Sildenafil orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sildenafil orally disintegrating tablet and a preparation method thereof. The sildenafil orally disintegrating tablet is prepared from the following raw materials in percentage by mass: 10 to 20 percent of sildenafil, 50 to 80 percent of filling agent, 5 to 15 percent of disintegrating agent, 2 to 6 percent of flavoring agent, 1 to 2 percent of flow aid and 1 to 2 percent of lubricating agent, the flavoring agent is aspartame and peppermint essence; the disintegrating agent is a mixture of cross-linked sodium carboxymethyl cellulose and low-substituted hydroxy propyl cellulose. The prepared sildenafil orally disintegrating tablet has good disintegration property, stability and dissolution rate, effectively covers bitter taste, and has wide application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sildenafil orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Erectile dysfunction (ED) is a common sexual dysfunction disease. ED brings anxiety, tension and other emotions to patients, affects the relationship between husband and wife and family, and even social work. In addition, ED is also an early signal of cardiovascular disease. Therefore, the development of drugs for the treatment of ED is very important for human health. Sildenafil is a PDE5 inhibitor, which is a drug for the treatment of male erectile dysfunction accidentally invented during the research and development of drugs for cardiovascular diseases, and is widely used for the treatment of erectile dysfunction.

[0003] Orally disintegrating tablets are convenient for administration and have a rapid onset of action, and are suitable for children, the elderly, mentally handicapped people, and patients with swallowing difficulties. Their preparation process is difficult, and it is necessary to simultaneously meet the requirements of disintegration in the oral cavity and good taste, and there are certain technical barriers. Traditional tablets need to be taken with water, and there are problems such as inconvenient medication and slow onset of action (about 30 - 60 minutes). Existing orally disintegrating tablet technologies have problems such as insufficient disintegration time. Some orally disintegrating tablets have a disintegration time exceeding 1 minute, which affects patient compliance; the taste is not good, the bitterness of sildenafil is obvious, and existing taste masking technologies (such as coating, adding sweeteners) may affect disintegration or stability, etc.; and most of the existing technologies use hygroscopic excipients, which are prone to cause the tablets to absorb moisture and agglomerate, affecting long-term storage.

[0004] For example, Chinese Patent CN103040835A discloses a pharmaceutical composition containing sildenafil citrate and PD-1 type pregelatinized starch and a preparation method thereof. The pharmaceutical preparation prepared by using the pharmaceutical composition containing sildenafil citrate and PD-1 type pregelatinized starch and the preparation method provided by the present invention can be completely disintegrated in water at 37°C within 15 seconds to 30 seconds, and can pass through a sieve with a mesh size of 600 - 710 μm. However, this invention does not involve the addition of a glidant. As is well known, a glidant can significantly improve the fluidity of powders or granules, thereby optimizing the filling uniformity during the production process (such as weight control in pharmaceutical tableting). Therefore, the impact of not adding a glidant on the final tableting performance cannot be ignored.

[0005] Wei Xiaolin from Hebei University of Science and Technology conducted pH solubility curve and particle size determination on the raw material sildenafil citrate in her master's thesis "Preparation Study of Sildenafil Citrate Orally Disintegrating Tablets", preliminarily determined the raw and auxiliary materials and carried out compatibility tests, established an analytical characterization method for orally disintegrating tablets, and analyzed the reference preparation as a reference standard for self-made orally disintegrating tablets. Orally disintegrating tablets were prepared by powder direct compression process and wet process respectively, and the influencing factors, accelerated and long-term tests were carried out on three batches of self-made orally disintegrating tablets to determine the stability of the process, providing a basis for the production, transportation, storage and establishment of the expiration date of the preparation. However, it is a study on generic drugs and does not deeply research the innovation of the formula.

[0006] Therefore, there is an urgent need to study a sildenafil citrate orally disintegrating tablet with a short disintegration time, no bitter taste and good stability. Summary of the Invention

[0007] Based on the deficiencies of the existing technology, the present invention aims to provide a sildenafil citrate orally disintegrating tablet with a short disintegration time, no bitter taste and good stability.

