JPH0357096B2 - - Google Patents
Info
- Publication number
- JPH0357096B2 JPH0357096B2 JP56175955A JP17595581A JPH0357096B2 JP H0357096 B2 JPH0357096 B2 JP H0357096B2 JP 56175955 A JP56175955 A JP 56175955A JP 17595581 A JP17595581 A JP 17595581A JP H0357096 B2 JPH0357096 B2 JP H0357096B2
- Authority
- JP
- Japan
- Prior art keywords
- crystals
- qsa
- melting point
- spray
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000013078 crystal Substances 0.000 claims description 51
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 claims description 25
- 238000002844 melting Methods 0.000 claims description 17
- 230000008018 melting Effects 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 11
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940005561 1,4-benzoquinone Drugs 0.000 claims 1
- 239000007921 spray Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000001694 spray drying Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000013081 microcrystal Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000004455 differential thermal analysis Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- VTWDKFNVVLAELH-UHFFFAOYSA-N 2-methylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=CC(=O)C=CC1=O VTWDKFNVVLAELH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone Ethanol Chemical compound 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 201000005857 malignant hypertension Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000004059 quinone derivatives Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Landscapes
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
６−（10−ヒドロキシデシル）−２，３−ジメト
キシ−５−メチル−１，４−ベンゾキノン（以下
QSA−10ということもある）は一連のキノン誘
導体のスクリーニング研究から見いだされた悪性
高血圧症及び脳血管障害に対し特異な治療効果を
有する化合物である。各種動物実験等により該化
合物は経口投与によつても薬理効果を示すことが
明らかになつたが、該化合物は水に対し難溶であ
り、良好でかつ再現性のあるバイオアベイラビリ
テイーを図るためには結晶の微粒化が必要であ
る。しかし該化合物は融点が46〜50℃と低く、通
常の粉砕機で結晶を微粒化しようとすると、粉砕
途中で粉砕機の温度上昇により該化合物が溶融し
工程の進行は不可能となる。最近では低融点の化
合物を粉砕するにはドライアイスや液体窒素と混
合し粉砕する方法や、粉砕機を冷却する冷凍粉砕
機を使用して行う方法が用いられているが、この
ためには膨大な装置が必要であつたり、周囲の酸
欠を防ぐための配慮が必要である。また、粉砕後
バルクが冷却されているため、バルク表面に水分
が凝集し、これを乾燥しようとすると、再び結晶
の固結がおこる等の問題点がある。
本発明者らは上記欠点に鑑み種々研究した結
果、QSA−10を溶媒中に溶解し、これを噴霧乾
燥して微細結晶を得、ついでこの結晶を特定の温
度に加熱することによつて安定な微細結晶が得ら
れるという知見を得た。
すなわち本発明は
１ 平均粒径が50ミクロン以下で融点が52〜53℃
の６−（10−ヒドロキシデシル）−２，３−ジメ
トキシ−５−メチル−１，４−ベンゾキノンの
結晶
２ ６−（10−ヒドロキシデシル）−２，３−ジメ
トキシ−５−メチル−１，４−ベンゾキノンの
溶液を噴霧乾燥して微細結晶を得、これを40〜
43℃に加熱することを特徴とする６−（10−ヒ
ドロキシデシル）−２，３−ジメトキシ−５−
メチル−１，４−ベンゾキノンの融点52〜53℃
の微細結晶の製造法
である。
本発明２におけるQSA−10の溶液は、QSA−
10を溶媒に溶かして液状にしたものである。この
溶媒としては沸点が70〜100℃、好ましくは80〜
90℃でQSA−10を10W／Ｖ％以上、好ましくは
50W／Ｖ％以上溶かし得るものが用いられ、たと
えばメタノール、エタノール、イソプロパノー
ル、アセトンおよびこれらと水との混合溶媒など
があげられる。この溶液はQSA−10を10％以上、
好ましくは50％以上溶かしているものがよい。溶
液中のQSA−10の濃度10W／Ｖ％より低い場合
