HARIOM roll no- 2101200566005 .pptx

FORMULATION AND IN VITRO STUDIES OF A FIXED-DOSE COMBINATION OF TABLETS CONTAINING METFORMIN- HCL AND MIGLITOL

1. FORMULATION AND IN VITRO STUDIES OF A FIXED-DOSE COMBINATION OF TABLETS CONTAINING METFORMIN- HCL AND MIGLITOL A Project Work Submitted in Partial Fulfillment of the Requirement or the Degree of MASTER OF PHARMACY in PHA RMACEUTICS by HARIOM JAISWAL (Enrollment No. 210120056030412) Under Supervision of Dr. Prabhu d utta Panda Institute of Technology and Management Gida, Gorakhpur U.P to Faculty of Pharmacy Dr. APJ Abdul Kalam Technical University (Formerly Uttar Pradesh Technical University) Lucknow 1

2. CONTENTS: INTRODUCTION REVIEW OF LITERATURE AIM AND OBJECTIVES PLAN OF WORK DRUG PROFILE PRE-FORMULATION STUDIES METHODOLOGY EVALUATION RESULT CONCLUSION ACKNOWLEDGEMENT REFERENCES 2

3. INTRODUCTION: Certain pharmacological treatments either benefit from the sequential delivery of medications. Metformin hydrochloride (HCl) is administered orally and is widely used in managing type 2 diabetes . Metformin is an agent belonging to the biguanide class of antidiabetics with antihyperglycemic activity Type 2 diabetes is a progressive illness and most patients will eventually need more than two oral agents to maintain glucose control. Miglitol is an alpha-glucosidase inhibitor that control intestinal absorption of carbohydrates and is used as adjunctive therapy in the management of type 2 diabetes. Metformin and Miglitol are combined to treat type 2 diabetes related elevated blood sugar level. The combination of metformin and miglitol helps the body handle elevated blood sugar more effectively due to their two distinct mechanisms of action. Miglitol immediate activity will help to reduce excess sugar and metformin later action help sustain that control sugar level. 3

4. REVIEW OF LITERATURE MN Singh et al., 2021 : Bi-layer tablet that provides instant patient relief while maintaining therapeutic levels for a longer time by managing medication release in a sustained way for improved patient compliance and acceptance. J Godbole et al., 2012: Matrix tablets are a sort of controlled medication delivery method that continuously releases the medicine. These drugs are released by both dissolution and diffusion-controlled methods. Ajay Kumar Tiwari et al., 2012: The current study used solvent evaporation and co-grinding techniques to investigate a novel bilayer tablet with an extended-release system of metformin HCl 4

5. 4. Basak et al., 2008: The current study's objectives were to create an oral sustained-release matrix tablet containing metformin HCl and to use response surface methods to optimise the drug release profile. HPMC K 15M was used as the matrix-forming polymer during the non-aqueous wet granulation process used to create the tablets. 5. Mandal et al., 2008: Using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, an emerging novel fixed dosage combination of metformin hydrochloride ( HCl ) as sustained release and glipizide as the immediate release was created, and the tablets were tested in in vitro experiments. 6. Basak et al., 2008: The current study's objectives were to create an oral sustained-release matrix tablet containing metformin HCl and to use response surface methods to optimise the drug release profile. 5

6. 7. Rama Adhitya Srikar SV, 2001: The oral route of medication administration is the most common route of drug administration for systemic effects. Except in rare situations, like insulin, the paternal route is not commonly employed for self-administration. 8. Won et al., 2022: The goal of this trial was to create a fixed dosage combination (FDC) tablet for the treatment of type 2 diabetes that contained a high dose (1000 mg) of sustained-release (SR) metformin HCl and a low dose (6.87 mg) of immediate-release alogliptin tartrate . 9. Patel et al., 2011: Matrix tablets are a sort of controlled medication delivery method that continuously releases the medicine. These drugs are released by both dissolution and diffusion-controlled methods. 6

7. AIM AND OBJECTIVE: The research work aims to formulate and perform in vitro studies of a fixed-dose combination of tablets containing metformin HCl and miglitol. To complete the aim following objectives will be opted. Objective: Collection of Drugs Pre-formulation studies of drugs. Formulation of tablets. Evaluations of tablets. 7

8. PLAN OF WORK : The whole work is classified into the following phases Phase 1 st Literature survey Sample and drugs collection Phase 2 nd Pre-Formulation studies Formulation and Optimization Phase 3 rd Evaluation 8

9. DRUG PROFILE: A. Drug name: Metformin HCL Molecular Formula: C 4 H 11 N 5 Molecular weight: 129.16 Boiling Point: 224.1℃ Melting point: 224℃ Solubility: W ater Structure of Metformin HCL image source- pubchem.ncbi.nlm.nih.gov/compound/Metformin 9

10. B. Drug name: Miglitol Molecular Formula: C 8 H 17 NO 5 Molecular weight: 207.22 Boiling Point: 453.7℃ Melting point: 114℃ Solubility: W ater Structure of Miglitol image source- Chemical-Structure.390074.html 10

