Compendium of the most significant studies with reference to properties, intake, effects.

Rowe RC, Patel HK. The effect of temperature on the conductivity of gels and emulsions prepared from cetrimide and cetostearyl alcohol. J Pharm Pharmacol. 1985 Aug;37(8):564-7. doi: 10.1111/j.2042-7158.1985.tb03068.x. 

Abstract. The conductivity of gels and emulsions containing cetrimide, cetostearyl alcohol, liquid paraffin and water has been studied over the temperature range +35 to -10 degrees C. All samples froze at temperatures below -5 degrees C and exhibited hysteresis on rewarming to room temperature with an initial increase in conductivity up to 15 degrees C followed by a decrease to 25 degrees C. The amount of hysteresis was dependent on the cetostearyl alcohol content and appeared to be related to changes in the microstructure of the liquid crystalline network.

Urbanetz NA. Stabilization of solid dispersions of nimodipine and polyethylene glycol 2000. Eur J Pharm Sci. 2006 May;28(1-2):67-76. doi: 10.1016/j.ejps.2005.12.009.

Abstract.  Previous investigations revealed that solid dispersions consisting of 20% (m/m) nimodipine and 80% (m/m) polyethylene glycol 2000 prepared by the melting method, represent supersaturated solid solutions of nimodipine recrystallizing upon storage at +25 degrees C. The objective of this study was the improvement of the storage stability by preventing recrystallization. The first approach in order to prevent recrystallization was the development of thermodynamically stable solid solutions by using solvents aiming to enhance the solubility of nimodipine in the carrier material. As potential solubility enhancing additives, polyethylene glycol 300, poly(ethylene/propylene glycol) copolymer, polypropylene glycol 1020, propylene glycol, glycerol and ethyl acetate were evaluated. The second approach enhancing storage stability was the addition of recrystallization inhibitors to supersaturated solid solutions, thereby delaying the transformation of the metastable supersaturated system to the thermodynamically stable state. Macrogol cetostearyl ether, macrogol glycerol monostearate, polysorbate 60, cetostearyl alcohol, glycerol monostearate and sodium lauryl sulphate as well as hydroxypropylcellulose, butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmethacrylat-copolymer, polyacrylic acid, polyvinyl alcohol and povidone K17 were included in the study. It could be shown that povidone K17 effectively prevents recrystallization in solid solutions containing 20% (m/m) of nimodipine during storage at +25 degrees C over silica gel thereby ensuring a substantial increase in the dissolution rate and degree of supersaturation in water. On the contrary, stabilization by solubility enhancement was only successful at drug loadings not exceeding 1% (m/m) using polyethylene glycol 300 as solubility enhancing additive.

Meira RZC, Biscaia IFB, Nogueira C, Murakami FS, Bernardi LS, Oliveira PR. Solid-State Characterization and Compatibility Studies of Penciclovir, Lysine Hydrochloride, and Pharmaceutical Excipients. Materials (Basel). 2019 Sep 27;12(19):3154. doi: 10.3390/ma12193154.

Abstract. The physical and chemical characterization of the solid-state properties of drugs and excipients is fundamental for planning new formulations and developing new strategies for the treatment of diseases. Techniques such as differential scanning calorimetry, thermogravimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy are among the most commonly used techniques for these purposes. Penciclovir and lysine are individually used to treat the herpes virus. As such, the development of a formulation containing both drugs may have therapeutic potential. Solid-state characterization showed that both penciclovir and lysine were crystalline materials with melting points at 278.27 °C and 260.91 °C, respectively. Compatibility studies of penciclovir and lysine indicated a possible interaction between these substances, as evidenced by a single melting point at 253.10 °C. The compatibility of several excipients, including ethylenediaminetetraacetic acid, cetostearyl alcohol, sodium lauryl sulphate, di-tert-butyl methyl phenol, liquid petrolatum, methylparaben, nonionic wax, paraffin, propylene glycol, and propylparaben, was evaluated in ternary (penciclovir-lysine-excipient) mixtures (1:1:1, w/w/w) to determine the optimal formulation. The developed formulation was stable under accelerated and ambient conditions, which demonstrated that the interaction between penciclovir and lysine was suitable for the development of a formulation containing both drugs.

