Preparation of orally disintegrating tablets from active ingredients of citrus peel by direct powder compression for the maintenance of brain function

Abstract

Citrus kawachiensis peel (PCK), a new functional food material, may prolong the healthy life expectancy of aging populations. Tableting PCK could facilitate its worldwide distribution and consumption. A PCK dosage form that is easy to swallow should be prepared for ease of use by the elderly. We investigated the fabrication of orally disintegrating (OD) tablets with the required commercial strength and disintegration time. We formulated OD tablets comprising PCK powder, crospovidone, vinylpyrrolidone vinyl acetate copolymer, light anhydrous silicic acid, D-mannitol, and magnesium stearate. The tablets were prepared using a rotary tableting press. Tableting was optimized by setting the target hardness to 30−50 N and target disintegration time to ≤ 2 min. When tableting was performed at a compression pressure of 7.5 kN, the hardness was 40 N and disintegration time was 1.5 min. The OD tablet containing a high proportion of PCK possessed the properties preferred and required for commercial products.

Introduction

Recently, national health care costs have risen in Japan partly because of increasing medical expenses for the elderly. According to the Ministry of Health, Labour, and Welfare, as of 2016, the proportion of national medical expenses by age group was 59.7 % for persons aged ≥ 65 y. The national health care cost per population had increased ∼4-fold from ∼184 000 yen for people < 65 y to ∼727 000 yen for those > 65 y ⁱ⁾. Therefore, efficacious prophylactic and therapeutic measures for the elderly are indispensable in reducing medical expenses. Extending healthy life span is considered an important objective ⁱⁱ⁾.

Improvements in the standard of living and advances in medical technology have enabled many people to become conscious of their health and longevity. There is a growing number of people seeking preventive or therapeutic products containing efficacious functional ingredients that are considered beneficial for health (Yasuda, 2002; Goda, 2015). Research has been conducted on the bioactive constituents in the peel of Citrus kawachiensis (PCK). This material is treated as a waste product during citrus beverage fabrication. PCK has been reported to show physiological activity in mouse brain (Amakura et al., 2013; Okuyama, 2015). Previous studies showed that the PCK constituent heptamethoxyflavone suppressed depression-like behavior, promoted hippocampal brain-derived neurotrophic factor production and neurogenesis, inhibited T cell growth, prevented cognitive impairment associated with type 2 diabetes, and exerted anti-stress and anti-inflammatory effects (Hamada et al., 2017; Sawamoto et al., 2017; Okuyama et al., 2018). In a mouse Parkinson's disease model, the PCK constituent auraptene suppressed dopaminergic neuron death via its anti-inflammatory action (Okuyama et al., 2016).

As PCK contains bioactive ingredients that help maintain normal brain function, it could serve as a novel functional food material that extends healthy life expectancy in an aging population. At present, beverages containing a paste obtained by finely grinding PCK are commercially available and said to be effective for maintaining or improving cognitive functions of middle-aged and elderly people (Fukuda et al., 2019). To promote and facilitate the global distribution of this supplement, it is preferable to manufacture it in tablet form as the quality of this format can be readily controlled and tablets are convenient and easy to transport, store, and consume. However, the estimated daily PCK dose required for efficacy in humans is 2 g d⁻¹ (Okuyama et al., 2014; Okuyama, 2015). If a tablet comprising 50 % PCK weighs 250 mg, then 15−18 tablets are required per day (5−6 tablets, 3× d⁻¹). In general, it is difficult to achieve and maintain patient compliance when a large number of tablets have to be consumed each day. Therefore, preparing tablets containing a high PKC content is convenient for ingesting them efficiently.

Herbal drug powders and plant-derived materials are generally hygroscopic as they contain large quantities of fiber. Moreover, their constituent particles have various shapes, low flowability, and high entrainment and adhesion. When such materials are tableted, they may have poor formability, slow disintegration, and inadequate hardness (von Eggelkraut-Gottanka et al., 2002; Mochizuki et al., 2005; Yamada and Takeuchi, 2011). Attempts have been made to improve powder handling and the physical properties of tablets by granulating their constituents with a fluidized bed granulator or roller compactor (Seko et al., 1993; Konishi et al., 2006a; Konishi et al., 2006b) or by producing wet tablets and subjecting them to microwave irradiation (Tanaka et al., 2016; Iwao et al., 2017). However, these methods require the installation of dedicated devices or the addition of water and may increase fabrication costs or destabilize the components. In contrast, direct powder compression may be effective. This process requires neither heating nor water injection and can tablet drugs that are heat- and moisture-sensitive.

