# Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems
## 4 Drug Release Mechanisms from Biodegradable Polymeric Formulations  
Control of drug release kinetics is mainly aimed at achieving a steady drug concentration in the circulating bloodstream with concentrations within the therapeutic range, i.e., between the minimum effective concentration (MEC) and minimum toxic concentration (MTC) [281]. Within this range, steady drug release per unit time from carriers is both effective and well-tolerated, and is called zero-order release kinetics [10]. The drug release profile is affected by several factors including the properties and ratio of compo  
Figure 9: Schematic illustration of the supercritical CO\({}_{2}\) method. The drug of interest is dissolved in scCO\({}_{2}\) and impregnated into the polymer, and the non-impregnated drug is removed with CO\({}_{2}\) through depressurization. (Adapted from [PERSON], et al. _Drug Delivery and Translation Research_, 2021 [264].) sitions for drug, polymer, and their additives, the physical and/or chemical interactions among the multiple components, and even the formulation methods [282]. According to the drug release mechanism, they can be categorized in terms of diffusion-controlled release, degradation-controlled release, and solvent-controlled release [283]. In a classic drug release process, the drug molecule moves from within the polymer matrix to the outside of the particle and finally it reaches the surrounding environment [284]. In the early stage of drug release, the drug molecule is released via diffusion through water-filled pores in the particle [285], mainly driven by the chemical potential gradient or osmotic pressure [286]. However, once polymer degradation commences, polymer erosion may occur on the polymer matrix surface (surface erosion) or within the matrix after water penetrates into the polymer bulk (bulk erosion) [287,288]. Although there are some examples of drug release associated with diffusion-controlled release only [289, 290, 291], most examples of drug release from biodegradable polymers involve the combination of diffusion and degradation/erosion simultaneously [287,292]. While zero-order drug release from polymeric particles is preferable to give the desired drug release profile [293,294], the actual drug release from biodegradable polymers is usually bi-phasic or even tri-phasic [287]. In a typical tri-phasic release process, there is an initial burst release whereby the non-encapsulated drug or drug encapsulated near the polymer surface is rapidly released by hydration [295]. The second phase and the third phase could be a slow/rapid process, driven by polymer degradation and erosion [296]. Notably, the first phase of burst release is not always a necessity [297] and in some circumstances, the release speeds of the second and third phases are interchanged. This is shown schematically in Figure 10.  
Figure 10: Schematic diagram showing typical drug release profiles over a 28-day period. The green and black lines show zero order drug release with and without initial burst release respectively. The orange line shows rapid phase 2 and slow phase 3 release, whereas the blue line shows slow phase 2 release followed by rapid phase 3 release (modified from [PERSON], et al., 2011 [287]). In drug delivery system applications, biodegradable polymers with hydrolysable bonds such as ester-, amide-, and anhydrides are widely studied [298; 299; 300]. Following hydrolytic and/or enzymatic breakdown of bonds in the polymer backbone, polymer degradation begins and initiates the onset of release of their encapsulated drugs [301]. Notably, in the realm of degradable polymers, people occasionally confuse the term 'degradation' with 'erosion'. For the term, degradation, it specifically refers to bond cleavage, whereas the term, erosion, commonly refers to depletion of material [302]. In other words, the degradation is a chemical process while the erosion is a physical phenomenon, which is mostly dominated by dissolution and diffusion processes at the polymer surface [33].