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By Peter Freed, Head of Global Pharma Customer Technical Support at Roquette
Think you know mannitol? Think again! Naturally sweet, stable and calorie-free, this highly functional polyol is one of the most widely used pharmaceutical excipients on the market today. Millions of tons of mannitol powder pass through drug production lines each year – a trend that only seems set to rise. Indeed, by 2024 the global mannitol market is estimated to reach a value of 418.3 million USD. The industry can’t get enough of this promising polyol, and yet we have only begun to scratch the surface of its full potential. From unlocking essential dosage forms to overhauling tableting quality and efficiency, and even serving as an active ingredient, let’s break open this mighty molecule, and take a closer look at some of its underrepresented functionalities.
1. Promoting patient acceptance
Medical non-compliance is the defining challenge of today’s pharma industry. Estimates suggest that medication non-adherence accounts for 50% of treatment failures in the US alone, resulting in an alarming 125,000 deaths each year. Fortunately, innovative dosage forms have emerged to help manufacturers improve patient compliance – many of which rely on mannitol excipients.
Dissolving swallowing issues
Orally dispersible tablets and films (ODTs & ODFs) are well-suited to the task of tackling patient compliance. Formulated to dissolve on contact with saliva in the mouth, they are ideal for patients who have difficulty swallowing conventional tablets and capsules and in paediatric applications. To achieve this desired effect, pharma producers need excipients with an excellent dispersibility profile, good mechanical strength and a pleasant taste and texture – the latter is especially important for delivery forms which dissolve in the mouth.
Roquette set out to identify the perfect excipient for ODTs in a recent comparison of four commercially available platforms: three conventional mannitol-based blends, as well as Roquette’s PEARLITOL Flash mannitol-starch compound. Tablets containing PEARLITOL Flash consistently returned the shortest disintegration times, regardless of tablet hardness, displaying increased resistance to compression-related stresses compared with the other blends tested. The mechanism behind such definitive results is wettability. Unlike the classic platforms, the synergistic effect of the mannitol-starch molecules within PEARLITOL Flash allow it to act as both a filler and disintegrant without the need for an additional superdisintegrant. This allows the formulation to exhibit better wettability, and therefore faster disintegration times. Through the study, we can see how mannitol’s inherent qualities can lead to advantages, not least giving patients access to the convenient dosage forms they need to stay well.
Slow(er) and simple(er) wins the race
Controlled or extended-release dosage forms also hold immense potential to turn the tide against pill fatigue. The slower, measured dosing capacity of these medications allows for reduced medication frequency and with it, a lower risk of patients feeling overwhelmed by polypharmacy.
The factor that unites all forms of modified release formulations is the need for a gradual-release excipient. These are typically substances with a polymeric base – such as hydroxypropyl methylcellulose (HPMC) – which form a gel-like matrix on contact with the moisture present in the gastrointestinal tract, slowing down the transfer of active compounds into the bloodstream. Incredibly effective in their primary purpose, polymeric excipients have one major drawback. With their fibrous molecular structure, most tend towards poor flowability and tabletability, meaning they must undergo the added step of wet granulation before they can be compressed into tablets. With its superior flow and excellent compressibility profile, mannitol offers producers of controlled release dosage forms the potential for a more efficient approach.
Co-processing is the key concept here. By physically combining HPMC with highly flowable mannitol, producers can, in theory, unlock faster, more cost-effective manufacturing. In a recent study, scientists at Roquette turned this from hypothesis to practical reality. Researchers tested the capabilities of the company’s PEARLITOL CR-H co-processed mannitol-HPMC excipient, both in terms of its processing properties and suitability for modified release applications. During the study, the new excipient achieved an impressive flow time on the ‘flow-through-orifice test’ and good Hausner ratio, meaning the solution displayed excellent flowability and compressibility. Turning to the question of API dissolution and diffusion, two separate tablet prototypes formulated with PEARLITOL CR-H were able to steadily release 40 mg of the API propranolol hydrochloride and 500 mg of metformin hydrochloride respectively over the course of twelve hours. Results like this highlight PEARLITOL CR-H as a truly viable solution for producing extended-release matrix tablets by direct compression. They also serve as a sign of things to come, where co-processed mannitol excipients could open up the benefits of controlled release medications to all.
2. Maximising manufacturing efficiency
As alluded to already, mannitol’s many process-optimising properties make it as beneficial to manufacturers as it is to patients. Experienced excipient suppliers can provide drug producers with a wide range of mannitol grades, each with their own unique characteristics. Talking manufacturing efficiency, however, the gold standard is a grade capable of facilitating – and optimising – the direct compression process.
Calling time on production waste
One of the most important, yet often overlooked, functions of a directly compressible excipient is mitigating defects and product loss. Oftentimes critical tableting defects only become evident well into the production process, resulting in entire batches being disposed of and the whole journey restarted. Capping – or a breakage across the horizontal plane of a tablet post-compression – and sticking are some of the most common causes of production delays and raw material wastage experienced by today’s drug developers. Since these issues directly correlate with applied compression force and tableting speed, manufacturers historically had to compromise on optimal tablet hardness and overall production efficiency to ward off capping and subsequent product waste.
Again, mannitol holds the answer to avoiding this trade-off – this time through the development of excipients specifically designed to mitigate tablet capping. During performance testing ahead of a new product launch, Roquette endeavoured to compare the tabletability of two leading excipients (one spray-dried, one granulated) against its new solution, PEARLITOL 200 GT. The results were conclusive: only tablets formulated using PEARLITOL 200 GT were able to deliver a drug load of 20-25%, exceed a compression force of 15kN, and achieve tablet hardness in excess of 100N. Data like this underpins the critical importance of excipient selection to the drug manufacturing process; choose wisely and producers and patients alike can reap the rewards of harder, smaller, stronger tablets.
3. The functional side of mannitol
Mannitol’s advantages as an excipient are reasonably well-explored at this point, but less well-known is its capacity to deliver therapeutic benefits of its own. Across multiple scientific and clinical studies, mannitol has been shown to impart pharmaceutic effects. This includes improved paediatric patient performance when used as the inhalation powder for a bronchial provocation challenge, lowered intraocular pressure in patients suffering from acute glaucoma, reduced cerebral oedema, intracranial pressure and cerebrospinal fluid, volume and pressure, as well as the promotion of diuresis before irreversible renal failure becomes established.
The mechanism of action behind these benefits is mannitol’s natural hygroscopicity – or resistance to dissolving in water. When absorbed into the bloodstream, mannitol elevates blood plasma osmolality (the balance of electrolytes to water) resulting in enhanced flow of water from tissues. In the event of excess fluid volume around the brain, spinal column or within the eyes, this characteristic is extremely advantageous, potentially saving a person’s sight, mobility and – in extreme cases – life.
Challenging standard perspectives
In a tightly regulated industry like pharmaceuticals there is a tendency to rely on the familiar. Widely accepted as safe and effective, mannitol has been a victim of its own success. Its evident reliability as a tableting ingredient has, for many years, left it pigeon-holed as ‘just an excipient’ in the minds of pharma producers. Its true potential though, is far more extensive. The many facets of mannitol revealed in this article raise two important questions: ‘are we, as an industry, using the ingredients at our disposal to their fullest extent?’, and perhaps more pressing, ‘how could harnessing a high-quality mannitol transform my next drug development project?’