Orally disintegrating (OD) tablets have attracted increasing attention in recent years. They can be easily swallowed without water as they rapidly disintegrate in the oral cavity in the presence of saliva. This dosage form is useful for the elderly and children and in emergency situations were potable water availability is limited. OD tablets may help improve patient quality of life ⁱⁱⁱ⁾ (Fu et al., 2004; Goel et al., 2008; Al-Husban et al., 2010; Badgujar and Mundada, 2011; Namiki, 2015). In view of its pharmacological activity, the PCK tested in the formulations developed in this study is expected to be consumed primarily by the elderly. However, aging individuals may have difficulty swallowing large numbers of tablets. Furthermore, if the patients present with dementia, they could be at risk of aspiration. Therefore, OD tablets could be very useful for this type of drug administration. Nevertheless, OD tablets are still required to have an appropriate hardness and a short disintegration time (Okuda et al., 2009; Douroumis et al., 2011; Stirnimann et al., 2013). Thus, several innovations are required for their production.

In this study, we investigated various additives that influence the strength and disintegration of tablets with high PCK content. We also explored the optimal conditions for continuous tableting with a rotary press in anticipation of mass production at the time of commercialization. Finally, we examined the fabrication of a tablet with a high PCK content and physical properties required for commercial products.

Materials and Methods

Materials    PCK sample was prepared and determined constituents as described in our previous study (Okuyama et al., 2014). The binders included low-substituted hydroxypropyl cellulose (L-HPC_20,21,22; L-HPC^® NBD-20, NBD-21, and NBD-22; Shin-Etsu Chemical Co., Ltd., Tokyo, Japan), microcrystalline cellulose (MCC; Ceolus^® uf-711; Asahi Kasei Corp., Tokyo, Japan), hydrogenated castor oil (HCO; Lubriwax^® 101; Freund Corp., Tokyo, Japan), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (PVA; Povacoat^®; Nisshin Kasei Co., Ltd., Osaka, Japan), aminoalkyl methacrylate copolymer (AMCE; Eudragit^® EPO; Evonik Industries AG, Essen, Germany), polyvinylpyrrolidone polyvinyl acetate (PVPA; Kollidon^® SR; BASF, Ludwigshafen, Germany), vinylpyrrolidone vinyl acetate copolymer (VA; Kollidon^® VA-64; BASF), and ammonioalkyl methacrylate copolymer (AMCRS; Eudragit^® RSPO; Evonik Industries AG). The fluidizing agent was light anhydrous silicic acid (LAS; Aerosil^® 200; Nippon Aerosil, Tokyo, Japan). Magnesium stearate (Mg-St; #5712; Mallinckrodt, Staines, UK) was the lubricant. Crospovidone (CP; Kollidon^® CL; CP_f; Kollidon^® CL-F; BASF), L-HPC₂₁ (Shin-Etsu Chemical Co., Ltd.), and croscarmellose sodium (CCS; Kiccolate™ ND-2HS; Asahi Kasei Corp.) were the disintegrants. D-Mannitol (Man; Granutol^® F; Freund Corp.) was the diluent for the OD tablets.

Preparation of PCK dry powder    PCK sample was sieve-classified for 30 min through a stainless-steel No. 100 sieve (aperture: 150 µm) and a sieve shaker (Analysette; Fritsch, Idar-Oberstein, Germany). PCK sample that did not pass through the sieve was pulverized (Crush Millser; Iwatani Corp., Osaka, Japan) for 2 min and reclassified with a No. 100 sieve. PCK dry powder particles that passed through the No. 100 sieve were measured with a laser diffraction particle size analyzer (SALD-2200; Shimadzu Corp., Kyoto, Japan) under 0.5 MPa compressed air and a 1.60–0.10i refractive index.

Preparation of model tablets    The pharmaceutical powder for model tablet preparation was weighed such that the total amount was ∼3.5 g and weight ratio was PCK:binder:Mg-St = 80:19:1 (w/w %). This sample was mixed by shaking in a 50-mL vial for 5 min and compressed with a tabletop tableting press (Handtab-100; Ichihashi Seiki Co., Ltd., Kyoto, Japan) fitted with an 8-mm diameter flat-face punch to generate 250 mg tablets. The tablets of all formulations were prepared by maintenance under a compression pressure of 10 kN for 10 s.

