Development of Fast Disintegrating Tablets Containing Loxoprofen Sodium by HYDROFLASH Manufacturing Method

Abstract

In order to create and offer superior pharmaceuticals for consumers who wish to be relieved of headache and fever as soon as possible, we established HYDROFLASH manufacturing method that enables us to offer fast disintegration tablets containing loxoprofen sodium (LX), which are difficult to disintegrate. As a result of screening excipients, tablets using mannitol showed the fastest disintegration time, about 2 min. From the result of viscosity measurement, we found that LX produced higher viscosity when dissolved in water. This suggests that tablets containing LX disintegrate slower by inhibiting the penetration of water into the tablet due to the viscosity caused of LX. Therefore, we created a manufacturing method to make it easy for water to penetrate the tablet. It is possible to achieve fastest disintegration in about 30 s for tablets containing LX by granulating in a fluidized-bed with spraying of the dispersion of light anhydrous silicic acid (LASA). LX-containing tablets manufactured by the HYDROFLASH method disintegrated immediately after contact with water. Furthermore, it was observed that LASA was uniformly dotted on the surface of tablets by HYDROFLASH method, compared with other manufacturing methods. We considered that by fluidized-bed granulation with LASA dispersion (HYDROFLASH manufacturing method), water permeates through LASA on the tablet surface regardless of viscosity of LX. Futhermore, LX-containing tablets by the HYDROFLASH method showed that the dissolution rate of LX was nearly 100% at 5 min after starting the test. We considered that the initial dissolution became faster because of the fast disintegration.

Introduction

Disintegration of tablets is the first step in absorption in the gastrointestinal tract. If disintegration of tablets is delayed in the gastrointestinal tract, absorption from the gastrointestinal tract may be delayed, making it difficult to ensure the efficacy of drug treatment. Therefore, the reduction of disintegration time of tablets can shorten the time to effect development, and it becomes an effective means for the symptom in which the speed of action is required.¹⁾ Headache and fever are one of the conditions in which early remediation is desired because they cause trouble in life, and there are many people who deal with them with OTC drugs.²⁾ In fact, headache and fever are symptoms that make up the top of drug store consultation items. In the clinical practice guideline for chronic headache, mild headache can be treated with OTC drugs, and treatment at medical institutions is not required unless specific severe headache attacks or OTC drugs are ineffective.³⁾ Therefore, there is a high demand for antipyretic analgesics that work quickly for OTC drugs. Currently, active pharmaceutical　ingredients　(APIs) of antipyretic analgesics in OTC drugs include loxoprofen sodium hydrate (LX), ibuprofen, acetaminophen, ethenzamide, and many of these are called non-steroidal anti-inflammatory drugs (NSAIDs) and inhibit cyclooxygenase, which is responsible for pain and fever. LX is prodrug of NSAIDs, therefore it has relatively few gastropathy which we are suffered from as side effects of NSAIDs conventionally, and LX has been reported potent analgesic action.^4–6) Since LX became a switch OTC drug in 2012, several preparations containing LX have been marketed, and LX preparations have secured a certain market in the antipyretic analgesic area of OTC drugs. However, LX has water solubility issues. It is reported that LX is a low solubility and high permeability drug classified into Class II in Biopharmaceutics Classification System (BCS) and that has low solubility in water under low pH conditions.^7,8) It is also reported that hydrates such as LX are inferior in solubility in water than anhydrates.⁹⁾ In addition, it has been reported that water-soluble salts such as LX remarkable changes its surface properties due to form hydrated ions with easy surface transfer on the solid surface in contact with water. It is considered that these cause troubles such as adhesion and viscosity.¹⁰⁾ Considering these physical properties, LX has unsuitable physical properties for fast disintegration of tablets, and it is considered that designing tablets containing LX with fast disintegration is extremely difficult. However, since OTC drugs of antipyretic analgesics in the country are mostly tablets and tablets are one of the most received dosage forms, LX fast-disintegrating tablets are considered to be very effective.^11,12)