には、ついで行なわれる噴霧乾燥に際し、溶媒の
除去に手間がかかり、経済的ではない。
QSA−10の溶液の噴霧乾燥は従来より用いら
れている噴霧乾燥装置を用いて行なうことがで
き、通常気流速10m／秒以上、好ましくは15m／
秒以上の気流中に気流量１m3当りQSA−10の溶
液１c.c.〜30c.c.、好ましくは５c.c.〜20c.c.の割合で
供
給して噴霧容器に噴霧することによつて行なわ
れ、噴霧容器内で溶液が分散すると同時に必然的
に乾燥されQSA−10の微粒子が噴霧容器底部に
落下集積する。噴霧室の溶積に対しQSA−10の
噴霧量が比較的多い場合には噴霧された溶液の乾
燥が十分行なわれるように噴霧容器内を減圧にし
ておくのがよい。噴霧する際の気流は空気、窒素
ガスなどQSA−10に対して不活性なものであれ
ばいかなるものでもよい。噴霧気流速は結晶の大
きさに影響を与え、気流速が遅すぎる場合には結
晶が大きくなりすぎ、またノズルが閉塞すること
があり好ましくない。気流量に対するQSA−10
の供給量が少なすぎると結晶の捕集効率が悪くな
り、逆に多すぎると乾燥が十分行なわれないこと
がある。
このようにしてQSA−10の結晶が得られるが、
この結晶は平均粒径が50ミクロン以下、通常１〜
50ミクロン、融点が48℃程度で第２図に示される
示差熱分析図を有するものである。なお、ここで
いう粒径diは粒子の長径をai、短径をbiとすると
き√・で表わされ、平均粒径Ｄは個々の粒径
d1，d2，d3……do-1，doの和を粒子の個数ｎで割
つて得られる値である。
本発明２の方法においてはこのようにして得ら
れる結晶はついで40〜43℃、好ましくは42℃程度
に加熱される。加熱時間は温度により異なるが、
通常１〜４日程度である。加熱温度が高すぎると
結晶が溶解するので好ましくなく、また低すぎる
と低融点結晶から高融点結晶への変換に長時間を
要するので実用的でない。
このようにしてQSA−10の安定な結晶をうる
ことができる。この結晶は、融点52〜53℃で第１
図に示される示差熱分析図を有し、その結晶の形
状および大きさは加熱前のもと同じであるが、第
３図に示されるＸ線回折図において、カツターミ
ルで粉砕して得られた結晶で加熱処理していない
もの（従来法の結晶）と噴霧乾燥して得られた結
晶を加熱処理した後のもの（本発明の微細結晶）
が全く異なつたピークシフトおよび微細構造を有
していることから、本発明の加熱処理によつて低
融点結晶が高融点結晶へと転移していることは明
らかである。
また、第４図が示すように、加熱処理して得ら
れた本発明の微細結晶の溶出性は経時的に変化し
ないので、本発明の微細結晶は製造時から使用時
までに長時間が経過しても一定のバイオアベイラ
ビリテイーを与える
本発明の結晶はこれを錠剤、粉剤、顆粒剤など
として人に投与されるが、上記のように安定であ
るため製造時から使用時までに長時間が経過して
も変化することなく、一定のバイオアベイラビリ
テイーを与える。
したがつて、本発明の結晶は上記のような各種
製剤の製剤設計を行ううえで有利に用いられる。
つぎに実施例を記載して本発明をより具体的に
説明する。
実施例 １
６−（10−ヒドロキシデシル）−２，３−ジメト
キシ−５−メチル−１，４−ベンゾキノン300g
をエタノール50W／Ｗ％水溶液（沸点79℃）300
c.c.に溶解し、これを断面積3.92mm2の噴霧ノズル
を有する噴霧乾燥機を用いて、室温下液速10c.c.／
分、気流量1.5m3／分で噴霧容器（容積49000cm3）
内に噴霧し、得られた微細結晶（融点が48℃で第
２図に示される示差熱分析図を有する）を42℃に
セツトした恒温真空乾燥機（圧力６mmHg）に仕
込み48時間保存して安定な結晶を得た。融点52〜
53℃，示差熱分析：第１図、平均粒径６ミクロ
ン。
実施例 ２
実施例１で得られた融点48℃の結晶を40℃にセ
ツトした恒温真空乾燥機（圧力６mmHg）に仕込
み96時間保存して安定な結晶を得た。融点52〜53
℃。この結晶の熱分析図は実施例１で得られた融
点52〜53℃の結晶のものと一致した。
比較例
特開昭51−128932号公報の実施例54の方法と同
様の処法により橙色針状晶を得た。乾燥後、その
平均粒径を測定したところ、140μであつた。
比較実験例 １
QSA−10として、カツターミル（昭和化学機
械製作所製，パワーミル）で粉砕した結晶（平均
粒径：約140〜150ミクロン）および該結晶と同一
ロツトの原料を用いて得られた本発明の微細結晶
（平均粒径：約30〜40ミクロン）それぞれ10mg用
い、Ｘ線分析を行つた。
Ｘ線分析の結果は第３図に示す。
比較実験例 ２
(1) 試料の調整
表１に示す処方で、常法に従い湿式法によつて
錠剤を製造した。
QSA−10は、特開昭51−128932号公報の実施
例54に記載の方法に従つて製造した橙色針状結晶
（平均粒径：140μ）を、エタノール50W／Ｗ％水
溶液に溶解し、これを噴霧乾燥して得られた結晶
を25℃で48時間保存した後のもの（―○―）及び
噴霧乾燥して得られた結晶を42℃にセツトした恒
温真空乾燥機（圧力６mmHg）に仕込み48時間保
存（加熱処理）した後の本発明の微細結晶（―△
―）、及びそれら（―○―及び―△―）を25℃で６
カ月保存した後の結晶（…●…及び…▲…）（前記
４種の結晶の平均粒径：30〜40μ）を用いた。ま
た、乳糖、トウモロコシデンプン、カルボキシメ
チルセルロースカルシウム、ステアリン酸マグネ
シウムは第11改正日本薬局方（局方）に適合した
ものを用いた。
6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (hereinafter
