Physicochemical properties evaluation methods

LOD is defined as the lowest concentration of an analyte that produces a signal above the background signal. LOQ is defined as the minimum amount of analyte that can be reported through quantitation. For these evaluations, a 3 x signal-to-noise ratio (S/N) value was employed for the LOD and a 10 x S/N was used to evaluate LOQ. The %RSD for the LOD had to be less than 20% and for LOQ had to be less than 10%. Table 6.2 lists the parameters for the LOD and LOQ for methyl paraben and rhodamine 110 chloride under the conditions employed. It is important to note that the LOD and LOQ values were dependent upon the physicochemical properties of the analytes (molar absorptivity, quantum yield, etc.), methods employed (wavelengths employed for detection, mobile phases, etc.), and instrumental parameters. For example, the molar absorptivity of methyl paraben at 254 nm was determined to be approximately 9000 mol/L/cm and a similar result could be expected for analytes with similar molar absorptivity values when the exact methods and instrumental parameters were used. In the case of fluorescence detection, for most applications in which the analytes of interest have been tagged with tetramethylrhodamine (TAMRA), the LOD is usually about 1 nM. 

Libraries of hundreds to thousands of spatially separate inhibitors have been prepared and screened to identify small molecule inhibitors of the human protease cathepsin D and the essential malarial proteases, plasmepsins I and II. The best inhibitors do not incorporate any amino adds and possess high affinity (Kj<5 nM).1241 Furthermore, these lead compounds were optimized by combinatorial methods for good physicochemical properties and minimal binding to human serum albumin. The optimized inhibitors effectively block cathepsin D-mediated proteolysis in human hippocampyl slices and are currently being used to evaluate the therapeutic potential of cathepsin D inhibition in the treatment of Alzheimer s disease. Additionally, the plasmepsin inhibitors serve as promising leads for the treatment of malaria. 

The physicochemical properties of the feeds were determined by appropriate ASTM methods. One of the key objectives of this study was to evaluate the possibility of using H-NMR spectra to predict these properties. 

A feasibility study on the application of H-NMR petroleum product characterization to predict physicochemical properties of feeds and catalyst-feed interactions has been performed. The technique satisfactorily estimates many feed properties as well as catalyst-feed interactions to forecast products yield. There are, however, limitations that have to be understood when using the H-NMR method. The technique, in general, is not capable either to estimate the level of certain contaminants such as nitrogen, sulfur, nickel, and vanadium when evaluating feed properties or the effect of these contaminants on products yields while testing catalyst-feed interactions. 

Among physicochemical properties, the stability of drug candidates is receiving increasing attention. Unfortunately, its evaluation very often requires a lot of experimental time and profiling of many molecules would be nearly impossible without new, computer-aided methods. Any effort useful to facilitate this first part of pharmaceutical investigation is appreciated because it can be converted to a considerable lowering of the research cost. 

Classes of Estimation Methods Table 1.1.1 summarizes the property estimation methods considered in this book. Quantitative property-property relationships (QPPRs) are defined as mathematical relationships that relate the query property to one or several properties. QPPRs are derived theoretically using physicochemical principles or empirically using experimental data and statistical techniques. By contrast, quantitative structure-property relationships (QSPRs) relate the molecular structure to numerical values indicating physicochemical properties. Since the molecular structure is an inherently qualitative attribute, structural information has first to be expressed as a numerical values, termed molecular descriptors or indicators before correlations can be evaluated. Molecular descriptors are derived from the compound structure (i.e., the molecular graph), using structural information, fundamental or empirical physicochemical constants and relationships, and stereochemcial principles. The molecular mass is an example of a molecular descriptor. It is derived from the molecular structure and the atomic masses of the atoms contained in the molecule. An important chemical principle involved in property estimation is structural similarity. The fundamental notion is that the property of a compound depends on its structure and that similar chemical stuctures (similarity appropriately defined) behave similarly in similar environments. 

II. General Principles of Assessment, Evaluation, and Validation of Methods for Physicochemical Property Estimation... 

II. GENERAL PRINCIPLES OF ASSESSMENT, EVALUATION, AND VALIDATION OF METHODS FOR PHYSICOCHEMICAL PROPERTY ESTIMATION... 

Various techniques exist to measure certain physicochemical properties. Table 4.1 sets out some views on their admissibility for reference data. This section discusses the problems of using data for evaluating predictive methods. 