[0008] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] On the one hand, the present invention provides a sildenafil citrate orally disintegrating tablet, which comprises the following raw materials in terms of mass percentage: 10-20% of sildenafil citrate, 50%-80% of filler, 5%-15% of disintegrant, 2%-6% of flavoring agent, 1-2% of glidant and 1-2% of lubricant.

[0010] Among them, the filler is selected from at least one of starch, mannitol, microcrystalline cellulose, and hydroxypropyl cellulose; the disintegrant is selected from at least one of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked carboxymethyl cellulose calcium; the flavoring agent is selected from at least one of aspartame, mint essence, steviol glycoside, acesulfame potassium, and sucralose; the glidant is selected from at least one of talc powder, sodium lauryl sulfate, colloidal silica, and fumed silica; the lubricant is selected from at least one of magnesium stearate and talc powder;

[0011] Among them, the filler can improve fluidity and disintegration; the disintegrants can interact with each other to accelerate disintegration; the flavoring agents can interact with each other to mask the bitter taste; the glidant can significantly improve the fluidity of powders or granules, thereby optimizing the filling uniformity during production.

[0012] Preferably, the flavoring agent is aspartame and mint essence; the disintegrant is a mixture of cross-linked carboxymethyl cellulose sodium and low-substituted hydroxypropyl cellulose; the filler is a mixture of mannitol and microcrystalline cellulose; the glidant is colloidal silica; the lubricant is magnesium stearate.

[0013] As a preferred embodiment, the sildenafil orally disintegrating tablet comprises the following raw materials: sildenafil (citrate), mannitol, microcrystalline cellulose, croscarmellose sodium, low-substituted hydroxypropyl cellulose (L-HPC), aspartame, peppermint essence and magnesium stearate.

[0014] As some preferred embodiments, the sildenafil orally disintegrating tablet comprises the following raw materials by mass percentage:

[0015] Active ingredient: sildenafil (citrate) 10-20%;

[0016] Filler: 40-60% of mannitol and 10-20% of microcrystalline cellulose;

[0017] Disintegrant: 5-10% of croscarmellose sodium and 2-5% of low-substituted hydroxypropyl cellulose (L-HPC);

[0018] Flavoring agent: 1-3% of aspartame and 1-3% of peppermint essence;

[0019] Glidant: 1-2% of colloidal silicon dioxide;

[0020] Lubricant: 1-2% of magnesium stearate.

[0021] Preferably, the mass ratio of mannitol to microcrystalline cellulose is 2-6:1; the mass ratio of croscarmellose sodium to low-substituted hydroxypropyl cellulose is 1-4:1; the mass ratio of aspartame to peppermint essence is 1-3:1.

[0022] Preferably, the mass ratio of mannitol to microcrystalline cellulose is 3.3:1; the mass ratio of croscarmellose sodium to low-substituted hydroxypropyl cellulose is 2:1; the mass ratio of aspartame to peppermint essence is 2:1.

[0023] As a preferred embodiment, the sildenafil orally disintegrating tablet comprises the following raw materials by mass percentage:

[0024] Active ingredient: sildenafil (citrate) 18%;

[0025] Filler: 50% of mannitol and 15% of microcrystalline cellulose;

[0026] Disintegrant: 8% of croscarmellose sodium and 4% of low-substituted hydroxypropyl cellulose (L-HPC);

[0027] Flavoring agent: 2% of aspartame and 1% of peppermint essence;

[0028] Glidant: 1% of colloidal silicon dioxide;

[0029] Lubricant: Magnesium stearate 1%.

[0030] On the other hand, the present invention also provides a method for preparing sildenafil orally disintegrating tablets, comprising the following steps:

[0031] (1) After mixing sildenafil evenly with a filler, add a disintegrant, a flavoring agent and a glidant, and mix three-dimensionally for 20 - 30 min. Then add a lubricant and continue to mix for 5 - 10 min to obtain a mixture;

[0032] (2) Directly compress the mixture obtained in step (1) into tablets, and control the tablet hardness to be 2 - 4 kPa.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The sildenafil orally disintegrating tablets prepared by the present invention can shorten the disintegration time to within 20 seconds; and the present invention uses a specific ratio of aspartame and mint essence to mask the bitter taste, without the need for a complex coating process;

[0035] (2) The sildenafil orally disintegrating tablets prepared by the present invention have good stability, and the preparation method is simple, having broad application prospects. Specific embodiments

[0036] The technical solutions of the present invention will be clearly and completely described below in specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention. The materials, reagents, etc. used, unless otherwise specified, are reagents and materials that can be obtained from commercial channels.