In this study, we attempted to create a manufacturing method that tablets containing LX disintegrate rapidly by because of meeting the expectations of consumers wishing to cure headache and fever as soon as possible. As a fast approach, we focused on light anhydrous silicic acid (LASA) that is an inorganic excipient, insoluble in water and hydrophilic.¹³⁾ LASA is a submicron-sized aggregate composed of nano-size and is often used as a glidant.¹⁴⁾ LASA is also used as a surface-modifying agent to improve wettability of water-insoluble drugs because of its excellent water absorption capacity along with particle size.^15–18) In this study, considering the versatility, cost, expansion of the manufacturing machine, and securing of the installation site, etc., we developed fast disintegrating technology of tablets containing LX with generally used manufacturing machines and excipients when we manufacture solid dosage forms. As a result, LX-containing tablets produced by the HYDROFLASH method using LASA dispersion as a granulation solvent in a fluidized bed granulator disintegrated faster than LX-containing tablets produced by the conventional fluidized bed granulation. The HYDROFLASH method is a granulation method in which sugar alcohol is used and LASA water dispersion instead of binder is sprayed onto the flowing powder in a fluidized bed granulator, forming liquid bridges between particles, and aggregating them. Unlike the conventional method, the HYDROFLASH method needs no binder to granulate, which results in faster disintegration of the tablets. Despite of using no binder, the tablets have sufficient tablet hardness comparable to that of conventional methods that use binder. The HYDROFLASH methods does not require special manufacturing equipment and can be manufactured using conventional equipment. Furthermore, the excipients are general-purpose mannitol and light anhydrous silicic acid, making it possible to manufacture at low cost. Therefore, the HYDROFLASH method is a useful method that can manufacture tablets with both rapid disintegration and sufficient hardness without the use of special equipment or excipients. The design of LX-containing tablets that disintegrate quickly and with sufficient hardness, which has not been achieved previously, provides a useful solution for people hoping early relief from headaches. By this technology, we can offer a useful solution for consumers who are suffered from headache.

Experimental

Materials

We used LX (Loxoprofen sodium hydrate) manufactured by Daiwa Pharmaceutical Co., Ltd. (Toyama, Japan). We used α-lactose hydrate (Lactose, powder grade) manufactured by DSM, anhydrous calcium hydrogen phosphate (Anhydrous calcium hydrogen phosphate-GS) manufactured by Kyowa Chemilcal Industy Co., Ltd. (Kagawa, Japan), and β-type d-mannitol (Mannit-P) manufactured by Mitsubishi Corporation Life Sciences Limited. (Tokyo, Japan), light anhydrous silicic acid (Aerosil-200) manufactured by NIPPON AEROSIL CO., LTD. (Tokyo, Japan), crospovidone (Kollidon CL) manufactured by BASF, and magnesium stearate (Magnesium Stearate) manufactured by Taihei Chemical Industrial Co., Ltd. (Osaka, Japan), as a lubricant.^19–21)

Methods

Preparation of Mixed Powders and Granulated Granules

The manufacturing flow of each formulation is shown in Fig. 1.

Fig. 1. Summary of the Manufacturing Process Flow

F1～F5: The powders were weighed at the ratios shown in Table 1 and mixed in a mortar to obtain a powder for tableting.

Table 1. Formulation of Tablets

Formulation code	F1	F2	F3	F4	F5	F6	F7
Method	DC*1	DC*1	DC*1	DC*1	DC*1	HSG*2	FG*3
Loxoprofen sodium dihydrate	204.3	204.3	204.3	204.3	204.3	204.3(a)	204.3(a)
Lactose	780	—	—	—	—	—	—
Anhydrous dibasic calcium phosphate	—	780	—	—	—	—	—
Mannitol	—	—	780	758	734	758	758
Light anhydrous silicic acid	20	20	20	42	66	42	42
Purified water(b)	—	—	—	—	—	500	500
Crospovidone	50	50	50	50	50	50	50
Magnesium stearate	10	10	10	10	10	10	10

