J. Cosmet. Sci., 64, 317–328 (September/October 2013) 317 Drug–excipient compatibility studies in binary mixtures of avobenzone RITA CERESOLE, YONG K. HAN, MARIA A. ROSASCO, LILIANA R. ORELLI, and ADRIANA SEGALL, Cátedra de Control de Calidad de Medicamentos (R.C., Y.K.H., M.A.R., A.S.) and Departamento Química Orgánica (L.R.O.), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Ciudad de Buenos Aires, Argentina. Accepted for publication February 25, 2013 Synopsis During preformulation studies of cosmetic/pharmaceutical products, thermal analysis techniques are very useful to detect physical or chemical incompatibilities between the active and the excipients of interest that might interfere with safety and/or effi cacy of the fi nal product. Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of avobenzone with some currently used cos- metic excipients. In the fi rst phase of the study, DSC was used as a tool to detect any interaction. Based on the DSC results alone, cetearyl alcohol, isopropyl myristate, propylparaben, diethylhexyl syringylidene malo- nate, caprylic capric triglyceride, butylated hydroxytoluene (BHT), glycerin, cetearyl alcohol/ceteareth 20, cetearyl alcohol/sodium lauryl sulfate/sodium cetearyl sulfate, and paraffi num liquidum exhibit interaction with avobenzone. Stressed binary mixtures (stored at 50°C for 15 days) of avobenzone and excipients were evaluated by high-performance liquid chromatography. Binary mixtures were further investigated by infra- red (IR) spectroscopy. Based on DSC, isothermal stress testing, and fourier transform infrared results avoben- zone is incompatible with caprylic capric triglyceride, propylparaben, and BHT. INTRODUCTION This work is part of an ongoing systematic study to fi nd and optimize a general method for the detection of drug–excipient interactions, with the aim of predicting rapidly and inexpensively the long-term stability of a cosmetic/pharmaceutical product and speed up its marketing. The study of drug–excipient compatibility represents an important phase in the preformulation stage for the development of a cosmetic/pharmaceutical form. In fact, potential physical and chemical interactions between actives and excipients can af- fect the chemical nature and the stability of a cosmetic product and, consequently, their effi cacy and safety. Among the different methods reported on drug–excipient’s compatibility studies, dif- ferential scanning calorimetry (DSC) has been shown to be an important tool at the outset Address all correspondence to Andriana Segall at asegall@ffyb.uba.ar.
JOURNAL OF COSMETIC SCIENCE 318 of any cosmetic/pharmaceutical product preformulation study to quickly obtain informa- tion about possible interactions among the formulation components according to appear- ance, shift, or disappearance of endothermic or exothermic peaks and/or variations in the corresponding enthalpy values in thermal curves of drug–excipient mixtures. Drug–excipient compatibility testing at an early stage helps in the selection of excipients that increase the probability of developing a stable dosage form (1–34). In particular, the low availability of the drug and the time constraints associated with the early stages of formulation development have made such predictability particularly desirable. Despite the importance of drug–excipient compatibility testing, there is no universally accepted protocol for this purpose. The term thermal analysis refers to a group of techniques in which a physical property of a substance and/or a reaction product is measured as a func- tion of temperature while the substance is subjected to a controlled temperature program. Differential scanning calorimeter (DSC) involves the application of a heating or a cooling signal to a sample and a reference. When the substance undergoes a thermal event, the difference in the heat fl ow to the sample and reference is monitored against time or tem- perature while the temperature is programmed in a specifi ed atmosphere. As a result, the energy associated with various thermal events (e.g., melting, glass transition, and crystal- lization) can be evaluated. This method has been extensively reported in the literature for testing compatibility of excipients with a number of drugs (1–34). Although DSC cannot replace chemical methods for quantitative determination of drug concentration in long- term stability test, it gives fast and adequate data to classify acceptable and unacceptable excipients through the appearance, shift, or disappearance of endothermic or exothermic peaks, as well as variations in the relevant enthalpy values in DSC profi les of drug–excipient combinations. Therefore, the results with the DSC method are comparable and in good agreement with the results obtained with other methods. DSC has, therefore, been proposed as a rapid method for evaluating physicochemical interactions between two components. However, caution needs to be exercised in the interpretation of DSC results. Interpretation of ther- mal data is not always straightforward and, to avoid misinterpretations and misleading of thermal analysis results, it must be emphasized that interactions observed at high tem- peratures may not always be relevant under ambient conditions. Moreover, the presence of a solid–solid interaction does not necessarily indicate incompatibility, but it might instead be advantageous, e.g., as a more desirable form of cosmetic/pharmaceutical for- mulation. DSC cannot replace chemical methods for quantitative determination of drug concentration in long-term stability tests. In this work, DSC was used as a screening technique for assessing the compatibility of avobenzone with some currently used cosmetic excipients. Isothermal stress testing (IST) is another method that involves storing the drug–excipient blends with or without moisture at high temperature to accelerate drug ageing and inter- action with excipients. The samples are then visually observed and the drug content is determined quantitatively. Stressed binary mixtures (stored at 50°C for 15 days) of avobenzone and excipients were evaluated by high-performance liquid chromatography (HPLC). Fourier transform infrared (FT-IR) spectroscopy is another approach used in compatibil- ity tests, based on the hypothesis that some functional groups change during drug– excipient interaction. In cases of suspected incompatibility, FT-IR spectrum of the pure
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