Ointments: towards the understanding of structure, stability and processing

The majority of the research on dermatological products and excipients was conducted before the 1980’s. Since then, the analytical techniques have significantly improved. Despite this increase in investigational possibilities, there is hardly any recent innovation in dermatological products. It is expected that a more thorough understanding of the physical properties of excipients and formulations will eventually lead to dermatological product innovation.

For one of the major ointment excipients, petrolatum (or Vaseline®), the critical properties were studied, such as its consistency. Synchrotron small- and wide-angle X-ray scattering, pulsed NMR, microscopy and rheometry were used to elucidate the petrolatum structure on nano-, micro- and macrometer scale. The combination of these techniques shows that petrolatum is composed of 21 % solid material at room temperature. This solid fraction consists of lamellar sheets which are packed in stacks. These lamellar sheets are formed during cooling. The rheological differences in petrolatum can be explained by the number of lamellar stacks present. When more lamellar stacks are present, the petrolatum is more rigid.

Furthermore, the influence of individual variables in the production process on ointment yield stress, a measure for spreadability, was studied. A design of experiments (DoE) approach was used. It was shown that by varying parameters in the production process substantial differences in the yield stress of the ointment were observed. Only 5 of the 14 produced batches were within the pre-defined requirements for yield stress. It was found that mixing rate and filling temperature significantly influence ointment yield stress (p = 0.0013 and 0.0065 respectively). The outcomes of this study were subsequently evaluated on industrial production scale. Similar impact of ointment filling temperature on product yield stress was found.

Additionally, the chemical stability of a corticosteroid, triamcinolone acetonide (TCA) in an ointment formulation was studied. The degradation mechanism of TCA and similar corticosteroids was elucidated. Interestingly, it is shown that the ointment excipients lanolin and petrolatum influence TCA degradation significantly. Lanolin and petrolatum contain small traces (few ppm) of metals such as copper, iron and nickel. These metals were shown to accumulate in the propyleneglycol phase in the ointment formulation. This is the phase in which TCA resides. The increase in trace metal content causes a significant increase in TCA degradation.

Furthermore, the degradation pathway for TCA was elucidated. The alcohol group in the 20-keto-21-hydroxyl sidechain of TCA first oxidizes to an aldehyde. This compound subsequently degrades to four other degradation products. Interestingly, the 20-keto-21-hydroxyl side chain is not unique for TCA but rather common for corticosteroids. Therefore, hydrocortisone (HC), desoximethasone (DS) and TCA were studied likewise. These all have the C17 bound 20-keto-21-hydroxyl group in common. However, in addition to the 20-keto-21-hydroxyl group, different groups are bound to this C17 atom. It was shown that this group influences both the qualitative and the quantitative degradation of these corticosteroids. In general, seven degradation products are formed for these corticosteroids. Especially HC was shown to degrade into the largest variety of degradation products (five in total) and generally showed the highest degradation constants.