(a) Loxoprofen sodium: 180. (b) Removed during processing. *1 DC: Direct compaction. *2 HSG: High shear wet granulation. *3 FG: Fluidized-bed granulation

F6: LX and mannitol were weighed and mixed at the ratios shown in Table 1. We prepared water dispersion of LASA as the granulation solvent. We used a high-shear granulator (VG-05, Powrex Co., Ltd., Hyogo, Japan). Granulation was performed under the conditions shown in Table 2, and the wet granules were dried using a fluidized-bed granulator (MP-01, Powrex Co., Ltd.) under the conditions shown in Table 3. Dried granules, Crospovidone and Magnesium Stearate were mixed to obtain a powder for tableting.

Table 2. Operating Conditions of High-Speed Shear Granulation

Total charge amount (kg)	0.8
Impeller speed (rpm)	297
Chopper speed (rpm)	1000
Wetting flow rate (g/min)	approx.90
Wet massing time (s)	approx.180
d50 (µm)	198.2
Loss on drying (%)	0.42

Table 3. Operating Conditions of Dry

Drying inlet air temperature (°C)	80
Inlet air volume (m3/min)	0.8

F7: LX and mannitol were weighed at the ratios shown in Table 1, mixed, and fluidized-bed granulation solvents were same granulation solvents of F6. The granulator was used a fluidized-bed granulator (MP-01, Powrex Co., Ltd.). Granules were prepared by granulation and drying under the conditions shown in Tables 3 and 4. Granules, crospovidone and Magnesium Stearate were mixed to obtain a powder for tableting.

Table 4. Operating Conditions of Fluidized-Bed Granulation

Total charge amount (kg)	0.5
Inlet air temperature (°C)	60
Inlet air volume (m3/min)	0.5
Product temperature (°C)	approx.30
Spray rate (g/min)	approx.7
d50 (µm)	180.0
Loss on drying (%)	0.35

Granules Size Distribution and Loss on Drying

About 5 g of granules were sieved by a sieving method particle size distribution measuring device (Robot Shifter RPS-01, Seishin Enterprise Co., Ltd., Tokyo, Japan). The mesh size was 710, 500, 355, 250, 180, 150, 106, 75 µm and measuring was vibrated for 3 min. From the results, d50 was calculated. D50 indicates the mass weighted average of particle diameter. The moisture content of granules F6, F7 was determined in triplicate by heating about 5 g of sample to 70 °C for 30 min was observed. The measurements were performed using a halogen moisture analyzer (MX-50, A&D). The obtained results were used as the loss on drying (LOD) values.

Preparation of Tablets

Tableting was carried out with a rotary tableting machine (Correct 12 HU, Kikusui Seisakusho, Ltd., Tokyo, Japan) by setting the tablet weight at 345 mg, with a diameter 9 mm flat surface punch, the machine rotation rate at 40 rpm, the compression pressure at 550–800 kgf and the tablet’s tensile strength at 0.5 MPa or higher.

Evaluation of Tablet Physical Properties

Tablet Hardness and Tablet Porosity

Using a tablet hardness tester (Schleuniger, 6 M tester, Pharmatron Dr.schleuniger), the tablet breaking force (breaking strength) was measured and broken vertically at the rate of 0.2 mm/s. From the result of this measurement, the tensile strength was calculated with the equation given below, and the mean of 10 tablets was adopted.²²⁾

  

• F: Tablet Hardness [N], D: Tablet Diameter [mm]. t: Tablet Thickness [mm]

The tablet porosity ε was calculated from the thickness and diameter of each tablet to obtain the apparent volume, using the following equation.²³⁾

  

• m: Mass of the tablet [mg], V: Apparent volume [mL] ρt: True density [g/mL]

Disintegration Test

The disintegration test was conducted in accordance with the Japanese Pharmacopeia’s General Testing Methods (Disintegration Test for Immediate-Release Dosage Forms).¹²⁾ Purified water with temperature kept at 37 ± 2.0 °C was used for the test, and no auxiliary disc was used. The mean disintegration time of 6 tablets was adopted.

