Oliver Luhn, a researcher with Suedzucker AG, reviews the effects of compression force, dwell time, magnesium stearate concentration and mixing time on tablet hardness using a new excipient marketed by Palatinit
The excipient, with its particular properties, is derived from sucrose in a two-stage production process. First, enzymatic transglucosidation converts the sucrose to the disaccharide 6-O-a-D-glucopyranosyl fructose (isomaltulose) - a significantly more stable reducing compound.
In the second step, the hydrogenation of isomaltulose leads to the stereoisomer disaccharide alcohol 1-O-a-D-glucopyranosyl-D-mannitol di-hydrate (1,1-GPM dihydrate) and 6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS) in an approximate equimolecular mixture. Through an additional special crystallisation process, the ratio between the main components can be varied.
As a result, specific qualities are obtained - for example, galenIQ enriched in 6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS) provides higher solubility. Depending on the quality, the mixture contains approximately 3-5% crystal water, which is bound to the GPM-crystal.
In its final state, galenIQ is a white, odourless, water-soluble, crystalline substance that complies with the isomalt monographs of the current Ph Eur, BP and USP29-NF24. It combines the benefits of many other bulk excipients, such as mannitol, sorbitol, lactose or microcrystalline cellulose. For example, it has a very low hygroscopicity. At 25°C, it adsorbs hardly any additional water up to 65% RH. Significant water uptake starts only above 85% RH.
With this characteristic, the excipient provides optimal protection even for moisture-sensitive APIs, which is a decisive advantage. Furthermore, the low hygroscopic nature combined with an anti-caking property will ease production processes such as mixing, agglomeration or tableting, and will reduce the need for costly protective packaging.
The ratio of the two constituent molecules is adjustable, so that two different solubility grades are commercially available. This enables the release rate of APIs to be directly influenced, making galenIQ a superior filler or binder.
Another advantage is the excellent chemical stability of galenIQ. Based on its chemical structure, it does not react with other components - e.g. with amino acids to form maillard reaction products - and is highly resistant to degradation by enzymes and acids. No changes in the molecular structure occur even when heated above the melting range, or when in aqueous solutions and heated above the boiling point to create high-boiled lozenges.
physiological benefits
In addition to its non-animal origin, the physiological advantages of the material include a very low glycemic and low insulinemic response, making it a highly suitable excipient in formulations for all patient target groups, even for individuals with carbohydrate metabolic disorders. Moreover, the very good organoleptic and non-cariogenic properties make it an attractive choice for many buccal applications, such as sucking tablets, chewables or lozenges.
Direct-compressible grades of the excipient exhibit first-rate tableting properties due to their excellent compactability and high dilution potential. With a well-defined particle size distribution they provide outstanding flow and mixing properties, ensuring a high content uniformity even in low-dosage formulations. Tablets show a smooth surface and can easily be film-coated or pan-coated with galenIQ to make them easier to swallow or to protect the active ingredients from moisture or light.
Besides direct-compressible grades, further particle engineering is leading to a product range that is tailor-made for specific solid-dosage forms such as pellets, capsule fillings, granules, pan coatings, high-boiled lozenges and low boilings.
The grade GalenIQ 720 is an agglomerated spherical isomalt (Ph.Eur./BP/ USP-NF) mainly for direct compression applications. Chemically it is a disaccharide alcohol in a 1:1 GPM/GPS composition. It was particularly designed for producing compressed products of superior hardness, improved sensory and fracture properties while using the lowest possible compression pressures.
Tablets are still the most frequent administered dosage form. The mechanical strength of a tablet is a complex function of: the material properties; the condition of compaction and the method by which the compact strength is measured.
Lubricants are necessary additives in tablet formulations and magnesium stearate is one of the most commonly used lubricants. Makoto et al reported that magnesium stearate reduces tablet hardness and prolongs drug release and recent studies have indicated that bulk drug powders and magnesium stearate interact with each other when thoroughly mixed before tablet compression.1
The ability of a powder to form a compact during tableting has also been recognised to be time-dependent and research has found that the time dependency is related to a consolidation mechanism. Therefore, the properties of tablets produced on high-speed rotary presses sometimes differ significantly from those produced on single punch or hydraulic presses.
A study of tablet hardness versus compression force verified the hypothesis that the compactability of galenIQ 720 is virtually independent of tableting speed, magnesium stearate concentration and the mixing time - a helpful characteristic in designing drug formulations with desirable properties.
