Solid dispersions stability

Fig. 4.1 Schematic representation of the amorphous solid dispersion stabilization by embedding the drug in the polymer matrix...

Inverse gas chromatography (IGC) has been used to detect surface crystallization and to predict solid dispersion stability (Miyanishi et al. 2012). The principle of IGC is out of scope of this chapter readers are encouraged to read elsewhere. In IGC, sample of the solid dispersion is placed in the capillary in the machine. Solvent vapor is continuously purged on the surface of the freshly made solid dispersion over a period of time the volume of the solvent retained on the surface can be measured over time. A retention volume will change if the surface crystallization occurs. Therefore, the retention volume will be an indication of solid dispersion instability. A retention volume versus time plot can be drawn from the IGC results. A retention volume change versus temperature plot can also be obtained if the experiment was carried out at different temperature. The steps to obtain the crystallization rate and finally the prediction of instability are shown below ... 

The DASPE nanoparticles have been synthesized by the ion association reaction between the dye cation (note that the native compound is an iodide salt DASPE-I) and the hydrophobic borate anion (TPB or TFPB-) in the presence of neutral polymer stabilizer polyvinylpyrrolidone (PVP) in aqueous solution [38, 39]. In the absence of PVP, mixing of aqueous TPB- (or TFPB-) and DASPE+ solutions at the same molar fraction yielded the orange opaque solid dispersion composed of the anion-exchanged dye species, DASPE-TPB (or... 

The effects of improved wettability, entropic repulsion, and sterical hindrance undoubtedly play a role in stabilizing dispersed solid particles by block or graft copolymers. However, since the dispersions of titanium dioxide in toluene stabilized by carboxylated styrene-butadiene block copolymers are so much more stable than dispersions stabilized by carboxylated homopolymers under otherwise identical conditions, we must assume that an additional factor comes into play when block copolymers are used. The model in Figure 1 is an attempt to explain this additional... 

Khoo, S.-M. et al. (2000) The formulation of halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions physical stability and absolute bioavailability assesbntiehtPharm.,... 

Both chemical and physical stability must be assured in the development of solid dispersions. Since the drug is either molecularly dispersed or intimately mixed with the carrier, there is potential for greater chemical interaction between them. Any physical instability that leads to phase transformations may result in poor performance of dosage forms, including changes in dissolution rates and oral bioavailability. 

Urbanetz, N. 2006. Stabilization of solid dispersions of nimodipine and polyethylene glycoBDOO. 

VNfeuts, I., D. Kempen, A. Decode, G. Verreck, J. Peeters, M. Brewster, and G. Van den Mooter. 2005. Physical stability of the amorphous state of loperamide and two fragment molecules in solid dispersions with the polymers PVP-K30 and PVP-VA6Sur J Pharm ScE5 313-320. 

Doherty, C. and York, P. (1989). Accelerated stability of an x-ray amorphous frusemide-PVP solid dispersion, Drug Dev. Ind. Pharm., 15 1969-1987. 

Fernando A. Alvearex-Ninez, Leonard, M.R., and Crawford, L.F. Glass transition temperature measurement as predictors of the physical stability of a poorly soluble pharmaceutical agent formulated as solid dispersion. AAPS 2002, Toronto, ON. 

More recently, Markovich et al. (91) utilized a combination of solid-state infra-red (IR) and NMR methods to study the amorphous to crystalline API transition of SCH 48461 in solid dispersion capsule formulations. In this illustrative study, dissolution testing initially revealed inter-and intralot variations of capsules stored under accelerated stability conditions (25°C/60% RH, 30°C/60% RH, and 40°C/80% RH). PXRD analysis could not explain the dissolution data being collected on lots stored at accelerated conditions and revealed no differences from original diffraction patterns. Two additional analytical techniques, attenuated total reflectance IR (ATR-IR) spectroscopy and solid-state 13C NMR spectroscopy, were employed to study the physical form in the actual solid dispersion formulations. 

First, evaluate the feasibility of solid dispersion such as a polyethylene glycol (PEG)-based semisolid or solid hard gelatin capsule formulation.32 33 When the molecular weight of PEG used in the formulation is greater than 3350 Da, PEG exists as a solid. Prerequisites for this formulation approach include (1) adequate solubility and (2) thermal-stability of the drug in molten PEG during processing. 

A distinction is made between dispersion stability and chemical bond stability the former refers to the tenacity of a reversible tertiary structure in its dispersion medium (solid, liquid, or gas) wherein any conformational shift is theoretically transient and finite, albeit in a possibly long interval. Chemical instability involves decomposition of the primary structure of covalently linked glycosides. Chemical bond rupture is irreversible and the decomposition Ea is much higher than the Ea of conformational distortions and viscous flow. 

The above description of foam destabilization mechanisms is only applicable to liquid foods. In solid dispersions, these mechanisms are significantly slowed or even eliminated. As mentioned earlier, solid matrixes such as aerated confectionery wiU hold air for up to years. Structure stabilization occurs for example in chocolate foams when the product is cooled to solidify and trap the bubbles formed within. The baking... 

In emulsions, amine hydrochloride constitutes the aqueous phase and acrylic ester the organic phase. Cetyltrimethylanunonium bromide (CTAB) or span/twin (S/T)-type surfactants are used for emulsion polymerization. Solid dispersants such as talc and colloidal silica are often used to stabilize emulsions which are difficult to stabilize with usual surfactants. HydrophiUc colloidal silica (Aerosil 200) drastically increases the stability of some emulsions provided high amounts (up to 10%) of Aerosil are used. Random copolymers containing 10% hydroxyl groups can be used as polymeric dispersants for preparing w/o emulsions. 

---