Dissolution Test

The dissolution test was conducted in accordance with the Japanese Pharmacopeia’s Generating Testing Methods (Paddle Method for Dissolution Test).¹³⁾ The test used a dissolution tester (RT-J2000, Dainippon Seiki Co., Ltd., Kyoto, Japan), with water serving as a solvent and the rotation rate set at 50 rpm. The eluate (5 mL) was collected at 5, 10 and 15 min after the start of the test, followed by assay of loxoprofen sodium hydrate in accordance with the Japanese Pharmacopeia’s method,¹³⁾ quantification with high performance HPLC (Shimadzu, type: LC20A) and calculation of LX dissolution rate. The mobile phase used was a mixture of methanol, water, acetic acid, triethylamine(600 : 400 : 1 : 1, v/v) with a flow rate of 1.0 mL/min, temperature of 40 °C, and injection volume of 10 µL. UV detection was carried out at 222 nm, and the analysis time was 7 min.

Disintegration Characterization of Tablets

Viscosity Measurements of Saturated Aqueous Solutions

Saturated aqueous solutions were prepared by dissolving LX, acetaminophen (Iwaki Seiyaku), lactose and mannitol with purified water. Viscosity of each of these saturated aqueous solutions was measured, using a vibrating viscometer (VISCOMATE VM-100A, Toki Sangyo Co., Ltd., Tokyo, Japan). The temperature of each aqueous solution was set at 23 ± 0.5 °C during measurement and the measured volume 30 mL.

Tablet Surface Observation

The tablet surface was observed using a low-vacuum scanning electron microscope (SU1510, Hitachi High-Technologies Co., Ltd., Tokyo, Japan, Accelerating voltage of 5 kV). Energy-dispersive X-ray spectroscopy (HORIBA X-max, Tokyo, Japan) was used to identify the elemental Si present on the tablet surface at 480 s scan times. The percentage of Si that occupied the surface of the tablet was also calculated.

Evaluation of Water Penetration into the Tablet

A purified water 50 mL at 37 °C in which a colorant (erythrosine B) 100 mg was dissolved was adjusted, and the adjusted purified water was poured into a filter paper. A tablet was placed on a filter paper containing purified water, and a tablet was taken out 5 s after the start of the test, and a tablet cross section was observed using a fiber scope (Model, manufactured by Keyence Co., Ltd., Osaka, Japan) The time for water to reach the top of the tablet was also measured, and the mean value was calculated (n = 3).

Statistical Analysis

The sample size calculation was 6 tablets for each group. Results are expressed as mean ± standard deviation (S.D.). We used Bonferroni’s multiple comparison test. Differences between groups were compared using unpaired t-test. All statistical analyses were performed using Microsoft^® Excel^® for Microsoft 365 MSO (version2201 16.0.14827.20180) 32 bit, and a p value of <0.05 was considered statistically significant.

Results and Discussions

Effect of Excipients on Disintegration of LX-Containing Tablets (F1～F3)

