Randomly methylated

Random methyl branch placement on the polyethylene backbone... 

Figure 8.12 Precise vs. random methyl placement in polyethylene. [Reproduced with permission from Macromolecules, 33, 3781-3794 (2000). Copyright 2000, American Chemical Society.]...

In this study, complexation of A9-THC and cannabidiol (prepared by freeze drying) with randomly methylated b-cyclodextrin and hydroxypropyl-b-cyclodextrin (HP-fi-CD) was studied by the phase-solubiHty method. The aqueous solubility of CBD and THC increased as a function of CD concentration, and the dissolution increased for THC and CBD cyclodextrin complexes significantly in contrast to plain THC and CBD. These results demonstrate that cyclodextrins increased both the aqueous solubility and dissolution rate... 

The ORAC assay proposed by Ou and others (2001) is limited to hydrophilic antioxidants because of the aqueous environment of the assay. However, lipophilic antioxidants play a critical role in biological defense systems. Huang and others (2002) expanded the assay to the lipidic fraction by introducing a randomly methylated 13-cyclodextrin (RMCD) as a water-solubility enhancer for lipophilic antioxidants. Various kinds of foods, including fruit juices and drinks, fruits, vegetables, nuts, and dried fruits, have been evaluated with this method (Zhou and Yu 2006 Wu and others 2004 Kevers and others 2007 Wang and Ballington 2007 Almeida and others 2008 Mullen and others 2007). 

Huang D, Ou B, Hampsch-Woodill M, Flanagan JA and Deemer EK. 2002. Development and validation of oxygen radical absorbance capacity assay for lipophilic antioxidants using randomly methylated (3-cyclodextrin as the solubility enhancer. J Agric Food Chem 50(7) 1815-1821. 

Chemical modification of cyclodextrins is achieved through reactions of their hydroxyl groups. Of the 21 hydroxyls ofP-CD, the seven primary ones (C-6) can easily be reacted. In addition, the C-2 secondary hydroxyl groups are also fairly reactive while the ones at C-3 resist modification (e.g. by methylation). Several CD derivatives are available commercially in large quantities including -among others- randomly methylated P-cylodextrin and hydroxypropyl-P-cylodextrin [2]. Chemical modifications substantially alter the solubility of cyclodextrins in water. For example, the solubility of P-CD... 

We begin with an excerpt from Environmental Science Technology (excerpt 4B). In a combined R D section, the authors tell us what happened when they coated different types of soil with randomly methylated P-cyclodextrins (RAMEB). Cyclodextrins are highly water-soluble, crystalline sugars their shape (referred to as toroidal) resembles a water pail without a bottom. The outer surfaces of the pail are hydrophilic (water-loving), which accounts for their solubility in water and their ability to attract water molecules. RAMEB alone adsorbs water molecules hence, the authors predicted that RAMEB-coated soils would adsorb more water than their noncoated counterparts. 

Let s begin with the excerpt on randomly methylated P-cyclodextrin (RAMEB)-enriched soils in chapter 4 (excerpt 4B). The authors use an iterative R D approach They state their first result (Rl), pertaining to clay-rich soils, and then immediately offer an interpretation (Dl) of that result. This is followed by a result and interpretation for clay-poor soils (R2D2) and a result and interpretation for medium-clay-content soils (R3D3). Thus, the result-discussion sequence is iterated three times. In each case, the discussion immediately follows the result hence, submove 1.1 (which reminds readers of the result) is not needed. 

P16 Two CD derivatives are most commonly used for soil remediation hydroxypropyl and random methylated P-cyclodextrins (HPBCD and... 

The experimental desorption isotherms for randomly methylated -cyclodextrin (RAMEB) and RAMEB-enriched minerals are presented in Figure 1. The isotherms were measured for the RAMEB in the forms of powder and crystals however, these were the same within the range of experimental error. (From Jozefaciuk et al., 2001)... 

Jozefaciuk, G. Muranyi, A. Fenyvesi, E. Effect of Randomly Methylated P-Cyclodextrin on Physical Properties of Soils. Environ. Sci. Technol 2003, 37, 3012-3017. 

Many CDs have been successfully used to solubilize insoluble drugs, here are a partial list of CD derivatives reported in the literature fflFCD, SBE-ft-CDs, randomly methylated-P-cyclodextrin (RM-p-CD), 2,3,6-partially methylat flcyclodextrin (PM-ft-CD), glucosyl-ft-CD (G1-P-CD), maltosyl-p-cyclodextrin (G2- -CD), hydroxyethyl-p-cyclodextrin (He-p-CD), diethyl-P-cyclodextrin (DE-p-CD)P-carboxymethyl-Qethyl- -cyclodextrin (CME-p-CD), and (2,6-oG>-methyl)-p-cyclodextrin (DOM-p-CD). 

Methylated derivatives are also highly soluble in water. The major methylated derivatives are the 2,6-dimethyl, 2,3,6-trimethyl and randomly methylated derivatives. The dimethyl and trimethyl derivatives are the derivatives most frequently described in the literature. The main advantage of the randomly methylated derivatives is lower cost. Production of the dimethyl and trimethyl derivatives involves several purification steps. Due to the random substitution and mixture of constituents, the randomly substituted derivatives are more soluble than the dimethyl and trimethyl derivatives. All methyl ethers have a decreased solubility at higher temperatures, similar to the behavior of other methylated carbohydrates. 

Scheme 5 Random methyl branching in polyethylene (from [72])...

