We are continuing our discussion on the importance of solid-state characteristics of the active pharmaceutical ingredient (API) on the quality and therapeutic efficacy of solid oral and inhaled dosage forms, and in this post the emphasis will be on particle size distribution (PSD). The PSD is a measurement that defines the number of particles present in a sample according to size. The PSD is plotted with frequency or percentage along the Y-axis and particle size diameter along the X-axis to obtain a bell-shaped (also called a normal) curve from which the “percentiles” can be derived (see figure below). Percentiles are used to indicate the particle size diameter (measured in µm) below which a certain quantity of the sample lies. Percentiles are denoted by the letter “D” followed by the % value. Thus, D10 = 83 µm, D50 = 330 µm, and D90 = 1600 µm mean that 10% of the sample is smaller than 83 µm, 50% is smaller than 330 µm, and 90% is smaller than 1600 µm, respectively. In this way the middle or central point of the distribution (D50), as well as the upper (D90) and lower (D10) ends are characterised with three values, which gives a good overview of the PSD.
The PSD is a critical quality attribute when the API has a low water solubility because it will then have an important influence on the dissolution rate – the larger the surface area of the drug particle (i.e., the smaller the particle size), the higher the dissolution rate of the drug and consequently, the higher its bioavailability. The converse is also true – large particles have small surface areas, and if the drug is lipophilic or fat-soluble, it will take a considerable time to go into solution. Hence, when such APIs are intended for formulation into solid dosage forms, they are often micronized to increase their surface areas, which will result in an enhanced dissolution rate and higher bioavailability.
Particle size also impacts the manufacturing process as it has important effects on bulk properties of powders such as bulk and tapped density, flowability, cohesivity, wettability, and so forth. It is critical that pharmaceutical powders flow freely into and out of storage containers, hoppers of tablet presses and capsule fillers so that a uniform tablet or capsule weight is achieved. Uneven particle flow can cause air entrapment that can affect content uniformity of tablets and capsules, which is especially important in the case of very potent, low-dose drugs.
The PSD depends on the method of sizing (i.e., micronization) and method of size determination. The two most common methods for determining PSD are sieve analysis and laser diffraction. Different PSDs are obtained with each method unless particles are spherical. In general, laser diffraction is preferred as it is suitable for a wide particle size range – from micro- to millimetres. According to the USP, sieve analysis may be used if at least 80% of particles are larger than 75 µm.
In setting acceptance criteria for particle size of micronized APIs, the PSD is usually measured at the three intervals using laser diffraction, as mentioned above: D10, D50 and D90. The reason for this is that two batches of an API with different PSDs may have the same D50 value (also known as the median particle size) but different PSD profiles, i.e., their D10 and D90 values are different (see figure below).
In the case of generic solid dosage forms, tests and acceptance criteria included in the specification for particle size, must be based on results of the API lot used to manufacture the product batch employed in bioequivalence studies, the so-called biobatch. Thus, when a final product manufacturer applies for an amendment for an alternate API supplier for a low-solubility API, it is important that the data submitted to support the amendment include a comparison of particle size measurements at D10, D50 and D90 for both the biobatch API lot and the API lot of the proposed supplier. Without such data that show similarity of the particle size profiles, the amendment will not be approved.
Setting acceptance criteria for PSD requires taking into account the variability of the method for determining particle size as well as the method of sampling. In particle size analysis by laser diffraction only method precision, as assessed by repeatability, is applicable. The USP <429> specifies that the coefficient of variations (COV) or relative standard deviation (RSD), must be less than 10% at D50 and less than 15% at D10 and D90. The COV or RSD is calculated by dividing the standard deviation by the mean of at least three measurements, multiplied by a 100 to express it as a percentage. If the particle size is less than 10 µm, the COV/RSD values can be doubled.
Specifications for particle size can either be expressed as a mean plus/minus its standard deviation, as a range with minimum and maximum values, but in most instances, it is expressed only as a single value (the mean) as shown below.
Specification (Laser diffraction): D10: NMT 35 µm
D50: NMT 75 µm
D90: NMT 120 µm
Finally, to determine if a specification should be set for particle size, readers are referred to Decision Tree #3 of ICH 6A, which is reproduced below.
Bibliography
Virden, A (2010). Method Development for Laser-Diffraction Particle-Size Analysis. Pharmaceutical Technology, Volume 34, Issue 11.
USP30–NF25 General Chapter <429>, “Light Diffraction Measurement of Particle Size,” pp. 1235–1241
ICH Topic Q 6 A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.
Csicsák D, Szolláth R, Kádár S, Ambrus R, Bartos C, Balogh E, Antal I, Köteles I, Tőzsér P, Bárdos V, et al. The Effect of the Particle Size Reduction on the Biorelevant Solubility and Dissolution of Poorly Soluble Drugs with Different Acid-Base Character. Pharmaceutics. 2023; 15(1):278. https://doi.org/10.3390/pharmaceutics15010278
Burgess, D.J., Duffy, E., Etzler, F. et al. Particle size analysis: AAPS workshop report, cosponsored by the Food and Drug Administration and the United States Pharmacopeia. AAPS J 6, 20 (2004). https://doi.org/10.1208/aapsj060320
Shekunov, Boris & Chattopadhyay, Pratibhash & Tong, Henry & Chow, Albert. (2007). Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications. Pharmaceutical research. 24. 203-27. 10.1007/s11095-006-9146-7.