Formulation and Evaluation of Immediate Release Tablet for Treatment of Overactive Bladder

Overactive bladder (OAB) is a combination of urinary symptoms that includes a sudden, strong need to urinate.
The major symptom of OAB is a sudden, strong urge to urinate that you can't ignore.
Leak urine or have “urge incontinence.” This means urine leaks when you feel the sudden urge to go.

1. Pre Submission Seminar Presentation Formulation and Evaluation of Immediate Release Tablet for Treatment of Overactive Bladder Presented by: Bhumin Nitin Jain Guided by: M. Pharmacy 2 nd Year Sem IV Dr. Monika Ola 22 MPH 10 07 Associate Professor Dept. of Pharmaceutics R. C. Patel Institute of Pharmaceutical Education & Research, Shirpur

2. Contents Introduction Aim, Need and Objective Plan of Work Drug Profile Excipients Profile Materials and Instruments Preformulation Studies Formulation Studies Evaluation Studies Stability Studies Test Product VS Reference Product References

3. Introduction Overactive bladder (OAB) is a combination of urinary symptoms that includes a sudden, strong need to urinate. Figure 1 Normal and Overactive Bladder The major symptom of OAB is a sudden, strong urge to urinate that you can't ignore. Reference: https://www.everydayhealth.com/overactive-bladder/causes/

4. Leak urine or have “urge incontinence.” This means urine leaks when you feel the sudden urge to go. Urinate frequently. You may need to go to the bathroom many times during the day. Wake up at night to pass urine. Risk Factors for OAB : Hormone changes Pelvic muscle weakness or spasms A urinary tract infection Side effects from a medication Reference : https://www.myrbetriqhcp.com/combination-treatment/# Figure 2 MOA of Drug

5. Aim, Need and Objective Aim: To formulate and evaluate immediate release tablet for treatment of Overactive Bladder Need: The cost for (branded) oral tablet 10 mg is around $411 for a supply of 30 tablets. It indicates that there is strong need of generic version for affordable healthcare. The data shows that number of people affected with overactive bladder is 37 million. Figure 3 No. of people affected by OAB Reference : https://www.urovantmedicalaffairs.com/overview-of-overactive-bladder

6. Objective: To formulate and evaluate immediate release tablets by Direct compression. To study dissolution profile and to compare their drug-release profiles with (innovator) To study stability of optimized formulation. To compare test product with reference product.

7. Plan of work Literature review Selection of Drug and Excipients Preformulation Studies Formulation Development Evaluation of Formulation Stability Studies of Formulation

8. Drug Profile Drug Name Drug X Category Antimuscarinic Antagonist Molecular weight 362.465 g/mol BCS class BCS class I Half-life 45-68 hrs Log P 1.69 Solubility It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Table 1 Drug Profile

9. Excipients Profile Parameter Lactose Monohydrate Corn Starch Hypromellose 2910 Magnesium Stearate Molecular formula C 12 H 22 O 11 H 2 O C 27 H 48 O 20 C 56 H 108 O 30 C 36 H 70 MgO 4 Molecular weight g/mol 360.31 692.65 1261.45 591.27 Solubility Freely soluble in water; practically insoluble in ethanol, diethyl ether and chloroform. Practically insoluble in cold ethanol and in cold water. Partially soluble in DMSO. Soluble in cold water,practically insoluble in hot water and ether, but soluble in mixtures of ethanol Practically insoluble in ethanol, ether and water; slightly soluble in warm benzene and warm ethanol . Melting point 201–202 C 256-258 O C 225–230 o C 117–150 o C Function Diluent / filler Disintegrant Binder Lubricant Table 2 Excipients Profile

