Cholesteryl myristate

Cholesteryl myristate [1989-52-2] M 597.0. Crystd from n-pentanol. Purified by column chromatography with MeOH and evaporated to dryness. Recrystd and finally, dried in vacuum over P2O5. [Malanik and Malat Anal Chim Acta 76 464 1975]. 

Liquid Crystals Liquid-crystal phases may occur between the solid and the liquid phase. Cholesteryl myristate, for example, exists in a liquid-crystal phase between 71 and 85°C [6]. The appearance of liquid-crystal phases depends on the molecular structure. Compounds with elongated structures that are fairly rigid in the central part of the molecule are likely candidates for liquid crystals. The homologous series of p-alkoxybenzylidene-p-n-butylanilines is just one example for compounds with liquid-crystal phases. An excellent introduction to liquid crystals and their properties has been written by Collings [6]. 

Price and Wendorff31 > and Jabarin and Stein 32) analyzed the solidification of cholesteryl myristate. Under equilibrium conditions it changes at 357.2 K from the isotropic to the cholesteric mesophase and at 352.9 K to the smectic mesophase (see Sect. 5.1.1). At 346.8 K the smectic liquid crystal crystallized to the fully ordered crystal. Dilatometry resulted in Avrami exponents of 2, 2, and 4 for the respective transitions. The cholesteric liquid crystal has a second transition right after the relatively quick formation of a turbid homeotropic state from the isotropic melt. It aggregates without volume change to a spherulitic texture. This process was studied by microscopy32) between 343 and 355.2 K and revealed another nucleation controlled process with an Avrami exponent of 3. 

Price, F. P. and Wendorff, J. H. Transitions in mesophase forming systems. I. Transformation kinetics and pretransition effects in cholesteryl myristate. J. Phys. Chem. 75, 2839 (1971)... 

Jabarin, S. A. and Stein, R. S. Light scattering and microscopic investigations of mesophase transitions of cholesteryl myristate. II. Kinetics of spherulite formation. J. Phys. Chem. 77, 409 (1973)... 

Figure 4.6-8 Optical rotation exhibited by a 0.2 mm thick sample of a mixture of cholesteryl chloride and cholesteryl myristate (molar ratio 1.67) at 1900 cm Scanning the temperature changes the pitch. At 59.5 °C the pitch corresponds to 1900 cm , at about 48 °C the twisting influences of the mixture components are mutually compensated so that the sample is nematic, at lower temperatures the structure is countercurrent. Above and below T em the rotatory dispersion follows a curve as derived by de Vries (1951).

The flow properties of cholesterics have scarcely been studied at all. Figure 10-26 shows one of the few sets of measurements of the viscosity of a cholesteric-forming small-molecule material, cholesteryl myristate, as a function of shear rate in flow through a eapillaiy at various temperatures (Sakamoto et al. 1969). As the temperature is lowered, cholesteryl myristate passes through isotropic, chiral nematir smectic, and nrystalline phases Figure... 

Figure 10.26 Viscosity versus shear rate of cholesteryl myristate in a cone-and-plate rheometer as a function of shear rate. At high temperatures, T > 83 C, the sample is a low-viscosity, Newtonian isotropic liquid. At intermediate temperatures, 83 > T > 78°C, the sample is a shear-thinning cholesteric. At low temperatures the sample is a shear-thinning smectic. (From Sakamoto et al., reprinted with permission from Mol. Cryst. Liq. Cryst. 8 443, Copyright 1969, Gordon and reach Publishers.)...

Craven, B. M., and DeTitta, G. T. Cholesteryl myristate structure of the crystalline solid and mesophases. J. Chem. Soc., Perkin Trans. 77,814-822 (1976). Templer, R., and Attard, G. The world of liquid crystals. The fourth state of matter. New Scientist 1767 25-29 (1991). 

Cholesteryl para-substituted benzoates give mesophases with transition temperatures and thermodynamic parameters which depend upon the para-substituent. " Crystal and mesophase structures of cholesteryl myristate appear to show some similarities in molecular packing. " X-Ray studies show that cholesteryl 17-bromoheptadecanoate crystals contain alternating regions with cholesterol and hydrocarbon-chain packing. ""... 

Cholesteryl myristate [1989-52-2] M 597,0, m 69-71°, [a] -25.4° (c 1, CHCI3). Crystallise the myristate ester from Me2CO, EtOH/EtOAc or EtOH/Et20 or n-pentanol. Purify it also by column chromatography on silica gel and eluting with MeOH then evaporating to dryness. Recrystallise it and finally, dry it in vacuo over P2O5 and store it at -20°. [Labariere et al. Analyt Chem 30 1466 1958, Malanik Malat Anal Chim Acta 76 464 1975, Beilstein 6 III 2638]. 

Fig. 4.1.16. Variation of inverse pitch with temperature in a 1.75 1 weight mixture of right-handed cholesteryl chloride and left-handed cholesteryl myristate as determined by laser diffraction. The mixture becomes nematic at 42 °C. (Sackmann...

