Plastic materials are widely encountered in the production and/or utilization of pharmaceutical solutions; for example, as packaging systems, delivery systems and devices and in the manufacturing suite. The nature and composition of these materials provide them with their necessary, desirable physical performance characteristics. These same two factors, nature and composition, also affect the material’s chemical performance characteristics, specifically with respect to interactions that can occur between a plastic material and the pharmaceutical solution it contacts. Of particular interest in this discussion is the migration or leaching of organic constituents of the plastic material into the contacted solution. This is a relevant consideration because the extent of leaching can impact the pharmaceutical solution’s suitability for use, specifically with respect to its safety and efficacy.
Much thought has been given to the processes, strategies and tactics by which leachables information is obtained and interpreted in the context suitability for use assessment. Given the link between leachables, those substances that accumulate in a pharmaceutical solution due to its contact with materials, and extractables, those substances that can be extracted from a material using a solvent, processes, strategies and tactics for performing and interpreting extractables assessments have similarly been extensively considered.
In the final analysis, the interaction between a plastic material and its contacting solution is governed by the same physiochemical processes, both thermodynamic and kinetic, that govern the interaction between any two immiscible phases. An understanding of these processes, and the contact variables that affect them, is useful in terms of the design and interpretation of efficient and effective extractables and leachables assessments. For example, such an understanding may provide insights in terms of the identification and justification of solvents that simulate a particular drug product, thus allowing for the extrapolation of extractables assessments to leachables scenarios. Similarly, such an understanding may be useful in interpreting, and even estimating, extractables and leachables accumulation levels and trends.
The purpose of this manuscript is to discuss these physiochemcial processes, generally in terms of their influence on material-solution interactions and specifically in terms of how they are affected by the nature of the solution, the nature of the material and the conditions of contact. The discussion will consider both thermodynamics, which defines the absolute maximal equilibrium interaction between a material and a solution and kinetics, which defines the rate at which that equilibrium is achieved and/or perturbed.
The Partitioning Phenomenon
The equilibrium distribution of a solute between two immiscible phases is defined by the distribution, or partition coefficient, P, as follows:
P = C2/C1
where C is the equilibrium concentration of the solute in either phase 1 or phase 2. When phase 1 and phase 2 have the same nature (e.g., both are liquids), the units of concentration cancel and P is dimensionless. Such is situation is not necessarily readily achieved in the plastic – solution situation as the convenient concentration units for these two phases differ. Thus for example, solute concentrations in a plastic material are typically expressed on a weight basis (e.g., mg/kg, ppm) while solute concentrations in solution are typically expressed on a volume basis (e.g., mg/L, ppm). While this issue of mixed units is not an insurmountable problem as it can be solved by converting solution concentrations from liquid to mass units via the density, it is a practical issue to be aware of. In cases where the solution’s density is approximately 1 g/mL, the term equilibrium interaction constant Eb, has been proposed to express the relationship between Cp and Cs:
Eb = Cp/Cs
where Cp is in units of mass (e.g., mg/kg) and Cs is in corresponding units of volume (e.g., mg/L).
Coupled with the material weight (Wm, in kg), the solution volume (Vs, in liters) and the total pool of a compound in a material (Tp, in mg/kg), the concentration of that compound in a solution in contact with a material can be calculated as :
Cs = (Tp x Wm)/ [(Wm x Eb) + Vs]