 Ferrari PC, Correia MK, Somer A, Ribeiro MA, Astrath NGC, Sato F, Novatski A. Hesperidin-Loaded Solid Lipid Nanoparticles: Development and Physicochemical Properties Evaluation. J Nanosci Nanotechnol. 2019 Aug 1;19(8):4747-4757. doi: 10.1166/jnn.2019.16355.

Abstract. Although nanocarrier systems have been investigated to function as therapeutic delivery agents to specific sites of the body, the drug encapsulation method is not always well elucidated. In this work, solid lipid nanoparticles (SLN) composed by stearic acid or cetostearyl alcohol were prepared by a hot homogenization method using poly(vinyl alcohol) or polysorbate as surfactant and loaded with hesperidin, a bioflavonoid that possesses many pharmacological properties. The obtained SLN were characterized by several physicochemical techniques to identify interactions between the constituents and to evaluate the drug incorporation into the nanoparticles. According to scanning electron microscopy and dynamic light scattering the hesperidin-loaded and unloaded SLN have spherical shapes, sizes ranging from 300 to 600 nm, zeta potentials varying from -35 to -20 mV, polydispersity indexes between 0.240 and 0.445, and entrapment efficiencies higher than 88%. X-ray diffraction showed the hesperidin amorphization due to its encapsulation in SLN, and also showed crystallization degree and polymorphic modification of the lipids after the SLN preparation. FTIR, Raman and Photoacoustic spectroscopy revealed no chemical reactions between drug and lipids, however, these results indicated that the drug was incorporated differently into nanoparticles based on the SLN composition. The analysis showed that stearic acid-based SLN prepared with polysorbate were more efficient to enclosure the hesperidin while the glycosydic part of the hesperidin was not entrapped in the cetostearyl alcohol-based SLN; instead, the hesperidin remained on the SLN surface due to lipid crystallization. The physicochemical characterization allowed identifying different types of hesperidin incorporation into the SLN, which can interact in a varied manner as targeted drug delivery systems.

Martinelli F, Balducci AG, Kumar A, Sonvico F, Forbes B, Bettini R, Buttini F. Engineered sodium hyaluronate respirable dry powders for pulmonary drug delivery. Int J Pharm. 2017 Jan 30;517(1-2):286-295. doi: 10.1016/j.ijpharm.2016.12.002.

Abstract. Sodium hyaluronate (HYA) warrants attention as a material for inhalation due to its (i) therapeutic potential, (ii) utility as a formulation excipient or drug carrier, and (iii) ability to target lung inflammation and cancer. This study aimed to overcome formulation and manufacturing impediments to engineer biocompatible spray-dried HYA powders for inhalation. Novel methodology was developed to produce HYA microparticles by spray drying. Different types of surfactant were included in the formulation to improve powder respirability, which was evaluated in vitro using cascade impactors. The individual formulation components and formulated products were evaluated for their biocompatibility with A549 respiratory epithelial cells. The inclusion of stearyl surfactants, 5% w/v, produced the most respirable HYA-powders; FPF 59.0-66.3%. A trend to marginally higher respirability was observed for powders containing stearylamine>stearyl alcohol>cetostearyl alcohol. Pure HYA was biocompatible with A549 cells at all concentrations measured, but the biocompatibility of the stearyl surfactants (based on lethal concentration 50%; LC50) in the MTT assay ranked stearyl alcohol>cetostearyl alcohol>stearylamine with LC50 of 24.7, 13.2 and 1.8μg/mL, respectively. We report the first respirable HYA powders produced by spray-drying. A lead formulation containing 5% stearyl alcohol was identified for further studies aimed at translating the proposed benefits of inhaled HYA into safe and clinically effective HYA products. Crown Copyright © 2016. 

Waters LJ, Pavlakis E. In vitro controlled drug release from loaded microspheres--dose regulation through formulation. J Pharm Pharm Sci. 2007;10(4):464-72. doi: 10.18433/j3cc7t.

