OIL-IN-WATER CREAM STABILITY 217 CREAM PREPARATION Glyceryl monostearate, cetyl alcohol, Syncrowax ERL-C, and Amerchol L-101 were heated to 80ø-85øC in a suitable container with mixing to produce the oil phase. In a separate 10-gallon Groen kettle equipped with an Arde-Barinco homogenizer set at 3000 rpm, edetate disodium, sodium citrate, and sodium metabisulfite were dissolved in a mixture of purified water, Glucam E-20, Tween 60, and propylene glycol heated to 80ø-85øC. A dispersion of aluminum hydroxide in purified water (previously homoge- nized) was added to the aqueous solution and the combined aqueous phase heated to 90ø-95øC. The oil phase heated to 90ø-95øC was added to the aqueous phase at 90ø-95øC. The combined mixture was homogenized for 30 minutes at 90ø-95øC. The batch was cooled to 70ø-75øC by passing cooling water through the jacket of the kettle. Dimethicone was added and the batch was further cooled to 54ø-56øC with continuous homogeniza- tion. Batch weight was adjusted with purified water at this temperature, followed by further cooling to 50 ø- 52øC with homogenization. At the onset of congealing, homog- enization was discontinued. Slow-speed Groen mixing was used to cool the cream to 44øC, whereupon mixing was discontinued. The cream was allowed to cool to 25ø-30øC by standing overnight. In order to allow the addition of the active drug to the batch, a portion of the propylene glycol was retained. In the placebo batches made as part of this study, a portion of the propylene glycol was also retained so as to simulate the manufacture of an active batch. This portion of the propylene glycol was added to the cream base at 25ø-30øC and mixed at slow speed for 30 minutes. In order to determine the reproducibility of the physical properties of a cream batch type, preparations were performed at least in duplicate. Full physical characterization was performed on each preparation, and the data reported reflect averages of these determinations. WIRE-MESH BLEED TEST A 30-g sample of cream was spread evenly with a spatula onto a rectangular stainless 1', steel 30-mesh wire screen (13 X 13") supported by a 1-oz clear-glass jar (height 15/8 ", base diameter 15/8 ", neck diameter 13") contained within a 4-oz clear-glass jar (height 2_v, base diameter 7_v, neck diameter 2"). During the transfer of the cream sample onto 2' --4' the screen, very little sheer, if any, was applied and no mixing was performed. The 4-oz jar was covered with a tight-fitting liner cap and stored at 20ø-25øC for observations of separated liquid until no further bleed was observed. Any separated liquid was collected at the bottom of the jars. This liquid was then removed and quantitated by weight. The reported percent bleed was obtained by dividing the mass of collected liquid by the total mass of the cream sample used for the test. Each reported data point represents an average of four individual determinations. UNIVERSAL CONE PENETROMETER FOR MEASUREMENT OF CREAM CONSISTENCY A universal grease cone made of brass with a steel stem and needle tip (wt. 102.5 g), affixed to the base of a metal rod, was initially held in a stationary position with needle tip just in contact with the surface of the cream sample, contained in an aluminum cup

218 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS (83 ml volume). The cream sample was placed with a spatula into the aluminum cup without applying any significant shear to the product. When the release mechanism was activated, the needle tip cone was allowed to penetrate the sample for 5 seconds. Depth of penetration was then measured in scale units up to 380 on scale dial. Consis- tency measurement was reported as scale units for convenience but could also be con- verted to mm (each scale unit is equal to 0.1 mm). Each reported data point represents an average of three individual determinations. DSC MEASUREMENTS DSC measurements were obtained on the DuPont model 9900 thermal analysis system. 1-mg samples were accurately weighed into the DSC pan, and the pans were hermeti- cally sealed. Conventional DSC curves were obtained by heating the samples at a rate of 10øC/minute, up to a final temperature of 100øC. The DSC profiles of thermally pro- cessed glyceryl monostearate materials were obtained by heating the sealed sample only to 95øC, maintaining this temperature for 10 minutes, allowing the system to cool back to room temperature, and then obtaining a conventional DSC thermogram of this melted and congealed material. The melting points of the various materials were ob- tained as the temperature maxima associated with the DSC melting endotherms. X-RAY DIFFRACTION MEASUREMENTS Powder x-ray diffraction (XRD) measurements were obtained on a Philips model APD 3720 powder diffraction system, equipped with a vertical goniometer in the theta/2- theta geometry. The x-ray generator (Philips model XRG 31000) was operated at 45 kV and 40 ma, using the K-alpha line of copper at 1. 544056A as the radiation source. The sample was scanned between 2 ø and 32 ø 2-theta, at a scan rate of 0.04 ø 2-theta/sec, and in steps sizes of 0.04 ø 2-theta. The XRD powder patterns of melted and congealed glyceryl monostearate materials were obtained using the Anton-Parr XRD hot stage, with the x-ray data being collected as just described. The powder pattern of initial material was obtained, and then the stage was heated to 95øC. The glyceryl monostea- rate was held at this temperature for 10 minutes and then allowed to cool back to room temperature, whereupon the full XRD powder pattern was remeasured. CHEMICAL TESTS The determination of acid value, saponification value, ester value, and iodine value of each lot of glyceryl monostearate was performed as described in USP XXI. RESULTS AND DISCUSSION CREAM FORMULATED WITH U.S.-SOURCED RAW MATERIALS A thixotropic cosmetic oil-in-water type vanishing cream base vehicle for a topical drug product was formulated using commercially available U.S.-sourced raw materials. Pen- etrometer consistency results for the cream initially after manufacture were within the range of 260-295. After storage at 24 ø ___ 3øC for several weeks, the cream developed firmer consistency due to formation of the gel structure (1) and exhibited penetrometer