QSA-10 (sometimes referred to as QSA-10) is a compound that has unique therapeutic effects on malignant hypertension and cerebrovascular disorders, and was discovered through a series of screening studies of quinone derivatives. Various animal experiments have revealed that the compound exhibits pharmacological effects even when administered orally; however, the compound is sparingly soluble in water and requires good and reproducible bioavailability. In order to achieve this, it is necessary to make the crystal grains finer. However, the compound has a low melting point of 46 to 50° C., and when attempting to atomize the crystals using a normal pulverizer, the compound melts due to an increase in the temperature of the pulverizer during pulverization, making it impossible to proceed with the process. Recently, to grind compounds with low melting points, methods have been used to grind them by mixing them with dry ice or liquid nitrogen, or to use a freezing grinder to cool the grinder, but this requires a huge amount of equipment is required, and consideration must be given to prevent oxygen deficiency in the surrounding area. In addition, since the bulk is cooled after pulverization, moisture aggregates on the surface of the bulk, and when an attempt is made to dry it, the crystals solidify again. The present inventors conducted various studies in view of the above drawbacks, and found that QSA-10 was dissolved in a solvent, spray-dried to obtain fine crystals, and then stabilized by heating the crystals to a specific temperature. We obtained the knowledge that fine crystals can be obtained. That is, the present invention has 1. The average particle size is 50 microns or less and the melting point is 52 to 53 °C.
Crystals of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone 2 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4 -Spray-dry a solution of benzoquinone to obtain fine crystals, which are
6-(10-hydroxydecyl)-2,3-dimethoxy-5-, characterized by heating to 43°C
Melting point of methyl-1,4-benzoquinone 52-53℃
This is a method for producing microcrystals. The solution of QSA-10 in the present invention 2 is QSA-10.
10 is dissolved in a solvent to form a liquid. This solvent has a boiling point of 70 to 100℃, preferably 80 to 100℃.
QSA-10 at 90℃ over 10W/V%, preferably
A solvent capable of dissolving 50 W/V% or more is used, such as methanol, ethanol, isopropanol, acetone, and a mixed solvent of these and water. This solution contains 10% or more of QSA-10,
Preferably, it is 50% or more dissolved. If the concentration of QSA-10 in the solution is lower than 10 W/V%, it will take time and effort to remove the solvent during the subsequent spray drying, which is not economical. Spray drying of the QSA-10 solution can be carried out using a conventionally used spray drying device, and the air flow rate is usually 10 m/sec or more, preferably 15 m/sec.
