Generic pharmaceuticals, regulatory aspects, bioequivalence investigation, and perception.

INTRODUCTION: The objective and significance of the topic is to draw attention toward regulatory aspects (and pharmacopoeias) for bioequivalence investigation, and perception for generic pharmaceuticals, especially their stereoselective bioequivalence evaluation for understanding the performance of the racemic generic products available in the market. AREAS COVERED: The areas covered include bioequivalence studies (and related USP and FDA requirements) on certain generic APIs for comparison, examples of concern related to inspection of pharmaceuticals for export/import. Literature methodology includes search through USP monographs, MDPI.com, msn.com, WHO Drug Information, certain specific web links, PubMed Central®, PubMed®, NLM's advanced biomedical information services, and several pdf published in relevant journals in the field for related authentic information. EXPERT OPINION: The USP, the USFDA, and the units alike internationally should enforce pharmaceutical companies to perform stereoselective investigations on generic APIs to show that their PK/PD parameters are (nearly) equal to the standards set by such units for allowing marketing of that API. This should be provided to professionals in the areas of patient care and every country should enforce such regulations at the time of export and import of generics.

Assessment and application of Marfey's reagent and analogs in enantioseparation: a decade's perspective.

Of the various methods available for high-performance liquid chromatography separation of enantiomers (of e.g. amino acids and amino group containing compounds) by the pre-column derivatization approach, use of Marfey's reagent has been most successful with continued application since its introduction in 1984. The reagent is prepared from difluoro dinitro benzene by nucleophilic substitution of one of its F atoms by l-alanine amide. There is flexibility to prepare several chiral variants (by substituting the F atom with different chiral auxiliaries) and to tailor the hydrophobicity and resolution, ultimately, of the diastereomeric derivatives. The present paper assesses and reviews applications of Marfey's reagent and its chiral variants (i.e. other FDNP reagents) for enantioseparation of certain amino group containing drugs/amino acids, and to provide some case studies on enantiomeric separations that are important for the pharmaceutical industry. Various explanations for separation mechanism and elution order using FDNP reagents are included and the question of the configuration of the corresponding enantiomer using an indirect approach has also been addressed.

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides.

The synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields.

Ensembling three multicomponent reactions for the synthesis of a novel category of pseudo-peptides containing dithiocarbamate and N,X-heterocylic groups.

Consecutive multicomponent reactions have been applied for the synthesis of novel pseudo-peptides bearing dithiocarbamate and N,X-heterocyclic groups (X = S, O) in only one structure. The first multicomponent reaction includes the synthesis of dithiocarbamates using an amine or amino acid, CS2 and an electrophile. The second MCR is synthesis of Asinger imines using 2-chloroisobutyraldehyde, NaXH (X = S, O), ketone and ammonia. The final MCR is Ugi reaction to afford the corresponding three-dimensional pseudo-peptides. Various Asinger imines, carboxylic acids and isocyanides were applied in this protocol to provide diversities of pseudo-peptides in high to excellent yields.

First catalyst-free CO2 trapping of N-acyliminium ions under ambient conditions: sustainable multicomponent synthesis of thia- and oxazolidinyl carbamates.

The first trapping of N-acyliminium ions by in situ generated carbaminic acid (product of carbon dioxide (CO2) and amine) is reported. This catalyst-free reaction provides a convenient and feasible approach to prepare N-acyl thia- and oxazolidinyl carbamates with good functional-group compatibility and high efficiency under green conditions. Furthermore, the multicomponent method features a broad substrate scope, facile product diversification, smooth scale-up and notable potential for polymer applications.

Chromatographic Enantioseparations in Achiral Environments: Myth or Truth?

Direct chromatographic enantioseparations are among the most important practical tasks of chromatography. The accepted rules and concepts of stereochemistry anticipated one type of chromatographic systems applicable only to such enantioseparations consisting either of chiral stationary phase, or chiral selector present in mobile phase. In such a model of chromatographic system, both racemic and non-racemic mixtures could be enantioseparated. Over the years, however, reports on successful chiral enantioseparations in non-chiral chromatographic systems have cumulated as well. To adapt the initial model to novel experimental evidence, an assumption had to be added stating that these were only non-racemic mixtures (and not racemic ones), which could be enantioseparated in achiral chromatographic systems, by granting them an inevitable chirality from the enantiomeric excess of a more abundant enantiomer. There still exists an overlooked portion of experimental evidence for successful enantioseparations of racemic mixtures in the non-chiral chromatographic systems, which cannot be explained by the accepted model. Facing this incompatibility between the model and practical results, we reflect on how to reconcile these two by questioning the possibility of pinpointing a true racemate with the help of our imperfect analytical tools.

Four-Component Reaction for the Synthesis of Dithiocarbamates Starting from Cyclic Imines.

An efficient one-pot, four-component reaction for the synthesis of dithiocarbamates using carbon disulfide, cyclic imines, acid chlorides, and commercially available primary or secondary amines has been developed by performing an acid chloride addition to a heterocyclic imine followed by subsequent nucleophilic substitution of in situ generated dithiocarbamic acid. With the aid of the newly developed and powerful multicomponent reaction, a direct route for the synthesis of 24 unknown dithiocarbamates in moderate to good yield under mild conditions is enabled.

Sequential Multicomponent Reactions and a Cu-Mediated Rearrangement: Diastereoselective Synthesis of Tricyclic Ketones.

