Biopharmaceuticals particle size

Deposition mechanisms Inhalation manoeuvre Pulmonary administration Pulmonary drug delivery Therapeutic aerosol Biopharmaceutics Particle size Dry powder inhaler Metered-dose inhaler Nebuhser Novel liquid inhaler... 

Song, X., Zhao, Y., Hou, S., Xu, F., Zhao, R., He, J., Cai, Z., Li, Y. and Chen, Q. (2008) Dual agents loaded PLGA nanopartides systematic study of particle size and drug entrapment efficiency. European Journal of Pharmaceutics and Biopharmaceutics, 69, 445-453. 

The Biopharmaceutics Classification System (BCS)3 defines four classes of compounds based upon solubility and permeability. Particle size and size distribution... 

The pharmacological activity, efficacy, and toxicity of an administered medicament may be profoundly affected by the physico-chemical properties of the drug and the drug dosage form. Thus, such parameters as solubility, particle size, diffusional characteristics, availability and rate of dissolution of the drug have been the areas emphasized in most biopharmaceutical studies. The effect of these parameters on drug absorption is the subject of this review. 

Several substance properties can affect dissolution and/or solubility, such as purity particle size and distribution surface area and the presence of polymorphs, hydrates or other solvates or amorphous forms. To avoid misleading or inconclusive results in extensive solubility or dissolution studies, it is important to characterise the drug substance form with respect to such properties, especially in the later biopharmaceutical preformulation phase. Methods for such characterisation are described in more detail in Chapters 3 and 7. 

Physicochemical profiling has gained considerable importance in the last years as most companies realized that inappropriate physicochemical properties could lead to compound withdrawal later in development. The basic physicochemical parameters of interest for drugability prediction are solubility and permeability, the two components of the Biopharmaceutical Classification Scheme. However, these two fundamental parameters are in turn influenced by other physicochemical parameters worth considering, particularly in the lead optimization phase. For example, permeability is influeneed by lipophilicity (induces membrane retention) and pH (ioniz-able compounds), solubility is influenced by pH (ionizable compounds), and dissolution rate is linked to particle size, polymorphism, and wettability. 

The particle size of solid substances of both excipients and active substances is important not just for biopharmaceutical properties (see Sect. 12.3.2) but also for the physical and chemical properties of cutaneous preparations. If the solid is dispersed in a liquid base, the particles must be sufficiently fine to obtain a physically stable suspension (see Sect. 18.4.2). However decrease of particle size may increase the rate of degradation. Additionally processing small particles may lead to agglomerates. 

For pharmaceutical or biopharmaceutical reasons, or both, requirements for the particle size are set for many active substances and excipients. See Sects. 16.1.2 and 23.1.8. Particle size reduction may be advantageous ... 

Early analytical activities focus on becoming familiar with the chemistry, physical properties, and stability of the new APIs. The purity of the test material(s) and preliminary solid-state and solution stability should be established for candidates prior to use in the Ames test. Candidates are also screened with respect to potential technical issues for further development. Purity and stability testing are performed using a combination of relatively simple chromatographic methods (i.e., HPLC, TLC, GC). A basic solubility profile is developed. Preliminary solid-state characterization is performed using DSC, TGA, and XRD. Early selection of a pharmaceutically acceptable chemical form (where applicable) becomes a key activity to ensure optimal bioavailability (BA), stability, and manufacturability. Biopharmaceutical properties such as potential of food effect, particle size effect, etc., of the proposed clinical candidates are assessed by in vitro and in silico methods. 

The use of nanoparticles for oral appHca-tion is an intensively studied concept for the delivery of poorly soluble drugs, as discussed above. Particle uptake has been known for more than 50 years via M-cells as specialized phagocytic enterocytes, but also via lymphoid tissue and normal intestinal enterocytes [75, 76]. The kinetics of particle uptake and translocation depend on biopharmaceutical parameters like accessibility through the mucus and contact with the enterocytes, as well as on the physical properties of the particle like its size, particle charge, surfactant coating and, sometimes, targeting devices. 

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