Optimization and Advantages of Molded Tablets Using Trehalose as a Binder

Abstract

Molded tablets are manufactured by molding wet powder at low pressure and drying. Typically, water-soluble polymers are used as a binder; however, the ratio to achieve both tablet strength and rapid disintegration is limited, and designing an optimal formulation according to the active ingredients can be challenging. In addition, production may be temporarily interrupted owing to the adherence of wet powder to the inside of the mortar, which can hamper stable production. Therefore, optimization was performed by design of experiments to utilize the disaccharide trehalose as a binder for molded tablets. We formulated placebo tablets with high tablet strength and rapid disintegration. On examining the tablet interior, we confirmed the formation of solid bridges between particles and high porosity, suggesting that trehalose can be used as a binder for molded tablets. The viscosity of the trehalose saturated solution was lower than that of the polyvinyl alcohol (PVA) solution (3.8 wt%). Moreover, the trehalose formulation exhibited a significantly lower wet powder adhesion rate to the upper punch than the PVA formulation. This study provided valuable results for the future formulation design of molded tablets.

Introduction

Orally disintegrating tablets (ODTs) are tablet formulations that can be taken even with a small amount of water or without water, which is a beneficial property for elderly individuals with impaired swallowing and patients with restricted fluid intake. In addition, ODTs are highly favored by pediatric patients and healthcare professionals in the field of pediatric pharmaceutical formulations, attracting considerable attention in recent years.^1,2) Moreover, it has been reported that 63% of physicians believe that appropriate ODTs could replace the most popular liquid formulations in pediatric dosage forms.³⁾ Children with a poorly developed swallowing ability find it difficult to swallow and take standard tablets, and the cooperation of medical professionals and family members is essential for appropriately administering the tablet formulation.⁴⁾ However, ODTs can be taken only with saliva in the oral cavity; hence, they can be deemed a child-friendly dosage form.

Some ODTs are defined as “molded tablets.” According to the Japanese Pharmacopoeia 18th Edition (JP 18), molded tablets are produced by embedding a wet kneaded mixture containing chemicals in a certain mold, molding, and then drying.⁵⁾ Considering one method for manufacturing a molded tablet, the wet powder is subjected to low-pressure molding in a pestle through a film using a unique molded tableting machine, followed by subsequent drying using a conveyor-type dryer to obtain tablets^6,7) (Fig. 1). Using this manufacturing method, it is possible to obtain tablets with adequate hardness and high porosity, allowing normal handling by molding the wet powder at low pressure (about 100 to 300 N); this high porosity enables rapid disintegration.⁸⁾ In addition, low-pressure molding can overcome the exudation of active pharmaceutical ingredients induced by high molding pressure (approximately 10 kN), typically attributed to general tableting machines, and the destruction of coating granules subjected to elution control and masking of bitterness.^8,9) Ikematsu et al. have succeeded in tableting vitamin E, a fat-soluble drug, without exudation from granules using low-pressure molding with a molded tableting machine.⁸⁾ Therefore, low-pressure molding with a molded tableting machine would allow the tableting of formulations that pose considerable challenges with a standard tableting machine.

Fig. 1. Manufacturing Method for Molded Tablets

Furthermore, given that molded tablets obtained by low-pressure molding comprise only three components, i.e., the active ingredient, excipient, and binder, excellent contact stability between the drug substance and additive is considered an additional advantage. The use of minimal additives is desirable in the field of pediatric pharmaceutical formulations. The “Addendum to guidance on clinical investigation of medicinal products in the pediatric population” (ICH E11 (R1))¹⁰⁾ states that, as certain additives can cause adverse reactions in children that are not observed in adults, the additives used and the additive content in the pharmaceutical formulation should be such that they are necessary to ensure product performance, stability, palatability, microbial control, and dose uniformity, with minimal risks.