Formulation of PCK tablets and preparation of pharmaceutical powder    Table 1 shows the composition of the pharmaceutical powder used to make the PCK tablets. The PCK content was 75 % w/w, disintegrant was 0 %, 5 %, or 10 % w/w, binder was 11 %, 16 %, or 21 % w/w, LAS was 3 % w/w, and Mg-St was 1 % w/w. The total amount of powder was 300 g. PCK, binder, disintegrant, and LAS weighed according to the formulation were premixed in a V-type mixer (DV-5, Dalton, Tokyo, Japan) for 10 min. Mg-St was added to the mixture and blending continued for another 10 min to obtain a pharmaceutical powder.

Table 1. Compositions and component weights per tablet in each PCK tablet formulation

	Rp. 1	Rp. 2	Rp. 3	Rp. 4	Rp. 5	Rp. 6	Rp. 7	Rp. 8	Rp. 9
PCK	187.5	187.5	187.5	187.5	187.5	187.5	187.5	187.5	187.5
(75 %)	(75 %)	(75 %)	(75 %)	(75 %)	(75 %)	(75 %)	(75 %)	(75 %)
VA	52.5	40	27.5	40	27.5	40	27.5	40	27.5
	(21 %)	(16 %)	(11 %)	(16 %)	(11 %)	(16 %)	(11 %)	(16 %)	(11 %)
CPf		12.5	25
		(5 %)	(10 %)
CP				12.5	25
				(5 %)	(10 %)
CCS						12.5	25
						(5 %)	(10 %)
L-HPC21								12.5	25
								(5 %)	(10 %)
LAS	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
	(3 %)	(3 %)	(3 %)	(3 %)	(3 %)	(3 %)	(3 %)	(3 %)	(3 %)
Mg-St	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
	(1 %)	(1 %)	(1 %)	(1 %)	(1 %)	(1 %)	(1 %)	(1 %)	(1 %)
Total weight	250	250	250	250	250	250	250	250	250
(mg)

PCK: peel of Citrus kawachiensis, VA: vinylpyrrolidone vinyl acetate copolymer, CP_f: fine particle grade of crospovidone, CP: crospovidone, CCS: croscarmellose sodium, L-HPC₂₁: low-substituted hydroxypropyl cellulose, LAS: light anhydrous silicic acid, Mg-St,: magnesium stearate.

*  The numerical values in the table represent weight (mg), and the numerical values shown in parentheses represent composition (w/w %).

Formulation of PCK-containing orally disintegrating tablets and preparation of pharmaceutical powder    Table 2 shows the composition of pharmaceutical powder used to make the PCK-containing orally disintegrating (PCK-OD) tablets. For Rp. 10, the tablet weight was 250 mg and it consisted of 75 % w/w PCK, 10 % w/w disintegrant, 6 % w/w binder, 3 % w/w LAS, 1 % w/w Mg-St, and 5 % w/w Man. For Rp. 11−13, the tablet weight was 300 mg and comprised 62.5 % w/w PCK, 18.5, 22.5, or 24.5 % w/w disintegrant, 4, 6, or 10 % binder, 3 % w/w LAS, 1 % w/w Mg-St, and 5 % w/w Man. The total amount of powder was 300 g. PCK, binder, disintegrant, LAS, and Man weighed out according to the formulation were premixed in a V-type mixer (DV-5, Dalton) for 10 min. Mg-St was added to the mixture and blending continued for another 10 min to obtain a pharmaceutical powder.

Table 2. Composition and component weight per tablet in each PCK-OD tablet formulation

	Rp. 10	Rp. 11	Rp. 12	Rp. 13
PCK	187.5	187.5	187.5	187.5
	(75 %)	(62.5 %)	(62.5 %)	(62.5 %)
VA	15	30	18	12
	(6 %)	(10 %)	(6 %)	(4 %)
CPf	25	55.5	67.5	73.5
	(10 %)	(18.5 %)	(22.5 %)	(24.5 %)
LAS	7.5	9	9	9
	(3 %)	(3 %)	(3 %)	(3 %)
Mg-St	2.5	3	3	3
	(1 %)	(1 %)	(1 %)	(1 %)
Man	12.5	15	15	15
	(5 %)	(5 %)	(5 %)	(5 %)
Total weight	250	300	300	300
(mg)

PCK: peel of Citrus kawachiensis, VA: vinylpyrrolidone vinyl acetate copolymer, CP_f: fine particle grade of crospovidone, LAS: light anhydrous silicic acid, Mg-St: magnesium stearate, Man: D-mannitol.

*  Numerical values in table represent weights (mg). Numerical values in parentheses represent compositions (w/w %).