Since numerous excipients are available for use in manufacture of pharmaceutical products, we confirmed the effect of excipients with various physical properties on the disintegration property of tablets containing LX. The excipients tested were lactose (a kind of sugar highly soluble in water and used also in the existing original product), mannitol (a sugar alcohol highly soluble in water and often used in orally disintegrating tablets) and anhydrous dibasic calcium phosphate (a general-purpose excipient practically insoluble in water).^13,24) Tablets of three compositions (F1 through F3) listed in Table 1 were prepared. The compression pressure for tableting and the tensile strength of tablets manufactured are shown in Table 5. The disintegration time of tablets is graphically showed in Fig. 2. With each of the compositions F1 through F3, tablets having a tensile strength of about 0.5 MPa was yielded. The disintegration time was about 12 min for the tablets containing lactose (highly soluble in water; F1). It was about 3 min for the tablets containing anhydrous dibasic calcium phosphate (practically insoluble in water; F2). It was about 2 min for the tablets containing mannitol (F3). Thus, the tablets with composition F3 disintegrated faster than those with composition F1 or F2. Regarding the reason why the disintegration time was much shorter with the F2 tablets containing anhydrous dibasic calcium phosphate (practically insoluble in water) than with the F1 tablets containing lactose (highly soluble in water), it seems likely that the high-water absorptivity of anhydrous dibasic calcium phosphate despite low solubility in water stimulated permeation of water into the tablet.²⁵⁾ Observation of disintegration showed that F1 was a dissolving-type in which the tablets gradually dissolved from the surface of the tablets in contact with water. On the other hand, F2 using calcium hydrogen phosphate anhydrous was a disintegrating-type in which the tablets were disintegrated. Therefore, we considered that F2 became a fast disintegration because the water was drawn from the tablet surface into the tablet inside by the anhydrous calcium hydrogen phosphate, and the penetration of water into the tablet inside was promoted. This suggestion is a useful tool for improving disintegration of tablets containing LX. Next, the reason why F3 using mannitol had more fast disintegration times than F1 was considered. The solubilities of mannitol and lactose are almost similar (1 g in 5.24 mL and 1 g in 5.5 mL, respectively, for water at 20 °C).²⁶⁾ The disintegration was observed in both F1, F3 to be the same dissolving type, while in F3 the tablet was observed to be dissolved at once. This may be due to differences in the dissolution rates of mannitol and lactose.^27,28) Since mannitol has a faster dissolution rate than lactose, it was presumed that F3 using mannitol had a faster disintegration even though the solubility was similar.²⁹⁾ These results allowed us that the use of an inorganic excipient having a high-water absorption capacity and the use of mannitol having a high dissolution rate are effective to be disintegrated rapidly tablets containing LX.²⁸⁾

Table 5. Compression Force and Tensile Strength of Tablets (n = 5, Mean ± Standard Deviation)

Formulation code	F1	F2	F3	F4	F5	F6	F7
Compression force (kgf)	800	600	600	550	700	500	400
Tensile strength (MPa)	0.52 ± 0.02	0.51 ± 0.02	0.60 ± 0.02	0.90 ± 0.03	0.62 ± 0.02	0.90 ± 0.01	1.01 ± 0.06
Tablet porosity	0.142	0.172	0.140	0.148	0.150	0.126	0.166

Fig. 2. Effect of Various Excipients on Disintegration Time

*: Multiple comparative test for p < 0.05 (Bonferroni, n = 6, mean + standard error of the mean (S.E.M.)).

Influence of Viscosity on Disintegration Behavior of Tablets Containing LX

Although LX is water-soluble, disintegration times of tablets containing LX are different by excipients. Following this finding, we inferred that the physical properties of LX in water may inhibit the penetration of water into the inside of the tablet and measured the viscosity.¹³⁾ As shown in Table 6, the viscosity of saturated aqueous solution of LX was 13.9 mPa·s, significantly higher than that of saturated aqueous solution of acetaminophen, which is the same antipyretic analgesic ingredient. Saturated aqueous solution of lactose or mannitol also showed low viscosity. This suggests that when LX is dissolved in water, the surface viscosity of the LX-containing tablet increases, resulting in suppression of water permeation into the tablet and slowing of tablet disintegration.^30–33)

Table 6. Viscosity of Saturated Solution

Solutions	LX	Acetaminophen	Lactose	Mannitol	Water
Temperature [°C]	22.8	22.7	22.8	22.7	22.7
Viscosity [mPa·S]	13.9	1.40	1.52	1.41	1.02
Concentration [g/100 mL]	100	1.4	16	18.1	—

