formulation design
HOW TO EFFECTIVELY COMBINE PARENTERAL SOLUTION FORMULATION APPROACHES ?
Parenteral formulations for poorly water-soluble active pharmaceutical ingredients (APIs) often use combinations of solubilization techniques to minimize possible side effects during or after injection. The underlying rationale is that a combination of techniques often has an additive effect on API solubility, while side effects are usually driven by the achievement of a threshold value of a single component (e.g. a cosolvent that causes haemolysis at high local concentrations). Combining multiple ingredients/techniques to reduce the concentration of potentially toxic components can therefore be beneficial. In some cases, however, combinations offer few advantages or even disadvantages in terms of solubilization. Below we summarize which combinations of techniques are useful and which are better avoided.
pH-adjustment + cosolvents
In the presence of a cosolvent, the total solubility of an ionizable solute is a function of the concentration of both the unionized and ionized species and the solubilization power of the cosolvent toward the un-ionized and ionized forms. Since cosolvent solubilization power is dependent on the hydrophobicity of the solute, the level of cosolvency decreases with increasing API ionization, potentially reducing the solubilization advantage of the cosolvent.
pH-adjustment + cosolvents
In the presence of a cosolvent, the total solubility of an ionizable solute is a function of the concentration of both the unionized and ionized species and the solubilization power of the cosolvent toward the un-ionized and ionized forms. Since cosolvent solubilization power is dependent on the hydrophobicity of the solute, the level of cosolvency decreases with increasing API ionization, potentially reducing the solubilization advantage of the cosolvent.
However, the reduction in solubilization capacity with increased API ionization is not sufficient to cause a decrease in the total API solubility, and the beneficial effect of increasing ionization on solubility outweighs the reduction in solubilization power of the cosolvent. This is illustrated in the figure. Thus, a solubility advantage of a combination strategy of cosolvent plus pH adjustment is evident, although the beneficial effects of pH adjustment are reduced at high cosolvent fractions.
As such, cosolvent-pH buffering combination strategies are widely used in the development of preclinical parenteral formulations and for commercial formulations.
pH-adjustment + surfactants
The properties of micelles formed by nonionic surfactants are largely independent of pH. However, changing pH can alter the micellar solubilization of ionizable APIs. For ionizable compounds, the total quantity of dissolved API is the sum of the concentrations of ionized and unionized API in free solution and the concentrations of ionized and unionized API in the micellar phase. The micelle-water partition coefficients for ionized API are lower than the corresponding values for the unionized form as a result of differences in solubility in the aqueous solvent. Under conditions of differing pH, the concentration of unionized API in solution remains unchanged, and assuming no change to the properties of the nonionic surfactant micelle with pH, then the affinity of the unionized form for the micelle phase is also unchanged.
The properties of micelles formed by nonionic surfactants are largely independent of pH. However, changing pH can alter the micellar solubilization of ionizable APIs. For ionizable compounds, the total quantity of dissolved API is the sum of the concentrations of ionized and unionized API in free solution and the concentrations of ionized and unionized API in the micellar phase. The micelle-water partition coefficients for ionized API are lower than the corresponding values for the unionized form as a result of differences in solubility in the aqueous solvent. Under conditions of differing pH, the concentration of unionized API in solution remains unchanged, and assuming no change to the properties of the nonionic surfactant micelle with pH, then the affinity of the unionized form for the micelle phase is also unchanged.
However, the reduction in solubilization capacity with increased compound ionization is not sufficient to cause a decrease in the total solubility, and the beneficial effect of increasing ionization on solubility outweighs the reduction in solubilization power of the cosolvent. This is illustrated in the figure. The combined use of pH adjustment and micellar solubilization with nonionic surfactants is a frequently used approach to construct solubility-enhancing formulations.