[0037] Example 1 A sildenafil orally disintegrating tablet

[0038] It is composed of the following raw materials:

[0039] Sildenafil 18%, mannitol 50%, microcrystalline cellulose 15%, cross-linked carboxymethylcellulose sodium 8%, low-substituted hydroxypropyl cellulose 4%, aspartame 2%, mint essence 1%, colloidal silicon dioxide 1% and magnesium stearate 1%.

[0040] It is prepared into sildenafil orally disintegrating tablets according to the following method:

[0041] (1) After mixing the formulated amount of sildenafil evenly with mannitol and microcrystalline cellulose, add cross-linked carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, aspartame, mint essence and colloidal silicon dioxide, and mix three-dimensionally for 25 min. Then add magnesium stearate and continue to mix for 5 min to obtain a mixture;

[0042] (2) Directly table the mixture obtained in step (1), controlling the tablet hardness to be 3 kPa to obtain the sildenafil orally disintegrating tablet.

[0043] Example 2 A sildenafil orally disintegrating tablet

[0044] It is composed of the following raw materials:

[0045] Sildenafil 10%, mannitol 60%, microcrystalline cellulose 10%, croscarmellose sodium 10%, low-substituted hydroxypropyl cellulose 2.5%, aspartame 3%, mint essence 1%, colloidal silicon dioxide 2% and magnesium stearate 1.5%.

[0046] Prepare it into a sildenafil orally disintegrating tablet according to the following method:

[0047] (1) After uniformly mixing the formula amount of sildenafil with mannitol and microcrystalline cellulose, add croscarmellose sodium, low-substituted hydroxypropyl cellulose, aspartame, mint essence and colloidal silicon dioxide, and perform three-dimensional mixing for 20 min, then add magnesium stearate and continue mixing for 10 min to obtain a mixture;

[0048] (2) Directly table the mixture obtained in step (1), controlling the tablet hardness to be 2 kPa to obtain the sildenafil orally disintegrating tablet.

[0049] Example 3 A sildenafil orally disintegrating tablet

[0050] It is composed of the following raw materials:

[0051] Sildenafil 20%, mannitol 40%, microcrystalline cellulose 20%, croscarmellose sodium 5%, low-substituted hydroxypropyl cellulose 5%, aspartame 3%, mint essence 3%, colloidal silicon dioxide 2% and magnesium stearate 2%.

[0052] Prepare it into a sildenafil orally disintegrating tablet according to the following method:

[0053] (1) After uniformly mixing the formula amount of sildenafil with mannitol and microcrystalline cellulose, add croscarmellose sodium, low-substituted hydroxypropyl cellulose, aspartame, mint essence and colloidal silicon dioxide, and perform three-dimensional mixing for 20 min, then add magnesium stearate and continue mixing for 10 min to obtain a mixture;

[0054] (2) Directly table the mixture obtained in step (1), controlling the tablet hardness to be 2 kPa to obtain the sildenafil orally disintegrating tablet.

[0055] Comparative Example 1 A sildenafil orally disintegrating tablet

[0056] Differing from Example 1, the mass ratio of sodium carboxymethylcellulose cross-linked and hypromellose phthalate is 1:2, and the rest is the same as in Example 1, namely: sildenafil 18%, mannitol 50%, microcrystalline cellulose 15%, sodium carboxymethylcellulose cross-linked 4%, hypromellose phthalate 8%, aspartame 2%, mint essence 1%, colloidal silicon dioxide 1% and magnesium stearate 1%.