The tableting behaviour of galenIQ 720 was investigated in the following way: the formulations were prepared by adding 0.5% and 2% w/w magnesium stearate (mg-stearate pharma veg, Baerlocher, Germany) as a lubricant. Formulations with 0.5% magnesium stearate were blended for 2, 5, 10 and 15 mins, and formulations with 2% magnesium stearate were blended for 5 and 15 mins at 120 rpm (Loedige M20 plough share mixer, batch size = 5000 g).
dwell times
Tablets were produced on a full-scale and fully instrumented tableting press (FETTE, type P1200iG) using an 8mm concave punch. No precompression step was used. Tablet hardness range was adjusted to 20N - 80N representing the range of the majority of common tablets.
Tablet weight was adjusted to 230 +/- 10mg and tablets were produced at three different dwell times of 150ms (5 rpm), 30ms (25 rpm) and 15ms (50 rpm) under low pressures ranging from approximately 1 to 3.5 kN. Dwell time calculations were derived from FETTE GmbH, Germany.
Tablet crushing strength was measured on a conventional tablet hardness tester (Erweka, type: TBH 300). SEM photographs were taken with a Scanning Electron Micrograph (Phillips, type: FEG-XL30). Particle size distribution was measured using laser diffraction technology, (Malvern, Type: Mastersizer 2000). Samples for the determination of the particle size distribution were taken out of the mixer at indicated time intervals. Each sample was composed of three subsamples taken from positions at the top, middle and close to the bottom of the powder bed.
A clear point of interest during product development is the particle engineering, which determines to a large extent the relationship between manufacturing conditions and tableting properties.
Considering the texture, it can be concluded that particles will undergo fragmentation during compression (Figure 1).
compact strength
It is well known that changes in the particle size distribution may influence the compact strength at given compression force. Vromans demonstrated that there is a relationship between compact strength and mean diameter of different sieve fractions of alpha-lactose-monohydrate.2
The figures 2-4 show the particle size distribution of galenIQ 720 before, after 2 mins and 15 mins of mixing utilising a high-shear, plough shear mixer. The biggest changes in particle size distribution occur during the first 2 mins of the mixing process. As tablet mixtures usually require a minimum of 2 mins of mixing time, it can be concluded that these early changes in particle size distribution are not likely to affect the resulting tablet hardness.
It can be observed that for the mixtures with a 0.5% magnesium stearate concentration, the mixing time does not have a significant influence on tablet hardness.
A concentration of 2% magnesium stearate exceeds, by far, the common concentration and was chosen to represent a worst-case scenario. Also, on the presumption that, with a 2% magnesium stearate concentration, an homogeneous mixture might not be achieved after only 2 mins of mixing, the time was adjusted to a minimum of 5 mins.
The comparison of the resulting tablet hardness showed that only after 15 mins of intensive mixing and tableting at the same compression forces, did a significantly lower tablet hardness occur (see figures 5 and 6).
In general, it is expected that higher pressures result in stronger tablets. There is a linear relationship between applied compression force and tablet hardness. However, tablet hardness can be dependent on tableting speed because with increased speed the dwell time - the time when the pressure is applied - decreases.3
In the tests, the speed increase had only minor effects on tablet hardness. Dwell times of 150 ms at 5 rpm reflect single punch tablet presses. At production scale speeds of 25 and 50 rpm with 30 and 15 ms dwell time, there was no significant effect (see figure 7).
This study on the new product galenIQ 720 (Isomalt Ph. Eur./ USP29-NF24) for direct compression should support formulation development as it shows the relationship between compression force, dwell time, magnesium stearate concentration, mixing time and tablet hardness. This is of importance to the formulator, especially during the challenges of scale-up, where different types of tableting machines with different tableting speeds are in use.
interesting alternative
The following conclusions can be drawn from the study:
- Most of the likely changes in particle size distribution for galenIQ 720 are not significant in terms of resultant tablet hardness.
- Results for the hardness of tablets compressed on high-speed, production-style rotary presses will, in most cases, differ slightly from those obtained on a low-speed laboratory single punch press.
- At production scale, an increase of tableting speed from 25 rpm up to 50 rpm did not lead to significant differences in tablet hardness.
- Extension of the mixing time in steps from 2 mins to 15 mins at a magnesium stearate concentration of 0.5% did not lead to changes in tablet hardness.
- Significant differences in tablet hardness occurred at a magnesium stearate concentration of 2% only when the mixing time was extended from 5 to 15 min.
- At a 5 mins mixing time no significant differences in tablet hardness were observed between the 2% or 0.5% magnesium stearate concentrations.
However, it can be said that galenIQ 720 exhibits excellent tableting properties and provides an interesting alternative to other excipients.