The Importance of Particle Size Analysis in Preformulation Studies

The size of the particles is called particle size. The particle size of the API is closely related to the homogeneity of the preparation process in terms of mixing, the accuracy of dosage, and compressibility, and it has an impact on the solubility, duration of action, site of action, stability, and safety of the drug formulation. And the particle size control of drugs has an important influence on drug effectiveness, strength, and security. Therefore, particle size is an essential object of study in preformulation studies for innovative medicines.

Preformulation research is a vital link in drug development, directly affecting the subsequent development process and final application of drugs.

Preformulation research aims to determine the pros and cons of potential drug molecules at the initial research stage and to screen candidates for drug molecules, involving the synthesis of new drug molecules, biological activity screening, pharmacokinetics, toxicology, safety evaluation, etc. From the perspective of preparation development, the development of new drugs is generally divided into three stages. The first stage is also called the drug discovery stage: from drug discovery to the identification of candidate compounds; the second stage is the preclinical research stage: from candidate compounds to concepts Confirmation (proof of concept, POC) proves that the drug is effective in vivo; the third stage is also called the clinical development stage, from POC to making a marketed dosage form.

The main content of pre-prescription research is to obtain various materials required for the dosage form and preparation design by consulting literature or conducting experimental research, including the physical properties of the drug, melting point, particle size, solubility, dissolution rate, crystal form, pKa, The inherent physical and chemical properties of the drug, such as partition coefficient and surface properties, the stability of the drug, the compatibility between the drug and excipients, the pharmacology, side effects and irritation of the drug, as well as the absorption, distribution, metabolism, and excretion of the drug in the body, etc.

The particle size and particle size distribution of drugs play a vital role in the pre-prescription research of drugs.

Product particle size and particle size distribution are essential indicators of good or bad product quality. For solid formulation development, according to the dissolution equation of stable formulation, it is known that the dissolution of insoluble drugs is related to the comparative area. The smaller the particle size and the larger the specific surface area, the better the dissolution performance and the higher the therapeutic efficacy.

Therefore, there may be a relationship between particle size and the absorption of insoluble oral solid formulations, and the dissolution process of drugs often becomes the rate-limiting process for the absorption of insoluble medicines or medications with prolonged dissolution rates. Decreasing the particle size of a drug increases its specific surface area. It increases the effective contact area between the drug and the medium, improving the dissolution degree and dissolution rate of the drug, so decreasing the particle size in preformulation studies is a proven method to enhance the bioavailability of insoluble drugs.

For aerosols, the size of the drug particles after nebulization is the primary determinant of efficacy. The particle size above a micron in the aerosol suspension has a very short existence time and cannot achieve a practical local therapeutic effect; however, if the particles are too small, they cannot be deposited in the respiratory tract and are quickly discharged through exhalation. Therefore, for the development of aerosols, reducing particle size is beneficial to enhance the therapeutic effect.

For drugs that enter the blood circulation system through infusion, factors such as particle size, uniformity, and stability of particle size distribution also affect the safety and effectiveness of the drug. In clinical applications, particle size reduction may have a positive effect on the bioavailability of the drug.

Suppose the particle size range is not reasonably controlled for drug development. In that case, there may be inconsistencies in vivo dissolution and absorption between batches and significant fluctuations in the peaks and valleys of the blood concentration profile, which may cause unsafe problems or lead to increased adverse reactions. It has been found that different particle sizes of extracts have other toxicity to model organisms.

 Therefore, there is a need to control the particle size of drug formulations in preformulation studies—medicilon preformulation research on formulation selection and pharmaceutical preparation features. 

As for the low number of active pharmaceutical ingredients or candidate compounds with medicinal properties, we provide professional preformulation services and explore valuable information. Medicilon's preformulation research team has extensive experience developing various compounds, helping our clients advance their compounds to early screening.

Caenorhabditis elegans (C.elegans) is a tiny soil C.elegans no more than 2mm long, transparent, odor-sensing, temperature- and light-responsive linear animal widely used as a model organism in biology and medicine. Some researchers investigated the toxic effects of different particle sizes of Panax ginseng alcoholic extracts on C.eleganss[1].

The method was to expose C.eleganss to three different particle sizes of Panax ginseng alcoholic extracts, coarse, medium, and fine powder, for 48 h. The survival rate, locomotor behavior, growth and development, reproductive capacity, apoptosis, and reactive oxygen radical levels of C.eleganss were observed under the microscope.

The results showed that the alcoholic extract of Panax notoginseng in different particle sizes in all dose groups reduced the reproductive capacity of C.eleganss (medium and fine high powder dose groups, P<0.05) and increased the number of C.elegans apoptosis (coarse and fine medium powder dose groups, P<0.05; coarse, medium and fine powder high dose groups, P<0.01). The high-dose group of fine powder could increase the level of ROS (P<0.05). All three particle sizes of Panax ginseng alcoholic extracts had some neurotoxicity, reproductive toxicity, and cytotoxicity to C.eleganss, among which fine powder was more prominent. Therefore, Panax ginseng's particle size must be controlled in preparation production.

In the preformulation study of pharmaceutical formulations, the analysis of particle size and particle size distribution is of great significance to ensure the quality of the drug, and a variety of methods have been developed to determine the particle size and its distribution, including microscopy, sieving, optical, resistance, and centrifugation methods. However, due to the sample's complexity and each technique's defects, more than one approach is often required to meet the quality control requirements, and the combined application of several different methods is the appropriate choice. Therefore, in studying particle size and particle size distribution of pharmaceutical preparations, it is also necessary to master the particle size determination methods.

[1] Study the toxic effects of alcoholic extracts of Panax notoginseng with different particle sizes on Cryptobacterium hidradenoma [J].