Yoshihito Yaginuma

Many orally disintegrating dosage forms have been developed over the past two decades to improve compliance, bioavailability, stability or other unique product requirements.

  Rapidly disintegrating tablets (RDTs) are also in demand. When an RDT is placed in a patient's mouth without water, it rapidly disintegrates with saliva, and the coated granules containing active ingredients are dispersed in saliva and swallowed. It is generally difficult to make an RDT containing a large amount of intensely bitter drug because taste masking must be effectively achieved.

Film coating spherical granules is considered one of the most effective methods to mask the taste of a bitter drug.

  However, film coating small granules is technically very difficult, particularly when a large dose of the drug is required whereas large granules in RDTs cause a gritty texture in the mouth. In this study, we attempted to develop an RDT (Figure 1) containing an intensely bitter drug by the following processes: 								

Layering a large quantity of the drug on the fine seed cores. 

Coating the layered granules with the taste masking film. 

Tabletting the coated granules and other excipients together. 

 A drug with a threshold value of bitter taste of about 30 mg/L and a solubility of about 0.5 mg/mL at 20 °C was chosen as model. We have referred to it (intensely bitter drug) throughout this article.  

Fine microcrystalline cellulose spheres (FMCS) (Celphere SCP-100) as seed cores, microcrystalline cellulose (MCC) (Ceolus KG-802), etylcellulose aqueous dispersion (ECAD) (Celioscoat EC-30A) as taste masking film, and croscarmelose sodium (CCS) (Kiccolate ND-2HS) were obtained in-house at Asahi Kasei Chemicals Corp. (Japan). D-Mannitol (Man) (Towa Chemical Industry Co., Ltd, Japan), hydroxypropyl cellulose (HPC) (NISSO HPC L grade) (Nippon Soda, Japan), triacetine (TAG) (Wako Pure Chemical Industries, Japan) and magnesium stearate (MgSt) (Taihei Chemical Industrial, Japan) were purchased.  

Figure 2 shows the procedure of preparing drug-layered microgranules. The layering liquid (IBD/HPC/water=10/2/88, solid content=12 wt%) was prepared by the following processes:  									

Water and HPC were mixed by a propeller for 60 min.  

Vigorously mixed with the IBD by a homogenizer at 4000 pm for 60 min. 

Strained through a sieve with a 210 μm opening. Ten kilograms of the layering liquid (1.2 kg as solid) was then layered on 500 g of FMCS using modified Wurster fluidized bed apparatus (Multiprex MP-01, type SPC; Powrex, Japan [Figure 3]) according to the operating conditions in Table 1. Subsequently, 2 wt% HPC aqueous solution was coated until the coated amount became about 0.3 wt% to the layered microgranules to prevent exfoliation of IBD. 

 Figure 4 shows the preparing procedure of coated microgranules. The coating liquid (ECAD(solid)/Man/TAG/water=11.4/5.7/2.9/80, solid content=20 wt%) was prepared by the following processes:  								

ECAD and TAG were vigorously mixed by a homogenizer at 4000 rpm for 60 min.  

It was strained through the sieve of 250 μm opening. 

It was mixed with Man by propeller and then 500 g of the layered microgranules were coated with 500 g of the coating liquid (100 g as solid) using modified Wurster fluidized bed apparatus (Figure 3) according to the operating condition in Table 1. Subsequently, the coated microgranules were cured at 80 °C for 60 min in the oven.  

 Figure 5 shows the preparation procedure of RDT. MCC (106 g), CCS (95 g) and Man (399 g) were granulated with 480 g of water as a binder using the fluidized bed apparatus (Multiprex MP-01, normal fluidized bed granulator type; Powrex) according to the operating conditions in Table 1. Then, 42.7 weight part of the coated microgranules was softly mixed with 0.5 weight part of MgSt for 30 s, and it was mixed with 56.8 weight part of the excipient granules for 5 min.  

Table 1 Operating conditions of layering, film coating and granulation.			

Subsequently, 600 mg of the mixture was compressed with flat-faced punches in a die of 11.3 mm internal diameter using a load tester (Test Stand Model-1321DW; Aikoh Engineering, Japan) at a compression force of 5 or 7 kN for 10 s. Table 2 shows the formulation of the RDT.  

 Tablet hardness was measured using a tablet hardness tester (Model 8M; Dr Schleuniger Pharmatron AG, Switzerland) for 10 tablets. 

The disintegration time of the RDT in water was determined using the apparatus of the Japanese Pharmacopoeia (JP) 14 disintegration test, without a disk for six tablets. The 1000 mL of deionized and reverse osmosis water at 37±2 °C was used as test fluid.  

The disintegration time of the RDT in the mouth was measured using three volunteers. A tablet was placed on the tongue, and each volunteer moved their tongue gently until the tablet disintegrated. This process was timed using a stopwatch. 