Based on the above evidence, molded tablets obtained by low-pressure molding exhibit characteristics distinct from ODTs manufactured using a general tableting machine (molding pressure of about 10 kN), and further formulation development can be achieved by exploiting these characteristics. In particular, the development of pediatric pharmaceutical formulations has attracted global attention in recent years.^11–13) It can be suggested that molded tablets, which can be easily taken by children and contain few additives, are advantageous in this field.

Although molded tablets typically exhibit high disintegration activity, issues with tablet strength, such as cracking and chipping due to porosity within the tablet, have been reported.¹⁴⁾ In addition, during low-pressure wet powder molding, the wet powder adheres to the interior surface of the mortar, resulting in a poor tablet appearance during production. Hence, interrupting production may be necessary to clean the mortar, hindering stable production.

Water-soluble polymers such as polyvinylpyrrolidone (PVP) and polyvinyl alcohol (PVA) are used as binders for manufacturing molded tablets with low-pressure molding. Enhanced tablet strength has been observed as the ratio of added polymer increases, along with reduced disintegration.⁷⁾ Therefore, to achieve suitable tablet strength and rapid disintegration, the ratio of added water-soluble polymer should not exceed approx. 2%. Notably, using a water-soluble polymer as a binder can reduce the degree of freedom of formulation design. Accordingly, we focused on saccharides as a new binder, given their capacity to achieve high solubility by forming solid bridges.

Trehalose, a type of disaccharide, is a non-reducing disaccharide in which the reducing groups of glucose are linked by α, α-1, 1. Moreover, trehalose is a natural carbohydrate widely present in microorganisms such as bacteria and yeast, as well as in animals and plants such as mushrooms and insects.¹⁵⁾ Following the introduction of industrial production, trehalose has been available since 1994 and is used as a food and pharmaceutical additive. Owing to its high binding property and high solubility (68.9 g/100 g·water, 20 °C),^16,17) trehalose is considered a suitable binder for molded tablets that require both high tablet strength and rapid disintegration. In addition, trehalose exerts flavoring effects and is odor-free,¹⁸⁾ both advantageous properties for molded tablets, given that the desire to take the tablet is an important factor. Furthermore, trehalose has a critical relative humidity of ≥90% and low hygroscopicity,¹⁷⁾ affording high storage stability. Accordingly, trehalose has excellent properties as a potential binder for molded tablets. Moreover, given that trehalose is a highly safe food additive that does not have an acceptable daily intake setting, it can be a suitable binder for pediatric pharmaceutical formulations. The use of trehalose as a binder for molded tablets would widen the ratio of added binder, thereby facilitating the design of an optimal formulation with both tablet strength and rapid disintegration according to the active ingredients. In addition, powder adhesion to the interior mortar surface during molding might decrease, given the loss of water-soluble polymer-induced high viscosity. Reducing powder adhesion within the mortar during molding is critical for stable production.

Therefore, in the present study, we investigated the optimization of placebo formulation and manufacturing conditions using the response surface methodology to develop molded tablets with trehalose as a binder. In addition, given that molded tablets can be taken on the go without water, we speculated that molded tableting of anti-motion sickness and cough medications would be beneficial for drug administration. Accordingly, we selected diprophylline (Dip; anti-motion sickness medication) and dextromethorphan hydrobromide hydrate (Dex; cough medication) as model drugs and evaluated the physical properties of model drug-molded tablets. Finally, we evaluated the powder adhesion rate to the upper punch when the wet powder was compression molded using water-soluble polymer (PVA) and trehalose as binders, respectively.

Results and Discussion

Optimization of Placebo Formulation and Manufacturing Conditions

A prototype of 15 conditions was evaluated according to the response surface design with the placebo formulation. The responses obtained are shown in Table 1. For molded tablets, maximizing hardness (N) (Y₁), minimizing friability (%) (Y₂), and minimizing disintegration time (s) (Y₃) are desirable characteristics. Therefore, to satisfy multiple response goals simultaneously, the value of each factor for which the overall desirability function is maximized was determined. Figure 2 shows the prediction profile that can maximize the overall desirability function. Considering Fig. 2, if the amount of trehalose (g) (X₁) added is set to 3.11 g, the amount of solvent (g) (X₂) is set to 3.63 g, the ethanol concentration of the solvent (%) (X₃) is set to 41.72%, and the molding pressure (N) (X₄) is set at 300 N, the desired result could be obtained for all responses. Therefore, the values of each of these factors were considered optimal values, and the optimal placebo formulation (Table 2) and manufacturing conditions (molding pressure of 300 N) were determined.

