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Starch Update 2007: the 4th International Conference on Starch Technology

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P-STARCH-20

TABLETING PROPERTIES OF DEBRANCHED WAXY RICE STARCH AND ITS BLENDS WITH CASSAVA STARCH

Songwut Yotsawimonwat1* , Jakkapan Sirithunyalug1, Sayam Kaewvichit1 and Pramoat Tipduangta1 1Department of Pharmaceutical Sciences, Faculty of Pharmacy,

Chiang Mai University, Chiang Mai 50200, *E-mail: [email protected]

1. Introduction

The application of direct compression (DC) process in tablet manufacturing has been increased steadily over the years. It offers advantages over other manufacturing processes, such as wet granulation due to the fact that the process is simple and requires only a few manufacturing steps, dry mixing and compression. Thus, it uses less processing time, labor costs and power consumption and fewer pieces of equipment are required. When formulating direct compression tablets, the choice of DC filler-binder is extremely important. It must process at least both the good binding functionality and powder flowability. In addition, it should have appropriate particle size distribution, be inert and be compatible with drugs and other excipients, and be able to carry high amounts of active ingredients. Although a wide range of DC filler-binders has been marketed, only a few materials meet the all criteria for classification as DC filler-binders. Moreover, some items are only available from one supplier and often cost more than comparable fillers used in wet granulation.

Nowaday, microcrystalline cellulose is the most compressible DC filler-binders available. Hydrogen bonds between adjacent cellulose molecules formed under compaction account for the high strength of tablets. Microcrystalline cellulose deforms plastically. When compressed, a large number of new clean surfaces are formed which results in the effective hydrogen bond formation. Therefore, it withstands the addition of alkaline stearate lubricants such as magnesium sterate without significant softening effects. Because the fluidity of microcrystalline cellulose is poor and the cost is considerably high, microcrystalline cellulose is not generally used as the only DC filler-binder in the formulation1.

Starch is an attractive raw material for DC filler-binders. It offers versatile functionality in tablet formulation, such as a binder, diluent and disintegrant2. It is available at low cost. However, native starch does not process sufficient compressibility and fluidity for making cosolidated compacts. Starch modification is needed to improve its binding and flow properties. Pregelatinized starch (Starch 1500®) has better compressibility and fluidity than native starch. However, it can carry minimal amount of active ingredients, thus, it is generally used as a disintegrant rather than DC filler-binders. Spray-dried rice starch is very compressible and highly fluid3. It is one of most effective DC filler-binders available in the market. For most pharmaceutical starch products, the disadvantage is the elastical deformation during compaction since few clean surfaces are formed under compression force. As a result, alkaline stearate lubricants tend to soften the tablet1.

Debranched waxy rice starch (DBS) can be prepared by incubating waxy rice starch paste with debraching enzyme under an appropriate condition. The hydrolysate product is


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consisted of short linear chain polyglucan which precipitates upon storage at low temperature into highly crystalline tiny particles, which might be called “microcrystalline starch”4. This study aimed at evaluating tableting properties, particularly compressibility of DBS. The investigation was extended to the evaluation of the blends of DBS and cassava starch as a DC filler-binder.

2. Material and Methods

2.1 Materials Waxy rice starch (Indica type, Thailand origin) was a gift from Cho-Heng Company,

Thailand. Cassava starch was obtained from Siam Modified Starch, Co, Ltd., Thailand. Pullulanase (Promozyme 400 L, NOVO, Denmark) was used without further purification for the preparation of debranched waxy rice starch (DBS). All other reagents used in the experiments were of analytical grade. 2.2 Preparation of DBS

Debranched waxy rice starch was prepared by incubating waxy rice starch paste in 0.05 M acetate buffer solution with Pullulanase enzyme (Promozyme 400L ) at a concentration of 45 PUN/g of dry starch at 55 C for 19 hours. After boiling to stop the enzymatic reaction, the hydrolysate product was stored at 4 C overnight for debranched waxy rice starch to precipitate. The precipitants were separated by centrifugation, washed 3 times with ethanol and then dried. The % -amylolysis limit of DBS powder was evaluated as described by Hood and Mercier (1978)5. 2.3 Preparation of DBS-cassava starch blends