[0057] Comparative Example 2 A sildenafil orally disintegrating tablet

[0058] Differing from Example 1, the mass ratio of aspartame and mint essence is 1:2, and the rest is the same as in Example 1, namely sildenafil 18%, mannitol 50%, microcrystalline cellulose 15%, sodium carboxymethylcellulose cross-linked 4%, hypromellose phthalate 8%, aspartame 1%, mint essence 2%, colloidal silicon dioxide 1% and magnesium stearate 1%.

[0059] Comparative Example 3 A sildenafil orally disintegrating tablet

[0060] Differing from Example 1, the mass ratio of mannitol and microcrystalline cellulose is 1:3.3, and the rest is the same as in Example 1, namely sildenafil 18%, mannitol 15%, microcrystalline cellulose 50%, sodium carboxymethylcellulose cross-linked 4%, hypromellose phthalate 8%, aspartame 1%, mint essence 2%, colloidal silicon dioxide 1% and magnesium stearate 1%.

[0061] Comparative Example 4 A sildenafil orally disintegrating tablet

[0062] Differing from Example 1, 4% of hypromellose phthalate is replaced with 4% of sodium carboxymethylcellulose cross-linked, and the rest is the same as in Example 1, namely: sildenafil 18%, mannitol 50%, microcrystalline cellulose 15%, sodium carboxymethylcellulose cross-linked 12%, aspartame 2%, mint essence 1%, colloidal silicon dioxide 1% and magnesium stearate 1%.

[0063] The sildenafil orally disintegrating tablet is prepared by the following method:

[0064] (1) After uniformly mixing the formula amount of sildenafil with mannitol and microcrystalline cellulose, add sodium carboxymethylcellulose cross-linked, aspartame, mint essence and colloidal silicon dioxide, and perform three-dimensional mixing for 25 min, then add magnesium stearate and continue mixing for 5 min to obtain a mixture;

[0065] (2) Directly tableting the mixture obtained in step (1), and controlling the tablet hardness to be 3 kPa to obtain the sildenafil orally disintegrating tablet.

[0066] Comparative Example 5 A sildenafil orally disintegrating tablet is prepared according to the formula of Example 3 of Patent CN103040835A, specifically as follows:

[0067] Sildenafil 20 g, lactose 12 g, pregelatinized starch PD-1 1 g, croscarmellose sodium 15 g, stevioside 0.5 g, aspartame 0.5 g, 2% hydroxypropyl methylcellulose 0.5 g, magnesium stearate 0.2 g.

[0068] The sildenafil orally disintegrating tablets are prepared by the following method:

[0069] (1) After mixing the formula amount of sildenafil with lactose and pregelatinized starch PD-1 evenly, add croscarmellose sodium, aspartame, mint essence and 2% hydroxypropyl methylcellulose, and mix three-dimensionally for 25 min, then add magnesium stearate and continue to mix for 5 min to obtain a mixture;

[0070] (2) Directly compress the mixture obtained in step (1) into tablets, and control the tablet hardness to be 3 kPa to obtain the sildenafil orally disintegrating tablets.

[0071] Comparative Example 6 A sildenafil orally disintegrating tablet was prepared according to the formula of Example 2 of Patent CN115337276B, specifically as follows:

[0072] Sildenafil 50 g, spray-dried lactose 345 g, croscarmellose sodium 30 g, steviol 15 g, mint essence 15 g, colloidal silicon dioxide 15 g, and magnesium stearate 10 g.

[0073] (1) After mixing the formula amount of sildenafil with spray-dried lactose evenly, add croscarmellose sodium, steviol, mint essence and colloidal silicon dioxide, and mix three-dimensionally for 25 min, then add magnesium stearate and continue to mix for 5 min to obtain a mixture;

[0074] (2) Directly compress the mixture obtained in step (1) into tablets, and control the tablet hardness to be 3 kPa to obtain the sildenafil orally disintegrating tablets.

