galenIQ™ – the smart new choice in pharmaceutical excipients

Description of a new non animal origin quality polyol. And evaluation of the effects of tabletting speed, magnesium stearate concentration and mixing time on the relationship between compaction pressure and strength of tablets made with galenIQ™ (isomalt Ph. Eur., BP, USP 29-NF24).

Abstract
Different formulations and scales of tableting machines are used in the course of formulation development. Single punch presses at lab scale exhibit low compression speeds whereas in production scale at modern rotary presses it increases drastically. Magnesium stearate is often used as a lubricant. It is well known that the compression speed, the concentration of magnesium stearate and the mixing time can have significant effects on the compaction properties of pharmaceutical powders. Another factor that challenges formulators is the change in compression rate during scale up and technology transfer as in extreme cases tablets from formulations developed in lab scale cannot be produced in production.

This article describes the new bulk excipient and the results of a compaction test serie of the tailor-made variant for direct compression – galenIQ™ 720. The study examined the effects of tableting speed on the compactability (tablet hardness vs. compaction pressure) of galenIQ™ 720 placebo formulations. The compactability was observed to be speed dependent, whereas the mixing time at 0,5% magnesium stearate concentration had no influence. At 2% magnesium concentration compactability was slightly affected when mixed for 15 min.

Introduction
Palatinit offers a newly developed multifunctional excipient range under the brand name galenIQ™. It offers the combined advantages of other well-known bulk excipients and thus will not only facilitate pharmaceutical development and formulation but also come up to the high quality standards the pharmaceutical industry is expecting today.

Chemically, galenIQ™ is based on hydrogenated isomaltulose (HI) and its modificiations. HI is a disaccharide alcohol and belongs to the group of polyols. With physical and chemical modifications galenIQ™ qualities are tailor-made for pharmaceutical applications mainly in the field of solid-dosage forms for oral delivery.

galenIQ™ qualities are derived from sucrose in a two-stage production process. First, in an enzymatic transglucosidation sucrose is converted to the disaccharide 6-0-?-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-?-D-glucopyranosyl-D-mannitol dihydrate (1,1-GPM dihydrate) and 6-O-?-D-glucopyranosyl-D-sorbitol (1,6-GPS) in an approximate equimolecular mixture. Through an additional special crystallization process, the ratio between the main components can be varied. As a result, specific galenIQ™ qualities are obtained, e.g. enriched in 6-O-?-D-glucopyranosyl-D-sorbitol (1,6-GPS) providing 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, odorless, water soluble, crystalline substance that complies with the isomalt monographs of the current Ph Eur, BP and USP29-NF24.

Description of the galenIQ™ bulk excipient range
galenIQ™ combines many benefits of other bulk excipients like mannitol, sorbitol, lactose or microcrystalline cellulose and even goes beyond.

For example, galenIQ™ has a very low hygroscopicity. At 25°C, it hardly adsorbs any additional water up to 65% RH. Significant water uptake starts only above 85% RH. With this characteristic, galenIQ™ provides optimal protection even for moisture-sensitive active pharmaceutical ingredients (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 help to eliminate the need for costly protective packaging.

The ratio of the two constituent molecules is adjustable so two different solubility grades are commercially available. Therefore the release rate of APIs can be directly influenced which makes galenIQ™ a superior filler/binder.

Another advantage is the excellent chemical stability of galenIQ™. Based on its chemical structure, it does not react with other components - for example, 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 heated above the boiling point, for example, to create high-boiled lozenges.

In addition to its non-animal origin, the physiological advantages of galenIQ™’ 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 disorders of carbohydrate metabolism. Moreover, the outstanding organoleptic and non-cariogenic properties make it an attractive choice for many buccal applications, such as sucking tablets, chewables or lozenges.

The direct-compressible grades of galenIQ™ 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 like pellets, capsule fillings, granules, pan coatings, high-boiled lozenges and low boilings.

Evaluation of galenIQ 720 in direct compression
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 especially designed for producing compressed products having a great 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 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. have reported that magnesium stearate reduces tablet hardness and prolongs drug release and that recent studies have indicated that bulk drug powders and magnesium stearate interact with each other when thoroughly mixed before tablet compression.

The ability of a powder to form a compact during tableting has also been recognized to be time dependent and research has found that the time dependency is related to a consolidation mechanism.

Therefore properties of tablets produced on high speed rotary presses sometimes differ
significantly from those produced on single punch or hydraulic presses.
A study about tablet hardness vs. compression force verified the hypothesis that the compactibility of galenIQ™ 720 is almost independent of tableting speed and magnesium stearate concentration as well as the mixing time in order to help design drug formulations with desired properties.

Experimental Layout
The tableting behavior of galenIQ™ 720 was investigated. The formulations were prepared by adding 0.5% and 2% w/w magnesium stearate (mg-stearate pharma veg, Bärlocher, Germany) as a lubricant. Formulations with 0,5% magnesium stearate were blended for 2, 5, 10, 15 min and formulations with 2% magnesium stearate were blended for 5 and 15 min at 120 rpm (Lödige M20 plough share mixer, batch size = 5000 g).
Tablets were produced on a full scale and fully instrumented tableting press (FETTE, type P1200iG) using an 8 mm 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 +/- 10 mg and tablets were produced at three different dwell times of 150ms (5 rpm), 30ms (25 rpm), 15ms (50 rpm) under low pressures ranging from approximately 1 to 3,5 kN. Dwell times calculation 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 the top, middle and close to the bottom position within the powder bed.