10. Materials and Instruments Sr no. Material Grade Function Supplier 1. Drug X - API Enaltec Labs Pvt. Ltd. 2. Lactose Monohydrate Super Tab 14, spray- Dried Diluent DFE Pharma 3. Corn Starch Maize Starch B Pharma Grade Disintegrant Roquette Freres 4. Hypromellose 2910 Methocel E5 Premium LV Binder Dow chemical company 5. Magnesium Stearate Hyqual, Vegetable Source Lubricant Avantor Performance materials Inc. 6. Opadry yellow Opadry yellow (03F520313) Coating Ingredient Colorcon Asia Pvt. Ltd. 7. Opadry pink Opadry pink (03F540267) Coating Ingredient Colorcon Asia Pvt. Ltd. Sr No. Equipments Name Name of Manufacturer with model 1. Weighing Balance Sartorius CP224S 2. Weighing Balance Mettler Toledo BBA422 3. Double Cone Blender Gansons 4. Compression Machine Cadmach CMB4-MT 5. Sieve Shaker Electromagnetic Sieve Shaker EMS-8 6. Vernier Caliper Mitutoyo Absolute AOS Digimatic 7. Moisture Analyzer Mettler Toledo HB43-S 8. Hardness Tester Dr. Schleuniger Pharmatron 8M 9. Friability Tester Electrolab EF-2 10. Disintegration Test Apparatus Electrolab ED-2SAPO 11. Tapped Density Apparatus Electrolab ETD-1020 12. Tablet Coating Machine Neocota 13. Differential Scanning Calorimeter Mettler DSC 1 star system, Mettler-Toledo, Switzerland 14. Dissolution Apparatus Electrolab ED-2SAPO 15. FTIR Thermo Scientific iD3 Table 3 List of Materials Table no 4 List of Instruments

11. Preformulation studies Organoleptic properties: Table 5 Organoleptic Properties UV Analysis: Test Results Description White Powder Taste and Odour Bitter and Odourless Loss on Drying 1.50 % Figure 4 UV Spectrum of Drug

12. Table 6 Absorbance of Drug Figure 5 Calibration curve of drug in water XRD : Figure 6 XRD Pattern of API Table 7 2θ Values of X-Ray

13. FTIR: Figure 7 FTIR of Drug Type of Vibrations Standard Peakcm -1 Observed Peakcm -1 C=O 1730-1715 1716.95 C-H 3000-2500 2876.85 C≡N 2500-2000 2298.10 C=C 2000-1500 1578.61 C-N 1500-1000 1352.98 S-O 700-500 548.29 Table 8 Reported IR Frequency of Drug

14. Melting Point: 1) Capillary Rise Method: 2) Differential scanning calorimetry: The melting point of Drug X was confirmed by differential scanning calorimetry which was performed at the scanning rate of 10°C/min with 80 mL/min of nitrogen purging. It was confirmed with the reported melting point of i.e., Drug X ranges between 144-149°C. Table no 9 Melting Point Figure no 8 DSC Curve of drug

15. Particle Size Determination : Conclusion: From above study, it was found that Drug used for observation was relatively fine. Sieve Analysis : Specification Particle Size d (10) 11 um d (50) 36 um d (90) 73 um Sieve Sizes Initial weight of sieves Final weight of sieves Difference in weights % retained Cumulative % retained 20# 366.6 366.6 40# 328.8 328.8 60# 334.2 338.0 3.8 19 19 80# 336.8 344.8 8.0 40 59 100# 328.0 331.6 3.6 18 77 Pan 531.6 536.2 4.6 23 100 Total 20.0 Conclusion: Drug was passed from respective sieves using sieve shaker and cumulative % retained was calculated . Table no 10 Particle Size Determination Table no 11 Sieve Analysis of drug

16. Flow Property : Conclusion: Based on the findings, Flow character of Lubricated blend is Passable. Properties Characters Bulk Density 0.571 gm/ml Tap Density 0.762 gm/ml Compressibility Index 25.065 % Hausner’s Ratio 1.335 Table no 12 Flow Property

17. Drug-Excipient Compatibility Study API Excipients Ratio used Drug X - - Drug X Lactose monohydrate (SuperTab 14SD) 1:21.4 Drug X Corn starch (Maize Starch B Pharma Grade) 1:6.3 Drug X Hypromellose 2910 (Methocel E5 Premium LV) 1:1.2 Drug X Magnesium stearate (Hyqual, Vegetable Source) 1:0.1 Drug X Opadry pink (03F540267) 1:0.45 Drug X Opadry yellow (03F520313) 1:0.90 Drug X All excipients (for 5 mg strength) 1:21.4:6.3:1.2:0.1:0.90 Drug X All excipients (for 10 mg strength) 1:21.4:6.3:1.2:0.1:0.45 Figure 9 Normal overlay diffractogram scan of API, Drug X tablets , 5 mg and Drug X tablets , 5 mg Placebo Figure 10 Normal overlay diffractogram scan of API, Drug X tablets, 10 mg and Drug X tablets, 10 mg Placebo The X-ray diffractogram DrugX API, Drug X tablets 5 and 10 mg, and Drug X tablets 5 and 10 mg placebo has shown sharp peaks at different angles (2ϴ) 13.5°, 15.5°, 17.6°, 18.1° and 21.8° . Table 13 Ratio of API & Excipients used

