product.

Preparation and Characterization of Novel Amphiphilic Hydrogels with Covalently Attached Drugs and Fluorescent Markers

This paper describes the synthesis of styrene-based macromonomers with covalently attached model drugs (ibuprofen and naproxen) or fluorescent markers (pyrene) and their incorporation into linear or hyperbranched p-(chloromethyl)styrene copolymers. Alternatively the copolymers were produced by postpolymerization modification of linear or hyperbranched poly[p-(chloromethyl)styrene], PPCMSt, with the same compounds. The incorporation of these copolymers into amphiphilic conetworks was achieved by two methods: Williamson ether synthesis between PPCMSt and poly(ethylene glycol), PEG, with hydroxyl end groups or by nucleophilic substitution between the chloromethyl moieties in PPCMSt and the amine end groups in poly(oxyalkylenediamine), Jeffamine. The dynamic and equilibrium swelling properties were studied on representative Jeffamine hydrogels. The swelling studies showed that the conetworks absorb water quickly and reach equilibrium in 1−2 h, the equilibrium swelling ratio of gels based on linear or hyperbranched copolymer being 181−358% and 244−480%, respectively. Preliminary drug release studies in different aqueous media showed that the release kinetics and the amount of drugs released from hydrogels depend on the physical properties of drugs, the microstructure of polymer network, and the drug−polymer interaction and more particularly on the hydrolysis dynamics of ester linkage between the drug and the polymer matrix.

Aerosol administration of antibiotics.

Aerosol administration of antibiotics is an attractive approach to the treatment of the recurrent respiratory infections experienced by patients suffering from cystic fibrosis (CF). Through aerosol administration, drugs can, theoretically, be delivered directly to the target site of infection, i.e. the lumen of the lower respiratory tract, thus enabling smaller doses to be given. This, in turn, should result in reduced costs and decreased potential for systemic toxicity. The efficacy of aerosol antibiotic therapy is, however, influenced by numerous variables, including the type of nebulizer device used to deliver the aerosol, the drug's physical properties, its concentration in the aerosol and particle size, carrier gas and patient factors. The efficacy of aerosol antibiotics in the treatment of CF is controversial. This appears to be due mainly of problems and inconsistencies with clinical trials. However, various antibiotics, including beta-lactams, polymyxins and aminoglycosides, have demonstrated clinical benefits when administered by inhalation to CF patients.

The principle of nonspecificity and acute toxicity

It was over 80 years ago that activities of general anaesthetics were observed to be correlated with their liposolubility rather than their molecular structures. Other evidence followed in support of this view of drug ‘nonspecificity’. However, in the last 20 years an overwhelming amount of data has been collected, which indicates that a pharmacological effect is always the result of a specific interaction between drugs and biochemical or biophysical processes. How can this apparently contradictory evidence be reconciled? To what extent should the physical properties of drugs be disregarded in determining their pharmacological potencies? We propose a scheme which allows specific and nonspecific drug interactions to coexist. It is a scheme which can account for these contradictions. It may also account for the discrepancies often found between affinity constants derived from binding experiments and from dose-response curves.