Table 1. Responses Obtained from Experimental Design

No.	Responses
	Hardness (N) (Y1)	Friability (%) (Y2)	Disintegration time (s) (Y3)
1	36.2	0.0	16
2	41.3	0.0	105
3	44.7	0.0	11
4	37.0	0.0	10
5	35.7	0.0	30
6	37.0	0.0	17
7	45.6	0.0	25
8	22.5	0.3	19
9	46.6	0.0	25
10	7.1	0.9	21
11	20.0	0.0	15
12	64.4	0.0	21
13	38.0	0.1	13
14	13.4	0.3	26
15	34.4	0.0	14

Fig. 2. Prediction Profile with the Overall Desirability Function Maximized

Table 2. Optimal Placebo and Active Ingredient-Containing Formulations

Compounding ingredients	Raw material name	Ratio (wt%)
		Placebo	Dip13	Dex15
Excipient	Pearlitol® 25C	89.6	78.8	77.1
Binder	Trehalose P	10.4	10.4	10.4
Active ingredient	Dip	─	10.8	─
	Dex	─	─	12.5
Solvent	99% ethanol	5.0a)	5.0a)	5.0a)
	Purified water	7.1a)	7.1a)	7.1a)
Total amount (excluding solvents)		100	100	100

a) Ratio with respect to solid content. Dex, dextromethorphan; Dip, diprophylline.

Figure 3a shows contour profiles of hardness versus solvent amount and molding pressure, and Fig. 3b shows contour profiles of disintegration time versus solvent amount and molding pressure. In all areas of this figure, the friability rate is 1.0% or less. Overlaying the contour profiles of hardness (Fig. 3a) in disintegration time (Fig. 3b) results in design space (Fig. 3c, white area) for a friability of ≤1.0%, a hardness of >40N, and a disintegration time of <20 s which meets the disintegration time of ODTs (within 30 s) recommended by the U.S. Food and Drug Administration (FDA).¹⁹⁾ The black circle in Fig. 3c exhibit the optimal condition that maximize the desirability function and it can be considered that the optimal condition is located in the center side of the design space, which exhibit high tablet strength and rapid disintegration.

Fig. 3. Contour Profiles of Responses versus Solvent Volume and Molding Pressure

Prototype Results under Optimal Conditions

Setting each factor to the optimal value, a molded tablet with 62.9 N hardness, −0.1% friability, and a 10 s disintegration time can be obtained; hence, a molded tablet was prepared, and the response was confirmed. As shown in Table 3, no large discrepancy was observed between predicted and measured values, with the response surface model exhibiting a high accuracy. The tablet exhibited sufficient strength with a hardness of 70.4 N and a friability of 0.0%, along with a rapid disintegration time of 16 s, meeting the disintegration time of ODTs (within 30 s) recommended by the FDA.¹⁹⁾ On examining the tablet interior using an electron microscope, we confirmed that numerous solid bridges were formed between particles (Fig. 4), which could explain the high tablet strength.

Table 3. Predicted and Measured Values of Optimal Condition Responses

	Responses
	Hardness (N)	Friability (%)	Disintegration time (s)
Predicted values	62.9	−0.1	10
Measured values	70.4	0.0	16

Fig. 4. Image of Table Interior Obtained Using an Electron Microscope (1500×, White Circle: Solid Bridges)