The effect of pH change on micellar API solubilization is more complex for ionic surfactants since pH change alters the ionization state of both the API and the head group of the surfactant. For an anionic surfactant, an increase in pH is expected to lead to greater ionization of the head group and an increase in the critical micelle concentration (CMC) through the combined effect of increased solubility and electrostatic repulsion between adjacent surfactant head groups at the micellar interface. Under these circumstances, a decrease in solubilization is expected for nonionizable or anionic compounds (where electrostatic repulsion from micellar head groups may reduce solubility further), but the potential to form ion pairs may increase solubilization for a weak base.
pH-adjustment + cyclodextrins
The mechanism here is largely analogous to that observed with nonionic surfactants combined with pH adjustment. For ionizable APIs, the degree of CD complexation of the unionized form is typically greater than the ionized (and more polar) equivalent. Although both ionized and unionized forms of an API may form an inclusion complex with the CD, it is more common that the more hydrophobic unionized form more readily complexes.
The mechanism here is largely analogous to that observed with nonionic surfactants combined with pH adjustment. For ionizable APIs, the degree of CD complexation of the unionized form is typically greater than the ionized (and more polar) equivalent. Although both ionized and unionized forms of an API may form an inclusion complex with the CD, it is more common that the more hydrophobic unionized form more readily complexes.
Although a pH change resulting in increased API ionization may reduce CD binding affinity, the higher aqueous solubility of the ionized form is often sufficient to compensate for decreased CD association, and total solubilized API concentrations increase. The general behaviour observed when combining CD complexation with pH adjustment is illustrated in the figure.
Surfactants + cosolvents
The net effect of this combination is difficult to predict and depends on relative efficiency of cosolvency versus micellar solubilization on API solubility. Increased cosolvent concentrations increase API solubility in the bulk medium, but also increase surfactant solubility, which reduces micelle formation and therefore holds the risk of reducing API solubilization. Another effect that occurs when combining cosolvents and surfactants in aqueous medium, is that the cosolvent partitions into the micelle core, reducing extramicellar cosolvent concentration and increasing the polarity of the apolar micelle core. Both these effects reduce solubilization.
The combined effect of cosolvents and surfactants on API solubility is therefore difficult to predict, and highly dependent on the relative efficiency with which the individual excipients solubilize API molecules.
The net effect of this combination is difficult to predict and depends on relative efficiency of cosolvency versus micellar solubilization on API solubility. Increased cosolvent concentrations increase API solubility in the bulk medium, but also increase surfactant solubility, which reduces micelle formation and therefore holds the risk of reducing API solubilization. Another effect that occurs when combining cosolvents and surfactants in aqueous medium, is that the cosolvent partitions into the micelle core, reducing extramicellar cosolvent concentration and increasing the polarity of the apolar micelle core. Both these effects reduce solubilization.
The combined effect of cosolvents and surfactants on API solubility is therefore difficult to predict, and highly dependent on the relative efficiency with which the individual excipients solubilize API molecules.
Cosolvents + cyclodextrins
Combinations of CDs with cosolvents may lead to net increases in API solubilization compared with cosolvent or CD alone. However, the combined effect is not always additive, as cosolvent molecules compete with API molecules for the CD hydrophobic cavity and also promote the solubility of the noncomplexed API in free solution. As such, API-CD binding may be reduced in presence of a cosolvent.
Combinations of CDs with cosolvents may lead to net increases in API solubilization compared with cosolvent or CD alone. However, the combined effect is not always additive, as cosolvent molecules compete with API molecules for the CD hydrophobic cavity and also promote the solubility of the noncomplexed API in free solution. As such, API-CD binding may be reduced in presence of a cosolvent.
Surfactants + cyclodextrins
Cyclodextrins form inclusion complexes with both nonionic and ionic surfactants, leading to potential competition between API and surfactant for CD binding sites. Furthermore, the complexed surfactant fraction is unable to participate in micelle formation, reducing micellar solubilization. Combinations of CDs and surfactants therefore often lead to a decrease in the concentration of solubilized API and are better avoided.
Cyclodextrins form inclusion complexes with both nonionic and ionic surfactants, leading to potential competition between API and surfactant for CD binding sites. Furthermore, the complexed surfactant fraction is unable to participate in micelle formation, reducing micellar solubilization. Combinations of CDs and surfactants therefore often lead to a decrease in the concentration of solubilized API and are better avoided.
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