Among the cyclodextrins, the use of DMpCD was shown to have the highest effect on the transnasal bioavailability of insulin in rats. Several studies reported on their concentration-dependent effect. Besides for peptides, the methylated p-cyclodextrins have shown to be useful in nasal delivery of lipophilic drugs. The toxicological profile of dimethyl p-cyclo-dextrins and of randomly methylated p-cyclodextrins appeared excellent. Attention should be paid, if possible, onbioavailability differences between animal and human models. 

The main derivatives under development as excipients are all derivatives of p-CD 1) a randomly methylated derivative with an average MS of 14 (M14-p-CD) 2) two different 2-hydroxypropyl derivatives, one with an average MS of approximately 3 ((2HP)3-p-CD) and the other with an average MS of 7 ((2HP)7-p-CD) and 3) a sulfobutyl ether derivative with an average MS of 7 (SBE7-p-CD). Glucosyl and maltosyl CDs which contain a mono- (Gi-p-CD) or disaccharide (G2-P-CD) substituent, have also been reported and show promise for the future. 

The aqueous solubility of these derivatives is adversely affected by temperature, however, and precipitation occurs during heat sterilization. The mixture of randomly methylated p-CD (M14-p-CD), however, exhibits a favorable water solubility (>50g/ 100ml) that increases as temperature increases. ... 

The mixture of randomly methylated p-CD, although partially derivatized at the 3-position, still maintains the favorable binding characteristics of 2,6-DM14-p-CD. One report demonstrated that M14-p-CD solubilized 26 drugs more effectively than p-CD and the extent of solubilization was on average 80% of that observed for the purified 2,6-DM-p-CD preparation. 

Finally, it has recently been reported that aqueous ATRP can be carried out conveniently in water in the presence of cyclodextrins [227]. Complexation by a randomly methylated yS-cyclodextrin rendered the catalyst CuBr/dNbpy fully water soluble, and allowed for the controlled polymerization of MMA at 80 °C in water. Due to the presence of the cyclodextrin, the monomer too is water soluble, but the PMMA polymer formed (M = 3.8x10" g moh, ATv/Mn=1.3) is insoluble. In this respect, this type of polymerization is akin to a precipitation polymerization. Further growth of a styrene block on the PMMA chain is possible, albeit the blocking efficiency was limited. 

In this section, an example case on the use of spray drying to prepare inclusion complex powders with randomly methylated P-CD (RM-P-CD) is given. The inclusion complexes were subjected to release experiments under constant RH and temperature, to investigate the effects of the two parameters on the release rates. 

Me randomly-methylated DM 2,6-di-O-methyl TM per-2,3,6-tri-0-methyl DMA peracetylated DM- -CyD 2-HE 2-hydroxyethyl 2-HP 2-hydroxypropyl 3-HP, 3-hydroxypropyl 2,3-DHP, 2,3-dihydroxypropyl Gi, glycosyl G2, maltosyl GUG, Glucuronyl-glucosyl DE 2,6-di-O-ethyl TE per-2,3,6-tri-0-ethyl CME O-carboxymethyl-0-ethyl TA per-2,3,6-tri-O-acyl (C2 Cig) TB per-2,3,6-tri-0-butanoyl TV per-2,3,6-tri-O-valeryl TO per-2,3,6-tri-0-octyl SBE4 d.s.4 of sulfobutyl ether group SBE7 d.s.7 of sulfobutyl ether group. Oi 25969 octasodium salt of octakis-S-(2-carboxyethyl)-octathio-y-CyD. 

Figure 4.7 Suzuki-reactions mediated by P-CD or Randomly Methylated CD (RM-P-CD) in the presence of metal catalyst in aqueous solution, a R = NO2, OH, OCH3, COCH3,...

A partieular methylated pCD, the heptakis (2,6-di-O-methyl-pCD, ealled DIMEB) is a erystalline produet. It is extremely soluble in eold water but insoluble in hot water, therefore, its purifieation, and also the isolation, of its complexes is teehnieally simple. Up to now, no better solubilizer was found among the CDs. It is available in better than 95% isomerie purity for injectable drug formulation. but for widespread industrial applieation, the cheaper randomly methylated pCD (called RAMEB) is produced and marketed. 

The catalytic performance of pendant poly (A -acryloyloxysuccinimide) (poly-NAS) bearing monoamino randomly methylated (3-CD (RAME-(3-CD—NH2) and ethanolamine (Scheme 2.11) was evaluated in aqueous Rh-catalyzed... 

CD-grafted polymers synthesized from poly(iV-acryloxysuccinimide) (poly-NAS), mono-amino randomly methylated p-CD (RAME-p-CD— NH2), and pendant water-soluble phosphane moieties were also used as additives in the aqueous Rh-catalyzed hydroformylation of 1-hexadecene [25]. Within these polymers, both the supramolecular properties of the CD and the coordination ability of the phosphane were combined into the same molecular object. The catalytic results show that increasing the local concentration of the metal-phosphane complex and the CDs at the water/organic interface improves the reaction conversion. The explanation is that—after recognition of the substrate by the CDs, and as they are both graft on the polymer (CD and phosphane)—they... 

Ruthenium on charcoal and randomly methylated p-cyclodextrin has been used as a recyclable catalyst system to form Qxs in water from benzoin and 1,2-diamines (Scheme 2.12) [88]. Molecular oxygen has been used perhaps to facilitate in situ formation of the 1,2-diketone from the benzoin and the final delydrogenation. 

As Monflier and coworkers [48] have shown, the rhodium-catalyzed hydroformylation of triglycerides in water pressure can be supported by the addition of randomly methylated P-cyclodextrines (RAME-P-CDs). Syngas pressure (20-80 bar), temperature (50-80 °C), nature of the sulfonated phosphine ligand, and the amount of R AME-P-CD had a profound influence of the catalytic results. 

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