[0075] Effect experiment

[0076] 1. Disintegration time

[0077] The sildenafil orally disintegrating tablets obtained in Examples 1-3 and Comparative Examples 1-6 were determined according to the disintegration time determination method for orally disintegrating tablets in General Chapter 0921 of the Chinese Pharmacopoeia 2020 Edition, and the disintegration time was recorded with a stopwatch. The results are shown in Table 1 below:

[0078] Table 1

[0079] Disintegration time (s) Example 1 16.2±0.68 Example 2 17.8±2.11 Example 3 17.1±2.05 Comparative Example 1 22.2±1.86* Comparative Example 2 17.8±0.68 Comparative Example 3 20.5±1.25* Comparative Example 4 26.1±2.73* Comparative Example 5 24.8±2.47* Comparative Example 6 28.3±2.49*

[0080] Note: Compared with Example 1, *p < 0.01.

[0081] 2. In vitro dissolution rate

[0082] The sildenafil orally disintegrating tablets obtained in Examples 1-3 and Comparative Examples 1-6 were subjected to dissolution testing according to the seventh method in General Chapter 0921 of the Chinese Pharmacopoeia 2020 Edition, and the dissolution rate within 15 minutes per tablet was calculated. The results obtained are shown in Table 2 below:

[0083] Table 2

[0084] Dissolution rate (%) Example 1 99.2±0.68 Example 2 98.1±0.68 Example 3 98.8±0.35 Comparative Example 1 90.8±2.79* Comparative Example 2 96.3±1.11* Comparative Example 3 91.3±2.0.5* Comparative Example 4 85.2±2.11* Comparative Example 5 88.0±1.82* Comparative Example 6 83.3±2.28*

[0085] Note: Compared with Example 1, *p < 0.01.

[0086] 3. Taste evaluation

[0087] Three subjects were selected from each group to conduct sensory evaluation and score the sildenafil orally disintegrating tablets obtained in Examples 1-3 and Comparative Examples 1-6. It was ensured that they had no smoking history, were aged 20-30 years old, with half male and half female. Each person placed 1 orally disintegrating tablet in the mouth each time. Before each test, they rinsed their mouths with warm water. The orally disintegrating tablet was placed in the middle of the tongue, the mouth was naturally closed, no water was needed to drink, and chewing was not allowed. Appropriate up and down movement of the tongue surface was permitted. Based on the subjective feeling after taking the medicine, the process of the tablet disintegrating in the mouth was felt, and whether there were strange smells, bitter tastes, numbness of the tongue, and irritation. When the tablet no longer changed, it was considered completely disintegrated. The test substances in the mouth were spit out, and after rinsing the mouth, the evaluation and scoring were carried out according to the taste scoring table in Table 3. The results obtained are shown in Table 4.

[0088] Table 3

[0089]

[0090] Table 4

[0091] Score Example 1 4.8±0.37 Example 2 4.6±0.47 Example 3 4.7±0.51 Comparative Example 1 4.3±0.47 Comparative Example 2 3.1±0.68 Comparative Example 3 4.2±0.67 Comparative Example 4 4.0±0.81 Comparative Example 5 3.5±0.95 Comparative Example 6 3.7±0.94

[0092] 4. Stability test

[0093] (1) Accelerated test: The sildenafil orally disintegrating tablets obtained in Examples 1-2 and Comparative Examples 1-6 were placed in a drug stability test chamber, and the conditions were set as temperature (40 ± 2) °C and relative humidity (75 ± 5)%, and an accelerated test was carried out for 6 months. Sampling and determination were carried out at the 6th month to examine the appearance shape, disintegration time, and dissolution rate of the orally disintegrating tablets. The results obtained are shown in Table 5.

[0094] (2) Long-term test: The sildenafil orally disintegrating tablets obtained in Examples 1-2 and Comparative Examples 1-6 were placed in a drug stability test chamber, and a long-term test was carried out under the conditions of temperature (25 ± 2) °C and relative humidity (60 ± 5)%. Sampling and determination were carried out at the 12th month to examine the appearance shape, disintegration time, and dissolution rate of the orally disintegrating tablets. The results obtained are shown in Table 5.