A novel Cu-mediated rearrangement reaction based on bisamides containing a thiazolidine substructure opens the possibility for diastereoselective synthesis toward a tricyclic annulated and bridged heterocyclic system. The required precursors are easily synthesizable by a two-step synthetic pathway using the concept of sequential multicomponent reactions, i.e. the Asinger and Ugi reactions. Due to this synthesis strategy, a number of unique tricyclic heterocycles, characterized by high diversity, are synthesized in an effective manner.

A new multicomponent reaction: unexpected formation of derivatizable cyclic α-alkoxy isothioureas.

An unexpected formation of cyclic α-alkoxy isothioureas has been achieved. As is known, the heterocyclic imines 2,5-dihydro-1,3-thiazoles are convertible to bisamides with the aid of a carboxylic acid and an isocyanide (Ugi reaction). Herein, it is shown that 2,5-dihydro-1,3-thiazole S-monoxides-the respective α-sulfinyl imines-are characterized by an altered reaction behavior. In a hitherto unknown multicomponent reaction the α-sulfinyl imines react with an isocyanide under acidic conditions in an alcoholic solution to the respective α-alkoxy isothioureas in good yields. In addition to the investigations on this unexpected synthesis the regioselectivity of the acylation of the synthesized compounds is described. A rearrangement, which is accelerated by EDC and HOBt, between both possible regioisomers was found.

Three-component reaction toward polyannulated quinazolinones, benzoxazinones, and benzothiazinones.

An efficient conversion of readily accessible cyclic imines with acid chlorides, that are able to take part in nucleophilic aromatic substitution (SNAr) reactions is realized in a new three-component, one-pot reaction, giving at least tricyclic annulated quinazolinones, benzoxazinones, and benzothiazinones as a result of the employed nitrogen, oxygen, or sulfur nucleophiles, respectively. Especially in the case of quinazolinones, this convenient strategy enables the access to heterocycles of heightened diversity, which offer the development of efficient derivatizations of the elaborated heterocyclic scaffolds. In a subsequent Heck or Ullmann cyclization, further annulations to the mentioned quinazolinones can be carried out.

Regioselective air oxidation of sulfides to O,S-acetals in a bubble column.

In this paper the use of a bubble column for a metal-free, selective oxidation of α-alkylthio-imines to O,S-acetals is presented. During the synthesis, which is straightforward to perform, the sulfides are oxidized to α-alkoxy- or, respectively, α-hydroxysulfide by adding activated carbon in the presence of atmospheric oxygen only. We show that the use of the bubble column, which is unusual on laboratory scale, improves the efficiency of the reaction in comparison to common laboratory techniques. As atmospheric oxygen alone is used for oxidation, this method is cost saving, environmentally friendly, and safe.

Multicomponent reaction for the first synthesis of 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines as scaffolds for various 3,4-dihydro-2H-1,3-thiazine derivatives.

A two-step sequence for the synthesis of various 3,4-dihydro-2H-1,3-thiazines is presented. In the first step, 2H-1,3-thiazines were prepared by a new multicomponent reaction (MCR). Starting from ß-chlorovinyl aldehydes, this MCR offers an efficient and facile access to 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines. The potential of these products in subsequent reactions was verified by the conversion to 3,4-dihydro-2H-1,3-thiazine-containing bisamides, ß-lactams, and methoxy amides.

Indicator methods to evaluate the hygienic performance of industrial scale operating Biowaste Composting Plants.

The hygienic performance of biowaste composting plants to ensure the quality of compost is of high importance. Existing compost quality assurance systems reflect this importance through intensive testing of hygienic parameters. In many countries, compost quality assurance systems are under construction and it is necessary to check and to optimize the methods to state the hygienic performance of composting plants. A set of indicator methods to evaluate the hygienic performance of normal operating biowaste composting plants was developed. The indicator methods were developed by investigating temperature measurements from indirect process tests from 23 composting plants belonging to 11 design types of the Hygiene Design Type Testing System of the German Compost Quality Association (BGK e.V.). The presented indicator methods are the grade of hygienization, the basic curve shape, and the hygienic risk area. The temperature courses of single plants are not distributed normally, but they were grouped by cluster analysis in normal distributed subgroups. That was a precondition to develop the mentioned indicator methods. For each plant the grade of hygienization was calculated through transformation into the standard normal distribution. It shows the part in percent of the entire data set which meet the legal temperature requirements. The hygienization grade differs widely within the design types and falls below 50% for about one fourth of the plants. The subgroups are divided visually into basic curve shapes which stand for different process courses. For each plant the composition of the entire data set out of the various basic curve shapes can be used as an indicator for the basic process conditions. Some basic curve shapes indicate abnormal process courses which can be emended through process optimization. A hygienic risk area concept using the 90% range of variation of the normal temperature courses was introduced. Comparing the design type range of variation with the legal temperature defaults showed hygienic risk areas over the temperature courses which could be minimized through process optimization. The hygienic risk area of four design types shows a suboptimal hygienic performance.

New supported beta-amino alcohols as efficient catalysts for the enantioselective addition of diethylzinc to benzaldehyde under flow conditions.

[formula: see text] Polymeric monoliths 10 containing an amino alcohol moiety derived from an industrial waste material represent one of the best ligands for the enantioselective catalytic addition of ZnEt2 to benzaldehyde (99% ee), being recoverable and usable under flow conditions.