Sackmann et have investigated the temperature variation of the pitch of a mixture of right-handed cholesteryl chloride and left-handed cholesteryl myristate by this method. At a certain temperature (7 ) there is an exact compensation of the two opposite helical structures and the sample becomes nematic. At this temperature only the central spot (zero order) is observed, while at the other temperatures, polarized diffraction maxima of higher order make their appearance. The inverse pitch varies almost linearly with temperature passing through zero at 7 (fig. 4.1.16). 

Fig. 4.5.6. Evidence of oscillatory behaviour in the variation of the apparent viscosity with temperature in a cholesteryl chloride-cholesteryl myristate mixture in the neighbourhood of the nematic point (see fig. 4.1.16). (After Bhattacharya,...

It is seen that for pitch values of the order of the sample thickness, t/ pp should exhibit oscillatory behaviour with varying pitch because of the term sin qh/qh in (4.5.30). A representative theoretical curve is presented in Fig. 4.5.5. This prediction has been verified qualitatively." Measurements of the apparent viscosity on the cholesteryl chloride-cholesteryl myristate mixture, whose pitch, as we have seen earlier, is sensitive to temperature (fig. 4.1.16), showed evidence of oscillations as the temperature was varied (fig. 4.5.6). 

Fig. 5.2.6. Measured intensity of X-ray scattering at the Bragg angle versus temperature for cholesteryl myristate. The dashed line is the calculated diffuse scattering and fluctuation scattering contribution. The full lines represent the theoretical curves for the total intensity due to Bragg, diffuse and fluctuation scattering derived from (a) the simpler model potential and (b) the refined one. The theoretical intensity has been adjusted to be equal to the experimental value at the lowest temperature. (After McMillan." )...

Fig. 5.3.7. Apparent viscosity versus shear rate for cholesteryl myristate at different temperatures full line, smectic A dashed line, cholesteric chain line, isotropic. (After Sakamoto, Porter and Johnson.

Mixture of 1.75 parts of cholesteryl chloride and 1 part of cholesteryl myristate by weight. 

FIG. 4. Variation of the birefringence factor a as a function of temperature at 6328 A for the mixture of cholesteryl chloride and cholesteryl myristate (1.75 1 by wieght). The solid curve is a smooth fit to the data points. 

Figure 10.9. DSC heating and cooling curves (5°C/min) of cholesteryl myristate in the bulk and in colloidal dispersion (5% CM, 2% PVA PCS z-average 172 nm, PDI 0.09). With kind permission from Springer Science + Business Media Fharm. Res. Supercooled smectic nanoparticles A potential novel carrier system for poorly water soluble drugs, 21, (2004), 1834-1843, J Kuntsche et al. Abbreviations DSC differential scanning calorimetry, PVA polyvinyl alcohol, PCS Photon correlation spectroscopy, PDI Polydispersity index.

Figure 10.10. Particle size (PCS) of 5% cholesteryl myristate dispersions stabilized with 3.2% purified soy bean phospholipid and 0.8% sodium glycocholate (SIOO/SGC), 4% pxjlyvinyl alcohol (PVA), poloxamer (POL) or poloxamine (TET). Data from Ref. 108...

Figure 10.12. Small (SAX) and wide (WAX) angle X-ray diffracion pattern of cholesteryl myristate dispersions stored at 23°C and 4°C and measured at 20°C (s=l/d=2sin6 /A where 29 is the scattering angle and A is the wavelength, equal to 0.15 nm). Data from reference 85.

As the supercooled smectic state is metastable, the recrystallization tendency of the nanoparticles during storage is of high interest. Due to its completely reversible phase behavior and favorable crystallization temperature in the colloidal state, cholesteryl myristate was used as model cholesterol ester for investigations of the recrystallization tendency and influencing parameters like particle size and stabilizer system. 

The smectic state of the nanoparticles can be confirmed by DSC scans (absence of the melting transition of the crystalline lipid upon heating of the respective dispersion) and X-ray diffraction (occurrence of the characteristic small angle reflection of the smectic phase, absence of any reflections due to crystalline material [Fig. 10.12 ]). Even small amounts of recrystallized material (< 1% of the incorporated cholesterol ester) could be detected in DSC for e.g. a 5% dispersion by comparison of the melting enthalpies of the 1st and 2nd heating run. While cholesteryl myristate nanoparticles retain the smectic state when stored at room temperature over a considerable period of... 

Table 10.3 Particle size (PCS) and amount of recrystallized matrix lipid in 5% cholesteryl myristate dispersions stabilized with different emulsifiers after storage for 8 or 9 months.

The stabilizer system strongly influences the crystallization tendency of cholesteryl myristate nanoparticles. Phospholipids and other emulsifiers containing fatty acid chains seem to promote recrystallization whereas the recrystallization tendency of nanoparticles stabilized with polymeric stabilizers like poloxamer and polyvinyl alcohol during storage was much lower in... 

Cholesteryl myristate nanoparticles are excellent model systems to study the phase behavior and influencing parameters like particle size and stabilizer system, but are not applicable as robust drug carrier system due to their relatively high crystallization temperature (above or around 0°C). As storage at 4°C appears advantageous with respect to the chemical stability of the dispersions a robust formulation should allow long-term storage at this temperature without nanoparticle crystallization. 

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