Effect of LASA on Disintegration of LX-Containing Tablets

As discussed in the preceding chapter, to promote the penetration of water into tablets of containing LX, tablets should be a disintegrating-type by using inorganic excipients that show high water absorption capacity, and the tablets should be quick dissolving-type by using mannitol. In this study, we confirmed effect of LASA, which has a higher water absorption capacity than calcium hydrogen phosphate anhydrous. LASA is a submicron size aggregate insoluble in water and hydrophilic. The primary particles constituting this aggregate are of nano size and are fine particles also used for surface modification of APIs. LX containing tablets using LASA formulations of various compounding weights were prepared (Table 1). The compression pressure and the tensible strength of these tablets are shown in Table 5, the disintegration time is graphically showed in Fig. 3. The disintegration time was about 2 min for the LX-containing tablets using a 1 : 0.1 mixture of LX and LASA (F3) and within 1 min for the LX-containing tablet using a 1 : 0.2 mixture of LX and LASA (F4) and using a 1 : 0.3 mixture of LX and LASA (F5). All of F3 through F5 tablets showed the disintegrating-type disintegration. We consider the reasons why the disintegration times became faster in F4 than in F5 as follow. By adding LASA, the wettability of the tablet is improved and water penetration into the tablet is promoted.^15,16) However, by adding 0.2% LASA to the formulation, we consider that there is enough LASA near LX. In F5 which contains 0.2% or more LASA, LASA exists both near and far from LX and draws in the water necessary for the disintegrant to swell.³⁴⁾ We considered that the physical properties of LASA affected as the reason why the disintegration times became faster in F4, F5 than in F3. LASA is hydrophilic and has high water absorption capacity.^17,34) Therefore, it was presumed that the increase in the amount of LASA promote penetration of water into the tablets and a reduction in the disintegration time.³⁵⁾ In addition, since the LASA is fine particles, a large number of LASA is present in the tablet, and also the LASA is dotted on the surface or in the vicinity of LX which generates the viscosity, so that it is considered that the water guide path by the LASA can be secured, and the promotion of the penetration of water into the inside of the tablet is improved without being affected by the viscosity.

Fig. 3. Effect of LASA Content on Disintegration Time of Tablets

*: Multiple comparative test for p < 0.05 (Bonferroni, n = 6, mean + S.E.M.).

Effect on Disintegration Time by HYDROFLASH Manufacturing Method

With the expectation that dot-formed distribution of LASA on the surface of and near the LX within the tablet would be useful in shortening the tablet disintegration time, we explored an optimum method of efficiently distributing LASA near the LX within the tablet. We considered that the use of LASA dispersed in a solvent for granulation would be more suitable than the use of a mixture of LASA and LX to achieve distribution of LASA on the surface of LX. We dispersed LASA in purified water and used this as a solvent for granulation to evaluate the high-shear granulation method and the fluidized-bed granulation method. Table 5 shows the compression pressure and tensile strength of tablets produced using the granulated granules, and Fig. 4 shows the disintegration time. The tensile strength of the tablets containing the granules prepared with either agitation granulation (F6) or fluidized-bed granulation (F7) was high (0.9 and 1.0 MPa, respectively). The tablet prepared by direct tableting (F4: the control group) had a tensile strength of 0.6 MPa, lower than the F6 and F7 tablets. The tablet containing the granules prepared by agitation granulation (F6) had a disintegration time close to 1 min, slightly longer than the time for the F4 tablet (direct tableting). On the other hand, the tablet containing granules prepared by fluidized-bed granulation (F7) had a disintegration time of about 30 s, shortest among the F1 through F7 tablets although its tensile strength was highest among all these tablets.

Fig. 4. Effect of Granulation Methods on Disintegration Time of Tablets

*: Multiple comparative test for p < 0.05 (Bonferroni, n = 6, mean + S.E.M.).