Tablets with high internal porosity reportedly exhibit rapid disintegration properties.⁸⁾ Therefore, assessing the typical normal tablet (disintegration time of approximately 10 min) and the molded tablet using an electron microscope, we confirmed that the molded tablet displayed more apparent voids between particles than the normal tablet (Fig. 5). Accordingly, it was inferred that the prepared molded tablet with rapid disintegration had higher porosity than the normal tablet. We measured the tablet porosity using X-ray computed tomography (CT). The normal and molded tablets exhibited porosities of 9.2 and 24.4%, respectively, revealing that the molded tablet with rapid disintegration had higher porosity than the normal tablet (Fig. 6). Based on the above findings, the use of trehalose as the binder instead of a water-soluble polymer could afford high tablet strength owing to the formation of solid bridges between particles. Moreover, the high porosity resulted in a molded tablet with rapid disintegration properties.

Fig. 5. Image of Table Interior Obtained Using an Electron Microscope (100×, Left: Normal Tablet, Right: Prepared Molded Tablet)

Fig. 6. Tablet Porosity Determined by Xray-CT

Molded Tablets Containing Model Drugs

We next measured the physical properties of prepared molded tablets (Table 2) by partly replacing Pearlitol^® 25C with the selected model drug (Dip or Dex). Both tablets had a high strength with a hardness of ≥40 N and a friability of 0.1%. Moreover, the disintegration time was ˂20 s, satisfying the ≤30 s recommended time set by the FDA (Table 4). Therefore, we confirmed that the molded tablets exhibiting sufficient tablet strength and rapid disintegration could be produced using trehalose as a binder, even in formulations containing selected model drugs. However, the model drug-containing molded tablets exhibited approx. 35% reduction in hardness when compared with that of the placebo molded tablets. This could be attributed to the addition of the model drug reducing the ratio of the added excipient, Pearlitol^® 25C.

Table 4. Physical Properties

Formulation	Hardness (N)	Friability (%)	Disintegration time (s)
Dip13	46.5	0.1	15
Dex15	44.2	0.1	16

Dex, dextromethorphan; Dip, diprophylline.

Herein, we obtained molded tablets with sufficient tablet strength and rapid disintegration by replacing excipients with model drugs; hence, further improvements in tablet physical properties could be achieved by conducting optimization studies with formulations containing model drugs.

Upper Punch Adhesion Rate of Wet Powder Using PVA or Trehalose as the Binder

We compared the physical properties of molded tablets prepared using polymer (PVA) or trehalose as a binder. Compression molding of wet powder using PVA as a binder revealed that the powder markedly adhered to the upper punch, and the tablet could not be produced. Therefore, the rate of powder adhesion to the upper punch when the wet powder was compression molded was evaluated. Considering the wet powder using PVA as a binder, 9.2% of powder adhered to the upper punch with respect to the powder filling amount in the mortar; however, only 0.1% of wet powder adhered to the upper punch on compression molding with trehalose as the binder (Fig. 7). Figure 8 presents an image of the upper punch after compression molding the wet powder. The wet powder using PVA as the binder substantially adhered to the upper punch, while the wet powder using trehalose as the binder hardly adhered to the punch. The wet powder is a state in which the powder and the solvent are kneaded; hence, the dissolved binder may exist on the powder surface. Therefore, we compared the viscosities of the PVA solution (3.8 wt%) of the PVA formulation (Table 5) and the trehalose saturated solution of the placebo optimal formulation using trehalose (Table 2). Accordingly, the PVA (3.8 wt%) and trehalose saturated solutions had viscosities of 13.8 mPa·s and 7.3 mPa·s, respectively, at a rotor rotational speed of 20 rpm, revealing that the trehalose saturated solution has a low viscosity (Fig. 9). Thereby, the wet powder using trehalose as a binder hardly adhered to the upper punch when compared with the PVA formulation.

Fig. 7. Upper Punch Adhesion Rate of Wet Powders Using PVA and Trehalose as a Binder

Mean±standard deviation (S.D.) (n = 3) is represented by bars. Student’s t-test was used to determine statistically significant differences for trehalose. * p < 0.05. PVA, polyvinyl alcohol.

Fig. 8. Image of Upper Punch after Compression Molding Wet Powder (Left: PVA Formulation, Right: Trehalose Formulation)

PVA, polyvinyl alcohol.

