Effects of particle size and tapped density on the content uniformity of repaglinide - metformin fixed dose tablet combination

Abstract

The study proposes a solution to content uniformity problem of repaglinide-metformin HCl fixed dose tablet combination with optimization of particle size distribution and tapped density of repaglinide and metformin granules. The developed dosage forms contain less than 0.5% w/w repaglinide and more than 75% w/w metformin hydrochloride in the composition, resulting in content uniformity problems. A route for, minimizing susceptibility to segregation during the tablet press operation, thereby improving content uniformity, was studied through adjusting the particle size distribution and tapped density of the granules. In this study, a new specification in manufacturing method was developed for obtaining repaglinide and metformin granules with particle size distribution and tapped density properties optimized for tablet homogeneity. Specific particle size distribution and tapped density specifications between metformin HCl and repaglinide granules were described as (i) particle size distribution (D90, D50 and D10) of metformin HCl granule should be less than or equal to three times of particle size distribution (D90, D50 and D10) of repaglinide granule; and (ii) tapped density of metformin HCl granule should be less than or equal to two times of tapped density of repaglinide granule. Assay and in vitro dissolution rate analysis were performed by validated HPLC methods.

Keywords

• Repaglinide
• metformin HCl
• fixed dose combination
• content uniformity
• particle size distribution
• tapped density

References

1. [1] IDF, International Diabetes Federation. About Diabetes. What is diabetes? https://www.idf.org/ aboutdiabetes/what-is-diabetes.html (accessed on 22 June 2020).
2. [2] Glucophage® (Metformin hydrochloride) Tablet product labelling. USA: Bristol-Myers Squibb.https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf (accessed on 10 February 2020).
3. [3] Raskin P. Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes. Diabetes Obes Metab. 2008; 10(12): 1167-1177. [CrossRef]
4. [4] Prandin® (Repaglinide) tablet product labeling. (2012). Germany: Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2012/020741s040lbl.pdf
5. [5] Bell DSH. Combine and conquer: advantages and disadvantages of fixed‐dose combination therapy. Diabetes Obes Metab. 2013; 15(4): 291-300. [CrossRef]
6. [6] Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, Donnelly T, Moffitt P, Hopkins H. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22(1): 119-124. [CrossRef]
7. [7] Moses R. Repaglinide in combination therapy with metformin in Type 2 diabetes. Exp Clin Endocrinol Diabetes. 1999; 107(04): 136-139. [CrossRef]
8. [8] Moses RG. Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update. Diabetes Metab Syndr Obes. 2010; 3: 145. [CrossRef]

9. [9] Prandimet® (repaglinide and metformin HCl) product labeling. US: Novo Nordisk. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2012/022386s007lbl.pdf (accessed on 10 February 2020).
10. [10] Block LC, Schmeling LO, Couto AG, Segatto MA, Tagliari MP, Bresolin TM, Mourao S. Effect of binders on 500mg metformin hydrochloride tablets produced by wet granulation. Rev Ciênc Farm Básica Apl. 2009; 30(2): 145-152.
11. [11] Zhaolu Z, Tianzhi Y, Yanan Z, Nannan G, Donglei L, Pingtian D. A simple method to improve the dissolution of repaglinide and exploration of its mechanism. Asian J Pharm Sci. 2014; 9(4): 218-225. [CrossRef]
12. [12] Kukkar V, Anand V, Kataria M, Gera M, Choudhury PK. Mixing and formulation of low dose drugs: Underlying problems and solutions. Thai J Pharm Sci. 2008; 32(3-4): 43-58.
13. [13] Ramírez-Aragón C, Alba-Elías F, González-Marcos A, Ordieres-Meré J. Segregation in the tank of a rotary tablet press machine using experimental and discrete element methods. Powder Technol. 2018; 328: 452-469. [CrossRef]
14. [14] Rohrs BR, Amidon GE, Meury RH, Secreast PJ, King HM, Skoug CJ. Particle size limits to meet USP content uniformity criteria for tablets and capsules. J Pharm Sci. 2006; 95(5): 1049-1059. [CrossRef]
15. [15] Zhang Y, Johnson KC. Effect of drug particle size on content uniformity of low-dose solid dosage forms. Int J Pharm. 1997; 154(2): 179-183. [CrossRef]
16. [16] Muselík J, Franc A, Doležel P, Goněc R, Krondlová A, Lukášová I. Influence of process parameters on content uniformity of a low dose active pharmaceutical ingredient in a tablet formulation according to GMP. Acta Pharm.2014; 64(3): 355-367. [CrossRef]
17. [17] EMEA, European Medicines Agency. Guideline on the investigation of bioequivalence. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf (accessed on 03 March 2020)
18. [18] Chow SC. Bioavailability and bioequivalence in drug development. Wiley Interdiscip Rev Comput Stat. 2014; 6(4):304-312. [CrossRef]
19. [19] EMEA, European Medicines Agency. ICH Topic Q1A(R2) Stability Testing of New Drug Substances and Products. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1-r2-stability-testing-new-drug-substances-products-step-5_en.pdf (accessed on 30 January 2020)