Loading Capacity and Entrapment Efficiency

The suitability of a carrier matrix for a particular application hinges on its ability to encapsulate the intended active compound. The loading capacity is a measure of concentration of active compounds encapsulated in the matrix. The entrapment efficiency gives a measure of how much of the active ingredient added during preparation has been successfully incorporated. The entrapment efficiency depends on the amount of actives added during preparation and the loading capacity of the matrix. The loading capacity is strongly influenced by the lipid component, the physical and chemical structure of the lipid and the interactions between the lipid and active compound. Successful encapsulation prerequisites solubility or miscibility of the actives in the lipid matrix.³⁹ The physicochemical structure of the lipid also determines the capacity of the lipid to hold actives; highly crystalline lipid arrangements hinder encapsulation and complex lipid mixtures give higher loading capacities by preventing the formation of a

‘perfect’ lattice.⁷¹ Another factor that affects the loading capacity is the chemical nature of the active compound. Hydrophilic actives give much lower loading capacities compared to hydrophobic drugs. Loading capacities exceeding 50% for hydrophobic compounds have been reported while this value is yet to be met with hydrophilic compounds.⁹⁴ The high solubility of hydrophilic actives in the aqueous phase facilitates partitioning of the actives from the lipid melt into the continuous phase, hence minimising effective encapsulation. The double emulsion method (i.e. the hydrophilic actives are emulsified in the lipid phase and then the lipid phase is emulsified in an aqueous phase before cooling) has been shown to enhance the incorporation of hydrophilic actives into solid lipid matrices. Peres et al., recently reported the encapsulation of hydrophilic dyes in a stearic acid matrix using the double emulsion method.⁹⁵

Solvent-assisted double emulsion method has been shown to enhance the encapsulation of a hydrophobic and lipid-insoluble drug, Raloxifen HCl.⁹⁶ The cold homogenisation method can also enhance the incorporation of hydrophilic active due to the immobilisation of the lipid/active component by freezing in liquid nitrogen. This prevents the partitioning of the hydrophilic molecules into the aqueous phase.

2.1.4.3. Model of Incorporation

There are three different models of incorporation suggested for solid lipid matrices, namely:

solid solution, enriched core model and enriched shell model (Figure 2.5).³⁹ The model of incorporation alludes to the localisation of the drug in the matrix. The model of incorporation is influenced by the chemical properties of the lipid and the active components and the interactions between them. The solid solution method of incorporation is where the active molecules are homogenously dispersed throughout the matrix. This method of incorporation is facilitated by strong interactions between the lipid and the active compound. Solid solution lipid matrices can be achieved using the cold homogenisation method; the active compound is dissolved in the lipid component and frozen in liquid nitrogen to give a solid solution before homogenisation.⁹⁷ The enriched shell model pertains to the localisation of the active molecules in the shell of the particles. SLN and SLM systems assume the enriched shell model of

Enriched shell Enriched core Solid solution

Crystalline lipid Molecularly

dispersed active

Active ingredient

Figure 2.5. Schematic presentation of suggested models of incorporation for solid lipid carrier matrices

incorporation during cooling when the lipid recrystallises and repartitions into the core of the particles, leaving a high concentration of the active molecules in the shell of the particles.⁹⁸ The enriched core method is achieved when the active molecule crystallises or precipitates before the lipid recrystallises. The active repartitions into the core of the dispersed phase and the lipid recrystallises around the active-enriched core upon further cooling.⁹⁸ This usually occurs where the concentration of the actives in the lipid melt is close to the saturation solubility.³⁹ DSC, X-ray diffraction and AFM have been used to determine the model of incorporation of enriched shell and solid solution SLN systems of Compritol 888 ATO and Dynasan 112.⁹⁷

2.1.4.4. Crystallinity and Polymorphic Modifications

Crystallinity and polymorphic modifications are important aspects in the characterisation of SLN and SLM systems as they strongly influence the incorporation, retention and release of actives. Amphipathic lipid molecules are capable of assuming highly stable 3D crystalline arrangements. A lipid can exist in different crystalline forms called polymorphs. There seven known crystal systems that crystalline materials can adopt (Figure 2.6).⁹⁹ Out of the seven possible crystal systems, the three main forms found in lipids are: hexagonal, triclinic and orthorhombic.¹⁰⁰ Hexagonal subcell packing, also known as the α-polymorph is the least thermodynamically stable of the three. ^101,102 The triclinic subcell packing, β-polymorph is the most thermodynamically stable form, while the orthorhombic subcell packing, β’ form is a metastable form that is intermediate between the α- and β-polymorph.^101,102 During production, the lipid solidifies in the α-form and transitions to the β’-polymorph and then β-polymorph upon cooling.¹⁰³ While the thermodynamic stability of the lipid improves with these transformations, the loading capacity of the lipid is diminished.^39,103 This results in premature release of the actives from the matrix; hence the lipid crystallinity and polymorphic transformations of the lipid affect the stability of SLN and SLM systems. DSC and X-Ray

scattering methods are used in the investigation of lipid crystalline forms in solid lipid matrices.^104,105 Different polymorphic forms exhibit different melting temperatures and enthalpy of fusion due to the differences in the thermodynamic stability; hence DSC can be used to distinguish between the different polymorphic forms. X-Ray diffraction methods can be used to determine the polymorphic form due to the fact that each subcell packing has a unique diffraction pattern. Using WAXS, the α-polymorph is characterised by one strong diffraction line at 4.15 Å, the β’-polymorph gives two strong diffraction lines at 3.8 Å and 4.2 Å, whereas the β-polymorph produces a whole series of diffraction lines with one prominent line at 4.6 Å.^102,106 Other analytical methods such as FTIR and Raman spectroscopy can also provide structural information in solid lipid matrix systems.³⁹

Cubic

Figure 2.6. Seven types of crystal systems found in crystalline materials where a, b and c are vectors in three different planes and α is the angle between b and c, β is the angle between a and c and γ is the angle between a and b