11. PREFORMULATION STUDIES : Sample of Drug Collection: 2. Preformulation studies of the drug: 11 S.N Name of Drug Gift Sample 1. Metformin HCL Zydus Cadila Pharmaceutical Unit 2 nd Gangotak , Sikkim, India 2 Miglitol Lupin Pharmaceutical Unit 1 st Ahmedabad, Gujarat, India S. No. Drug Physical appearance Melting point 1 Metformin HCl White, solid 222.5 ℃ 2 Miglitol Off-white, solid powder 115 ℃

12. 1. UV- Vis Spectral Analysis: A. Lambda Max Determination: Metformin HCL : Wavelength is 230nm. b. Miglitol : Wavelength is 210 nm. 12

13. 13 S. No. Wavelength (nm) Absorbance 1 200 nm 1.011 2 210 nm 0.725 3 220 nm 0.536 4 230 nm 1.102 5 240 nm 0.712 6 250 nm 0.258 7 260 nm 0.052 8 270 nm 0.042 9 280 nm 0.032 10 290 nm 0.031 11 300 nm 0.033 12 310 nm 0.033 13 320 nm 0.021 14 330 nm 0.02 15 340 nm 0.018 16 350 nm 0.004 17 360 nm 0.005 18 370 nm 0.005 19 380 nm 0.005 20 390 nm 0.005 21 400 nm 0.005 S. No. Wavelength (nm) Absorbance 1 200 nm 0.875 2 210 nm 1.125 3 220 nm 0.81 4 230 nm 0.769 5 240 nm 0.712 6 250 nm 0.521 7 260 nm 0.241 8 270 nm 0.075 9 280 nm 0.042 10 290 nm 0.041 11 300 nm 0.032 12 310 nm 0.025 13 320 nm 0.025 14 330 nm 0.025 15 340 nm 0.025 16 350 nm 0.025 17 360 nm 0.025 18 370 nm 0.026 19 380 nm 0.025 20 390 nm 0.025 21 400 nm 0.025

14. B. Standard calibration curve preparation : Determination of Metformin HCl & Miglitol Different Concentrations 10, 20, 30, 40, 50, and 60 Metformin HCL : Wavelength is 230nm. b. Miglitol : Wavelength is 210nm. 14

15. S. No. Conc. (mg/ml) Absorbance 1 10 0.012 2 20 0.053 3 30 0.098 4 40 0.158 5 50 0.198 6 60 0.239 15 S. No. Conc. (mg/ml) Absorbance 1 10 0.021 2 20 0.056 3 30 0.098 4 40 0.142 5 50 0.201 6 60 0.256

16. 2. Solubility of Drug: A. Different Solvent : Methanol, Ethanol, Chloroform, Ethyl Acetate, Propanol Petroleum ether, Distilled water 16 S. No. Solvent Absorbance Metformin HCl Miglitol 1 Methanol 0.921 0.789 2 Ethanol 0.823 0.725 3 Chloroform 0.096 0.068 4 Ethyl acetate 0.074 0.045 5 Propanol 0.725 0.658 6 Petroleum ether 0.012 0.056 7 Distilled water 1.231 1.024

17. B. Different PH : Determination of Metformin HCl & Miglitol at different PH 2, 4, 5, 6, 7, 8, 9, 10 and 12. 17 S. No. pH Absorbance Metformin HCl Miglitol 1 2 0.014 0.047 2 4 0.052 0.036 3 5 1.025 1.131 4 6 1.152 1.108 5 7 0.039 0.587 6 8 0.0142 0.09 7 9 0.066 0.069 8 10 0.042 0.057 9 12 0.052 0.096

18. METHODOLOGY: Tablet Preparation: Granulation of Metformin HCL of the SR Layer . All component through mesh (1150) After mesh the Metformin HCL and HPMC, MCC, PVPK30 was mixed for 5min Again sived through a mesh (100m) Then granulated with isopropyl alcohol and dried at 40 ℃ for 2hr. Then Magnesium Stearate and Talc combined with dried granules After being sized by a mesh (250m) stired for 2min. The final weight was adjusted by weighing the all granules total weight is 950mg. 18

19. Granulation of IR Layer: Miglitol , lactose and erythrosine lake was mixed for 5min After the mixing passed through a mesh (1150m) the mixture was dried at 50 ℃ for 3hr. Before being ground with starch paste and pass a screen (100m) then dried granules were sized using a screen (250m) then add the talc, citric acid, sodium bicarbonate and magnesium stearate mixed for 2min. Final weight set at 200mg 19

20. Final Compression of Bilayer tablets: Used a 16 station double rotary tablet punching machine with 19.58.9 Caplet tooling and rotating speed 35 rpm Both of IR and SR layer are compressed and 1150mg prepared. 20

21. RESULT: Formulation of Metformin HCL and Miglitol: All Ingredients calculated in micrograms. a. Metformin HCL b. Miglitol : 21 Ingredients Amount of drug (in mg) Talcum powder 1mg Erythrosine lake 1mg Lactose 169mg Starch 20mg Sodium bicarbonate 2mg Citric acid 1mg Magnesium stearate 1mg Miglitol 5mg Total weight 200mg