Table 5. Formulation Using PVA as the Binder

Compounding ingredients	Raw material name	Ratio (wt%)
Excipient	D-Mannitol	99.6
Binder	PVA	0.4
Solvent	99% ethanola)	2.6
Solvent	Purified watera)	7.8
Total solid content (excluding solvents)		100

a) Ratio with respect to solid content. PVA, polyvinyl alcohol.

Fig. 9. Viscosities of PVA (3.8 wt%) and Trehalose Saturated Solutions

PVA, polyvinyl alcohol.

Based on the above findings, we confirmed that using trehalose instead of PVA as a binder for preparing molded tablets could reduce the adhesiveness of the wet powder. During compression molding using a molded tableting machine, the wet powder is compressed using a pestle through a film, and the wet powder does not adhere to the pestle directly; however, the decreased adhesiveness of the wet powder may reduce production issues associated with powder adhesion to the mortar. In addition, in molded tableting machines, a lubricant is applied to the film to enhance the mold releasability of wet powder and film; however, using trehalose as the binder may eliminate the need for this operation. Therefore, reducing wet powder adhesiveness by using trehalose as a binder instead of the widely used water-soluble polymer would be markedly beneficial in future formulation design.

Conclusion

By performing an optimization study using the response surface methodology, we determined the optimal placebo formulation and conditions (molding pressure) for molded tablets using trehalose as a binder. Furthermore, we confirmed that molded tablets with high tablet strength and rapid disintegration could be obtained even in the formulations in which the excipient was partially replaced with model drugs. In addition, we demonstrated that the adhesiveness of the wet powder using trehalose as the binder was significantly reduced when compared with that of the wet powder using PVA, a commonly used binder, potentially improving the poor tablet appearance attributed to powder adhesion in the mortar, avoiding interrupted production for cleaning. Our findings suggest that trehalose can be a new binder for preparing molded tablets.

Experimental

Optimization of Placebo Formulation and Manufacturing Conditions

Materials

Given that D-mannitol, an excipient, is considered to increase the contact area between small particles and improve tablet strength, Pearlitol^® 25C (D50: about 25 µm), which has a smaller particle size, was adopted among the grades of mannitol. Pearlitol^® 25C was purchased from Roquette Japan K.K. (Tokyo, Japan), trehalose was purchased from Hayashibara Co., Ltd. (Okayama, Japan), and 99% ethanol was purchased from Japan Alcohol Trading Co., Ltd. (Tokyo, Japan). Purified water was used.

Experimental Design by Response Surface Methodology

The response surface methodology was used to optimize the placebo formulation and manufacturing conditions of molded tablets with trehalose as the binder. Statistical analysis software (JMP ver.15, SAS Institute, U.S.A.) was used for the design of experiments and to analyze responses. The experimental design was created according to the I optimization criterion, which minimizes the mean variance of predictions over the entire experimental domain and is a suitable criterion for predicting responses.²⁰⁾ The response was analyzed by fitting a least-squares model.

Regarding factors, trehalose amount (g) (X₁), solvent (mixed solution of ethanol and water) amount (g) (X₂), the ethanol concentration of solvent (wt%) (X₃), and molding pressure (N) (X₄), which were confirmed to impact tablet strength and disintegration time by preliminary studies, were selected. Considering responses, hardness (N) (Y₁), friability (%) (Y₂), and disintegration time (s) (Y₃) were selected.

Table 6 shows the factors and their study range, and Table 7 shows the experimental design for 15 batches determined by JMP.

