j. Soc. Cosmet. Chem., 40, 215-229 (July/August 1989) Effects of variations in physicochemical properties of glyceryl monostearate on the stability of an oil-in- water cream R. O'LAUGHLIN, C. SACHS, H. BRITTAIN, E. COHEN, P. TIMMINS, and S. VARIA,* The Squibb Institute for Medical Research, New Brunswick, NJ 08903-0191 (R.O., C.S., H.B., E.C., S. V. ), and International Development Labs, E. R. Squibb & Sons, Reeds Lane, Moreton, Merseyside, U.K. (P.T.). * To whom correspondence should be addressed. Received March 22, 1989. Synopsis During the development of an oil-in-water cream formulation, syneresis of the aqueous phase was observed. A quantitative syneresis test was devised to study the separation of the aqueous phase. Variations in the physical and chemical characteristics of glyceryl monostearate obtained from various sources were identified as the principal factors influencing syneresis of the formulation. A group of diagnostic tests, including variable temperature x-ray diffraction analysis developed for screening various lots of glyceryl monostearate, was used to successfully predict the possibility of the occurrence of syneresis in a cream batch. The acid value of the various lots of glyceryl monostearates correlated well with the propensity of the cream to produce syneresis. Increasing the acid value of the glyceryl monostearate by the addition of small amounts of fatty acids eliminated the observed syneresis. Further, the storage temperature had a profound effect on the syneresis and consistency. INTRODUCTION Pharmaceutical cream bases are essentially semisolid emulsion systems that appear "creamy white" due to reflection of light by the internal dispersed phase. The most common creams are oil-in-water emulsion systems, whose structure or semisolid char- acter is dependent upon emulsified liquid droplets or particles that comprise the in- ternal phase. Creams are usually prepared at high temperature (fusion method) using internal-phase materials such as mineral or vegetable oils, liquid emollient esters, solid long-chain fatty acids, alcohols, and esters. Upon cooling, these ingredients exist as dispersed or emulsified microscopic droplets, liquid crystals, solid particles, or spheres, creating a three-dimensional gel structure or matrix that entraps the aqueous external phase (1,2). In many formulations the gel structure may be metastable. Creams are dynamic compositions that are influenced by temperature storage and shear forces. The gel structure may stiffen, contract, and shrink at cold temperatures, or soften, expand, and fluidize at warm temperatures. Gel structure may be broken down due to shear thinning by mechanical mixing, pumping, or rubbing. Many creams possess thixo- tropic properties that allow recovery of gel structure upon storage after exposure to shear thinning. 215

216 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Some of the general indications of emulsion instability are: 1. Inversion of emulsion type (e.g., oil-in-water emulsion changes to water-in-oil type emulsion or vice versa) 2. Coalescence of dispersed internal-phase droplets, globules, spheres, or particles 3. Phase separation characterized by liquid "bleed" or syneresis 4. Decrease in viscosity or loss of consistency resulting in softness or fluidity External factors such as packaging, storage time, temperature conditions, and shear forces may induce emulsion instability. Internal factors of cream composition related to variability of the excipients or raw materials and their source may also affect emulsion stability and cream consistency. Most commercially available cosmetic raw materials used in oil-in-water emulsion-type creams are not pure excipients, but mixtures of two or more components. Some are complex mixtures that may vary depending on the vendor source. Glyceryl monostea- rate is an excellent example of a commonly used cream excipient that exhibits a wide range of variability in its constituent composition, and also in its effect on the consis- tency and quality of the finished cream formulation (3). Glyceryl monostearate is a mixture of the monoglycerides of stearic and palmitic acids, together with variable quantities of di- and triglycerides. It usually contains not less than 90% of total fatty acid glycerides, of which at least 35% are monoglycerides (4). Small quantities of free stearic, palmitic and oleic acids, glycerol, water, and oleate,esters may also be present. Since glyceryl monostearate is used mainly as an emollient lipophilic thickening agent and stabilizer for oil-in-water and water-in-oil emulsion-type creams and lotions, vari- ability of this raw material can result in manufacturing problems. This report discusses some of the causes resulting in soft consistency and syneresis encountered during the scale-up phase of development for an oil-in-water emulsion cream product, when raw materials from multiple vendor sources were used. The main objectives of the present work were: 1. Investigate the cream formulation and its method of manufacture to determine the cause of the soft consistency and syneresis 2. Identify test methods to evaluate cream consistency and syneresis potential 3. Identify methods to test the raw materials to predict their propensity to cause soft cream consistency and syneresis 4. Recommend options to the manufacturing plants to overcome variable cream con- sistency and syneresis problems EXPERIMENTAL MATERIALS Glyceryl monostearate NF XII, cetyl alcohol NF, Syncrowax ERL-C (ethylene glycol ester of C18-36 wax fatty acids), Amerchol L-101 (mineral oil and lanolin alcohol), Glucam E-20 (methyl gluceth-20), Tween 60 (polysorbate 60 NF), propylene glycol U.S.P., sodium citrate U.S.P., edetate disodium U.S.P., sodium metabisulfite NF, aluminum hydroxide wet gel, dimethicone, and purified water U.S.P. were used as received. These materials were obtained from a variety of sources.