18. Stability condition – Initial Binary mixture Ratio Assay (%w/w) Related Substances (%w/w) Method I Method II Total Impurities (Method I and II) Impurity-I N-Oxide impurity Any other individual impurity R-(-)-3-Quinuclidinol impurity (Imp.-E) 90.0 – 110.0 NMT 0.5 NMT 0.5 NMT 0.2 NMT 0.5 NMT 2.0 Drug XAPI - 99.90 0.002 0.015 0.030 ND 0.096 Drug X+ SuperTab 14SD 1:21.4 99.94 0.006 0.014 0.018 ND 0.059 Drug X+ Maize Starch B Pharma Grade 1:6.3 99.94 0.004 0.019 0.013 ND 0.064 Drug X+ Methocel E5 Premium LV 1:1.2 99.91 0.006 0.017 0.027 ND 0.089 Drug X+ Hyqual, Vegetable Source 1:0.1 99.94 0.004 0.017 0.017 ND 0.065 Drug X+ Opadry Yellow 0.3F520313 1:0.90 99.94 0.005 0.019 0.019 ND 0.058 Drug X+ Opadry Pink 03F540267 1:0.45 99.93 0.002 0.018 0.020 ND 0.069 Drug X+ all excipient for 5 mg strength - 99.93 0.004 0.026 0.021 ND 0.069 Drug X+ all excipients for 10 mg strength - 99.93 0.003 0.009 0.033 ND 0.071 Table no 14 Initial data of drug-excipient compatibility study Table no 15 Stability data of drug-excipient compatibility study

19. Formulation studies Trial no. Trial name Observations 1. To take trial batch by DC and to study physicochemical parameters All parameters were found satisfactory and meet the specification. Dissolution of generic Drug X tablets, 10 mg was observed more than 85% in 15 minutes. 2. To take trial batch using reduced particle size to study impact on dissolution of drug It was concluded that reduced API PSD has no impact on dissolution of drug product. 3. To take trial batch 5mg using reduced particle size of API to study impact on dissolution of drug It was concluded that reduced API PSD has no impact on dissolution of drug product. Sr. No. Name of Ingredient Qty (mg) / tablet T1 (10 mg) T2 (10 mg) T3 (5 mg) Optimized Batch 5 mg 10 mg 1. Drug X 10.00 10.00 5.00 5.00 10.00 2. Lactose Monohydrate 102.00 125.00 130.00 130.00 125.00 3. Corn Starch 31.50 7.50 7.50 7.50 7.50 4. Hypromellose 2910 6.00 6.00 6.00 6.00 6.00 5. Magnesium Stearate 0.50 1.50 1.50 1.50 1.50 6. Opadry Pink 3.75 3.75 - - 3.75 7. Opadry Yellow - - 3.75 3.75 - 8. Purified Water q.s q.s q.s q.s q.s

20. Table no 16 Physical In process Parameters of Core Tablets Table no 17 Physical In process Parameters of Coated Tablets

21. In Vitro Dissolution Release 1) Trial Batch 1   RLD Trial batch 1 Table no 18 Dissolution profiles of Drug X tablets, 10 mg in water Figure no 11 Dissolution profiles of Drug X tablets, 10 mg

22. 2) Trial Batch 2 d90:110.38 µm d90: 45.2 µm Table no 19 Dissolution profile of Drug X tablets, 10 mg with different API PSD Figure no 12 Dissolution profile of Drug X tablets, 10 mg with different API PSD

23. 3) Trial Batch 3 RLD Trial batch 3 Table no 20 Dissolution profiles of RLD and Drug X tablets, 5 mg Figure no 13 Dissolution profiles of RLD and Drug X tablets, 5 mg

