Key Material Attributes of API Particle Size in Formulation Development

The particle size of the API, as a key material attribute in the development of formulations, not only affects the powder properties of the API (such as fluidity), the uniformity of the formulation content, the chemical stability of the API and the formulation, but also affects the dissolution of the formulation, which in turn affects To the release and absorption of the preparation in the human body, the final bioavailability of the drug preparation and the exertion of the drug’s curative effect. The decision tree drawn in ICH Q6A provides a direction for the specification of API particle size standards.

Particle size and dissolution

　　 Preparation dissolution is widely circulated as a means of evaluating the quality of preparations during the development of solid preparations. The development of one or more discriminative dissolution profiles has become a work that must be completed in the formulation development process. In the formulation development process, R&D personnel will also pay great attention to the control of the particle size of different batches of raw materials, especially insoluble drugs. Although the particle size of the raw materials is reduced, the solubility of the raw materials cannot be changed. To a certain extent, through The micronization of the bulk drug can increase the contact area between the drug and the solvent, thereby increasing the dissolution rate of the drug, and ultimately the dissolution rate of the preparation. Note: The solubility of easily soluble drugs is not affected by the particle size, and the particle size of poorly soluble drugs is reduced to below 100nm, and the reduction in particle size will affect the solubility of the bulk drug.

　　The difference in the particle size of the drug substance will affect the dissolution of the preparation, and the dissolution of the preparation of the drug substance of different particle size can also be used as a favorable evidence for evaluating whether the developed dissolution method is discriminating.

　　Example 1: The API in the case is a poorly soluble drug, and preparations are prepared using raw materials of different particle sizes. Dissolution experiments are conducted under the conditions of the target dissolution method. The dissolution results show that there are differences in the dissolution of the preparations prepared with different particle size materials. Firstly, it explains the influence of the particle size of the drug substance on the dissolution of the preparation. In the subsequent development of the preparation, the particle size of the raw material can be changed to improve the dissolution of the preparation. . (Reference 1)

　　 Example 2: Dronedarone hydrochloride is a new type of drug developed by Sanofi-Aventis to treat atrial fibrillation. Dronedarone hydrochloride is a low-solubility drug, and the particle size of its raw material has a greater impact on the in vitro dissolution of dronedarone hydrochloride tablets. The API was crushed mechanically to obtain APIs with particle diameters of D90: 100.538 μm and D90: 55.828 μm, and the APIs with particle diameters of D90: 22.470 μm, D90: 14.918 μm and D90: 3.463 μm were obtained by jet pulverization. Use the APIs of the above particle sizes for tableting and dissolution. The dissolution results show that the larger the particle size and the larger the specific surface area of ​​the drug substance, the greater the dissolution rate, so as to achieve the purpose of improving the dissolution of the preparation. (Reference 2)

Particle size and preparation production

　　 A good preparation product not only needs to meet product safety, stable properties, and effective treatment, but also needs to meet the needs of robust technology, simple preparation process, and smooth mass production in the workshop. In the production process of preparations, the preparation materials are required to have good fluidity. Materials flow due to unbalanced forces, and the forces on the materials are manifold, including the gravity of the material particles, the cohesion between the particles, and the friction between the particles and the surface of the equipment. At the same time, the fluidity of the material is affected by many factors, including the surface morphology (or ball or strip) of the prepared material, the size of the particle size, the electrostatic force between the materials and even the humidity in the environment where the test is located. The impact of particle size on the fluidity of materials is particularly obvious, especially for small-size formulations.

　　 In general, for small-size formulations, in order to meet the uniformity of the formulation, the raw materials need to be micronized, thereby reducing the particle size of the API. Of course, poorly soluble drugs will also use micro-powder raw materials to improve the dissolution of the drug. This brings about problems. The particle size of the raw material decreases, especially in the micron level, the particle size decreases, the surface energy of the particles increases, the activity increases, or the energy in the system increases, just like water flows to a low place, at high energy. The state is destined not to be “secure” and easy to gather together.

　　Theoretical explanation: The specific surface area of ​​the powder is inversely proportional to the particle size. The smaller the particle size of the powder, the larger the specific surface area. As the particle size of the powder decreases, the molecular attraction and electrostatic attraction between the powders gradually increase, reducing the fluidity of the powder particles; secondly, the smaller the particle size of the powder, the easier it is for the particles to adsorb, agglomerate, and bond. The increase of the permeability leads to the increase of the angle of repose and the deterioration of the fluidity; again, the particle size of the powder decreases, and the particles are easy to form a close packing, which makes the air permeability decrease, the compression rate increases, and the fluidity of the powder decreases. (Quotation 3)

Particle size and formulation stability

“According to relevant data, most of the currently developed compounds are polymorphic drugs, which means that most of the compounds are crystalline drugs. Through mechanical action, the crystal structure of the crystal drug is ground and hammered, and the scale of the crystal structure is reduced, which is mostly manifested as a reduction in particle size. In order to ensure the stability of the crystal form, the stability of the crystal form in the compound preparation process is generally studied, such as crushing, grinding, sieving, granulating, drying, tableting and coating, etc., the stability of the crystal form during the preparation process . That is to say, the micronization of raw materials only reduces the particle size of the crystalline compound without changing the basic structure (unit cell) of its crystal form.

　　 Then, the crystal form of the bulk drug remains unchanged and the particle size is reduced. How about the stability of the formulation?

As we all know, when testing the compatibility of raw materials and excipients, we generally choose APIs with relatively small particle size, because this can increase the contact area between the API and the excipients, increase the reaction speed of the two, increase the intensity of the reaction, and also increase the speed of the reaction. The risk of incompatibility between the two. Of course, this can guide us in prescription screening and find suitable excipients for us. If the particle size of the selected raw material changes significantly in the final formulation, it is also necessary to pay special attention to the stability of the particle size change.

Particle size and uniformity of preparation content

“Content uniformity” refers to the extent to which the content of each tablet (unit) of small-dose or single-dose solid preparations, semi-solid preparations and heterogeneous liquid preparations meets the labeled amount. The 2020 edition of the Chinese Pharmacopoeia stipulates: Unless otherwise specified, for tablets, hard capsules, granules or powders, etc., each single-dose labelled amount is less than 25mg or the content of the main drug is less than 25% of the weight of each single-dose, should be checked Content uniformity. This also indicates a trend that there is a great risk of content uniformity problems for small-sized drugs. In order to better predict the effect of particle size on the uniformity of formulation content through the model, formulation scientists deduced based on the research results and data The relationship between content uniformity and particle size is obtained. Generally known formulation specifications, that is, the amount of the bulk drug in the solid preparation, through the measurement of its particle size (D90) and geometric standard deviation, it can be determined that 99% of the bulk drug size required to meet the content uniformity can be determined. (Quoting 4 and 5) In the development process of small-size formulations, the effect of particle size on its content uniformity is paid attention to in advance, and the general corresponding relationship can be found to eliminate the influencing factor of particle size when there is a problem with the content uniformity of the formulation. To help the rapid advancement of formulation development,

Summary: In the development process of formulations, not only the impact of particle size on the solubility of poorly soluble drugs, but also the impact of particle size on the manufacturability and stability of formulations should be paid special attention to. Based on the theory of QbD, analyze the impact of particle size, a key material attribute, on the CQA of the preparation, and conduct risk assessment. In the process of research and development, we will continue to accumulate data and gradually establish API particle size control standards.