(T1430-11-63) Advancements in Sustainable Moisture Activated Dry Granulation: Optimizing Excipients and Process for Diosmin 500 mg Tablet Formulation

Purpose: The experimental work aimed to develop a robust, high dose formulation for Diosmin 500 mg tablets utilizing an alternative, cost-effective, and sustainable process, such as Moisture Activated Dry Granulation or MADG. Diosmin is a flavonoid found in citrus fruit peels, which is known for its anti-inflammatory and antioxidant effects. It is commonly used to treat conditions like haemorrhoids and leg ulcers caused by poor circulation.¹. MADG offers several advantages over traditional wet granulation, making it an attractive option for pharmaceutical formulation. By utilizing existing equipment and eliminating the need for drying, MADG simplifies the formulation process, reducing materials, labor, and energy costs. Furthermore, MADG offers straightforward scalability, facilitating efficient production across different scales. These factors contribute to MADG's potential as a cost-effective and environmentally friendly alternative to wet granulation, but also as reliable process to fulfill the criteria for bioavailability of the formulation.².

Methods: MADG uses moisture for granule formation without subsequent heat drying. At early development stage, optimization of the necessary water quantity, water accepting excipient and suitable binder was done. Calculation of the final applied water quantity depends on the initial moisture input from the selected excipient and is in direct correlation to the maximal acceptable moisture content of the final granulate. During the laboratory trials formulation development and optimization was done, using high shear mixer granulator. The added moisture was evenly distributed during mixing process, facilitated by microcrystalline cellulose, grade 200 LM and the other components. Several water-absorbent excipients were tested based on their water absorption capacity and particle size. Cellulose microcrystalline (grade 200 LM) enhanced blend wettability by attracting more humidity and facilitating water distribution. Silica colloidal anhydrous improved blend flowability, reduced the surface charge of the active substance, and aided moisture distribution. For improvement of the blend cohesion, several binders such as different grades of povidone, copovidone and hydroxypropyl cellulose were tested. Hydroxypropyl cellulose (EXF) acted as a potent binder, enhancing water uptake and agglomeration. Croscarmellose sodium, an absorbent material, aided disintegration, and drug dissolution through swelling. Stearic acid provided better die lubrication and aided in the compression process. Flow ability of the final blend was evaluated using Carr index and Hausner ration determination. Following compression into tablet cores using standard laboratory rotary press machine. Critical quality attributes of the tablets such as tablet weight, resistance of crushing, friability and disintegration were assessed using standard laboratory in process control instruments. Dissolution testing was performed using dissolution apparatus type II, rotating paddle (900 ml 0.2N NaOH, 75 rpm). Drug release was evaluated using UV visible spectrophotometer at 268 nm wavelength, where Diosmin showed good absorbance when previously dissolved in 0.2 N NaOH.³. Overall, this approach aimed to optimize formulation and process parameters to achieve efficient tablet production while ensuring product quality and sustainability.

Results: During the production process low amount of water as a granulation liquid (moisturization) was used (6%) which was accordingly calculated as a cumulative moisture with initial moisture of every single excipient. The powder blend, after preparation using MADG, exhibited a bulk density of 0.45 g/ml, tapped density of 0.60 g/ml, Carr's Index of 25%, and a Hausner ratio of 1.33, suggesting moderate powder flow. Friability of the produced tablets was 0.14% and the disintegration time was 3 minutes. Experimental dissolution testing has showed drug release of not more than 40% for 3 hours.

Conclusion: Moisture Activated Dry Granulation (MADG) represents a significant advancement in pharmaceutical formulation, particularly for heat and moisture-sensitive APIs. Experimental dissolution test for the MADG formulated tablet and market reference tablets formulated with wet granulation technique (Daflon 500 mg film-coated tablets) has shown that both formulations exhibit low release rate due to the Diosmin low solubility.As the pharmaceutical industry increasingly emphasizes sustainability, MADG is very promising alternative in shaping the future of formulation development.

References: 1. Anti-inflammatory and antiradical effects of a 2% diosmin cream in a human skin organ culture as model, Boisnic S, Branchet M-C, Gouhier-Kodas C, Verriere F, Jabbour V., J Cosmet Dermatol. 2018; 17: 848–854.
2. Comparison of the Absorption of Micronized (Daflon 500mg) and Nonmicronized 14C-Diosmin Tablets After Oral Administration to Healthy Volunteers by Accelerator Mass Spectrometry and Liquid Scintillation Counting, R. C. Garner, J. V. Garner, S. Grewgory, M. Whattam, A. Calam, D. Leong, Journal of Pharmaceutical Sciences, Vol. 91, No. 1, January 2002
3. Development and Validation of UV Spectrophotometric Method for Simultaneous Estimation of Hesperidin and Diosmin in the Pharmaceutical Dosage Form, D. Srilatha, M. Nasare, B. Nagasandhya, V. Prasad, and P. Diwan, Volume 2013, Article ID 534830, 4 pages

Acknowledgements: The authors would like to thank Dioma for Diosmin and International Flavors and Fragrances Inc. (IFF) for providing excipient support.


Figure 2: Dissolution test results of Diosmin 500 mg tablets and reference product (Dissolution conditions: 900 ml 0.2N NaOH, 75 rpm)