Results and discussion
A clear point of interest during product development is the particle engineering that determines to a large extent the relationship between manufacturing conditions and tableting properties (picture 1). Considering the texture it can be concluded that particles will undergo fragmentation during compression.

Figure1. REM photograph of galenIQ™ 720, magnification: 100x

Figure 2. REM photograph of galenIQ™ 720, magnification: 400x

It is well known that changes in the particle size distribution may influence the compact
strength at given compression force. Vromans2 demonstrated in his Ph. D. thesis that there is a relationship between compact strength and mean diameter of different sieve fractions of alpha-lactose-monohydrate.

The graphs 1-3 show the particle size distribution of galenIQ™ 720 before, after 2 min and 15 min of mixing utilizing a high shear plough shear mixer. Biggest changes in the particle size distribution occur during the first 2 min of the mixing process. As only mixtures with a minimum of 2 min of mixing time are tableted, it can be concluded that the changes in particle size distribution are most likely neglectable regarding resulting tablet hardness.

Figure 1. Particle size distribution by volume of galenIQ™ 720 before mixing

Figure 2. Particle size distribution by volume of galenIQ™ 720 after 2 min of mixing in Lödige
plough shear mixer at 120 rpm

Figure 3. Particle size distribution by volume of galenIQ™ 720 after 15 min of mixing in Lödige
plough shear mixer at 120 rpm

It can be observed that the mixing time does not have a significant influence on the tablet hardness at 0,5% magnesium stearate concentration

A concentration of 2% magnesium stearate is by far exceeding common concentrations and was choosen to represent a worst case scenario. Presuming that an ordered mixture with 2% magnesium stearate concentration might not be obtained after 2 min of mixing the mixing time was adjusted to a minimum of 5 min. The comparison of the resulting tablet hardness shows that only after 15 min intensive mixing, tableting at the same compression forces resulted in significant lower tablet hardness. (see graph 4 and 5)

Figure 4. Tablet hardness – compression force profile of galenIQ™ 720 mixed with 0,5%
magnesium stearate for 2, 5,10,15 min mixing time at a dwell time of 15ms

Figure 5. Comparison of tablet hardness – compression force profile for galenIQ™ 720 mixed with 2% magnesium stearate mixed for 5min and 15 min

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 as with increased speed the dwell time which is the time when the pressure is applied decreases.
The speed increase has only minor effects on tablet hardness. Nevertheless 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 is no significant effect anymore. (see graph 6)

Figure 6. Tablet hardness – compression force profile for galenIQ™ 720 mixed with 0,5%
magnesium stearate for 10 min mixing time at dwell times of 150 ms, 30 ms and 15ms

Conclusion
galenIQ™ 720 (Isomalt Ph.Eur./ USP29-NF24) for direct compression is a new product in the pharmaceutical market. This study 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 especially during the challenge of scale up where different types of tableting machines with different tableting speeds are in use.

The following conclusions form the study can be drawn:
- Moste likely changes in particle size distribution of galenIQ™ 720 are not significant for tablet hardness yield.
- Results for tablet hardness of tablets compressed at production speeds on high speed rotary presses will in most cases slightly differ 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 min to 15 min at a magnesium stearate concentration of 0,5% did not lead to changes in tablet hardness.
- Significant differences in tablet hardness occured at a magnesium stearate concentration of 2% only as the mixing time was extended from 5 min to 15 min.
At 5 min mixing time no significant differences in tablet hardness in comparison to 0,5% magnesium stearate concentration can be observed.

Further investigations will have to investigate the consolidation mechanism of this material with the aim to reduce tablet speed dependency.
As a result it can be said that, galenIQ™ 720 exhibits excellent tableting properties and is an interesting alternative to other excipients.

Literature
1. Theo Bayerköhler et al., 2002. Method for producing a tablet made of Isomaltulose,
Isomalt or Isomalt variants and corresponding products. EP 1214 093 B1,
Patent pending.
2. H.Vromans.1987. Studies on consolidation and compaction properties of Lactose.
PHD Thesis: 95; 38. University of Groningen
3. Makoto Otsuka et al.. 2001. Comparative Evaluation of Tableting Compression
Behaviors by Methods of Internal and External Lubricant Addition: Inhibition of
Enzymatic Activity of Trypsin Preparation by Using External Lubricant Addition
During the Tableting Compression Process.
AAPS PharmSci. 2001; 3 (3): article 20. DOI: 10.1208/ps030320
4. Ching Kim Tye et al.. 2004. Evaluation of the effects of tableting speed on the
relationship between compaction pressure, tablet strength and tablet solid
fraction. J.Pharm. Sci. 94: 465–472
5. Kees van der Voort Marsschalk. 1997. Origin and consequences of stress relief
in tablet formulation. PHD Thesis: 1. University of Groningen, NL

Author
Oliver Luhn
Central Department of Research Development and Services Pharmaceutical Technology Südzucker AG / Palatinit

Contact Details
Palatinit GmbH
Gotttlieb-Daimler-Strasse 12
68165 Mannheim/Germany
Tel +49 621 421 150
Fax +49 621 421 160
e-mail: galeniq@palatinit.com

Press Contact
Claudia Meissner
Palatinit GmbH
Gotttlieb-Daimler-Strasse 12
68165 Mannheim/Germany
Tel +49 621 421 148
Fax +49 621 421 160
e-mail: Claudia.meissner@palatinit.de