DBS dispersion in water of varying concentrations (5%, 10%, 15% and 20% w/w) was boiled until the clear solutions were obtained. After rapidly cooled down to room temperature, 172.95 g of DBS solution was mixed with 300 g of cassava starch, passed through the screen no. 16 mesh to make wet granules, dried, and then comminuted through sieve no. 16 mesh using an oscillating granulator (KSL 380V3PH, Thailand). 2.4 Electron Microscopic Characteristics

Scanning electron micrographs of DBS and DBS-cassava starch blends were taken from ascanning electron microscope (JEOL JSM-5910LV, France). 2.5 Flow Property

Flowability of cassava starch, DBS and DBS-cassava starch blends were evaluated by determining repose angle and compressibility. 2.6 Compression Properties

Three hundred mgs of DBS, cassava starch, DBS-cassava starch blends and some commercial DC-filler binders, i.e. Starch 1500® (Pregelatinized starch), Emcompress® (Dibasic calcium phosphate) and Vivapur® (Microcrystalline cellulose) were compressed under various pressures from 12.5 to 311.8 MPas on the instrumented single station tableting machine equipped with a flat-faced punch with a diameter of 10 mm (Wilhelm Fette, Germany).


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2.6.1 Pressure-Hardness Profiles: The crushing strength of tablets was measured with a tablet hardness tester (Pharma Test PTB311, Gemany). The relationship between the compression pressures and the crushing strengths were plotted.

2.6.2 Heckel’s Plot: The Heckel’s equation is described as follows.

AkPD1

1ln

D is the relative density of a powder compact at presssure P. The relative density is the ratio of the apparent density of a powder compact at pressure P and the true density of a powder. Constant k is a measure of the plasticity of a compressed material. Constant A is related to the die filling and particle rearrangement before deformation and bonding of the discrete particles6. It is used for interpretation of mechanism of bonding and the degree of plasticity of materials.

In this study, the diameters (diameter and thickness) of compacts were measured immediately after the ejection and were used as one parameter for calculation of the apparent density. The true density of the compact was performed on a gas pycnomerter (Accupyc 1330, America).

2.7 Disintegration Property: The disintegration time of the tablets was evaluated according to the monograph of

dinintegration specified in the United States Pharmacopiea7. 3. Results and discussion

The beta-amylolysis limit of the DBS was 97.5 %, indicating that DBS was almost linear. The yield of the DBS prepared from DBS was approximately 80 % of the starch used. The scanning electron micrographs (Fig. 1a) revealed that DBS was composed of the aggregates of tiny particles with sizes of less than 1 micron. Its particle sizes were substantially smaller than cassava starch granules (Fig. 1b). The DBS-cassava starch blends were prepared by a regular wet granulation process. DBS solutions (5%, 10%, 15% and 20%) was mixed with cassava starch, granulated and dried to obtain granules. The concentrations of DBS in the dried DBS-cassava starch granules were 2.8%, 5.6%, 8.4% and 10.2% for the formulations using DBS solutions of 5%, 10%, 15% and 20% concentrations, respectively. The scanning electron micrographs of DBS-cassava starch blends demonstrated that DBS covered or formed tiny aggregates on the surfaces of cassava starch granules (Fig. 1c-f). All DBS-cassava starch blends in a granular form exhibited a better flowability than cassava starch, rice starch and DBS. Their repose angles and % compressibility were between 29º - 31º and 8% - 9% and their flowability therefore can be classified as good to excellent. The pressure-hardness profiles demonstrated that DBS exhibited good response to compression pressure. The hardness described in terms of the crushing strength of the tablets prepared from DBS was greater than those made from rice starch, Starch 1500®, Emcompress® and cassava starch, repectively, but slightly lower than Vivapur® (Fig. 2a). It can be seen that cassava starch had the least binding property. Therefore, the addition of DBS into cassava starch was expected to enhance the hardness of tablets. Fig 2(b) shows that DBS-cassava starch blends had a better response to pressure than cassava starch. However, the tablet hardness did not increase directly corresponding to the increased concentration of DBS solutions from 5 to 20%. The plasticity of the materials was investigated by Heckel’s equation and the results are shown in Table 1. DBS had a very high plastic deformation. Its k


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value was close to that of Vivapur101 . The k values of all other starches were very low, which represented that starches hardly undergoes plastic deformation under compression. The plasticity of the DBS-cassava starch blends increased with the increase in DBS concentration as a result of the very high plasticity of DBS. This might be especially useful when tablets are produced and use alkaline stearate as a lubricant. The softening effect is usually decreased following the degree of plasticity of the substances. Tablets prepared from all DBS-cassava starch blends in every proportion disintegrated very fast in distilled water. They completely disintegrated within 1 minute (Table 2). The slight delay in disintegration time of the DBS-cassava starch blend tablets might result from their higher tablet hardness.