Continuous tableting of PCK tablets and PCK-OD tablets    PCK tablets were prepared by the direct powder compression method with a rotary tableting press (VELA 5; Kikusui Seisakusho, Kyoto, Japan). The pharmaceutical powder was supplied with an open feeder, and the distance between the feeder and turntable was 8 mm. Four sets of 8-mm diameter flat-face punches were used. The tablet weights were 250 mg for Rps. 1−10 and 300 mg for Rps. 11−13. The turntable rotation speed was 10 rpm, and the compression pressure was 5, 7.5, 10, or 15 kN. The tablets were collected 2 min after the onset of tableting.

Physical properties of the model, PCK, and PCK-OD tablets    The model, PCK, and PCK-OD tablets were desiccated for ≥ 24 h, and their weight variations, hardness, friability, and disintegration times were determined.

Weight variations were evaluated by weighing ten randomly selected tablets in an electronic balance (TE214S; Sartorius, Göttingen, Germany) and calculating the coefficients of variation (% CV).

Tablet hardness was measured with a load cell-type tablet hardness tester (PC-30; Okada Seiko Co. Ltd., Tokyo, Japan). The average hardness was calculated for ten tablets.

Tablet friability was measured with a tablet friability tester (TFT-120; Toyama Sangyo Co., Osaka, Japan). Fine powder adhering to the surfaces of 26 tablets was entirely removed with a brush, and the clean tablets were weighed. The tablets were placed in the friability tester and rotated 100 × at 25 ± 1 rpm. Then, the tablets were removed from the device, brushed as described above to remove any fine powder adhering to their surfaces, and reweighed. Friability was calculated based on the loss of tablet weight following rotation. The averages of triplicate measurements for each formulation were taken as the friability values.

The disintegration time was measured with a disintegration tester (NT-1HM; Toyama Sangyo Co.). Distilled water, first fluid, and second fluid of the Japanese Pharmacopoeia were the test media, and the operating temperature was 37 ± 2 °C ^iv). One tablet was placed in a glass tube in the test basket; six measurements were made per formulation, and the averages were recorded as the disintegration times.

Table 3 shows the criteria for approving the physical properties of each tablet.

Table 3. The criteria for approving the physical properties of each tablet

		Model tablet	PCK tablet	PCK-OD tablet
Hardness		≥ 50 N	≥ 50 N	≥ 30 N, ≤80 N
Disintegration time
	in water	≤ 30 min	≤ 30 min	≤ 2 min
	in first fluid	≤ 30 min	≤ 30 min	≤ 2 min
	in second fluid	≤ 30 min	≤ 30 min	≤ 2 min
Weight variation		(without setting)	≤ 1 %	≤ 1 %
Friability		(without setting)	≤ 0.5 %	≤ 2 %

Results and Discussion

Selection of binders suitable for the manufacture of tablets with high PCK content    The average particle size of the PCK used in this study was 46.28 ± 3.88 µm, and the geometric standard deviation was 2.93 ± 0.11. Auraptene concentration in this PCK was 2.92 mg g⁻¹. The daily auraptene intake required to achieve the expected efficacy was reported to be 6 mg (Okuyama et al., 2014; Okuyama, 2015). Therefore, it was necessary to integrate ∼2 g PCK per day. Assuming that 3−4 tablets are taken thrice daily, each tablet will contain ∼200 mg PCK. It was also necessary to avoid tablet enlargement for elderly patients. Therefore, we investigated the preparation of 250 mg tablets containing 70 %−80 % w/w PCK.

PCK alone could not be formed as a tablet. Consequently, to improve the compressibility of PCK, we decided to use a pharmaceutical powder. To prepare a model tablet containing 80 % w/w PCK, 10 different additives with various physical properties were tested as binder candidates. We sought an optimal binder based on tablet hardness and disintegration time. Figure 1 shows the hardness and disintegration time of model tablets prepared using PCK and various binders. Most binders had hardness ≤ 40 N. However, AMCE and VA had hardness ≥ 50 N, which is a practical strength standard (Fig. 1a).

Fig. 1.

Hardness and disintegration time of model tablets prepared with various binders. The model tablet had the composition of PCK:binder:Mg-St = 80:19:1 (w/w %), and was prepared as an 8-mm flat-face tablet under a compression pressure of 10 kN and compression time of 5 s. Distilled water was the medium for the disintegration test. a: hardness (n = 10); b: disintegration time (n = 6). Data represent the mean ± standard deviation.

The disintegration times of AMCE and VA were slightly longer than those for the tablets containing other binders (∼12 min; Fig. 1b). Nevertheless, this disintegration time meets the requirement for uncoated tablets (≤ 30 min) stipulated in the Seventeenth Japanese Pharmacopoeia ^iv) and was considered to be comparable to those for general pharmaceutical tablets. Therefore, AMCE and VA are suitable for the preparation of tablets with practical hardness and disintegration.

