(M1330-08-51) Moisture Activated Dry Granulation: A Sustainable Process with Excipients and Process Consideration

Purpose: Wet granulation (WG) is a widely used process in the pharmaceutical industry for a plethora of active pharmaceutical ingredients (APIs). However, its limitation on working with moisture and heat sensitive APIs open avenues for exploring new approaches. Moisture Activated Dry Granulation (MADG) is one such technique best suited for APIs that are heat-sensitive and cannot be processed using a typical wet granulation process.¹ The work undertaken was conceptualized based on the requirements of the pharmaceutical industry to formulate paracetamol tablets by a simple and environmentally friendly process as an alternative to WG. MADG was explored as a processing technology that met the requirements set forth by our customers. It works as a viable and sustainable alternative over WG. Additionally, the concept of sustainability is slowly gaining traction in the pharmaceutical formulation world. As MADG uses the same equipment as standard wet granulation and does not demand drying, the technique offers simplicity, cost-effectiveness, and scalability saving on material, labour, and energy costs.² MADG thus provides for an energy efficient infrastructure for formulation development. The present work explores the potential of MADG using paracetamol as an API and Avicel^® PH-200 LM as a moisture adsorbent.

Methods: As the name implies, MADG is a process where moisture is used to activate the granule formation, however, the granules are not subjected to drying by heat. The study was executed in three steps: 1. Screening and optimization of the required quantity of water, water-absorbent excipient, and binder for MADG: To optimize the water quantity required to activate the granulation, moisture input of raw material and maximum acceptable moisture content of final granulation was determined. The difference between them resulted in the amount of water available for MADG. Water absorbent excipient was selected based on its particle size and water absorption capacity. In the compactibility study, a suitable binder was selected. 2. Formulation of paracetamol tablet: On selecting a suitable water-absorbent excipient and binder, paracetamol tablets were prepared using following procedure: Paracetamol, Corn Starch, Kollidon^® K30 were mixed in rapid mixer granulator for 5 mins at a low speed. Optimized water quantity was sprayed on the blend surface and mixed for another 5 mins. Avicel^® PH 200 LM, sodium starch glycolate was added and mixing continued for another 10 mins. Finally, 40# passed colloidal silicon dioxide, talc, and magnesium stearate were added in the blend and mixing continued for 5 mins before compressing the blend into tablets. 3. Dissolution profiling: Dissolution of the formulated paracetamol tablets by the MADG process and a standard market reference (Sanmol tablet) was performed and compared.

Results: The quantity of water required during MADG was found to be 2.92%. MADG requires coarse, free flowing water-absorbent excipient(s) to match the wet granule morphology and bind free water. Owing to low moisture level (NMT 1.5%) and larger particle size (180 µm), Avicel^® PH-200 LM was selected as an ideal water-absorbent for blending with moist granulates. This excipient absorbs more water from the granule than Avicel^® PH-200, enabling compression without further drying. The final powder blend prepared using MADG resulted in bulk density of 0.507g/ml, tapped density of 0.61g/ml, Carr's Index of 17% and Hausner ratio of 1.2, indicating fair flow of the powder. During the compactibility study of MADG formulations containing 63% Paracetamol, PVP K-12 was found to be the superior binder compared to PVP K-30. Also, when the compactibility of MADG, wet granulation, and direct compression formulations containing 63% Paracetamol was compared, MADG formulation clearly outperforms the WG formulation while no tablets were obtained with the direct compressed formulation. Dissolution result for both MADG formulated tablet and market reference meet USP requirement of not less than 80% of Paracetamol dissolved within 30 minutes.

Conclusion: MADG is a simple, cost-effective processing methodology to create granules that can offer specific solutions to formulation issues. As this technique does not require a drying step, it saves on material, labour, and energy costs. This technique also helps formulators looking to reproduce and scale up, as there is a much lower chance of failure compared to wet granulation. Additionally, it inspires formulators in Pharmaceutical Industry to adopt sustainable alternatives for efficient formulation development.

References: 1. The molecular-basis of moisture effects on the physical and chemical-stability of drugs in the solid-state, Claes Ahlneck, George Zografi, International Journal of Pharmaceutics 1990;62(2-3):87-95
2. A Review: Overall Insights of Novel Moisture Activated Dry Granulation Technology, Pankaj Deshmukh, Abhijit Ahirrao, Santoshi Deshmukh, Vaibhav Mahale, Dr. Vishal Pande, Journal of Emerging Technologies and Innovative Research 2020;7(4):1551-1566

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

Figure 1: Effect of PVP on the tablet compactibility

Figure 2: Compactibility of MADG, wet granulation and direct compression formulations containing 63% Paracetamol

Figure 3: Dissolution Test Result of MADG formulated tablet and marketed product (Dissolution condition: pH 5.8 phosphate buffer, paddle apparatus 50 rpm)