The dissolution test was measured in accordance with the JP 14 dissolution test method 2 (paddle method). The paddle was rotated at 55 rpm, and 900 mL of 0.07 mol/L hydrochloric acid aqueous solution was used as dissolution media. The drug concentration was measured by a UV-visible (UV-vis) spectrophotometer and the drug release ratio was calculated.  

Human sensory evaluations of grittiness and bitterness were performed by three volunteers. The coated microgranules or the RDT was held in mouth for about 2 min, and then both levels were recorded respectively. The degree of grittiness was scored as follows: 0=not gritty, 1=slightly gritty and 2=markedly gritty. The degree of bitterness was scored as follows: 0=tasteless, 1=slight, 2=moderate and 3=intense.  

Table 3 Physical properties of FMCS, layered microgranules, coated microgranules and excipient granules.			

Morphologies of the each granule were observed by a scanning electron microscope (SEM [JSM-5510LV; JEOL, Japan]).  

Table 3 and Figure 6 show the results of layering and film coating. As a result of the amount of high drug-layering, the process of drug spraying needed to be performed in 2 days. This negatively affected the yield (79 wt%) of drug-layered microgranules, but the amount of coarse particles (more than 425 μm) was still very low (3.7 wt%). In general, layering on small seed cores is very difficult and it tends to result in producing many coarse (aggregated) particles. However, a good result was obtained in this experiment because FMCS has the ideal physical characteristics for seed core; not water-soluble, but has approximately 120% of water binding capacity.

  IBD and the layered granules were intensely bitter, and the average of sensory bitterness level was 3. The grittiness could not be evaluated because of bitterness. The results of film coating were excellent in view of yield and minimal coarse granules. Bitterness of coated microgranules was sensed to some extent when coating amount was lower than 20 wt%, however when the coating amount exceeded 20 wt%, the bitterness level was very low (1.3 on average) and its average grittiness level was 1 because of very small particles (D

As a result of preformulation experiment by direct compression of powder materials, it had been known that Man/MCC/CCS (66.5/17.7/15.8 [weight parts]) was a suitable excipient formulation for RDT regarding compactibility, disintegration property and mouth feel. These excipients were granulated using a fluidized bed granulator with water as a binder to prevent segregation with coated granules, and they were used as excipient granules for RDT. Figure 7 and Table 3 show the morphology and the properties of the excipient granules, and Figure 8 shows the results of tabletting. The hardness and disintegration time in water came up to the practical level at 5 kN of compression force. In this RDT, the disintegration time in mouth was 90 s, the average of sensory bitterness level was 1.3 and the average of sensory grittiness level was 1.  

Figure 9 shows the dissolution profiles of the IBD powder, the layered microgranules, the coated microgranules and the RDT. The dissolution speed of the IBD powder was not fast because of its low solubility in water. The release of IBD from the layered microgranules was slower than that from IBD powder because of the smaller specific surface area. The release from the coated microgranules was even slower than that from layered microgranules, however, the total amount of drug released reached more than 70% after 45 min. The release from the RDT was almost the same as that from coated microgranules, which, as well as the result of sensory bitterness evaluation, shows that the film of coated microgranules did not suffer any damage during tabletting. We infer that the reason for this is that it was compressed at low compression force and that the coated microgranules were enough small.  

Formulation and preparation methods of RDTs containing an intensely bitter drug were investigated. As a result, small taste-masked granules with a large quantity of drug (average particle size 277 μm and drug content  59 wt%) were obtained by a two-step production method, which was composed of drug layering on fine seed cores and subsequent film coating for taste masking. Grittiness and bitterness levels were practically acceptable for granules of RDTs. Furthermore, RDTs show a favourable dissolution profile of 72.3% after 45 min despite excellent masking performance of bitterness in mouth. This is achieved by compressing the film-coated granules with ideal excipient granules of high compactibility, fast disintegration properties and good mouth feel. Moreover, it contains as much as 21 wt% of drug. This experiment suggests that it is possible to reliably produce RDTs despite the general belief that formulating large amount of intensely bitter drug into RDTs is quite difficult. 

 is a chief engineer in the functional additives R&D department at Asahi Kasei Chemicals Corp. (Japan). He has more than 20 years' experience in the R&D of new pharmaceutical and food additives including MCC. 

 is an engineer in the functional additives R&D department at Asahi Kasei Chemicals Corp. Yoshida graduated from Miyakonojo Technical College (Japan), and joined Asahi Chemical Industry Co., Ltd in 1990. He is responsible for the development of new pharmaceutical technologies of controlled release dosage using MCC seed cores. 

Articles

This article describes how rapidly disintegrating tablets containing a large quantity of an intensely bitter drug were successfully developed with a suitable level of masking, tablet hardness, disintegration property, dissolution profile and mouth feel.