Extractions in the Pharmaceutical Industry

One example of a commercial application is the isolation of diosgenin, the most important starting material for partial synthesis of steroids. Drivsun, a Chinese company, is isolating this compound on a scale of 300 tpy by SCFE from tubers of 

Dioscorea species (dry content up to 6%), plants which grow in the wild and can be found in Mexico, China, India, and South Africa [20, 21]. 

Impr nations with Supercritical Carbon Dioxide 

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Larson, K. A. King, M. L. Evaluation of Supercritical Fluid Extraction in the Pharmaceutical Industry. Biotechnol. Prog. 1986, 2 (2) 73-82. 

Larson KA, King ML. Evaluation of supercritical fluid extraction in the pharmaceutical industry. Biotechnol Prog 1986 2 73-82. 

The behavior of drops in the centrifugal field has been studied (211) and the residence times and mass-transfer rates have been measured (212). PodbieHiiak extractors have been widely used in the pharmaceutical industry, eg, for the extraction of penicillin, and are increasingly used in other fields as weU. Commercial units having throughputs of up to 98 m /h (26,000 gal/h) have been reported. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

Direct injection of plasma or supernatant after protein precipitation on a short column with a high liquid flow rate is a common method for reducing analysis time in the pharmaceutical industry. The direct injection of a sample matrix is also known as the dilute-and-shoot (DAS) approach.62 DAS can be applied to all types of matrices and approaches and is the simplest sample preparation method with matrix dependency. Direct injection can also be approached through the extraction of eluent from PPT, SPE, and LLE onto a normal phase analytical column. The procedure is called hydrophilic interaction liquid chromatography (HILIC)70110111 and it avoids the evaporation and reconstitution steps that may cause loss of samples from heat degradation and absorption. 

Protein precipitation is used routinely in bioanalytical laboratories in the pharmaceutical industry. Plasma is mixed with an excess (3 to 5 times) of organic solvent (typically acetonitrile or methanol) or an acid such as formic acid. The proteins precipitate out of solution, the sample is centrifuged, and the supernatant is analyzed. While this method is relatively fast and simple, the extract contains salts and lipids that can interfere with subsequent analyses. Often, a second technique such as SPE is used for further cleanup. Table 2.4 exhibits various samples that... 

Another common qualitative TLC test in the pharmaceutical industry is identity testing. A standard is applied to the plate side by side with the extracted sample, such as a tablet. The plate is developed in mobile phase and dried, then detected in accordance with the validated procedure. If the Rf value of the sample is consistent with that of the standard, then they are said to be of the same entity, and thus meet the identity test as shown in Fig. 13.15. 

A different issue is one that is quite common in the Pharmaceutical industry. A relatively frequent situation that arises is the need to identify a 0.1% impurity from a reaction mixture or metabolism sample. These samples are often quite convoluted in terms of the amount of compounds present as well as the general complexity of the separation, akin to a natural products extract, as can be seen in Fig. 19.19. However, to simplify this scenario to just a two-component mixture is appropriate for this section. Under common LC-NMR systems, it is typically required to have at least 50 pg of material for a complete structure elucidation (to enable the collection of long-range heteronu-clear correlation data, HMBC). Therefore, one must be able to load 50 mg of the mixture on the column. Keep in mind, that if a ID 1H spectrum is all that is needed (in the case of a regiochemical issue in an aromatic system) this task becomes more amenable. The point trying to be made is that LC-NMR is a fantastic technique, but it must be used in... 

The progress made in interfacingHPLC instruments with mass spectrometry has been a significant development for laboratory analyses in the pharmaceutical industry. The low concentrations of test drugs in extracts of blood, plasmas, serums, and urine are no problem for this highly sensitive HPLC detector. In addition, the analysis is extremely fast. Lots of samples with very low concentrations of the test drugs can thus be analyzed in a very short time. At the MDS Pharma Services facility in Lincoln, Nebraska, for example, a very busy pharmaceutical laboratory houses over 20 LC-MS units, and they are all in heavy use daily. 

Liquid-liquid extraction is extensively used in the pharmaceutical industry for the production of drugs and isolation of natural products [9]. These products are often heat sensitive and cannot be recovered by methods such as atmospheric distillation or evaporation. Owing to competition, little detailed information is available on current commercial operations. A classic example and the best documented, which has encountered problems... 

Solvent extraction procedures provide simple methods for separating the analyte from excipients in formulations. The analytical method applied to the isolated analyte can be for example either gravimetric, volumetric, spectrophotometric or chromatographic. In most cases in the pharmaceutical industry chromatographic methods are preferred. The extraction method adopted is governed by the need to remove excipients and by the properties of the analyte. 

Raw materials employed in the pharmaceutical industry may have two different origins. They are either naturally occurring substances or synthesized drugs. Among the natural products are active ingredients from plant extracts or animals, chemicals,... 

The subject of extractables and leachables in drug products is an area of active discussion in the pharmaceutical industry. Further the regulatory agencies have issued guidances on this subject in recent years. The FDA guidance on container closure systems defines extractables and leachables as follows [124] Extractables are compounds that can be extracted from elastomeric or plastic components of the container closure system when in the presence of a solvent. Leachables are compounds that leach into the formulation from elastomeric or plastic components of... 

Opium has been known and used for 4000 years or more. In recent times, attempts have been made at governmental and international levels to control the cultivation of the opium poppy, but with only limited success. In endeavours to reduce drug problems involving opium-derived materials, especially heroin, where extremely large profits can be made from smuggling relatively small amounts of opium, much pharmaceutical production has been replaced by the processing of the bulkier poppy straw . The entire plant tops are harvested and dried, then extracted for their alkaloid content in the pharmaceutical industry. Poppy straw now accounts for most of the medicinal opium alkaloid production, but there is still... 

Isolation and purification of unknowns can be accomplished by a variety of techniques (e.g., preparative HPLC or TLC, flash chromatography, extraction, etc.) (65). Preparative HPLC, RP or NP, is probably the most widely used technique in the pharmaceutical industry for purification of milligram to gram quantities of low-level impurities. Once an unknown is isolated, spectroscopic characterization by MS and NMR is usually sufficient to unambiguously assign structures. UV, IR, and/or Raman are often used to identify specific chromophores or functional groups. Spectroscopic characterization of unknown impurities leading to structure elucidation is a process that has been discussed extensively elsewhere (66-68) and need not be reproduced here. 

Natural products have been identified as the active principle of herbs and extracts used in folk medicine [1], The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 506) or derivatives thereof [3]. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. 

Solvent extraction has been used extensively in the pharmaceutical industry because many pharmaceutical intermediates and products are heat sensitive and cannot be processed by methods such as distillation, etc. However, few details of current commercial operations have been published. 

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