Abstract. Purpose: Drug release profiles were established for ibuprofen encapsulated within several types of microspheres and a range of dissolution buffer media to study the effect these variables have in controlling the rate and extent of drug release. Methods: Fatty acid microspheres containing ibuprofen were prepared by a process previously developed and refined to produce microspheres of a known size and composition, namely 80-125 mum diameter and an excipient to ibuprofen ratio of 3:1. Drug release profiles from these encapsulated formulations were compared with those obtained for the dissolution of ibuprofen alone under the same conditions. Results: Stearic acid microspheres were found to only partially retard the release of ibuprofen over a twenty minute period compared with the dissolution of ibuprofen alone. However, a significant retardation of ibuprofen release was observed with cetostearyl alcohol microspheres over the same period of time. Secondly, drug release profiles for encapsulated ibuprofen were determined using five distinct dissolution buffer media; sodium phosphate, potassium phosphate, citric acid and phosphate mix, MOPS and tris. Significant differences in the extent and rate of drug release were recorded between the different dissolution buffer solutions. These differences were also shown to be independent of variations in pH, temperature, buffer concentrations and the type of cations present. Conclusions: The presence and choice of microsphere formulation, and the choice of buffer present in the dissolution solution, can influence drug release in vitro, i.e. it is possible to achieve controlled drug release from microspheres. To explain the control achieved through the choice of buffer in solution it is proposed that the buffer anion exerts a stabilising influence on the ibuprofen-microsphere matrix.

Hong L, Altorfer H. Radiolysis characterization of cetostearyl alcohol by gas chromatography-mass spectrometry. J Pharm Biomed Anal. 2003 Mar 26;31(4):753-66. doi: 10.1016/s0731-7085(02)00658-1.

Abstract. Methods for sample preparation, assay test and impurity test were established. Degrees of cetostearyl alcohol (CSA) radiolyses in pure state, ointment base and in chloramphenicol eye ointment (CAPEO) were determined at doses of 25 and 50 kGy. Radiolyses of CSA occur in all cases. The degrees are directly proportional to the irradiation dose in each case. Forty-two impurities and radiolysis products were identified using gas chromatography-mass spectrometry. The radiolysis products were assigned to be n-alkane, n-aldehyde and 2-methyl-1-alcohol. Accordingly, the degradation pathways of cetosteary alcohol were elucidated. Radiolysis behaviors of CSA in pure state, eye ointment base and CAPEO were studied by assay and impurity analyses. The influence of eye ointment matrixes is modest and chloramphenicol molecule exhibits slight scavenger function for cetostearyl. Both qualitative and quantitative data confirm that the radiolysis products of CSA do not cause safety concerns for human use.

Patel HK, Rowe RC, McMahon J, Stewart RF. An investigation of the structural changes occurring in a cetostearyl alcohol/cetrimide/water gel after prolonged low temperature (4 degrees C) storage. J Pharm Pharmacol. 1985 Dec;37(12):899-902. doi: 10.1111/j.2042-7158.1985.tb04997.x.

 Abstract. Structural changes in a ternary gel prepared using the mixed emulsifier system of cetrimide and cetostearyl alcohol after prolonged low temperature (4 degrees C) storage have been studied using freeze-etch transmission electron microscopy and other techniques. The system changed from an opaque smooth gel of high viscosity, low conductivity and low free water, to a pearlescent milky lotion of low viscosity, high conductivity and high free water. Subsequent equilibration of the thinned system to room temperature (25 degrees C) over 48 h produced an opaque granular gel of similar consistency, but slightly higher conductivity and higher free water than the initial sample. Microscopical examination by both differential interference contrast and freeze-etch electron microscopy showed the system changed from one consisting of a liquid crystalline network localized around cetostearyl alcohol particles, to a system consisting of large waxy plates coexisting with some residual liquid crystalline network. A supportive mechanism for the thinning of the ternary gel at prolonged low temperature storage has been inferred by comparing data with that produced by other workers studying the fusion of phospholipid membranes considered to be morphologically similar to the liquid crystalline network observed in this ternary gel.

Mace AW. The composition of cetostearyl alcohol. J Pharm Pharmacol. 1975 Mar;27(3):209-11. doi: 10.1111/j.2042-7158.1975.tb09443.x.