Retsch 加强在制药应用领域的研发工作

Retsch mills are used to grind active pharmaceutical ingredients (APIs) and excipients to a specific particle size, which is crucial for ensuring consistent drug efficacy and bioavailability. The particle size can significantly affect the dissolution rate, absorption, and distribution of the drug within the body. Excipients, which are inactive substances formulated alongside the active ingredient of a medication, require proper sizing and homogenization to ensure they function correctly within the formulation. Special applications require nanotechnology, cocrystals or mechanosynthesis to find new APIs, both sophisticated approaches where Retsch can assist. In this section, eight different use cases with their best practises are highlighted:

Browse through the topics covered in this chapter:

Retsch 研磨设备用于研磨样品材料，如活性药物成分（APIs）

药物活性成分和辅料可在不同型号的Retsch研磨设备中进行粉碎。根据物质性质，建议采用密闭容器进行研磨，例如Retsch球磨仪的研磨罐，以避免高活性物质产生粉尘。例如，100 ml 乳糖一水合物可在 PM 100 中以 450 rpm 的转速在 1 小时内研磨，将 D90 值从 100 µm 降低至 5 µm。研磨在湿磨条件下进行，即样品与 90 ml 丙醇混合。 湿磨通常在氧化锆研磨罐中进行，本例中使用250毫升容量的研磨罐，内装150毫升直径2毫米的氧化锆球。氧化锆是一种耐磨性极强的材料，可减少精细研磨阶段因球体间剧烈摩擦导致的磨损。通过延长研磨时间并使用更小的研磨球，可在Retsch行星式球磨仪中获得更细小的样品颗粒。

药理学上无害的样品材料，如用作辅料的淀粉或乳糖，可在ZM 300或RM 200中进行研磨。例如，初始粒径为400 µm的100 ml乳糖样品可在RM 200中研磨至粒径小于100 µm，耗时仅需10分钟。可使用多种研磨工具材料，包括硬质陶瓷或玛瑙。较大样品量可使用ZM 300进行处理。 对于易粘附或团聚的样品，可通过液氮冷冻处理实现脆化后进行研磨。建议使用旋风分离器。例如，100克3毫米样品可在1分钟内研磨至粒径小于500微米。根据样品特性，ZM 300也可实现最终粒度低于40微米。

温度控制研磨以保护温度敏感物质

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.

结论：Retsch 提供适合的设备，可安全地将小到中型样品量粉碎，并保持温度稳定。

在制剂开发过程中，通常使用混合机将药物活性成分（APIs）与辅料进行混合。

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.

Nanotechnology research – benefits from Retsch mills

High-energy ball mills from Retsch, like the Emax, the PM series or the MM 500 nano and control, are used in the development of nano particles. These nano formulations can offer improved drug delivery characteristics and are a growing area of interest in pharmaceutical R&D. TiO₂ is used as a model substance here.

PM300 湿法纳米研磨

湿法研磨用于获得 5 µm 以下的颗粒，因为小颗粒表面容易带电并聚集在一起，这使得干法研磨难以继续进行。

要通过湿法研磨产生 100 nm 或更小的超细颗粒（纳米级研磨），需要使用摩擦而不是冲击。这可以通过使用大量小磨球来实现，这些磨球表面大，摩擦点多。

有关罐子填充、湿法研磨和样品回收的更多详情，请观看视频。

^{视频展示了行星式球磨机 PM 100 的湿磨过程。}

使用125毫升研磨罐处理二氧化钛样品

该图显示了在PM 300中以650rpm和800rpm粉碎二氧化钛（TiO2）的结果和净处理时间。在800rpm下更高的能量输出时，颗粒尺寸减小得更快。然而，在800转/分的转速下增加的升温团聚效应也应该考虑在内，因为它们可能需要更长的间隔时间。

^{二氧化钛使用0.1mm研磨球和六偏磷酸钠分散剂的净研磨时间}

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.

Conclusion: Temperature-control, Nano-grinding, mixing – Retsch´s ball mills are suitable for all applications.

Milling plants or insects to identify ingredients

Plants often have natural ingredients which are useful in pharma applications, known for decades for their pharmaceutical purposes. Also other materials like insects offer some interesting compounds. The traditional Chinese medicine TCM or other traditional healing methods make use of the natural resources. Research activities aim to unreveal the API compounds in those classical plant or animal samples in order to use them as new drug and pharmaceutical substances. Depending on the initial sample size, the sample amount, the sample quantity and the required final fineness, Retsch Cutting Mills, Rotor Mills or Ball Mills are used predominantly to pulverize such samples.