Table 6. Factors and Study Range

Factors	Study range
	Lower limit	Upper limit
Trehalose amount (g) (X1)	2	5
Solvent amount (g) (X2)	2	5
Ethanol concentration of solvent (wt%) (X3)	25	50
Molding pressure (N) (X4)	100	300

Table 7. Experimental Design of Response Surface Methodology (I Optimization Criterion)

No.	Study factors
	Trehalose amount (g) (X1)	Solvent amount (g) (X2)	Ethanol concentration of solvent (wt%) (X3)	Molding pressure (N) (X4)
1	3.5	3.5	25	100
2	5	5	25	300
3	2	5	50	300
4	5	5	50	100
5	5	2	50	300
6	3.5	3.5	50	200
7	3.5	5	36.75	200
8	3.5	2	25	200
9	5	3.5	37.5	200
10	5	2	50	100
11	2	2	50	300
12	3.5	3.5	32.375	300
13	2	3.5	25	200
14	2	2	37.5	100
15	2	5	50	100

Optimization of Placebo Formulation and Molding Pressure

One strategy to identify optimal values using the response surface methodology uses the desirability function, in which the overall desirability function (scale: 0 to 1) for multiple response variables is determined as the geometric mean of the desirability function of each response variable and the value of the factor for which this reaches a maximum is the optimal value.²¹⁾ Therefore, the value of each factor for which the overall desirability function reached a maximum was determined as the optimal value.

Preparation of Placebo Molded Tablets

The batch size was 30 g. According to the experimental design in Table 2, 15 batches of prototypes were prepared. The excipient Pearlitol^® 25C (30 g-X₁) and the binder trehalose (X₁) were placed in a mill (R-8, Nippon Rikagaku Kikai Co., Ltd., Tokyo, Japan) and mixed for 10 s. Next, the solvent X₂ (mixed solution of ethanol and water) with an ethanol concentration of X₃ was added to this mixture and kneaded for 30 s to obtain a wet powder.

Briefly, 120 mg of wet powder was filled as solid content into a 7-mm mortar, compressed at a molding pressure of X₄ using a Tensilon universal testing machine (RTG-1210, A&D) and a 7-mm diameter double R (9.8 × 2.8) shape pestle, and subsequently dried.

Tablet Hardness

Ten tablets were measured using a hardness tester (KHT-20N, Fujiwara Scientific Co., Ltd., Japan), and the average value was calculated.

Friability Measurement

Friability was measured using a tablet friability tester (TFT-120, Toyama Sangyo, Japan). Twenty tablets were placed in the drum, and the drum was rotated at 25 rpm for 4 min. Then, the weights of all tablets remaining in the drum were measured, and the difference in weight before and after rotation was calculated.

Disintegration Time

The disintegration time of six tablets was measured using a disintegration tester (NT-60H, Toyama Sangyo, Japan) with 37 ± 2 °C purified water as the test solvent, and the average value was calculated.

X-ray CT

X-ray CT (Phoenix v|tome|x m 240/180, Baker Hughes Japan, Japan) was used to examine the internal tablet structure. The tube voltage and current were set at 90 kV and 200 µA, respectively. The focus-to-rotation center distance (SRD) was 22 mm, and the rotation center-to-detector distance was 785.53 mm, resulting in a voxel size of 5.4 µm. VG Studio MAX 3.2 (Volume Graphics, Japan) was used for image analysis, and 2 × 2 × 2 mm of the center of the tablet was set as a region of interest. After binarizing the region of interest, the ratio of void voxels of ≥50 µm diameter to all voxels was obtained as the porosity. Two tablets of each optimal placebo formulation (Table 2) using trehalose or PVA (Table 5) as the binder were examined, and the average value of the porosity was calculated.

Examining the Tablet Interior

The tablet was split diametrically, and the split cross section was observed using a scanning electron microscope (S-3400N, Hitachi High-Technologies, Japan).

Molded Tablets Containing Model Drugs

Materials

Considering model drugs, Dex was purchased from Alps Pharmaceutical Ind. Co., Ltd. (Gifu, Japan) and Dip from Shizuoka Coffein Co., Ltd. (Shizuoka, Japan). All other additives were the same as those used in “Optimization of Placebo Formulation and Manufacturing Conditions.”

