Polyanhydrides stability

Domb, A., and Danger, R., Polyanhydrides Stability and novel composition, Makromol. Chem. Macromol. Symp., 19, 189-200, 1988. 

The stability of polyanhydrides composed of the diacids sebacic acid (SA), bis( -carboxyphenoxy)methane (CPM), l,3-bis(g-carboxyphe-noxy)propane (CPP), l,6-bis( -carboxyphenoxy)hexane (CPH), and phenylenedipropionic acid (PDP), in solid state and in organic solutions, was studied over a 1-year period. Aromatic polyanhydrides such as poly(CPM) and poly(CPH) maintained their original molecular weight for at least a year in both solid state and solution (20). 

FIGURE 16 Stability of various polyanhydrides versus time. The molecular weight of various polyanhydrides stored in vacuo in glass ampules at room temperature was measured by GPC at various times. Details as described in the text. 

Proteins may be stabilized by encapsulation in polyanhydride microspheres. Stability of proteins with respect to water-induced aggregation has been demonstrated to be a function of polymer hydrophobicity for insulin and bovine somatotropin as model proteins (Ron et al., 1993). Encapsulation and enzymatic activity of a variety of other proteins encapsulated in P(SA FAD) was studied by Tabata et al. (1993). 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

Crosslinking of amine- or hydroxy-terminated PAMAM dendrimers using cyclic anhydride - amine or cyclic anhydride - hydroxy addition reactions was employed for preparation of crosslinked thin films of very low permeability [73], Polyanhydrides, such as maleic anhydride-methyl vinyl ether copolymers, were used as crosslinking components. In the case of amine-terminated PAMAM, crosslinking and chemical stability were further increased by imidization of the maleamic acid groups retro-Michael eliminations were followed by Michael additions to further crosslink the film. 

Polyanhydrides were first developed by Carothers and coworkers in the early 20th century for applications in the textile industry. The interest in these polymers waned soon thereafter because of their instability. However it was the poor hydrolytic stability that made these polymers attractive candidates for drug delivery applications (17). 

Polyanhydrides have been chosen for the preparation of microspheres because of their degradation by surface erosion into apparently non-toxic small molecules.f The mixture of polymer and active ingredient is suspended in a miscible solvent, heated 5°C above the melting point of the polymer and stirred continuously. The emulsion is stabilized by cooling below the melting point until the droplets solidify. 

Poly(anhydrides) are polymers containing the group -C(0)-0-C(0)- in their backbone. Several polyanhydrides such as poly(oxyisophthaloyl), poly(oxycarbonyl-1,4-phenylene methylene-1,4-phenylene carbonyl), poly(oxycarbonyl-1,4-phenylene isopropylidene-1,4-phenylene carbonyl), and poly(oxycarbonyl-1,4-phenylene isobutylidene-1,4-phenylene carbonyl) were synthesized with the expectation of good biodegradability. They do have good hydrolytic stability as opposed to aliphatic polyanhydrides [1]. The structures of these polymers are shown below. 

To understand the properties that make polyanhy-drides suitable drug carriers, their chemical, physical, and thermal behavior need to be characterized. This section discusses the methods to determine the chemical structure and composition, the molecular weight, the thermal properties, the phase behavior, the stability, and the erosion mechanism of polyanhydrides. 

The stability of polyanhydrides in a solution was studied using chloroform under dry nitrogen atmosphere at 37°C.f The aromatic polyanhydrides remained stable under these conditions during a three-day period, while copolymers with aliphatic S A had a significant molecular weight loss during the same time period. Therefore, polyanhydrides can be processed in a solution environment as long as the time is not extended more than this period. 

Determan AS, Trewyn BG, Lin VSY, et al. Encapsulation, stabilization, and release of BSA-FTTC from polyanhydride microspheres. J Control Release 2004 100(1) 97-109. 

In the past decade, extensive research has been carried out on the characterization of polyanhydrides. This section will describe the methods used for the characterization of polyanhydrides and data obtained about their chemical composition and structure, crystallinity and thermal properties, mechanical properties, and thermodynamic and hydrolytic stability. 

This method was adopted to prepare polyanhydride copolymer of poly(bis(p-carboxy phenoxy) propane anhydride) with sebacic acid. In this method, the polymer is first melted and then mixed with solid particles of the drug. The mixture is suspended in a nomniscible solvent (e.g., silicone oil), continuously stirred, and heated to 5°C above the melting point of the polymer. Once the emnision is stabilized, it is cooled until the polymer particles solidify. The resniting microspheres are washed by decantation with petroleum ether. The primary objective for developing this method is to develop a microencapsulation process suitable for the water-labile polymers, for example, polyanhydrides. Microsphere with diameter of 1-1000 pm can be obtained, and the size distribution can be easily controlled by altering the stirring rate. 

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