ABSTRACT: The transformations of tristearin were examined by modulated temperature differential scanning calorimetry (MTDSC) in order to study the effect of operational parameters on the nature of information obtained from this technique. Tris- tearin has been used as a model polymorphic system showing metastable phases and complicated transformation routes oc- curring at relatively slow rates. The parameters examined were underlying heating/cooling rates and the amplitude of modula- tion. The first conclusion is that MTDSC enables overlapping α- melting and β-crystallization events to be separated, thus in- creasing the information obtained compared to normal thermal analysis. Other general conclusions are that observation of re- versible processes is strongly influenced by the underlying heat- ing rate; low to moderate heating rates are recommended. Am- plitude of modulation has a complicated effect on the phenom- enon being studied; when studying systems that exhibit metastable or polymorphic transitions, it is recommended that a range of amplitudes be tested to enable confirmation of whether an observed “recrystallization” effect is a new phase or the same phase as the one melting. Cooling with modulation disturbs the crystallization process, possibly leading to smaller or imperfect crystals; however, the phases obtained are not dif- ferent compared to normal DSC. The usefulness of MTDSC in analyzing these types of complicated systems is primarily quali- tative at the moment. Some recommendations have been made as to the combinations of parameters for studying such systems. Paper no. J8832 in JAOCS 76, 499–505 (April 1999) KEY WORDS: Differential scanning calorimetry, metastable forms, MTDSC, modulated temperature, oscillating, phase be- havior, polymorphism, triglycerides, tristearin. Lipids are important excipients in the pharmaceutical industry, finding use as matrix formers, binders, lubricants, etc. The major components of these commercial excipients obtained from nat- ural fats are blends of triglycerides. Pure monoacid triglycerides can serve as simple models for studying these blends. The physical properties of triglycerides are mostly deter- mined by their complex polymorphism. Generally, triglyc- erides exhibit three different polymorphic forms character- ized by particular chain packing and thermal stability: alpha (α), beta-prime (β′), and beta (β). The transformations are monotropic and theoretically take place from α to β′ to β (1). The different polymorphic forms of triglycerides have been extensively studied (1–6), and the transformations are summarized in Figure 1. The melt crystallizes primarily into the α form on cooling, although special thermal treatment or very slow cooling can lead to the formation of the β′ or β form, respectively (7,8). The transformation from the metastable α form to the most stable β form may occur in the solid state through aging of the α form at temperatures below its melting point. Heating the α form slowly can also lead to its transformation to the β form; the amount or extent of β′ formation during this process depends on the fatty acid chain- length. The existence of two (or even more) forms of the β′ form is debated as to whether there are two distinct phases (7) or whether the β′ 2 consists simply of imperfect β′ crystals (8). Differential scanning calorimetry (DSC) is a powerful tool in the study of the polymorphic transformations in these sub- stances (5,8). The recently developed technique of modulated temperature DSC (MTDSC), also known as modulated DSC or oscillating DSC, has been cited as having several advan- tages in this area (9). These include the ability to improve sep- aration of reversible and irreversible thermal events (over the time scale of the experimental parameters), and improved res- olution of closely occurring or overlapping events. The theo- retical background of this technique has been presented else- where (9,10) and is briefly summarized below. Crystallization of a stable phase from a liquid can be re- garded as a reversible event at the equilibrium temperature. Melting of a metastable phase is normally an irreversible Copyright © 1999 by AOCS Press 499 JAOCS, Vol. 76, no. 4 (1999) *To whom correspondence should be addressed at Pharmacia and Upjohn, Inc., 7000 Portage Road, Kalamazoo, MI 49001, USA. E-mail: satish.singh@am.pnu.com Modulated Temperature Differential Scanning Calorimetry for Examination of Tristearin Polymorphism: I. Effect of Operational Parameters Satish K. Singh a, *, Ali Fathe Jalali b and Maggie Aldén b a Department of Pharmaceutical Technology, Pharmacia and Upjohn AB, S-751 82 Uppsala, Sweden, b Department of Pharmaceutical Chemistry, Physical and Inorganic Chemistry, Biomedical Center, Uppsala University, S-751 23 Uppsala, Sweden FIG. 1. Schematic of polymorphic phase transitions in saturated monoacid triglycerides. Dotted lines represent transitions that occur via special thermal treatments only. Adapted from Reference 4.