Erythritol: A New Multipurpose Excipient

The success of an excipient depends on its physical and chemical properties, which must meet the pharmaceutical industry's increasingly stringent criteria. Erythritol, a natural non-caloric and non-cariogenic polyol (sugar alcohol) present at low levels in many fruits and fermented foods,1 is an excipient that meets these requirements.

Production and properties

Erythritol is the first polyol to be industrially manufactured by a fermentation process. Glucose, obtained by the enzymatic hydrolysis of starch, is fermented by a yeast-like fungus to yield erythritol, which is then crystallized at a purity of more than 99.5% (Figure 1).2

Erythritol's nutritional properties are unique; it behaves differently from all other polyols because of the way it passes through the digestive system (Figure 2).3–10 It has a very low caloric value of 0.2 Kcal/g,11,12 and because it is rapidly and easily absorbed by the small intestine, the excipient has a high digestive tolerance, exceeding that of lactose. Erythritol does not affect blood glucose or insulin levels and is, therefore, suitable for diabetics.13 Because it cannot be metabolized by bacteria in the mouth, erythritol does not cause tooth decay.14-17

Figure 1: Fermentation of erythritol from glucose; the hexose monophosphate pathway and Table I: Storage stability of erythritol (20 °C, 50% RH).

It also shows cariostatic properties similar to those attributed to xylitol and provides superior sensorial benefits.

Erythritol is a white crystalline powder with a sweetness of 70% relative to sucrose and a pleasant, strong cooling effect because of its negative heat of solution (243 cal/g), more than any other polyol.2 One of erythritol's key properties is related to its interaction with water. Although readily soluble in water at 37% w/w at 25 °C, it remains practically non-hygroscopic at conditions of up to 90% relative humidity (RH). Under these conditions, the absorbed moisture remains significantly below 0.5% - lower than the moisture absorption of mannitol (Figure 3).

Figure 2: Metabolism of erythritol, Table II: Vitamin C granulated with erythritol, and Table III: Pharmacopoeial specifications of erythritol.

Advantages

An important advantage of erythritol is its high stability, which means

• it does not react with most active ingredients

• it is very stable during storage (Table I)

• it stays intact at temperatures up to 160 °C

• it is stable in the pH range of 2–10.2,17,18

In liquid form, erythritol exhibits synergies with intense sweeteners and, in some cases, masks bitter or metallic tastes. It also adds smoothness and "body" to liquid preparations.19–22

Applications

Erythritol can be used in a wide range of solid and liquid formulations, including

• granulated powders

• tablets

• tablet coating

• lozenges

• medicated chewing gum

• syrups

• oral care products.

Because it is non-hygroscopic, the excipient offers superior flowability and stability, making it an ideal carrier for actives in sachets and capsules.

Erythritol can be used as a diluent in wet granulation in combination with moisture-sensitive actives. It can be easily granulated by methods such as fluid bed or high shear. Granulating 95% erythritol with 5% DE malto- dextrin results in a narrow particle size distribution without sieving, and a superior flowability with a Carr index of 8.3.

Active ingredients such as vitamin C can be granulated with erythritol, producing coarser granules with improved flowability; for example, 30% vitamin C can be granulated with 60% erythritol using 5% maltodextrin and 5% microcrystalline cellulose as binder in a high shear granulator. The final granulates exhibit significantly improved flowability (Table II).

Erythritol's ability to crystallize easily is an advantage when producing sugar-free lozenges with a hard, crunchy texture. Lozenges with a pleasant, cool taste and good storage stability can be prepared using conventional manufacturing processes. Erythritol also improves the flexibility and shelf-life of medicated chewing gum. Used in combination with other polyols in coating, it can improve crunchiness and moisture resistance.

Figure 3: Water sorption isotherm of erythritol (crystalline material, 25 °C) and Figure 4: Hardness of erythritol tablets (1 cm2 flat surface round tablets, 350 mg; formulation: granulated erythritol 1 0.25% Mg stearate).

Erythritol can also be used as a sweetening agent in syrups, provide sensorial profile modifying properties with intense sweeteners and can mask unwanted aftertastes. The excipient can partly replace sucrose or other polyols in syrups to improve digestive tolerance and reduce the total caloric value. In toothpaste and mouthwash solutions, erythritol can be used as a non-cariogenic sweetener in combination with intense sweeteners and active substances.2,18

The properties of erythritol make it a very promising excipient for direct compression.23 The tablets produced by this method can reach a hardness comparable with that of directly compressible sorbitol (Figure 4).