Figure 2 shows the model tablets prepared with PVA (lowest hardness), AMCE (highest hardness), and VA. The surfaces of the tablets prepared from PVA were rough and presented with cracks because the PCK particles could not be sufficiently filled with PVA (Fig. 2a). The plastic deformation of PVA was considered small. In contrast, the surfaces of tablets prepared with AMCE and VA were smooth and had no visible cracks or scratches (Fig. 2b, 2c). AMCE and VA were potentially plastically deformed by the compression pressure applied during tableting and sufficiently covered the PCK particles present on the tablet surface. VA, especially, is a highly plastic material (Chaudhary et al., 2018; Kolter and Flick, 2000). Therefore, tablet strength was enhanced by increasing the contact area between the PCK particles and VA.

Fig. 2.

Model tablets with PVA, AMCE, and VA as binder. The model tablet had the composition of PCK:binder:Mg-St = 80:19:1 (w/w %), and was prepared as an 8-mm flat-face tablet under a compression pressure of 10 kN and a compression time of 5 s. a: PVA; b: AMCE; c: VA. PVA: polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, AMCE: aminoalkyl methacrylate copolymer, VA: vinylpyrrolidone vinyl acetate copolymer.

Figure 3 shows the results of disintegration test using the first and second fluids as test media on tablets with AMCE and VA. When VA was used, the disintegration property was the same for all test media and distilled water (Fig. 1b). As AMCE is a gastric polymer, it was predicted that its disintegration time could be shortened in the first fluid (pH 1.2) by promoting water penetration via rapid AMCE dissolution. However, in both cases, for the first and second fluids, the disintegration time was extended to ≥ 30 min. The reason for this response could not be elucidated in the present study. Nevertheless, AMCE and VA have different functional groups. Therefore, it is believed that the components in PCK and functional groups in AMCE interacted in the first and second fluids, resulting in an increase in adhesion between particles and delay in water penetration. The aforementioned results showed that PCK tableted using VA as the binder satisfies the conditions generally required for commercial tablets in terms of both hardness and disintegration time.

Fig. 3.

Disintegration times in the first and second fluids for the model tablets using AMCE and VA as binders. Data represent the mean ± standard deviation (n = 6). Differences with the data for water as test medium were assessed using the t-test; n.s.: not significant, **: p < 0.005. AMCE: aminoalkyl methacrylate copolymer, VA: vinylpyrrolidone vinyl acetate copolymer.

Continuous PCK tableting    To assess the feasibility of commercial high-content PCK tablet production, we examined the conditions required for continuous tableting with a rotary tableting press. VA was added as the binder as it generated the best results in the model tablets. When tableting was performed using a pharmaceutical powder with the same composition as that of the model tablet, the pharmaceutical powder bridged in the hopper, and we could not generate a smooth powder supply. In the subsequent experiments, the PCK content was reduced to 75 %, and 3 % LAS was added as a fluidizing agent (Rp. 1). Table 1 shows the compositions and component weights per tablet in each PCK tablet formulation.

Figure 4 shows the relationship between the compression pressure and physical properties of PCK tablets. The weight variation was ∼0.7 %−0.85 % at all compression pressures (Fig. 4a). The addition of 3 % LAS improved the flowability of the pharmaceutical powder and reduced the weight variation to ≤ 1 % CV.

Fig. 4.

Relationship between the compression pressure and physical properties of PCK tablets. The tablets were prepared as 8-mm flat-face tablets based on Rp. 1. a: weight variation (n = 10); b: hardness (n = 10); c: friability (n = 3). Differences with the data at a compression pressure at 10 kN were assessed using the t-test; **: p < 0.005.

As shown in Fig. 4b, the hardness was ∼20 N at a compression pressure of 5 kN, and the tablet strength was inadequate. However, at a compression pressure of ≥ 10 kN, the hardness was ≥ 60 N, and a practical hardness was obtained. Moreover, the friability was significantly reduced to ∼0.5 % by compression at 10 kN (p < 0.005, t-test) (Fig. 4c). Thus, tableting at high compression pressure could produce a strong tablet despite the high contents of brittle PCK. Both the surface and internal strengths of the tablet could have increased because of the plastic deformation of the VA.

