## 3 Synergism in Mixtures of Sweeteners  
### Binary Mixtures of Sweeteners  
Initially, research on sweeteners' synergy was mainly focused on high-intensity artificial sweeteners such as acesulfame-K, aspartame, cyclamate and sucralose. For example, early in 1969, [PERSON] and [PERSON] reported that cyclamate was synergistic with sucrose and saccharin [30]. In 1989, [PERSON] summarized the sweetener combinations exhibiting synergism, most of which were high potency sweeteners [31]. The most popular high-intensity sweeteners in these mixtures were acesulfame-K, cyclamate and saccharin. For instance, both acesulfame-K and cyclamate were synergistic with alitame, aspartame, stevioside and sucralose, respectively, while saccharin was synergistic with aspartame, cyclamate, neohesperidin dihydrochalcone (NHDC) and the sweet-tasting protein thaumatin. Based on these findings, it could be presumed that the high-intensity artificial sweeteners could have more potency to elicit synergy than natural sweeteners. Many other sweetener combinations showing synergism have also been reported [11; 17]. However, there is no physicochemical or structural patterns or principles found in these mixtures of sweeteners that exhibit synergism. Later, it was found that natural sugars and proteins could also elicit synergistic effects. In 1995, [PERSON] et al. systematically examined the presence and degree of synergism among all binary mixtures of 14 sweeteners including 3 sugars (fructose, glucose and sucrose), 2 polyhydric alcohols (mannitol and sorbitol), 2 natural glycosides (rebaudioside-Aand stevioside), 2 dipeptide derivatives (alitame and aspartame), 1 sweet-tasting protein (thaumatin), 1 sulfamate (sodium cyclamate), 2 amides (acesulfame-K and sodium sacchar) and NHDC [32]. Notably, the results of the synergism assessment were obviously concentration-dependent. Specifically, when two sweeteners with a sweetness equal to 3% sucrose were respectively added in the mixture, significant synergistic effects were found. However, only a few mixtures of sweeteners with a sweetness equal to 5% sucrose exhibited synergism, and no synergy was found for mixtures of sweeteners with a sweetness equal to 7% sucrose. Furthermore, two evaluation methods (Method I and II) were separately used in their investigation but led to some different conclusions, especially for mixtures of two sweeteners with a sweetness equal to 5% and 7% sucrose, respectively. [PERSON] et al. advanced sweetener synergy research through an isobole analysis using Method III in 2019 [22]. They used 15 representative sweeteners at 3 different concentrations equal to 4%, 6% and 8% sucrose in sweet intensity, respectively, to investigate their synergism. However, no obvious effect of the concentrations on the results was found with this evaluation method. Furthermore, as expected, the highly synergistic mixtures (I \(<\) 0.6, see the equation in 2.3 Method III) included most high-intensity artificial sweeteners such as acesulfame-K and NHDC. For instance, the long-tested combinations acesulfame-K/aspartate and acesulfame-K/rebaudioside-A exhibited full synergistic effects, and NHDC showed significant synergism with acesulfame-K, sacrolase, thaumatin and rebaudioside-A, respectively. The natural fructose showed partial synergy (I = 0.6-0.9) with acesulfame-K or rebaudioside-A. However, a few findings in their study, such as the mixture of acesulfame-K/rebaudioside-A, showed full synergy conflicts with the previously reported corresponding data that were revealed with Method I or II [22; 32]. A lot of results about binary sweeteners' synergism have been reported up to now [11; 17; 33; 34; 35; 36; 37; 38; 39], which cannot be elaborated herein due to the page limit. In addition, alternative models were also proposed to account for the interaction between sweeteners in binary mixtures [40]. However, these models seem to be too mathematically complicated to be popularly used.