Pharmaceuticals   8th January 2024  5 min read

Beyond sustainable ingredients – moisture-activated dry granulation

In the last decade, the top pharma players have ramped up their efforts to improve their environmental footprint. Sustainability enhancement efforts in the pharmaceutical industry have primarily been targeted at API synthesis, given its well-known high energy intensiveness and far less attention has been given to the formulation steps that come after. As the demand for more sustainable medicines rises, more sustainable pharma manufacturing practices are being highly sought after.

Technical Challenge

High or low dose APIs are often challenged with flowability and processability issues.  API(s) and excipients will therefore typically undergo a multistep process that begins with the dry mixing, followed by high shear or wet granulation (HSG or WG). The granules then undergo a milling or sieving step to improve their size distribution, after which the granules are sent to a drying unit to produce dry granules with good flowability and compactability. Following this, the dry granules undergo a second mixing step in which they are blended with extragranular excipients. 
Due to the high energy consumption of the multistep process, HSG is known to have a large environmental impact as demonstrated by a few LCA (life cycle assessment) studies.3,4

Efforts to reduce the environmental impact of tablet production have been pursued, with, for example, a batch to continuous transition in the WG step3, and meticulous selection of speciality pharmaceutical excipients.

The LCA result showed that the resource extraction and carbon emissions of API tablet production were reduced by roughly 25% and 16% respectively, upon transitioning to continuous WG.3,4
The environmental impact of API tablet production can also be lowered by using direct compression (DC) in place of HSG where the steps are even less and the drying step is omitted 4. Despite DC’s attractive environmental sustainability profile, less than 20% of APIs can be transformed into tablets by DC because most API particles typically do not possess sufficient flowability for successful tableting.5

IMCD Solution

IMCD wanted to tackle this challenge and expand the boundaries on processability by selecting one API in different grades and exploring the limitations and possibilities of making a tablet with that API.

In our Cologne lab, we worked with naturally-derived and purified diosmin (API) from a local API supplier– making the API less environmentally burdened from the start. The high dosage and the micronized nature of diosmin leads many manufacturers towards high shear granulation (HSG), which is cumbersome and an energy-consuming process. By carefully choosing a coarser, non-micronized diosmin (NM), we successfully manufactured high dose diosmin tablets (equivalent to the originator) via moisture-activated wet granulation (MADG).
MADG uses a key ingredient, a low-moisture coarse microcrystalline cellulose that can absorb the residual moisture present in the blend whilst serving as a filler and granulation binder simultaneously. This way, there is no drying step as a calculated amount of water is added that is taken up by our speciality ingredient. 

We successfully used the same MADG process for two other grades of the diosmin, simplifying the process for customers by pre-selecting the grades that they might use in their production. 
MADG is a simple, clean, and lean process that is economical, energy saving, and environmentally friendly. Some limitations are the inability to process moisture-sensitive drugs or working with other, non-water-based solvents. However, MADG excels as a potential candidate for many APIs where traditional wet granulation is the golden standard. Ultimately, along with reduced steps, the equipment required is the same as that used in traditional wet granulation – which is what most manufacturing sites are equipped with – so mass implementation would be relatively easy to achieve.
Our study aims to be an example for various actives that can be used via alternative manufacturing methods without changing existing equipment. 

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IMCD is on a mission to champion our partners' journeys towards utilising sustainable solutions every day to make a positive impact on their organisation and the world. Curious to know more? Contact us today.
1. Matilde Milanesi, Andrea Runfola, Simone Guercini, Pharmaceutical industry riding the wave of sustainability: Review and opportunities for future research,Journal of Cleaner Production,Volume 261,2020
3. Wouter De Soete, Lieselot Boone, Filip Willemse, Erik De Meyer, Bert Heirman, Herman Van Langenhove, Jo Dewulf, Environmental resource footprinting of drug manufacturing: Effects of scale-up and tablet dosage,Resources, Conservation and Recycling,Volume 91,2014,
4. Kunn Hadinoto, The-Thien Tran, Angeline Chua, Wean Sin Cheow, Comparing environmental impacts of direct compaction versus wet granulation tableting methods for drugs with poor flowability by life cycle assessment,Chemical Engineering Research and Design,Volume 183, 2022,
5. Zhe Li, LiJie Zhao, Xiao Lin, Lan Shen, Yi Feng, Direct compaction: An update of materials, trouble-shooting, and application, International Journal of Pharmaceutics,Volume 529, Issues 1–2, 2017,