Figure 5 shows the relationship between the compression pressure and disintegration time of PCK tablets. For all test media, the disintegration time increased with compression pressure. The pores in the tablet could have decreased because of plastic deformation of the particles under high compression pressure and penetration of the test medium was inhibited. The tablets took slightly longer to disintegrate in the first fluid than they did in distilled water and the second fluid (Fig. 5b). Thin gel layers formed around the PCK tablets in the first fluid. It was presumed that acidity affected the components in the PCK tablets, and the protective hydrogel layers around them prevented penetration of the test medium and swelling of the tablets. As shown in Fig. 4b, a compression pressure of ≥ 10 kN was required to obtain a practical hardness of ≥ 50 N. Moreover, the disintegration time of the tablets prepared under these conditions was ∼10 min in all test media and increased with compression pressure. Even at a compression pressure of 15 kN, the resultant tablets met the criteria for uncoated tablet prescribed in the Japanese Pharmacopoeia ^iv). Thus, it is feasible to obtain tablets with the strength and disintegration time required for general tablets via continuous PCK-rich tableting.

Fig. 5.

Relationship between compression pressure and disintegration time of PCK tablets. The tablets were prepared as 8-mm flat-face tablets according to Rp. 1. a: distilled water; b: first fluid; c: second fluid. Data represent the mean ± standard deviation (n = 6). Differences with the data at a compression pressure of 10 kN were assessed using the t-test; **: p < 0.005.

To improve PCK tablet disintegration, various disintegrants were added to the formulations, and the physical properties of the tablet products were evaluated (Rps. 2−9). Figure 6 shows the physical properties of PCK tablets containing various disintegrants. For each disintegrant, the weight variation slightly increased with an increase in the amount of disintegrant added relative to that for the preparation without disintegrant (Fig. 6a). As shown in Fig. 6b, the hardness decreased with increasing disintegrant content. However, CP_f had a smaller particle size than CP and the former had a lower degree of hardness reduction than the other disintegrants. Hardness ≥ 50 N was maintained even when 10 % CP_f was added (average particle sizes: CP, 79.85 ± 2.59 µm; CP_f, 41.25 ± 1.53 µm). In contrast, L-HPC and CCS had the same (small) particle sizes as CP_f (average particle sizes: L-HPC, 47.91 ± 1.55 µm; CCS, 39.21 ± 0.91 µm) but did not maintain as high a hardness as CP_f. We were unable to elucidate the causes for these phenomena in the present study. Nevertheless, it is presumed that plastic deformation and particle strength were contributing factors. For the aforementioned amendments, friability showed the same tendency as hardness. When 10 % disintegrant (except CP_f) was added, the weight loss was ≥ 1 %. In the case of CP_f, however, the friability was < 1 % even at 10 % (Fig. 6c). Thus, as CP_f had a small particle diameter, it was readily deformed plastically, penetrated the gaps between the other components in the tablet, and could not decrease interparticle adhesion.

Fig. 6.

Physical properties of PCK tablets with various disintegrants. The tablets were prepared as 8-mm flat-face tablets according to Rps. 1–9 at compression pressure of 10 kN. a: weight variation (n = 10); b: hardness (n = 10); c: friability (n = 3). Differences with the data under no disintegrant were assessed using the t-test; n.s.: not significant, *: P<0.05, **: p < 0.005. CP_f: fine particle grade of crospovidone, CP: crospovidone, CCS: croscarmellose sodium, L-HPC: low-substituted hydroxypropyl cellulose.

Figure 7 shows the disintegration times of the PCK tablets containing various disintegrants. In all test media, disintegration time decreased with increasing disintegrant content. CP_f and CP tablets had superior disintegration properties and disintegration time to CCS and L-HPC tablets when CP_f and CP were added at 10 % concentration. The phenomenon may be explained by the relative differences in speed, including swelling and wicking, in response to water absorption. CP in contact with water swells rapidly, increasing the porosity inside the tablet (Katsuno, 2010). Subsequently, the established water channels promote water uptake into the tablet. Consequently, CP-based disintegrants may have strong disintegration properties because they cause rapid swelling and wicking upon water absorption. In particular, CP_f does not markedly lower tablet hardness as it has a small particle size. OD tablets are not clearly defined in the current Seventeenth Japanese Pharmacopoeia but are defined in the European Pharmacopoeia as those that disintegrate within 3 min ^v). To add another patient-oriented property to the PCK tablets prepared here, we attempted to shorten their disintegration time and make them meet the criteria for OD tablets.

Fig. 7.

Disintegration times of PCK tablets with various disintegrants. The tablets were prepared as 8-mm flat-face tablets according to Rps. 1–9 at compression pressure of 10 kN. a: distilled water; b: first fluid; c: second fluid. Data represent mean ± standard deviation (n = 6). Differences with the data under no disintegrant were assessed using the t-test; **: p < 0.005. CP_f: fine particle grade of crospovidone, CP: crospovidone, CCS: croscarmellose sodium, L-HPC: low-substituted hydroxypropyl cellulose.

