Hydroxypropyl-CDs

Hydroxylpropyl-j8-CDs (HP-y3-CDs), a hydroxyalkyl derivative, is an alternate to native CD, with improved water solubility and may be slightly more toxicolog-ically benign. As the first approved CD derivatives by FDA, HP-)3-CDs have wide applications in food, agriculture and the pharmaceutical fields. 

For many years, CDs were considered to have rigid truncated-cone structures although this concept was incompatible with the ease of their complex formation and several experimental findings (mainly obtained by NMR technique). Recent experimental results demonstrate that the complexes, held together by weak nonbonded interactions, must be flexible not only in solution but also in the solid state. The truncated-cone structure of HP-)3-CDs became more flexible since the intramolecular hydrogen bond is broken by the hydroxylpropyl substituent. This flexibility preferably explains the improvement of complex forming ability and dynamic character of the complexes of HP- -CDs [22]. 

The water solubility of HP-/3-CDs is greatly increased ( 500g/L, 20°C) because of substitution, and is hygroscopic. Usually, HP-/3-CD is a white amorphous powder. However, if the DS of HP-/3-CDs is above 10, it is hard to dry them. In this case, HP-/3-CDs are like transparent sticky gels. The DS of HP-jS-CDs 

Chao Yuan [25] has optimized the preparation process of HP-)3-CDs. Reaction time (A) reaction temperature (B), dialysis time (C) were employed in the single factor experiment. Then, a central composite design of response surface methodology was used with the DS and yield response values. 

According to the results of the single factor experiment, reaction time was set in the range of 10-20 h, reaction temperature 20°C-40°C, dialysis time 6-10 h, DS and yield were employed as response value. A response surface method experiment was designed by a software — Design Expert 6.0. The results are shown in Table 5.2. 

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Schematic principle of ACE interaction between a hydroxypropylated CD and propranolol.

Hydroxypropylated CDs are statistically substituted derivatives because hydroxy-propylation does not result in selective substitution as with methylation. While the reaction proceeds, the reactivity of the hydroxyl group changes, and this results in a mixture of products with various degrees of substitution. Their dissolution is endothermic so there is no decrease in solubility with increasing temperature [6,13]. It is necessary to note that degree of substitution in hydroxypropylated CDs is inversely correlated with their inclusion capability [14,15]. Hydroxyalkylated CDs are commercially available as tablets, ocular collyrs [16], and excipients under the trademarks Encapsin and Molecusol. 

Tee s group has reported on the catalysis of enolization of indan-2-one (200) by a-CD, ) -CD, y-CD, hydroxyethyl-) -CD, and hydroxypropyl-) -CD, all of which accelerate the reaction by up to 22-fold but dimethyl-) -CD slows it by about half These workers have also looked at the effect of alcohols on the basic cleavage of m-nitrophenyl hexanoate by )8-CD. Finally, they have been examining the reaction of a-amino acid anions with p-nitrophenyl acetate and hexanoate in the presence of )S-CD. ... 

The formation of the complexes leads to significant changes of the solubility and reactivity of the guest molecules without any chemical modification. Thus, water insoluble molecules may become completely water soluble simply by mixing with an aqueous solution of native CD and CD derivatives, e.g. methylated (Me) or hydroxypropylated CD. The water solubility of these inclusion compounds enables detection of complex formation in solution by spectroscopic methods, such as NMR [16], UV, fluorescence, or circular dichroism spectroscopy, as well as by thermodynamic methods, e.g. microcalorimetry [17] or density [18,19], or by solubility measurements. Likewise, mass spectrometry was used [20],... 

Other applications of CE to analyze food additives include the determination of vitamin C and preservatives (benzoate and sorbate) by both conventional CE and microchip electrophoresis with capacitively coupled contactless conductivity detection. The separation was optimized by adjusting the pH value of the buffer and the use of hydroxypropyl- -CD (HP- -CD) and CTAB as additives. For conventional CE, optimal separation conditions were achieved in a histidine/tartrate buffer at pH 6.5, containing 0.025% HP-f)-CD and 0.25 mM CTAB with a LOD ranging from 0.5 to 3 mg/L, whereas a histidine/tartrate buffer with 0.06% HP-fl-CD and 0.25 mM CTAB gave a LOD ranging from 3 to 10 mg/mL. By using a microchip electrophoresis format, a considerable reduction of analysis time was accomplished. ... 

The so-called first-generation cyclodextrin (CD), i.e. the native a-CD, -CD and y-CD, each has its limitations in application. -CD exhibits poor solubility a-CD owns a small cavity which restricts the size of the guest molecules y-CD has a larger cavity but expensive. Thus, to expand the application area, native CDs are usually modified to improve their physiochemical properties [ 1 ]. Until now, various branched-CDs, such as methyl-CD, hydroxypropyl-CD, glucosyl-CD (Gl-CD) and maltosyl-CD (Mal-CD) have already been commercialized. 

Reagents could react with different hydroxyls in different solvents. A typical example is the preparation of hydroxypropyl CD. In weak alkaline conditions, propylene oxide prefers to replace the 2-hydroxyl, 3-hydroxyl, but replaces the 6-hydroxyl in strong alkaline solution. This phenomenon is caused by reactivity and steric hindrance of the three free hydroxyl groups. In the selective modification, the substituents could partly replace the specific hydroxyl through the regulation of pH, modifiers, solvents (water, water-ethanol) and reaction time. 

A detailed photophysical study of the inclusion interaction of this drug and three CD (j6-CD, hydroxypropyl-/ -CD (HP-/5-CD) and carboxymethyl-/ -CD (CM-j6-CD)) was carried out [55]. Analysis of the data revealed the following inclusion ability j -CD > CM-jS-CD > HP-jff-CD. For P-CD complexes, a 1 2 (guest host) complex was suggested to form [55]. The authors concluded that the inclusion behaviour depends on the size fit between guest and host. Based on NMR data, Scheme 5 shows the proposed conformation modes of the piroxicam in the nanocavities [55]. Table 2 gives the apparent binding constants for the related complexes in aqueous acidic media. 

Derivatization of the structure of CDs at the hydroxyl groups represents an alternative route to improve their hydrosolubility and enhance enantioselectivity. For that purpose, several CD derivatives have been produced so far and used as CMPAs, for example, hydroxypropyl- -CD (HP- -CD) [17,18,24,30], hydroxyethyl-i8-CD (HE-i8-CD) [17,24], maltosyl-i8-CD (Malt-)8-CD) [22], dimethyl-i8-CD (DIME- -CD) [22], methyl-j8-CD (Met- -CD) [17], hydroxy-trimethylpropyl-ammonium- -CD (HTMA-j8-CD), carboxymethyl- -CD (CM- -CD), and malto-dextrins [18],... 

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