Depending on the sample size and toughness, about 20 s to 3 min are required to grind up to 1 kg dried roots, fruits, stems parts and other plant materials or insects to 1-8 mm samples. Here, ideally SM 100 is used, for more robust samples like nutmeg the SM 300. A cyclone helps in any case to discharge the light samples from the grinding chamber. The ZM 300 accepts feed sizes up to 10 mm, Cutting Mills accept up to 60 mm sample pieces. For really tough materials, the 6-disc rotor instead of the parallel section rotor should be taken. Sometime finer particles than 1 mm are required- here the use of Retsch Ball mills is beneficial.

结论: Even tough or larger plant materials can be easily homogenized with Retsch Cutting Mills or Rotor Mills.

Mechanochemistry for new or enhanced APIs

Mechanochemistry, the study of chemical reactions that occur due to mechanical energy, has increasingly become a significant field of research in pharmaceuticals. This method involves inducing chemical reactions through grinding, milling, or shearing solid reactants. Mechanochemical processes offer several advantages over traditional solution-based chemistry, including reduced solvent use, enhanced reaction rates, and the ability to synthesize novel compounds. Mechanochemical reactions can be used for the synthesis of new drug molecules. This method is particularly advantageous for reactions that are difficult or inefficient in liquid solvents, allowing for the exploration of new chemical space and the potential discovery of novel therapeutic compounds. For example, the group of Professor Duncan Browne, UCL School of Pharmacy, worked on the formation of Carbon-Nitrogen bonds, a favourite process for drug discovery and development. They synthesized an intermediate in the synthesis of Vortioxetine, which is a known antidepressant [1].

Another publication of the group shows the option to use mechanochemistry in the MM 400 in direct amidation of esters [2], in just 1 h compared to 8 h in EtOH solution at 70°C. In the same paper, the synthesis of 2.4 g of the antidepressant Moclobemide in the MM 400 in just 1 h is demonstrated. Another important aspect are the various findings, that heating can improve the mechanochemical reactions, thus enabling or accelerating the reactions. Using a heat gun or heating jackets are common methods for the MM 400 as shown by the groups of Professor Ito or Professor Browne [3][4][5]. A more commercial version of temperature control and heating options is given by the MM 500 control, which also allows temperatures up to 100 °C.

Co-grinding, cocrystal formation and polymorph screening

1. Cocrystals consist of two or more crystalline components, typically an active pharmaceutical ingredient (API) and a coformer, in a definite stoichiometric ratio, held together by non-covalent bonds. Ball mills are used to produce pharmaceutical cocrystals, which can improve drug solubility, stability, and bioavailability without altering the molecular structure of the API.
2. Different crystalline forms (polymorphs) of a drug can exhibit significantly different physical and chemical properties, such as solubility and melting point. Polymorph screening can help to identify stable forms of a drug that have desirable characteristics, improving drug formulation and performance.
3. Co-grinding often refers to simultaneous grinding of an API and a (amorphous) excipients. Co-grinding can improve the solubility, stability, and bioavailability of drugs by creating fine and uniform particles and improved fluidity. The excipient can be another API, an amino acid or a polymer like cellulose or starch. Excipients as binders help hold the ingredients of a tablet together. Common fillers include lactose, mannitol, and dibasic calcium phosphate. Other excipients act as lubricants, preservatives, colouring or flavoring agents

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.

Metal-Organic Frameworks (MOFs) in Drug Delivery

MOFs are coordination networks with organic ligands and metal ion nodes. They have a high surface area and tunable porosity, making them excellent candidates for drug delivery systems. Mechanochemistry is used to synthesize MOFs that can encapsulate drugs, providing controlled release and targeted delivery mechanisms. Here, the use of thermically controlled mills is very useful. If for example the MM 500 control is used with a chiller, the temperature can be lowered so that intermediates of the chemical reactions can be stabilized and thus the yield of those substances is drastically increased. With the right choice of the milling instrument, completely different educts can be obtained!

Reproducible Particle size analysis with Retsch sieving machines

Retsch sieving machines are renowned for their precision and reliability in various industries, including pharmacy. These machines are essential for particle size analysis, ensuring that materials meet the stringent quality standards required in pharmaceutical applications. The AS 200 control and AS 200 jet are two notable models in Retsch's lineup. The AS 200 control is a vibratory sieve shaker that offers precise control over sieving parameters, making it ideal for quality control and research and development in the pharmaceutical industry. It features an electromagnetic drive that ensures consistent sieving results, and its digital controls allow for the storage of up to 99 sieving programs, ensuring reproducibility and compliance with ISO 9001 guidelines.

On the other hand, the AS 200 jet is an air jet sieving machine designed for the efficient dispersion and deagglomeration of fine powders. This model is particularly suitable for pharmaceutical materials that require precise particle size distribution. Unlike the vibratory sieving method used by the AS 200 control, the AS 200 jet employs a rotating air jet that disperses and deagglomerates fine powders more effectively. This air jet creates a vacuum that pulls the particles through the sieve, ensuring that even the finest particles are separated efficiently. Thus, the sample may be “finer” when analysed with the air jet sieving machine. This can be seen for example with a fine powder sample. Test sieves with mesh sizes 40, 75, 125 and 150 µm were used. The AS 200 control was operated at an amplitude of 1.2 mm with 10 s interval function, over 5 min. The AS 200 jet was operated in the Swiss Mode with a speed of 55 rpm and a negative pressure of 30 mbar – the total procedure also required 5 min work.