Preparation of Molded Tablets Containing Active Ingredients

Briefly, a portion of the Pearlitol^® 25C from the optimal placebo formulation was replaced with the model drug; each prepared tablet (120 mg) contained 13 mg of Dip or 15 mg of Dex (Table 2). The content of Dip or Dex in each tablet was referred to the content as a pharmaceutical product. The wet powder was prepared using the same procedure as in “Preparation of Placebo Molded Tablets” according to the formulation in Table 2. The wet powder (120 mg) was filled into a 7-mm mortar as a solid content, compressed at a molding pressure of 300 N using a Tensilon universal testing machine (RTG-1210, A&D) and a 7-mm diameter double R (9.8 × 2.8) shape pestle, followed by drying.

Evaluation of Wet Powder Adhesion Rate to the Upper Punch

Materials

Table 5 shows the formulation of molded tablets using a water-soluble polymer (PVA) as the binder. The formulation was cited from the example of the published patent publication (JP 2018-24632: Applicant Elmed Eisai Co., Ltd.). D-Mannitol (Mannite P, D50: approx. 50 µm) was purchased from Mitsubishi Corporation Life Sciences Ltd. (Tokyo, Japan), and PVA (Gohsenol EG-05P) was purchased from Mitsubishi Chemical Corporation (Tokyo, Japan). All other additives were the same as those used in “Optimization of Placebo Formulation and Manufacturing Conditions.”

Preparation of Wet Powder Using PVA or Trehalose as the Binder

The batch size of the wet powder using PVA as the binder was 30 g, and the addition rate of each component was in accordance with Table 5. D-Mannitol was placed in a mill (R-8, Nippon Rikagaku Kikai) and mixed for 10 s. Next, after adding the ethanol solution (ethanol/water) with dissolved PVA, the mixture was kneaded for 30 s to obtain a wet powder.

The wet powder formulation using trehalose as the binder was the optimal placebo formulation (Table 2), and the wet powder was prepared using the same procedure as in “Preparation of Placebo Molded Tablets.”

Powder Adhesion Rate to the Upper Punch

Briefly, wet powder using PVA or trehalose as the binder was filled into a 7-mm mortar, such that the solid content was 110 mg. Compression was performed at a molding pressure of 200 N using a Tensilon universal testing machine (RTG-1210, A&D) and a 7-mm diameter double R (9.8 × 2.8) shape pestle. The powder adhesion rate to the upper punch (wt%; powder adhesion amount to the upper punch/filling amount in the mortar) was measured in triplicate, and the average value was calculated.

Viscosity Measurement

A saturated solution of trehalose was prepared with the optimal placebo formulation using trehalose (Table 2). In addition, a PVA solution (3.8 wt%) was prepared with the formulation (Table 5) using PVA as a binder.

A B-type viscometer (TVB-10, Toki Sangyo Co., Ltd., Tokyo, Japan) was equipped with an M1 rotor and a guard, and the viscosity of the above solution was measured. The viscosity was measured 60 s after initiating the measurement, and the solution temperature during measurement was maintained at 20 °C. After performing two measurements each at rotor rotational speeds of 5, 10, 20 and 30 rpm, we calculated the average value for each rotational speed.

Acknowledgments

The authors would like to express their gratitude to Executive Officer Yasushi Arai and Advisor Yukiya Yamaguchi (Sannova Co., Ltd., Japan) for providing the opportunity to undertake this research. The authors also thank Kenji Asao and Masafumi Nomura (Sannova Co., Ltd., Japan) for their advice and consideration regarding this research. Finally, the authors would like to express their gratitude to Yuichi Takahashi of the Gunma Prefectural Gunma Industrial Technology Center for measuring the X-ray CT of tablets.

Funding

This research received no external funding.

Author Contributions

Yuki Takahashi: Conceptualization, methodology, data organization, and writing. Takayuki Furuishi: Conceptualization, methodology, writing review, and editing. Etsuo Yonemochi: Conceptualization, methodology, writing review, and editing.

Conflict of Interest

Yuki Takahashi is an employee of Sannova Co., Ltd. This research does not receive specific grants from the public, commercial, or non-profit sector funding agencies.

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