Application of PCK to OD tablets    The foregoing experiments showed that the addition of VA as a binder and CP_f as a disintegrant to PCK tablets increased compressibility and disintegration. Therefore, we tried to restrict the disintegration time to 3 min by modifying the tablet formulation with the aforementioned additives. Man, which is frequently used in the formulation of OD tablets, was added to PCK to improve tablet water uptake (Rp. 10). To increase the disintegrant content without reducing the total PCK weight in the tablet, the tablet weight was increased to 300 mg (Rps. 11−13). OD tablets readily disintegrate in the oral cavity. Thus, a slight increase in tablet weight would not be expected to make tablet swallowing more difficult. Table 2 shows the composition and component weights per tablet per formulation. Here, tablets containing Man was referred to as PCK-OD tablets.

Figure 8 shows the hardness and disintegration times of PCK (Rps. 1,3) and PCK-OD (Rps. 10−13) tablets. The addition of CP_f significantly reduced the disintegration time (P < 0.005, t-test) (Fig. 8b). The hardness of Rp. 3 was slightly lower than that of Rp. 1 but was sufficient for commercial products (> 30 N) (Fig. 8a). The addition of Man further reduced the disintegration time. In contrast, replacing VA with Man significantly reduced the formability and lowered the hardness to ≤ 30 N (P < 0.005, t-test). To increase the VA content, the tablet weight was increased from 250 mg to 300 mg. The tablet composition was designed to ensure constant PCK weight per tablet. The hardness was ≥ 60 N for Rps. 11−13. Therefore, these formulations furnished sufficient tablet strength. Moreover, the disintegration times were in the range of only ∼2−4 min. Although the tablet weight had increased to 300 mg, it was presumed that the tablet could be easily consumed as it disintegrated orally and was readily broken down in the oral cavity. Thus, the objective was to identify the tableting conditions that could ensure disintegration within 2 min.

Fig. 8.

Effects of D-mannitol (Man) addition on tablet hardness and disintegration time. 8-mm flat-face tablets were prepared at a compression pressure of 10 kN. Distilled water was the test medium. a: hardness (n = 10); b: disintegration time (n = 6). Data represent mean ± standard deviation. Differences with Rp. 3 data were assessed using the t-test; **: p < 0.005.

Optimization of tableting conditions for the manufacture of PCK-OD tablets with physical properties required for commercial products    We analyzed the relationships among compression pressure, hardness, and disintegration time of tablets based on Rp. 13 to optimize the conditions necessary for the fabrication of tablets with the physical properties of commercial products. Figure 9 shows the hardness and disintegration times in distilled water when the compression pressures were 5, 10, and 15 kN. Both hardness and disintegration time increased with compression pressure. Figure 9 shows the relationships among these metrics in the form of a regression curve. For ordinary uncoated tablets, a hardness range of ∼50−80 N is required. For OD tablets, however, the preferred hardness is ∼30 N. In this study, the target tablet hardness range was set to 30−80 N. The target disintegration time was set to < 2 min, which was shorter than the time specified in the European Pharmacopoeia (≤ 3 min) ^v). Figure 9 indicates that tableting should be performed at a compression pressure range of 6.2−12.4 kN to achieve the desired hardness. To reach the target disintegration time, the tablet must be compressed at ≤ 9.1 kN. Therefore, the target hardness and disintegration time may be achieved by using an overlapping compression pressure range of 6.2−9.1 kN. The compression pressure in this range was that which was necessary to produce PCK-OD tablets with the physical properties required for commercial products.

Fig. 9.

Optimization of tableting conditions based on hardness and disintegration time of PCK-OD tablets. The tablets were prepared as 8-mm flat-face tablets based on Rp. 13 and under compression pressures of 5, 10, and 15 kN. Distilled water was the medium for the disintegration test.

Figure 10 shows the physical properties of tablets prepared at compression pressures of 5, 10, and 15 kN. It also presents the physical properties of a tablet prepared at 7.5 kN as representative compression pressure within the optimized range (6.2−9.1 kN) shown in Fig. 9. The weight variation decreased with increasing compression pressure and was a function of the adhesive forces between the tablet component particles. In other words, the use of higher compression pressures generated denser tablets that were not prone to friction abrasion caused by contact with the tableting press or other tablets. When the tablets were prepared at optimized compression pressure, their hardness was ∼40 N, which was within the target range. Tablet friability had the same tendency as tablet hardness and decreased with increasing compression pressure. Tablet strength increased with compression pressure. Tablets with the desired hardness were produced by controlling the compression pressure.