Therefore, heterogeneous catalysts present a greater potential for the application of HT and Combinatorial methods, because they involve diverse compositional phases that are usually formed by interfacial reactions during their synthesis, which in turn produce a variety of structural and textural properties, often too vast to prepare and test by traditional methods. In this respect the HT and Combinatorial methods extend the capabilities of the R D cycle, which comprises the synthesis, the characterization of physicochemical properties and the evaluation of catalytic properties. The primary screening HT method gives the possibility of performing a rapid test of hundreds or thousands of compounds using infrared detection methods [27-29]. Alternatively, a detection method called REMPI (Resonance Enhanced Multi Photon Ionization) has been used, which consists of the in situ ionization of reaction products by UV lasers, followed by the detection of the photoions or electrons by spatially addressable microelectrodes placed in the vicinity of the laser beam [30, 31]. 

Simplistic and heuristic similarity-based approaches can hardly produce as good predictive models as modern statistical and machine learning methods that are able to assess quantitatively biological or physicochemical properties. QSAR-based virtual screening consists of direct assessment of activity values (numerical or binary) of all compounds in the database followed by selection of hits possessing desirable activity. Mathematical methods used for models preparation can be subdivided into classification and regression approaches. The former decide whether a given compound is active, whereas the latter numerically evaluate the activity values. Classification approaches that assess probability of decisions are called probabilistic. 

We have shown that the changes in the shape selectivity can be explained by changes in diffusivity by using ZSM-5 (MFI type) and Y type zeolites as model zeolites. However, it is very difficult to derive the model equations for representing the deactivation mechanisms for every types of zeolites, since each type of zeolite has different pore structure Hence, the mechanism of deactivation should be clarified for each type of zeolites. Reports on the activity of zeolites which were determined experimentally are omitted here. However, it is still impossible to evaluate physicochemical properties of a catalyst from the spectrum of ammonia TPD, which is usually employed to evaluate the acidic properties of a catalyst, since the spectrum is affected by various factors. Therefore, it is difficult to obtain the exact relationship between acidic properties and the change in activity due to deactivation. However, if an accurate method to evaluate the acidic properties is developed, it is expected that we can clarify whether the coverage of acid sites or pore blockage is the dominant factor of decrease in the activity due to coke deposition. 

We reported that greater transfection efficiency in medium with serum was obtained in human cervical carcinoma HeLa cells, using (I) DC-Chol/DOPE liposomes (molar ratio, 1 2) than liposomes (1 1 or 3 2), (2) a modified ethanol injection (MEI) method to prepare liposomes than the dry-film method (13, 14), and (3) a dilution method to form lipoplex than direct mixing. The physicochemical properties of liposomes and lipoplexes can be examined by measuring particle size. Transfection efficiency was evaluated by using plasmid DNA encoding luciferase gene and the cells. 

This level of preformulation should be initiated in the beginning of the development cycle. The data consist of physicochemical properties of the chemical substance and analytical properties useful in the development of analytical methods, the evaluation of material quality, and testing for the acceptance of the formulation developed. In the early stage of development, the synthetic scheme is developed and the material available for preformulation may be limited. Thus the lack of supply quantities may affect the quality of data obtained. As the development cycle is pushed forward and the drug availability improves, data should be updated or refined with the use of more complicated and accurate methods. Part 1 of the preformulation report may be published before the establishment of specifications. The portion of this report consisting of analytical data may be known as an analytical profile in some organizations. 

During the preformulation and formulation stages of a parenteral dosage form, the physicochemical properties and excipient compatibility of the pharmaceutical active ingredient (API) should be thoroughly evaluated. The test method requirements are similar to those for oral dosage forms. 

Examination of the synthetic route used in production allows for the prediction of potential residual synthetic impurities present in the drug substance. The API structure allows for the postulation of degradation pathways via hydrolytic, oxidative, catalytic, and other mechanisms. Both of these evaluations serve to facilitate the interpretation of (subsequent) identification tests. An examination of the physicochemical properties also allows for the rational establishment of method screening experiments by precluding certain conditions. For example, the use of normal-phase HPLC will be eliminated if the API is a salt or shows limited solubility in nonpolar organic solvents. Similarly, if the API (or suspected related substances) has no significant chromophore above 250 nm, the use of tetrahydrofuran (THE) and other solvents as mobile-phase components is severely limited. For compounds with an ionizable group, variation of pH will have considerable influence on elution behavior and can be exploited to optimize the selectivity of a reversed-phase separation. 

The Hammett-type correlation for the rate constants of 5-allyl-5-R-barbiturates has been reported by Carstensen et al. and suggested for use in stability predictions.569 Similar correlations were also found for the hydrolysis of 5-arylidenebarbituric acids.363,567 Linear free energy relationships have also been reported for dissociation constants,45,51 polarographic half-wave potentials,570 fluorescence70 and luminescence phenomena,71 and 13C-NMR chemical shifts129 for different classes of barbituric acid derivatives. Application of the dual substituent parameters method in LFER analysis of barbiturates, using Taft s polar and steric constants for various chemical and physicochemical properties, was also evaluated.571... 

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