A solution of QSA-10 is supplied into a spray container at a rate of 1 c.c. to 30 c.c., preferably 5 c.c. to 20 c.c., per 1 m3 of airflow in an air flow for more than 2 seconds. As the solution is dispersed in the spray container, it is inevitably dried and fine particles of QSA-10 fall and accumulate at the bottom of the spray container. When the amount of QSA-10 sprayed is relatively large relative to the volume of the spray chamber, it is preferable to reduce the pressure inside the spray container so that the sprayed solution is sufficiently dried. The airflow during spraying may be of any type, such as air or nitrogen gas, as long as it is inert to QSA-10. The spray air flow rate affects the size of the crystals, and if the air flow rate is too slow, the crystals will become too large and the nozzle may become clogged, which is undesirable. QSA−10 for airflow
If the amount supplied is too small, the crystal collection efficiency will be poor, while if it is too large, drying may not be carried out sufficiently. In this way, QSA-10 crystals are obtained,
These crystals have an average particle size of less than 50 microns, usually 1~
It has a diameter of 50 microns, a melting point of about 48°C, and a differential thermal analysis diagram shown in Figure 2. Note that the particle diameter di here is expressed as √・, where the major axis of the particle is ai and the minor axis is bi, and the average particle diameter D is the individual particle diameter.
d 1 , d 2 , d 3 ... is a value obtained by dividing the sum of d o-1 and d o by the number of particles n. In the method of the second invention, the crystals thus obtained are then heated to 40 to 43°C, preferably about 42°C. Heating time varies depending on the temperature, but
Usually it takes about 1 to 4 days. If the heating temperature is too high, the crystals will melt, which is undesirable; if the heating temperature is too low, it will take a long time to convert a low melting point crystal into a high melting point crystal, which is not practical. In this way, stable crystals of QSA-10 can be obtained. This crystal has a melting point of 52-53℃ and is the first crystal.
The shape and size of the crystals are the same as before heating, but in the X-ray diffraction diagram shown in Figure 3, the crystals obtained by crushing with a cutter mill Crystals that have not been heat-treated (crystals of the conventional method) and crystals obtained by spray drying that have been heat-treated (microcrystals of the present invention)
It is clear that the heat treatment of the present invention transforms the low-melting point crystals into high-melting point crystals since they have completely different peak shifts and microstructures. Furthermore, as shown in FIG. 4, the dissolution properties of the microcrystals of the present invention obtained by heat treatment do not change over time, so the microcrystals of the present invention require a long time to elapse from the time of manufacture to the time of use. The crystals of the present invention are administered to humans in the form of tablets, powders, granules, etc.; Provides constant bioavailability without changing over time. Therefore, the crystals of the present invention can be advantageously used in designing various formulations as described above. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Example 1 300 g of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone
Ethanol 50W/W% aqueous solution (boiling point 79℃) 300
cc, and using a spray dryer with a spray nozzle with a cross-sectional area of 3.92 mm2 , the liquid rate was 10 c.c./c.c. at room temperature.
spray container (volume 49000cm3 ) with air flow rate 1.5m3 /min
The resulting fine crystals (with a melting point of 48°C and a differential thermal analysis diagram shown in Figure 2) were placed in a constant temperature vacuum dryer (pressure 6 mmHg) set at 42°C and stored for 48 hours. Stable crystals were obtained. Melting point 52~
53℃, differential thermal analysis: Figure 1, average particle size 6 microns. Example 2 The crystals obtained in Example 1 with a melting point of 48°C were placed in a constant temperature vacuum dryer (pressure 6 mmHg) set at 40°C and stored for 96 hours to obtain stable crystals. Melting point 52-53
℃. The thermal analysis diagram of this crystal was consistent with that of the crystal obtained in Example 1 with a melting point of 52-53°C. Comparative Example Orange needle-shaped crystals were obtained by the same method as in Example 54 of JP-A-51-128932. After drying, the average particle size was measured and found to be 140μ. Comparative Experiment Example 1 As QSA-10, the present invention was obtained using crystals (average particle size: approximately 140 to 150 microns) pulverized with a cutter mill (manufactured by Showa Kagaku Kikai Seisakusho, Power Mill) and raw materials from the same lot as the crystals. X-ray analysis was performed using 10 mg of each fine crystal (average particle size: approximately 30 to 40 microns). The results of the X-ray analysis are shown in FIG. Comparative Experimental Example 2 (1) Preparation of Samples Tablets were manufactured using the formulation shown in Table 1 by a wet method according to a conventional method. QSA-10 was prepared by dissolving orange needle-shaped crystals (average particle size: 140μ) produced according to the method described in Example 54 of JP-A-51-128932 in a 50W/W% aqueous solution of ethanol. The crystals obtained by spray drying were stored at 25℃ for 48 hours (-○-) and the crystals obtained by spray drying were placed in a constant temperature vacuum dryer (pressure 6 mmHg) set at 42℃. Microcrystals of the present invention after storage (heat treatment) for 48 hours (-△
-), and them (-○- and -△-) at 25℃ 6
The crystals (...●... and...▲...) (average particle size of the above four types of crystals: 30 to 40μ) after being stored for a month were used. In addition, lactose, corn starch, carboxymethyl cellulose calcium, and magnesium stearate were used that complied with the 11th edition of the Japanese Pharmacopoeia (Pharmacopoeia).