(a) DBS

(b) Cassava starch

(c) DBS (5%)-cassava starch blends (d) DBS (10%)-cassava starch blends

(e) DBS (15%)-cassava starch blends (f) DBS (20%)-cassava starch blends

Fig. 1 Scanning electron micrographs of DBS, cassava starch and DBS-cassava starch blends obtained from DBS solutions of varying concentrations from 5-20%.


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020406080100120140160180

0 100 200 300 400Compression Pressure (MPas)

Cru

shin

g S

treng

th (N

)

Cassava starch Rice starch Starch 1500

Emcompress Vivapur 101 DBS

0102030405060708090

0 100 200 300 400Compression Pressure (MPas)

Crus

hing

Stre

ngth

(N)

0% 5% 10% 15% 20%

(a) (b)

Fig. 2 Pressure-hardness profiles of (a) cassava starch, rice starch, DBS and some commercial DC-filler binders and (b) DBS-cassava starch blends obtained from DBS solutions of varying concentrations from 5-20%.

Table 1 k values obtained from the regression analysis following Heckel’ equation

Materials k Cassava Starch Rice Starch Starch 1500 Emcompress Vivapur101 DBS DBS-cassava starch blends 5% 10% 15% 20%

0.0009 0.0006 0.0013 0.0011 0.0134 0.0119

0.0008 0.0014 0.0018 0.0029

Table 2 Disintegration times of DBS-cassava starch blend tablets compressed under various pressures

DBS concentration

Disintegration Time (sec) 62.4 MPas 124.7 MPas 187.1 MPas 249.5 MPas 311.8 MPas

0% 29.8 ± 1.1 49.8 ± 1.8 50.5 ±1.0 54.0±0.8 54.2 ± 0.7 5% 38.6 ± 1.1 63.8 ± 3.7 71.2 ± 3.6 66.3 ±3.2 66.0 ± 4.2

10% 41.8 ± 2.1 63.0 ± 2.0 64.2 ± 5.0 66.7 ± 3.0 63.8 ± 1.5 15% 42.0 ± 1.4 60.2 ± 1.9 60.5 ± 4.5 63.5 ± 1.5 67.7 ± 3.8 20% 39.3 ± 0.08 52.3 ± 3.2 64.8 ± 3.2 69.8 ± 4.3 69.7 ± 4.6

4. Conclusions

DBS is an interesting material for use as a tableting excipient since it has a very high binding functionality under compression pressure. Due to its highly plastic deformation, DBS has a potential to withstand the tablet softening effect caused by


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alkaline stearate. Blending of DBS into cassava starch increased the crushing strength of the tablets, but causing a slight delayed disintegration time. 5. References

1. Shangraw, R.F. (1989) Compressed Tablets by Direct Compression, In Lieberman, H.A. and Lachman, L (ed.), Pharmaceutical Dosage Forms : Tablets, Vol 1., 2nd ed. Marcel Dekker, New York, pp. 195-246

2. Rowe, R.C., Sheskey, P.J. and Weller, P.J.(2003) Handbook of pharmaceutical excipients, 4th ed., The Pharmaceutical Press, London, pp. 603-611.

3. Bos C.E., Bolhius G.K., Lerk C.F., Duineveld C.A.A. (1992) Evaluation of modified RS: a new excipient for direct compression. Drug Dev Ind Pharm.18, 93-106.

4. Yotsawimonwat S., Sriroth K., Kaewvichit S., Piyachomkwan K., Sirithunyalug J. (2004) CMUJ. 3, 235-251.

5. Hood, L. F. & Mercier, C. (1978). Molecular structure of unmodified and chemically

modified manioc starches. Carbohydr. Res. 61, 53-66.

6. Paronen P., Iilla J. (1996) Porosity-pressure functions. In: Alderborn G, Nyström C (ed.), Pharmaceutical Powder Compaction Technology. Marcel Dekker Inc, New York, pp. 55-75.

7. USP 28 NF 23 The Official Compendia of Standard, Asian Edition (2005) United States Pharmacopieal Convention Inc., Webcom Ltd., Toronto.

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