Terpene bioconversion--how does its future look?

The usage of essential oils as such or of volatile fractions thereof is widespread in the flavor and fragrance industry to aromatize perfumery and cosmetic products, foodstuffs, and many household and pharmaceutical products. The increased market share of convenience food together with consumers' request for constant high quality and natural products have established a lasting increase in the demand for natural flavorings that cannot be satisfied by the traditional plant materials. This review summarizes selected work on terpene bioconversion/transformation and focuses on recently published papers dealing with novel strains and products, high product yields, intriguing genetic engineering approaches, and integrated bioprocesses. The future perspectives of an industrial realization of a biotechnological production of terpene-derived natural flavors are critically evaluated.     

Electrospray ionization mass spectrometry: a key analytical tool for the characterization of regioselectively derivatized maltooligosaccharides obtained starting from natural beta-cyclodextrin

The development of natural cyclodextrins (CDs) for various industrial applications (agroalimentary, cosmetic or pharmaceutical) constitutes a continuous challenge. For the integration of these agricultural plant products in the creation of super-absorbent biodegradable and hypoallergenic materials (water-retaining agents, cosmetic hydrating and texturing, pharmaceutical and horticultural products) to replace synthetic polymers, we have developed chemical methods to access regioselectively C-6-derivatized maltooligosaccharides starting from CDs. These compounds are highly suitable for further chemical modifications and are expected to give access to a new class of polymeric materials with potential applications such as water-retaining agents in the disposable nappies industry. For the structural analysis of carbohydrates, electrospray ionization mass spectrometry (ESI-MS) offers precise results, analytical versatility and very high sensitivity. We report herein the rapid and convenient follow-up of chemical reactions, the purity evaluation of intermediates and final products, and the structural characterization of derivatized maltooligosaccharides, obtained by acidic cleavage (acetolysis) of halogenated and esterified CDs, using ESI-MS in combination with the high-resolution (HRMS) and tandem mass spectrometry (MS/MS) capabilities of a quadrupole orthogonal time-of-flight (Q-TOF) mass spectrometer.     

高效液相色谱-质谱联用技术的应用进展

高效液相色谱-质谱联用技术具有高分离能力、高灵敏度、应用范围广和极强的专属性等特点。对高效液相色谱-质谱联用技术在药物分析、食品分析和环境分析等领域的应用,特别是在中草药成分分析、中药指纹图谱研究、药物代谢研究、体内药代动力学研究、西药及中成药成分分析、药物筛选研究等方面的应用进行了综述。     

Confronting the challenges of natural product-based antifungal discovery

Starting with the discovery of penicillin, the pharmaceutical industry has relied extensively on natural products (NPs) as an unparalleled source of bioactive small molecules suitable for antibiotic development. However, the discovery of structurally novel and chemically tractable NPs with suitable pharmacological properties as antibiotic leads has waned in recent decades. Today, the repetitive "rediscovery" of previously known NP classes with limited antibiotic lead potential dominates most industrial efforts. This limited productivity, exacerbated by the significant financial and resource requirements of such activities, has led to a broad de-emphasis of NP research by most pharmaceutical companies, including most recently Merck. Here we review our strategies--both technological and philosophical--in addressing current antifungal discovery bottlenecks in target identification and validation and how such efforts may improve NP-based antimicrobial discoveries when aligned with NP screening and dereplication.     

A generic platform for the immobilisation of engineered biocatalysts

The application of biocatalysis in the pharmaceutical industry is rapidly growing as a result of increased access to enzymes that meet the demands of industrial processes. This expansion of activity has led to a corresponding increase in the demand for immobilised enzymes. EziG? (EnginZyme AB, Sweden) is marketed as a general matrix for enzyme immobilisation on controlled porosity glass. In this work we identified criteria for a “general” enzyme immobilisation technology in the context of the requirements of the pharmaceutical industry. We subsequently evaluated EziG? for generality in a series of case studies for the application of immobilised biocatalysts. In this study we have focussed on the challenges facing both academic and industrial applications such as enzyme stability, multistep reactions and reactions in continuous flow.     

An Overview on Food Applications of the Instant Controlled Pressure-Drop Technology,an Innovative High Pressure-Short Time Process

Food processing systematically aims at meeting the needs of consumers who are looking for total high quality and perfect food safety. As the various thermal and non-thermal food preservation technologies often affect the natural properties in terms of sensation, flavor, texture, etc., instant controlled pressure drop (DIC) has been conceived as a relevant, innovative process in this field. DIC uses high saturated steam pressure and short duration to provide a new way to expand biological matrices, improve drying, decontaminate, and extract biologically active compounds, among other attributes. Therefore, this review focuses on describing the applications of DIC technology on a wide range of products such as foods and by-products that have been processed both in the laboratory and on an industrial scale. The application of DIC has shown the possibility of a significant leap in quality improvement and cost reduction in the food industry. DIC reduces the drying time of fruits and vegetables, and improves the extraction of essential oils, vegetable oils, and antioxidant components. It also provides strong decontamination, eliminates vegetative microorganisms and spores, and reduces non-nutritional and allergenic components. Over the past 33 years, this technology has continued to expand its food applications and improve its characteristics on an industrial scale. But there are still many food unit operations that can be taken to the next level with DIC.     