【表】
(2) 溶出試験
第11改正日本薬局方溶出試験第２法に従い、試
験液としてラウリル硫酸ソーダの0.3％水溶液900
mlを用い、バドル回転数100回転で行つた。
溶出したQSA−10は、高速液体クロマトグラ
フイー（Shimaszu LC−3A）で測定を行つた。
測定の結果は第４図に示す。[Table] (2) Dissolution test According to Method 2 of the 11th revised Japanese Pharmacopoeia dissolution test, the test liquid was a 0.3% aqueous solution of sodium lauryl sulfate 900
ml at a paddle rotation speed of 100 revolutions. The eluted QSA-10 was measured using high performance liquid chromatography (Shimaszu LC-3A).
The measurement results are shown in Figure 4.
第１図、第２図はいずれもQSA−10の熱分析
（示差熱分析）図であり、第２図は噴霧乾燥して
得られる結晶に、第１図は42℃２日間乾燥した後
の結晶に対応する。
また、第３図は従来法で得られたQSA−10の結
晶および本発明の微細結晶のｘ線回折図であり、
第４図は噴霧乾燥して得られたQSA−10の結晶
の加熱処理前後の結晶を用いて得られる錠剤の、
溶出性の経時的変化を示すものである。
Figures 1 and 2 are thermal analysis (differential thermal analysis) diagrams of QSA-10. Corresponds to crystals. In addition, FIG. 3 is an x-ray diffraction diagram of a crystal of QSA-10 obtained by a conventional method and a fine crystal of the present invention,
Figure 4 shows tablets obtained using the crystals of QSA-10 obtained by spray drying before and after heat treatment.
This shows the change in dissolution over time.
Claims (1)
の６−（10−ヒドロキシデシル）−２，３−ジメト
キシ−５−メチル−１，４−ベンゾキノンの結晶 ２ ６−（10−ヒドロキシデシル）−２，３−ジメ
トキシ−５−メチル−１，４−ベンゾキノンの溶
液を噴霧乾燥して微細結晶を得、これを40〜43℃
に加熱することを特徴とする６−（10−ヒドロキ
シデシル）−２，３−ジメトキシ−５−メチル−
１，４−ベンゾキノンの融点52〜53℃の微細結晶
の製造法。[Claims] 1. Average particle size is 50 microns or less and melting point is 52 to 53°C.
Crystals of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone 2 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4 -Spray-dry a solution of benzoquinone to obtain fine crystals, which are heated at 40-43°C.
6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-, which is characterized by heating to
A method for producing fine crystals of 1,4-benzoquinone with a melting point of 52 to 53°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17595581A JPS5877839A (en) | 1981-11-02 | 1981-11-02 | Stable fine crystal and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17595581A JPS5877839A (en) | 1981-11-02 | 1981-11-02 | Stable fine crystal and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5877839A JPS5877839A (en) | 1983-05-11 |
| JPH0357096B2 true JPH0357096B2 (en) | 1991-08-30 |
Family
ID=16005170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17595581A Granted JPS5877839A (en) | 1981-11-02 | 1981-11-02 | Stable fine crystal and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5877839A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2588770T3 (en) | 2010-08-16 | 2016-11-04 | Santhera Pharmaceuticals (Schweiz) Ag | Benzoquinone derivatives for the treatment of mitochondrial eye diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51128932A (en) * | 1975-04-30 | 1976-11-10 | Takeda Chem Ind Ltd | Organic compounds |
-
1981
- 1981-11-02 JP JP17595581A patent/JPS5877839A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51128932A (en) * | 1975-04-30 | 1976-11-10 | Takeda Chem Ind Ltd | Organic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5877839A (en) | 1983-05-11 |
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