Water Penetration Behavior of Tablets

To confirm the penetration behavior of water into the tablet, the tablet cross section was observed 5 s after contact with water, and the measurement was based on.³⁶⁾ The results of the penetration behavior are shown in Fig. 5, and the penetration time required for the tablets to penetrate from the bottom to the top is shown in Table 7. For the F4 tablets, water did not penetrate to the top of the tablets in 5 s, and the penetration time was 43.33 s. F6 tablets like F4 tablets also did not penetrate to the top of the tablets in 5 s, and the penetration time was 51.67 s. On the other hand, in F7 by HYDROFLASH method, it was confirmed that water permeated into the upper portion of the tablet at 5 s, penetration time was 4.92 s. As the reason why the disintegration time of F7 is about half that of F4 and F6 (Fig. 4) although the penetration time is about 1/10 (Table 7), we consider that in observation of cross-section of tablets upon exposure to distilled water, the difference between formulations is figured prominently because only one surface of tablets is in contact with water in a static state, while in the disintegration test, it was showed smaller difference because all surfaces of the tablets are in contact with water in a state of up and down movement. Therefore, it was confirmed that F7 by HYDROFLASH penetrate water into tablets more quickly.

Fig. 5. Observation of Cross-section of Tablets upon Exposure to Distilled Water for 5 s: (A) F4, (B) F6, (C) F7, Control Tablet Is Not Soaked in Distilled Water

Table 7. Water Penetration Time of Tablets

Formulation	F4	F6	F7
Average time (s)	43.33	51.67	4.92
Standard deviation	3.51	4.04	0.88

Disintegration Mechanism of Tablets

Distribution of LASA on the Tablet Surface

The disintegration behavior of tablets was examined in detail. We evaluated the tablet surface using SEM-EDX (Fig. 6) and the distribution ratio of Si (Table 8). We analyzed the distribution of Si, a constituent element of LASA, not included in other APIs or excipients.³⁷⁾ In F4 LX tablets surface by the direct tableting method, Si was present inhomogeneously and agglomerated, and the distribution ratio of Si was low. In F6 LX tablets surface by high-shear granulation method, Si was uniformly dispersed and not agglomerated, but the distribution ratio was as low as that of F4. In spite of using LASA dispersion, we considered that LASA is kneaded into LX and mannitol (Supplementary Fig. 1) and is less present on the tablet surface because a strong shearing force is applied in the high-shear granulation method.³⁸⁾ On the other hand, in F7 LX tablets surface by HYDROFLASH method (fluidized-bed granulation method) were uniformly dispersed, and the distribution ratio was higher. We considered that the LASA were dotted uniformly on the surface of the granules (Supplementary Fig. 1), because granules are porous by fluidized-bed granulation and spraying the LASA dispersion.^38,39) Therefore, it became apparent that LASA was uniformly dispersed on the tablet surface by fluidized-bed granulation with the LASA dispersion. It has been reported that hydrophilic LASA improves wettability by improving hydrophobic particle surface to hydrophilicity, and that LASA is porous and improves disintegration of tablets by capillary action.^14,40,41) Therefore, it was considered that the wettability of the tablet surface was improved by uniform distribution of LASA on tablet surface, and that penetration of water into tablets was accelerated from LASA on the tablet surface by the capillary action because of porous LASA. Therefore, it was considered that LX-containing tablets by HYDROFLASH manufacturing method was able to be uniformly dispersed LASA on the tablet surface, be promoted the penetration of water, and fast disintegration time of tablets could be achieved.^14,29)

Fig. 6. Scanning Electron Micrographic Images and X-Ray Maps of Tablet Surface: (A) F4, (B) F6, (C) F7

Table 8. Silicon Composition (%) of Tablet Surface Obtained from Energy Dispersive X-Ray Spectroscopic (EDX) Analysis (n = 3 Mean ± Standard Deviation)

Formulation	F4	F6	F7
Silicon composition (%)	2.27	2.16	15.07
Standard deviation	0.45	0.13	1.35
Max.	2.56	2.3	17.05
Min.	1.74	2.03	14.03

Dissolution of Tablets Containing LX by HYDROFLASH Method

The dissolution profile of LX-containing tablets manufactured by each method were shown in Fig. 7. The F1 tablet containing lactose (used also in existing products) had a disintegration time of about 12 min and a dissolution rate as low as 20% at 5 min after the start of the test. The dissolution rate of this tablet did not reach 85% or higher even at 15 min after the start of the test, indicating a slow initial dissolution. The initial dissolution was shown to be slow for the LX-containing tablets which take much time for disintegration.