Chlorherstellung mit Sauerstoffverzehrkathoden. Energieeinsparung bei der Elektrolyse

Chlorine is one of the most important base chemicals and is required for the manufacture of about two‐thirds of all chemical products such as polymers, crop protection and pharmaceutical products, products for drinking water purification, and ultrapure silicon for photovoltaics and electronics applications. The industrial chlorine production through the chlor‐alkali electrolysis has since 1975 mainly been based on the advanced membrane process. Chlorine recycling by manufacturing processes based on hydrogen chloride has also become increasingly important. The still very high energy demand for the electrochemical chlorine synthesis can be significantly reduced by up to 30 % if the hydrogen evolving cathodes in the classical processes are replaced by oxygen depolarized cathodes (ODC) which are well known from fuel cells. Hydrogen chloride electrolysis with ODCs is already carried out in world‐scale plants. The more important chlor‐alkali process with ODCs will be realized for the first time in 2011 in a demonstration unit with a chlorine capacity of 20000 tons per year in Uerdingen, Germany.     

Electrochemical Sensors,a Bright Future in the Fabrication of Portable Kits in Analytical Systems

Analysis of food, pharmaceutical, and environmental compounds is an inevitable issue to evaluate quality of the compounds used in human life. Quality of drinking water, food products, and pharmaceutical compounds is directly associated with human health. Presence of forbidden additives in food products, toxic compounds in water samples and drugs with low quality lead to important problems for human health. Therefore, attention to analytical strategy for investigation of quality of food, pharmaceutical, and environmental compounds and monitoring presence of forbidden compounds in materials used by humans has increased in recent years. Analytical methods help to identify and quantify both permissible and unauthorized compounds present in the materials used in human daily life. Among analytical methods, electrochemical methods have been shown to have more advantages compared to other analytical methods due to their portability and low cost. Most of big companies have applied this type of analytical methods because of their fast and selective analysis. Due to simple operation and high diversity of electroanalytical sensors, these types of sensors are expected to be the future generation of analytical systems. Therefore, many scientists and researchers have focused on designing and fabrication of electroanalytical sensors with good selectivity and high sensitivity for different types of compounds such as drugs, food, and environmental pollutants. In this paper, we described the mechanism and different examples of DNA, enzymatic and electro‐catalytic methods for electroanalytical determination of drug, food and environmental compounds.     

HPLC determination of thiol drugs in pharmaceutical formulations using ethacrynic acid as a precolumn ultraviolet derivatization reagent

Summary A high performance liquid chromatographic method has been developed for the determination of aliphatic thiol drugs, such as N-acetyl-L-cysteine, captopril and mercaptopropionylglycine in pharmaceutical formulations. The procedure involves a precolumn derivatization of the thiol drug with ethacrynic acid followed by reversedphase HPLC separation and UV detection. The conditions for a rapid and selective reaction of the thiols with ethacrynic acid have been investigated. The method proved to be suitable for a reliable and selective quality control of commercial dosage forms of the examined thiol drugs.     

The Process Analytical Technology initiative and multivariate process analysis, monitoring and control

Process analytical technology is an essential step forward in pharmaceutical industry. Real-time analyzers will provide timely data on quality properties. This information combined with process data (temperatures, flow rates, pressure readings) collected in real time can become a powerful tool for this industry, for process understanding, process and quality monitoring, abnormal situation detection and for improving product quality and process reliability. A very important tool for this achievement is the multivariate analysis. Dr. Theodora Kourti is Research Manager in the McMaster Advanced Control Consortium (MACC) and Adjunct Professor in the Chemical Engineering Department at McMaster University. She is the co-recipient of the 2003 University – Industry Synergy Award for Innovation, given by the Natural Science & Engineering Research Council of Canada. Dr. Kourti has been working on Multivariate Statistical Methods for Process and Product Improvement and Abnormal Situation Detection in Process Industries since 1992 and has been involved in more than 80 major industrial applications in North America and Europe. These are either off-line or real-time applications for batch and continuous processes, in diverse industries such as Chemicals, Pharmaceuticals, Semiconductor, Mining, Pulp and Paper, Petrochemicals, Photographic and Steel Industry. She has published extensively in this area and has provided training for numerous industrial practitioners.     

