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To establish the orthogonal effects between formulation or process variables and selected CQAs, the Taguchi design is mainly employed. This design helps not only in filtering the most significant critical variables from the insignificant ones but also in optimizing further the formula for the development of topical ophthalmic emulsions. Figure 2.5a–c depict the Pareto charts for screening of influential formulation and process variables as per Taguchi design using selected CQAs. The standard t limit and Bonferroni limit are depicted as a black line and a red line, respectively, in the Pareto chart. Similarly, the positive and negative effects of each formulation and process variables on each CQAs are also depicted using yellow and blue box in the Pareto chart, respectively.

TABLE 2.5. Taguchi Design Matrix Portraying the Layout of Various Experimental Runs for Factor Screening of Topical Ophthalmic Emulsions

Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs, also Called as Independent Variables) with Their Code	Levels	Critical Quality Attributes (CQAs, also Called as Dependent Variables)
Low (−1)	High (+1)
A:Castor oil (ml)	1	2	Mean particle size (MPS, nm) Polydispersity index (PDI) Zeta potential (ZP, mV)
B:Chitosan (mg)	6	18
C:Poloxamer (mg)	75	100
D:Premixing time (min)	10	15
E:Homogenization time (min)	15	20
F:Homogenization speed (min)	15,000	17,000
G:Probe sonication time (min)	5	10
Run	A	B	C	D	E	F	G
1	1	−1	1	−1	1	−1	1
2	−1	1	1	−1	−1	1	1
3	−1	−1	−1	−1	−1	−1	−1
4	1	−1	1	1	−1	1	−1
5	1	1	−1	−1	1	1	−1
6	−1	1	1	1	1	−1	−1
7	−1	−1	−1	1	1	1	1
8	1	1	−1	1	−1	−1	1

If a particular formulation and process variables showed an effect that exceeds the standard t limit in the Pareto chart, then the variables produced a significant effect on the CQAs. On the other side, any of the formulation and process variables showing the effect that is lower than the standard t limit will be considered to produce a nonsignificant influence on the CQAs. In a similar manner, the significances of the formulation and process variables are also determined by the Bonferroni limit in the Pareto chart.

The formulation and process variable such as homogenization speed was found to exceed either t value limit or Bonferroni limit for the MPS (Fig. 2.5a). This indicates that this formulation and process variable might produce the most significant influence on MPS. Although the homogenization speed was found to produce a significant influence on MPS, it did not influence the PDI and ZP values. Taking the insignificant influence of homogenization speed on PDI and ZP into consideration, the homogenization speed was kept at a constant value of 15,000 rpm. For PDI and ZP, none of the formulation and process variables has shown significant influence (Fig. 2.5b, c) as they did not cross the t value limit in the Pareto chart. However, the premixing time deliberately omitted and considered as dummy factor since this variable involves in the initial dispersion/mixing of oil and water phases during the emulsion preparation step. The formulation and process variables such as premixing time, homogenization time, homogenization speed, and probe sonication time were decided to fix at constant values of 10 min, 15 min, 15,000 rpm, and 5 min, respectively, due to their insignificant influence on the selected three CQAs of the topical ophthalmic emulsions. By taking our previous experience in making of topical ophthalmic emulsions into consideration, the formulation and process variables such as the amounts of castor oil, chitosan, and poloxamer were, however, selected as critical formulation and process variables that were ultimately needed to be further optimized using the face‐centered CCD.