Pharmaceutical industry applications cyclodextrins

With capillary electrophoresis (CE), another modern primarily analytically oriented separation methodology has recently found its way into routine and research laboratories of the pharmaceutical industries. As the most beneficial characteristics over HPLC separations the extremely high efficiency leading to enhanced peak capacities and often better detectability of minor impurities, complementary selectivity profiles to HPLC due to a different separation mechanism as well as the capability to perform separations faster than by HPLC are frequently encountered as the most prominent advantages. On the negative side, there have to be mentioned detection sensitivity limitations due to the short path length of on-capillary UV detection, less robust methods, and occasionally problems with run-to-run repeatability. Nevertheless, CE assays have now been adopted by industrial labs as well and this holds in particular for enantiomer separations of chiral pharmaceuticals. While native cyclodextrins and their derivatives, respectively, are commonly employed as chiral additives to the BGEs to create mobility differences for the distinct enantiomers in the electric field, it could be demonstrated that cinchona alkaloids [128-130] and in particular their derivatives are applicable selectors for CE enantiomer separation of chiral acids [19,66,119,131-136]. 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

In addition to their use in pharmaceutical formulations, cyclodextrins have also been investigated for use in various industrial applications. Analytically, cyclodextrin polymers are used in chromatographic separations, particularly of chiral materials. 

In the chemistry of inclusion compounds, there is no doubt that cyclodextrins (CDs) belong to the most important class of host molecules. The remarkable career of cyclodextrins in research and industrial applications is due to their ability to incorporate selectively many organic/inorganic molecules, ions and even radicals. CDs have found numerous applications in many areas, especially in the pharmaceutical, agrochemical, food and tobacco industries, as well as in cosmetics and toiletry [8]. 

A wide area of supramolecular chemistry focuses on host-guest interactions between two or more molecules that are not covalently bonded (1). A special part of this chemistry deals with cyclodextrins and their derivatives (2). It is well known that cyclodextrins tend to include several types of hydrophobic guest molecules into their cavity. Accordingly, a large number of applications have been found in many areas, eg, in food chemistry as well as in the pharmaceutical (3) and cosmetic industries. Furthermore, cyclodextrins may be used in organic chemistry and also in polymer chemistry. 

It is significant to note that the cyclodextrins have good water solubilities. They are finding extensive use in the pharmaceutical industries of some countries as vehicles either to solubilize drugs or to protect them as they pass through the digestive system. Other applications in such diverse areas as that of food additives and in pesticide formulations have been realized. 

Most industrial uses of cyclodextrins are based on their ability to form supramolecular inclusion complexes with diverse guests [4]. They are used as solubilizers or drug transporters for pharmaceutical applications [5], as stabilizers and taste protectors in food and cosmetic industries [6], and as static phase in chromatography [7] for the separation of chiral entities. The required properties of cyclodextrin derivatives vary depending on the desired application, such as enantioselectivity for the separation of enantiomers or stability of the inclusion complex for encapsulation of drugs. Native cyclodextrins rarely match perfectly to the application so their modification is necessary to fine-tune their properties. In that context, efficient and selective methodologies have to be developed to access new derivatives that could be adapted to the desired application. Cyclodextrins are a particular class of complex carbohydrate derivatives, as they are easily produced... 

There are many classes of CSPs applicable in different mobile-phase modes. In particular, CSPs based on derivatized polysaccharides, native and derivatized cyclodextrins, macrocyclic glycopeptides, and Pirkle-type chiral selectors operate quite well in four separation modes, i.e RP, polar organic phase, NP, and super- or subcritical fluid chromatography (SFC) conditions. It is common that a chiral compound can be separated on the same CSP in more than one separation mode [58, 160, 166, 170-176]. For example, Nutlin-3, a small molecule antagonist of MDM2, has been baseline resolved from its enantiomer in all four mobile-phase conditions (Fig. 16) [170]. Multimodal enantioseparation on the same CSP would be greatly beneflcial for chiral method development in pharmaceutical industry. 

A very interesting field in membrane bioreactors is the production of cyclodextrins or oligosaccharides. In general, they have applications in food pharmaceutical, cosmetic agricultural, and plastics industries as emulsifiers, antioxidant, and stabilizing agents. In the food industry cyclodextrins are employed for the preparation of cholesterol-free products. The use of enzymatic membrane reactors to produce... 

There are two general types of applications of cycloflmctans. First, they have been used as bulk additives in various industrial formulations, in much the same manner as cyclodextrins, another type of cyclic oligosaccharides, have. For example, cyclofructans have been be used as the coating material for inkjet recording media [6,7] and silver halide photographic materials [8-11], as food additives [12-16], and as excipients in pharmaceutical applications [17-21]. Second, cyclofructans have... 

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