Current experiences with a quality management system for non-clinical research and development in pharmaceutical industry

Quality management is one of the most important issues in pharmaceutical research as it determines the validity and reliability of data, data and data evaluation being the central products of all research activities. In this business it is of outstanding importance to generate valid data for the assessment of drug development candidates to assure that the huge financial investment, which is based on such assessments, can be successful. Efficacy and safety of products are the final goals of such developments. Therefore, Merck/Merck Serono implemented an additional specifically developed quality management system that covers all areas and locations in Merck Serono Research that were not yet regulated by an existing regulatory quality management system, e.g. GLP (Good Laboratory Practice). The system is known under the name Merck Serono Research-Quality Management System (MSR-QMS). Thus, we describe the implementation process of MSR-QMS as a research specific quality management system in a global company. Furthermore, the implementation process in one specific research department will be highlighted. Using a practical example, the validation of an analytical instrument in a MSR-QMS-regulated research laboratory will be shown and compared to a validation process in a strictly GLP-regulated area. A summary of the experiences with the new quality system will complete this article and the advantages of high quality research results in industry will be discussed.     

Process analytical technology (PAT) for biopharmaceutical products

The “Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century—A Risk Based Approach” initiative announced by the FDA in August 2002 to improve and modernize pharmaceutical manufacturing facilitated adoption of process analytical technology (PAT) by the pharmaceutical industry. The potential for improved operational control and compliance resulting from continuous real-time quality assurance was highlighted as a likely benefit that would result from PAT implementation. A considerable amount of work has been done on this topic by academic and industrial contributors in the last decade. In this paper, we will start with a brief overview of evolution of PAT concepts and a review of their application in the wider pharmaceutical industry. The rest of the paper focuses on PAT applications for biotech processes with emphasis on developments in the last five years. It is our observation that while significant advances have been accomplished with regard to our ability to analyze/monitor key process and quality attributes in the biotech industry, much more needs to be done with regard to utilizing the collected data for subsequent control of the process, to achieve optimum yield and product quality. The latter is necessary to achieve the benefits that will result from PAT implementation.     

Crystal Engineering: An Outlook for the Future

Crystal Engineering has traditionally dealt with molecular crystals. It is the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties. We outline here five areas which come under the umbrella of Crystal Engineering and where we feel that a proper planning of research efforts could lead to higher dividends for science together with greater returns for humankind. We touch on themes and domains where science funding and translation efforts could be directed in the current climate of a society that increasingly expects applications and utility products from science and technology. The five topics are: 1) pharmaceutical solids; 2) industrial solid state reactions; 3) mechanical properties with practical applications; 4) MOFs and COFs framework solids; 5) new materials for solar energy harvesting and advanced polymers.     

Molecular detection of Burkholderia cepacia in toiletry, cosmetic, and pharmaceutical raw materials and finished products

A polymerase chain reaction (PCR) assay was developed and compared with standard methods for rapid detection of Burkholderia cepacia, a major industrial contaminant, in cosmetic and pharmaceutical raw materials and finished products. Artificially contaminated samples were incubated for 24 h in trypticase soy broth containing 4% Tween 20 and 0.5% soy lecithin. DNA was extracted from each sample using a proteinase K-tris-EDTA-Tween 20 treatment at 35 degrees C. The extracted DNA was added to Ready-To-Go PCR beads and specific DNA primers for B. cepacia. The B. cepacia DNA primers coded for a 209-base pair (bp) fragment of the 16S rRNA ribosomal gene. No DNA amplification was observed in samples that were not spiked with B. cepacia. However, all contaminated samples showed the specific 209-bp fragment for B. cepacia. There was a 100% correlation between standard methods and the PCR assay. Standard microbiological methods required 5-6 days for isolation and identification of spiked microorganisms, whereas PCR detection and identification was completed in 27 h. PCR detection of B. cepacia allows for rapid quality evaluation of cosmetic and pharmaceutical raw materials and finished products.     

Solid-phase synthesis of nucleoside analogues

The synthesis of a 25 000 member library of nucleoside analogues as discrete compounds in milligram quantities is described. The use of the Nanokan technology developed by IRORI (Discovery Partners International) together with macroporous solid support allowed us to develop a highly reliable and practical synthetic route for the high-throughput derivatization of both the pyrimidine and purine nucleoside scaffold. A 2',3'-acetal linkage of the scaffolds to the solid support proved to be stable enough for the chemical transformations employed, yet labile enough for mild cleavage conditions to yield final products in high purity. The publication represents an example for combining synthetic organic chemistry on advanced scaffolds with the latest technologies of combinatorial chemistry in order to provide both industrial and academic institutions with compounds in high number and quality, thereby accelerating the search for novel biological targets and drug development.     