In pharmaceutical applications, these sieving machines are used to ensure the uniformity, stability, and purity of drug formulations. Accurate particle size analysis is crucial for determining the dissolution rate, bioavailability, and overall efficacy of pharmaceutical products.

结论: Retsch sieving machines are most suitable to assure quality control – whether we are talking about incoming inspection of raw materials, results of R&D trials or production control of substances in manufacturing.

公斤级共晶合成

Retsch滚筒式磨机，如TM 300，用于制药共晶的机械化学合成，规模可达公斤级。该方法环保且高效，能降低能耗并最大限度减少环境影响，因其几乎不使用溶剂。例如，TM 300在90分钟内成功制备了3.2千克的氘代布洛芬：烟酰胺共晶，纯度高达99%。 [6]

TM 500 316L 是一款实验室球磨机，专为研磨大容量样品（最大容量达 35 升）而设计。该设备可处理最大初始进料粒度为 20 毫米的样品，并通过摩擦和冲击作用实现最小研磨粒度达 15 微米。TM 500 316L 特别适用于需要确保样品在任何情况下均不被污染的应用场景。该设备采用 316L 不锈钢滚筒和料斗，确保加工过程无污染。球磨机的转速范围为 10 至 50 rpm，可适应不同应用需求。TM 500 316L 配备电子倾斜功能，便于排空，并可编程设置研磨间歇，适用于处理热敏性样品材料。

制药生产中的筛分分析

Retsch筛分仪是制药生产中确保颗粒尺寸分析精确性的关键设备。其中，AS 200control和AS 200jet尤为突出，前者可精确控制筛分参数，后者则因采用空气喷射分散技术，特别适合处理细粉。这些设备有助于维持药物制剂的均匀性、稳定性和纯度，这些因素对确定药品的溶解速率、生物利用度及整体疗效至关重要。此外，Retsch筛分机符合ISO 9001标准，确保实验结果的可重复性和高品质。

Retsch EasySieve 软件是制药生产中颗粒尺寸分析的强大工具。它能够自动化注册、评估和管理测量数据，使筛分过程更加高效和准确。该软件采用逻辑设计和自解释测量协议，将复杂数据转化为图表和表格。EasySieve CFR 作为该软件的版本，符合 FDA 21 CFR 第 11 部分的规定，确保数据完整性和安全性。该软件还包含一个集成的审计跟踪功能，可对筛分过程中的每个工作步骤进行一致的文档记录，所有数据均以加密形式存储在数据库中。审计追踪软件提供从管理员到标准用户及主管共三个不同的用户级别，

参考资料

[1] Group of Professor Duncan L. Browne, Department of Pharmaceutical and Biological Chemistry, University College London: Robust Buchwald-Hartwig amination enabled by ball-milling; Org. Biolol. Chem. 2019, 17, 1722 DOI: 10.1039/c8ob01781f

[2] Group of Professor Duncan L. Browne, Department of Pharmaceutical and Biological Chemistry, University College London: Direct Amidation of Esters by Ball Milling; Angew. Chem. Int. Ed. 2021, 60, 21868-21874; doi.org/10.1002/anie.202106412

[3] Group of Professor Hajime Ito, Division of Applied Chemistry, Faculty of Engineering, Hokkaido University: Solvent-free zinc-mediated Bechamp reduction using mechanochemistry; DOI: 10.1039/d4mr00138a

[4] Group of Professor Hajime Ito, Division of Applied Chemistry, Faculty of Engineering, Hokkaido University: Solid-state aromatic nucleophilic fluorination: a rapid, practical, and environmentally friendly route to N-heteroaryl fluorides; Green Chem., 2025, 27, 1771; DOI: 10.1039/d4gc06362g

[5] Group of Professor Duncan L. Browne, Department of Pharmaceutical and Biological Chemistry, University College London: Temperature-Controlled Mechanochemistry for the Nickel-Catalyzed Suzuki-Miyaura Coupling of Aryl Sulfomates via Ball Milling and Twin-Screw Extrusion; Angew. Chem. Int. Ed. 2022, 61, e202210508; doi.org/10.1002/anie.202210508

[6] Jan-Hendrik Schöbel, Frederik Winkelmann, Joel Bicker, and Michael Felderhoff; Mechanochemical kilogram-scale synthesis of rac:ibuprofen:nicotinamide co-crystals using a drum mill; RSC Mechanochemistry, 2025, DOI: 10.1039/D4MR00096J