22. Evaluation: 1. Hardness and Thickness test: The hardness of all formulations was found in the range of 7.20to 8.10 kg/cm2. 22 Formulation Thickness (mm) Hardness (kg/cm2) F1 7.5 8.1 F2 7.4 8.2 F3 7.5 7.1 F4 7.51 7.2 F5 7.49 7.1 F6 7.48 8.2 F7 7.58 8.1 F8 7.6 7

23. 2 . Friability and weight variation: 23 Formulation Friability per cent Weight variation per cent F1 0.37 0.48 F2 0.28 0.68 F3 0.44 0.33 F4 0.17 0.24 F5 0.22 0.44 F6 0.16 0.22 F7 0.18 0.34 F8 0.22 0.54

24. 3. Drug Content uniformity: It was found that all batches show a per cent drug content of more than 98. 24 Formulation Metformin-HCl (mg/ml) Miglitol (mg/ml) F1 98.12 97.14 F2 97.25 98.4 F3 97.4 97.3 F4 98.4 99 F5 99.2 98.4 F6 97.68 98.1 F7 98.5 97.4 F8 98 97

25. 4. Drug Release Studies: 25

26. CONCLUSION : SR fixed dose bilayer matrix tablets containing 500 mg metformin HCl as SR from one layer and 5 mg Miglitol as IR from another layer have been successfully prepared by the wet granulation method. HPMC used as a matrix-forming polymer for the metformin layer enables desired drug release for up to 08 hours, where as Miglitol gives IR from the second layer. Among the different grades of HPMC investigated, no significant difference in the resulting metformin release profiles from the SR layer of the tablets was found. This indicates that the viscosity of the polymer does not affect the drug release rate when the drug is water-soluble and the dose is high. These formulations will be further tested in vivo in an animal model for their pharmacokinetic and pharmacodynamic characteristics as well as to establish optimum drug: polymer conditions leading to desired bioavailability. 26

27. ACKNOWLEDGEMENT : Above all, I thank my beloved God and my parents for giving me the encouragement and ability to complete the task I take this opportunity to express my profound sense of gratitude to my supervisor Dr Prabhudutta Panda, Director of Pharmacy, I.T.M College Gida, Gorakhpur UP It is a delightful moment for me, to put into words all my profound wisdom of gratitude to my mam Mrs. Shweta Singh Pharmacy Head of Department and Mrs. Nidhi Gupta Dean of Pharmacy, I.T.M College Gida, Gorakhpur UP. I would like to express my sincere thanks to Mr. Dheeraj Kumar & Mr. Sachin Kumar for their helping nature and support whenever needed during work. Last but not least , I would like to extend my most sincere sympathies to my dear parents Mr. Manoj Jaiswal and Mrs. Madhuri Jaiswal . 27

28. REFERENCES: Ding X, Robinson JR. Extended-release and targeted drug delivery system. In Remington: The Science and Practice of Pharmacy. 20th edition, Gennaro; A. R., Ed. Lippincott Williams and Wilkins, 2000; 1:939. Lieberman H, Lachman L, Schwartz B. Pharmaceutical dosage forms: Tablets. Second edition. New York; Marcel Dekker inc , 1989; 1:274-284. Goodman LS, Gilman AG. The Pharmacological Basis of Therapeutics. New York; McGraw-Hill Book Company. 1989, 2608-2630. Criag CR, Stitzel RE. Modern Pharmacology with Clinical Applications. 6th edition, New York; Lippincott Williams &Wilkins Publication, 2005, 763-775. Amrutkar JR, Kalaskar MG, Shrivastav VG, Yeole PG. The bilayer tablet formulation of metformin hydrochloride and gliclazide: a novel approach in the treatment of diabetes. International Journal of Pharma Research and Development. 2009; 6:13-19. 28

29. 6. Fiona Palmer, Marina Levina and Ali Rajabi-Siahboomi.Investigation of a Directly Compressible Metformin HCl 500 mg Extended Release Formulation Based on Hypromellose, Reprint of the poster presented at CRS, June 2005. 7. Basawaraj S. Patil1, N. G. Raghavendra rao , Formulation and Evaluation of Fast Dissolving Granisetron Hydrochloride Tablets: Effect of Functionality of Superdisintegrants,International Journal of Advances in Pharmaceutical Sciences2 (2011) 33-39 8. Praveen Nasa and Sheefali Mahant, Floating drug delivery system using Methocel K100M and E50: Formulation and characterization, Acta Pharmaceutica Sciencia53: 57-65 (2011) 9. Durga Prasad Pattanayak , Subash C. Dinda , Bilayer tablet formulation of metformin hydrochloride and glimepiride: A novel approach to improve therapeutic efficacy, International Journal Of Drug Discovery And Herbal Research (IJDDHR)1(1): Jan-Mar: (2011), 1-4. 10. Lian-Dong Hu, Yang Liu, Xing Tang, Qian Zhang, Preparation and in vitro/in vivo evaluation of sustained-release metformin hydrochloride pellets, European Journal of Pharmaceutics and Biopharmaceutics64 (2006) 185–192. 29

30. Thank You 30