High-performance liquid chromatography of timolol and potential degradates on dynamically modified silica

A novel method for the determination of timolol in pharmaceutical products has been developed and is described. The method employs high-performance liquid chromatography (HPLC) on silica dynamically modified with the cetyltrimethylamomonium cation to quantitate the analyte. The use of this type of reversed-phase HPLC system for timolol determinations results in improved quality of chromatography, especially in terms of peak tailing and peak efficiency, in comparison to chromatography on bonded-phase silica. Column-to-column as well as manufacturer-to-manufacturer reproducibility for this separation on silica columns has been obtained and is better in our hands than that encountered with bonded-phase column packings. The method has been shown to be linear for the compounds studied, comparably accurate and precise to bonded-phase methods and specific for timolol in a variety of pharmaceutical formulations. Under the conditions specified, timolol can be successfully separated from its three potential degradates. Possible explanations of the primary retention mechanisms for the analytes are offered.     

Chemometrics-Based Process Analytical Technology (PAT) Tools: Applications and Adaptation in Pharmaceutical and Biopharmaceutical Industries

Process analytical technology (PAT) is used to monitor and control critical process parameters in raw materials and in-process products to maintain the critical quality attributes and build quality into the product. Process analytical technology can be successfully implemented in pharmaceutical and biopharmaceutical industries not only to impart quality into the products but also to prevent out-of-specifications and improve the productivity. PAT implementation eliminates the drawbacks of traditional methods which involves excessive sampling and facilitates rapid testing through direct sampling without any destruction of sample. However, to successfully adapt PAT tools into pharmaceutical and biopharmaceutical environment, thorough understanding of the process is needed along with mathematical and statistical tools to analyze large multidimensional spectral data generated by PAT tools. Chemometrics is a chemical discipline which incorporates both statistical and mathematical methods to obtain and analyze relevant information from PAT spectral tools. Applications of commonly used PAT tools in combination with appropriate chemometric method along with their advantages and working principle are discussed. Finally, systematic application of PAT tools in biopharmaceutical environment to control critical process parameters for achieving product quality is diagrammatically represented.     

Characterization and identification of suspected counterfeit miltefosine capsules

Recently, it was revealed that generic miltefosine capsules for the treatment of visceral leishmaniasis, a fatal parasitic disease, were possibly counterfeit products. Here we report on the methods to characterize and identify miltefosine in pharmaceutical products and the procedures that were used to assess the quality of these suspected counterfeit products. Characterization and identification of miltefosine were done with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), Fourier transform infrared (FT-IR) spectroscopy and near-infrared (NIR) spectroscopy. Moreover, a simple, rapid and inexpensive colorimetric test was developed and evaluated for the detection of miltefosine in pharmaceutical products that can be used in the field. The complementary analytical techniques presented here were able to determine qualitatively or (semi-)quantitatively the presence or absence of miltefosine in pharmaceutical preparations and could identify suspected counterfeit miltefosine capsules. This finding of a suspected counterfeit drug intended to treat a neglected disease in a resource-poor country emphasizes the urgent need to develop more simple inexpensive assays to evaluate drug quality for use in the field.     

Validation of standardized high-performance thin-layer chromatographic methods for quality control and stability testing of herbals

In herbal medicinal products the entire herbal drug or an herbal drug preparation is regarded as the active pharmaceutical ingredient, regardless of whether constituents with defined therapeutic activity are known. In quality control and stability testing of herbal medicinal products, fingerprint chromatograms are used as powerful tools to evaluate and compare the composition of compounds in such products. To fulfill the International Conference on Harmonization and Good Manufacturing Practice-based regulatory requirements in pharmaceutical quality control, chromatographic fingerprint analysis needs to be validated. Based on a standardized methodology, this paper provides a comprehensive concept for evaluating validation parameters for planar chromatographic fingerprinting by considering the stationary phase, sample application, developing solvent, chromatogram development, plate labeling, derivatization, documentation, and chromatographic equipment. Validation parameters addressed include stability of the analyte, selectivity, robustness testing, and method reproducibility.     

Methodology for the validation of analytical methods involved in uniformity of dosage units tests

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving the quality of the end products starting from its early design stage. However, no regulatory guideline or none of the published methodologies to assess method validation propose decision methodologies that effectively take into account the final purpose of developed analytical methods. In this work a solution is proposed for the specific case of validating analytical methods involved in the assessment of the content uniformity or uniformity of dosage units of a batch of pharmaceutical drug products as proposed in the European or US pharmacopoeias. This methodology uses statistical tolerance intervals as decision tools. Moreover it adequately defines the Analytical Target Profile of analytical methods in order to obtain analytical methods that allow to make correct decisions about Content uniformity or uniformity of dosage units with high probability. The applicability of the proposed methodology is further illustrated using an HPLC-UV assay as well as a near infra-red spectrophotometric method.