Fig. 10.

Physical properties of tablets prepared under optimized tableting conditions. The tablets were prepared as 8-mm flat-face tablets based on Rp. 13 and at a compression pressure of 7.5 kN. a: weight variation (n = 10); b: hardness (n = 10); c: friability (n = 3). Differences with the data under a compression pressure of 7.5 kN were assessed using the t-test; **: p < 0.005.

Figure 11 shows the disintegration times of tablets prepared at compression pressures of 5, 10, and 15 kN and those prepared at the optimized compression pressure of 7.5 kN. The tablets achieved the target disintegration time of 2 min in all test media. Controlling the tableting compression pressure as well as the composition of the formulation enables the production of OD tablets with the physical properties required for commercial products even when the tablets contain high proportions of PCK.

Fig. 11.

Disintegration of tablets prepared under optimized tableting conditions. Based on Rp. 13, the tablets were prepared as 8-mm flat-face tablets at a compression pressure of 7.5 kN. a: distilled water; b: first fluid; c: second fluid. Data are mean ± standard deviation. Differences with data under a compression pressure of 7.5 kN were assessed using the t-test; n.s.: not significant, *: p < 0.05, **: p < 0.005.

Conclusion

When we used AMCE or VA as the binder for the preparation of a PCK-rich tablet, we generated tablets meeting the target or required hardness and water disintegration time criteria. These are the general requirements for uncoated tablets. However, ACME disintegration was delayed in the first and second fluids. Thus, there may have been an interaction between PCK and AMCE. Therefore, it was determined that VA was suitable as the binder for the preparation of PCK tablets. When any disintegrant was added at a concentration of 10 %, the disintegration time decreased. The addition of disintegrant also reduced hardness. When CP_f with a relatively small particle diameter was added, the decrease in hardness was mitigated and the disintegration time was improved. When Man was added to the formulation, it improved disintegration even further but decreased tablet hardness. Nevertheless, both hardness and disintegration could be improved by increasing the tablet weight via an increase in the ratio of VA to PCK. In this way, an OD tablet having physical properties, such as hardness and disintegration required for commercial products, was prepared despite containing a high proportion of PCK, a natural plant-derived raw material having low formability. The OD tablets were prepared by direct powder compression method without processing the raw material. This is thought to be a useful method that can reduce waste parts of raw materials in the food processing industry and extend the healthy life expectancy of consumers.

Acknowledgements    The authors thank Mr. Naohiro Fukuda of the Ehime Institute of Industrial Technology for his assistance with PCK dry powder sample preparation. We also thank Mr. Hiroyoshi Tanaka of the Ehime Industrial Promotion Foundation for his advice in conducting this study. We would also like to thank Ehime Beverage Inc. for providing the Citrus kawachiensis peel, polyvinylpyrrolidone polyvinyl acetate (Kollidon^® SR), vinylpyrrolidone vinyl acetate copolymer (Kollidon^® VA-64), and crospovidone (Kollidon^® CL, CL-F) (all manufactured by BASF), low-substituted hydroxypropyl cellulose (L-HPC^® NBD-20, NBD-21, and NBD-22) manufactured by Shin-Etsu Chemical Co. Ltd., microcrystalline cellulose (Ceolus^® UF-711) and croscarmellose sodium (Kiccolate™ ND-2HS) manufactured by Asahi Kasei Corp., hydrogenated castor oil (Lubriwax^® 101) and D-mannitol (Granutol^® F) manufactured by Freund Corp., and aminoalkyl methacrylate copolymer (Eudragit^® EPO) and ammonioalkyl methacrylate copolymer (Eudragit^® RSPO) manufactured by Evonik Industries AG.

Funding    This work was not supported by any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abbreviations

AMCE

aminoalkyl methacrylate copolymer

AMCRS

ammonioalkyl methacrylate copolymer

CCS

croscarmellose sodium

CP

crospovidone

HCO

hydrogenated castor oil

LAS

light anhydrous silicic acid

L-HPC

low-substituted hydroxypropyl cellulose

Man

D-mannitol

MCC

microcrystalline cellulose

Mg-St

magnesium stearate

OD

orally disintegrating

PCK

peel of Citrus kawachiensis

PVA

polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer

PVPA

polyvinylpyrrolidone polyvinyl acetate

VA

vinylpyrrolidone vinyl acetate copolymer

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