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# Reformulation Strategies Based On Design Of Experiments (DOE) Enhancement Of Performance Than A Market Competitor

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Reformulation Strategies Based On Design Of Experiments (DOE) Enhancement Of Performance Than A Market Competitor

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### Reformulation Strategies Based On Design Of Experiments (DOE) Enhancement Of Performance Than A Market Competitor

1. 1. DISCLAIMER: Certain details used here, pertaining to proprietorship of the project had been altered. This exercise is solely for enhancement of knowledge-base and not for any “for-profit” venture.
2. 2.  Gastric Floating Drug Delivery System (RAFT based system)  Raft-based Systems – Mechanism CaCO3 + Alginic acid Ca Alginate (raft) KHCO3 + HCl (stomach) CO2 (buoyancy)  Model Formulation XXX - Lasting Effects (Competitor’s Product Performs Better in Acid Neutralization Capacity for longer hours)
3. 3.  Understanding floating raft behavior and performance  Optimizing Formulation Variables using Design of Experiments (DOE)  Mathematical Modeling & Validation of the raft-based system
4. 4.  Response Surface Methodology (RSM) ◦ Box – Behnken Design X1 = CaCO3 level X2 = KHCO3 level X3 = Alginic Acid level a-f = Coefficients (-) = Low level (+) = High level Y = Raft Desirability k = constant Y = aX1 + bX2 + cX3 + dX1X2 +eX2X3 + f X1X3 + k (Y = Raft Duration/Strength/Weight/Volume)
5. 5. CODE CaCO3 (mg) Alginic Acid (mg) KHCO3 (mg) Duration (hrs) Raft Strength (g) Raft Vol (ml) Raft Wt (g) Std 1 1000 300 210 2:00 24.167 33.33 18.552 Std 2 1000 500 210 3:18 30.133 33.33 23.407 Std 3 1000 300 250 2:06 27.37 56.667 18.263 Std 4 1000 500 250 3:16 33.867 30.000 23.175 Std 5 750 300 280 1:58 22.845 46.667 18.421 Std 6 750 500 280 3:14 27.967 28.333 21.717 Std 7 1250 300 280 7:00 23.070 61.667 20.552 Std 8 1250 500 280 1:45 21.991 23.33 23.298 Std 9 750 400 210 2:33 21.7013 31.667 20.741 Std 10 750 400 250 2:29 29.244 48.333 22.170 Std 11 1250 400 210 2:45 26.311 26.667 19.843 Std 12 1250 400 250 3:18 30.133 33.33 23.407 Std 13 1000 400 280 4:08 29.811 41.667 23.471 Std 14 1000 400 280 4:15 31.8 38.33 22.083 Std 15 1000 400 280 4:19 27.9833 41.667 24.081 V1 1244.67 302.98 280 5:11 21.131 51.667 21.4542 V2 1245.81 497.05 280 3.01 15.051 31.67 25.3625 V3 759.02 302.53 280 2:28 25.7523 41.67 21.1036 NB: Box-Behnken Design, 3 Factors, 4 Responses, 3 replicates of center point 3 factors 4 responses
6. 6. 0 1 2 3 4 5 6 7 8 9 0 50 100 150 200 250 Time (mins) pH Std14 Std7 Std5 75%CaCO3,75%AA,100%KHCO3 125%CaCO3,75%AA, 100%KHCO3 Marketed Formula; 100%CaCO3 100%AA 100%KHCO3
7. 7. Std 14, Marketed Formula; 100%CaCO3, 100%AA 100%KHCO3 Std 7 125%CaCO3,75%AA,100%KHCO3 Std 5 75%CaCO3,75%AA,100%KHCO3
8. 8. Raft Strength = -104.13 + 0.23A + 0.03B + 0.17C
9. 9. Duration = -2488.43 + 3.8A + 7.52B + 1.7C >4 CaCO3 1185.65 mg KHCO3 280 mg AA 415.54 mg CaCO3 1008.45 mg KHCO3 280 mg AA 326.48 mg
10. 10. Raft Weight = 13.64 + 0.02A Raft Volume = 63.34 – 0.1A + 0.08B
11. 11. 0 100 200 300 400 500 1 2 3 mins Predicted Actual Validation Batch Predicted Time (mins) Actual Time (mins) 1 365.80 311 2 157.79 181 3 114.66 148 (R2 = 0.72)
12. 12.  Raft performance is a function of CaCO3, KHCO3 and Alginic Acid concentrations  Raft Duration Model -2488.43 + 3.8 [Alginic Acid] + 7.52[KHCO3] + 1.7 [CaCO3]  Applications: ◦ To predict the duration of any formulation within the design space  151.26 AA + 140 KHCO3 + 981.82 CaCO3 = 2 hours ◦ To obtain formulation variables at fixed time point  For 4 hr Raft:  1000 CaCO3 + 400 AA + 280 KHCO3 (marketed formula)  1245.6 CaCO3 + 413.3 AA + 306.49 KHCO3  750 CaCO3 + 456.08 AA + 293.05 KHCO3 ◦ To fix a certain ingredient and vary other ingredients at a fixed time point  CaCO3 fixed at 750 mg, Time at fixed at 4 hours  336.78 KHCO3 + 499.66 AA  258.6 KHCO3 + 461.34 AA  In other words, optimum “desirability” can be achieved using the raft model
13. 13.  Tableting of selected blends or using micronized varities  Replacement of Alginic Acid with Sodium Alginate; addition of colloidal silicon dioxide for better raft durability  Establishing the feasibility to incorporate other drugs, such as proton pump inhibitor for better management of gastric acidity