Fig. 7. Dissolution Profile of LX-Containing Tablets

◆: F1 (Lactose: Direct compaction), ▲: F2 (CaHPO4: Direct compaction), ×: F4 (Mannitol: Direct compaction), 〇: F6 (Mannitol: High-shear granulation), ■: F7 (HYDROFLASH, Mannitol: Fluidized-bed).

With the F2 tablet containing anhydrous dibasic calcium phosphate which showed a shorter disintegration time (about 3 min), on the other hand, the dissolution rate was about 60% at 5 min after the start of the test although not reaching 85%. The F7 tablet prepared by HYDROFLASH method which recorded the shortest disintegration time (about 30 s) achieved an 85% or higher dissolution rate at 5 min after the start of the test, confirming that this tablet has a dissolution profile characterized by quite fast initial dissolution. These results indicate that fast initial dissolution of LX is enabled by shortening of the tablet disintegration time. Therefore, assigning the rapidly disintegrating feature to LX-containing tablets is expected to provide a solution useful for people desiring early alleviation of headache during daily living.

Conclusion

In order to create and offer superior pharmaceuticals for consumers who wish to to be relieved of headache and fever as soon as possible, we established HYDROFLASH manufacturing method that enables us to offer fast disintegration tablets containing LX which are difficult to disintegrate and verified its disintegration mechanism. It became clear that LX produces high viscosity when dissolved in water, and the reason why the disintegration property of the tablet containing LX was poor is considered that the penetration of water into tablets was inhibited by the viscosity of LX dissolved when the tablet contacted with water. Therefore, we studied formulations and manufacturing methods for promoted the penetration of water into tablets regardless of viscosity of LX, and established HYDROFLASH method that was used mannitol as an excipient and granules obtained by fluidized-bed granulation with dispersion of LASA which is a highly water-absorbing and hydrophilic porous fine particle. Whereby we developed a fast disintegrating tablet technology containing LX, LX tablets manufactured using that technology disintegrated in 30 s. To clarify the fast disintegration mechanism by HYDROFLASH manufacturing method, the tablets were observed. As a result, it was confirmed that the tablet surface produced by the HYDROFLASH manufacturing method was uniformly dotted with LASA as compared with other manufacturing methods. It is known that LASA is hydrophilic and improves the disintegration property by capillary action by its porous structure. From this, we considered that the HYDROFLASH manufacturing method did not affect the viscosity of LX, and that the wettability of the tablet surface was improved by the uniform dispersion of LASA on the tablet surface, and that the water was able to penetrate into tablet by the capillary action due to the porous area of the LASA, thereby achieving fast disintegration. We have succeeded in designing LX-containing tablets characterized by quite short disintegration time (about 30 s) and quite fast initial dissolution while keeping sufficient hardness, by mehods of combination of common excipients (mannitol and LASA) and HYDROFLASH method, without using any special manufacturing machine or excipients. The technique also does not require specialized facilities or equipment, so it can be applied not only to LX but also to other APIs. The tablets with these become useful solutions for consumers suffered from headache during daily living. Furthermore, our success in designing the core technology for fast disintegrating tablets is expected to contribute to realization of rapidly disintegrating tablets of drugs like LX whose initial release from solid dosage forms was conventionally slow.

Conflict of Interest

Aya Kuwata is currently an employee of Taisho Pharmaceutical Co., Ltd.

Supplementary Materials

This article contains supplementary materials.

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