Regulations

Erythritol has been approved for use in food in many countries. It has been granted generally regarded as safe status in the US and a petition is pending in Europe. An acceptable daily intake of "not specified" has been awarded by the joint World Health Organization/Food and Agriculture Organization expert committee on food additives (JECFA). Additionally, the excipient is listed in the Codex Alimentarius (INS-number 968) on the general standard for food additives list and in the drug master file. It is also described in monographs of both the European and Japanese Pharmacopoeia (Table III).

There are advantages to developing formulations based on erythritol because it is a safe excipient that combines the low hygroscopicity of a polyol such as mannitol with better digestibility than lactose and contains almost no calories. This unique combination of characteristics makes erythritol a superior candidate for modern drug formulations.

References

1. J. Goossens and M. Gonze, "Nutritional Properties and Applications of Erythritol: A Unique Combination?" in T.H. Grenby, Ed., Advances in Sweeteners (Aspen Publishers, Inc., New York, New York, USA, 1996) p 153.

2. M.E. Embuscado and S.K. Patil, "Erythritol," in Food Science and Technology, Vol. 17, Alternative Sweeteners (Marcel Dekker, Inc., New York, New York, USA, 2001) pp 235–254.

3. M. Romana et al., "Gas Chromatographic Analysis of Lens Monosaccharides,"

J. Lab. Clin. Med. 103(1), 137–142 (1974).

4. J. Roboz et al., "Determination of Polyols in Serum by Selected Ion Monitoring," Clin. Chem. 30(10), 1611–1615 (1984).

5. C. Servo, J. Pabo and E. Pitkaenen, "Gas Chromatographic Separation and Mass Spectrometric Identification of Polyols in Human Cerebrospinal Fluid and Plasma," Acta Neurol. Scand. 56, 104–110 (1977).

6. P. Storset, O. Stooke and E. Jellum, "Monosaccharides and Monosaccharide Derivatives in Human Seminal Plasma," J. Chrom. 145, 351–357 (1978).

7. G.P. Robert, A. MacDiarmid and P. Gleed, "The Presence of Erythritol in the Fetal Fluids of Fallow Deer," Res. Vet. Sci. 20, 154–256 (1976).

8. M. Hiele et al., "Metabolism of Erythritol in Humans: Comparison with Glucose and Lactitol," Br. J. Nutr. 69, 169–176 (1993).

9. I.C. Munro et al., "Erythritol: An Interpretive Summary of Biochemical, Metabolic, Toxicological and Chemical Data," Food Chem. Toxicol. 36, 1139–1174 (1998).

10. F.R.J. Bornet et al., "Plasma and Urine Kinetics of Erythritol After Oral Ingestion by Healthy Humans," Regul. Toxicol. Pharm. 24, 280–286 (1996).

11. F.R.J. Bornet et al., "Etude de Devenir Mábolique, Apr`Ingestion Chez l'Homme Sain, d'un Nouvel õlcorant de Charge Basse Calorie: l'Erythritol," Gastroenterol. Clin. Biol. 16, A 169 (1992).

12. GRAS Affirmation Petition (GRASP 7 GO 422).

13. M. Ishikawa et al., "Effects of Oral Administration of Erythritol on Patients with Diabetes," Regul. Toxicol. Pharmacol. 24, 303–308 (1996).

14. J. Kawanabe et al., "Noncariogenicity of Erythritol as a Substrate," Caries Res. 26, 358–362 (1992).

15. P.M. Olinger and V.S. Velasco, "Opportunities and Advantages of Sugar Replacement," Cereal Foods World 41, 110–113 (1996).

16. H. Schiweck and S.C. Ziesenitz, "Physiological Properties of Polyols in Comparison with Easily Metabolisable Saccharides" in T.H. Grenby, Ed., Advances in Sweeteners (Aspen Publishers, Inc., New York, New York, USA, 1996) pp 56–84.

17. C. Leutner, Ed., Geigy Scientific Tables, Vol. 1 (Ciba Geigy Ltd, Basle, Switzerland, 1981) pp 84–85.

18. F.J.R. Bornet "Undigestible Sugars in Food Products," Am. J. Clin. Nutr. 59, 763–769 (1994).

19. J. Goossens and H. Rý, "Erythritol: A New Sweetener," Food Sci. Tech. Today 8, 144–148 (1994).

20. H. Rý and J. Goossens, "Erythritol: A New Raw Material for Food and Non-Food Applications," Starch/Stke 45, 400–405 (1993).

21. J. Goossens and M. Gonze, "Nutritional and Application Properties of Erythritol: A Unique Combination? Part I: Nutritional and Functional Properties," Agro-Food-Industry Hi-Tech July/August (1997) pp 3–9.

22. T. Kasumi, "Fermentative Production of Polyols and Utilisation for Food and Other Products in Japan," Jpn Agric. Res. 29, 49–55 (1995).

23. Patent EP 0 497 0439 B1; Cerestar Holding BV, Erythritol compositions (1995).