24. Optimized Batch Table 21 Multimedia dissolution profiles of Drug X tablets, 5 mg Figure 14 Multimedia dissolution profiles of Drug X tablets, 5 mg Table 22 Multimedia dissolution profiles of Drug X tablets, 10 mg Figure 15 Multimedia dissolution profiles of Drug X tablets, 10 mg Product Drug XTablets, 5 mg Dissolution condition USP II / 900 mL water / 50 rpm USP II / 900 mL 0.1 N HCl / 50 rpm USP II / 900 mL pH 4.5 acetate buffer / 50 rpm USP II / 900 mL pH 6.8 phosphate buffer / 50 rpm Time (minutes) % Release % RSD % Release % RSD % Release % RSD % Release % RSD 10 49 28.55 44 26.01 47 18.32 49 23.15 15 75 18.98 72 24.37 79 13.64 76 16.93 30 96 4.03 101 1.48 101 0.51 92 2.94 45 97 3.5 102 1.66 101 0.93 93 2.13 Product Drug X tablets, 10 mg Dissolution condition USP II / 900 mL water / 50 rpm USP II / 900 mL 0.1 N HCl / 50 rpm USP II / 900 mL pH 4.5 acetate buffer / 50 rpm USP II / 900 mL pH 6.8 phosphate buffer / 50 rpm Time (minutes) % Release % RSD % Release % RSD % Release % RSD % Release % RSD 10 59 29.5 65 9.98 67 15.23 61 22.82 15 78 22.62 84 8.22 90 11.19 82 17.86 30 97 1.42 98 1.8 100 1.27 93 1.65 45 97 1.55 98 1.41 100 1.59 93 1.24

25. RLD Dissolution Product Innovator drug , 5 mg Dissolution condition USP II / 900 mL water / 50 rpm USP II / 900 mL 0.1 N HCl / 50 rpm USP II / 900 mL pH 4.5 acetate buffer / 50 rpm USP II / 900 mL pH 6.8 phosphate buffer / 50 rpm Time (minutes) % Release % RSD % Release % RSD % Release % RSD % Release % RSD 10 37 15.89 53 7.68 62 5.83 37 23.69 15 72 12.33 72 6.54 86 4.69 56 20.78 30 97 2.48 94 4.3 101 2.58 81 8.47 45 97 1.01 99 2.45 102 1.69 85 3.6 Table 23 Multimedia dissolution profile of Innovator drug , 5 mg Figure 16 Multimedia dissolution profile of Innovator drug , 5 mg Product Innovator drug , 10 mg Dissolution condition USP II / 900 mL water / 50 rpm USP II / 900 mL 0.1 N HCl / 50 rpm USP II / 900 mL pH 4.5 acetate buffer / 50 rpm USP II / 900 mL pH 6.8 phosphate buffer / 50 rpm Time (minutes) % Release % RSD % Release % RSD % Release % RSD % Release % RSD 10 67 7.05 60 5.54 48 28.37 48 30.06 15 88 5.23 79 5.64 70 23.68 69 23.91 30 101 1.84 99 1.65 97 6.55 92 9.39 45 101 1.49 102 1.35 100 2.04 95 2.27 Table 24 Multimedia dissolution profile of Innovator drug , 10 mg Figure 17 Multimedia dissolution profile of Innovator drug , 10 mg

26. Evaluation Studies Trial no Dose Tablet wt. (mg) Thickness(mm) Diameter(mm) Hardness(N) Friability(% w/w) Assay(% w/w) T1 10 mg 146.0 -153.0 3.35 -3.40 7.51 - 7.52 39 -55 0.22 99.0 T2 10 mg 149.1 – 152.3 3.46 – 3.49 7.52 – 7.54 45 -50 0.09 98.2 T3 5 mg 148.3 – 154.9 3.39 – 3.46 7.50 – 7.53 37 -47 0.11 96.9 Optimi-zed Batch 5 mg 149.00 – 156.00 3.44 - 3.52 7.49 -7.52 41 – 49 0.13 97.90 10 mg 146.00 – 154.00 3.40 – 3.47 7.53 -7.55 43- 51 0.10 98.0 RLD 5 mg 146.00-157.00 3.44- 3.51 7.48- 7.53 40- 49 0.13 100.4 10 mg 145.00-154.00 3.39-3.47 7.52-7.58 40- 50 0.10 100.4

27. Stability Studies

28. Test Product VS Reference Product

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