[0095] Table 5

[0096]

[0097]

[0098] It can be seen from the data in Tables 1, 2, 4, and 5 that the sildenafil orally disintegrating tablets prepared in the embodiments of the present invention, compared with the comparative examples, through the synergistic effect of croscarmellose sodium and L-HPC in a specific ratio, exhibit good disintegration properties, and the disintegration time does not exceed 20 s; and through specific ratios of fillers, disintegrants, glidants, and lubricants, the sildenafil orally disintegrating tablets prepared in the present invention have high dissolution degrees, all of which can reach more than 98%; and have good stability, and there are no obvious changes in appearance, disintegration time, and dissolution degree after 12 months of accelerated test.

[0099] Moreover, the present invention uses aspartame and mint essence in specific ratios. Aspartame provides sweetness, and mint essence provides a cool feeling. The two work synergistically to effectively mask the bitterness of sildenafil.

[0100] In summary, the sildenafil orally disintegrating tablets prepared in the present invention have good disintegration properties, stability, dissolution degree, effectively mask bitterness, and have broad application prospects.

[0101] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several modifications or equivalent substitutions can be made to the technical solutions, and these modifications or equivalent substitutions should also be regarded as the protection scope of the present invention.

Claims

1. A sildenafil orally disintegrating tablet, characterized in that: The raw materials are as follows, measured by mass percentage: 10-20% sildenafil, 50%-80% filler, 5%-15% disintegrant, 2%-6% flavoring agent, 1-2% glidant and 1-2% lubricant; the flavoring agent is aspartame and mint essence; the disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

2. The sildenafil orally disintegrating tablet according to claim 1, characterized in that: The filler is selected from at least one of starch, mannitol, microcrystalline cellulose and hydroxypropyl cellulose.

3. The sildenafil orally disintegrating tablet according to claim 2, characterized in that: The filler is a mixture of mannitol and microcrystalline cellulose.

4. The sildenafil orally disintegrating tablet according to any one of claims 1 to 3, characterized in that The glidant is selected from at least one of talc, sodium lauryl sulfate, colloidal silicon dioxide and differential silica gel; the lubricant is selected from at least one of magnesium stearate and talc.

5. The sildenafil orally disintegrating tablet according to claim 4, characterized in that: The glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.

6. The sildenafil orally disintegrating tablet according to claim 5, characterized in that: Calculated by mass percentage, the composition includes the following raw materials: 10-20% sildenafil, 40-60% mannitol, 10-20% microcrystalline cellulose, 5-10% cross-linked sodium carboxymethyl cellulose, 2-5% low-substituted hydroxypropyl cellulose, 1-3% aspartame, 1-3% mint flavor, 1-2% colloidal silicon dioxide and 1-2% magnesium stearate.

7. The sildenafil orally disintegrating tablet according to claim 6, characterized in that: The mass ratio of mannitol to microcrystalline cellulose is 2-6:1; the mass ratio of cross-linked sodium carboxymethyl cellulose to low-substituted hydroxypropyl cellulose is 1-4:1; and the mass ratio of aspartame to mint essence is 1-3:

1.

8. The sildenafil orally disintegrating tablet according to claim 7, characterized in that: The mass ratio of mannitol to microcrystalline cellulose is 3.3:1; the mass ratio of cross-linked sodium carboxymethyl cellulose to low-substituted hydroxypropyl cellulose is 2:1; and the mass ratio of aspartame to mint flavor is 2:

1.

9. The sildenafil orally disintegrating tablet according to claim 8, characterized in that: Calculated by mass percentage, it includes the following raw materials: 18% sildenafil, 50% mannitol, 15% microcrystalline cellulose, 8% cross-linked sodium carboxymethyl cellulose, 4% low-substituted hydroxypropyl cellulose, 2% aspartame, 1% mint flavor, 1% colloidal silicon dioxide and 1% magnesium stearate.

10. The method for preparing the sildenafil orally disintegrating tablet according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) After sildenafil and filler are uniformly mixed, disintegrant, flavoring agent and glidant are added, three-dimensionally mixed for 20-30 minutes, and then lubricant is added, and mixing is continued for 5-10 minutes to obtain a mixture; (2) The mixture obtained in step (1) is directly compressed into tablets, and the tablet hardness is controlled to be 2-4 kPa.

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