製薬・医療機器業界向けのRetschソリューション

Another example is temperature controlled wet grinding of APIs (or excipients) – here the MM 500 control or the High Energy Ball Mill Emax are beneficial. 15 g of API substance were mixed with 25 ml of Isopropanol and ground in 50 ml zirconium oxide grinding jars with 110 g of 2 mm grinding balls. The grinding process was carried out using an external chiller set to 5 °C for 30 minutes at 2000 rpm. To maintain a specific temperature range, the unique temperature mode of the Emax was utilized. The minimum temperature was set to 40 °C and the maximum to 50 °C, ensuring that grinding occurred only within this range. When the jar reached 50 °C, grinding was paused until it cooled to 40 °C, at which point grinding resumed. This special mode guarantees that the sample does not overheat during milling, with all operations, including the duration of grinding breaks, being automated.

After just 30 minutes of total process time, the original 1 mm sample was milled down to 4 µm particles. Higher fineness can be achieved by pre-grinding to less than 200 µm with 10 mm balls, followed by fine grinding with 0.5 mm balls and extended grinding time. For larger sample amounts, 125 ml grinding jars can be used. Some APIs require cryogenic grinding at -196°C, where approximately 8 g of sample can be placed in a 50 ml jar of the Cryomill. Pulverization to 100-200 µm is typically completed within 20 minutes, including pre-cooling time.

Mixing APIs with excipients is a common topic in pharmaceutical research. Efficient mixing can be achieved using Mixer Mills, which can handle up to 6 x 20 ml samples, or Retsch Planetary Ball Mills, which offer sample volumes of up to 4 x 200 ml. For example, 196 g of starch were mixed with 4 g of pigment to demonstrate mixing efficiency. The mixture, along with 200 grinding balls of 10 mm, was placed in 500 ml grinding jars. After 5 minutes at 200 rpm, a moderate speed that ensures only mixing effects without particle crushing, the mixing was perfect.

湿式粉砕は5μm以下の粒径を得るために行われます。小さな粒子は表面に帯電して凝集する傾向があり、乾式でさらに粉砕することが難しくなるからです。液体や分散媒を添加することで、粒子を分散したままにすることが出来ます。

湿式粉砕で100nm以下の超微粒子（ナノスケール粉砕）を作るには、衝撃よりも摩擦による粉砕が重要です。そのためには、表面積が大きく、摩擦点が多い小さな粉砕ボールを多数使用します。粉砕ジャーの充填量は、小径の粉砕ボールが60％程度が理想とされています。

ジャーへの充填、湿式粉砕、試料回収の具体的な様子については、こちらの動画をご覧ください。

動画は、遊星ボールミルPM100での湿式粉砕の様子です。

図に示すのは、PM300で二酸化チタン（TiO2）を650rpmと800rpmで粉砕した結果と粉砕にかかった時間です。800 rpmでの高いエネルギー投入により、粒子径はより速く粉砕されますが、高い回転数で粉砕を行う場合は粉砕による昇温に関しても考慮する必要があります（休止時間を設定するなどの対応が必要となる場合があります）。

0.1mm粉砕ボールを用いたリン酸ナトリウム水溶液中での二酸化チタンの処理時間

12 g of API (15 µm particles) were mixed with 26 ml of Heptane and 110 g of 0.5 mm zirconium oxide grinding balls. This mixture was placed in a 50 ml zirconium oxide grinding jar. The grinding process was carried out in the High Energy Ball Mill Emax for 2.5 hours at 2000 rpm, resulting in a very narrow particle size distribution with a D90 value of 80 nm.

Nanoparticles smaller than 100 nm can also be produced using the MM 500 nano or MM 500 control. Typically, a grinding time of 2-3 hours at 35 Hz is required in the MM 500 nano, while the MM 500 control requires a longer grinding time at 30 Hz. The MM 500 control offers temperature regulation, allowing the jars to be counter-cooled with 4°C cold water. If the grinding medium does not freeze at zero degrees, wet grinding can also be performed at temperatures as low as -10°C to ensure the preservation of temperature-sensitive APIs.

To find the optimal coformer or excipient for an API and a specific purpose, a screening approach is typically required. Different ratios of the API and the other substance need to be investigated, resulting in numerous combination options. Since substances can be very expensive, the screening is usually performed on a small scale. The special screening adapter for planetary ball mills can significantly aid this process by using disposable vials, such as 1.5 ml GC glass vials. The adapter features 24 positions arranged in an outer ring with 16 positions and an inner ring with 8 positions. The outer ring can hold up to 16 vials, allowing for the screening of up to 64 samples simultaneously with exact same energy input conditions when using the Planetary Ball Mill PM 400. In total, 96 samples can be screened in one batch. First upscaling trial can be done in the adapter capable of keeping 7 x 20 ml glass vials.

コクリスタルのスクリーニングはミキサーミルで効果的に実施できます。MM 400を用いたある研究[9]では、2 mlのスチールチューブと対応するPTFEアダプターを使用し、テオフィリンとベンズアミドを1:1の比率で以下の条件下で共結晶化しました。

• 粉砕時間：60分
• 周波数：30 Hz
• 各チューブに6 mmのスチールボールを1個
• 溶媒なしで4回、エタノール20 µLを加えて4回の実験

得られた8つのサンプルのX線粉末回折パターン（緑で表示）は、ターゲットのコクリスタルのシミュレーション参照パターンと非常に近い一致を示しています。観測された信号はすべて目的の生成物に対応し、顕著な追加信号はなく、コクリスタル形成が成功し再現性があることを示しています。MM 400と2 mLスチールチューブは一貫した結果を提供し、この互換性はMM 500シリーズにも拡張され、同様に2 mLスチールチューブを使用できます。

XRD patterns after the co-crystal formation of theophylline and benzamide after 60 min milling time in the MM 400 against a simulated reference. Results presented by experiments of Dominik Al-Sabbagh.[7]